[Role of endogenous prostaglandins in the mechanism of action of CO2 and O2 on the morphofunctional state of the capillary system in the cat cerebral cortex].
In acute experiments on cats hypocapnia produces an appreciable diminution in the mean diameter of the capillaries and an increase in the number of the non-functioning capillaries of the brain cortex. Hypercapnia and hypoxia raise the mean diameter of the capillaries. The former leads to the opening of the non-functioning capillaries whereas the latter one does not affect this indicator. Despite the fact that the indomethacin-induced inhibition of prostaglandin biosynthesis produces no effect on the morphofunctional shifts in brain microcirculation during hypocapnia it averts the effects of hypercapnia and hypoxia on the capillary diameter. An assumption is made about the heterogeneity of receptor formations in the smooth muscles of the arterioles and precapillary sphincters responding to CO2.


Actin-based spindle positioning: new insights from female gametes.
Asymmetric divisions are essential in metazoan development, where they promote the emergence of cell lineages. The mitotic spindle has astral microtubules that contact the cortex, which act as a sensor of cell geometry and as an integrator to orient cell division. Recent advances in live imaging revealed novel pools and roles of F-actin in somatic cells and in oocytes. In somatic cells, cytoplasmic F-actin is involved in spindle architecture and positioning. In starfish and mouse oocytes, newly discovered meshes of F-actin control chromosome gathering and spindle positioning. Because oocytes lack centrosomes and astral microtubules, F-actin networks are key players in the positioning of spindles by transmitting forces over long distances. Oocytes also achieve highly asymmetric divisions, and thus are excellent models to study the roles of these newly discovered F-actin networks in spindle positioning. Moreover, recent studies in mammalian oocytes provide a further understanding of the organisation of F-actin networks and their biophysical properties. In this Commentary, we present examples of the role of F-actin in spindle positioning and asymmetric divisions, with an emphasis on the most up-to-date studies from mammalian oocytes. We also address specific technical issues in the field, namely live imaging of F-actin networks and stress the need for interdisciplinary approaches.


Occurrence and Distribution of Proteinase of Streptococcus faecalis var. liquefaciens.
Shugart, Lee R. (University of Tennessee, Knoxville), and Raymond W. Beck. Occurrence and distribution of proteinase of Streptococcus faecalis var. liquefaciens. J. Bacteriol. 92:338-341. 1966.-The proteolytic enzyme produced by Streptococcus faecalis var. liquefaciens (ATCC 13398) was shown to be an exoenzyme. The production of the proteinase was followed in growing cultures, and its distribution was compared with that of the intracellular enzymes reduced nicotinamide adenine dinucleotide (NADH(2)) peroxidase and lactate dehydrogenase. The proteinase appeared in the culture medium prior to the stationary phase of growth, whereas the other enzymes could be found only in whole cells. Fractionation of whole cells by sonic treatment and by treatment with lysozyme showed the proteinase to be associated primarily with the cell wall and cell membrane, and NADH(2) peroxidase to be associated only with the cytoplasmic fractions.


Using conformational constraints at position 6 of Angiotensin II to generate compounds with enhanced AT2R selectivity and proteolytic stability.
The Renin-Angiotensin System (RAS) plays a crucial role in numerous pathological conditions. Two of the critical RAS players, the angiotensin receptors AT1R and AT2R, possess differential functional profiles, although they share high sequence similarity. Although the main focus has been placed on AT1R, several epidemiological studies have evidenced that activation of AT2R could operate as a multimodal therapeutic target for different diseases. Thus, the development of selective AT2R ligands could have a high clinical potential for different therapeutic directions. Furthermore, they could serve as a powerful tool to interrogate the molecular mechanisms that are mediated by AT2R. Based on our recently established high affinity and AT2R selective compound [Y]6-AII we developed several analogues through modifying aminoacids located at positions 6 and 7 with various conformationally constrained analogues to enhance both the selectivity and stability. We report the development of high-affinity AT2R binders, which displayed high selectivity for AT2R versus AT1R. Furthermore, all analogues presented enhanced stability in human plasma with respect to the parent hormone Angiotensin II as also [Y]6-AII.


Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway.
Calcitriol (1,25-dihydroxyvitamin D3), the active form of vitamin D, promotes growth inhibition and differentiation in prostate cancer (PCa) cells. To unravel the molecular pathways of calcitriol actions, cDNA microarray analysis was used to identify novel calcitriol target genes including two that play key roles in the metabolism of prostaglandins (PGs), known stimulators of PCa growth and progression. Calcitriol significantly decreases the expression of the PG synthesizing cyclooxygenase-2 (COX-2) gene, while increasing that of PG inactivating 15-prostaglandin dehydrogenase (15-PGDH). Calcitriol also inhibits the expression of the PG receptors EP2 and FP. It reduces the levels of biologically active PGs and inhibits PG actions in PCa cells, thereby decreasing the proliferative stimulus of PGs. We postulate that the regulation of the PG pathway contributes to the growth inhibitory actions of calcitriol. We also propose that calcitriol can be combined with non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit COX enzyme activity, as a potential therapeutic strategy in PCa.


Type 2 diabetes and glucose intolerance in a population with intellectual disabilities: the STOP diabetes cross-sectional screening study.
Adults with intellectual disabilities (ID) may be at increased risk of developing type 2 diabetes and cardiovascular disease, due to lifestyle factors, medications and other diagnosed conditions. Currently, there is lack of evidence on prevalence and prevention in this population. The aim of this study was to conduct a diabetes screening programme to determine prevalence of previously undiagnosed type 2 diabetes and impaired glucose regulation in people with ID. Screening was conducted in a variety of community settings in Leicestershire, UK. Adults with ID were invited via: general practices; the Leicestershire Learning Disability Register; ID psychiatric services; and some people directly contacted the research team due to publicity about the study. Screening involved collection of anthropometric, biomedical and questionnaire data. Type 2 diabetes and impaired glucose regulation were defined according to (venous) fasting plasma glucose or HbA1c, following current World Health Organisation criteria. Nine hundred thirty adults (29% of those approached) participated. Mean age was 43 years, 58% were male and 16% of South Asian ethnicity. Most participants were either overweight or obese (68%). Diabetes status was successfully assessed for 675 (73%) participants: Nine (1.3%, 95% confidence interval 0.6 to 2.5) were found to have undiagnosed type 2 diabetes, and 35 (5.2%, 95% confidence interval 3.6 to 7.1) had impaired glucose regulation. Key factors associated with abnormal glucose regulation included the following: non-white ethnicity and a first degree family history of diabetes. Results from this large multi-ethnic cohort suggest a low prevalence of screen-detected (previously undiagnosed) type 2 diabetes and impaired glucose regulation in adults with ID. However, the high levels of overweight and obesity we found emphasise the need for targeted lifestyle prevention strategies, which are specifically tailored for the needs of people with ID.


[Crimes committed by mentally ill persons in the years 1977-1999. Development, number and causes].
In line with many other countries, Denmark has reorganised psychiatric care with closure of 50% of the psychiatric beds in favour of community mental health. Parallel to this reorganisation the number of forensic patients has increased. In Denmark, the majority of forensic patients are under supervision by a probation officer. As from 1977, The Department of Prison and Probation has registered the monthly prevalence of forensic patients, from 1989 also the monthly incidence and decrease. These data have been used to analyse the trends in the number of forensic patients. The number of forensic patients increased from 297 in 1980 to 1134 in 1999, the increase in prevalence being exponential with an annual growth rate of 6.79%. The incidence figures showed an exponential increase with an annual growth rate of 5.96% (95% confidence interval 4.76%-7.27%). The annual growth rate for the decrease is 6.18%. Thus, the three growth rates do not differ, meaning that the increasing number of forensic patients is the result of an increasing intake. The growing number of mentally ill offenders cannot be explained by changes of the Danish penal law concerning mentally abnormal offenders nor by changes in administrative or diagnostic practice. The number of reported crimes in Denmark has remained unchanged from 1987. The main reason for the exponential growth rate is an increasing number of schizophrenic patients committing crimes. It is concluded that deinstitutionalisation is the main reason for this development.


Effect of reactive adhesives on the tensile bond strength of polyvinyl siloxane impression materials to methyl methacrylate tray material.
The effect of new adhesives on the bond strength of elastomeric impression materials to acrylic trays was evaluated. Two polyvinyl siloxane impression materials (Fusion and Imprinsis) with reactive adhesives and one (Examix) with a conventional adhesive were tested. Flat, double-sided plates of auto-polymerizing methyl methacrylate (10 x 10 x 2.5 mm) were prepared with one of the adhesives. Five specimens were prepared by injecting each impression material into a 2-mm gap between the two plates. Tensile tests were conducted until separation failure occurred. The mean bond strengths of Fusion (1.0 MPa) and Imprinsis (0.8 MPa) were significantly greater than that of Examix (0.2 MPa). On the contrary, one of five Fusion showed adhesive failure mode while all the Imprinsis exhibited mixed failure. The conflicting results were presumably attributed to the mean tear strength of Fusion (0.8 N/mm) being higher than that of Imprinsis (0.5 N/mm).


Automated clinical pathways in the patient record legal implications.
Nurses have long been taught the need for precise documentation of patient care. Yet, as demands on nurses' time increases, maintaining an accurate and informative patient record becomes more difficult. The use of an automated clinical pathway that contains both the plan of care and a record of the care, while increasing communication between the care providers, is a promising solution to the problem. In this article, the process of moving a clinical pathway from paper to a computerized format is discussed. Legal issues related to its status as a permanent part of the patient record are considered. The legal implications of the pathway as a standard of care are also examined. As clinical pathways and computers merge, effective automated plans of care that also can serve as a documentation tool will benefit both the caregiver and the patient, while decreasing the risk of liability.


