Executive and perceptual distraction in visual working memory.
The contents of visual working memory are likely to reflect the influence of both executive control resources and information present in the environment. We investigated whether executive attention is critical in the ability to exclude unwanted stimuli by introducing concurrent potentially distracting irrelevant items to a visual working memory paradigm, and manipulating executive load using simple or more demanding secondary verbal tasks. Across 7 experiments varying in presentation format, timing, stimulus set, and distractor number, we observed clear disruptive effects of executive load and visual distraction, but relatively minimal evidence supporting an interactive relationship between these factors. These findings are in line with recent evidence using delay-based interference, and suggest that different forms of attentional selection operate relatively independently in visual working memory. (PsycINFO Database Record


A prospective study of preoperative computed tomographic angiography for head and neck reconstruction with anterolateral thigh flaps.
During anterolateral thigh flap harvest, inadequate perforators may necessitate modification of the flap design, exploration of the contralateral thigh, or additional flap harvest. Computed tomographic angiography may facilitate perforator mapping and optimize flap design. The authors performed this pilot study to determine the predictive power of computed tomographic angiography in anterolateral thigh flap planning and execution. : Sixteen consecutive computed tomographic angiography-mapped anterolateral thigh flaps for head and neck reconstruction were studied. Perforator location, origin, caliber, and course were compared between computed tomographic angiography and intraoperative findings. The relationship of patient characteristics, imaging studies, and intraoperative factors to flap design and surgical outcomes was analyzed. : Among the 16 anterolateral thigh flaps, 40 of 54 perforators identified intraoperatively were visible on computed tomographic angiography, resulting in 74 percent sensitivity. Intraoperative perforator location averaged 0.35 cm from the computed tomographic angiography-predicted location. The overall ability of computed tomographic angiography to predict perforator size was 67.5 percent. Its overall accuracy in predicting whether a perforator took a septocutaneous or intramuscular course before perforating the deep fascia was 77.5 percent. Preoperative angiography resulted in surgeons modifying the operative plan in 37 percent of cases and 57 percent of double-island flap cases. All flaps were elevated successfully and survived. : Computed tomographic angiography identified larger perforators better than smaller ones and proximal perforators better than distal ones. It accurately predicted the location and origin of visible perforators and less accurately predicted the size and course of visible perforators. Most importantly, the information it provided influenced surgeons to modify their reconstructive strategy, resulting in a higher level of recipient-site specificity.


A new gene inventory of the ubiquitin and ubiquitin-like conjugation pathways in Giardia intestinalis.
Ubiquitin (Ub) and Ub-like proteins (Ub-L) are critical regulators of complex cellular processes such as the cell cycle, DNA repair, transcription, chromatin remodeling, signal translation, and protein degradation. Giardia intestinalis possesses an experimentally proven Ub-conjugation system; however, a limited number of enzymes involved in this process were identified using basic local alignment search tool (BLAST). This is due to the limitations of BLAST's ability to identify homologous functional regions when similarity between the sequences dips to < 30%. In addition Ub-Ls and their conjugating enzymes have not been fully elucidated in Giardia. To identify the enzymes involved in the Ub and Ub-Ls conjugation processes using intelligent systems based on the hidden Markov models (HMMs). We performed an HMM search of functional Pfam domains found in the key enzymes of these pathways in Giardia's proteome. Each open reading frame identified was analysed by sequence homology, domain architecture, and transcription levels. We identified 118 genes, 106 of which corresponded to the ubiquitination process (Ub, E1, E2, E3, and DUB enzymes). The E3 ligase group was the largest group with 82 members; 71 of which harbored a characteristic RING domain. Four Ub-Ls were identified and the conjugation enzymes for NEDD8 and URM1 were described for first time. The 3D model for Ub-Ls displayed the β-grasp fold typical. Furthermore, our sequence analysis for the corresponding activating enzymes detected the essential motifs required for conjugation. Our findings highlight the complexity of Giardia's Ub-conjugation system, which is drastically different from that previously reported, and provides evidence for the presence of NEDDylation and URMylation enzymes in the genome and transcriptome of G. intestinalis.


Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1.
This study aims to uncover the progression of thyroid carcinoma influenced by the m6A methyltransferase METTL3 through regulating m6A methylation on TCF1 mRNA and the activated Wnt pathway. Thyroid carcinoma tissues and paracancerous ones were collected for detecting levels of METTL3 and TCF1. Potential correlation between levels of METTL3 and TCF1 was analyzed by Pearson analysis. Survival of thyroid carcinoma patients influenced by METTL3 level was assessed by Kaplan-Meier method. Regulatory effect of METTL3 on migratory ability in TPC-1 cells was examined by wound healing assay. The interaction between METTL3 with TCF1 and IGF2BP2 was verified by RNA-Binding Protein Immunoprecipitation (RIP) assay. Meanwhile, the activity of the Wnt pathway was reflected by TOP/FOP-Flash. At last, rescue experiments were conducted to clarify the involvement of TCF1 in phenotype changes of thyroid carcinoma cells that were regulated by METTL3. METTL3 and TCF1 were upregulated in thyroid carcinoma. Similarly, METTL3 was highly expressed in thyroid carcinoma cells as well. Kaplan-Meier method uncovered poor prognosis in thyroid carcinoma patients expressing a high level of METTL3. Silence of METTL3 inhibited migratory ability and Wnt activity in TPC-1 cells. RIP assay confirmed the interaction between TCF1 and METTL3 or IGF2BP2. Moreover, METTL3 positively regulated the enrichment abundance of TCF1 in anti-IGF2BP2. Rescue experiments demonstrated that TCF1 was responsible for METTL3-regulated thyroid carcinoma progression via the m6A methylation. Upregulated m6A methyltransferase METTL3 promotes the progression of thyroid carcinoma through m6A methylation on TCF1.


Vascular risk factors and clinical progression in spinocerebellar ataxias.
The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known. We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account. Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.


Regulating patient access to therapeutics in Denmark: a rhetorical analysis of welfare imaginaries in public controversy.
In this article, I argue that the social imaginaries that inform biomedical regulation circulate not only in technical spheres populated by experts but that they are equally articulated (and vehemently contested) in national public spheres in more popular forms of communication. I examine the relation between a national healthcare imaginary and the regulation of therapeutics through a public controversy about access to an innovative therapeutic indicated for spinal muscular atrophy. The establishment of the Danish Medicines Council, a new health technology assessment institution, and its decision to restrict access to an innovative therapeutic sparked controversy in 2017 involving political proponents, adversaries, and patients, among others. In a variety of ways, they rhetorically mobilized or contested the Danish universalist welfare imaginary which contains promises and prospects of solidarity, security, and absence of market forces in universal healthcare, including access to therapeutics. I use a combination of media content analysis and rhetorical close reading methods to analyze how the imaginary was drawn upon in arguments for and against the new regulatory institution.


Removing hepatitis C virus from polytetrafluoroethylene-coated orthodontic archwires and other dental instruments.
The efficacy of removing, rather than destroying, hepatitis C virus (HCV) from polytetrafluoroethylene (PTFE)-coated orthodontic archwirs was tested. PTFE-coated archwires, pieces of PTFE and endodontic files (20 each) were immersed in HCV-infected blood for 24 hours. Half were washed under running water for 10 seconds while the remainder were thoroughly scrubbed with a toothbrush under running water for 10 seconds. Items were kept in separate dishes of distilled water for 24 hours. Reverse transcription polymerase chain reaction was used for viral replication. Viruses were detected by the gel method using a transilluminator. Only scrubbed PTFE pieces and coated archwires were negative for HCV. This suggests that PTFE coating of dental instruments inhibited HCV adhesion when thoroughly scrubbed.


Specific intraluminal nutrients alter mucosal blood flow during gut ischemia/reperfusion.
We have previously demonstrated in a rodent model the differential effects that specific intraluminal nutrients exert on gut ischemia/reperfusion (I/R) injury. Alanine was shown to amplify, whereas glucose protected against, gut I/R injury and associated gut dysfunction. The objective of this study was to determine whether these specific nutrients are associated with alterations in mucosal perfusion during gut I/R. Sprague-Dawley rats had either a laser doppler probe or a tonometer inserted into a jejunal sac filled with either 10 mmol/L alanine, glucose, or mannitol (osmotic control) followed by 60 minutes of superior mesenteric artery occlusion and 60 minutes of reperfusion. Laser doppler mucosal blood flow and regional PCO2 (PrCO2) measurements were obtained. Mucosal blood flow was significantly increased during both ischemia and reperfusion when intraluminal glucose was present compared with intraluminal alanine. Blood flow changes were reflected by lower jejunal PrCO2 measurements with intraluminal glucose compared with intraluminal alanine. Intraluminal glucose can augment mucosal blood flow during gut I/R and may explain the protective effect we previously observed.


[Physiology and pathology of zinc. Recent data].
This review summarizes our current knowledge on the role of zinc in physiology and pathology. After recalling that this knowledge was acquired after improvements of assay procedures, the authors go on to present normal zinc metabolism, especially its absorption and its role as a coenzyme. In a second part, disorders accompanying abnormal blood zinc levels are successively examined.


A scalable approach for high throughput branch flow filtration.
Microfluidic continuous flow filtration methods have the potential for very high size resolution using minimum feature sizes that are larger than the separation size, thereby circumventing the problem of clogging. Branch flow filtration is particularly promising because it has an unlimited dynamic range (ratio of largest passable particle to the smallest separated particle) but suffers from very poor volume throughput because when many branches are used, they cannot be identical if each is to have the same size cut-off. We describe a new iterative approach to the design of branch filtration devices able to overcome this limitation without large dead volumes. This is demonstrated by numerical modelling, fabrication and testing of devices with 20 branches, with dynamic ranges up to 6.9, and high filtration ratios (14-29%) on beads and fungal spores. The filters have a sharp size cutoff (10× depletion for 12% size difference), with large particle rejection equivalent to a 20th order Butterworth low pass filter. The devices are fully scalable, enabling higher throughput and smaller cutoff sizes and they are compatible with ultra low cost fabrication.


