NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity.
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition. We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual γH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well. Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of γH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor. The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.


Self-Report After Randomly Assigned Supervision Does not Predict Ability to Practice Motivational Interviewing.
The objective of this study was to investigate the relation between self-report and objective assessment of motivational interviewing (MI) skills following training and supervision. After an MI workshop, 96 clinicians from 26 community programs (age 21-68, 65% female, 40.8% Black, 29.6% Caucasian, 24.5% Hispanic, 2.0% Asian, 3.1% other) were randomized to supervision (tele-conferencing or tape-based), or workshop only. At four time points, trainees completed a self-report of MI skill, using items from the MI understanding questionnaire (MIU), and were objectively assessed by raters using the Motivational Interviewing Treatment Integrity (MITI) system. Correlations were calculated between MIU and MITI scores. A generalized linear mixed model was tested on MIU scores, with MITI scores, supervision condition and time as independent variables. MIU scores increased from pre-workshop (mean = 4.74, SD = 1.79) to post-workshop (mean = 6.31, SD = 1.03) (t = 8.69, p < .0001). With supervision, scores continued to increase, from post-workshop to week 8 (mean = 7.07, SD = 0.91, t = 5.60, p < .0001) and from week 8 to week 20 (mean = 7.28, SD = 0.94, t = 2.43, p = .02). However, MIU scores did not significantly correlate with MITI scores, with or without supervision. Self-reported ability increased with supervision, but self-report was not an indicator of objectively measured skill. This suggests that training does not increase correspondence between self-report and objective assessment, so community treatment programs should not rely on clinician self-report to assess the need for ongoing training and supervision and it may be necessary to train clinicians to accurately assess their own skill.


Early screw removal for correction of occlusal discrepancies following rigid internal fixation in orthognathic surgery.
Occlusal discrepancies that occur after orthognathic surgery in which rigid internal fixation was used are technically difficult to correct. These discrepancies often lead to prolonged postoperative orthodontics and possibly to compromised results. The effectiveness of the removal of rigid internal fixation in correcting these changes was studied retrospectively. Of 169 patients who underwent bilateral sagittal osteotomies of the mandible, 13 developed postoperative malocclusions, and their rigid internal fixation was removed (an average of 21 days postoperatively). Occlusion was improved in 11 of the patients. In the two patients who showed no improvement in occlusion, fixation had been removed at 5 weeks in one and at 6 weeks in the other. One patient had a slight relapse 6 months postoperatively. All other patients had stable occlusions and experienced no complications. Recommendations for use of the technique and potential complications are discussed.


Application of DArT seq derived SNP tags for comparative genome analysis in fishes; An alternative pipeline using sequence data from a non-traditional model species, Macquaria ambigua.
Bi-allelic Single Nucleotide Polymorphism (SNP) markers are widely used in population genetic studies. In most studies, sequences either side of the SNPs remain unused, although these sequences contain information beyond that used in population genetic studies. In this study, we show how these sequence tags either side of a single nucleotide polymorphism can be used for comparative genome analysis. We used DArTseq (Diversity Array Technology) derived SNP data for a non-model Australian native freshwater fish, Macquaria ambigua, to identify genes linked to SNP associated sequence tags, and to discover homologies with evolutionarily conserved genes and genomic regions. We concatenated 6,776 SNP sequence tags to create a hypothetical genome (representing 0.1-0.3% of the actual genome), which we used to find sequence homologies with 12 model fish species using the Ensembl genome browser with stringent filtering parameters. We identified sequence homologies for 17 evolutionarily conserved genes (cd9b, plk2b, rhot1b, sh3pxd2aa, si:ch211-148f13.1, si:dkey-166d12.2, zgc:66447, atp8a2, clvs2, lyst, mkln1, mnd1, piga, pik3ca, plagl2, rnf6, sec63) along with an ancestral evolutionarily conserved syntenic block (euteleostomi Block_210). Our analysis also revealed repetitive sequences covering approximately 12% of the hypothetical genome where DNA transposon, LTR and non-LTR retrotransposons were most abundant. A hierarchical pattern of the number of sequence homologies with phylogenetically close species validated the approach for repeatability. This new approach of using SNP associated sequence tags for comparative genome analysis may provide insight into the genome evolution of non-model species where whole genome sequences are unavailable.


Radioprotective and cytoprotective activity of Tinospora cordifolia stem enriched extract containing cordifolioside-A.
The present study was undertaken to evaluate the radioprotective and cytoprotective potential of cordifolioside-A, a primary active constituent of n-butanol fraction of Tinospora Cordifolia (NBTC) against 4 Gy-γ radiation in mice and cyclophosphamide induced genotoxicity. Presence of cordifolioside-A in NBTC stem ethanolic extract was confirmed by high performance thin layer chromatography (HPTLC) analysis. Radioprotective activity was evaluated at 80 and 120 mg/kg, intraperitoneal (i.p.) dose of NBTC administered 15 days prior to whole body radiation exposure by observing survival rate, change in body weight, hematology, spleen colony forming unit (CFU), and micronucleus (MN) expression. Cytoprotective activity of NBTC was evaluated at 5, 10, and 15 mg/ml concentrations on Allium cepa root meristem growth against cyclophosphamide. HPTLC analysis of standard cordifolioside A, and NBTC confirmed the presence of cordifolioside-A in NBTC with the retention factor value of 0.86. Administration of NBTC (120 mg/kg, i.p.) produced significant protection against radiation in terms of increased survival rate, body weight retention, hematological parameters, spleen CFU assay (P < 0.01), and decreased MN expression (P < 0.01). Cytoprotectivity was observed maximally at 10 mg/ml NBTC concentration with significant increase in root growth (P < 0.01), non-toxic mitotic index (MI) (65.9%) and lesser chromosomal aberrations (15.4%). NBTC at 10 mg/ml concentration showed very few C-anaphase compared to aberrations like fragmentation, C-anaphase, multipolarity and sticky chromosome in cyclophosphamide alone. The results suggest that enriched NBTC containing cordifolioside-A has a potential in vivo radioprotective effect as well as in vitro cytoprotective activity.


The persistences of vision.
Human observers continue to experience a visual stimulus for some time after the offset that stimulus. The neural activity evoked by a visual stimulus continues for some time after its offset. The information extracted from a visual stimulus continues to be registered in a visual form of memory ('iconic memory') for some time after its offset. We may thus distinguish three distinct senses in which a visual stimulus may be said to persist after its physical offset: there is phenomenological persistence, neural persistence and informational persistence. Various assumptions have been made about the relation between these forms of visual persistence. The most frequent assumption is that they correspond simply to three different methods for studying a single entity. Detailed consideration of what is known about the properties of these three forms of persistence suggests, however, that this assumption is not correct. It can reasonably be proposed that visible persistence is the phenomenological correlate of neural persistence occurring at various stages of the visual system: photoreceptors, ganglion cells and the stereopsis system. Iconic memory on the other hand, does not correspond to visible persistence, nor to neural persistence in any stage of the visual system. Recent work, in fact, suggests that iconic memory is a property of some relatively late stage in the visual information-processing system, rather than being a peripheral sensory buffer store. This suggestion raises some fundamental theoretical issues concerning the psychology of visual perception, issues with which cognitive psychology has yet to come to grips.


Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans.
The inability to produce insulin endogenously precipitates the clinical symptoms of type 1 diabetes mellitus. However, the dynamic trajectory of beta cell destruction following onset remains unclear. Using model-based inference, the severity of beta cell destruction at onset decreases with age where, on average, a 40% reduction in beta cell mass was sufficient to precipitate clinical symptoms at 20 years of age. While plasma C-peptide provides a surrogate measure of endogenous insulin production post-onset, it is unclear as to whether plasma C-peptide represents changes in beta cell mass or beta cell function. The objective of this paper was to determine the relationship between beta cell mass and endogenous insulin production post-onset. Model-based inference was used to compare direct measures of beta cell mass in 102 patients against contemporary measures of plasma C-peptide obtained from three studies that collectively followed 834 patients post-onset of clinical symptoms. An empirical Bayesian approach was used to establish the level of confidence associated with the model prediction. Age-corrected estimates of beta cell mass that were inferred from a series of landmark pancreatic autopsy studies significantly correlate (p>0.9995) with contemporary measures of plasma C-peptide levels following onset. Given the correlation between beta cell mass and plasma C-peptide following onset, plasma C-peptide may provide a surrogate measure of beta cell mass in humans. The clinical relevance of this study is that therapeutic strategies that provide an increase in plasma C-peptide over the predicted value for an individual may actually improve beta cell mass. The model predictions may establish a standard historical "control" group - a prior in a Bayesian context - for clinical trials.


Associations between food and beverage groups and major diet-related chronic diseases: an exhaustive review of pooled/meta-analyses and systematic reviews.
Associations between food and beverage groups and the risk of diet-related chronic disease (DRCD) have been the subject of intensive research in preventive nutrition. Pooled/meta-analyses and systematic reviews (PMASRs) aim to better characterize these associations. To date, however, there has been no attempt to synthesize all PMASRs that have assessed the relationship between food and beverage groups and DRCDs. The objectives of this review were to aggregate PMASRs to obtain an overview of the associations between food and beverage groups (n = 17) and DRCDs (n = 10) and to establish new directions for future research needs. The present review of 304 PMASRs published between 1950 and 2013 confirmed that plant food groups are more protective than animal food groups against DRCDs. Within plant food groups, grain products are more protective than fruits and vegetables. Among animal food groups, dairy/milk products have a neutral effect on the risk of DRCDs, while red/processed meats tend to increase the risk. Among beverages, tea was the most protective and soft drinks the least protective against DRCDs. For two of the DRCDs examined, sarcopenia and kidney disease, no PMASR was found. Overweight/obesity, type 2 diabetes, and various types of cardiovascular disease and cancer accounted for 289 of the PMASRs. There is a crucial need to further study the associations between food and beverage groups and mental health, skeletal health, digestive diseases, liver diseases, kidney diseases, obesity, and type 2 diabetes.


