Heart rate regulation by G proteins acting on the cardiac pacemaker channel.
Heart rate is determined by pacemaker currents, of which the most important is the hyperpolarization-activated current I(f). Heart rate and I(f) are increased by beta-adrenergic agonists and decreased by muscarinic agonists released from cardiac sympathetic and vagal nerves, respectively. The hypothesis that the receptors for each agonist are directly coupled to I(f) channels by G proteins was tested. Under substrate-free conditions, preactivated G protein Gs stimulated and preactivated G protein G(o) inhibited I(f) channels of sinoatrial node pacemaker cells. These effects were mimicked by the corresponding preactivated alpha subunits of the G proteins. Unexpectedly, the two G proteins acted simultaneously, with G(o) being the more potent. This result may explain in molecular terms the classical observation in cardiac physiology, that vagal inhibition of heart rate is much greater on a background of sympathetic stimulation.


Transcriptional repression of Bim by a novel YY1-RelA complex is essential for the survival and growth of Multiple Myeloma.
Multiple Myeloma (MM) is an incurable plasma cell cancer that is caused by several chromosomal translocations and gene deletions. Although deregulation of several signaling pathways including the Nuclear Factor-Kappa B (NF-κB) pathway has been reported in MM, the molecular requirement and the crosstalk between NF-κB and its target genes in MM cell survival has been largely unclear. Here, we report that Yin Yang1 (YY1), a target gene for NF-κB, is hyperexpressed in most MM tumor cells obtained from human patients, exhibits constitutive nuclear localization, and is essential for survival of MM cells. Mechanistically, we report a novel YY1-RelA complex formation, which is essential to transcriptionally repress a proapoptotic gene Bim. In line with this, depletion of YY1 or RelA resulted in elevated levels of Bim and apoptosis. Moreover, both YY1 and RelA are recruited to the Bim promoter and are required to repress the Bim promoter. Importantly, depletion of YY1 or RelA almost completely impaired the colony forming ability of MM progenitor cells suggesting that both RelA and YY1 are essential for the survival and growth of MM progenitor cells. Moreover, depletion of either YY1 or RelA completely inhibited MM tumor growth in xenograft models for human myeloma. Thus, a novel RelA-YY1 transcriptional repression complex is an attractive drug target in MM.


Devices for endometrial sampling. A comparison.
To compare the clinical performance of two endometrial sampling devices, the GynoSampler and Pipelle. During a single office visit, gynecology patients at Women's Hospital, Los Angeles, and the teaching clinic of the University of Florida Health Science Center, Jacksonville, underwent two endometrial biopsies, one with each device. The specimen adequacy, pain associated with the sampling procedure and ease of use of the two devices were compared. One hundred women, 50 at each clinical center, were evaluated. No significant differences in specimen adequacy were noted, with at least 90% of specimens retrieved with each device sufficient for diagnosis. Patient discomfort ratings were similar for the two devices. However, physicians performing the biopsies noted that the GynoSampler device was easier to use than the Pipelle based on three parameters (P < .05). Although the GynoSampler and Pipelle appear comparable from the perspectives of diagnostic performance and patient discomfort, the GynoSampler was easier to use.


[Effects of leukemia inhibitory factor combined with basic fibroblast growth factor on proliferation and differentiation of human bone marrow mesenchymal stem cells].
To study the effects of leukemia inhibitory factor (LIF) and basic fibroblast growth factor (bFGF) on the proliferation and differentiation of human bone marrow mesenchymal stem cells (hBMSCs). hBMSCs at passage 4 were divided into 4 groups according to different culture conditions: cells were treated with complete medium (a-MEM containing 10%FBS, group A), with complete medium containing 10 ng/mL LIF (group B), with complete medium containing 10 ng/mL bFGF (group C), and with complete medium containing 10 ng/mL LIF and 10 ng/mL bFGF (group D). The growth curves of hBMSCs at passage 4 in different groups were assayed by cell counting kit 8; cellular morphologic changes were observed under inverted phase contrast microscope; the surface markers of hBMSCs at passage 8 including CD44, CD90, CD19, and CD34 were detected by flow cytometry. The cell growth curves of each group were similar to the S-shape; the cell proliferation rates in 4 groups were in sequence of group D > group C > group B > group A. Obvious senescence and differentiation were observed very early in group A, cells in group B maintained good cellular morphology at the early stage, with slow proliferation and late senescence; a few cells in group C differentiated into nerve-like cells, with quick proliferation; and the cells in group D grew quickly and maintained cellular morphology of hBMSCs. The expressions of CD44 and CD90 in groups A and C at passage 8 cells were lower than those of groups B and D; the expressions of CD19 and CD34 were negative in 4 groups, exhibiting no obvious difference between groups. LIF combined with bFGF can not only maintain multiple differentiation potential ofhBMSCs, but also promote proliferation of hBMSCs.


Hypertonic saline dextran resuscitation of thermal injury.
Burn treatment requires large volumes of crystalloid, which may exacerbate burn-induced cardiopulmonary dysfunction. Small-volume hypertonic saline dextran (HSD) resuscitation has been used for effective treatment of several types of shock. In this study isolated coronary perfused guinea pig hearts were used to determine if HSD improved left ventricular contractile response to burn injuries. Parameters measured included left ventricular pressure (LVP) and maximal rate of LVP rise (+dP/dt max) and fall (-dP/dt max) at a constant preload. Third-degree scald burns comprising 45% of total body surface area (burn groups, N = 75), or 0% for controls (group 1, N = 25) were produced using a template device. In group 2, 25 burned guinea pigs were not fluid resuscitated and served as untreated burns; 20 burns were resuscitated with 4 mL lactated Ringer's (LR) solution/kg/% burn for 24 hours (group 3); additional burn groups were treated with an initial bolus of HSD (4 mL/kg, 2400 mOsm, sodium chloride, 6% dextran 70) followed by either 1, 2, or 4 mL LR/kg/% burn over 24 hours (groups 4, 5, and 6, respectively). Untreated burn injury significantly impaired cardiac function, as indicated by a fall in LVP (from 88 +/- 3 to 68 +/- 4 mmHg; p = 0.01) and +/- dP/dt max (from 1352 +/- 50 to 1261 +/- 90 and from 1150 +/- 35 to 993 +/- 59; p = 0.01, respectively) and a downward shift of LV function curves from those obtained from control hearts. Compared to untreated burns, hearts from burned animals treated with LR alone showed no significant improvement in cardiac function. However hearts from burned animals treated with HSD + 1 mL LR/kg/% burn had significantly higher LVP (79 +/- 4 vs. 68 +/- 4 mmHg, p = 0.01) and +/- dP/dt max (+dP/dt: 1387 +/- 60 vs. 1261 +/- 90 mmHg/sc, p = 0.01; -dP/dt: 1079 +/- 50 vs. 993 +/- 59 mmHg/sc, p = 0.01) than hearts from untreated burned animals and generated left ventricular function curves comparable to those calculated for hearts from control animals. Mortality 24 hours after burn was 29% for untreated burns was 0% for control animals, as well as for groups treated with the Parkland formula or HSD plus 1 or 2 mL/kg/% burn lactated Ringer's. The only deaths after treatment occurred in those animals given HSD plus 4 mL/kg/% burn, Parkland formula (17% mortality).(ABSTRACT TRUNCATED AT 400 WORDS)


The pattern of RNA integrity and the expression of housekeeping genes are influenced by sodium hypochlorite and ascorbic acid.
Basic biological science research deals with nucleic acid isolation. Post-isolation nucleic acid integrity has a pivotal role in further elucidating gene expression and other molecular mechanisms. RNA (ribonucleic acid), cDNA (complementary deoxyribonucleic acid), and PCR (Polymerase chain reaction) products' integrity and quality are affected by several factors in biochemical and biophysical degradation modes. Inadequate evidence was noted about the direct effects of sodium hypochlorite and L-ascorbic acid. This study aims to test the effects of sodium hypochlorite (SHC) and L-ascorbic acid (LAA) in total RNA and PCR products, respectively, in an acellular condition. The study was categorized into three steps total RNA, cDNA, and PCR product evaluations. mBM-MSCs were used to extract RNA and then treated with SHC. Crude total RNA and, after DNase 1 treatment, the bands of total RNA samples were visualized by agarose gel electrophoresis. cDNAs were synthesized from SHC-treated (0.25%) and untreated RNAs, which were also expressed on the gel. LAA (5 µM, 15 µM, 25 µM, and 50 µM) were added to cDNAs synthesized from SHC- and non-SHC-treated samples. Housekeeping genes, Gapdh (Glyceraldehyde 3-phosphate dehydrogenase), and 18S rRNA (18S Ribosomal ribonucleic acid) were amplified in both groups. SHC-treated samples produced clearer bands on an agarose gel. Its treatment did not affect the integrated densities of agarose bands which revealed non-significant (P ≤ 0.05) differences in SHC-treated, untreated RNA, and cDNA. However, significant variations were observed at the PCR level. SHC-treated samples expressed decreased housekeeping gene expression in amplified products (Gapdh and 18S rRNA) and slightly but non-significantly high band intensities appeared in the presence of LAA. Significant variable differences (*P ≤ 0.05) were observed between SHC-treated and non-treated groups after LAA treatment. SHC (0.25%) is favorable in removing RNases and maintaining the integrity of RNA. cDNA synthesis did not affect by SHC treatment, and it follows the same as untreated samples after DNase 1 treatment. LAA drew a positive impact to improve the quality of PCR products in terms of band intensities, which is insignificant in SHC-treated RNA. Interestingly, it was revealed from our study that 5-25 µM LAA has the most beneficial role in the acquisition of PCR products, i.e. gene expression. These concentrations can be safely used to improve the quality of gene expression. This phenomenon can be used to achieve other, rarer, desired gene expressions. Further research is needed to explore the effects of SHC on the acquisition of PCR products using other solutions.