Dietary fish oil n-3 polyunsaturated fatty acids and alpha-linolenic acid differently affect brain accretion of docosahexaenoic acid and expression of desaturases and sterol regulatory element-binding protein 1 in mice.
Whether preformed dietary docosahexaenoic acid (DHA) is required for brain accretion has not been clearly determined. In this study, we investigated in mice the different effects of dietary longer-chain n-3 polyunsaturated fatty acids (PUFAs) and α-linolenic acid (LNA) on brain accretion of DHA and the expression of associated desaturases and transcription factors. C57 BL/6J mice were fed for 3 months with four fish oil n-3 PUFA diets--lower, low, high and higher (0.46%, 0.91%, 1.73% and 4.29% total energy, respectively); a flaxseed oil n-3 PUFA (5.01% total energy) diet; and an n-3 PUFA-deficient diet, respectively. Either fish oil or flaxseed oil n-3 PUFA diets increased DHA concentrations in the brain. However, the flaxseed oil n-3 PUFA diet was less effective than the fish oil diet with higher amount of n-3 PUFA in increasing brain DHA content. Furthermore, the expressions of delta-6 desaturase (D6D) and sterol regulatory element binding protein 1 (SREBP-1) in the liver were down-regulated by all fish oil diets with different amounts of n-3 PUFAs, as well as by the flaxseed oil n-3 PUFA diet, whereas in the brain, D6D, delta-5 desaturase (D5D) and SREBP-1 expressions were down-regulated by the higher fish oil n-3 PUFA diet rather than by other fish oil n-3 PUFA and the flaxseed oil n-3 PUFA diets. These results suggest that preformed dietary DHA, different from those converted by LNA inside the body, is better for brain accretion. Dietary longer-chain n-3 PUFAs affect expressions of D6D, D5D and SREBP-1 in the brain differently from their precursor LNA.


In vitro metabolism of the new cardiotonic agent denopamine (TA-064) by rat and rabbit liver preparations. Oxidation, methylation, and glucuronidation.
The metabolic pathways of the cardiotonic agent denopamine, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, were studied in vitro with rat and rabbit liver preparations. 4'-O-Demethylated (M-1), 3'-O-demethylated (iso-M-1), and 3-hydroxylated (M-4) metabolites of denopamine were formed by incubation of denopamine with the rat liver microsomal fraction containing the NADPH-generating system. The ratio of M-1 to iso-M-1 formed in this system was 33:1. 3-Methoxydenopamine (M-2) and 3-hydroxy-4-O-methyldenopamine (iso-M-2) were formed via the catechol intermediate M-4, when denopamine was incubated with the rat liver 9000g supernatant fraction in the presence of the NADPH-generating system and S-adenosyl-L-methionine. The ratio of M-2 to iso-M-2 in this system was 7:1. Conversion of iso-M-2 to M-2, i.e. 4-O-demethylation followed by 3-O-methylation, but not vice versa, took place in this system. M-2 was demethylated at 4' to form M-3 by the above microsomal system. M-1 was not ring-hydroxylated by this system, excluding the metabolic route to M-3 via M-1. Denopamine, M-1, M-2, and M-3 were glucuronidated in vitro by the rabbit liver microsomal fraction. The glucuronides of denopamine and M-2 were conjugated at the 4-phenolic hydroxy group, and the glucuronides of M-1 and M-3, which possess two phenolic hydroxy groups, were preferentially conjugated at the 4'-hydroxy group. The order of the rates of in vitro glucuronidation was M-3 greater than M-1 greater than M-2 greater than denopamine.


A stereoselective and atom-efficient approach to multifunctionalized five- and six-membered rings via a novel michael-initiated intramolecular Diels-Alder furan reaction.
[reaction: see text] A variety of key precursors to the intramolecular Diels-Alder reaction of furan diene (IMDAF) have been prepared via a very facile 1,4-addition of O-, S-, N-, and C-centered nucleophiles possessing unsaturated tether to beta-furyl nitroethylene. Subsequent IMDAF reaction of the 1,4-adducts, carried out under thermal conditions, provided five- and six-membered carbocycles and heterocycles fused to an easily cleavable oxabicycloheptene moiety. The structure and stereochemistry of the cycloadducts were determined by 2D-NMR experiments and further confirmed by X-ray crystallography. The salient features of the strategy include high degree of stereoselectivity (>80:20) in the cycloaddition, atom and step economy, and generation of multiple chiral centers and functionalities. The feasibility of the cleavage of the oxa bridge in the cycloadducts to afford novel multifunctional molecules has also been demonstrated.


[Poorer physician continuity after care choice for patients with diabetes. A comparison before and after introduction of hälsoval Skåne in Malmö].
Continuity of care is one of the core values of family medicine and both patients and doctors consider it a vital aspect of the care of patients with chronic diseases. In 2009 a national health care reform was implemented in primary care in Sweden. This study compared the longitudinal continuity of care in primary care before and after this reform in 7121 adult diabetes patients living in Malmö. Our findings reveal that continuity of care decreased substantially after the reform. The decrease was independent of sex, type of diabetes, age and income. Both before and after the reform men had a significantly higher rate of continuity of care than women. The number of visits to GPs by diabetes patients decreased slightly each investigated year. This possibly illustrates the crowding out of diabetes patients, as earlier research showed an increased overall number of GP visits for the whole population in Skåne (the county where Malmö is situated) after the reform.


Rumen effective degradability of amino acids from soybean meal corrected for microbial contamination.
Rumen degradation kinetics and effective degradability of individual amino acids, total analysed amino acids (TAA) and crude protein (CP) of soybean meal were measured on four rumen-cannulated wethers using the nylon bag technique. Microbial contamination of the incubated residues was corrected using a continuous 15N intraruminal infusion and isolated solid associated bacteria as a reference sample. TAA showed a lower soluble fraction (14.9 vs. 20.8%; P < 0.01), a similar insoluble-degradable fraction (79.0 vs. 79.2%) and a higher degradation rate (11.5 vs. 8.4% x h(-1); P < 0.05) than CP. As a consequence, effective degradability was similar for TAA and CP (74.7 vs. 75.7%). Degradability values of individual amino acids varied moderately (range: +/-6% of TAA degradability). Valine, isoleucine, leucine, alanine, aspartic acid and tyrosine showed significantly lower degradability than TAA, while the opposite effect was observed for histidine, threonine and glutamic acid. Degradability of individual amino acids was related to their soluble fraction (r = 0.877; P<0.001).


Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement.
Two distinct leukemia syndromes are associated with abnormalities of chromosome band 8p11. First, a myeloproliferative disorder with features characteristic of both chronic myeloid leukemia and non-Hodgkin's lymphoma and second, an acute myeloid leukemia (AML) with French-American-British (FAB) M4/5 morphology and prominent erythrophagocytosis. The two syndromes are exemplified by a t(8;13)(p11;q12) and a t(8;16)(p11;p13), respectively, but cytogenetic variants of both have been described. Recently, the t(8;16) has been cloned and shown to fuse the MOZ gene at 8p11 to the CBP gene at 16p13. We have used fluorescence in situ hybridization (FISH), Southern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) to refine the 8p11 breakpoint in three cases with t(8;13)(p11;q12) and in a single case of AML-M5 with a clinical picture apparently identical to that found in patients with a t(8;16), but characterized by an inv(8)(p11q13). FISH analysis was performed with several 8p11 CEPH yeast artificial chromosome (YAC) clones. YAC 782H11 was centromeric to the one case with t(8;13) tested, but was telomeric to the inv(8). YAC 847B12 was telomeric to both the t(8;13) and the inv(8), whereas YAC 829D12 was centromeric to the t(8;13), but split by the inv(8). Southern blotting and PCR of YAC 829D12 showed that it contained the MOZ gene. A 900-bp MOZ fragment encompassing the published t(8;16) breakpoint was amplified by PCR from normal peripheral blood leukocyte cDNA and used to probe Southern blots of patient DNA. A rearrangement was detected in the case with inv(8), but not in any of the three cases with t(8;13). Southern blotting with a CBP probe and RT-PCR with MOZ and CBP primers suggested that the inv(8) does not result in a cryptic MOZ-CBP fusion. It is likely, therefore, that MOZ is fused to a novel gene at 8q13 in this case. We conclude that the t(8;13) breakpoint is flanked by YACs 782H11 and 847B12 and is at least 1 Mb telomeric to MOZ. MOZ is involved, however, in a new variant of the t(8;16).


The effects of the formation of Stone-Wales defects on the electronic and magnetic properties of silicon carbide nanoribbons: a first-principles investigation.
Detailed first-principles density functional theory (DFT) computations were performed to investigate the geometries, the electronic, and the magnetic properties of both armchair-edged silicon carbide nanoribbons (aSiCNRs) and zigzag-edged silicon carbide nanoribbons (zSiCNRs) with Stone-Wales (SW) defects. SW defects in the center of aSiCNRs can remarkably reduce their band gaps, irrespective of the orientation of the defect, whereas zSiCNRs with SW defects in the center or at the edges exhibit degenerate energies of their ferromagnetic (FM) and antiferromagnetic (AFM) states, in which metallic and half-metallic behavior can be observed, respectively; half-metallic behavior can even be observed in both the FM and AFM states simultaneously. Further, it was shown that the formation energies of the SW defects in SiCNRs are orientation dependent, and the formation of edge defects is always favored over the formation of interior defects in zSiCNRs. The possible existence of SW defects in SiCNRs was further validated through exploring the kinetic process of their formation. These findings can be anticipated to provide valuable information in promoting the potential applications of SiC-based nanomaterials in multifunctional and spintronic nanodevices.