Quantifying uncertainty in the measurement of arsenic in suspended particulate matter by Atomic Absorption Spectrometry with hydride generator.
Arsenic is the toxic element, which creates several problems in human being specially when inhaled through air. So the accurate and precise measurement of arsenic in suspended particulate matter (SPM) is of prime importance as it gives information about the level of toxicity in the environment, and preventive measures could be taken in the effective areas. Quality assurance is equally important in the measurement of arsenic in SPM samples before making any decision. The quality and reliability of the data of such volatile elements depends upon the measurement of uncertainty of each step involved from sampling to analysis. The analytical results quantifying uncertainty gives a measure of the confidence level of the concerned laboratory. So the main objective of this study was to determine arsenic content in SPM samples with uncertainty budget and to find out various potential sources of uncertainty, which affects the results. Keeping these facts, we have selected seven diverse sites of Delhi (National Capital of India) for quantification of arsenic content in SPM samples with uncertainty budget following sampling by HVS to analysis by Atomic Absorption Spectrometer-Hydride Generator (AAS-HG). In the measurement of arsenic in SPM samples so many steps are involved from sampling to final result and we have considered various potential sources of uncertainties. The calculation of uncertainty is based on ISO/IEC17025: 2005 document and EURACHEM guideline. It has been found that the final results mostly depend on the uncertainty in measurement mainly due to repeatability, final volume prepared for analysis, weighing balance and sampling by HVS. After the analysis of data of seven diverse sites of Delhi, it has been concluded that during the period from 31st Jan. 2008 to 7th Feb. 2008 the arsenic concentration varies from 1.44 ± 0.25 to 5.58 ± 0.55 ng/m3 with 95% confidence level (k = 2).


Extracorporeal life support for adults with severe acute respiratory failure.
Extracorporeal life support (ECLS) is an artificial means of maintaining adequate oxygenation and carbon dioxide elimination to enable injured lungs to recover from underlying disease. Technological advances have made ECLS devices smaller, less invasive, and easier to use. ECLS might, therefore, represent an important step towards improved management and outcomes of patients with acute respiratory distress syndrome. Nevertheless, rigorous evidence of the ability of ECLS to improve short-term and long-term outcomes is needed before it can be widely implemented. Moreover, how to select patients and the timing and indications for ECLS in severe acute respiratory distress syndrome remain unclear. We describe the physiological principles, the putative risks and benefits, and the clinical evidence supporting the use of ECLS in patients with acute respiratory distress syndrome. Additionally, we discuss controversies and future directions, such as novel technologies and indications, mechanical ventilation of the native lung during ECLS, and ethics considerations.


Sensing applications of luminescent carbon based dots.
Carbon based dots (CDs) including carbon quantum dots and graphene quantum dots exhibit unique luminescence properties, such as photoluminescence (PL), chemiluminescence (CL) and electrochemiluminescence (ECL). This review summarizes the sensing application of the CDs taking advantage of their luminescence properties. The working principle, merits, and prospects of CD based sensors are presented.


Gp96-Ig/Costimulator (OX40L, ICOSL, or 4-1BBL) Combination Vaccine Improves T-cell Priming and Enhances Immunity, Memory, and Tumor Elimination.
T-cell costimulation typically occurs in a defined microenvironment that is not recapitulated by agonistic antibody therapy. To deliver such stimulation under more favorable conditions, we investigated whether an allogeneic cell-based vaccine that secreted Fc-OX40L, Fc-ICOSL, or Fc-4-1BBL would activate and expand T cells comparably with systemically administered agonist antibodies. Among these costimulators, locally secreted Fc-OX40L provided superior priming of antigen-specific CD8(+) T cells, compared with combinations with OX40 antibodies or vaccine alone. Vaccine-expressed Fc-OX40L also stimulated IFNγ, TNFα, granzyme B, and IL2 by antigen-specific CD8(+) T cells similarly to OX40 antibodies, without off-target consequences such as proinflammatory cytokine induction. Vaccine-secreted Fc-OX40L increased CD127(+)KLRG-1(-) memory precursor cells during the contraction phase, resulting in improved proliferation upon secondary antigen challenge, as compared with OX40 antibody. A cell-based vaccine cosecreting gp96-Ig and Fc-OX40L led to even more pronounced tumor control, complete tumor rejection, and increased tumor antigen-specific T-cell proliferation, including in tumor-infiltrating lymphocytes, as compared with combinations of gp96-Ig vaccine and OX40 antibodies, in mice with established melanoma or colorectal carcinoma. These data suggest that local modulation of the vaccine microenvironment has unexpected advantages over systemic costimulation with agonistic antibodies, which may simplify the clinical translation of such combination immunotherapies into humans. Cancer Immunol Res; 4(9); 766-78. ©2016 AACR.


The calcareous brown alga Padina pavonica in southern Britain: population change and tenacity over 300 years.
Understanding long-term persistence and variability in species populations can help to predict future survival, growth and distribution; however, sustained observations are exceedingly rare. We examine and interpret a remarkable record of the calcareous brown alga Padina pavonica (Phaeophyceae) at its northern limit on the south coast of England (50°N, 1-3°W) from 1680 to 2014, which is probably the longest compilation and review of any marine algal species. Over this period, which extends from the middle of the Little Ice Age to the present, there has been considerable variability in temperature and storminess. We identified a significant number of site extinctions in the second half of the nineteenth century, which coincided with cooler conditions and stormier weather. To interpret these changes, we measured recruitment, growth and production of tetraspores at sheltered and exposed sites in 2012-2014, years which had low and high spring temperatures. Potential spore production was greater at the sheltered site due to a longer growing period and survival of larger fronds. Delayed growth in the cooler spring resulted in smaller fronds and lower potential production of tetraspores by early summer. Yet in the warmer year, rapid initial growth caused higher sensitivity to damage and dislodgement by summer storms, which also limited potential spore production. Antagonistic responses to multiple stressors and disturbances make future predictions of survival and distribution difficult. Fronds of Padinapavonica are sensitive to both temperature and physical disturbances, yet vegetative perennation appears to have enabled population persistence and explained the longevity of remaining populations.


Insecticide susceptibility of three species of cutworm (Lepidoptera: Noctuidae) pests of grapes.
Climbing cutworms in the genus Abagrotis are economically important pests of grapes in the Okanagan Valley of British Columbia (BC). Grapes are recently introduced into many areas of the region, and the association between crop and pest is new and still evolving. This has led to limited information being available on pest management strategies, including the evaluation of chemical controls compatible with local production practices. Few insecticides are currently registered in Canada for cutworm control on grapes, and our study was initiated to provide information on the efficacy of potential control materials. We were also interested in the relative susceptibilities of the three most common cutworm species attacking grape buds in BC--Abagrotis orbis (Grote), Abagrotis reedi Buckett, and Abagrotis nefascia (Smith). Dose-response bioassays with nine insecticides were conducted on neonate larvae using Bok Choy leaf disks, and on fourth-instar larvae using diet incorporation. There were considerable differences in the toxicity of insecticides within species for neonates and fourth instars. For some materials, the relative toxicity to neonates and fourth instars were not correlated. Response to insecticides among the three species showed variation as well, and correct identification of the species complex present in individual locations is important in choosing the best available control material.


Consequences of intrathymic TCR engagement by partial agonist on selection events and peripheral T cell activation program.
Functions elicited from mature T cells depend on the nature of the Ag. Thus, an agonist induces a larger set of cytokine responses than a partial agonist. Additionally, Ags present in the thymus influence both the selection of TCRs generated by gene rearrangement and the potential functional program of developing thymocytes. This can be approached by analysing the development of T cells in mice expressing the same transgenic TCR (tgTCR) under different conditions of intrathymic selection. H-2Kbm8 was found to act as a partial agonist for CD8+ T cells expressing a tgTCR specific for the H-2Kb alloantigen. Intrathymic exposure to full or to partial agonist affected the development of thymocytes at different stages, consistent with the respective CD8-independent and -dependent characteristic of the tgTCR/Ag interaction. The presence of the partial agonist led to the accumulation of a major population of thymocytes (tgTCR(high) CD4- CD8(low)) originating from TCR engagement at the immature single-positive CD8(low) stage as evidenced by: 1) results from reaggregated thymic organ culture in the presence of H-2(k/bm8) thymic stromal cells; 2) the absence of CD4+ thymocytes, the development of which depends on rearrangements of endogenous TCR alpha genes; and 3) the identification of the CD8(low) thymocytes as cycling cells. Peripheral CD8(low) T cells selected in an H-2(k/bm8) thymus expressed a partial functional program in response to H-2Kb, akin to the response of CD8(high) T cells to a partial agonist. The analysis of the molecular bases for partial reactivity revealed a correlation with inefficient AP-1, but efficient NF-kappaB transactivation.