Solution conformation of N-terminal fragments of trichosanthin small domain (TCS 182-200). Circular dichroic studies.
Three peptides, T14, T18 and TDK, derived from the N-terminus of trichosanthin small domain (TCS 182-200) have been investigated by circular dichroism. Secondary structure and structural transitions of the above peptides under different conditions were studied. Alcohol prompts a transition of the T18 peptide from a beta-sheet to an alpha-helical structure. It also increases the alpha-helicities of T14 and TDK. The beta-sheet of T18 peptide appears more hydrophobic than the alpha-helix of T14 or TDK. The effects of polypeptide sequence and solvent on secondary structure formation of these model peptides are discussed.


Two-dimensional wavelet transform by wavelength multiplexing.
The wavelet transform is a useful tool for data compression, analysis of short transient pulses, optical correlators, etc. This transform was obtained optically by the use of the spatial or temporal multiplexing approaches. A two-dimensional wavelet transform is obtained with only one spatial channel. The information of the different scalings is carried in different wavelengths and summed incoherently at the output plane. Laboratory experimental results are demonstrated.


Development of a three dimensional, lattice-free multiscale model of the mammary terminal end bud.
The terminal end bud (TEB) is a bulbous structure composed of highly proliferative cells that is responsible for mammary gland development during the pubertal stage. This is a highly organized process, involving cellular differentiation hierarchies regulated by endocrine and paracrine signaling. Here, we present development of a lattice-free, three dimensional multiscale agent based model of the TEB to study the effects of cellular phenotypic hierarchies, endocrine and paracrine signaling, and proliferation demographics on pubertal mammary gland development. Cells in the TEB experience complex physical interaction during the active growth involved in pubertal ductal elongation, which we represent mathematically based on the physical forces involved in cell-cell and cell-microenvironment interactions. We observe that maximum ductal elongation rates are achievable due to each progenitive phenotype cell only undergoing a couple proliferation cycles before losing the progenitive capability, and that molecular signaling is necessary to restrict ductal elongation to biologically relevant rates. Cellular proliferation and growth is sufficient to achieve these elongation rates in the absence of other cellular behaviors such as migration or conformational changes. This model serves as a valuable tool to gain insights into the cell population dynamics of mammary gland development, and can serve as a foundation to study the early stages of breast cancer development based on endocrine-mediated phenotypic population shifts.


Level of agreement between physician and patient assessment of non-medical health factors.
GPs need to consider assorted relevant non-medical factors, such as family or work situations or health insurance coverage, to determine appropriate patient care. If GPs' knowledge of these factors varies according to patients' social position, less advantaged patients might receive poorer care, resulting in the perpetuation of social inequalities in health. To assess social disparities in GPs' knowledge of non-medical factors relevant to patient care. Observational survey of GPs who supervise internships in the Paris metropolitan area. Each of the 52 enrolled GPs randomly selected 70 patients from their patient list. Their knowledge of five relevant factors (coverage by publicly funded free health insurance, or by supplementary health insurance, living with a partner, social support and employment status) was analysed as the agreement between the patients' and GPs' answers to matching questions. Occupational, educational and financial disparities were estimated with multilevel models adjusted for age, sex, chronic disease and GP-patient relationship. Agreement varied according to the factor considered from 66% to 91%. The global agreement score (percentage of agreement for all five factors) was 72%. Social disparities and often gradients, disfavouring the less well-off patients, were observed for each factor considered. Social gradients were most marked according to perceived financial situation and for health insurance coverage. GPs must be particularly attentive toward their least advantaged patients, to be aware of the relevant non-medical factors that affect these patients' health and care, and thus provide management adapted to each individual's personal situation.


The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21Cip1 and p27Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post-translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21Cip1 and p27Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects . Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS.


Biochemical characterization of the nuclease StoNurA from the hyperthermophilic archaeon Sulfolobus tokodaii.
The DNA nuclease gene ST2109 has been cloned from the hyperthermophilic archaeon Sulfolobus tokodaii and expressed in Escherichia coli. The recombinant protein StoNurA has been purified to homogeneity by affinity chromatography and gel filtration chromatography. Biochemical analyses demonstrated that StoNurA exhibited DNA binding and 5'-3' exonuclease activities towards ssDNA and dsDNA. The temperature and pH optima of StoNurA were determined to be 65 °C and 8.0, respectively. The activity of StoNurA was found to be dependent of Mn2+, and its half-life of heat inactivation at 100 °C was 5 min. Gel filtration chromatography revealed that StoNurA could form dimers in solution. Pull-down assays also showed that StoNurA physically interacted with a DNA helicase (StoHerA). Our data suggest that NurA may play a key functional role in the processing of DNA recombinational repair.


Protein composition of the human heart: the construction of a myocardial two-dimensional electrophoresis database.
Molecular changes occurring in myocardial diseases are not well understood. Proteins, as regulatory molecules, should play an important role in the etiology of these diseases. The method of two-dimensional electrophoresis (2-DE) allows the analysis of some thousand proteins with one experiment. An important prerequisite for this kind of investigation is the possibility of identifying the proteins separated by 2-DE. We resolve 3239 proteins of the human myocardium and tried to identify 33 proteins by amino acid analysis and microsequencing. Twenty proteins were identified by search for the protein-chemical data obtained in the Martinsried Institute Protein Sequence Database. Comparisons of 2-DE patterns of different size, which were obtained in different laboratories, were performed with the result that proteins identified on a 2-DE map of one laboratory can be assigned to spots of 2-DE maps produced by another laboratory. Our results show the usefulness of a myocardial 2-DE database; they can be used in different laboratories and make it possible to generate a collection of important human myocardial proteins in a 2-DE database for comparative studies worldwide.


Two-step yielding and directional strain-induced strengthening in dilute colloidal gels.
We investigate the nonlinear rheology of dilute, depletion-induced colloidal gels and report that these systems yield via a two-step process. We propose the two yield points to be associated with interparticle bond rotation and bond breakage, respectively. These distinct yielding mechanisms lead to remarkable creep profiles at intermediate values of the applied stress, highlighted by an anisotropic shear-induced strengthening and flow arrest at very large accumulated strains (γ∼ 80). The possible microstructural origins of this behavior are discussed.


Modulation of the Innate Immune Response through the Vagus Nerve.
The innate immune system is a defense mechanism that is of vital importance to our survival. However, excessive or unwanted activation of the innate immune system, which can occur in major surgery, sepsis, trauma, ischemia-reperfusion injury and autoimmune diseases, can lead to damage of the kidneys and other organs. Therefore, therapeutic approaches aimed at attenuating the innate immune response could have beneficial effects in these conditions. The vagus nerve exerts anti-inflammatory effects through the so-called cholinergic anti-inflammatory pathway. Since its discovery, numerous animal studies have shown beneficial effects of stimulation of this pathway in models of inflammatory diseases, either through (electrical) stimulation of the vagus nerve or pharmacological approaches. However, human data are very scarce. In this review, we present an overview of the molecular and anatomical bases of the cholinergic anti-inflammatory pathway, but mainly focus on human studies. We discuss the difficulties and drawbacks associated with investigating this pathway in humans, and finally, we provide future perspectives.


New Frameworks for Understanding Sudden Unexpected Deaths in Infancy (SUDI) in Socially Vulnerable Families.
Sociological frameworks may enhance understanding of the complex and multidimensional nature of disadvantage, which is prevalent among families who experience Sudden Unexpected Death in Infancy (SUDI). SUDI is the largest category of postneonatal death and largely associated with the social determinants of health. The highly successful 'Back to Sleep' campaign has resulted in a more than 85% decrease in SUDI. However, social inequalities have accompanied this decrease, and the burden of SUDI now lies with the most disadvantaged and socially vulnerable families. A considerable body of research on the phenomena of SUDI and disadvantage has been published over the last decade, demonstrating the widening social gradient in SUDI, and the importance in recognising structural factors and the multifactorial nature of disadvantage. Gaps in understanding of risk factors and scepticism about the received wisdom of health professionals have emerged as central themes in understanding why socially vulnerable families may adopt unsafe infant care practices. The direct impact of social disadvantage on infant care has also been recognised. The translation of epidemiological findings regarding SUDI risk into public health recommendations for health professionals and families alike has to date focused on eliminating individual level risk behaviours. Unfortunately, such a model largely ignores the broader social, cultural, and structural contexts in which such behaviours occur. Translating the new knowledge offered by sociological frameworks and the principles of behavioural economics into evidence based interventions may assist in the reduction of SUDI mortality in our most socially vulnerable families.


Despite Blocking Doxorubicin-Induced Vascular Damage, Quercetin Ameliorates Its Antibreast Cancer Activity.
Quercetin is a naturally occurring flavonol present in many foods. Doxorubicin is an effective anticancer agent despite its dose-limiting cardiovascular toxicity. Herein, we investigated the potential protective effects of quercetin against doxorubicin-induced vascular toxicity and its effect on the therapeutic cytotoxic profile of doxorubicin in breast cancer cell lines. The incubation of isolated aortic rings with doxorubicin produced concentration-dependent exaggeration of vasoconstriction responses to phenylephrine but impaired vasodilation responses to acetylcholine. Coincubation with quercetin completely blocked the exaggerated vasoconstriction responses and the impaired vasodilation. In addition, doxorubicin incubation increased reactive oxygen species generation from the isolated aorta, while coincubation with quercetin inhibited ROS generation back to normal values. On the other hand, quercetin in combination with doxorubicin, doubled the IC50 of doxorubicin alone in MCF-7 cells from 0.4 ± 0.03 to 0.8 ± 0.06 μM. To a lesser extent, the IC50 of doxorubicin did not change after combination with quercetin in MDA-MB-231 cells. These findings indicate a significant antagonistic interaction between quercetin and doxorubicin in the aforementioned cell lines. Only in T47D cells, quercetin combination with doxorubicin was an additive interaction (CI - value = 1.17). Yet, quercetin significantly impaired the immediate phase of intracellular ROS generation by doxorubicin within breast cancer cells from 125.2 ± 3.6% to 102.5 ± 3.9% of control cells. Using annexin-V/FITC staining technique, the quercetin/doxorubicin combination showed a significantly lower percent of apoptotic cells compared to doxorubicin alone treated cells. Cell cycle distribution in breast cancer cells was performed using DNA content flowcytometry after propidium iodide staining. Quercetin induced significant accumulation of cells in the S phase as well as in the G2/M phase within both MCF-7 and MDA-MB-231 cell lines and interfered with doxorubicin-induced cell cycle effects. Interestingly, quercetin was found to inhibit the P-glycoprotein ATPase subunit with a consequent enhanced intracellular concentration of doxorubicin in MDA-MB-231 and T47D cells. In conclusion, quercetin, despite its potent vascular protective activity against doxorubicin, was found to influence doxorubicin-induced antibreast cancer effects via pharmacodynamic as well as cellular pharmacokinetic aspects.