Profiling diverse compounds by flux- and electrophysiology-based primary screens for inhibition of human Ether-à-go-go related gene potassium channels.
Compound effects on cloned human Ether-à-go-go related gene (hERG) potassium channels have been used to assess the potential cardiac safety liabilities of drug development candidate compounds. In addition to radioactive ligand displacement tests, two other common approaches are surrogate ion-based flux assays and electrophysiological recordings. The former has much higher throughput, whereas the latter measures directly the effects on ionic currents. Careful characterization in earlier reports has been performed to compare the relative effectiveness of these approaches for known hERG blockers, which often yielded good overall correlation. However, cases were reported showing significant and reproducible differences in potency and/or sensitivity by the two methods. This raises a question concerning the rationale and criteria on which an assay should be selected for evaluating unknown compounds. To provide a general basis for considering assays to profile large compound libraries for hERG activity, we have conducted parallel flux and electrophysiological analyses of 2,000 diverse compounds, representative of the 300,000 compound collection of NIH Molecular Library Small Molecular Repository (MLSMR). Our results indicate that at the conventional testing concentration 1.0 μM, the overlap between the two assays ranges from 32% to 50% depending on the hit selection criteria. There was a noticeable rate of false negatives by the thallium-based assay relative to electrophysiological recording, which may be greatly reduced under modified comparative conditions. As these statistical results identify a preferred method for cardiac safety profiling of unknown compounds, they suggest an efficient method combining flux and electrophysiological assays to rapidly profile hERG liabilities of large collection of naive compounds.


Hormonal regulation of calcium current in freshly isolated airway smooth muscle cells.
Single freshly isolated smooth muscle cells of adult bovine trachea were voltage clamped, and the calcium inward current was separated from K+ currents by blocking the large outward currents with intra- and extracellular Cs+ and extracellular tetraethylammonium chloride. Isoproterenol stimulated peak calcium current (ICa) in a dose-dependent manner through the beta-adrenergic receptor. The isoproterenol effect was not mediated or caused by the stimulation of a K+ or Na+ current, a decrease in the intracellular concentrations of Ca2+ or H+, the stimulation of the Na(+)-H+ or the Na(+)-Ca2+ exchanger. Neither basal nor isoproterenol-stimulated ICa was affected by internal dialysis of the cell with adenosine 3',5'-cyclic monophosphate (cAMP), cAMP analogues, or the catalytic subunit of cAMP-kinase. Internal dialysis of the cells with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) blocked the stimulation of isoproterenol whereas dialysis with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) induced an isoproterenol-like maximal increase of ICa. These results show that the beta-adrenergic receptor stimulates the L-type calcium current of isolated tracheal smooth muscle cells independent of cAMP and cAMP-kinase through a GTP/GDP regulated protein.


Self administration of heroin and cocaine in morphine-dependent and morphine-withdrawn rhesus monkeys.
Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking. This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine. Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56-560 microg/kg/infusion) or cocaine (1-100 microg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose-effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose-effect curves and withdrawal signs were determined daily following termination of morphine administration. Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 microg/kg of heroin and 10 microg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17-53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3-4 days after morphine; however, the number of infusions remained elevated for 8 weeks. Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions.


The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma.
Oncolytic viruses that selectively replicate in cancer cells have been described for over 50 years. Despite the observation by several groups that multimutated herpes simplex type 1 vectors are oncolytic in a variety of murine tumor models, the oncolytic potential of ICP0 null mutants has not been described. This study characterizes a novel second-generation oncolytic herpes simplex type 1 vector null for the ICP0 gene. We tested three mutant viruses and found that all were selectively cytotoxic in a variety of human and murine tumor cells in vitro. Furthermore, we provide evidence of a mechanistic link between ICP0's function in interferon signaling pathways and the observed oncolytic capacity of ICP0 mutants. Using an immunocompetent murine model of breast adenocarcinoma we demonstrate that the ICP0 mutant KM100 completely eradicates tumors in approximately 80% of treated animals and significantly increases survival. Our data suggest that active viral replication is necessary for effective tumor regression. In addition, we characterized the potential of KM100 as an anti-tumor vaccine since cured mice were found to elicit a robust anti-tumor immune response and were refractory to subsequent tumor growth upon rechallenge.


Mineral and Vitamin Intakes of Latvian Women during Lactation Period.
Studies from Europe and the United States indicate that women during the lactation period do not consume sufficient amounts of essential micronutrients. Previously reported data from Latvia indicates a low vegetable, fruit, fish, cereal, and milk and dairy products intake among lactating women. This raises concerns that nutrient (especially minerals and vitamins) intakes could also be insufficient. Therefore, this study aimed to assess mineral and vitamin intakes among lactating women in Latvia in comparison to nutritional guidelines at both a national and European level. 72-h food diaries were collected from 62 participants during the period November 2016 till December 2017 and from 68 participants during the period from January 2020 to December 2020. This also allowed us to evaluate whether nutrient intakes among lactating women in Latvia have changed in recent years. The Fineli Food Composition Database was used to calculate micronutrient intakes among the participants. MS Excel 2019 and IBM SPSS Statistics 23 were used for the statistical data analysis. The results revealed that dietary intakes of calcium, iron, iodine, and vitamins A, D, B1, and B9 among the participants of both study periods did not meet dietary recommendations. Low mineral and vitamin intakes could potentially affect the composition of human milk, and therefore micronutrient intakes, for breastfed infants. This indicates a need to develop dietary guidelines in order to improve diets among lactating women in Latvia.


Automated Contouring of Contrast and Noncontrast Computed Tomography Liver Images With Fully Convolutional Networks.
The deformable nature of the liver can make focal treatment challenging and is not adequately addressed with simple rigid registration techniques. More advanced registration techniques can take deformations into account (eg, biomechanical modeling) but require segmentations of the whole liver for each scan, which is a time-intensive process. We hypothesize that fully convolutional networks can be used to rapidly and accurately autosegment the liver, removing the temporal bottleneck for biomechanical modeling. Manual liver segmentations on computed tomography scans from 183 patients treated at our institution and 30 scans from the Medical Image Computing & Computer Assisted Intervention challenges were collected for this study. Three architectures were investigated for rapid automated segmentation of the liver (VGG-16, DeepLabv3 +, and a 3-dimensional UNet). Fifty-six cases were set aside as a final test set for quantitative model evaluation. Accuracy of the autosegmentations was assessed using Dice similarity coefficient and mean surface distance. Qualitative evaluation was also performed by 3 radiation oncologists on 50 independent cases with previously clinically treated liver contours. The mean (minimum-maximum) mean surface distance for the test groups with the final model, DeepLabv3 +, were as follows: μContrast(N = 17): 0.99 mm (0.47-2.2), μNon_Contrast(N = 19)l: 1.12 mm (0.41-2.87), and μMiccai(N = 30)t: 1.48 mm (0.82-3.96). The qualitative evaluation showed that 30 of 50 autosegmentations (60%) were preferred to manual contours (majority voting) in a blinded comparison, and 48 of 50 autosegmentations (96%) were deemed clinically acceptable by at least 1 reviewing physician. The autosegmentations were preferred compared with manually defined contours in the majority of cases. The ability to rapidly segment the liver with high accuracy achieved in this investigation has the potential to enable the efficient integration of biomechanical model-based registration into a clinical workflow.


Taste and aroma of fresh and stored mandarins.
During the last decade there has been a continuous rise in consumption of fresh easy-to-peel mandarins. However, mandarins are much more perishable than other citrus fruit, mainly due to rapid deterioration in sensory acceptability after harvest. In the current review we discuss the biochemical components involved in forming the unique flavor of mandarins, and how postharvest storage operations influence taste and aroma and consequently consumer sensory acceptability. What we perceive as mandarin flavor is actually the combination of basic taste, aroma and mouth-feel. The taste of mandarins is principally governed by the levels of sugars and acids in the juice sacs and the relative ratios among them, whereas the aroma of mandarins is derived from a mixture of different aroma volatiles, including alcohols, aldehydes, ketones, terpenes/hydrocarbons and esters. During postharvest storage and marketing there is a gradual decrease in mandarin sensory acceptability, which has been attributed to decreases in acidity and typical mandarin flavor, paralleling an accumulation of off-flavor. Biochemical analysis of volatile and non-volatile constituents in mandarin juice demonstrated that these changes in sensory acceptability were concomitant with decreases in acidity and content of terpenes and aldehydes, which provide green, piney and citrus aroma on the one hand, and increases in ethanol fermentation metabolism products and esters on the other, which are likely to cause 'overripe' and off-flavors. Overall, we demonstrate the vast importance of the genetic background, maturity stage at harvest, commercial postharvest operation treatments, including curing, degreening and waxing, and storage duration on mandarin sensory quality.


Effects of ovarian source, patient age, and menstrual cycle phase on in vitro maturation of immature human oocytes.
To determine the efficiency of in vitro maturation, expressed by nuclear maturation, of oocytes aspirated during gynecologic surgeries or collected from excised ovaries. To assess the effect of patient age and cycle phase at collection on the oocyte's ability to mature in vitro. To examine the time course of oocyte maturation in vitro. Nuclear maturation based on patient criteria compared. University-based IVF program and research center. Consented patients undergoing gynecologic surgeries or patients undergoing oophorectomy. Oocytes were maintained in culture for 48 hours and evaluated for maturation. Nuclear maturation evaluated as germinal vesicle breakdown (GVBD) or progression to the metaphase II (MII) stage. A significantly higher percentage of oocytes collected during the follicular phase of the menstrual cycle underwent GVBD than did oocytes collected during the luteal phase (60% versus 48%, respectively). The percentage of oocytes reaching the MII stage, from these two groups, was not different. No statistically significant differences in maturation were observed in oocytes from different ovarian sources or from patients >40 or <40 years of age. These data suggest that oocytes collected during the follicular phase are more likely to undergo GVBD than oocytes collected during the luteal phase. In this study, ovarian source, age, or cycle phase did not influence the final meiotic maturation of oocytes to metaphase II.