The effect of small class sizes on mortality through age 29 years: evidence from a multicenter randomized controlled trial.
Limiting the number of students per classroom in the early years has been shown to improve educational outcomes. Improved education is, in turn, hypothesized to improve health. The authors examined whether smaller class sizes affect mortality through age 29 years and whether cognitive factors play a role. They used data from the Project Student Teacher Achievement Ratio, a 4-year multicenter randomized controlled trial of reduced class sizes in Tennessee involving 11,601 students between 1985 and 1989. Children randomized to small classes (13-17 students) experienced improved measures of cognition and academic performance relative to those assigned to regular classes (22-25 students). As expected, these cognitive measures were significantly inversely associated with mortality rates (P < 0.05). However, through age 29 years, students randomized to small class size nevertheless experienced higher mortality rates than those randomized to regular size classes (hazard ratio (HR) = 1.58, 95% confidence interval (CI): 1.07, 2.32). The groups at risk included males (HR = 1.73, 95% CI: 1.05, 2.85), whites/Asians (HR = 1.68, 95% CI: 1.04, 2.72), and higher income students (HR = 2.20, 95% CI: 1.06, 4.57). The authors speculate that small classes might produce behavior changes that increase mortality through young adulthood that are stronger than the protective effects of enhanced cognition.


Correlation between the detection of specific mouse mammary tumor proviral sequences and the presence of pulmonary metastases in mice bearing spontaneous mammary tumors.
Pulmonary metastases in C3H/He mice bearing spontaneous mammary tumors were detected and characterized by histological criteria and immunocytochemical staining for mouse mammary tumor virus antigens. The same lungs containing metastases were also positive when assayed for a specific subset of mouse mammary tumor virus proviral DNA sequences. These sequences, termed tumor-associated sequences, have previously been shown to be present in the DNA of spontaneous mammary tumors that arise before 1 yr of age in C3H/He mice but are absent in DNA's of apparently normal tissues of C3H/He mice. Reconstruction experiments demonstrated that the nucleic acid hybridization method will detect at least one mammary tumor cell/250 cells. While DNA from 13 lungs of apparently normal C3H/He mice did not contain sequences homologous to mouse mammary tumor virus tumor-associated-sequence RNA, DNA from lungs of 9 of 12 C3H/He mice bearing spontaneous mammary tumors did contain these sequences. Since the entire DNA content of the lung can be assayed as one sample, the hybridization method minimizes false negatives resulting from histological analysis of random biopsy sampling. The hybridization procedure described here thus represents a sensitive and quantitative element as an adjunct for the detection of micrometastatic lesions in mice bearing viral-mediated spontaneous mammary carcinomas.


A new strain of rat for functional analysis of PINA.
Long Evans cinnamon (LEC) rat is an animal model for human Wilson disease (WD) due to a deletion in Atp7b, the copper transporter defective in WD patients. Previously, we have demonstrated presence of an alternative product termed PIneal Night-specific ATPase (PINA) generated by an intronic promoter in Atp7b gene. Analysis of LEC rat in this study demonstrates that PINA is absent in the LEC pineal establishing its usefulness for investigating PINA function. Studies of the LEC pineal, however, revealed an additional defect in serotonin N-acetyltransferase (NAT), the key enzyme in melatonin production. Linkage studies confirm that the NAT phenotype is entirely independent of PINA mutation in the pineal gland of LEC rats, and sequence analysis demonstrates that NAT defect is due to a point mutation in NAT coding region. In addition, we demonstrate that the cinnamon coat color of the LEC rat is unlinked to PINA and NAT deficiencies in these animals. To facilitate further functional analysis of PINA in pineal physiology, we crossed LEC rats with PVG rats that are wildtype for PINA, NAT and coat color, and obtained rats that are defective only in PINA/Atp7b locus (termed LPP rats) and normal for NAT activity and coat color. Furthermore, we have identified the deletion breakpoint of Atp7b gene in LPP rats, which allows simplified genotyping of mutant animals. The separation of PINA mutation from both NAT and coat color mutations in the new LPP rats will permit better functional studies of PINA in pineal circadian physiology.


Structures of new dammarane-type Triterpene Saponins from the flower buds of Panax notoginseng and hepatoprotective effects of principal Ginseng Saponins.
The saponin fraction from the flower buds of Panax notoginseng exhibited protective effect on liver injury induced by d-galactosamine and lipopolysaccharide. From the saponin fraction with hepatoprotective effect, five new dammarane-type triterpene saponins, notoginsenosides-O (1), -P (2), -Q (3), -S (4), and -T (5), were isolated together with nine known protopanaxadiol oligoglycosides. The structures of the new saponins were elucidated on the basis of chemical and physicochemical evidence. The principal dammarane-type triterpene saponins from the roots and flower buds of Panax notoginseng were found to show potent hepatoprotective effects.


High throughput flow cytometry.
Conventional flow cytometry does not allow the rapid analysis of multiple samples. This has limited its uses in drug discovery, for which the standard for throughput is 100,000 samples per day. We describe a simple method in which commercial peristaltic tubing is connected from a commercial autosampler to a flow cytometer. The samples are delivered via a peristaltic pump from source wells in a multiwell plate. The samples are separated by air bubbles. Throughput rates approach the limit of the autosampler (up to 100 wells per minute). Using optimal tubing and flow rates, particles remain within appropriate light scatter and fluorescence gates. The carryover between wells is typically less than 5% without and 1% with a wash step. The volumes of sample delivered are in the microliter scale. The approach has been validated with instruments from three manufacturers. Flow cytometry has potential throughput of 100,000 samples or more per day starting with the method described. The method is currently best suited to end-point assays. However, combined with high-speed sorting and single- cell assays, the number of assays could approach 1 billion per day.


Improving Biochemical Named Entity Recognition Using PSO Classifier Selection and Bayesian Combination Methods.
Named Entity Recognition (NER) is a basic step for large number of consequent text mining tasks in the biochemical domain. Increasing the performance of such recognition systems is of high importance and always poses a challenge. In this study, a new community based decision making system is proposed which aims at increasing the efficiency of NER systems in the chemical/drug name context. Particle Swarm Optimization (PSO) algorithm is chosen as the expert selection strategy along with the Bayesian combination method to merge the outputs of the selected classifiers as well as evaluate the fitness of the selected candidates. The proposed system performs in two steps. The first step focuses on creating various numbers of baseline classifiers for NER with different features sets using the Conditional Random Fields (CRFs). The second step involves the selection and efficient combination of the classifiers using PSO and Bayesisan combination. Two comprehensive corpora from BioCreative events, namely ChemDNER and CEMP, are used for the experiments conducted. Results show that the ensemble of classifiers selected by means of the proposed approach perform better than the single best classifier as well as ensembles formed using other popular selection/combination strategies for both corpora. Furthermore, the proposed method outperforms the best performing system at the Biocreative IV ChemDNER track by achieving an F-score of 87.95 percent.


Donor MHC class II antigen is essential for induction of transplantation tolerance by bone marrow cells.
Posttransplant infusion of donor bone marrow cells (BMC) induces tolerance to allografts in adult mice, dogs, nonhuman primates, and probably humans. Here we used a mouse skin allograft model and an allogeneic radiation chimera model to examine the role of MHC Ags in tolerance induction. Infusion of MHC class II Ag-deficient (CIID) BMC failed to prolong C57BL/6 (B6) skin grafts in ALS- and rapamycin-treated B10.A mice, whereas wild-type B6 or MHC class I Ag-deficient BMC induced prolongation. Removal of class II Ag-bearing cells from donor BMC markedly reduced the tolerogenic effect compared with untreated BMC, although graft survival was significantly longer in mice given depleted BMC than that in control mice given no BMC. Infusion of CIID BMC into irradiated syngeneic B6 or allogeneic B10.A mice produced normal lymphoid cell reconstitution including CD4+ T cells except for the absence of class II Ag-positive cells. However, irradiated B10.A mice reconstituted with CIID BMC rejected all B6 and a majority of CIID skin grafts despite continued maintenance of high degree chimerism. B10.A mice reconstituted with B6 BMC maintained chimerism and accepted both B6 and CIID skin grafts. Thus, expression of MHC class II Ag on BMC is essential for allograft tolerance induction and peripheral chimerism with cells deficient in class II Ag does not guarantee allograft acceptance.


Techniques of Online Citation Verification in NLM Databases.
This article is an exploration of techniques for identifying items in the health related literature using NLM system databases. Examples used are derived from reference desk and interlibrary loan files, but the techniques should be useful to any medical librarian who needs to verify a citation. A knowledge of NLM indexing practices and system commands is assumcd. Because of mace limitations the TOXLINE. TOXBACK74, TOXBACK65,AVLINE files have been omitted, but other bibliographic files and SERLINE are included. Tables designed for at-terminal use are presented.


[Improvement in Hygiene of the slaughter line (author's transl)].
Those factors which are of importance in the contamination of carcases in modern slaughter lines are reviewed. Short-term measures (for instance, improving the technique of dressing carcases) and long-term procedures (for instance, developing other methods of slaughter) are suggested to improve hygiene on the slaughter line. Attention is paid to a number of methods to prevent contamination.


Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials.
Ginger (Zingiber officinale) is often advocated as beneficial for nausea and vomiting. Whether the herb is truly efficacious for this condition is, however, still a matter of debate. We have performed a systematic review of the evidence from randomized controlled trials for or against the efficacy of ginger for nausea and vomiting. Six studies met all inclusion criteria and were reviewed. Three on postoperative nausea and vomiting were identified and two of these suggested that ginger was superior to placebo and equally effective as metoclopramide. The pooled absolute risk reduction for the incidence of postoperative nausea, however, indicated a non-significant difference between the ginger and placebo groups for ginger 1 g taken before operation (absolute risk reduction 0.052 (95% confidence interval -0.082 to 0.186)). One study was found for each of the following conditions: seasickness, morning sickness and chemotherapy-induced nausea. These studies collectively favoured ginger over placebo.