Connected Filtering on Tree-Based Shape-Spaces.
Connected filters are well-known for their good contour preservation property. A popular implementation strategy relies on tree-based image representations: for example, one can compute an attribute characterizing the connected component represented by each node of the tree and keep only the nodes for which the attribute is sufficiently high. This operation can be seen as a thresholding of the tree, seen as a graph whose nodes are weighted by the attribute. Rather than being satisfied with a mere thresholding, we propose to expand on this idea, and to apply connected filters on this latest graph. Consequently, the filtering is performed not in the space of the image, but in the space of shapes built from the image. Such a processing of shape-space filtering is a generalization of the existing tree-based connected operators. Indeed, the framework includes the classical existing connected operators by attributes. It also allows us to propose a class of novel connected operators from the leveling family, based on non-increasing attributes. Finally, we also propose a new class of connected operators that we call morphological shapings. Some illustrations and quantitative evaluations demonstrate the usefulness and robustness of the proposed shape-space filters.


Reconstruction of time-delay systems using small impulsive disturbances.
We propose a method for the reconstruction of time-delayed feedback systems from time series. The method is based on the analysis of the system response to a weak external disturbance having the form of rectangular pulses. To apply the method one must have access to the state variable of the system in order to perturb it and the time series of the driving signal and the system response having at least about one hundred points on the time interval equal to the delay time. The method is intended to recover delays in low-order time-delay systems performing periodic oscillations, but can also be applied to systems in chaotic regimes in the presence of high level of noise. We verify the method by applying it to both numerical and experimental data.


Residues accessible in the binding-site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor.
We have used the substituted-cysteine accessibility method (SCAM) to map the residues in the sixth membrane-spanning segment of the CB2 cannabinoid receptor that contribute to the surface of the water-accessible binding-site crevice. Using a background of the mutant C2.59S which is relatively insensitive to the methanethiosulfonate (MTS) reagents, we mutated to cysteine, one at a time, 34 consecutive residues in TMH6 of the CB2 receptor. These mutant receptors were then expressed in HEK293 cells. By incubating HEK293 cells stably transfected with CB2 receptors with the small, charged, hydrophilic, thiol-specific reagent methanethiosulfonate ethylammonium (MTSEA), [(3)H]CP55940 binding was significantly inhibited for six mutant receptors. All six of the mutants that reacted with MTSEA were protected from the reaction when pretreated with the cannabinoid agonist WIN55212-2, suggesting that MTSEA modification occurred within the binding crevice. Therefore, the side chains of the residues at these reactive loci (V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62) are on the water-accessible surface of the binding-site crevice. These residues are extracellular to the TMH6 CWXP hinge motif. The pattern of accessibility is consistent with a alpha-helical conformation for this segment of TMH6. Molecular modeling studies performed in the context of the CB2 model show that V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62 face into the CB2 binding pocket, further confirming our SCAM results. These results are similar to the accessibility patterns determined by SCAM studies of TMH6 in the opioid and dopamine D2 receptors.


Dependence of product formation from decomposition of nitroso-dithiols on the degree of nitrosation. Evidence that dinitroso-dithiothreitol acts solely as an nitric oxide releasing compound.
Hitherto, the decay mechanisms of nitrosated dithiols as well as formation of related products have not been conclusively elucidated. In this paper, we demonstrate that nitrosated dl-dithiothreitol (DTT) decays via two independent pathways, that is, one producing exclusively nitric oxide and one producing (initially) nitroxyl (HNO/3NO-). The importance of the two decomposition pathways depends on the degree of nitrosation of DTT. Dinitroso-dithiothreitol (NODTTNO) generates quantitatively nitric oxide, whereas mononitroso-dithiothreitol (NODTT) yields initially nitroxyl. Since NODTT and DTT are both targets for nitroxyl, their availability governs the HNO-derived formation of nitric oxide (with NODTT as reactant) or hydroxyl amine and ammonium ion (with DTT as reactant). The formation of NH4+ from the HNO-DTT reaction probably proceeds by a stepwise, NH2OH-independent mechanism, because DTT-derived sulfinamide was identified by N-15 NMR spectrometry as an intermediate. Our data are in line with the assumption that triplet nitroxyl (3NO-) is formed by a unimolecular decay of the deprotonated (thiolate) form of NODTT, because CBS-QB3 calculations predict the existence of a low-lying triplet state of the latter species. The identified pathways are proposed to be of general importance for physiological systems because control experiments showed that the physiological dithiol thioredoxin reacts in a similar manner.


Measurement of food and alcohol intake in relation to chronic liver disease.
It is well established that the consumption of alcohol is implicated in both the cause and progression of chronic liver disease. The quantity of drink that is consumed, the pattern of drinking and type of alcoholic beverages consumed are all possible factors in disease aetiology. The impact of specific dietary components on the cause and progression of chronic liver disease is unclear although it is known that obesity, and hence the over-consumption of energy, is a predictor of fatty liver. Work to elucidate the role of both diet and alcohol in the aetiology of liver disease is hindered by the methods currently available to measure dietary (including alcohol) intake. The validity and reliability of retrospective methods of assessing diet are limited by their reliance on memory and, for the 24 h recall, the short-time period of intake assessed and its inability to assess variability across the week. Prospective methods which measure food and drink intake at the time of consumption, and include weighed or estimated food diaries, are useful for prospective cohort studies but are expensive and have a high respondent burden. For estimation of alcohol intake retrospectively, the Cognitive Lifetime Drinking questionnaire, which prompts responses using a lifetime calendar, is a useful tool but still depends on memory. More work is required to develop valid, reliable and easily administered tools for measurement of both diet and alcohol.


Perioperative chemotherapy for resectable gastric cancer - what is the evidence?
The UK MAGIC trial published in 2006 was the first RCT to identify improved long-term survival rates using preoperative chemotherapy for resectable gastric or gastroesophageal cancer. Overnight, the treatment regimen impacted European guidelines. However, the majority of patients underwent limited lymph node dissection, and analyses of the rates of curative resection, downsizing and downstaging were not by intention to treat, rightfully raising concerns about their validity. For the subset of true gastric cancers, meta-analyses may even question the claims of improved long-term survival rates by present-day regimens. A rhetorical question can be posed as to whether downstaging and improved survival rates by preoperative (radio)-chemotherapy for cancers of the distal esophagus or gastric cardia, has confounded our conclusions on the (lack of) effect of present-day regimens of perioperative chemotherapy for true gastric cancers, let alone in a situation with proper lymph node dissection. At present, a plea can be made to move one step back and revert to an RCT with a surgery alone arm. Inclusion criteria and analyses of future RCTs must stratify on tumor location and the Lauren type and embrace the newly developed scheme of sub-classification of gastric cancers based on extensive molecular profiling as reported in the seminal Cancer Genome Atlas Study.


A rebreathing method to determine carbon monoxide diffusing capacity in children: reference values for 6- to 18-year-olds [corrected] and validation in adult volunteers.
The diffusing capacity of carbon monoxide (D(L,CO)) and its value normalized to alveolar volume (D(L,CO)/V(A)) are usually estimated with the single breath method at total lung capacity (TLC). Severely ill patients and small children are not able to deliver a satisfactory vital capacity (VC) or hold their breath for 10 s at TLC. The aim of this study was to develop a rebreathing procedure in which diffusing capacity can be determined during spontaneous tidal breathing. The conventional rebreathing method during hyperventilation was modified so that rebreathing volume and gas concentrations were kept constant by CO2 absorption and O2 supplementation. In adult healthy volunteers and in patients who were able to perform both tests, the diffusion indices obtained with this rebreathing method during resting ventilation were compared with those obtained by the single breath method. Predicted (reference) values for rebreathing D(L,CO) and D(L,CO)/V(A) for children were determined. D(L,CO)/V(A) decreased with alveolar volume (V(A)) and increased with alveolar ventilation (V'(A)). In adults at V'(A) above 35 L x min(-1) rebreathing D(L,CO)/V(A) was similar to single breath D(L,CO)/V(A) at similar alveolar volumes. The D(L,CO)/V(A) relative to their corresponding reference values were the same for both methods in adult patients, irrespective of ventilation distribution disturbances. In children the newly described diffusing capacity obtained by the rebreathing method during resting ventilation can serve as a valuable index to assess and follow a diffusion disorder.


Factors associated with using research evidence in national sport organisations.
The purpose of this study was to explore factors associated with the use of research evidence in Canadian National Sport Organisations (NSOs). Data were collected via individual semi-structured interviews with 21 representatives from Canadian NSOs. A qualitative description approach was used. Interviews were transcribed verbatim and subjected to an inductive-to-deductive thematic analysis. A research implementation framework (Rycroft-Malone, 2004) was used to organise inductively derived themes into the higher-order categories of evidence (use of evidence, disconnection between research and practice), context (lack of capacity, organisational structure), and facilitation (personal connections with researchers and sport scientists, formal meetings with stakeholders). Overall, NSO representatives did not have a clear understanding of evidence and lacked capacity to access and translate research. However, some context factors, along with internal and external facilitators, were in place and could be used to enhance research implementation.


Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma.
Recent investigations have suggested that the activation of factor IX by factor VII/tissue factor may be an important alternative route to the generation of factor Xa. Accordingly, we have compared the tissue factor-dependent activation of tritium-labeled factor IX and factor X in a human plasma system and have studied the role of proteases known to stimulate factor VII activity. Plasma was defibrinated by heating and depleted of its factors IX and X by passing it through antibody columns. Addition of human brain thromboplastin, Ca2+, and purified 3H-labeled factor X to the plasma resulted, after a short lag, in burst-like activation of the factor X, measured as the release of radiolabeled activation peptide. The progress of activation was slowed by both heparin and a specific inhibitor of factor Xa, suggesting a feedback role for this enzyme, but factor X activation could not be completely abolished by such inhibitors. In the case of 3H-factor IX activation, the rate also increased for approximately 3 min after addition of thromboplastin, but was not subsequently curtailed. A survey of proteases implicated as activators of factor VII in other settings showed that both factor Xa and (to a much smaller extent) factor IXa could accelerate the activation of factor IX. However, factor Xa was unique in obliterating activation when present at concentrations greater than approximately 1 nM. Heparin inhibited the tissue factor-dependent activation of factor IX almost completely, apparently through the effect of antithrombin on the feedback reactions of factors Xa and IXa on factor VII. These results suggest that a very tight, biphasic control of factor VII activity exists in human plasma, which is modulated mainly by factor Xa. Variation of the factor IX or factor X concentrations permitted kinetic parameters for each activation to be derived. At saturation of factor VIIa/tissue factor, factor IX activation was significantly more rapid than was previously found in bovine plasma under similar conditions. The activation of factor X at saturation was slightly more rapid than in bovine plasma, despite the presence of heparin.


Assessment of body composition with bioelectrical impedance analysis in pregnant women with hyperemesis gravidarum before and after treatment.
More than half of pregnant women suffer from nausea and vomiting, in 0.5-1% of the pregnant women, if nausea and vomiting are severe and persistent, condition can progress to hyperemesis. We evaluated the fluid volume parameters in pregnant women with hyperemesis gravidarum, before and after treatment using the bioelectrical impedance vectors. A total of 70 pregnant women who had weight loss exceeding 5% of pre-pregnancy body weight were recruited for the study in the first trimester. The measurement of multi-frequency bioelectrical impedance analysis parameters was performed on the day of hospitalisation before any treatment and after treatment at 24 h and 72 h with the same procedure. Total body water, extracellular water, intracellular water, and fat-free mass index increased after treatment at 24 h (P < 0.01). Also, the mean pregnancy-unique quantification of emesis and nausea score was significantly lower after treatment (11.3 ± 2.1 at enrolment, 5.1 ± 1.4 at 24 h and 4.3 ± 1.1 at 72 h) (P < 0.01), which correlated with the patients' clinical improvement and changes in hydration. In pregnant women with moderate-to-severe hyperemesis gravidarum, significant body composition changes occur and fluid replacement therapy performed during a short period of time, such as 24 h, provides improvement in body composition.


The impact of hospital volume on clinical and economic outcomes in ventral hernia repair: an analysis with national policy implications.
The objectives of this study are to evaluate the associations between ventral hernia repair procedure volume and patient outcomes, including both clinical and economic outcomes. The 2014 National Inpatient Sample was queried for patients who underwent elective, open ventral (incisional) hernia repair with or without mesh. Outcomes included occurrence of major or wound-based in-hospital complications, extended length of stay (> 4 days), and increased costs (> $12,816). High-volume hospitals were defined as the 90th percentile of case volume or higher (> 60 cases/year). Multivariate regression was performed to access the outcomes associated with high-volume hospitals. 54,075 patients at 2049 hospitals were retrieved. 41.4 percent of patients were treated at high-volume hospitals. Patients treated at high-volume hospitals were less likely to experience a major complication (OR 0.88; 95% CI 0.82-0.96; p = 0.002) or wound-based complication (OR 0.84; 95% CI 0.76-0.92; p < 0.001). However, in terms of resource utilization, patients treated at high-volume hospitals were more likely to experience an extended length of stay (OR 1.14; 95% CI 1.09-1.12; p < 0.001) and an increase in costs (OR 1.23; 95% CI 1.17-1.29; p < 0.001). Hospitals that perform a larger number of ventral hernia repairs, despite caring for a more complex patient population, may be associated with better patient outcomes than lower volume hospitals. However, these same high-volume centers demonstrate an extended length of stay and increased costs. Further research is needed to understand the reason for this gap in proper resource utilization in high-volume ventral hernia repair centers.


Graphene/Sulfur/Carbon Nanocomposite for High Performance Lithium-Sulfur Batteries.
Here, we report a two-step synthesis of graphene/sulfur/carbon ternary composite with a multilayer structure. In this composite, ultrathin S layers are uniformly deposited on graphene nanosheets and covered by a thin layer of amorphous carbon derived from β-cyclodextrin on the surface. Such a unique microstructure, not only improves the electrical conductivity of sulfur, but also effectively inhibits the dissolution of polysulfides during charging/discharging processes. As a result, this ternary nanocomposite exhibits excellent electrochemical performance. It can deliver a high initial discharge and charge capacity of 1410 mAh·g-¹ and 1370 mAh·g-¹, respectively, and a capacity retention of 63.8% can be achieved after 100 cycles at 0.1 C (1 C = 1675 mA·g-¹). A relatively high specific capacity of 450 mAh·g-¹ can still be retained after 200 cycles at a high rate of 2 C. The synthesis process introduced here is simple and broadly applicable to the modification of sulfur cathode for better electrochemical performance.


Experience with antithrombin concentrates in neurotrauma patients.
Plasma coagulation results from 2,100 injured patients were sequentially and systematically evaluated in a large natural history study of neurotrauma. A significant correlation became apparent between the severity of and morbidity from head injury and the degree of abnormality in coagulation results, especially for young injured victims. Subsequent studies in the United States, Europe, and Japan have supported the significant correlation between final clinical outcome and these measurements of plasma coagulation, as well as inflammatory proteins, performed soon after injury. This discussion reviews the data from many published reports that support this conclusion, especially data that corroborate the strong clinical association between head trauma and disseminated intravascular coagulation (DIC). The data that demonstrate a high predisposition for head-injured individuals to develop DIC serve as a the rationale for therapeutic intervention with coagulation protease inhibitors, especially antithrombin (AT). A large, double-blind, placebo-controlled trial that evaluates the therapeutic use of AT concentrate for DIC in such patients has yet to be completed. Described here is the design for such a clinical trial that examined the impact of mortality as an outcome. However, this trial was terminated for nonscientific reasons soon after it began. Very truncated data collected from this aborted study support both the scientific rationale for and the feasibility of such a study in the future. Data from such a clinical trial are needed to support the use of AT concentrate to treat DIC in this and other morbid diseases.


Multistep nature of X-ray-induced neoplastic transformation in mammalian cells: genetic alterations and instability.
X-ray-induced neoplastic transformation has been studied in Syrian hamster embryo cells. Unirradiated cells had a limited life span, whereas the irradiated cells escaped senescence, showed altered morphology, and acquired anchorage-independence and tumorigenicity in a stepwise manner during successive transfers after irradiation. Multiple genetic changes may be associated with the expression of various transformed phenotypes. In fact, sequential alterations of various chromosomes were required for the malignant progression of irradiated cells. Oncogene activation was examined by the NIH3T3 transfection assay, no detectable changes having been identified so far. The only difference in oncogene expression detected was the augmented expression of the c-myc gene which was observed consistently. These findings indicate the multistep nature of X-ray-induced neoplastic transformation. Although the molecular changes involved in these process are still to be elucidated, recent studies have indicated that the instability induced by irradiation inherited through the progeny of irradiated cells is associated with those changes. This genetic instability provides a new way with which to elucidate the multistep process of radiation oncogenesis. The predicted mechanism and future studies are discussed.


Effects of osmotic pressure on the oxidative metabolism of Leishmania major promastigotes.
Leishmania major promastigotes were washed and resuspended in an iso-osmotic buffer. The rate of oxidation of 14C-labeled substrates was then measured as a function of osmolality. An acute decrease in osmolality (achieved by adding H2O to the cell suspension) caused an increase in the rates of 14CO2 production from [6-14C]glucose and, to a lesser extent, from [1,(3)-14C]glycerol. An acute increase in osmolality (achieved by adding NaCl, KCl, or mannitol) strongly inhibited the rates of 14CO2 production from [1-14C]alanine,[1-14C]glutamate, and [1,(3)-14C]glycerol. The rates of 14CO2 formation from [1-14C]laurate,[1-14C]acetate, and [2-14C]glucose (all of which form [1-14C]acetyl CoA prior to oxidation) were also inhibited, but less strongly, by increasing osmolality. These data suggest that with increasing osmolality there is an inhibition of mitochondrial oxidative capacity, which could facilitate the increase in alanine pool size that occurs in response to hyper-osmotic stress. Similarly, an increase in oxidative capacity would help prevent a rebuild up of the alanine pool after its rapid loss to the medium in response to hypo-osmotic stress.


Use of ferro-electric liquid crystal shutters for time-resolved fluorescence microscopy.
A technique is described to modify a standard fluorescence microscope for time-resolved visualization of delayed luminescing substances with decay times from 50 microseconds to several milliseconds. The modification consists of synchronized operation of a mechanical shutter, positioned in an aperture plane in the excitation pathway, simultaneously with a ferro-electric liquid crystal (FLC) shutter on the emission side. Operation of the microscope is through a microprocessor interfaced keypad by which all timing parameters can be adjusted for optimal suppression of fast decaying luminescence. Accuracy of the timing was within 1 microsecond. Prompt fluorescence was suppressed up to 10(6) times, as determined for bright prompt fluorescing microspheres. The use of the FLC shutter resulted in a reduction in emission intensity by a factor of 8 (due to the use of polarizers, the lower transmission of the FLC devices, and IR blocking filters). No significant image degradation due to shutter operations was observed. The modified microscope was successfully used for the visualization of delayed luminescing immunolabels, such as inorganic phosphor particles and lanthanide chelates, as well as naturally phosphorescing materials.