Duration of antiresorptive effects of low-dose zoledronate in osteopenic postmenopausal women: a randomized, placebo-controlled trial.
Annual intravenous administration of 5 mg zoledronate decreases fracture risk, but the optimal dosing regimen for zoledronate has not been determined. We set out to evaluate the antiresorptive effects of a single administration of lower doses of zoledronate. A total of 180 postmenopausal women with osteopenia enrolled in a double-blind, randomized, placebo-controlled trial over 2 years at an academic research center. Participants were randomized to a single baseline administration of intravenous zoledronate in doses of 1 mg, 2.5 mg, or 5 mg, or placebo. The primary endpoint was change in bone mineral density(BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body, and changes in biochemical markers of bone turnover. After 2 years, the change in spine BMD was greater in each of the zoledronate groups than in the placebo group; values are mean (95% confidence interval [CI]) difference versus placebo: zoledronate 1 mg 4.4% [2.7% to 6.1%]; 2.5 mg 5.5% [3.9% to 7.2%]; 5 mg 5.3% [3.8% to 6.7%], p < 0.001 for each dose). Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group (mean [95% CI] difference versus placebo: zoledronate 1 mg 2.6% [1.5% to 3.7%]; 2.5 mg 4.4% [3.5% to 5.3%]; 5 mg 4.7% [3.7% to 5.7%], p < 0.001 for each dose). Each of the bone turnover markers, β-C-terminal telopeptide of type I collagen (β-CTX) and procollagen type-I N-terminal propeptide (P1NP), was lower in each of the 2.5-mg and 5-mg zoledronate groups than the placebo group throughout the trial (p < 0.001 versus placebo for each marker for each dose at each time point). For each endpoint, changes were similar in the 2.5-mg and 5-mg zoledronate groups, whereas those in the 1-mg group were smaller than those in the other zoledronate groups. These data demonstrate that single administrations of zoledronate 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years. Trials assessing the antifracture efficacy of intermittent low doses of zoledronate, in particular the 2.5-mg dose, are justified.


Elicitation of Protective Antibodies against a Broad Panel of H1N1 Viruses in Ferrets Preimmune to Historical H1N1 Influenza Viruses.
Most preclinical animal studies test influenza vaccines in immunologically naive animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have preexisting immunity to influenza. In this study, novel, broadly reactive influenza vaccine candidates were assessed in preimmune ferrets. These animals were infected with different H1N1 isolates before being vaccinated or infected with another influenza virus. Previously, our group has described the design and characterization of computationally optimized broadly reactive hemagglutinin (HA) antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with hemagglutination inhibition (HAI) activity against more H1N1 viruses in the panel than VLP vaccines expressing wild-type HA proteins. Specifically, ferrets infected with the 1986 virus and vaccinated with a single dose of the COBRA HA VLP vaccines elicited antibodies with HAI activity against 11 to 14 of the 15 H1N1 viruses isolated between 1934 and 2013. A subset of ferrets was infected with influenza viruses expressing the COBRA HA antigens. These COBRA preimmune ferrets had superior breadth of HAI activity after vaccination with COBRA HA VLP vaccines than COBRA preimmune ferrets vaccinated with VLP vaccines expressing wild-type HA proteins. Overall, priming naive ferrets with COBRA HA based viruses or using COBRA HA based vaccines to boost preexisting antibodies induced by wild-type H1N1 viruses, COBRA HA antigens elicited sera with the broadest HAI reactivity against multiple antigenic H1N1 viral variants. This is the first report demonstrating the effectiveness of a broadly reactive or universal influenza vaccine in a preimmune ferret model.IMPORTANCE Currently, many groups are testing influenza vaccine candidates to meet the challenge of developing a vaccine that elicits broadly reactive and long-lasting protective immune responses. The goal of these vaccines is to stimulate immune responses that react against most, if not all, circulating influenza strains, over a long period of time in all populations of people. Commonly, these experimental vaccines are tested in naive animal models that do not have anti-influenza immune responses; however, humans have preexisting immunity to influenza viral antigens, particularly antibodies to the HA and NA glycoproteins. Therefore, this study investigated how preexisting antibodies to historical influenza viruses influenced HAI-specific antibodies and protective efficacy using a broadly protective vaccine candidate.


Efficient reduction for diagnosing Hopf bifurcation in delay differential systems: Applications to cloud-rain models.
By means of Galerkin-Koornwinder (GK) approximations, an efficient reduction approach to the Stuart-Landau (SL) normal form and center manifold is presented for a broad class of nonlinear systems of delay differential equations that covers the cases of discrete as well as distributed delays. The focus is on the Hopf bifurcation as a consequence of the critical equilibrium's destabilization resulting from an eigenpair crossing the imaginary axis. The nature of the resulting Hopf bifurcation (super- or subcritical) is then characterized by the inspection of a Lyapunov coefficient easy to determine based on the model's coefficients and delay parameters. We believe that our approach, which does not rely too much on functional analysis considerations but more on analytic calculations, is suitable to concrete situations arising in physics applications. Thus, using this GK approach to the Lyapunov coefficient and the SL normal form, the occurrence of Hopf bifurcations in the cloud-rain delay models of Koren and Feingold (KF) on one hand and Koren, Tziperman, and Feingold on the other are analyzed. Noteworthy is the existence of the KF model of large regions of the parameter space for which subcritical and supercritical Hopf bifurcations coexist. These regions are determined, in particular, by the intensity of the KF model's nonlinear effects. "Islands" of supercritical Hopf bifurcations are shown to exist within a subcritical Hopf bifurcation "sea"; these islands being bordered by double-Hopf bifurcations occurring when the linearized dynamics at the critical equilibrium exhibit two pairs of purely imaginary eigenvalues.


Single-step isolation of extracellular vesicles by size-exclusion chromatography.
Isolation of extracellular vesicles from plasma is a challenge due to the presence of proteins and lipoproteins. Isolation of vesicles using differential centrifugation or density-gradient ultracentrifugation results in co-isolation of contaminants such as protein aggregates and incomplete separation of vesicles from lipoproteins, respectively. To develop a single-step protocol to isolate vesicles from human body fluids. Platelet-free supernatant, derived from platelet concentrates, was loaded on a sepharose CL-2B column to perform size-exclusion chromatography (SEC; n=3). Fractions were collected and analysed by nanoparticle tracking analysis, resistive pulse sensing, flow cytometry and transmission electron microscopy. The concentrations of high-density lipoprotein cholesterol (HDL) and protein were measured in each fraction. Fractions 9-12 contained the highest concentrations of particles larger than 70 nm and platelet-derived vesicles (46%±6 and 61%±2 of totals present in all collected fractions, respectively), but less than 5% of HDL and less than 1% of protein (4.8%±1 and 0.65%±0.3, respectively). HDL was present mainly in fractions 18-20 (32%±2 of total), and protein in fractions 19-21 (36%±2 of total). Compared to the starting material, recovery of platelet-derived vesicles was 43%±23 in fractions 9-12, with an 8-fold and 70-fold enrichment compared to HDL and protein. SEC efficiently isolates extracellular vesicles with a diameter larger than 70 nm from platelet-free supernatant of platelet concentrates. Application SEC will improve studies on the dimensional, structural and functional properties of extracellular vesicles.


A farm-level precision land management framework based on integer programming.
Farmland management involves several planning and decision making tasks including seed selection and irrigation management. A farm-level precision farmland management model based on mixed integer linear programming is proposed in this study. Optimal decisions are designed for pre-season planning of crops and irrigation water allocation. The model captures the effect of size and shape of decision scale as well as special irrigation patterns. The authors illustrate the model with a case study on a farm in the state of California in the U.S. and show the model can capture the impact of precision farm management on profitability. The results show that threefold increase of annual net profit for farmers could be achieved by carefully choosing irrigation and seed selection. Although farmers could increase profits by applying precision management to seed or irrigation alone, profit increase is more significant if farmers apply precision management on seed and irrigation simultaneously. The proposed model can also serve as a risk analysis tool for farmers facing seasonal irrigation water limits as well as a quantitative tool to explore the impact of precision agriculture.


Impact of logging on a mangrove swamp in south Mexico: cost/benefit analysis.
Environmental changes caused by logging in a mangrove swamp were studied in Barra de Tecoanapa, Guerrero, Mexico. Original forest included Rhizophora mangle, Laguncularia racemosa, Avicennia germinans and halophytic vegetation, and produced wood (164.03 m3/ha) and organic matter (3.9 g/m2/day). A total of 3.5 tons of wood per year were harvested from this area. Later, an average of 2,555 kg of maize per planting cycle were obtained (market value of 88 USD). Succession when the area was abandoned included strictly facultative and glycophyte halophytes (16 families, Cyperaceae and Poaceae were the best represented). After logging, temperatures increased 13 degrees C in the soil and 11 degrees C in the air, whereas salinity reached 52 psu in the dry season. These modified soil color and sand content increased from 42.6 to 63.4%. Logging was deleterious to species, habitat, biogeochemical and biological cycles, organic matter production, seeds, young plants, genetic exchange conservation of soil and its fertility, coastal protection, and aesthetic value; 3,000 m2 had eroded as the river advanced towards the deforested area (the cost/benefit analysis showed a ratio of 246:1). There was long-term economic loss for the community and only 30% of the site has recovered after five years.


Biomarkers for sepsis: a review with special attention to India.
Sepsis is a serious infection and still a common cause of morbidity and mortality in resource-limited settings such as India. Even when microbiologic diagnostics are available, bacteremia is only identified in a proportion of patients who present with sepsis and bloodstream infections. Biomarkers have been used in a variety of disease processes and can help aid in diagnosing bacterial infections. There have been numerous biomarkers investigated to aid with diagnosis and prognostication in sepsis with the majority suffering from lack of sensitivity or specificity. Procalcitonin has been heralded as the biomarker that holds the most promise for bloodstream infections. Data are emerging in India, and in this review, we focus on the current data of biomarkers in sepsis with particular attention to how biomarkers could be used to augment diagnosis and treatment in India.