Reproductive seasonality in captive wild ruminants: implications for biogeographical adaptation, photoperiodic control, and life history.
Many ruminant species show seasonal patterns of reproduction. Causes for this are widely debated, and include adaptations to seasonal availability of resources (with cues either from body condition in more tropical, or from photoperiodism in higher latitude habitats) and/or defence strategies against predators. Conclusions so far are limited to datasets with less than 30 species. Here, we use a dataset on 110 wild ruminant species kept in captivity in temperate-zone zoos to describe their reproductive patterns quantitatively [determining the birth peak breadth (BPB) as the number of days in which 80% of all births occur]; then we link this pattern to various biological characteristics [latitude of origin, mother-young-relationship (hider/follower), proportion of grass in the natural diet (grazer/browser), sexual size dimorphism/mating system], and compare it with reports for free-ranging animals. When comparing taxonomic subgroups, variance in BPB is highly correlated to the minimum, but not the maximum BPB, suggesting that a high BPB (i.e. an aseasonal reproductive pattern) is the plesiomorphic character in ruminants. Globally, latitude of natural origin is highly correlated to the BPB observed in captivity, supporting an overruling impact of photoperiodism on ruminant reproduction. Feeding type has no additional influence; the hider/follower dichotomy, associated with the anti-predator strategy of 'swamping', has additional influence in the subset of African species only. Sexual size dimorphism and mating system are marginally associated with the BPB, potentially indicating a facilitation of polygamy under seasonal conditions. The difference in the calculated Julian date of conception between captive populations and that reported for free-ranging ones corresponds to the one expected if absolute day length was the main trigger in highly seasonal species: calculated day length at the time of conception between free-ranging and captive populations followed a y = x relationship. Only 11 species (all originating from lower latitudes) were considered to change their reproductive pattern distinctively between the wild and captivity, with 10 becoming less seasonal (but not aseasonal) in human care, indicating that seasonality observed in the wild was partly resource-associated. Only one species (Antidorcas marsupialis) became more seasonal in captivity, presumably because resource availability in the wild overrules the innate photoperiodic response. Reproductive seasonality explains additional variance in the body mass-gestation period relationship, with more seasonal species having shorter gestation periods for their body size. We conclude that photoperiodism, and in particular absolute day length, are genetically fixed triggers for reproduction that may be malleable to some extent by body condition, and that plasticity in gestation length is an important facilitator that may partly explain the success of ruminant radiation to high latitudes. Evidence for an anti-predator strategy involving seasonal reproduction is limited to African species. Reproductive seasonality following rainfall patterns may not be an adaptation to give birth in periods of high resource availability but an adaptation to allow conception only at times of good body condition.


Carotid artery stenting 2008.
In an effort to minimize interventions, in the last decade carotid artery stenting (CAS) has been suggested as an alternative to surgical carotid endarterectomy (CEA) for patients with symptomatic and asymptomatic extra cranial obstructive disease. CAS is relatively new compared to CEA and it should be acknowledged that CAS is an evolving technique. As technology has improved, procedural risks have declined and are approaching those reported for CEA. From the individual randomised clinical trial it can be concluded that in patients at high risk for CEA, CAS is an equivalent, maybe better alternative. In symptomatic patients at standard risk for CEA, CAS has not proven non-inferior, and is worse when performed by relatively inexperienced operators without embolic protection device compared to highly experienced CEA surgeons.


Planning ability improves in a yogic education system compared to a modern.
Planning skills play a key role in higher developmental processes. The Tower of London test not only measures planning skills, but also the ability to execute plans. Yoga practices aim to bring about higher development. Can a Yoga-based education system be shown to meet this challenge? This study was aimed at comparing a Modern Education System (MES) with the ancient Yoga-based system of education, the Gurukula Education System (GES), in developing planning skills. Forty-nine boys with ages ranging from 11 to 13 years were selected from each of two residential schools, one MES and the other GES, providing similar ambience and daily routines. The boys were matched for age and socio-economic status. The GES educational program is based around integrated yoga modules while the MES provides a conventional modern education program. Planning and executive abilities were assessed using the Tower of London test at the start and the end of an academic year. Within groups, the pre-post test differences were significant for both groups. However, the between-groups results showed improvement in the GES group compared to the MES group at a P < 0.001 significance level. The study suggests that whereas both MES and GES Yoga-based education improve planning and execution skills in school boys, GES is more effective of the two systems.


Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepine receptors.
The interactions of zopiclone and suriclone, representatives of nonbenzodiazepine cyclopyrrolone anxiolytics, with central-type benzodiazepine receptors have been characterized in rat and bovine brain. While zopiclone potently (IC50 approximately 50 nM) inhibits [3H]Ro-15-1788 binding in an apparent mass action fashion, suriclone and its metabolite 35,489 RP are extremely potent (IC50 approximately 350 pM and 1 nM, respectively) and display Hill coefficients of approximately 2.0. Like classical benzodiazepines, none of the cyclopyrrolones studied display selectivity for type I or type II benzodiazepine receptors. Using [3H]suriclone, saturable high affinity sites for cyclopyrrolone anxiolytics were directly labeled in rat and bovine brain. The regional distribution and pharmacologic specificity of [3H]suriclone and [3H]Ro-15-1788 binding sites are similar, suggesting that [3H]suriclone recognition sites reside on the benzodiazepine receptor complex. Unlike classical benzodiazepine agonists, such as diazepam, the binding of [3H]suriclone is not modulated by GABA, Cl-, pentobartibal, or tracazolate. Unlike those of [3H]diazepam, [3H]suriclone-binding sites are only minimally affected by photoaffinity labeling with flunitrazepam. Whereas the binding affinities of [3H]Ro-15-1788, [3H]flunitrazepam, and [3H]ethyl beta-carboline 3-carboxylate increase at lower temperatures, [3H]suriclone binds with higher affinity at higher temperatures. Scatchard analysis of [3H]flunitrazepam, [3H]ethyl beta-carboline 3-carboxylate, and [3H]Ro-15-1788 binding in the presence of all cyclopyrrolones studied reveals an apparent noncompetitive pattern of inhibition of binding in each case; by contrast, inhibition of [3H]suriclone binding by Ro-15-1788 flunitrazepam, methyl beta-carboline 3-carboxylate and all of the cyclopyrrolones studied appears competitive. The dissociation kinetics of [3H]Ro-15-1788 indicate that cyclopyrrolones, but not benzodiazepines, increase the dissociation rate of [3H]Ro-15-1788 from its membrane receptors; the converse is true for [3H]suriclone dissociation kinetics. The association kinetics of [3H]suriclone suggest that suriclone induces a conformational change upon binding to receptors. Taken together, these results indicate that [3H]suriclone labels a site on the benzodiazepine receptor complex allosteric to the recognition site for benzodiazepines. A model is proposed to describe the interaction between benzodiazepines and cyclopyrrolones.


Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging.
A novel bis-hydroxymethyl-substituted DTTA chelator N'-Bz-C(4,4')-(CH(2)OH)(2)-DTTA () and its DTPA analogue C(4,4')-(CH(2)OH)(2)-DTPA () were synthesized and characterized. A variable-temperature (1)H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln(3+) complexes showed them to be rigid when compared with analogous Ln(3+)-DTTA and Ln(3+)-DTPA complexes, as a result of their C(4,4')-(CH(2)OH)(2) ligand backbone substitution. The parameters that govern the water (1)H relaxivity of the [Gd()(H(2)O)(2)](-) and [Gd()(H(2)O)](2-) complexes were obtained by (17)O and (1)H NMR relaxometry. While the relaxometric behaviour of the [Gd()(H(2)O)](2-) complex is very similar to the parent [Gd(DTPA)(H(2)O)](2-) system, the [Gd()(H(2)O)(2)](-) complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd()(H(2)O)(2)](-) complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by (1)H NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and l-lactate anions, indicating that the two inner-sphere water molecules of the [Gd()(H(2)O)(2)](-) complex are not located in adjacent positions in the coordination sphere of the Gd(3+) ion. The transmetallation reaction rate of [Gd()(H(2)O)(2)](-) with Zn(2+) in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H(2)O)(2)](-), but twice faster than for [Gd(DTPA-BMA)(H(2)O)]. The in vivo biodistribution studies of the (153)Sm(3+)-labelled ligand () in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.


Heat-generating property of a local plasmon resonator under illumination.
We have investigated the heat generation from gold nanoparticles resulting from their local plasma resonance. We have demonstrated the self-assembly of Au nanoparticle arrays/dielectric layer/Ag mirror sandwiches, i.e., a local plasmon resonator, using a dynamic oblique deposition technique. The thicknesses of the Au and dielectric layers were changed combinatorially on a single substrate. As a result, local plasmon resonator chips were successfully fabricated. Because of strong interference, their optical absorption can be controlled between 0.0% and 97% in the near-IR region, depending on the thickness of the dielectric layer. We evaluated the heat generation from Au nanoparticles by measuring the temperature of water with which a cell prepared on a chip is filled under laser illumination. The change in the water temperature is proportional to the optical absorption of the local plasmon resonator chips. This suggests that the photothermal conversion efficiency can be controlled by interference. These features make the application of the local plasmon resonator to nanoheaters, which can spatiotemporally control heat generation, suitable.


Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas.
There is controversy regarding the pattern of lymphatic spread in unilateral stage I invasive ovarian carcinomas. The purpose of this study is to describe the incidence and distribution of lymph node (LN) metastases in ovarian carcinomas clinically confined to one ovary. Ninety-six patients with disease visibly confined to one ovary were identified. Pathology reports were reviewed to identify metastatic LN involvement, number of involved nodes, and their locations. Patients with gross disease in the pelvis or abdomen or those who had grossly positive LNs removed for debulking were excluded from this review. Fourteen of ninety-six patients (15%) had microscopically positive LNs on pathologic review. All of these 14 patients had grade 3 tumors. Grade 3 tumors were more commonly seen in LN-positive versus LN-negative patients (P < 0.001). Pelvic nodes were positive in 7 patients (50%), paraaortic nodes in 5 patients (36%), and both in 2 patients (14%). Forty-two patients had LN sampling only on the side ipsilateral to the neoplastic ovary, 4 of whom (10%) had LN metastases. Fifty-four patients had bilateral sampling performed, 10 of whom (19%) had LN metastases. Of these 10 patients, isolated ipsilateral LN metastases were seen in 5 (50%) cases. Isolated contralateral LN metastases were seen in 3 (30%) cases, and bilateral metastases were seen in 2 (20%). In this cohort of patients with clinical stage I ovarian carcinoma with disease limited to one ovary, bilateral LN sampling increased the identification of nodal metastases. Ipsilateral sampling may result in the understaging of patients. Bilateral pelvic and paraaortic LN sampling is recommended to accurately stage ovarian carcinoma.


Electrogastrography associated with symptomatic changes after prokinetic drug treatment for functional dyspepsia.
To evaluate the effect of prokinetic drugs on electrogastrography (EGG) parameters according to symptomatic changes in patients with functional dyspepsia (FD). Seventy-four patients with FD were prospectively enrolled in this study between December 2006 and December 2010. We surveyed the patients using a questionnaire on dyspeptic symptoms before and after an 8-wk course of prokinetic drug treatment. We also measured cutaneous pre-prandial and post-prandial EGG recordings including percentage of gastric waves (normogastria, bradygastria, tachygastria), dominant frequency (DF), dominant power (DP), dominant frequency instability coefficient (DFIC), dominant power instability coefficient (DPIC), and the ratio of post-prandial to fasting in DP before and after the 8-wk course of prokinetic drug treatment. Fifty-two patients (70%) achieved symptomatic improvement after prokinetic drug treatment. Patients who had normal gastric slow waves showed symptom improvement group after treatment. Post-prandial DF showed a downward trend in the symptom improvement group, especially in the itopride group. Post-prandial DP was increased regardless of symptom improvement, especially in the itopride group and mosapride group. Post-prandial DFIC and DPIC in the symptom improvement group were significantly increased after the treatment. The EGG power ratio was increased after treatment in the symptom improvement group (0.50 ± 0.70 vs 0.93 ± 1.77, P = 0.002), especially in the itopride and levosulpiride groups. Prokinetics could improve the symptoms of FD by regulating gastric myoelectrical activity, and EGG could be a useful tool in evaluating the effects of various prokinetics.


Effects of combined robotic therapy and repetitive-task practice on upper-extremity function in a patient with chronic stroke.
This article describes the effect of a robotic device combined with repetitive-task practice (RTP) on upper-extremity function in a patient with chronic stroke. The client was a 32-year-old woman, 11 months after stroke, with minimal wrist and finger movement. She received approximately 48 hr of intervention split evenly between a robotic device (Hand Mentor) and RTP during 3 weeks. Favorable scores in the Wolf Motor Function Test were observed from pre- to postevaluation. Active range of motion, from pre- to postintervention, increased by 35 degrees in the shoulder, 65 degrees in the wrist, and 70 degrees in the thumb. Kinetic analysis of a bimanual dexterity task indicated improved specification of grasping forces for both limbs. Improvements in upper-extremity motor functioning and functional performance in daily tasks followed this client's engagement in distal initiation of movement during an RTP exercise regimen that was robotically reinforced.


Molecular definitions of autophagy and related processes.
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.


Childhood overweight and cardiovascular disease risk factors: the National Heart, Lung, and Blood Institute Growth and Health Study.
To estimate the prevalence and incidence of overweight in African-American and Caucasian girls, and to examine associations between adolescent overweight and cardiovascular disease (CVD) risk factors. In the National Heart, Lung and Blood Institute Growth and Health Study (NGHS), annual measurements were obtained from girls followed longitudinally between age 9 or 10 and 18 years; self-reported measures were obtained at age 21 to 23 years. A total of 1166 Caucasian girls and 1213 African-American girls participated in the study. Childhood overweight as defined by the Centers for Disease Control and Prevention (CDC) was the independent variable of primary interest. Measured outcomes included blood pressure and lipid levels. Rates of overweight increased through adolescence from 7% to 10% in the Caucasian girls and from 17% to 24% in the African-American girls. The incidence of overweight was greater at age 9 to 12 than in later adolescence. Girls who were overweight during childhood were 11 to 30 times more likely to be obese in young adulthood. Overweight was significantly associated with increased percent body fat, sum of skinfolds and waist circumference measurements, and unhealthful systolic and diastolic blood pressure, high-density lipoprotein cholesterol, and triglyceride levels. A relationship between CVD risk factors and CDC-defined overweight is present at age 9.


Thermal dissociation of inter-layer excitons in MoS2/MoSe2 hetero-bilayers.
We describe photoluminescence (PL), PL excitation, and time-resolved PL spectroscopy of hetero-bilayers comprising monolayers (1L) of MoS2 and MoSe2 at cryogenic temperatures. A PL peak showing a decay time of 2.5 ns was observed below 100 K, which can be attributed to an inter-layer exciton emission in the 1L-MoS2/1L-MoSe2 hetero-bilayers. An inter-layer exciton binding energy of ∼90 meV is determined from its thermal dissociation behavior; the band offset of each layer obtained from this value is consistent with previously reported first-principles calculations. Moreover, generation of inter-layer charged excitons (trions) is implied from the gate modulation of the inter-layer exciton PL spectra.


Detection and interpretation of metabolite-transcript coresponses using combined profiling data.
Studying the interplay between gene expression and metabolite levels can yield important information on the physiology of stress responses and adaptation strategies. Performing transcriptomics and metabolomics in parallel during time-series experiments represents a systematic way to gain such information. Several combined profiling datasets have been added to the public domain and they form a valuable resource for hypothesis generating studies. Unfortunately, detecting coresponses between transcript levels and metabolite abundances is non-trivial: they cannot be assumed to overlap directly with underlying biochemical pathways and they may be subject to time delays and obscured by considerable noise. Our aim was to predict pathway comemberships between metabolites and genes based on their coresponses to applied stress. We found that in the presence of strong noise and time-shifted responses, a hidden Markov model-based similarity outperforms the simpler Pearson correlation but performs comparably or worse in their absence. Therefore, we propose a supervised method that applies pathway information to summarize similarity statistics to a consensus statistic that is more informative than any of the single measures. Using four combined profiling datasets, we show that comembership between metabolites and genes can be predicted for numerous KEGG pathways; this opens opportunities for the detection of transcriptionally regulated pathways and novel metabolically related genes. A command-line software tool is available at http://www.cin.ufpe.br/~igcf/Metabolites. firstname.lastname@example.com; firstname.lastname@example.com


The relationship of bottle feeding and other sucking behaviors with speech disorder in Patagonian preschoolers.
Previous studies have shown that children's nonnutritive sucking habits may lead to delayed development of their oral anatomy and functioning. However, these findings were inconsistent. We investigated associations between use of bottles, pacifiers, and other sucking behaviors with speech disorders in children attending three preschools in Punta Arenas (Patagonia), Chile. Information on infant feeding and sucking behaviors, age starting and stopping breast- and bottle-feeding, pacifier use, and other sucking behaviors, was collected from self-administered questionnaires completed by parents. Evaluation of speech problems was conducted at preschools with subsequent scoring by a licensed speech pathologist using age-normative standards. A total of 128 three- to five-year olds were assessed, 46% girls and 54% boys. Children were breastfed for an average of 25.2 (SD 9.6) months and used a bottle 24.4 (SD 15.2) months. Fifty-three children (41.7%) had or currently used a pacifier for an average of 11.4 (SD 17.3) months; 23 children (18.3%) were reported to have sucked their fingers. Delayed use of a bottle until after 9 months appeared to be protective for subsequent speech disorders. There was less than a one-third lower relative odds of subsequent speech disorders for children with a delayed use of a bottle compared to children without a delayed use of a bottle (OR: 0.32, 95% CI: 0.10-0.98). A three-fold increase in relative odds of speech disorder was found for finger-sucking behavior (OR: 2.99, 95% CI: 1.10-8.00) and for use of a pacifier for 3 or more years (OR: 3.42, 95% CI: 1.08-10.81). The results suggest extended use of sucking outside of breastfeeding may have detrimental effects on speech development in young children.


Dementia, Work and Employability: Using the Capability Approach to Understand the Employability Potential for People Living with Dementia.
The importance of remaining in, or re-entering, the labour market is emphasised by governments internationally. While this may bring benefits, progressive disabilities such as dementia affect an individual's employability. Although employers have legal obligations to support employees with disabilities, research suggests that employers are not providing this support to employees living with dementia and are undermining their capabilities. Drawing on interview data from 38 key informants collected over two studies, we explore the potential for supporting and promoting the employability of people living with dementia. A model of sustainable employability based on the Capability Approach is used as a lens to explore this issue. The findings demonstrate the implications of progressive disabilities for employability when the worker and their family are faced with dealing with a disability in a period of uncertainty with a lack of public and workplace understanding.