The evolution of rigid contact lens prescribing.
Rigid contact lenses have long been known to be a versatile form of optical correction. However, as documented in this report of the results of annual prescribing surveys conducted over the past 12 years, there has been a steady decline in rigid lens fitting over this period. This is attributed to factors such as the initial discomfort of rigid lenses and the increased sophistication of soft lens materials and designs. There is an apparent trend for rigid lenses to be used more for 'specialist' fits, such as sophisticated toric designs, multifocals and orthokeratology.


Residual anterior pituitary function following transsphenoidal resection of pituitary macroadenomas.
A series of 84 patients with pituitary adenomas greater than 1 cm in diameter is presented. Full preoperative and postoperative endocrine evaluations were carried out, and the effects of transsphenoidal surgery on remaining anterior pituitary function were analyzed. Of the patients who had normal anterior pituitary function before surgery, 78% retained normal function after surgery. Thirty-three percent of those patients with pituitary deficits who did not have panhypopituitarism before surgery had improved function after surgery; 33% had worsened function after surgery. None of the patients with panhypopituitarism before surgery regained function after surgery. Transsphenoidal surgery carries an acceptable risk for sacrificing anterior pituitary function, but the risk is greater in patients with larger tumors and preoperatively compromised pituitary function.


Pentraxin 3 as a biomarker of local inflammatory response to vascular injury in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disorder with organ injury related to vasculitis. Inflammation of blood vessels results from auto-immunological activation of endothelial cells. The pentraxin 3 (PTX3), might act as an indicator of vasculitides in many diseases. The aim of this study was to determine whether PTX3 might be useful as a marker of vascular injury in SLE. This study was carried out in a group of 56 SLE women, and in the 28 female volunteers control group. All participants' plasma and serum samples were collected to estimate concentrations (ELISA) of PTX3, soluble thrombomodulin, soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble form of vascular cell adhesion molecule 1 (sVCAM-1), soluble inter-cellular adhesion molecule-1 (sICAM-1), soluble platelet endothelial cell adhesion molecule 1, monocyte chemotactic protein-1 (MCP-1) and von Willebrand factor (vWF) activity. Anthropometric, demographic and lifestyle characteristics of SLE patients were also performed. The SLE patients had higher PTX3, vWF, MCP-1, sE-selectin and sVCAM-1 levels than the controls (1.82 ± 1.56 ng/mL, 237 ± 101%, 70.05 ± 18.31 ng/mL, 111.16 ± 49.15 ng/mL and 978.78 ± 462.35 ng/mL vs. 0.86 ± 0.40 ng/mL, 138 ± 43%, 58.56 ± 13.91 ng/mL, 66.04 ± 27.18 ng/mL and 499.07 ± 125.67 ng/mL, respectively). The independent factors affecting PTX3 expression included Systemic Lupus Erythematosus Disease Activity Index, prednisone dose and anemia severity. Moreover, the PTX3 areas under the curve-receiver operating characteristics curves 0.717 ± 0.056 with cut-off level of 1.96 ng/mL was comparable to vWF, MCP-1, sE-selectin, sP-selectin and sICAM-1. PTX3 and sVCAM-1 were the only factors related to SLE activity. Other vascular injury indicators associated with PTX3 were vWF and sVCAM-1. In conclusion, PTX3 concentrations in SLE patients might serve as a indicator of the activation/dysfunction of vascular endothelium.


Synthesis, characterization and in vitro biological activity studies of Cu-M (M = Cu2+, Co2+, Ni2+, Mn2+, Zn2+) bimetallic complexes.
Six new bimetallic complexes of the type CuCu, CuCo, CuNi, CuZn and CuMn were prepared. The structures of these complexes and the ligand have been proposed on the basis of FAB mass, elemental analysis, UV-vis, IR, EPR and CV studies. All the complexes completely cleave pBS (SK-) DNA at a concentration of 10 microM; however, even at lower concentrations of 2 microM and 0.1 microM, the complexes (I and Ia) showed partial cleavage. The results of the fluorescence binding studies of the metal complexes with CT-DNA showed that the presence of aliphatic ligands added additional binding effects including electrostatic, hydrogen binding and vander Waals interactions. Complexes (I, Ia) showed 50% inhibition of COX-1 and COX-2 activities at as low a concentration as 12.5 microM, 13.5 microM, 14 microM and 14.5 microM. Inhibition assay of top I and top II by different complexes in mutant yeast strains (JN394, JN394 t(-1) and JN394 t(2-5)) with all the complexes showed significant inhibition of topoisomerase at 5 microM concentration. Complexes I and Ia exhibited good anti-microbial activities against all human pathogens tested except Klebsiella pneumoniae. The following studies showed that among the synthesized bimetallic complexes, complexes I and Ia seem to be promising candidates possessing DNA cleavage activities besides anti-microbial and anti-inflammatory properties to serve as chemical nucleases and chemotherapeutic agents.


Boosting Slime Mould Algorithm for High-Dimensional Gene Data Mining: Diversity Analysis and Feature Selection.
Slime mould algorithm (SMA) is a new metaheuristic algorithm, which simulates the behavior and morphology changes of slime mould during foraging. The slime mould algorithm has good performance; however, the basic version of SMA still has some problems. When faced with some complex problems, it may fall into local optimum and cannot find the optimal solution. Aiming at this problem, an improved SMA is proposed to alleviate the disadvantages of SMA. Based on the original SMA, Gaussian mutation and Levy flight are introduced to improve the global search performance of the SMA. Adding Gaussian mutation to SMA can improve the diversity of the population, and Levy flight can alleviate the local optimum of SMA, so that the algorithm can find the optimal solution as soon as possible. In order to verify the effectiveness of the proposed algorithm, a continuous version of the proposed algorithm, GLSMA, is tested on 33 classical continuous optimization problems. Then, on 14 high-dimensional gene datasets, the effectiveness of the proposed discrete version, namely, BGLSMA, is verified by comparing with other feature selection algorithm. Experimental results reveal that the performance of the continuous version of the algorithm is better than the original algorithm, and the defects of the original algorithm are alleviated. Besides, the discrete version of the algorithm has a higher classification accuracy when fewer features are selected. This proves that the improved algorithm has practical value in high-dimensional gene feature selection.


Correlation between alteration of enamel roughness and tooth color.
To establish the correlation between enamel roughness and color change of tooth. Enamel/dentin blocks (5 x 5 x 3.2 mm) were serially ground with the following abrasive paper: 1200-grit, 800-grit, and 600-grit SiC papers. In the paired model, the analyses of color (L*, a*, b*, ΔE) and roughness (Ra) were performed among the sandpaper exposure. The data were subjected to ANOVA using models for repeated measures followed by the Tukey test. The Pearson correlation test was used to determine whether there was a relationship between Ra values and color results (α = 0.05). The L* values decreased in accordance with the increase of Ra, with statistical difference between all the times (p<0.05). A correlation was found between the Ra vs. the L* values (r = -0.67; p<0.0001) and ∆Ra vs. ∆a* values (r = 0.29; p = 0.05); besides that, there was no significant correlation with b* values or significant alteration in the ∆E values (p>0.05). The alteration of enamel roughness acted on the lightness and the green-red axis of tooth color. However, there was no significant correlation between the alteration of roughness of enamel and general color change of tooth. Key words:Surface properties, tooth discoloration, color.


A Connection between Lysine and Serotonin Metabolism in Rice Endosperm.
Cereal endosperms produce a vast array of metabolites, including the essential amino acid lysine (Lys). Enhanced accumulation of Lys has been achieved via metabolic engineering in cereals, but the potential connection between metabolic engineering and Lys fortification is unclear. In mature seeds of engineered High Free Lysine (HFL) rice (Oryza sativa), the endosperm takes on a characteristic dark-brown appearance. In this study, we use an integrated metabolomic and transcriptomic approach combined with functional validation to elucidate the key metabolites responsible for the dark-brown phenotype. Importantly, we found that serotonin biosynthesis was elevated dramatically and closely linked with dark-brown endosperm color in HFL rice. A functional connection between serotonin and endosperm color was confirmed via overexpression of TDC3, a key enzyme of serotonin biosynthesis. Furthermore, we show that both the jasmonate signaling pathway and TDC expression were strongly induced in the late stage of endosperm development of HFL rice, coinciding with serotonin accumulation and dark-brown pigmentation. We propose a model for the metabolic connection between Lys and serotonin metabolism in which elevated 2-aminoadipate from Lys catabolism may play a key role in the connection between the jasmonate signaling pathway, serotonin accumulation, and the brown phenotype in rice endosperm. Our data provide a deeper understanding of amino acid metabolism in rice. In addition, the finding that both Lys and serotonin accumulate in HFL rice grains should promote efforts to create a nutritionally favorable crop.


Analysis of core region from egg white lysozyme forming amyloid fibrils.
Some of the lysozyme mutants in humans cause systemic amyloidosis. Hen egg white lysozyme (HEWL) has been well studied as a model protein of amyloid fibrils formation. We previously identified an amyloid core region consisting of nine amino acids (designated as the K peptide), which is present at 54-62 in HEWL. The K peptide, with tryptophan at its C- terminus, has the ability of self-aggregation. In the present work we focused on its structural properties in relation to the formation of fibrils. The K peptide alone formed definite fibrils having β-sheet structures by incubation of 7 days under acidic conditions at 37°C. A substantial number of fibrils were generated under this pH condition and incubation period. Deletion and substitution of tryptophan in the K peptide resulted in no formation of fibrils. Tryptophan 62 in lysozyme was suggested to be especially crucial to forming amyloid fibrils. We also show that amyloid fibrils formation of the K peptide requires not only tryptophan 62 but also a certain length containing hydrophobic amino acids. A core region is involved in the significant formation of amyloid fibrils of lysozyme.