Protected early motion versus cast immobilization in postoperative management of ankle fractures.
Sixty-one active-duty military personnel with operatively treated ankle fractures were randomized into two postoperative immobilization regimens: Group I--six weeks short-leg cast, nonweight-bearing; Group II--six weeks removable orthosis, nonweightbearing. Group I began physical therapy at six weeks postoperatively, and Group II began physical therapy within the first postoperative week. Objective measurements of swelling, strength, range of motion, and functional tests were examined. Subjective scores of pain, function, cosmesis, and motion were recorded. Patients in Group II (early mobilization) had significantly better subjective scores at three and six months postoperatively; however, time to return to duty was not significantly different. Objective tests of swelling, strength, range of motion, and functional tests were not significantly different at three months postoperatively for either group. Early mobilization in a removable orthosis, while not objectively altering the postoperative course, provides a safe, preferable method of treatment in the reliable and cooperative patient.


Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.
Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.


Understanding mental retardation in Down's syndrome using trisomy 16 mouse models.
Mental retardation in Down's syndrome, human trisomy 21, is characterized by developmental delays, language and memory deficits and other cognitive abnormalities. Neurophysiological and functional information is needed to understand the mechanisms of mental retardation in Down's syndrome. The trisomy mouse models provide windows into the molecular and developmental effects associated with abnormal chromosome numbers. The distal segment of mouse chromosome 16 is homologous to nearly the entire long arm of human chromosome 21. Therefore, mice with full or segmental trisomy 16 (Ts65Dn) are considered reliable animal models of Down's syndrome. Ts65Dn mice demonstrate impaired learning in spatial tests and abnormalities in hippocampal synaptic plasticity. We hypothesize that the physiological impairments in the Ts65Dn mouse hippocampus can model the suboptimal brain function occuring at various levels of Down's syndrome brain hierarchy, starting at a single neuron, and then affecting simple and complex neuronal networks. Once these elements create the gross brain structure, their dysfunctional activity cannot be overcome by extensive plasticity and redundancy, and therefore, at the end of the maturation period the mind inside this brain remains deficient and delayed in its capabilities. The complicated interactions that govern this aberrant developmental process cannot be rescued through existing compensatory mechanisms. In summary, overexpression of genes from chromosome 21 shifts biological homeostasis in the Down's syndrome brain to a new less functional state.


Older age and steroid use are associated with increasing polypharmacy and potential medication interactions among patients with inflammatory bowel disease.
Comorbidity and polypharmacy, more prevalent among older persons, may impact the treatment of patients with inflammatory bowel disease (IBD). The aims of this study were to assess the frequency of polypharmacy and medication interactions within a cohort of older patients with IBD and describe IBD treatment patterns. Cohort study of 190 patients with IBD 65 years or older followed at a tertiary IBD referral center from 2006 to 2012. Data collected included demographics, IBD-specific characteristics including disease activity, and comorbidity. Medication histories were extracted from medical records, and data were used to classify polypharmacy, frequency, and severity of potential medication interactions and inappropriate medication use. Older patients with IBD were prescribed an average of 9 routine medications. Severe polypharmacy (≥10 routine medications) was present in 43.2% of studied patients and associated with increasing age, greater comorbidity, and steroid use. Overall, 73.7% of patients had at least 1 potential medication interaction, including 40% of patients with potential IBD medication-associated interactions. Chronic steroids were prescribed to 40% of the older patients including 24% who were in remission or with mild disease activity. Only 39.5% of patients were on immunomodulators and 21.1% on biologics. Approximately, 35% of patients were given at least 1 Beers inappropriate medication and almost 10% were receiving chronic narcotics. Older patients with IBD are at increased risk for severe polypharmacy and potential major medication interactions especially with increasing comorbidity and chronic steroid use. Steroid-maintenance therapies are prevalent among the older patients with IBD with lower utilization of steroid-sparing regimens.


Arteriography in leprosy.
Arterial pattern of hands and feet-vessels was studied in 26 patients of leprosy by percutaneous arteriography, and in these cases muscle biopsy was also done. The vessels in leprosy were showing smooth tapering, absence of collaterals, occlusion of the artery and rippling (tortousity) of vessels. Such abnormal pictures were seen in all the arteriograms studied, and in 82% of of cases moderate to severe vascular changes were seen. Decreased blood flow through the arteries in the distal part of the limb leading to ischaemia, is probably the cause for deformity and/or ulceration in the leprosy. Presence of vascular thickening, perivascular granuloma and lymphocytic infiltration in the muscle may be possible explanation for angiographic findings and is felt to be related to trophic ulceration.


A microbial signature approach to identify fecal pollution in the waters off an urbanized coast of Lake Michigan.
Urban coasts receive watershed drainage from ecosystems that include highly developed lands with sewer and stormwater infrastructure. In these complex ecosystems, coastal waters are often contaminated with fecal pollution, where multiple delivery mechanisms that often contain multiple fecal sources make it difficult to mitigate the pollution. Here, we exploit bacterial community sequencing of the V6 and V6V4 hypervariable regions of the bacterial 16S rRNA gene to identify bacterial distributions that signal the presence of sewer, fecal, and human fecal pollution. The sequences classified to three sewer infrastructure-associated bacterial genera, Acinetobacter, Arcobacter, and Trichococcus, and five fecal-associated bacterial families, Bacteroidaceae, Porphyromonadaceae, Clostridiaceae, Lachnospiraceae, and Ruminococcaceae, served as signatures of sewer and fecal contamination, respectively. The human fecal signature was determined with the Bayesian source estimation program SourceTracker, which we applied to a set of 40 sewage influent samples collected in Milwaukee, WI, USA to identify operational taxonomic units (≥ 97 % identity) that were most likely of human fecal origin. During periods of dry weather, the magnitudes of all three signatures were relatively low in Milwaukee's urban rivers and harbor and nearly zero in Lake Michigan. However, the relative contribution of the sewer and fecal signature frequently increased to > 2 % of the measured surface water communities following sewer overflows. Also during combined sewer overflows, the ratio of the human fecal pollution signature to the fecal pollution signature in surface waters was generally close to that of sewage, but this ratio decreased dramatically during dry weather and rain events, suggesting that nonhuman fecal pollution was the dominant source during these weather-driven scenarios. The qPCR detection of two human fecal indicators, human Bacteroides and Lachno2, confirmed the urban fecal footprint in this ecosystem extends to at least 8 km offshore.


[The motor dominant in man].
Study of the motor dominant in man has shown that in aftereffect of rhythmic electrocutaneous stimulation of hand, a latent focus of excitation is formed in the CNS. When using sensory stimuli (light, sound) and also stimuli, addressed to the second signal system, a hand motor reaction appears in the rhythm of earlier electrocutaneous stimulation, what testifies to preservation of rhythmic nature of excitation in the dominant focus. Summation process in the dominant focus is not reflected in human consciousness. Study of the brain biopotentials has shown that at formation of human motor dominant, typical changes of spectral-coherent characteristics of the neocortex electrical activity appear: within the "dominant" hemisphere, the spectrum power, increases in the range of low frequencies; highly coherent connections of electrical processes appear in the delta-range of the frontal-parietal area at conjugate decrease of combination of processes in the parietal-occipital area of the cerebral cortex. Formation of the dominant focus in one hemisphere causes general reconstruction of the structure of intercentral relations of both hemispheres electrical activity.


Central adenosine receptor signaling is necessary for daily torpor in mice.
When calorically restricted at cool ambient temperatures, mice conserve energy by entering torpor, during which metabolic rate (MR), body temperature (T(b)), heart rate (HR), and locomotor activity (LMA) decrease. Treatment with exogenous adenosine produces a similar hypometabolic state. In this study, we conducted a series of experiments using the nonspecific adenosine receptor antagonists aminophylline and 8-sulfophenyltheophylline (8-SPT) to test the hypothesis that adenosine signaling is necessary for torpor in fasted mice. In the first experiment, mice were subcutaneously infused with aminophylline while T(b), HR, and LMA were continuously monitored using implanted radiotelemeters. During a 23-h fast, saline-treated mice were torpid for 518 ± 43 min, whereas aminophylline-treated mice were torpid for significantly less time (54 ± 20 min). In a second experiment, aminophylline was infused subcutaneously into torpid mice to test the role of adenosine in the maintenance of torpor. Aminophylline reversed the hypometabolism, hypothermia, bradycardia, and hypoactivity of torpor, whereas saline did not. In the third and fourth experiments, the polar adenosine antagonist 8-SPT, which does not cross the blood-brain barrier, was infused either subcutaneously or intracerebroventricularly to test the hypothesis that both peripheral and central adenosine receptor signaling are necessary for the maintenance of torpor. Intracerebroventricular, but not subcutaneous, infusion of 8-SPT causes a return to euthermia. These findings support the hypothesis that adenosine is necessary for torpor in mice and further suggest that whereas peripheral adenosine signaling is not necessary for the maintenance of torpor, antagonism of central adenosine is sufficient to disrupt torpor.


[Should the ophthalmologist prescribe generic drugs?].
It seems obvious that an ophthalmologist should encourage the use of generic drugs. However, it is important to know the exact definition of a generic drug and the type of studies to be conducted before a generic drug is released on the market. A generic drug is a drug that has the same composition quantitatively as well as qualitatively of the active compound as the original drug. It also has the same pharmaceutical mode of action and the same bioavailability, as determined with bioavailability studies. Ophthalmic drops contain both an active compound and many adjuvants used to stabilize the drug. Globally speaking, the active compound corresponds to the efficacy of a topical drug and the adjuvant to its tolerance. It is likely that the efficacy of a generic drug is identical to that of the brand-name drug, even though only bioavailability studies in non-human models are required to evaluate tolerance which is less likely to be identical, as adjuvants can differ. A survey of 520 French ophthalmologists has recently been conducted. It shows that doctors rarely think of prescribing generic drugs, as they do not consider cost as a major issue in treating glaucoma. However, they see no reason not to prescribe generic drugs. This mixed perception is shared by patients who willingly accept that doctors prescribe a generic drug, but do not wish the pharmacist to take the initiative of filling a prescription with a generic drug, which sometimes gives patients the impression of being less well treated. The use of generic drugs should be encouraged, keeping in mind that good tolerance should be ensured.