A fusion intermediate gp41 immunogen elicits neutralizing antibodies to HIV-1.
The membrane-proximal external region (MPER) of the human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein subunit gp41 is targeted by potent broadly neutralizing antibodies 2F5, 4E10, and 10E8. These antibodies recognize linear epitopes and have been suggested to target the fusion intermediate conformation of gp41 that bridges viral and cellular membranes. Anti-MPER antibodies exert different degrees of membrane interaction, which is considered to be the limiting factor for the generation of such antibodies by immunization. Here we characterize a fusion intermediate conformation of gp41 (gp41(int)-Cys) and show that it folds into an elongated ∼ 12-nm-long extended structure based on small angle x-ray scattering data. Gp41(int)-Cys was covalently linked to liposomes via its C-terminal cysteine and used as immunogen. The gp41(int)-Cys proteoliposomes were administered alone or in prime-boost regimen with trimeric envelope gp140(CA018) in guinea pigs and elicited high anti-gp41 IgG titers. The sera interacted with a peptide spanning the MPER region, demonstrated competition with broadly neutralizing antibodies 2F5 and 4E10, and exerted modest lipid binding, indicating the presence of MPER-specific antibodies. Although the neutralization potency generated solely by gp140(CA018) was higher than that induced by gp41(int)-Cys, the majority of animals immunized with gp41(int)-Cys proteoliposomes induced modest breadth and potency in neutralizing tier 1 pseudoviruses and replication-competent simian/human immunodeficiency viruses in the TZM-bl assay as well as responses against tier 2 HIV-1 in the A3R5 neutralization assay. Our data thus demonstrate that liposomal gp41 MPER formulation can induce neutralization activity, and the strategy serves to improve breadth and potency of such antibodies by improved vaccination protocols.


Evidence that in vivo constriction of cerebral arterioles by local application of tert-butyl hydroperoxide is mediated by release of endogenous thromboxane.
Pial arterioles of mice were suffused in situ with tert-butyl hydroperoxide (TBHP). This agent has been reported to stimulate synthesis or release of the constrictor, thromboxane. In the present study we observed pial arterioles by in vivo microscopy. Locally applied TBHP produced dose-dependent constriction, significantly inhibited by each of three drugs: acetylsalicylic acid, OKY-046, and SQ-29548. These drugs are respectively a cyclooxygenase inhibitor, a thromboxane synthetase inhibitor, and a thromboxane receptor blocker. Since each acts by a different mechanism to interfere with thromboxane-mediated responses and each inhibited the contractile response to TBHP, thromboxane appears to be a mediator of this response. Platelet aggregation was not seen after local application of TBHP, and the dwell time of platelets at the site of TBHP application is less than 1 second. Thus, platelets are an unlikely source of the thromboxane mediating the local constriction. It is much more likely that the source of thromboxane is either the wall of the pial vessels or the underlying brain and/or its vessels. These data do not distinguish between the latter two possibilities, but if this suggestion is correct, then the data show for the first time that thromboxane can be released from normal brain and/or brain vessels in amounts sufficient to cause arteriolar constriction.


Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells.
The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM) followed by ceramide release in brain endothelial cells. In response to N. meningitidis infection, ASM and ceramide are displayed at the outer leaflet of the cell membrane and condense into large membrane platforms which also concentrate the ErbB2 receptor. The outer membrane protein Opc and phosphatidylcholine-specific phospholipase C that is activated upon binding of the pathogen to heparan sulfate proteoglycans, are required for N. meningitidis-mediated ASM activation. Pharmacologic or genetic ablation of ASM abrogated meningococcal internalization without affecting bacterial adherence. In accordance, the restricted invasiveness of a defined set of pathogenic isolates of the ST-11/ST-8 clonal complex into brain endothelial cells directly correlated with their restricted ability to induce ASM and ceramide release. In conclusion, ASM activation and ceramide release are essential for internalization of Opc-expressing meningococci into brain endothelial cells, and this segregates with invasiveness of N. meningitidis strains.


The L2/HNK-1 carbohydrate of neural cell adhesion molecules is involved in cell interactions.
We investigated whether the L2/HNK-1 carbohydrate epitope, expressed by two unusual glycolipids and several neural adhesion molecules, including L1, neural cell adhesion molecule, J1, and the myelin-associated glycoprotein, is involved in adhesion. Monoclonal L2 antibodies, the L2/HNK-1-reactive, sulfate-3-glucuronyl residue carrying glycolipids (L2 glycolipid) and a tetrasaccharide derived from the L2 glycolipid (L2 tetrasaccharide) were added to microexplant cultures of early postnatal mouse cerebellum, and cell migration and process extension were monitored. On the substrate poly-D-lysine, Fab fragments of L2 antibodies, L2 glycolipid, and L2 tetrasaccharide inhibited outgrowth of astrocytic processes and migration of cell bodies, but only L2 glycolipid and L2 tetrasaccharide reduced neurite outgrowth. On laminin, L2 antibodies, L2 glycolipid, and L2 tetrasaccharide inhibited outgrowth of astrocytic processes. Additionally, L2 glycolipid and L2 tetrasaccharide inhibited cell migration and neurite outgrowth. Several negatively charged glycolipids, lipids, and saccharides were tested for control and found to have no effect on outgrowth patterns, except for sulfatide and heparin, which modified outgrowth patterns in a similar fashion as L2 glycolipid and L2 tetrasaccharide. On astrocytes none of the tested compounds interfered with explant outgrowth. In short-term adhesion assays L2 glycolipid, sulfatide, and heparin inhibited adhesion of neural cells to laminin. L2 glycolipid and sulfatide interfered with neuron to astrocyte and astrocyte to astrocyte adhesion, but not with neuron-neuron adhesion. The most straightforward interpretation of these observations is that the L2/HNK-1 carbohydrate and the sulfated carbohydrates, sulfatide and heparin, act as ligands in cell adhesion.


Iris transillumination defects in patients with primary open angle glaucoma.
To examine the incidence and pattern of iris transillumination defects in patients with primary open angle glaucoma (POAG) with and without vascular dysregulation, in comparison to controls. We prospectively examined 24 patients with POAG (M/F 10:14; mean age 59 +/- 14, range 21-76 years) and 23 controls (M/F 10:13; mean age 52 +/- 15, range 25-86 years). Vascular dysregulation was presumed if patients had a typical medical history of vasospasm and a pathological result in nailfold capillaroscopy. Iris transillumination defects were visualized by video-taped, digitized diaphanoscopy and assessed by two blinded observers. We found significantly more iris transillumination defects in POAG than in controls (54.2% vs. 8.7%; chi2 = 8.85; df = 1; p = 0.002). The defects in POAG showed a characteristic radially-streaked pattern different from those described, for instance, in pigment dispersion syndrome, pseudoexfoliation syndrome, and acute glaucoma. Glaucoma patients with vascular dysregulation had a tendency to a higher incidence of transillumination defects than non-vasospastic patients, though this finding was not significant. Patients with POAG have a higher incidence of iris transillumination defects than controls. The underlying mechanisms are not yet clear and call for further investigation.


Ligand binding properties of bacterial hemoglobins and flavohemoglobins.
Bacterial hemoglobins and flavohemoglobins share a common globin fold but differ otherwise in structural and functional aspects. The bases of these differences were investigated through kinetic studies on oxygen, carbon monoxide, and nitric oxide binding. The novel bacterial hemoglobins from Clostridium perfringens and Campylobacter jejuni and the flavohemoglobins from Bacillus subtilis and Salmonella enterica serovar Typhi have been analyzed. Examination of the biochemical and ligand binding properties of these proteins shows a clear distinction between the two groups. Flavohemoglobins show a much greater tendency to autoxidation compared to bacterial hemoglobins. The differences in affinity for oxygen, carbon monoxide, and nitric oxide between bacterial hemoglobins and flavohemoglobins are mainly due to differences in the association rate constants. The second-order rate constants for oxygen and carbon monoxide binding to bacterial hemoglobins are severalfold higher than those for flavohemoglobins. A similar trend is observed for NO association with the oxidized iron(III) form of the proteins. No major differences are observed among the values obtained for the dissociation rate constants for the two groups of bacterial proteins studied, and these constants are all rather similar to those for myoglobin. Taken together, our data suggest that differences exist between the mechanisms of ligand binding to bacterial hemoglobins and flavohemoglobins, suggesting different functions in the cell.


Eating disorders, obesity and addiction.
An addiction model of both eating disorders and obesity has received increasing attention in the popular and scientific literature. The addiction is viewed as a brain disease that must be directly targeted if treatment is to succeed. Evidence from laboratory feeding studies, epidemiology, genetic and familial research, psychopathological mechanisms, and treatment outcome research on cognitive behaviour therapy (CBT) is inconsistent with the clinical validity or utility of the addiction model of eating disorders. Neurobiological research has shown commonalities in brain reward processes between obesity and substance abuse disorders. Yet emphasis on apparent similarities overlooks important differences between obesity and drug addiction. Interest in obesity as a brain disease should not detract from a public health focus on the 'toxic food environment' that is arguably responsible for the obesity epidemic and related nutrition-based chronic disease.


Synthetic food colors and hyperactivity in children: a double-blind challenge experiment.
Nine hyperactive male subjects, selected on the basis of showing a favorable "response" to the Feingold diet in an earlier study, were maintained on a strict elimination (Feingold) diet for 11 weeks, and were given multiple trials of placebo and challenge food materials. Parental and teacher ratings, classroom behavior observations, and neuropsychological test scores obtained during baseline, placebo, and challenge conditions, in general, were not found to be adversely affected by the artificial color challenge materials. As expected, comparable data gathered on a matched control group showed them to receive substantially better ratings than the hyperactive subjects on the majority of the comparison measures employed. Possible explanations for the discrepancy between the dramatic clinical-anecdotal reports that have been given and the much more equivocal findings from formal experimental projects are presented.