Further validity testing of the Abu-Saad Paediatric Pain Assessment Tool.
This paper reports on the results of two studies conducted to further validate the Abu-Saad Paediatric Pain Assessment Tool, a Dutch-language questionnaire developed to assess pain in school-age children. Children of 5 to 15 years of age reported in the first study their post-operative pain before and after the administration of analgesic medication using word descriptors of pain, the 10-cm scale, the Oucher, and a visual analogue scale (VAS). Lower mean pain scores at 4-hourly intervals post-analgesia supported the construct validity of the tool. Convergent validity was supported in both studies when scores on all concurrently administered measures positively correlated with the pain tool. In the second study, the correlations between pain and fear, a concurrently used measure with the pain instruments, were low, substantiating the discriminant validity of the pain tool. The significance of the results in relation to instrument development and multidimensional pain assessment in children are further discussed and elaborated.


Association of KIR Genes and MHC Class I Ligands with Atopic Dermatitis.
Atopic dermatitis (AD) is a chronic illness that is associated with immune dysregulation. NK cell function has previously been associated with AD. NK cells directly interact with polymorphic HLA class I ligand variants using killer cell Ig-like receptors (KIRs). The purpose of this study was to identify potential associations between NK cell function and AD by evaluating variation in the presence of KIR genes as well as KIR gene interactions with the appropriate HLA class I KIR-specific ligands. Human DNA from the genetics of AD case-control study was used to genotype HLA class I KIR-specific ligands and the presence of KIR genes. In the full cohort, an increased risk of AD was noted for KIR2DL5 (1.51 [1.13, 2.01]), KIR2DS5 (1.72 [1.26, 2.34]), and KIR2DS1 (1.41 [1.04, 1.91]). Individuals with KIR2DS5 or KIR2DS1 and the HLA-C*C2 epitope were at an increased risk of AD (1.74 [1.21, 2.51] and 1.48 [1.04, 2.12], respectively). The HLA-B*-21T (TT) leader sequence increased the risk of AD across ethnicity. African Americans with KIR2DL2, KIR2DS1, KIR2DL5, and KIR2DS5 are more likely to have AD, and the risk increased for KIR2DS1 and KIR2DS5 in the presence of appropriate HLA-C C2 epitope. The risk of AD also increased for individuals with the HLA-B*-21T leader sequence. Future studies should focus on KIR gene allelic variation as well as consider cell-based measurements of KIR and the associated HLA class I epitopes.


Effect of pattern scanning laser on macular thickness in diabetic retinopathy.
This study investigates the effect of pattern scanning laser (PASCAL) panretinal photocoagulation (PRP) on central macular thickness (CMT) and visual acuity (VA) in patients with proliferative diabetic retinopathy (PDR). This retrospective non-randomized comparative case series included 262 eyes (163 with macular edema) of 177 patients with PDR. Treatment was PRP alone (137), PRP + anti-vascular endothelial growth factor (VEGF) (69), PRP + focal laser (28), or all three (89). CMT and central macular volume 3 and 6 mm from fovea were analyzed before and 1, 3, and 6 months after PRP. Spot number was plotted against CMT, and linear regression analysis was performed. For each treatment group and time point, there was a non-significant relationship between spot number and CMT. In eyes receiving all three treatment modalities, a significant negative relationship was found between spot number and 3-mm volume at 6 months (p = 0.04) and 6-mm volume at 1 month (p = 0.002) and 6 months (p = 0.011). There was no significant change in VA in any treatment group at the 6-month time point. PASCAL PRP ± focal laser or anti-VEGF was not associated with increased development of macular edema or change in VA. PASCAL PRP with focal laser and anti-VEGF may result in a decrease in macular edema.


Changes in neck and upper trunk muscle activities according to the angle of movement of the neck in subjects with forward head posture.
[Purpose] This study investigated changes in neck and upper trunk muscle activities according to the angle of movement of the neck in subjects with Forward Head Posture. [Subjects and Methods] Twenty subjects with forward head postures were recruited. The activities of the sternocleidomastoid muscle, splenius capitis and splenius cervicis muscles, upper trapezius muscle, and middle trapezius muscle during flexion and extension were assessed. [Results] The activity of the sternocleidomastoid muscle showed significant differences between the 30° flexed position and the full range of motion position, and between the neutral position and the full ROM position. The activity of the middle trapezius muscle showed a significant reduction in the 30° extended position and the full ROM position as compared to the neutral position. [Conclusion] In the full flexed position, sternocleidomastoid muscle activity increased significantly, and during extension position, the middle trapezius muscle reduced its activities.


Color calibration and fusion of lens-free and mobile-phone microscopy images for high-resolution and accurate color reproduction.
Lens-free holographic microscopy can achieve wide-field imaging in a cost-effective and field-portable setup, making it a promising technique for point-of-care and telepathology applications. However, due to relatively narrow-band sources used in holographic microscopy, conventional colorization methods that use images reconstructed at discrete wavelengths, corresponding to e.g., red (R), green (G) and blue (B) channels, are subject to color artifacts. Furthermore, these existing RGB colorization methods do not match the chromatic perception of human vision. Here we present a high-color-fidelity and high-resolution imaging method, termed "digital color fusion microscopy" (DCFM), which fuses a holographic image acquired at a single wavelength with a color-calibrated image taken by a low-magnification lens-based microscope using a wavelet transform-based colorization method. We demonstrate accurate color reproduction of DCFM by imaging stained tissue sections. In particular we show that a lens-free holographic microscope in combination with a cost-effective mobile-phone-based microscope can generate color images of specimens, performing very close to a high numerical-aperture (NA) benchtop microscope that is corrected for color distortions and chromatic aberrations, also matching the chromatic response of human vision. This method can be useful for wide-field imaging needs in telepathology applications and in resource-limited settings, where whole-slide scanning microscopy systems are not available.


Energy Efficient Cluster Based Scheduling Scheme for Wireless Sensor Networks.
The energy utilization of sensor nodes in large scale wireless sensor network points out the crucial need for scalable and energy efficient clustering protocols. Since sensor nodes usually operate on batteries, the maximum utility of network is greatly dependent on ideal usage of energy leftover in these sensor nodes. In this paper, we propose an Energy Efficient Cluster Based Scheduling Scheme for wireless sensor networks that balances the sensor network lifetime and energy efficiency. In the first phase of our proposed scheme, cluster topology is discovered and cluster head is chosen based on remaining energy level. The cluster head monitors the network energy threshold value to identify the energy drain rate of all its cluster members. In the second phase, scheduling algorithm is presented to allocate time slots to cluster member data packets. Here congestion occurrence is totally avoided. In the third phase, energy consumption model is proposed to maintain maximum residual energy level across the network. Moreover, we also propose a new packet format which is given to all cluster member nodes. The simulation results prove that the proposed scheme greatly contributes to maximum network lifetime, high energy, reduced overhead, and maximum delivery ratio.


Heterogeneous susceptibility to spontaneous and induced apoptosis characterizes two related transplantable melanomas with different biological properties.
A family of phenotypically and biologically different transplantable hamster melanomas was derived from a single tumor more than 40 yr ago. In this work, we were seeking the differences between the abilities of the cells from two biologically heterogeneous (melanotic and amelanotic) members of this family to undergo spontaneous or camptothecin-induced apoptosis. We studied these differences by looking at three important features of the apoptotic process, i.e. binding of annexin V, DNA fragmentation and caspase-3 activity. Of these, annexin binding and DNA fragmentation were more pronounced in the parental, melanotic line while the activity of caspase-3 was stronger in the amelanotic tumor cells. We concluded that a spontaneous alteration of the original, melanotic melanoma line into an amelanotic one, associated with more aggressive tumor progression, was accompanied by significant decrease in ability to undergo spontaneous and camptothecin-induced apoptosis, and that apoptosis of these two cell types may not depend on the activity of caspase-3.


Sympathetic activation by hypoxia and hypercapnia--implications for sleep apnea.
In normal humans, both hypoxia and hypercapnia result in sympathetic nerve activation, and when combined, i.e. hypoxic hypercapnia, synergistically increase sympathetic activity. Apnea during the hypoxic and hypercapnic stress results in further increases in sympathetic activity. Borderline hypertensive humans have exaggerated sympathetic nerve responses to hypoxia. Hypertensives are also prone to sleep apnea. We suggest that sleep apnea may result in very high levels of sympathetic activity which may contribute to daytime hypertension and/or precipitate cardiovascular catastrophe in hypertensive people during sleep.


BCMA-targeting Bispecific Antibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against Multiple Myeloma.
B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein expressed on malignant plasma cells of patients with multiple myeloma (MM), and it is a defined therapeutic target. Major histocompatibility complex class I-related chain A (MICA) is frequently expressed in lymphoproliferative malignancies including MM. MICA activates natural killer (NK) cells and costimulates T cells by interaction with its immunoreceptor NK cell receptor G2D (NKG2D). Nonetheless, during full-blown MM, tumor cells promote efficient MICA shedding, which evokes NKG2D internalization and immune suppression. To enhance the directional killing efficacy of immune cells against myeloma cells, we constructed a novel bispecific antibody 2A9-MICA and explored its potential antimyeloma activity against MM. 2A9-MICA consists of human MICA extracellular region and a single-chain antibody fragment (scFv) that targets BCMA generated by phage display technology. In vitro, 2A9-MICA activated NK cell-mediated cytotoxicity and induced NK cells to kill BCMA-positive human myeloma cells. Moreover, in BCMA-positive, MM-bearing nude mice, 2A9-MICA specifically targeted tumor tissue, where it effectively recruited immune cells and inhibited tumor tissue growth showed superior antitumor activity. Taken together, bispecific antibody 2A9-MICA provides a new approach for MM-targeting immunotherapy and has attractive potential for clinical applications.