Cephalostatin 1 inactivates Bcl-2 by hyperphosphorylation independent of M-phase arrest and DNA damage.
Cephalostatin 1 is a marine product that induces a novel cytochrome c-independent apoptotic pathway in Jurkat leukemia T cells (Cancer Res 63:8869-8876, 2003). Here, we show that overexpression of the antiapoptotic protein Bcl-2 protects cells only partially against cephalostatin 1-induced apoptosis. The mechanism of Bcl-2 inactivation by cephalostatin 1 is based on hyperphosphorylation of Bcl-2 on Thr69 and Ser87 because Jurkat cells overexpressing a Bcl-2 protein with mutations on both phosphorylation sites were completely protected against cephalostatin 1. In search of the kinase responsible for Bcl-2 phosphorylation, c-Jun NH2-terminal kinase (JNK) was found to be activated by cephalostatin 1. Reduction of Bcl-2 phosphorylation by the specific JNK inhibitor (anthra(1,3-cd)pyrazol-6(2H)-one) SP600125 suggested a crucial role for JNK in this process. JNK activation was not a consequence of DNA damage, a known stimulus of JNK, because cephalostatin 1 did not induce DNA lesions as shown by the comet assay. Arrest in M-phase is also demonstrated to be associated with JNK activation. However, cephalostatin 1 does not evoke an arrest in M-phase as shown by flow cytometry. Together, cephalostatin 1 is shown to induce JNK activation with subsequent Bcl-2 phosphorylation and inactivation. Reported triggers, such as the induction of an M-phase arrest or DNA damage are not involved in this process, suggesting a novel mechanism for cephalostatin 1-mediated Bcl-2 hyperphosphorylation.


Expression of a Pseudomonas aeruginosa citrate synthase gene in tobacco is not associated with either enhanced citrate accumulation or efflux.
Aluminum (Al) toxicity and poor phosphorus (P) availability are factors that limit plant growth on many agricultural soils. Previous work reported that expression of a Pseudomonas aeruginosa citrate synthase gene in tobacco (Nicotiana tabacum; CSb lines) resulted in improved Al tolerance (J.M. de la Fuente, V. Ramírez-Rodríguez, J.L. Cabrera-Ponce, L. Herrera-Estrella [1997] Science 276: 1566-1568) and an enhanced ability to acquire P from alkaline soils (J. López-Bucio, O. Martínez de la Vega, A. Guevara-García, L. Herrera-Estrella [2000] Nat Biotechnol 18: 450-453). These effects were attributed to the P. aeruginosa citrate synthase increasing the biosynthesis and efflux of citrate from roots. To verify these findings we: (a) characterized citrate efflux from roots of wild-type tobacco; (b) generated tobacco lines expressing the citrate synthase gene from P. aeruginosa; and (c) analyzed selected CSb lines described above. Al stimulated citrate efflux from intact roots of wild-type tobacco and root apices were found to be responsible for most of the efflux. Despite generating transgenic tobacco lines that expressed the citrate synthase protein at up to a 100-fold greater level than the previously described CSb lines, these lines did not show increased accumulation of citrate in roots or increased Al-activated efflux of citrate from roots. Selected CSb lines, similarly, failed to show differences compared with controls in either citrate accumulation or efflux. We conclude that expression of the P. aeruginosa citrate synthase gene in plants is unlikely to be a robust and easily reproducible strategy for enhancing the Al tolerance and P-nutrition of crop and pasture species.


Microplastic contamination in Thai vinegar crabs (Episesarma mederi), giant mudskippers (Periophthalmodon schlosseri), and their surrounding environment from the Bang Pu mangrove forests, Samut Prakan province, Thailand.
The mangrove ecosystem becomes the receptacle for both land- and marine-based plastic waste. This study examines MPs contamination in the Bang Pu mangrove forests (BPMFs) in the inner Gulf of Thailand. For this, Thai vinegar crabs (TVCs) (Episesarma mederi) and giant mudskippers (GMs) (Periophthalmodon schlosseri) were investigated with their surrounding environment in both rainy and dry seasons. Two-step digestion was employed for biota samples. MPs abundance ranged from 7.5 ± 3.8 to 15.9 ± 6.7 items/individual in TVCs and 6.2 ± 5.0 to 10.6 ± 2.6 items/individual in GMs. MPs in small-size ranges (<0.5 mm) were predominant. Fiber MPs were mostly detected in the rainy season. Most MPs were transparent with polyethylene and polypropylene as dominant polymers in all samples. Bioaccumulation was not observed in GMs. The results indicated the imperiled status of MPs contamination in TVCs and GMs with contaminated surrounding environments.


mu-Opioid receptors in NTS elicit pressor responses via sympathetic pathways.
We have evaluated the relative contributions of the sympathetic and parasympathetic nervous systems to the increased mean arterial pressure (MAP) and heart rate (HR) elicited by the selective mu-agonist D-Ala2, MePhe4, Gly-ol5 enkephalin (DAGO) following microinjection (100 nl) into the nucleus of tractus solitarius (NTS) of anesthetized, artificially ventilated Sprague-Dawley rats. The effects of anesthesia and central opioid-receptor activation on baroreflex function were also examined. All cardiovascular responses elicited by DAGO were eliminated by complete C1 spinal transection. Pretreatment with the alpha-adrenergic antagonist phentolamine attenuated the increase in MAP, but not the tachycardia; the beta-blocker propranolol abolished the tachycardia but not the pressor response to DAGO. Adrenalectomy, vagotomy, or pretreatment with atropine methyl nitrate were all without effect. Baroreflexes were attenuated in animals anesthetized with pentobarbital sodium, but were present in urethan-anesthetized rats. DAGO attenuated the increases in MAP and HR elicited following carotid occlusion, but not the bradycardia elicited by a phenylephrine-induced pressor response. These data indicate that mu-receptors in the NTS elicit cardiovascular responses that are mediated by increased sympathetic nerve activity, and accompanied by selective attenuation of baroreflex function.


[Analysis of the form of cortical neuron reaction to acetylcholine].
Reaction patterns of 90 cortical neurons to acetylcholine approximated by two parabolas have been divided on simple and complex. The participation of different types of cholinoreceptors in complex reactions to transmitter is proposed.


Transformation of waist parameters of a Gaussian beam by a thick lens.
This paper presents a theory of the transformation of the waist position and waist size of a Gaussian beam by a thick lens. We clarify the effects of lens thickness and shape on the transformed waist parameters. For equiconvex and equiconcave lenses, the effects of the thickness on the transformed parameters are significant when the Rayleigh length of the incident beam is small compared with the focal length of a thin positive lens. For plano-convex and plano-concave lenses, the waist parameters of the transmitted beam depend largely on whether the flat or curved side faces the incident beam. The conditions for locating the waist at a prescribed position in a spherical shell or a sphere are also given in terms of the waist parameters of the incident beam.


p27 and Barrett's esophagus: a review*.
The rising prevalence of Barrett's esophagus and Barrett's associated adenocarcinoma in the Western world has stimulated increasing interest in this disease. This has resulted in a plethora of articles concerning its molecular biology, but the tumor suppressor gene, p27, has received little attention. In this article, we review the literature concerning the role of p27 in Barrett's esophagus and its malignant transformation, and we evaluate its possible role as an important clinical biomarker, as well as potential chemopreventive clinical agents aimed at substituting its antitumoral activity.


Development and Implementation of a School-Wide Institute for Excellence in Education to Enable Educational Scholarship by Medical School Faculty.
Educational scholarship is an important component for faculty at Academic Medical Centers, especially those with single-track promotion systems. Yet, faculty may lack the skills and mentorship needed to successfully complete projects. In addition, many educators feel undervalued. To reinvigorate our school's educational mission, the Institute for Excellence in Education (IEE) was created. Here we focus on one of the IEE's strategic goals, that of inspiring and supporting educational research, scholarship, and innovation. Using the 6-step curriculum development process as a framework, we describe the development and outcomes of IEE programs aimed at enabling educational scholarship at the Johns Hopkins University School of Medicine. Four significant programs that focused on educational scholarship were developed and implemented: (a) an annual conference, (b) a Faculty Education Scholars' Program, (c) "Shark Tank" small-grant program, and (d) Residency Redesign Challenge grants. A diverse group of primarily junior faculty engaged in these programs with strong mentorship, successfully completing and disseminating projects. Faculty members have been able to clarify their personal goals and develop a greater sense of self-efficacy for their desired paths in teaching and educational research. Faculty require programs and resources for educational scholarship and career development, focused on skills building in methodology, assessment, and statistical analysis. Mentoring and the time to work on projects are critical. Key to the IEE's success in maintaining and building programs has been ongoing needs assessment of faculty and learners and a strong partnership with our school's fund-raising staff. The IEE will next try to expand opportunities by adding additional mentoring capacity and further devilment of our small-grants programs.


Reported lifetime aberrant drug-taking behaviors are predictive of current substance use and mental health problems in primary care patients.
The aim of this report is to determine the frequency of aberrant drug behaviors and their relationship to substance abuse disorders in a large primary sample of patients receiving opioids for chronic pain. The data utilized for this report was obtained from 904 chronic pain patients receiving opioid therapy from their primary care physician. A questionnaire was developed based on 12 aberrant drug behaviors reported in the clinical literature. The diagnosis of a current substance use disorder was determined using Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition(DSM-IV) criteria. The average duration of chronic pain in the sample was 16 years and for opioid therapy, 6.4 years. Of the patients, 80.5% reported one or more lifetime aberrant drug behaviors. The most frequent behaviors reported included early refills (41.7%), increase dose without physician consent (35.7%), and felt intoxicated from opioids (32.2%). Only 1.1% of subjects with 1-3 aberrant behaviors (N = 464, 51.2%) met DSM-IV criteria for current opioid dependence compared with 9.9% of patients with four or more behaviors (N = 264, 29.3%). Persons with positive urine toxicology tests for cocaine were 14 times more likely to report four or more behaviors than no behaviors (14.1% vs 1.1%). A logistic model found that subjects who reported four or more aberrant behaviors were more likely to have a current substance use disorder (odds ratio [OR] 10.14; 3.72, 27.64), a positive test for cocaine (odds ratio [OR] 3.01; 1.74, 15.4), an Addiction Severity Index (ASI) psychiatric composite score >0.5 (OR 2.38; 1.65, 3.44), male gender (OR 2.08: 1.48, 2.92), and older age (OR 0.69; 0.59, 0.81) compared with subjects with three or fewer behaviors. Pain levels, employment status, and morphine equivalent dose do not enter the model. Patients who report four or more aberrant drug behaviors are associated with a current substance use disorder and illicit drug use, whereas subjects with up to three aberrant behaviors have a very low probability of a current substance abuse disorder. Four behaviors--oversedated oneself, felt intoxicated, early refills, increase dose on own--appear useful as screening questions to predict patients at greatest risk for a current substance use disorders.