Generalized and Heuristic-Free Feature Construction for Improved Accuracy.
State-of-the-art learning algorithms accept data in feature vector format as input. Examples belonging to different classes may not always be easy to separate in the original feature space. One may ask: can transformation of existing features into new space reveal significant discriminative information not obvious in the original space? Since there can be infinite number of ways to extend features, it is impractical to first enumerate and then perform feature selection. Second, evaluation of discriminative power on the complete dataset is not always optimal. This is because features highly discriminative on subset of examples may not necessarily be significant when evaluated on the entire dataset. Third, feature construction ought to be automated and general, such that, it doesn't require domain knowledge and its improved accuracy maintains over a large number of classification algorithms. In this paper, we propose a framework to address these problems through the following steps: (1) divide-conquer to avoid exhaustive enumeration; (2) local feature construction and evaluation within subspaces of examples where local error is still high and constructed features thus far still do not predict well; (3) weighting rules based search that is domain knowledge free and has provable performance guarantee. Empirical studies indicate that significant improvement (as much as 9% in accuracy and 28% in AUC) is achieved using the newly constructed features over a variety of inductive learners evaluated against a number of balanced, skewed and high-dimensional datasets. Software and datasets are available from the authors.


A phase-based approach to the estimation of the optical flow field using spatial filtering.
We introduce a new technique for estimating the optical flow field, starting from image sequences. As suggested by Fleet and Jepson (1990), we track contours of constant phase over time, since these are more robust to variations in lighting conditions and deviations from pure translation than contours of constant amplitude. Our phase-based approach proceeds in three stages. First, the image sequence is spatially filtered using a bank of quadrature pairs of Gabor filters, and the temporal phase gradient is computed, yielding estimates of the velocity component in directions orthogonal to the filter pairs' orientations. Second, a component velocity is rejected if the corresponding filter pair's phase information is not linear over a given time span. Third, the remaining component velocities at a single spatial location are combined and a recurrent neural network is used to derive the full velocity. We test our approach on several image sequences, both synthetic and realistic.


Multiple tumor-associated microRNAs modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2 signaling pathways.
Tumors use a wide array of immunosuppressive strategies, such as reducing the longevity and survival of dendritic cells (DCs), to diminish immune responses and limit the effect of immunotherapy. In this study, we found that tumors upregulate the expression of multiple microRNAs (miRNAs), such as miR-16-1, miR-22, miR-155, and miR-503. These tumor-associated miRNAs influenced the survival and longevity of DCs by affecting the expression of multiple molecules that are associated with apoptotic signaling pathways. Specifically, miR-22 targeted YWHAZ to interrupt the PI3K/Akt and MAPK signaling pathways, and miR-503 downregulated Bcl2 expression. The result of the increased expression of miR-22 and miR-503 in the tumor-associated DCs was their reduced survival and longevity. Thus, tumor-associated miRNAs can target multiple intracellular signaling molecules to cause the apoptosis of DCs in the tumor environment. Use of miR-22 and miR-503 as inhibitors may therefore represent a new strategy to improve DC-based immunotherapies against tumors.


An investigation into the role of prostaglandins in zebrafish oocyte maturation and ovulation.
This study explored the potential for ovarian-derived prostaglandins (PGs) to be involved in the regulation of oocyte maturation and ovulation in zebrafish. It was demonstrated that cultured vitellogenic follicles have the capacity to produce prostaglandin E(2) (PGE(2)) and PGF(2alpha) in response to arachidonic acid (AA) in a concentration-dependent manner, and that AA stimulates the in vitro production of 17beta-estradiol (E(2)). The production of AA-stimulated PGF(2alpha) was significantly reduced by treatment with the non-selective cyclooxygenase (COX) inhibitor, indomethacin (INDO). Treatment of full-grown follicles with AA did not induce oocyte maturation as assessed by germinal vesicle breakdown, but INDO significantly decreased the rate of spontaneous maturation. Using Real-Time PCR, it was shown that follicles of different developmental size classes (primary growth and pre-vitellogenic, early-vitellogenic, and mid- to full-grown vitellogenic) express enzymes that release (cytosolic phospholipase A(2) (cPLA(2)); phospholipase Cgamma1) or metabolize (COX-1, COX-2, and prostaglandin synthase-2) AA to PG metabolites. The expression of cPLA(2) was found to be significantly greater in full-grown follicles compared to follicles of the pre- and early-vitellogenic stages. In vivo studies demonstrated that breeding groups of zebrafish exposed to 100 microg/L INDO exhibited reduced spawning rates and clutch sizes compared with control and 1 microg/L INDO exposed fish. In other studies, it was shown that naturally spawning groups of females exhibit increased ovarian levels of PGF(2alpha), E(2), and 17alpha,20beta-dihydroxy-4-pregnen-3-one (a maturation-inducing hormone in zebrafish) near the time of ovulation compared with non-breeding females. Collectively, these experiments indicate that the AA pathway in zebrafish ovaries is involved in the regulation of oocyte maturation and ovulation and a non-selective inhibitor of COX disrupts these processes.


Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.
The aim of this study was to evaluate 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) in gastric and oesophageal carcinoma. 16 patients with biopsy proven oesophageal or gastric carcinoma had PET scans. Four patients had advanced disease and received palliative treatment. The remaining 12 patients were randomized to immediate surgery or neoadjuvant chemotherapy. Three patients had repeat PET scans following chemotherapy. PET detected the primary tumour in all cases including stage T1 lesions. Involved locoregional nodes (N1, N2) were not identified separately from the primary tumour. Semiquantitative analysis was performed in the form of tumour to liver activity ratios (TLR). In general, the TLR values were higher in the higher T stages, although there was only one case each of T1 and T2 lesions. PET scanning using 18F-FDG is a sensitive method for detecting primary oesophageal and gastric cancers but is limited in locoregional staging.


Discriminative multimodal learning via conditional priors in generative models.
Deep generative models with latent variables have been used lately to learn joint representations and generative processes from multi-modal data, which depict an object from different viewpoints. These two learning mechanisms can, however, conflict with each other and representations can fail to embed information on the data modalities. This research studies the realistic scenario in which all modalities and class labels are available for model training, e.g. images or handwriting, but where some modalities and labels required for downstream tasks are missing, e.g. text or annotations. We show, in this scenario, that the variational lower bound limits mutual information between joint representations and missing modalities. We, to counteract these problems, introduce a novel conditional multi-modal discriminative model that uses an informative prior distribution and optimizes a likelihood-free objective function that maximizes mutual information between joint representations and missing modalities. Extensive experimentation demonstrates the benefits of our proposed model, empirical results show that our model achieves state-of-the-art results in representative problems such as downstream classification, acoustic inversion, and image and annotation generation.


Thermodynamics of native point defects in α-Fe2O3: an ab initio study.
The native point defects in Fe2O3 are theoretically investigated using ab initio methods based on the GGA + U formalism. We consider vacancies and interstitials of Fe and O atoms as well as the electron polaron as Fe(II) defects at the host Fe(III) site. The formation energies and charge transition levels are computed for each defect type with careful elimination of size effects of the supercell. It is found that the Fe interstitial and vacancy form donor and acceptor levels close to band edges, respectively, thereby allowing for charge carriers at room temperature. We determine the oxygen deficiency under high-temperature equilibrium conditions and find an excellent agreement with experiment. In the quenched condition, it is found that the Fermi level is pinned at ~0.5 eV below the conduction band minimum, which may limit the performance of Fe2O3 as a photoanode in solar water-splitting cells. Furthermore, the oxygen vacancy is mostly neutral and the Fe interstitial is responsible for electron carriers.


Inhibition of Escherichia coli precursor-16S rRNA processing by mouse intestinal contents.
The correlation between ribosome content and growth rate found in many bacterial species has proved useful for estimating the growth activity of individual cells by quantitative in situ rRNA hybridization. However, in dynamic environments, the stability of mature ribosomal RNA causes problems in using cellular rRNA contents for direct monitoring of bacterial growth activity in situ. In a recent paper, Cangelosi and Brabant suggested monitoring the content of precursors in rRNA synthesis (pre-rRNAs) as an alternative approach. These are rapidly broken down after the cessation of bacterial growth. We have applied fluorescence in situ hybridization of pre-16S rRNA to Escherichia coil cells growing in vitro in extracts from two different compartments of the mouse intestine: the caecal mucus layer, where E. coli grew rapidly, and the contents of the caecum, which supported much slower bacterial growth. The amounts of 23S rRNA and pre-16S rRNA measured for E. coil growing in intestinal mucus corresponded to that expected for bacteria with the observed growth rate. In contrast, the slow-growing E. coli cells present in intestinal contents turned out to have an approximately ninefold higher content of pre-16S rRNA than cultures of the same strain growing rapidly in rich media. We present results suggesting that the mouse intestinal contents contain an agent that inhibits the growth of E. coli by disturbing its ability to process pre-16S rRNA.


Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta).
Adipose tissue deposition is highly responsive to estrogen; ovariectomy increases adipose deposition, and estrogen replacement reverses this. Estrogen receptor alpha (ERalpha) plays a major role in adipose tissue. ERalpha knockout (alphaERKO) mice show an increase in adipose tissue of over a 100 % compared to wild-type mice. However, alphaERKO mice undergo a 10-fold increase in 17beta-estradiol (E2), and persistent or even increased signaling through ERbeta could be a factor in obesity of alphaERKO mice. To test the hypothesis that ERbeta plays a role in adipose tissue, adult female alphaERKO mice were ovariectomized or sham-ovariectomized and fed a phytoestrogen-free diet. Ovariectomized mice were treated with vehicle or E2, and bodyweights and food consumption were measured. Mice were killed after 28 days and inguinal and parametrial fat pads collected. Sham-ovariectomized alphaERKO mice had increased body weight, ovariectomized alphaERKO mice showed a 6 % decrease, and E2 replacement restored body weight to sham levels. Fat pads of ovariectomized alphaERKO mice showed 45 % and 16 % decreases in weight and adipocyte circumference, respectively, compared to sham-ovariectomized or E2-replaced ovariectomized alphaERKO mice. Ovariectomized alphaERKO mice showed a trend towards decreased feed consumption that did not reach significance. Blood glucose levels were lower both before and after glucose injection in ovariectomized compared to sham alphaERKO mice, and E2 treatment reversed this. Insulin levels following glucose challenge were lower in ovariectomized compared to sham-ovariectomized alphaERKO mice, indicating that ovariectomy ameliorated the glucose intolerance and insulin resistance in alphaERKO mice. Immunohistochemical analysis revealed strong staining for ERbeta in adipose tissue. These observations indicate that removing E2/ERbeta signaling in alphaERKO mice by ovariectomy decreases body and fat-pad weights and adipocyte size, while improving insulin and glucose metabolism. ERbeta mediated effects on adipose tissue are opposite those of ERalpha, although E2 effects on adipose tissue are predominately through ERalpha.