Canine granulocytic anaplasmosis: a review.
Anaplasma phagocytophilum is an emerging pathogen of humans, horses, and dogs worldwide that is transmitted by Ixodid ticks and maintained in a variety of small wild mammal species. Recent studies suggest that multiple strains of A. phagocytophilum may be circulating in wild and domestic animal populations, and these strains may have differential host tropisms and pathogenicity. The organism infects and survives within neutrophils by disabling key neutrophil functions, including neutrophil motility, phagocytosis, the oxidative burst mechanism, and neutrophil-endothelial cell interactions, as well as interfering with neutrophil apoptosis. Coinfections with other tick-borne pathogens may occur, especially Borrelia burgdorferi. A. phagocytophilum causes an acute febrile illness in dogs with lethargy and inappetence. Less frequent signs include lameness, coughing, polydipsia, intermittent vomiting, and hemorrhages. Diagnosis is based on finding morulae within granulocytes in the peripheral blood, the combination of acute and convalescent serology using immunofluorescent antibody techniques, and detection of the DNA of A. phagocytophilum using specific polymerase chain reaction assays. Whether persistent infection or reinfection with A. phagocytophilum occurs after natural infection requires additional study, with most reports suggesting that anaplasmosis is a self-limiting disease in dogs that responds well to a 2-week course of doxycycline therapy.


interRAI home care quality indicators.
This paper describe the development of interRAI's second-generation home care quality indicators (HC-QIs). They are derived from two of interRAI's widely used community assessments: the Community Health Assessment and the Home Care Assessment. In this work the form in which the quality problem is specified has been refined, the covariate structure updated, and two summary scales introduced. Two data sets were used: at the client and home-care site levels. Client-level data were employed to identify HC-QI covariates. This sample consisted of 335,544 clients from Europe, Canada, and the United States. Program level analyses, where client level data were aggregated at the site level, were also based on the clients from the samples from Europe, Canada, and the United States. There were 1,654 program-based observations - 22% from Europe, 23% from the US, and 55% from Canada.The first task was to identify potential HC-QIs, including both change and prevalence measures. Next, they were reviewed by industry representatives and members of the interRAI network. A two-step process adjustment was followed to identify the most appropriate covariance structure for each HC-QI. Finally, a factor analytic strategy was used to identify HC-QIs that cluster together and thus are candidates for summary scales. The set of risk adjusted HC-QIs are multi-dimensional in scope, including measures of function, clinical complexity, social life, distress, and service use. Two factors were identified. The first includes a set of eleven measures that revolve around the absence of decline. This scale talks about functional independence and engagement. The second factor, anchored on nine functional improvement HC-QIs, referenced positively, this scale indicates a return to clinical balance. Twenty-three risk-adjusted, HC-QIs are described. Two new summary HC-QI scales, the "Independence Quality Scale" and the "Clinical Balance Quality Scale" are derived. In use at a site, these two scales can provide a macro view of local performance, offering a way for a home care agency to understand its performance. When scales perform less positively, the site then is able to review the HC-QI items that make up the scale, providing a roadmap for areas of greatest concern and in need of targeted interventions.


Switchable Fe/Co Prussian blue networks and molecular analogues.
With the long term objective to build the next generation of devices from the molecular scale, scientists have explored extensively in the past two decades the Prussian blue derivatives and their remarkable physico-chemical properties. In particular, the exquisite Fe/Co system displays tuneable optical and magnetic behaviours associated with thermally and photo-induced metal-to-metal electron transfer processes. Recently, numerous research groups have been involved in the transfer of these electronic properties to new Fe/Co coordination networks of lower dimensionality as well as soluble molecular analogues in order to facilitate their manipulation and integration into devices. In this review, the most representative examples of tridimensional Fe/Co Prussian blue compounds are described, focusing on the techniques used to understand their photomagnetic properties. Subsequently, the different strategies employed toward the design of new low dimensional Prussian blue analogues based on a rational molecular building block approach are discussed emphasizing the advantages of these functional molecular systems.


Lost in centrifugation: accounting for transporter protein losses in quantitative targeted absolute proteomics.
In drug development, considerable efforts are made to extrapolate from in vitro and preclinical findings to predict human drug disposition by using in vitro-in vivo extrapolation (IVIVE) approaches. Use of IVIVE strategies linked with physiologically based pharmacokinetic (PBPK) modeling is widespread, and regulatory agencies are accepting and occasionally requesting model analysis to support licensing submissions. Recently, there has been a drive to improve PBPK models by characterizing the absolute abundance of enzymes, transporters, and receptors within mammalian tissues and in vitro experimental systems using quantitative targeted absolute proteomics (QTAP). The absolute abundance of proteins relevant to processes governing drug disposition provided by QTAP will enable IVIVE-PBPK to incorporate terms for the abundance of enzymes and transporters in target populations. However, most studies that report absolute abundances of enzymes and transporter proteins do so in enriched membrane fractions so as to increase the abundance per sample, and thus the assay's sensitivity, rather than measuring the expected lower abundance in the more biologically meaningful whole cells or tissues. This communication discusses the balance between protein enrichment and potential loss during the preparation of membrane fractions from whole cells or tissues. Accounting for losses with recovery factors throughout the fractionation procedure provides a means to correct for procedural losses, thereby enabling the scaling of protein abundance from subcellular fractions to whole-cell or organ abundances. PBPK models based on corrected abundances will more closely resemble biological systems and facilitate development of more meaningful IVIVE scaling factors, producing more accurate quantitative predictions of drug disposition.


Structural factors and best practices in implementing a linkage to HIV care program using the ARTAS model.
Implementation of linkage to HIV care programs in the U.S. is poorly described in the literature despite the central role of these programs in delivering clients from HIV testing facilities to clinical care sites. Models demonstrating success in linking clients to HIV care from testing locations that do not have co-located medical care are especially needed. Data from the Antiretroviral Treatment Access Studies-II project ('ARTAS-II') as well as site visit and project director reports were used to describe structural factors and best practices found in successful linkage to care programs. Successful programs were able to identify recently diagnosed HIV-positive persons and ensure that a high percentage of persons attended an initial HIV primary care provider visit within six months of enrolling in the linkage program. Eight categories of best practices are described, supplemented by examples from 5 of 10 ARTAS-II sites. These five sites highlighted in the best practices enrolled a total of 352 HIV+ clients and averaged 85% linked to care after six months. The other five grantees enrolled 274 clients and averaged 72% linked to care after six months. Sites with co-located HIV primary medical care services had higher linkage to care rates than non-co-located sites (87% vs. 73%). Five grantees continued linkage to care activities in some capacity after project funding ended. With the push to expand HIV testing in all U.S. communities, implementation and evaluation of linkage to care programs is needed to maximize the benefits of expanded HIV testing efforts.


Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner.
Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and diet factors. We used hens genotyped as FMO3 c.984 A>T as well as those with the homozygous normal genotype. For each genotype, hens were provided with either a corn-soybean meal basal diets (SM), which contains lower levels of TMA precursor, or the basal diets supplemented with 21% of rapeseed meal (RM), which contains higher levels of TMA precursor. An integrative analysis of metabolomic and transcriptomic was used to explore the metabolic patterns of FMO3 genetic variant in hens that were fed the two defined diets. In birds that consumed SM diets, the T329S mutation increased levels of plasma TMA and lipids, FMO3 mRNA levels, and the expression of genes involved in long chain polyunsaturated fatty acid biosynthesis. In birds that consumed RM diets, the T329S mutation induced fishy odor syndrome, a repression in LXR pathway and a reciprocal change in lipid metabolism. Variations in TMA and lipid metabolism were linked to the genetic variant in FMO3 in a diet-specific manner, which suggest FMO3 functions in TMA metabolism and lipid homeostasis. LXR pathway and polyunsaturated fatty acid metabolism are two possible mechanisms of FMO3 action in response to dietary TMA precursor.


Viewpoint: Carbon isotope effect predictions for enzymes involved in the primary carbon metabolism of plant leaves.
Carbon isotope effects of enzymes involved in primary carbon metabolism are key parameters in our understanding of plant metabolism. Nevertheless, some of them are poorly known because of the lack of in vitro experimental data on purified enzymes. Some studies have focused on theoretical predictions of isotope effects. Here we show how quantum chemical calculations can be adapted for calculation of isotope effects for the Rubisco-catalysed carboxylation and oxygenation reactions and the citrate synthase reaction. The intrinsic isotope effect of the carboxylation by Rubisco appears to be much smaller than previously thought, being close to the overall isotope effect of the reaction that is, between 25 and 30 per mil. The same applies to the enzyme citrate synthase, that catalyses the first step of the Krebs cycle, with an isotope effect of around 23 per mil. Combined with the isotope effects of equilibrium reactions calculated with β-factors, the Krebs cycle then has an overall isotope effect that depletes organic acids in 13C.


Microfluidic acoustophoretic force based low-concentration oil separation and detection from the environment.
Detecting and quantifying extremely low concentrations of oil from the environment have broad applications in oil spill monitoring in ocean and coastal areas as well as in oil leakage monitoring on land. Currently available methods for low-concentration oil detection are bulky or costly with limited sensitivities. Thus they are difficult to be used as portable and field-deployable detectors in the case of oil spills or for monitoring the long-term effects of dispersed oil on marine and coastal ecosystems. Here, we present a low-concentration oil droplet trapping and detection microfluidic system based on the acoustophoresis phenomenon where oil droplets in water having a negative acoustic contrast factor move towards acoustic pressure anti-nodes. By trapping oil droplets from water samples flowing through a microfluidic channel, even very low concentrations of oil droplets can be concentrated to a detectable level for further analyses, which is a significant improvement over currently available oil detection systems. Oil droplets in water were successfully trapped and accumulated in a circular acoustophoretic trapping chamber of the microfluidic device and detected using a custom-built compact fluorescent detector based on the natural fluorescence of the trapped crude oil droplets. After the on-line detection, crude oil droplets released from the trapping chamber were successfully separated into a collection outlet by acoustophoretic force for further off-chip analyses. The developed microfluidic system provides a new way of trapping, detecting, and separating low-concentration crude oil from environmental water samples and holds promise as a low-cost field-deployable oil detector with extremely high sensitivity. The microfluidic system and operation principle are expected to be utilized in a wide range of applications where separating, concentrating, and detecting small particles having a negative acoustic contrast factor are required.