Analgesic drug use associated with statin prescription--a cross-sectional study in primary care settings.
To investigate whether features of muscular complaints (MC) differ between receivers of a statin prescription and non-receivers. To analyze the relationship between analgesics prescription, statin prescription and/or musculoskeletal disorders. Cross-sectional study. Consecutive patients in offices of family practitioners were interviewed using a standardized questionnaire. Target variables: Rates of features of MC in patients with or without a statin prescription and rates of analgesic drug prescription in patients with or without statin prescription and/or musculoskeletal disorders. Odds ratios (adjusted for age, sex, and socio-economic status) were calculated using logistic regression analysis. 1135 patients in 26 general practitioners' offices were asked to participate, and 1031 patients agreed. Features of MC did not differ between the two groups of patients. Analgesic prescription was found to be associated with statin prescription in patients without musculoskeletal disorders (OR 2.2, CI 1.1-4.7 without statin, OR 2.5, CI 0.9-6.9 with statin) and particularly in those with musculoskeletal disorders (OR 5.2, CI 2.9-9.3 without statin, OR 9.3, CI 4.5-19.1 with statin). Analgesic prescriptions are probably positively associated with statin prescription. Assuming that analgesics attenuate MC, an even stronger association between MC and statin use seems likely. The results generate the hypothesis that statin use contributes to analgesic use in primary care patients.


Effect of pulmonary blood flow on leukocyte uptake and release by dog lung.
The effect of pulmonary blood flow on leukocyte uptake and release by the lung was examined in 10 anesthetized spontaneously breathing dogs. Pulmonary arterial and pulmonary venous blood was sampled with catheters placed into the right ventricle and aorta, respectively. Pulmonary blood flow was lowered by inflating a balloon catheter located in the inferior vena cava. In five experiments simultaneous blood samples were drawn from the right ventricle and aorta at 10-s intervals during a control period, a 2- to 3-min period of low flow, and a recovery period. In five additional experiments, less frequent samples were taken over periods of 15-60 min. Total leukocyte concentrations and differential counts were determined for each blood sample. The study shows that large numbers of leukocytes become sequestered within the lung when pulmonary blood flow is low and that an equivalent number of cells are released from the lung after deflation of the balloon catheter. Both the polymorphonuclear leukocytes and the lymphocytes were taken up by the lung when pulmonary blood flow was reduced. We conclude that pulmonary blood flow has a marked effect on the uptake and release of leukocytes by the dog lung.


Genetic Toxicology and Safety Pharmacological Evaluation of Forsythin.
Forsythin is the main ingredient of Forsythia suspensa and is widely used in treatment of fever, viral cold, gonorrhea, and ulcers clinically. This study aimed to evaluate the potential genetic toxicity of forsythin and its safety for human use. Based on the Good Laboratory Practice regulations and test guidelines, the genetic toxicity of forsythin was assessed by the Ames test, chromosome aberration (CA) test, and bone marrow micronucleus (MN) test in vivo. In the Ames test, five strains of Salmonella typhimurium were exposed to different concentrations of forsythin in the presence or absence of the S9 mixture, and then, the number of His + revertant colonies was counted. In the CA test, Chinese hamster lung (CHL) fibroblast cells were treated with different concentrations of forsythin, mitomycin C, or cyclophosphamide in the presence or absence of the S9 mixture, and the chromosomal aberrations were determined. In the MN test, bone marrow was isolated from the mice with different treatments, and the ratios of polychromatic erythrocytes (PCE) and erythrocytes (PCE/(PCE + NCE)) were measured. Finally, beagle dogs were divided into four groups (negative control, low dose, medium dose, and high dose groups), and then, a telemetry system was used to evaluate the safe use of forsythin. Ames test results showed that the number of colonies in all test strains with different treatments showed no significantly dose-dependent increase in the presence or absence of the S9 mixture (p > 0.05). In the CA test, the number of cells with aberrations in the CHL fibroblast cells treated with low, medium, and high doses of forsythin for 24/48 h in the absence of the S9 mixture was, respectively, 5.0/2.5, 4.5/1.5, and 5.0/5.0, and in the presence of the S9 mixture, the number was, respectively, 5.0, 5.0, and 4.5. These results showed that there was no significant difference compared to the negative control group either in the presence (2.0) or in the absence (4.0/2.5 for 24/48 h) of the S9 mixture (p > 0.05). The MN test showed that the values of PCE/(PCE + NCE) in the negative, positive controls, and forsythin treatment groups were all more than 20%, which indicated that forsythin had no cytotoxicity. Additionally, no significant toxicological effects of forsythin on blood pressure, respiration, temperature, electrocardiogram, and other physiological indicators in the conscious beagle dogs of different groups were observed by the telemetry method. Our findings showed that forsythin has low probability of genetic toxicity and no significant toxicological effects, which implied that forsythin is suitable for further development and potential application.


[Multifactorial etiology of obesity: nutritional and central aspects].
World-wide obesity and its effects are public health problems. Research on way of life and eating habits give some indications of etiological factors. Breast feeding and quantity of proteins intake in formulas are factors influencing the risks of obesity later on in life. Research undertaken by Rolland Cachera shows us the importance of the curve of BMI and how the obesity rebound can be predictive of obesity in later years allowing early decisions of weight control. Energy intake and energy expenditure are regulated by the central nervous system. It is a complex mechanism of afferent and efferent systems through the hypothalamus. The inverse effects of ghreline and of leptine on energy balance are more and more studied and cases of precocious obesity are explained by the identification of rare forms of monogenic obesity linked to the metabolism of leptine. The importance of inherited genes has a role and genetic predisposition is a reality. This new approach allows a clinical, etiological and, in the future, probably therapeutic attitude in case of severe precocious obesity.


Attention-deficit hyperactivity disorder. Pharmacotherapy and beyond.
Management of ADHD is a challenge that requires time, commitment, and great sensitivity on the part of the physician. Use of stimulant medications is often successful at improving symptoms, but it has become the knee-jerk treatment response for many. Given the wide-ranging effects of ADHD on aspects of patients' lives and the availability of various treatment alternatives, a multimodal approach is considered optimal. As more studies evaluate nonpharmacologic approaches such as behavior therapy, parent education, and neurofeedback and more physicians implement multimodal treatment, outcomes for patients with ADHD are expected to be even more positive.


Recent advances in engineering polyvalent biological interactions.
Polyvalent interactions, where multiple ligands and receptors interact simultaneously, are ubiquitous in nature. Synthetic polyvalent molecules, therefore, have the ability to affect biological processes ranging from protein-ligand binding to cellular signaling. In this review, we discuss recent advances in polyvalent scaffold design and applications. First, we will describe recent developments in the engineering of polyvalent scaffolds based on biomolecules and novel materials. Then, we will illustrate how polyvalent molecules are finding applications as toxin and pathogen inhibitors, targeting molecules, immune response modulators, and cellular effectors.


Injecting partially digested cartilage fragments into a biphasic scaffold to generate osteochondral composites in a nude mice model.
This study proposed a novel scaffold with heterogeneous morphology that mimics the natural tissue. Its upper part contains a hollow cavity surrounded by a wall of poly(L-lactic-co-glycolic acid) (PLGA) porous membrane for injecting cartilage tissue and cells. An interconnecting porous structure located under the hollow cavity was made of composite materials that combined PLGA and beta-tricalcium phosphate (beta-TCP) to simulate the subchondral bone. Adult pig articular cartilage was cut and sieved into small fragments. The tissue fragments was partially digested by 0.1% collagenase for 0, 2, 4, and 6 h and injected into the hollow cavity of the biphasic scaffold. The biphasic scaffolds were then implanted into the subcutaneous pocket of nude mice for 4 weeks. No tissue bonding or new cartilaginous tissue formation was identified in the cartilage fragment without enzymatic treatment. The cartilage fragments digested with 2 h of collagenase digestion were partially integrated after implantation. The integrative properties of the cartilage fragment depended on the extent of enzymatic digestion. Releasing cells at the tissue surface enhanced confluence and bonding of the cartilage fragment matrix. Complete integration of the cartilage fragments and cartilage remodeling were achieved by digestion of the tissue fragments with 4 h of enzymatic treatment. The neocartilage grew from the upper hollow cavity into the lower PLGA/beta-TCP porous structure, forming an interface similar to that formed between cartilage and subchondral bone. This study combined the osteochondral scaffold and limited cartilage tissues to generate cartilage tissue in vivo intending for repairing full-thickness articular cartilage defects.


Development of AE147 Peptide-Conjugated Nanocarriers for Targeting uPAR-Overexpressing Cancer Cells.
An AE147 peptide-conjugated nanocarrier based on PEGylated liposomes was developed in order to target the metastatic tumors overexpressing urokinase-type plasminogen activator receptor (uPAR), which cancer progression via uPA signaling. Therefore, the AE147 peptide-conjugated nanocarrier system may hold the potential for active targeting of metastatic tumors. The AE147 peptide, an antagonist of uPAR, was conjugated to the PEGylated liposomes for targeting metastatic tumors overexpressing uPAR. Docetaxel (DTX), an anticancer drug, was incorporated into the nanocarriers. The structure of the AE147-conjugated nanocarrier, its physicochemical properties, and in vivo biodistribution were evaluated. The DTX-loaded nanocarrier showed a spherical structure, a high drug-loading capacity, and a high colloidal stability. Drug carrying AE147 conjugates were actively taken up by the uPAR-overexpressing MDA-MB-231 cancer cells. In vivo animal imaging confirmed that the AE147-conjugated nanoparticles effectively accumulated at the sites of tumor metastasis. The AE147-nanocarrier showed potential for targeting metastatic tumor cells overexpressing uPAR and as a nanomedicine platform for theragnosis applications. These results suggest that this novel nano-platform will facilitate further advancements in cancer therapy.


X-ray Detectors Based on Ga2O3 Microwires.
X-ray detectors have numerous applications in medical imaging, industrial inspection, and crystal structure analysis. Gallium oxide (Ga2O3) shows potential as a material for high-performance X-ray detectors due to its wide bandgap, relatively high mass attenuation coefficient, and resistance to radiation damage. In this study, we present Sn-doped Ga2O3 microwire detectors for solar-blind and X-ray detection. The developed detectors exhibit a switching ratio of 1.66 × 102 under X-ray irradiation and can operate stably from room temperature to 623 K, which is one of the highest reported operating temperatures for Ga2O3 X-ray detectors to date. These findings offer a promising new direction for the design of Ga2O3-based X-ray detectors.