Older age, longer procedures and tandem endoscopic-ultrasound as risk factors for post-endoscopic retrograde cholangiopancreatography bacteremia.
Clinically significant post-endoscopic retrograde cholangiopancreatography (ERCP) bacteremia (PEB) occurs in up to 5% of cases, while antibiotic prophylaxis is recommended only when an ERCP is unlikely to achieve complete biliary drainage. However, the current recommendations may not cover all potential risk factors for PEB. To identify novel risk factors for PEB and evaluate appropriateness of antibiotic prophylaxis. A retrospective study of 1082 ERCP procedures performed between January 2012 - December 2013 in a single tertiary medical center. Data collection included: Demographic and clinical characteristics such as pre and post procedure antibiotic treatment and bacterial blood cultures. Exclusion criteria were: (1) Age < 18 years; (2) Positive bacterial blood culture before ERCP; (3) Scheduled antibiotic treatment prior to ERCP; (4) Hospitalization longer than 14 d before ERCP; and (5) missing critical data. Stepwise Logistic Regression analysis and Decision Tree algorithms were used for prediction modeling of PEB. A total of 626 ERCPs performed in 434 patients were included. Mean age 66.49 ± 15.4 years and 46.5% were males. PEB prevalence was 3.7%. Antibiotic prophylaxis was administrated in 139/626 (22.2%) cases but was indicated according to the guidelines only in 44/626 (7%) cases. In all the PEB cases, prophylaxis was deemed not indicated. A stepwise logistic regression [receiver operating characteristic (ROC), 0.766], identified 3 variables as independent risk factors for PEB: Age at ERCP ≥ 75 years (OR, 3.780, 95%CI: 1.519-9.408, P = 0.004); Tandem EUS/ERCP with fine needle aspiration (FNA) (OR, 14.528, 95%CI: 3.571-59.095, P < 0.001); ERCP duration longer than 60 min (OR, 5.396, 95%CI: 1.86-15.656, P = 0.002). In a decision tree model (ROC, 0.778) the probability for PEB without any risk factors was 1% regardless of prophylaxis administration. The prevalence of PEB in our study is similar to previous reports, despite the fact that antibiotic prophylaxis was administrated more readily than recommended. ERCP duration longer than 60 min, tandem EUS-ERCP with FNA and age above 75 years are significant risk factors for PEB. These factors should be further evaluated as indications for prophylactic antibiotic treatment before ERCP.


[Indirect immunofluorescence in filariasis. I. Standardization of the technique. Cuba, 1983].
Indirect immunofluorescence was standardized for the diagnosis of human filiariae, using antigens of Dipetalonema viteae. Due to the determined sensibility and specificity, the tier of 1:512 was recommended for aiding clinicians in the individual diagnosis of suspicious patients and that of 1:256 for epidemiologic studies. The titers of cross reactions were less than 1:128.


Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study.
To examine the rates of acute myocardial infarction (AMI) and ischaemic stroke (IS) and to examine the predictive value of total cholesterol (TC) and triglycerides (TG) for AMI and IS in patients with rheumatoid arthritis (RA) and people without RA. In the Apolipoprotein MOrtality RISk (AMORIS) Study 480 406 people (including 1779 with RA, of whom 214 had an AMI and 165 an IS) were followed for 11.8 (range 7-17) years. Cox regression analysis was used to calculate HR per SD increase in TC or TG with 95% CI. All values were adjusted for age, diabetes and hypertension. The levels of TC and TG were significantly lower in patients with RA than in people without RA. Despite this, the rate of AMI and IS per 1000 years was at least 1.6 times higher in RA than non-RA. TC was nearly significantly predictive for AMI (HR/SD 1.13 (95% CI 0.99 to 1.29), p=0.07) and significantly predictive for future IS in RA (HR/SD 1.20 (95% CI 1.03 to 1.40), p=0.02). TG had no relationship to development of AMI (1.07, 0.94 to 1.21, p=0.29), but was weakly related to IS (1.13, 0.99 to 1.27, p=0.06). In contrast, both TC and TG were significant predictors of AMI and IS in people without RA. Patients with RA had 1.6 times higher rate of AMI and IS than people without RA. TC and TG were significant predictors of AMI and IS in people without RA, whereas the predictive value in RA was not consistent.


Purification, cloning, and functional expression of dihydroneopterin triphosphate 2'-epimerase from Escherichia coli.
Dihydroneopterin triphosphate (H2NTP) 2'-epimerase from Escherichia coli catalyzes the epimerization of H2NTP to dihydromonapterin triphosphate (H2MTP). The enzyme was purified 954-fold to apparent homogeneity by a combination of ammonium sulfate fractionation and column chromatography of Cibacron blue 3GA dye ligand, phenyl-Sepharose CL-4B, methotrexate-agarose, and Superdex 200 HR 10/30 FPLC column. The molecular mass of the epimerase determined on a Superdex column was 82.6 kDa, while the subunit molecular mass determined on SDS-polyacrylamide gel electrophoresis was 13.7 kDa. This implies that the epimerase most probably exists as homohexamer. The 20-amino acid sequence from the N terminus was determined (AQPAAIIRIKNLRLRTFIGI). Based on this sequence, the gene encoding the epimerase was cloned using a simple polymerase chain reaction approach. Translation of the nucleotide sequence of the cloned gene revealed the presence of an open reading frame containing 120 amino acids with a predicted molecular mass of 13,993 Da. The epimerase gene located in a 2.3-kilobase BamHI-EcoRI fragment from Kohara's clone 406 was overexpressed 300-fold, which was confirmed by the prominent increase in the 14-kDa protein band on SDS-polyacrylamide electrophoresis gels. It showed no homology with the sequences of isomerases or other enzymes in GenBank/EMBL data bases.


Translation-rotation decoupling of tracers reflects medium-range crystalline order in two-dimensional colloid glasses.
The dynamic heterogeneity and the translation-rotation decoupling are the dynamic signatures of glasses and supercooled liquids. Whether and how the dynamic heterogeneity would relate to the local structure of glasses has been a puzzle for decades. In this work we perform molecular dynamics simulations for tracers in both two-dimensional polydisperse colloids (2DPC) and two-dimensional binary colloids (2DBC). In 2DPC glasses, hexatic local structures develop at low enough temperatures and grow quickly along with the dynamic correlation length of the 2DPC, which is well known as the medium-range crystalline order (MRCO). In 2DBC glasses, on the other hand, any explicit local structure has not been reported to grow significantly with the dynamic correlation length at low temperatures. We introduce two different types of tracers into colloidal systems: A diamond tracer that resembles the MRCO of 2DPC glasses and a square tracer that is dissimilar to any local structure of glasses. The translation-rotation decoupling of the diamond tracer in 2DPC glasses is much more significant than that of the square tracer in the same 2DPC glasses. On the other hand, such a tracer shape-dependence of the decoupling is not observed in 2DBC glasses where the local hexatic structure does not develop significantly. We introduce a shape-dependency parameter of the decoupling and find that the shape-dependency parameter grows along with the dynamic correlation length in 2DPC glasses but not in 2DBC glasses. This illustrates that the dynamic heterogeneity and the translation-rotation decoupling of tracers could reveal the local structure that develops in glasses.


Isolation of bovine viral diarrhea virus-like pestiviruses from roe deer (Capreolus capreolus).
Cytopathogenic pestiviruses were isolated from two seronegative free-ranging roe deer (Capreolus capreolus) from northern Germany (Schleswig-Holstein): an adult female and a young buck collected on 6 December 1990 and 26 July 1991, respectively. The two isolates were identified by polymerase chain reaction as pestiviruses. However, they were negative when primers specific for bovine virus diarrhea virus or classical swine fever virus were used, indicating that the two isolates might belong to a separate group of pestiviruses of wild ruminants different from BVDV.


A systematic review of quality improvement initiatives for continuous sedation until death.
Extensive debate surrounds the practice of continuous sedation until death within end-of-life care. To provide insight into existing initiatives to support the practice of continuous sedation until death and assess their feasibility and effectiveness. Systematic review and narrative synthesis, registered on PROSPERO (CRD42020149630). Records were searched through MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science from inception to April 16 2020. Peer-reviewed studies reporting original data on initiatives to support the practice of continuous sedation were included for review. Twenty-one studies met the criteria and were included. Initiatives were focused on assessment tools of consciousness and discomfort (9), the use of guidelines and protocols (8), and expert consultation (3). All initiatives were reported as useful, acceptable, and feasible. Studies on the use of monitoring devices showed that a small proportion of patients were found to be awake, despite the patient being unresponsive according to the observer-based sedation scales. However, the wide range of values of these monitoring devices for comfortable and adequately sedated patients seems to hamper its overall implementation in daily clinical practice. Physicians reported changes in practice conform to guideline recommendations but the shift was modest at best. Expert consultation was regarded as supportive when sufficient expertise is lacking and helpful in avoiding possibly unnecessary sedations. The reviewed initiatives may contribute to improvement of continuous sedation until death, though their evidence base is rather limited. More insight is needed into their feasibility, preconditions for effective implementation and impact in actual practice.