A novel aldose-aldose oxidoreductase for co-production of D-xylonate and xylitol from D-xylose with Saccharomyces cerevisiae.
An open reading frame CC1225 from the Caulobacter crescentus CB15 genome sequence belongs to the Gfo/Idh/MocA protein family and has 47 % amino acid sequence identity with the glucose-fructose oxidoreductase from Zymomonas mobilis (Zm GFOR). We expressed the ORF CC1225 in the yeast Saccharomyces cerevisiae and used a yeast strain expressing the gene coding for Zm GFOR as a reference. Cell extracts of strains overexpressing CC1225 (renamed as Cc aaor) showed some Zm GFOR type of activity, producing D-gluconate and D-sorbitol when a mixture of D-glucose and D-fructose was used as substrate. However, the activity in Cc aaor expressing strain was >100-fold lower compared to strains expressing Zm gfor. Interestingly, C. crescentus AAOR was clearly more efficient than the Zm GFOR in converting in vitro a single sugar substrate D-xylose (10 mM) to xylitol without an added cofactor, whereas this type of activity was very low with Zm GFOR. Furthermore, when cultured in the presence of D-xylose, the S. cerevisiae strain expressing Cc aaor produced nearly equal concentrations of D-xylonate and xylitol (12.5 g D-xylonate l(-1) and 11.5 g D-xylitol l(-1) from 26 g D-xylose l(-1)), whereas the control strain and strain expressing Zm gfor produced only D-xylitol (5 g l(-1)). Deletion of the gene encoding the major aldose reductase, Gre3p, did not affect xylitol production in the strain expressing Cc aaor, but decreased xylitol production in the strain expressing Zm gfor. In addition, expression of Cc aaor together with the D-xylonolactone lactonase encoding the gene xylC from C. crescentus slightly increased the final concentration and initial volumetric production rate of both D-xylonate and D-xylitol. These results suggest that C. crescentus AAOR is a novel type of oxidoreductase able to convert the single aldose substrate D-xylose to both its oxidized and reduced product.


Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography.
We report a series of studies that assess the feasibility and sensitivity of imaging of herpes virus type one thymidine kinase (HSV1-tk) gene transfer and expression with [124I]-5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil ([124I]-FIAU) and positron emission tomography (PET) and the ability of [124I]-FIAU-PET imaging to discriminate different levels of HSV1-tk gene expression. Studies were performed in rats bearing multiple s.c. tumors derived from W256 rat carcinoma and RG2 rat glioma cells. In the first set, we tested the sensitivity of [124I]-FIAU-PET imaging to detect low levels of HSV1-tk gene expression after retroviral-mediated gene transfer. HSV1-tk gene transduction of one of preestablished wild-type W256 tumor in each animal was accomplished by direct intratumoral injection of retroviral vector-producer cells (W256-->W256TK* tumors). Tumors produced from W256 and W256TK+ cells served as the negative and positive control in each animal. Highly specific images of [124I]-FIAU-derived radioactivity were obtained in W256TK* tumors (that were transduced in vivo) and in W256TK+ tumors but not in nontransduced wild-type W256 tumors. The level of "specific" incorporated radioactivity in transduced portions of both W256TK* and W256TK+ tumors was relatively constant between 4 and 50 h. In the second set, we tested whether [124I]-FIAU and PET imaging can measure and discriminate between different levels of HSV1-tk gene expression. Multiple s.c. tumors were produced from wild-type RG2 cells and stably transduced RG2TK cell lines that express different levels of HSV1-tk. A highly significant relationship between the level of [124I]-FIAU accumulation [% injected dose/g and incorporation constant (Ki)] and an independent measure of HSV1-tk expression (sensitivity of the transduced tumor cells to ganciclovir, IC50) was demonstrated, and the slope of this relationship was defined as a sensitivity index. We have demonstrated for the first time that highly specific noninvasive images of HSV1-tk expression in experimental animal tumors can be obtained using radiolabeled 2'-fluoro-nucleoside [124I]-FIAU and a clinical PET system. The ability to image the location (distribution) of gene expression and the level of expression over time provides new and useful information for monitoring clinical gene therapy protocols in the future.


Apraxia and aphasia for a visual-gestural language.
Since signed languages utilize visual-gestural channels, their study allows a unique opportunity for insight into the ways language and gesture may be represented in the brain. The separability of apraxia and aphasia for sign language was examined in four deaf signers who had unilateral brain damage, three to the left hemisphere and one to the right hemisphere. These patients were administered various tests for apraxia and a test of pantomime recognition. The patient with damage to the right hemisphere was not apraxic as we would expect. For the patients with damage to the left hemisphere, all of whom were aphasic for sign language, strong dissociations emerged between their capacities for sign language and their nonlinguistic motor skills. The language deficits of these patients seemed related to specific linguistic components of sign language rather than to an underlying motor disorder or an underlying disorder in the capacity to express and comprehend symbols of any kind. This separation between linguistic and nonlinguistic function is all the more striking, because sign language and gesture are transmitted in the same modality.


Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha.
p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing. p105 can form various heterodimers with other NF-kappaB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IkappaB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKbeta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGPsi motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IkappaBalpha, -beta, and -epsilon. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules betaTrCP1 and betaTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKgamma, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.


The preparation of reach-to-grasp movements in adults, children, and children with movement problems.
This study explored the use of advance information in the control of reach-to-grasp movements. The paradigm required participants to reach and grasp illuminated blocks with their right hand. Four target blocks were positioned on a table surface, two each side of the mid-saggital plane. In the complete precue condition, advance information precisely specified target location. In the partial precue condition, advance information indicated target location relative to the midsaggital plane (left or right). In the null condition, the advance information was entirely ambiguous. Participants produced fastest responses in the complete precue condition, intermediate response times in the partial condition, and the slowest responses in the null condition. This result was observed in adults and four groups of children including a group aged 4-6 years. In contrast, children with Developmental Coordination Disorder (DCD, n=11, aged 7--13 years) showed no advantage of partial precueing. Movement duration was determined by target location but was unaffected by precue condition. Movement duration was a clear function of age apart from children in the DCD group who showed equivalent movement times to those of the youngest children. These findings provide important insights into the control of reach-to-grasp movements and highlight that partial cues are exploited by children as young as 4 years but are not used in situations of abnormal development.


Na+/Ca2+ exchange in coated microvesicles.
Coated microvesicles isolated from bovine neurohypophyses could be loaded with Ca2+ in two different ways, either by incubation in the presence of ATP or by imposition of an outwardly directed Na+ gradient. Na+, but not K+, was able to release Ca2+ accumulated by the coated microvesicles. These results suggest the existence of an ATP-dependent Ca2+-transport system as well as of a Na+/Ca2+ carrier in the membrane of coated microvesicles similar to that present in the membranes of secretory vesicles from the neurohypophysis. A kinetic analysis of transport indicates that the apparent Km for free Ca2+ of the ATP-dependent uptake was 0.8 microM. The average Vmax. was 2 nmol of Ca2+/5 min per mg of protein. The total capacity of microvesicles for Ca2+ uptake was 3.7 nmol/mg of protein. Both nifedipine (10 microM) and NH4Cl (50 mM) inhibited Ca2+ uptake. The ATPase activity in purified coated-microvesicles fractions from brain and neurohypophysis was characterized. Micromolar concentrations of Ca2+ in the presence of millimolar concentrations of Mg2+ did not change enzyme activity. Ionophores increasing the proton permeability across membranes activated the ATPase activity in preparations of coated microvesicles from brain as well as from the neurohypophysis. Thus the enzyme exhibits properties of a proton-transporting ATPase. This enzyme seems to be linked to the ion accumulation by coated microvesicles, although the precise coupling of the proton transport to Ca2+ and Na+ fluxes remains to be determined.


Ligand Redox Noninnocence in [CoIII(TAML)]0/- Complexes Affects Nitrene Formation.
The redox noninnocence of the TAML scaffold in cobalt-TAML (tetra-amido macrocyclic ligand) complexes has been under debate since 2006. In this work, we demonstrate with a variety of spectroscopic measurements that the TAML backbone in the anionic complex [CoIII(TAMLred)]- is truly redox noninnocent and that one-electron oxidation affords [CoIII(TAMLsq)]. Multireference (CASSCF) calculations show that the electronic structure of [CoIII(TAMLsq)] is best described as an intermediate spin (S = 1) cobalt(III) center that is antiferromagnetically coupled to a ligand-centered radical, affording an overall doublet (S = 1/2) ground-state. Reaction of the cobalt(III)-TAML complexes with PhINNs as a nitrene precursor leads to TAML-centered oxidation and produces nitrene radical complexes without oxidation of the metal ion. The ligand redox state (TAMLred or TAMLsq) determines whether mono- or bis-nitrene radical complexes are formed. Reaction of [CoIII(TAMLsq)] or [CoIII(TAMLred)]- with PhINNs results in the formation of [CoIII(TAMLq)(N•Ns)] and [CoIII(TAMLq)(N•Ns)2]-, respectively. Herein, ligand-to-substrate single-electron transfer results in one-electron-reduced Fischer-type nitrene radicals (N•Ns-) that are intermediates in catalytic nitrene transfer to styrene. These nitrene radical species were characterized by EPR, XANES, and UV-vis spectroscopy, high-resolution mass spectrometry, magnetic moment measurements, and supporting CASSCF calculations.