A sub-100 fs self-starting Cr:forsterite laser generating 1.4 W output power.
Without cavity dumping or external amplification, we report a femtosecond Cr:forsterite laser with a 1.4 W output power and 2 W in continuous wave (CW) operated with a crystal temperature of 267 K. In the femtosecond regime, the oscillator generates Kerr-lens-mode-locked 84 fs pulses with a repetition rate of 85 MHz, corresponding to a high 16.5 nJ pulse energy directly from a single Cr:forsterite resonator. This intense femtosecond Cr:forsterite laser is ideal to pump varieties of high power fiber light sources and could be thus ideal for many biological and spectroscopy applications.


Systematic review of digital imaging screening strategies for retinopathy of prematurity.
Retinal imaging with remote interpretation could decrease the number of diagnostic eye examinations that premature infants need for the detection of retinopathy of prematurity and thus decrease the time demand on the relatively small pool of ophthalmologists who perform retinopathy of prematurity examinations. Our goal was to review systematically the evidence regarding the reliability, validity, safety, costs, and benefits of retinal imaging to screen infants who are at risk for retinopathy of prematurity. We searched Medline, the Cochrane library, CINAHL, and the bibliographies of all relevant articles. All English-language studies regardless of design with primary data about our study questions were included. We excluded (1) studies that only included subjects with retinopathy of prematurity, (2) hypothetical models other than cost-effectiveness studies, and (3) validity studies without sufficient data to determine prevalence, sensitivity, and specificity or that only evaluated subjects for 1 component of retinopathy of prematurity (eg, plus disease only). Studies of only 1 retinal imaging device (RetCam [Clarity Medical Systems, Inc, Pleasanton, CA]) met the inclusion criteria. There was a wide range in reported sensitivity, but specificity was high. There were several important limitations noted, including the eye as the unit of analysis instead of the individual or variations in the criteria for determining a true-positive or true-negative screening result. The risk of retinal hemorrhage resulting from imaging is low, and systemic effects (eg, bradycardia, hypertension, decreased oxygen saturation) are mild. No generalizable cost-effectiveness data were found. The evidence base is not sufficient to recommend that retinal imaging be routinely adopted by NICUs to identify infants who have serious retinopathy of prematurity.


Fluorescence to measure light intensity.
Despite the need for quantitative measurements of light intensity across many scientific disciplines, existing technologies for measuring light dose at the sample of a fluorescence microscope cannot simultaneously retrieve light intensity along with spatial distribution over a wide range of wavelengths and intensities. To address this limitation, we developed two rapid and straightforward protocols that use organic dyes and fluorescent proteins as actinometers. The first protocol relies on molecular systems whose fluorescence intensity decays and/or rises in a monoexponential fashion when constant light is applied. The second protocol relies on a broad-absorbing photochemically inert fluorophore to back-calculate the light intensity from one wavelength to another. As a demonstration of their use, the protocols are applied to quantitatively characterize the spatial distribution of light of various fluorescence imaging systems, and to calibrate illumination of commercially available instruments and light sources.


Elevation of cytoplasmic calcium concentration stimulates hydrolysis of phosphatidylinositol bisphosphate in chick heart cells: effect of sodium channel activators.
The sodium channel activators veratridine and batrachotoxin, the sodium ionophore gramicidin, and the calcium ionophore ionomycin stimulated phosphoinositide breakdown, as indicated by the increased accumulation of [3H]inositol monophosphate in embryonic chick heart cells. The levels of [3H]inositol trisphosphate and [3H]inositol bisphosphate were also increased by veratridine, indicating that there was increased hydrolysis of phosphatidylinositol bisphosphate by phospholipase C. The response to veratridine required both extracellular sodium and calcium, suggesting that calcium entry via Na/Ca exchange might activate phospholipase C. Fluorescence measurements with fura-2 confirmed that the sodium agents greatly increased the cytoplasmic calcium concentration. Veratridine (100 microM) increased cytoplasmic calcium from 94 +/- 4 nM to 862 +/- 103 nM, giving a maximal calcium increase in about 2 min. Batrachotoxin (1 microM) induced an even greater increase in calcium but required a longer time. Gramicidin also induced a large increase in cytoplasmic calcium which was maximal within 0.5 min. To directly test the calcium dependency of phospholipase C, we permeabilized the chick heart cells with saponin and monitored the production of inositol phosphates at different calcium concentrations. Raising the calcium concentration from 3 to 1000 nM increased the accumulation of [3H]inositol phosphates by nearly 4-fold with a half-maximal effect at about 200 nM calcium. The guanine nucleotide guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) also stimulated accumulation of the InsPs and the response to (GTP gamma S) was potentiated by increasing the calcium concentration. The data suggest that the effect of the sodium agents on phosphoinositide hydrolysis results from an elevation of intracellular calcium which increases GTP-dependent phospholipase C activity. Thus, drugs or other conditions that elevate cytoplasmic calcium in heart cells may increase the hydrolysis of membrane phosphoinositides.


Preliminary investigation into the use of Raman spectroscopy for the verification of Australian grass and grain fed beef.
Australian grass and grain-fed beef products attract premium prices at sale and several beef processors market beef underwritten by production system claims. This preliminary investigation assessed the feasibility of using Raman spectroscopy to detect differences in the chemical composition of subcutaneous fat from cattle raised in extensive and intensive production systems. Raman spectra, fatty acid composition, β-carotene composition and objective colour measurements were measured on 150 grass and 150 grain-fed cattle. Spectral differences at peaks including 1069 cm-1, 1127 cm-1, 1301 cm-1 and 1445 cm-1 suggest that Raman spectra is able to detect differences in saturated fatty acids, which were significantly higher in carcases from grain-fed cattle. Differences in spectra at 1658 cm-1 were observed, however further research is required to investigate the cause of this spectral feature. Overall, this study indicated that Raman spectroscopy is a potential tool for the authentication of beef carcases from grass and grain-fed production systems.


The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence.
Since improved prediction of illness course early in bipolar disorder is required to guide treatment planning, the authors evaluated recovery, first recurrence, and new illness onset following first hospitalization for mania. Bipolar disorder patients (N=166) were followed 2-4 years after their first hospitalization for a manic or mixed episode to assess timing and predictors of outcomes. Three aspects of recovery were measured: syndromal (DSM-IV criteria for disorder no longer met), symptomatic (Young Mania Rating Scale score </=5 and Hamilton Depression Rating Scale score </=8), and functional (regaining of premorbid occupational and residential status). Rates of remission (syndromal recovery sustained >/=8 weeks), switching (onset of new dissimilar illness before recovery), relapse (new episode of mania within 8 weeks of syndromal recovery), and recurrence (new episode postremission) were also assessed. By 2 years, most subjects achieved syndromal recovery (98%, with 50% achieving recovery by 5.4 weeks); 72% achieved symptomatic recovery. Factors associated with a shorter time to syndromal recovery for 50% of the subjects were female sex, shorter index hospitalization, and lower initial depression ratings. Only 43% achieved functional recovery; these subjects were more often older and had shorter index hospitalizations. Within 2 years of syndromal recovery, 40% experienced a new episode of mania (20%) or depression (20%), and 19% switched phases without recovery. Predictors of mania recurrence were initial mood-congruent psychosis, lower premorbid occupational status, and initial manic presentation. Predictors of depression onset were higher occupational status, initial mixed presentation, and any comorbidity. Antidepressant treatment was marginally related to longer time to recovery and earlier relapse. Within 2-4 years of first lifetime hospitalization for mania, all but 2% of patients experienced syndromal recovery, but 28% remained symptomatic, only 43% achieved functional recovery, and 57% switched or had new illness episodes. Risks of new manic and depressive episodes were similar but were predicted by contrasting factors.


A novel conversion prediction method of MCI to AD based on longitudinal dynamic morphological features using ADNI structural MRIs.
Mild cognitive impairment (MCI) is a pre-existing state of Alzheimer's disease (AD). An accurate prediction on the conversion from MCI to AD is of vital clinical significance for potential prevention and treatment of AD. Longitudinal studies received widespread attention for investigating the disease progression, though most studies did not sufficiently utilize the evolution information. In this paper, we proposed a cerebral similarity network with more progression information to predict the conversion from MCI to AD efficiently. First, we defined the new dynamic morphological feature to mine longitudinal information sufficiently. Second, based on the multiple dynamic morphological features the cerebral similarity network was constructed by sparse regression algorithm with optimized parameters to obtain better prediction performance. Then, leave-one-out cross-validation and support vector machine (SVM) were employed for the training and evaluation of the classifiers. The proposed methodology obtained a high accuracy of 92.31% (Sensitivity = 100%, Specificity = 82.86%) in a three-year ahead prediction of MCI to AD conversion. Experiment results suggest the effectiveness of the dynamic morphological feature, serving as a more sensitive biomarker in the prediction of MCI conversion.