An automated quantitative image analysis tool for the identification of microtubule patterns in plants.
High throughput confocal imaging poses challenges in the computational image analysis of complex subcellular structures such as the microtubule cytoskeleton. Here, we developed CellArchitect, an automated image analysis tool that quantifies changes to subcellular patterns illustrated by microtubule markers in plants. We screened microtubule-targeted herbicides and demonstrate that high throughput confocal imaging with integrated image analysis by CellArchitect can distinguish effects induced by the known herbicides indaziflam and trifluralin. The same platform was used to examine 6 other compounds with herbicidal activity, and at least 3 different effects induced by these compounds were profiled. We further show that CellArchitect can detect subcellular patterns tagged by actin and endoplasmic reticulum markers. Thus, the platform developed here can be used to automate image analysis of complex subcellular patterns for purposes such as herbicide discovery and mode of action characterisation. The capacity to use this tool to quantitatively characterize cellular responses lends itself to application across many areas of biology.


Immature NK cells, capable of producing IL-22, are present in human uterine mucosa.
NK cells are the dominant population of immune cells in the endometrium in the secretory phase of the menstrual cycle and in the decidua in early pregnancy. The possibility that this is a site of NK cell development is of particular interest because of the cyclical death and regeneration of the NK population during the menstrual cycle. To investigate this, we searched for NK developmental stages 1-4, based on expression of CD34, CD117, and CD94. In this study, we report that a heterogeneous population of stage 3 NK precursor (CD34(-)CD117(+)CD94(-)) and mature stage 4 NK (CD34(-)CD117(-/+)CD94(+)) cells, but not multipotent stages 1 and 2 (CD34(+)), are present in the uterine mucosa. Cells within the uterine stage 3 population are able to give rise to mature stage 4-like cells in vitro but also produce IL-22 and express RORC and LTA. We also found stage 3 cells with NK progenitor potential in peripheral blood. We propose that stage 3 cells are recruited from the blood to the uterus and mature in the uterine microenvironment to become distinctive uterine NK cells. IL-22 producers in this population might have a physiological role in this specialist mucosa dedicated to reproduction.


400 mW low noise continuous-wave single-frequency Er,Yb:YAl3(BO3)4 laser at 1.55 μm.
We build up a LD end-pumped Er,Yb:YAB laser at 1.55 μm and improve the laser performance by end cooling the gain medium efficiently through a sapphire plate. 680 mW cw single transverse mode laser output was obtained with the slope efficiency of 16.3%. Using an etalon placed in the laser cavity, 400 mW cw single frequency 1.55 μm laser output was achieved with the slope efficiency of 11.8%. The laser power fluctuation was less than ± 1.3% in a given period of 1.5 hours. The 1.55 μm laser presents low noise properties, that the intensity and the phase noise reach the shot noise level for the analysis frequencies higher than 4 MHz and 5 MHz, respectively.


Knowledge of PCSK9 and continued educational gaps: evaluating the impact of continuing medical education.
Reducing serum levels of low-density lipoprotein-cholesterol (LDL-C) is an important treatment objective in both the primary and secondary prevention settings. Although statin therapy remains the gold standard for reducing LDL-C, for a variety of reasons, many patients taking statins do not achieve adequate cholesterol lowering. This has created a need for new treatment approaches to manage dyslipidemia. One potential emerging treatment option to promote greater LDL-C reduction is the class of proprotein convertase subtilisin/kexin 9 (PCSK9) monoclonal antibodies, currently in phase 3 development. This study evaluated the impact of continuing medical education (CME) on increasing knowledge and awareness of the role of PCSK9 in lipid metabolism and analyzed persistent educational gaps to determine needs for future education. For cardiologists who participated in the CME activity, comparison of individually linked preassessment question responses to their respective postassessment question responses demonstrated improvement (n = 83; P < 0.05). Correct responses on postassessment questions ranged between 63% and 253% higher after CME, with an overall effect size of 0.72. Between 24% and 47% of learners showed improvement in understanding individual learning concepts. In the ever-evolving landscape of dyslipidemia management, CME demonstrably impacted knowledge of the PCSK9 monoclonal antibodies.


The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions.
C-Kit (CD117), the receptor for the stem cell factor, a growth factor for melanocyte migration and proliferation, has shown differential immunostaining in various benign and malignant melanocytic lesions. The purpose of this study is to compare c-Kit immunostaining in benign nevi and in primary and metastatic malignant melanomas, to determine whether c-Kit can aid in the differential diagnosis of these lesions. c-Kit immunostaining was performed in 60 cases of pigmented lesions, including 39 benign nevi (5 blue nevi, 5 intradermal nevi, 3 junctional nevi, 15 cases of primary compound nevus, 11 cases of Spitz nevus), 18 cases of primary malignant melanoma and 3 cases of metastatic melanoma. The vast majority of nevi and melanomas examined in this study were positive for c-Kit, with minimal differences between benign and malignant lesions. C-Kit cytoplasmatic immunoreactivity in the intraepidermal proliferating nevus cells, was detected in benign pigmented lesions as well as in malignant melanoma, increasing with the age of patients (P=0.007) in both groups. The patient's age at presentation appeared to be the variable able to cluster benign and malignant pigmented lesions. The percentage of c-Kit positive intraepidermal nevus cells was better associated with age despite other variables (P=0.014). The intensity and percentage of c-Kit positivity in the proliferating nevus cells in the dermis was significantly increased in malignant melanocytic lesions (P=0.015 and P=0.008) compared to benign lesions (compound melanocytic nevi, Spitz nevi, intradermal nevi, blue nevi). Immunostaning for c-Kit in metastatic melanomas was negative. Interestingly in two cases of melanoma occurring on a pre-existent nevus, the melanoma tumor cells showed strong cytoplasmatic and membranous positivity for c-kit, in contrast with the absence of any immunoreactivity in pre-existent intradermal nevus cells. C-Kit does not appear to be a strong immunohistochemical marker for distinguishing melanoma from melanocytic nevi, if we consider c-Kit expression in intraepidermal proliferating cells. The c-Kit expression in proliferating melanocytes in the dermis could help in the differential diagnosis between a superficial spreading melanoma (with dermis invasion) and a compound nevus or an intradermal nevus. Finally, c-Kit could be a good diagnostic tool for distinguishing benign compound nevi from malignant melanocytic lesions with dermis invasion and to differentiate metastatic melanoma from primary melanoma.


Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.


Ghost Cell Odontogenic Carcinoma Arising Denovo with Distant Metastasis: A Case Report and Review of Literature.
Ghost Cell Odontogenic Carcinoma (GCOC) is a rare malignant odontogenic tumour of epithelial origin accounting about 0.37% to 2.1% of all odontogenic tumours. They are characterized by the presence of ameloblastic islands along with ghost cells representing aberrant keratinization. The aim of this case report is to present a rare case that was diagnosed in a 37-year-old male patient and to describe the behavior of the tumour.


Exploring Implementation of the Ontario School Food and Beverage Policy at the Secondary-School Level: A Qualitative Study.
The purpose of this study was to explore the implementation of the Ontario School Food and Beverage Policy (P/PM 150) from the perspective of secondary-school students. This research, informed by the ANGELO framework, undertook three focus groups with secondary students (n = 20) in 2 school boards representing both high- and low-income neighbourhoods in fall 2012. Focus groups were transcribed verbatim for subsequent analysis. Key themes were generated deductively from the research objectives and inductively as they emerged from transcripts. Perceived impacts of P/PM 150 included high-priced policy-compliant food for sale, lower revenue generation, and food purchased off-campus. Limited designated eating spaces, proximity to external, nonpolicy-compliant food, and time constraints acted as key local level barriers to healthy eating. Pricing strategies are needed to ensure that all students have access to nutritious food, particularly in the context of vulnerable populations. Recognition of the context and culture in which school nutrition policies are being implemented is essential. Future research to explore the role of public health dietitians in school nutrition policy initiatives and how to leverage local resources and stakeholder support in low income, rural and remote populations is needed.


Towards automated binding affinity prediction using an iterative linear interaction energy approach.
Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only.


Homologous expression of soluble methane monooxygenase genes in Methylosinus trichosporium OB3b.
An homologous expression system has been developed for soluble methane monooxygenase (sMMO) genes from Methylosinus trichosporium OB3b. sMMO-minus mutants were previously obtained after marker-exchange mutagenesis, by the insertion of a kanamycin-resistance cassette into the mmoX gene of the sMMO operon. Complementation of the sMMO-minus genotype was achieved by conjugation with broad-host-range plasmids containing the native promoter and sMMO operon from Ms. trichosporium OB3b (pVK100Sc and pHM2). In wild-type methanotrophs, copper ions present in the growth medium at concentrations greater than 0.25 microM inhibit transcription of sMMO genes. The stable maintenance of pVK100Sc resulted in transconjugant methanotrophs with a decreased sensitivity to copper, since expression of sMMO occurred at copper sulphate concentrations of 7.5 microM. sMMO activity was only detected in soluble extracts after the addition of purified sMMO reductase component, which is inhibited by copper ions in vitro. This phenomenon could have arisen due to the increased number of sMMO gene copies (derived from pVK100Sc) in the cell. Transconjugants obtained from conjugations with pHM2 expressed sMMO at copper concentrations of 0-2.5 microM only and sMMO activity was not restored by the addition of purified reductase component at copper concentrations higher than 2.5 microM. Southern hybridization showed that the plasmid had integrated into the chromosome, probably by a single homologous recombination event. This is the first report of homologous sMMO expression in a methanotroph with enzyme activities that are comparable to the activity reported in wild-type strains. This expression system will be useful for site-directed mutagenesis of active-site residues of sMMO from Ms. trichosporium OB3b.