Considerations in the efficacy and effectiveness of virtual reality interventions for stroke rehabilitation: moving the field forward.
In the past 2 decades, researchers have demonstrated the potential for virtual reality (VR) technologies to provide engaging and motivating environments for stroke rehabilitation interventions. Much of the research has been focused on the exploratory phase, and jumps to intervention efficacy trials and scale-up evaluation have been made with limited understanding of the active ingredients in a VR intervention for stroke. The rapid pace of technology development is an additional challenge for this emerging field, providing a moving target for researchers developing and evaluating potential VR technologies. Recent advances in customized games and cutting-edge technology used for VR are beginning to allow for researchers to understand and control aspects of the intervention related to motivation, engagement, and motor control and learning. This article argues for researchers to take a progressive, step-wise approach through the stages of intervention development using evidence-based principles, take advantage of the data that can be obtained, and utilize measurement tools to design effective VR interventions for stroke rehabilitation that can be assessed through carefully designed efficacy and effectiveness trials. This article is motivated by the recent calls in the field of rehabilitation clinical trials research for carefully structured clinical trials that have progressed through the phases of research.


Methodology for estimating removable quantities of agricultural residues for bioenergy and bioproduct use.
A methodology was developed to estimate quantities of crop residues that can be removed while maintaining rain or wind erosion at less than or equal to the tolerable soil-loss level. Six corn and wheat rotations in the 10 largest corn-producing states were analyzed. Residue removal rates for each rotation were evaluated for conventional, mulch/reduced, and no-till field operations. The analyses indicated that potential removable maximum quantities range from nearly 5.5 million dry metric t/yr for a continuous corn rotation using conventional till in Kansas to more than 97 million dry metric t/yr for a corn-wheat rotation using no-till in Illinois.


Simultaneous extraction of acidic and basic drugs via on-chip electromembrane extraction using a single-compartment microfluidic device.
In this study, a new chip was designed for simultaneous extraction of acidic and basic drugs by a single chamber on-chip electromembrane extraction (CEME) followed by high performance liquid chromatography. Diclofenac (DIC) and nalmefene (NAL) were selected as acidic and basic model analytes, respectively. In this device, simultaneous extraction of the analytes was carried out using a single compartment. The chip was composed of three PMMA (polymethyl methacrylate) parts with sandwiched structures and carved spiral microfluidic channels in each part. The middle part was cut and an "M" pattern provided interfaces for contact between the sample solution flow and two porous polypropylene sheets on both sides. Two other parts had the same spiral channels dedicated to the corresponding acceptor phases of the acidic and basic analytes and were located at both sides. Each polypropylene sheet was impregnated with the appropriate organic solvent for the acidic and basic analytes. Two platinum electrodes connected to a power supply were mounted at the bottom of the acceptor channels. These electrodes provided the electrical fields across SLMs to extract the analytes from a single sample flow. When the extraction was completed, the acceptor solutions were collected, mixed, and then injected into the chromatographic system. The effective parameters on the extraction efficiency were investigated and optimized. Under the optimal conditions, the calibration curves were linear in the range of 9.0-500 μg L-1 for NAL and 11.0-500 μg L-1 for DIC with the coefficient of determination (R2) higher than 0.9913. The relative standard deviations (RSD%) based on five replicate measurements were less than 6.3%. LOD values were 4.0 and 3.0 μg L-1 for DIC and NAL, respectively. Finally, the method was successfully applied to determine DIC and NAL in the human urine samples and satisfactory results were obtained (recovery ≥90).


Molecular characterisation of Cryptosporidium isolates from pre-weaned calves in Romania: is there an actual risk of zoonotic infections?
Diarrheic fecal samples from 258 pre-weaned calves (1-30 day-old) from 9 dairy farms located in Banat region, Romania, were microscopically examined for the presence of Cryptosporidium oocysts. Overall, 65 (25%) samples were found positive. A higher percent of infection was recorded in calves aged between 8 and 14 days compared with other age categories (1-7, 8-14, 15-21 and 22-30 days; p<0.05). Genetic characterization was carried out on all Cryptosporidium-positive samples. After DNA extraction, Cryptosporidium species were determined by a nested PCR of the small subunit rRNA gene (18S) followed by RFLP analysis with SspI, VspI and MboII restriction enzymes. The restriction patterns showed that animals were infected with Cryptosporidium parvum. Subsequently, subtyping of 13 C. parvum isolates, based on sequence analysis of the 60 kDa glycoprotein (GP60) gene, showed 2 subtypes (IIaA15G2R1 and IIaA16G1R1) belonging to the subtype family IIa. This is the first molecular study of bovine Cryptosporidium infection in Romania.


Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016.
IntroductionEnterovirus A71 (EV-A71) is an emerging pathogen that causes a wide range of disorders including severe neurological manifestations. In the past 20 years, this virus has been associated with large outbreaks of hand, foot and mouth disease with neurological complications in the Asia-Pacific region, while in Europe mainly sporadic cases have been reported. In spring 2016, however, an EV-A71 outbreak associated with severe neurological cases was reported in Catalonia and spread further to other Spanish regions.AimOur objective was to investigate the epidemiology and clinical characteristics of the outbreak.MethodsWe carried out a retrospective study which included 233 EV-A71-positive samples collected during 2016 from hospitalised patients. We analysed the clinical manifestations associated with EV-A71 infections and performed phylogenetic analyses of the 3'-VP1 and 3Dpol regions from all Spanish strains and a set of EV-A71 from other countries.ResultsMost EV-A71 infections were reported in children (mean age: 2.6 years) and the highest incidence was between May and July 2016 (83%). Most isolates (218/233) were classified as subgenogroup C1 and 217 of them were grouped in one cluster phylogenetically related to a new recombinant variant strain associated with severe neurological diseases in Germany and France in 2015 and 2016. Moreover, we found a clear association of EV-A71-C1 infection with severe neurological disorders, brainstem encephalitis being the most commonly reported.ConclusionAn emerging recombinant variant of EV-A71-C1 was responsible for the large outbreak in 2016 in Spain that was associated with many severe neurological cases.


Severity of anxiety and work-related outcomes of patients with anxiety disorders.
This study examined associations between anxiety and work-related outcomes in an anxiety disorders clinic population, examining both pretreatment links and the impact of anxiety change over 12 weeks of treatment on work outcomes. Four validated instruments were used to also allow examination of their psychometric properties, with the goal of improving measurement of work-related quality of life in this population. Newly enrolled adult patients seeking treatment in a university-based anxiety clinic were administered four work performance measures: Work Limitations Questionnaire (WLQ), Work Productivity and Activity Impairment Questionnaire (WPAI), Endicott Work Productivity Scale (EWPS), and Functional Status Questionnaire Work Performance Scale (WPS). Anxiety severity was determined using the Beck Anxiety Inventory (BAI). The Clinical Global Impressions, Global Improvement Scale (CGI-I) was completed by patients to evaluate symptom change at a 12-week follow-up. Two severity groups (minimal/mild vs. moderate/severe, based on baseline BAI score) were compared to each other on work measures. Eighty-one patients provided complete baseline data. Anxiety severity groups did not differ in job type, time on job, job satisfaction, or job choice. Patients with greater anxiety generally showed lower work performance on all instruments. Job advancement was impaired for the moderate/severe group. The multi-item performance scales demonstrated better validity and internal consistency. The WLQ and the WPAI detected change with symptom improvement. Level of work performance was generally associated with severity of anxiety. Of the instruments tested, the WLQ and the WPAI questionnaire demonstrated acceptable validity and internal reliability.


Nuclear magnetic resonance solution structure of the Escherichia coli DNA polymerase III theta subunit.
The catalytic core of Escherichia coli DNA polymerase III holoenzyme contains three subunits: alpha, epsilon, and theta. The alpha subunit contains the polymerase, and the epsilon subunit contains the exonucleolytic proofreading function. The small (8-kDa) theta subunit binds only to epsilon. Its function is not well understood, although it was shown to exert a small stabilizing effect on the epsilon proofreading function. In order to help elucidate its function, we undertook a determination of its solution structure. In aqueous solution, theta yielded poor-quality nuclear magnetic resonance spectra, presumably due to conformational exchange and/or protein aggregation. Based on our recently determined structure of the theta homolog from bacteriophage P1, named HOT, we constructed a homology model of theta. This model suggested that the unfavorable behavior of theta might arise from exposed hydrophobic residues, particularly toward the end of alpha-helix 3. In gel filtration studies, theta elutes later than expected, indicating that aggregation is potentially responsible for these problems. To address this issue, we recorded 1H-15N heteronuclear single quantum correlation (HSQC) spectra in water-alcohol mixed solvents and observed substantially improved dispersion and uniformity of peak intensities, facilitating a structural determination under these conditions. The structure of theta in 60/40 (vol/vol) water-methanol is similar to that of HOT but differs significantly from a previously reported theta structure. The new theta structure is expected to provide additional insight into its physiological role and its effect on the epsilon proofreading subunit.