Operation-driven heterogeneity and overlooked feed-associated populations in global anaerobic digester microbiome.
Anaerobic digester (AD) microbiomes harbor complex, interacting microbial populations to achieve biomass reduction and biogas production, however how they are influenced by operating conditions and feed sludge microorganisms remain unclear. These were addressed by analyzing the microbial communities of 90 full-scale digesters at 51 municipal wastewater treatment plants from five countries. Heterogeneity detected in community structures suggested that no single AD microbiome could be defined. Instead, the AD microbiomes were classified into eight clusters driven by operating conditions (e.g., pretreatment, temperature range, and salinity), whereas geographic location of the digesters did not have significant impacts. Comparing digesters populations with those present in the corresponding feed sludge led to the identification of a hitherto overlooked feed-associated microbial group (i.e., the residue populations). They accounted for up to 21.4% of total sequences in ADs operated at low temperature, presumably due to ineffective digestion, and as low as 0.8% in ADs with pretreatment. Within each cluster, a core microbiome was defined, including methanogens, syntrophic metabolizers, fermenters, and the newly described residue populations. Our work provides insights into the key factors shaping full-scale AD microbiomes in a global scale, and draws attentions to the overlooked residue populations.


Community ambulation: environmental impacts and assessment inadequacies.
Community ambulation is an important goal for both clients and health professionals yet it is an outcome only variously achieved by clients discharged from rehabilitation settings back into their community. To review the available literature about the assessment tools that are currently used to determine community ambulation status and to determine from an evaluation of these tools the effectiveness of the evaluation when compared to known environmental dimensions that impact on ambulation in the community. A review of published papers from English language literature using CINAHL, ProQuest, Medline and other databases was conducted. Only eight papers were found in the literature to inform health professionals about the impact of the environment on community ambulation. No current mobility assessment tools were identified that assess all the environmental demands that can impact on the activity of community ambulation. From the tools reviewed the most frequently evaluated environmental mobility dimensions were walking distance and time constraints. Health professionals need assessment tools that evaluate the impact of the environment on an individual's mobility in order to determine community ambulation status. The literature to date provides little guidance about the impact of the environment and current evaluation tools are limited in clinical usefulness with respect to the depth and breadth of information gained.


Alternative splicing at C terminus of Ca(V)1.4 calcium channel modulates calcium-dependent inactivation, activation potential, and current density.
The Ca(V)1.4 voltage-gated calcium channel is predominantly expressed in the retina, and mutations to this channel have been associated with human congenital stationary night blindness type-2. The L-type Ca(V)1.4 channel displays distinct properties such as absence of calcium-dependent inactivation (CDI) and slow voltage-dependent inactivation (VDI) due to the presence of an autoinhibitory domain (inhibitor of CDI) in the distal C terminus. We hypothesized that native Ca(V)1.4 is subjected to extensive alternative splicing, much like the other voltage-gated calcium channels, and employed the transcript scanning method to identify alternatively spliced exons within the Ca(V)1.4 transcripts isolated from the human retina. In total, we identified 19 alternative splice variations, of which 16 variations have not been previously reported. Characterization of the C terminus alternatively spliced exons using whole-cell patch clamp electrophysiology revealed a splice variant that exhibits robust CDI. This splice variant arose from the splicing of a novel alternate exon (43*) that can be found in 13.6% of the full-length transcripts screened. Inclusion of exon 43* inserts a stop codon that truncates half the C terminus. The Ca(V)1.4 43* channel exhibited robust CDI, a larger current density, a hyperpolarized shift in activation potential by ∼10 mV, and a slower VDI. Through deletional experiments, we showed that the inhibitor of CDI was responsible for modulating channel activation and VDI, in addition to CDI. Calcium currents in the photoreceptors were observed to exhibit CDI and are more negatively activated as compared with currents elicited from heterologously expressed full-length Ca(V)1.4. Naturally occurring alternative splice variants may in part contribute to the properties of the native Ca(V)1.4 channels.


Attenuation of acute phase shear stress by somatostatin improves small-for-size liver graft survival.
The major concern of living donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be developed. To investigate the protective effect of somatostatin related to hemodynamic stress on small-for-size liver graft injury, we applied a treatment regimen of low-dose somatostatin in a rat orthotopic liver transplantation model using small-for-size grafts (median, 38.7%; range, 35-42%). Somatostatin was given at 5 minutes before total hepatectomy and immediately after reperfusion in the recipient (20 microg/kg). Graft survival, portal hemodynamics, intragraft gene expression and hepatic ultrastructural changes were compared between the rats with or without somatostatin treatment. Seven-day graft survival rates in the somatostatin treatment group were significantly improved compared to the control group (66.7% vs. 16.7%, P = 0.036). In the treatment group, portal pressure and hepatic surface blood flow were significantly decreased within the first 30 minutes after reperfusion, whereas in the control group, transient portal hypertension and excessive hepatic blood flow were observed. Intragraft expression (both messenger RNA and protein) of endothelin-1 was significantly downregulated accompanied with upregulation of heme oxygenase-1 and A20. Better preservation of liver function was found in the treatment group. Hepatic ultrastructure, especially the integrity of sinusoids, was well protected in the treatment group. In conclusion, low-dose somatostatin rescues small-for-size grafts from acute phase injury in liver transplantation by attenuation of acute-phase shear stress that resulted from transient portal hypertension.


MBMD coping styles and psychiatric indicators and response to a multidisciplinary pain treatment program.
Psychosocial and personality factors are known to contribute to the maintenance of and recovery from chronic pain conditions but less is known about their influence on the efficacy of pain treatment programs. The purpose of the present study is to examine the ability of the Millon Behavioral Medicine Diagnostic (MBMD), a broadband measure of personality and psychosocial characteristics, to predict response to multidisciplinary pain treatment. 93 patients completed the MBMD, and ratings of current pain and average pain on an 11 point scale, prior to a multidisciplinary pain management program. Ratings of current and average pain were completed upon program completion. Participants were classified as "successful" or "unsuccessful" program completers based on pain reductions of ≥2 points. After program completion, 47 % of participants evidenced successful pain reductions. These successful participants had lower scores on depression and on coping style scales measuring introversive, inhibited, and dejected tendencies at baseline. Additionally, lower pre-treatment depression scores and lower scores on each of these coping style scales predicted lower pain ratings at discharge independent of educational level and pre-treatment pain ratings. The MBMD may be a useful tool to delineate patients who are likely to make significant treatment gains in intense, multidisciplinary pain treatment programs.


Myoepithelial cells are the main component in pleomorphic adenomas?
The aim of this study was to quantify by immunohistochemistry the number of myoepithelial cells (MyECs) in pleomorphic adenomas (PAs). We retrieved the paraffin cubes of 27 PAs, new slides were done and they were stained with anti-S100 protein antibody. The amount of S-100 protein positive cells was quantified, their morphology was recorded and comparison among MyEC number with age, gender and involved gland were also done. With S-100 protein, MyECs in normal salivary gland tissue were seen surrounding the ductual structures only. In the analysed PAs a mean of 27.4% of the neoplastic cells were positive to the antibody. With the exception of one PA, in all the analysed cases the plasmacytoid cells were the most commonly identified cells (48,6%). Results of this study suggest that MyECs do not constitute the main cellular component of the neoplastic compartment in PAs and corroborate the previously reported evidence by different authors, who studying the PAs suggested that MyECs does not comprise the main cellular neoplastic component of these entities.


Sulodexide suppresses inflammation in human endothelial cells and prevents glucose cytotoxicity.
Sulodexide is a mixture of heparin and dermatan sulfate with antithrombotic and profibrynolytic activity. Individual reports suggest the anti-inflammatory action of sulodexin. The goal of this study was to evaluate the effect of sulodexide on the release of the inflammatory mediators from endothelium in normal conditions and in cells chronically exposed to glucose. The experiments were performed on in vitro cultured human umbilical endothelial cells kept for 7 days in standard medium or in the same medium but supplemented with glucose 30 mmol/L. Sulodexide was added to the culture medium in concentrations of 0.125 lipase releasing unit (LRU)/mL, 0.25 LRU/mL, and 0.5 LRU/mL Spontaneous generation of oxygen-derived free radicals and the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) from the studied cells was evaluated. Additionally, the healing of the injured mesothelium was studied in the presence of sulodexide and glucose. Sulodexide caused the inhibition of the intracellular generation of free radicals in a dose-dependent manner (maximally by 32%, P < 0.01), as well as the inhibition of MCP-1 (maximally by 60%, P < 0.001) and IL-6 (maximally by 69%, P < 0.01). Cells cultured in a medium with glucose 30 mmol/L generated more free radicals (+20%, P < 0.05) and released more MCP-1 (+113%, P < 0.001) and IL-6 (+26%, P < 0.05). Cell monolayers treated with glucose had a decreased ability to heal after mechanical injury (-28%, P < 0.001). All these glucose effects were reversed when cells were exposed to sulodexide simultaneously. The results of our study demonstrate a significant anti-inflammatory action of sulodexide in the endothelial cells and a protective effect of that drug against glucose cytotoxicity.


Identification of a novel, tunable interface in the S.pombe HP1 protein, Swi6, that underpins epigenetic inheritance.
HP1 proteins bind dynamically to H3K9 methylation and are essential for establishing and maintaining transcriptionally silent epigenetic states, known as heterochromatin. HP1 proteins can dimerize, forming a binding interface that interacts with and recruits diverse chromatin-associated factors. HP1 proteins rapidly evolve through sequence changes and gene duplications, but the extent of variation required to achieve functional specialization is unknown. To investigate how changes in amino acid sequence impact epigenetic inheritance, we performed a targeted mutagenesis screen of the dimerization and protein interaction domain of the S.pombe HP1 homolog Swi6. We discovered that substitutions mapping to an auxiliary motif in Swi6 outside the dimerization interface can lead to complete functional divergence. Specifically, we identified point mutations at a single amino acid residue that resulted in either persistent gain or loss of function in epigenetic inheritance without affecting heterochromatin establishment. These substitutions increase Swi6 chromatin occupancy in vivo and alter Swi6-protein interactions that selectively affect H3K9me inheritance. Based on our findings, we propose that relatively minor changes in Swi6 amino acid composition can lead to profound changes in epigenetic inheritance, underscoring the remarkable plasticity associated with HP1 proteins and their ability to evolve new functions.