Sustainable green approach to synthesize Fe3O4/α-Fe2O3 nanocomposite using waste pulp of Syzygium cumini and its application in functional stability of microbial cellulases.
Synthesis of nanomaterials following green routes have drawn much attention in recent years due to the low cost, easy and eco-friendly approaches involved therein. Therefore, the current study is focused towards the synthesis of Fe3O4/α-Fe2O3 nanocomposite using waste pulp of Jamun (Syzygium cumini) and iron nitrate as the precursor of iron in an eco-friendly way. The synthesized Fe3O4/α-Fe2O3 nanocomposite has been extensively characterized through numerous techniques to explore the physicochemical properties, including X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, Ultraviolet-Vis spectroscopy, field emission scanning electron microscope, high resolution transmission electron microscope and vibrating sample magnetometer. Further, efficiency of the Fe3O4/α-Fe2O3 nanocomposite has been evaluated to improve the incubation temperature, thermal/pH stability of the crude cellulase enzymes obtained from the lab isolate fungal strain Cladosporium cladosporioides NS2 via solid state fermentation. It is found that the presence of 0.5% Fe3O4/α-Fe2O3 nanocomposite showed optimum incubation temperature and thermal stability in the long temperature range of 50-60 °C for 15 h along with improved pH stability in the range of pH 3.5-6.0. The presented study may have potential application in bioconversion of waste biomass at high temperature and broad pH range.


The gap of visual impairment between economic groups in Shahroud, Iran: a Blinder-Oaxaca decomposition.
The authors assessed the role of economic inequality in visual impairment and decomposed the gap between high and low income groups. Study data were extracted from the first phase of the Shahroud Eye Cohort Study, performed in 2009, with 5,190 participants aged between 40 and 64 years. The participants were divided into low, medium, and high economic groups according to their assets by using a principal component analysis. The gap between low and high economic groups was decomposed to its determinants by using the Blinder-Oaxaca method. The prevalence of visual impairment, a presenting vision worse than 20/40 in the better eye, was 3.57% and 11.07% in the high and low economic groups, respectively. Age and education were the major factors in the decomposition model, contributing to 41.38% of the gap. Insurance status, gender, and education of the head of the household had no effect on this gap. Economic inequality in visual impairment was noteworthy. Although part of the gap between low and high economic groups was explained by differences in age and education, the greater part (58.62%) could be due to differences in health-care access and utilization.


A method of selecting for auxotrophic mutants of HeLa cells.
1. Aminopterin prevents the multiplication of HeLa cells in Eagle's medium. The joint addition of adenine and thymidine removes the inhibition. 2. The aminopterin-induced thymine deficiency specifically results in a cessation of cell division and a doubling in the average protein content of the cells. Continued starvation for thymine results in the inability of cells to proliferate after aminopterin is removed. After 6 days only 10(-6) to 10(-5) of the original population proliferates. 3. The omission of a single essential amino acid, such as arginine or glutamine, from the medium during deprivation of thymine prevents a net increase in protein and results in about a 10(5)-fold greater cell survival after 6 days, when aminopterin is removed and the missing amino acid is supplied. 4. Glutamine-requiring, auxotrophic mutants of HeLa exhibit a high survival after exposure to aminopterin in a glutamine-free medium. Glutamine-independent HeLa cells show a much lower survival in the same medium. Low frequencies of the auxotrophs can be specifically and efficiently selected for in artificial mixtures of the two cell types by treatment with the glutamine-free medium containing aminopterin.


ACOG committee opinion. Risk of breast cancer with estrogen-progestin replacement therapy.
Recent articles have examined the association between the use of combination estrogen-progestin regimens for hormone replacement therapy (HRT) and the risk of breast cancer. The objective of this Committee Opinion is to evaluate critically the presented evidence. Although epidemiologic studies suggest that the addition of progestins to estrogens may increase the risk of breast cancer, this increased risk has not been proved. The American College of Obstetricians and Gynecologists continues to recommend that HRT be considered as a treatment to relieve vasomotor symptoms and genitourinary tract atrophy and to reduce the risk of osteoporosis and, potentially, cardiovascular disease. Postmenopausal women should be apprised of the current understanding of the risks and benefits of HRT. When considering the use of HRT for longer than 5 years, the clinician and individual patient should weigh the benefits versus the potential side effects and risks for that particular patient.


Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.
Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function, whereas RPA1T270A has binding properties similar to wild-type protein. To study the mutational effect in a cellular system, CRISPR/Cas9 was used to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patients with RPA1E240K, we discovered somatic genetic rescue in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the 2 somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.


Single dose oral aspirin for acute pain.
Aspirin has been known to be an effective analgesic for many years and is commonly used throughout the world for many different pain conditions. It is important for both prescribers and patients to have the best possible information about the efficacy and safety of analgesics, and this need is reflected in patient surveys which show that postoperative pain is often poorly managed. We also need to benchmark relative efficacy and safety of current analgesics so that we can compare them with new analgesics. To quantitatively assess the analgesic efficacy and adverse effects of a single-dose of aspirin in acute pain of moderate to severe intensity. Randomised trials were identified by searching Medline (1966 to March 1998), Embase (1980 to January 1998), the Cochrane Library (Issue 1,1998) and the Oxford Pain Relief Database (1950 to 1994). The inclusion criteria used were: full journal publication, postoperative pain or a mixture of postoperative and acute trauma pain, oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared aspirin with placebo. Summed pain relief or pain intensity difference over four to six hours was extracted, and converted into dichotomous information yielding the number of patients with at least 50% pain relief. This was then used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. Seventy-two randomised single-dose trials met our inclusion criteria, with 3253 patients given aspirin, and 3297 placebo. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg and 1200 mg, NNTs for at least 50% pain relief of 4.4 (4.0 to 4.9), 4.0 (3.2 to 5.4) and 2.4 (1.9 to 3.2) respectively. Single-dose aspirin 600/650 mg produced significantly more drowsiness and gastric irritation than placebo, with a number-needed-to-harm (NNH) of 28 (19 to 52) and 38 (22 to 174) respectively. Type of pain model, pain measurement, sample size, quality of study design, and study duration had no significant impact on the results. Aspirin is an effective analgesic for acute pain of moderate to severe intensity with a clear dose-response. Drowsiness and gastric irritation were seen as significant adverse effects even though the studies were single-dose. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol.


Scrotal calcification: ultrasound appearances, distribution and aetiology.
This pictorial review illustrates the ultrasound appearances of scrotal calcification, distinguishing between intratesticular and extratesticular calcification. Intratesticular calcification may be due to phleboliths, spermatic granulomas or vascular calcification, or it may occur in association with tumours. Extratesticular calcification is more frequently encountered and is usually related to previous inflammatory disease of the epididymis. Testicular microlithiasis, a rare condition characterized by multiple scattered echogenic foci within the testis, is produced by the formation of microliths from degenerating cells in the seminiferous tubules. Testicular microlithiasis has been demonstrated as an incidental finding as well as in association with both benign and malignant tumours of the testis.


Power of crowdsourcing: novel methods of data collection in psoriasis and psoriatic arthritis.
Crowdsourcing is a novel method of collecting research data from diverse patient populations. The quality of research data obtained through crowdsourcing is unknown. The primary aim of this pilot study was to examine how data collected from an online crowdsourcing World Wide Web site compare with those from published literature in psoriasis and psoriatic arthritis (PsA). Crowdsourced data were collected from a health crowdsourcing site from August 23, 2008, to June 27, 2011. The crowdsourced data were compared with findings from systematic reviews, meta-analyses, and clinical trials. A total of 160 online patients with psoriasis or PsA were included in the analysis. Among them, 127 patients with psoriasis provided 313 complete responses on psoriasis symptoms and 276 complete responses to psoriasis treatments; 33 patients with PsA provided 91 complete responses on PsA symptoms and 79 responses to PsA treatments. We compared topical treatments, phototherapy, and systemic treatments for psoriasis and PsA from crowdsourced data with the published literature. For the treatment with the largest response rates, equivalency testing was performed comparing crowdsourced data and the published literature. Overall, crowdsourced data were not equivalent to those published in the medical literature. Crowdsourcing sites used different outcomes measures from those reported in clinical trials. Differences existed in assessment of treatment effectiveness between crowdsourced data and those published in the literature. With improvements in the collection of crowdsourced data, crowdsourcing can be a valuable tool for collecting patient data in real-world settings for psoriasis and PsA.


Association of Historical Redlining and Present-Day Social Vulnerability with Cancer Screening.
The Healthy People 2030 initiative has set national cancer screening targets at 77.1%, 74.4%, and 84.3% for breast, colon, and cervical cancers, respectively. We sought to assess the association between historical redlining relative and present-day social vulnerability on screening targets for breast, colon, and cervical cancer. Data on national census-tract level cancer screening prevalence and social vulnerability index in 2020 was extracted from the CDC PLACES and CDC social vulnerability index databases, respectively. Census tracts were then assigned Home-Owners Loan Corporation grades (A: "Best", B: "Still Desirable", C: "Definitely Declining," and D: "Hazardous/Redlined"). Mixed-effects logistic regression and mediation analyses were conducted to evaluate the association between Home-Owners Loan Corporation grades and achievement of cancer screening targets. Among 11,831 census tracts, 3,712 were classified as redlined (A: n = 842, 7.1% vs B: n = 2,314, 19.6% vs C: n = 4,963, 42.0% vs D: n = 3,712, 31.4%). Notably, 62.8% (n = 7,427), 21.2% (n = 2,511), and 27.3% (n = 3,235) of tracts met screening targets for breast, colon, and cervical cancer, respectively. After adjusting for present-day social vulnerability index and access to care metrics (population to primary care physician ratio and distance to nearest healthcare facility), redlined tracts were markedly less likely to meet breast (odds ratio [OR] 0.76, 95% CI 0.64 to 0.91), colon (OR 0.34, 95% CI 0.28 to 0.41), and cervical (OR 0.21, 95% CI 0.16 to 0.27) cancer screening targets compared with the "Best" tracts. Notably, poverty, lack of education, and limited English proficiency, among others, mediated the adverse effect of historical redlining on cancer screening. Redlining as a surrogate for structural racism continues to adversely impact cancer screening. Policies that aim to make access to preventive cancer care more equitable for historically marginalized communities should be a public priority.