Determination of the correlation between physical measurements of roughness, optical properties, and perception of frosted glass surfaces.
Chemical frosting is used as a surface decorating method by many glass package producers. After immersion in an acid frosting bath, glass items present the desired frosted effect. The perception of this particular effect is due to the formation of a microscopic crystalline pattern on the glass surface, which scatters light passing through the glass surface. The chemical composition of the frosting bath influences these properties by modifying the surface roughness, the depth, and the average slopes of the crystalline pattern. Perception of the final aspect can be modified according to the chemical composition of the frosting bath. Different correlations between all these parameters exist and have been quantified.


Improving outcomes for patients with acute myeloid leukemia in first relapse: a single center experience.
The outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory, with few available effective therapies. Increased understanding of the biology of the disease has led to the identification of novel therapeutic agents, several of which have been evaluated in recently conducted clinical trials. We sought to determine whether the introduction of these agents as well as modern supportive care measures has already translated to better outcomes. We examined the outcomes of 1,056 patients with AML in first relapse treated between January 1993 and December 2013 at our institution. As previously reported, the independent prognostic factors for survival after first relapse included age at relapse, cytogenetics, and duration of first complete remission. Upon multivariable analysis, treatment era was an independent predictor of survival, with significant improvement in overall survival between 2008 and 2013 as compared to prior time periods. Modern supportive care measures as well as participation in clinical trials of novel agents are already improving the outcomes in first relapse.


Interlaboratory Comparison Study on Ribodepleted Total RNA High-Throughput Sequencing for Plant Virus Diagnostics and Bioinformatic Competence.
High-throughput sequencing (HTS) technologies and bioinformatic analyses are of growing interest to be used as a routine diagnostic tool in the field of plant viruses. The reliability of HTS workflows from sample preparation to data analysis and results interpretation for plant virus detection and identification must be evaluated (verified and validated) to approve this tool for diagnostics. Many different extraction methods, library preparation protocols, and sequence and bioinformatic pipelines are available for virus sequence detection. To assess the performance of plant virology diagnostic laboratories in using the HTS of ribosomal RNA depleted total RNA (ribodepleted totRNA) as a diagnostic tool, we carried out an interlaboratory comparison study in which eight participants were required to use the same samples, (RNA) extraction kit, ribosomal RNA depletion kit, and commercial sequencing provider, but also their own bioinformatics pipeline, for analysis. The accuracy of virus detection ranged from 65% to 100%. The false-positive detection rate was very low and was related to the misinterpretation of results as well as to possible cross-contaminations in the lab or sequencing provider. The bioinformatic pipeline used by each laboratory influenced the correct detection of the viruses of this study. The main difficulty was the detection of a novel virus as its sequence was not available in a publicly accessible database at the time. The raw data were reanalysed using Virtool to assess its ability for virus detection. All virus sequences were detected using Virtool in the different pools. This study revealed that the ribodepletion target enrichment for sample preparation is a reliable approach for the detection of plant viruses with different genomes. A significant level of virology expertise is needed to correctly interpret the results. It is also important to improve and complete the reference data.


Intravenous transplantation of bone marrow-derived mononuclear cells prevents memory impairment in transgenic mouse models of Alzheimer's disease.
Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimer's disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-β (Aβ) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow-derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Aβ deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy.


γ-Silylboronates in the chiral Brønsted acid-catalysed allylboration of aldehydes.
The use of functionalised allylboronic esters in the catalytic enantioselective allylboration of aldehydes is described for the first time. γ-Silylallyl pinacolate derivatives give rise to α-silyl homoallylic alcohols in high yields, with complete diastereoselectivities and high enantioselectivities, in most of the cases. The usefulness of such intermediates is showcased by their transformation into fluorinated allylic alcohols.


Mood and sexual side effects of hormonal contraception: physicians' and residents' knowledge, attitudes, and practices.
To explore physicians' knowledge, attitudes, and practices related to sexual and mood side effects of hormonal contraceptives, and to compare residents with practising doctors. A mixed-method study with faxed or e-mailed surveys and semistructured telephone interviews. British Columbia. A random sample of family doctors, all gynecologists, and all residents in family medicine and gynecology in the College of Physicians and Surgeons of British Columbia registry. A subsample was interviewed. Estimates of rates of mood and sexual side effects of contraceptives in the practice population and how the physicians informed and advised patients about these side effects. There were 79 residents and 76 practising doctors who completed the questionnaires (response rates of 42.0% and 54.7% of eligible residents and physicians, respectively). The reference sources most physicians reported using gave the rates of sexual and mood side effects of hormonal contraceptives as less than 1%, and yet only 1 (0.6%) respondent estimated similar rates for mood side effects, and 12 (7.8%) for sexual effects among their patients. The most common answers were rates of 5% to 10%, with residents reporting similar rates to practising doctors. Practising doctors were more likely to ask about sexual and mood side effects than residents were (81.1% vs. 24.1% and 86.3% vs. 40.5%, respectively; P < .001). Practising doctors were also more likely to recommend switching to barrier methods (37.3% vs. 16.5%; P = .003) or intrauterine devices (54.7% vs. 38.0%; P = .038) than residents were and more likely to give more responses to the question about how they managed sexual and mood side effects (mean of 1.7 vs. 1.1 responses, P = .001). In 14 of the 15 interviews, practising doctors discussed how they had learned about side effects mainly from their patients and how this had changed their practices. Physicians' perceived rates of mood and sexual side effects from hormonal contraception in the general population were higher than the rate of less than 1% quoted in the product monographs. Practising doctors reported that they learned about the type, frequency, and severity of side effects from their patients.


Flavonoid-membrane interactions: a protective role of flavonoids at the membrane surface?
Flavonoids can exert beneficial health effects through multiple mechanisms. In this paper, we address the important, although not fully understood, capacity of flavonoids to interact with cell membranes. The interactions of polyphenols with bilayers include: (a) the partition of the more non-polar compounds in the hydrophobic interior of the membrane, and (b) the formation of hydrogen bonds between the polar head groups of lipids and the more hydrophilic flavonoids at the membrane interface. The consequences of these interactions are discussed. The induction of changes in membrane physical properties can affect the rates of membrane lipid and protein oxidation. The partition of certain flavonoids in the hydrophobic core can result in a chain breaking antioxidant activity. We suggest that interactions of polyphenols at the surface of bilayers through hydrogen bonding, can act to reduce the access of deleterious molecules (i.e. oxidants), thus protecting the structure and function of membranes.


Firm rib mass aspirate from a dog.
A 9-year-old intact male Miniature Schnauzer presented laterally recumbent, cachexic, and dehydrated with multiple firm bone masses and a bilaterally enlarged prostate. Fine-needle aspiration of a rib mass revealed numerous basophilic polygonal to fusiform cells predominantly found in small to large clusters. The cells exhibited cytologic criteria of malignancy and infrequently displayed large cytoplasmic vacuoles containing finely- to coarsely-stippled azurophilic material. The cytologic diagnosis was metastatic adenocarcinoma and was suspected to be prostatic or transitional cell in origin because of the azurophilic vacuoles within malignant cells. Gross and histologic findings confirmed the clinical and cytologic diagnosis of prostatic adenocarcinoma with widespread metastasis. Cytochemical and immunohistochemical investigation confirmed glycogen was a component of the vacuolar material. The vacuoles observed in the tumor in this case are not a consistent finding in tumors of the prostate or urinary bladder; however, when associated with an epithelial tumor, they may aid in limiting the differentials of the primary tumor and in the selection of further diagnostics.


Anatomic Considerations in the Lateral Transpsoas Interbody Fusion: The Impact of Age, Sex, BMI, and Scoliosis.
This is a retrospective case series. Define the anatomic variations and the risk factors for such within the operative corridor of the transpsoas lateral interbody fusion. The lateral interbody fusion approach has recently been associated with devastating complications such as injury to the lumbosacral plexus, surrounding vasculature, and bowel. A more comprehensive understanding of anatomic structures in relation to this approach using preoperative imaging would help surgeons identify high-risk patients potentially minimizing these complications. Age-sex distributed, naive lumbar spine magnetic resonance imagings (n=180) were used to identify the corridor for the lateral lumbar interbody approach using axial images. Bilateral measurements were taken from L1-S1 to determine the locations of critical vascular, intraperitoneal, and muscular structures. In addition, a subcohort of scoliosis patients (n=39) with a Cobb angle >10 degrees were identified and compared. Right-sided vascular anatomy was significantly more variant than left (9.9% vs. 5.7%; P=0.001). There were 9 instances of "at-risk" vasculature on the right side compared with 0 on the left (P=0.004). Age increased vascular anatomy variance bilaterally, particularly in the more caudal levels (P≤0.001). A "rising-psoas sign" was observed in 26.1% of patients. Bowel was identified within the corridor in 30.5% of patients and correlated positively with body mass index (P<0.001). Scoliosis increased variant anatomy of left-sided vasculature at L2-3/L3-4. Nearly all variant anatomy in this group was found on the convex side of the curvature (94.2%). Given the risks and complications associated with this approach, careful planning must be taken with an understanding of vulnerable anatomic structures. Our analysis suggests that approaching the intervertebral space from the patient's left may reduce the risk of encountering critical vascular structures. Similarly, in the setting of scoliosis, an approach toward the concave side may have a more predictable course for surrounding anatomy. Level 3-study.