Electrical conductivity of polyelectrolyte solutions in the presence of added salt: The role of the solvent quality factor in light of a scaling approach.
The effects of added salt on the electrical conductivity behavior of a polyelectrolyte solution are described in light of the scaling approach recently proposed by Dobrynin and Rubinstein [Macromolecules 28, 1859 (1995); 32, 915 (1999)], taking into account the influence of the solvent quality factor. The coupling between the conformation of the chain and the local charge distribution, giving rise to different conductometric behaviors, has been investigated under different conditions, in a wide concentration range of added salt. The polyion equivalent conductances lambda(p) have been evaluated in different concentration regimes for a hydrophilic polyion in good solvent condition and compared with the experimental values obtained from electrical conductivity measurements. The agreement is rather good in the wide range of concentration of the added salt investigated. In the case of poor solvent conditions, we find the appropriate expressions for the electrical conductivity when the polyion chain consists into collapsed beads alternating with stretched segments in the framework of the necklace globule model.


Effect of far infrared therapy on arteriovenous fistula maturation: an open-label randomized controlled trial.
Malfunction of the arteriovenous fistula (AVF) is an important cause of morbidity and hospitalization in hemodialysis (HD) patients. The aim of this study is to evaluate the effect of far infrared therapy on the maturation and patency of newly created AVFs in patients with chronic kidney disease stage 4 or 5. Randomized controlled study. Patients with estimated glomerular filtration rate of 5-20 mL/min/1.73 m². 40 minutes of far infrared therapy 3 times weekly for a year. The primary outcome is the rate of AVF malfunction within 12 months, with malfunction defined as either: (1) thrombosis without thrill for AVFs not undergoing HD or (2) receiving any type of interventional procedure due to a lower Kt/V (<1.2) for patients undergoing HD. Secondary outcomes include: (1) cumulative primary unassisted AVF patency, defined as time from creation of the AVF to the first episode of AVF malfunction; (2) physiologic maturation of the AVF by the definition of AVF access blood flow (Qa) ≥500 mL/min and AVF diameter ≥4 mm at 3 months; and (3) clinical maturation of the AVF suitable for HD at 1 year. AVF Qa was measured by Doppler ultrasonography at 2 days and 1, 2, 3, and 12 months. We enrolled 122 patients who were randomly allocated to the intervention (n = 60) and control (n = 62) groups. In comparison to controls, patients in the intervention group had higher Qa values at 1, 2, 3, and 12 months; a higher rate of physiologic maturation (90% vs 76%; P = 0.04) at 3 months; and a lower rate of AVF malfunction (12% vs 29%; P = 0.02) but higher rates of AVF cumulative unassisted patency (87% vs 70%; P = 0.01) and clinical maturation (82% vs 60%; P = 0.008) within 12 months. This is a single-center nonblinded study. Far infrared therapy improves the access flow, maturation, and patency of newly created AVFs in patients with chronic kidney disease stages 4 and 5.


Spatio-temporal characterization of few-cycle pulses obtained by filamentation.
Intense sub-5-fs pulses were generated by filamentation in a noble gas and subsequent chirped-mirror pulse compression. The transversal spatial dependence of the temporal pulse profile was investigated by spatial selection of parts of the output beam. Selecting the central core of the beam is required for obtaining the shortest possible pulses. Higher energy efficiency is only obtained at the expense of pulse contrast since towards the outer parts of the beam the energy is spread into satellite structures leading to a double-pulse profile on the very off-axis part of the beam. Depending on the requirements for a particular application, a trade-off between the pulse duration and the pulse energy has to be done. The energy of the sub-5-fs pulses produced was sufficient for the generation of high order harmonics in Argon. In addition, full simulation is performed in space and time on pulse propagation through filamentation that explains the double-pulse structure observed as part of a conical emission enhanced by the plasma defocusing.


Genome-wide analysis of the soybean root transcriptome reveals the impact of nitrate on alternative splicing.
In plants, nitrate acts not only as a signaling molecule that affects plant development but also as a nutrient. The development of plant roots, which directly absorb nutrients, is greatly affected by nitrate supply. Alternative gene splicing plays a crucial role in the plant stress response by increasing transcriptome diversity. The effects of nitrate supply on alternative splicing (AS), however, have not been investigated in soybean roots. We used high-quality high-throughput RNA-sequencing data to investigate genome-wide AS events in soybean roots in response to various levels of nitrate supply. In total, we identified 355 nitrate-responsive AS events between optimal and high nitrate levels (NH), 335 nitrate-responsive AS events between optimal and low nitrate levels (NL), and 588 nitrate-responsive AS events between low and high nitrate levels (NLH). RI and A3SS were the most common AS types; in particular, they accounted for 67% of all AS events under all conditions. This increased complex and diversity of AS events regulation might be associated with the soybean response to nitrate. Functional ontology enrichment analysis suggested that the differentially splicing genes were associated with several pathways, including spliceosome, base excision repair, mRNA surveillance pathway and so on. Finally, we validated several AS events using reverse transcription-polymerase chain reaction to confirm our RNA-seq results. In summary, we characterized the features and patterns of genome-wide AS in the soybean root exposed to different nitrate levels, and our results revealed that AS is an important mechanism of nitrate-response regulation in the soybean root.


Large epidemiologic studies of gout: challenges in diagnosis and diagnostic criteria.
Large epidemiologic studies of gout can improve insight into the etiology, pathology, impact, and management of the disease. Identification of monosodium urate monohydrate crystals is considered the gold standard for diagnosis, but its application is often not possible in large studies. Therefore, under such circumstances, several proxy approaches are used to classify patients as having gout, including ICD coding in several types of databases or questionnaires that are usually based on the existing classification criteria. However, agreement among these methods is disappointing. Moreover, studies use the terms acute, recurrent, and chronic gout in different ways and without clear definitions. Better definitions of the different manifestations and stages of gout may provide better insight into the natural course and burden of disease and can be the basis for valid approaches to correctly classifying patients within large epidemiologic studies.


Ostrich nutrition: a review from a Zimbabwean perspective.
The ostrich is an important animal in many livestock industries and, in the developing world, the export of meat and skins is a valuable source of foreign currency. As the successful growth and reproductive performance of ostriches depends on good nutrition it is extremely important to provide the correct diet. Some researchers have incorrectly assumed that poultry diets are useful for ostriches, but the vitamin and mineral requirements of these birds are unique and their diets should never be substituted with poultry or other livestock feeds. Producers should be knowledgeable about how different ingredients provide the essential nutrients for growth and development. Adequate nutrition is key to good flock performance and more research into ostrich nutrition is required. In Zimbabwe, one of the greatest costs involved in the keep of ostrich breeder birds is purchased feed, which can cost approximately US$ 4,555 for every 10 birds per annum. In order to cover these costs, the producer needs to ensure an adequate supply of birds for slaughter.


Mediators of Stereotype Threat among Black College Students.
We hypothesize that the manner in which stereotype threat affects college grade achievement is mediated by institutional context as well as individual characteristics. Drawing on a sample of black students from the National Longitudinal Survey of Freshmen we find weak and inconsistent evidence that institutional characteristics influence the operation of stereotype threat. We find more consistent evidence to indicate that the effect of stereotype threat is conditioned by individual factors such as skin color, multiracial origins, and an integrated upbringing. Most of the effect on grade achievement occurs through the internalization pathway, in which the internalization of negative stereotypes leads to disinvestment manifested by a reduction in academic effort. The reduction in work effort, in turn, lowers grades. We also find evidence that immigrant origin confers protection from the negative effects of stereotype threat through both internalization and externalization mechanisms, though the ultimate effect of grade achievement is rather small.


Asthma medications: basic pharmacology and use in the athlete.
Asthma is a chronic disease that affects athletes at all levels of sport. Several categories of drugs, including relatively new agents, are available to treat the asthmatic patient. By understanding the appropriate uses and effects of these drugs, the athletic trainer can assist the asthmatic athlete in improving therapeutic outcomes from the asthma therapy. The appropriate use of these medications includes not only the use of the appropriate drug(s), but also appropriate technique for administration, compliance with the prescribed dosing intervals, and sufficient care to avoid side effects. I searched MEDLINE and CINAHL from 1982 to 1999 and International Pharmaceutical Abstracts from 1990 to 1999. Terms searched were "asthma," "athlete,""athletic," "exercise-induced," "exercise," "performance," "therapy," and "treatment." Bronchodilators include beta2 agonists, anticholinergics, and methylxanthines. Of these, the beta2 agonists used by inhalation are the drugs of choice to treat an acute asthma attack or to prevent an anticipated attack (such as before exercise). Anti-inflammatory agents include corticosteroids mast cell-stabilizing agents, and antileukotrienes. Corticosteroids by inhalation are the drugs of choice for long-term treatment to curb the inflammatory process in the lung. Each of these drug categories has a unique mechanism of action. The athletic trainer who understands the appropriate use of these medications can help the athlete to obtain optimal results from drug therapy. Encouraging the athlete to comply with appropriate therapy, monitoring the effectiveness of the therapy, and recognizing the stimuli that initiate asthmatic attacks can improve the patient's therapeutic outcomes. The athletic trainer has an opportunity to play a key role in ensuring that the asthmatic athlete achieves the desired outcomes from treatment. The athletic trainer can help to minimize the effect of asthma on athletic performance by ensuring that the athlete uses inhaler devices properly, is compliant with the prescribed drug therapy, monitors pulmonary function appropriately, uses medications properly before exercise, and is aware of the factors that initiate asthma symptoms.