Relationship between Glasgow Outcome Scale and neuropsychological measures after brain injury.
The present study was conducted to further our understanding of the relationship between performance on neuropsychological tests and functional status after head injury and to provide information on the relative usefulness of neuropsychological tests as outcome measures in clinical trials of brain injury. We sought to select the fewest number of 19 neuropsychological tests administered to 110 patients that, in combination, were most closely related to outcome (as measured by the Glasgow Outcome Scale (GOS) and to the remaining neuropsychological measures. The relationship of memory and intellectual deficits to functional status was also considered. To address these questions, we analyzed 19 neuropsychological measures and GOS scores of 110 severely brain injured patients from the Traumatic Coma Data Bank. Of 19 neuropsychological measures compared with GOS at 3 and 6 months, four tests (Controlled Oral Word Association, Grooved Pegboard, Trailmaking Part B, and Rey-Osterrieth Complex Figure Delayed Recall) provided the closest relationship to GOS and to the remaining 15 tests. Similar analyses were performed on 30 moderately injured patients to test the generality of our findings across different levels of patient severity. The same four tests were found to be highly predictive of GOS. Grooved Pegboard, a test of fine motor coordination, accounted for 80% of the variation in GOS. Fifteen percent of 116 patients with severe brain injury could not complete a neuropsychological battery and 39% were excluded because of previous brain injury or known substance abuse.


"Adolescents who feel depressed are rejected but do not withdraw: A longitudinal study of ethnically diverse friendship networks in England, Sweden, and Germany".
Adolescents who feel depressed are likely to experience social isolation from friends. Previous studies have put forward at least four hypotheses that can account for the association between felt depression and social isolation. The hypotheses are: (1) adolescents who are rejected tend to feel more depressed, (2) adolescents who feel depressed tend to become rejected, (3) adolescents who withdraw from friends tend to feel more depressed, and (4) adolescents who feel depressed tend to withdraw from friends. The present study aims to test these four hypotheses in ethnically diverse contexts in three countries. Two waves of data from England (n = 515), Sweden (n = 1,228), and Germany (n = 869) were obtained from the Children of Immigrants Longitudinal Survey in Four European Countries (CILS4EU). One separate stochastic actor-oriented model of the longitudinal coevolution of friendship networks and felt depression was estimated for each of the three countries using the statistical package RSiena. The results consistently indicated that, in all three countries, adolescents who felt depressed were rejected by their peers. Also, the results consistently indicated that adolescents who felt depressed sought more friends, and the results therefore refuted the suggestion that adolescents who feel depressed withdraw from their friends. The findings of the study can inform health-promotion interventions that attempt to limit the social isolation of adolescents who feel depressed in ethnically diverse contexts. More specifically, the study suggests that the social isolation of adolescents who feel depressed may be limited through interventions that reduce the rejection that these adolescents experience from their peers.


Comparative morphometric analysis of terminal vascularization of hippocampal CA1 and CA3 sectors in Mongolian gerbils.
Comparative morphometric analysis of terminal vascularization (vessels with a diameter lower than 12.5 microns) in the ischemia-sensitive sector CA1 and the ischemia-resistant sector CA3 of Ammon's horn in Mongolian gerbils was performed. Basing on numerous computer-counted parameters characterizing the terminal vascular network in both hippocampal sectors and its relationship to the surrounding tissue, it was shown that a number of capillary vessels, their average diameter, and exchange and flow surfaces were to a statistically significant degree lower in the pyramidal layer of the CA1 sector as compared with those in CA3 sector. The number of pyramidal neurons in the pyramidal layer, counted per surface unit was in sector CA1 higher than in sector CA3. The obtained data indicate clearly an angioarchitectonically dependent lower microvascular capacity of sector CA1. However, these differences do not indicate per se a leading role of the vascular factor in the pathomechanism of selective vulnerability to ischemia. They may be a factor facilitating neuronal damage evoked by the excitotoxic action of glutamate, observed in CA1 sector as a result of forebrain ischemia.


[The social and ethno-cultural prerequisites of suicidal behavior of adolescents in the Republic of Buryatia].
The article considers social and ethno-cultural risk factors of suicidal behavior in Buryat adolescents. The analysis of life-style of children and adolescents in actual conditions was implemented. The immediate family and external social environment were characterized. The system of vital values was analyzed. The study demonstrated that in Buryat population the is a leading one. The system of relationship of adolescents with parents, school teachers and peers was analyzed. It is established that only 62.35 of adolescents are satisfied with these relationships. It is established that Buryat adolescents changing of life-style resulted in transformation of family and decreasing of its fostering function can be considered as risk factor of suicidal behavior. The frustration of affiliation needs i.e. need in the relationship most important for Buryat ethnos is considered as the ethno-cultural factor. The risk of suicidal behavior increases when such factors as rudeness or hardheartedness of teacher, school community turning down are added.


Field and numerical evaluation of breakthrough suction effects in lysimeter design.
Lysimetry has been acknowledged in the literature as the most effective means of assessing deep percolation rates through landfill final covers. Designing lysimeters requires several tools, including thorough laboratory testing and numerical modelling. This paper focuses on a fundamental boundary condition, namely breakthrough suction, and how it affects lysimeter design. This study was triggered by a multi-year database of suction and seepage data collected from a large-scale lysimeter constructed at the St-Nicephore landfill, Quebec, Canada. Tensiometers were installed at several levels near and at the interface between the cover material and the drainage layer inside the lysimeter, and outflow was measured using tipping counters. Based on field results and an analysis thereof, different geometry scenarios were simulated with HYDRUS-2D, and it was observed that in lysimeters designed using the linear method, breakthrough suction at the lower boundary can result in a greater than 90% percolation performance. With climate change, lysimeter percolation rate estimates may also be affected by rainfall events of varying magnitudes. Lastly, we were able to assess the existing design procedures and suggest a simple and conservative approach.


The Pawnee earthquake as a result of the interplay among injection, faults and foreshocks.
The Pawnee M5.8 earthquake is the largest event in Oklahoma instrument recorded history. It occurred near the edge of active seismic zones, similar to other M5+ earthquakes since 2011. It ruptured a previously unmapped fault and triggered aftershocks along a complex conjugate fault system. With a high-resolution earthquake catalog, we observe propagating foreshocks leading to the mainshock within 0.5 km distance, suggesting existence of precursory aseismic slip. At approximately 100 days before the mainshock, two M ≥ 3.5 earthquakes occurred along a mapped fault that is conjugate to the mainshock fault. At about 40 days before, two earthquakes clusters started, with one M3 earthquake occurred two days before the mainshock. The three M ≥ 3 foreshocks all produced positive Coulomb stress at the mainshock hypocenter. These foreshock activities within the conjugate fault system are near-instantaneously responding to variations in injection rates at 95% confidence. The short time delay between injection and seismicity differs from both the hypothetical expected time scale of diffusion process and the long time delay observed in this region prior to 2016, suggesting a possible role of elastic stress transfer and critical stress state of the fault. Our results suggest that the Pawnee earthquake is a result of interplay among injection, tectonic faults, and foreshocks.


Sarcopenia.
Sarcopenia is defined as a combination of low muscle mass with low muscle function. The term was first used to designate the loss of muscle mass and performance associated with aging. Now, recognized causes of sarcopenia also include chronic disease, a physically inactive lifestyle, loss of mobility, and malnutrition. Sarcopenia should be differentiated from cachexia, which is characterized not only by low muscle mass but also by weight loss and anorexia. Sarcopenia results from complex and interdependent pathophysiological mechanisms that include aging, physical inactivity, neuromuscular compromise, resistance to postprandial anabolism, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, mitochondrial dysfunction, and inflammation. The prevalence of sarcopenia ranges from 3% to 24% depending on the diagnostic criteria used and increases with age. Among patients with rheumatoid arthritis 20% to 30% have sarcopenia, which correlates with disease severity. Sarcopenia exacts a heavy toll of functional impairment, metabolic disorders, morbidity, mortality, and healthcare costs. Thus, the consequences of sarcopenia include disability, quality of life impairments, falls, osteoporosis, dyslipidemia, an increased cardiovascular risk, metabolic syndrome, and immunosuppression. The adverse effects of sarcopenia are particularly great in patients with a high fat mass, a condition known as sarcopenic obesity. The diagnosis of sarcopenia rests on muscle mass measurements and on functional tests that evaluate either muscle strength or physical performance (walking, balance). No specific biomarkers have been identified to date. The management of sarcopenia requires a multimodal approach combining a sufficient intake of high-quality protein and fatty acids, physical exercise, and antiinflammatory medications. Selective androgen receptor modulators and anti-myostatin antibodies are being evaluated as potential stimulators of muscle anabolism.


Management of Hospitalized Febrile Neonates Without CSF Analysis: A Study of US Pediatric Hospitals.
Management of febrile neonates includes obtaining blood, urine, and cerebrospinal fluid (CSF) cultures with hospitalization for empiric parenteral antibiotic therapy. Outcomes and management for neonates were compared based on whether CSF was obtained. This multicenter retrospective review of the 2002 to 2012 Pediatric Health Information System database included hospitalized infants aged ≤28 days (neonates) admitted to an inpatient ward with a diagnosis code for fever or neonatal fever. Patients admitted to an ICU or with a complex chronic condition diagnosis code were excluded. Neonates were categorized as full septic workup (FSW; charge codes for blood, urine, and CSF culture or cell count) or as partial septic workup (PSW; charge codes for blood and urine cultures only), and their data were compared. Of 27 480 neonates with a diagnosis code for fever, 14 774 underwent the FSW and 3254 had a PSW. Median length of stay was 2 days for both groups, with no significant difference in readmissions, disposition, or parenteral antibiotic administration. Neonates with a PSW had significantly greater odds of having charge codes for additional laboratory testing and imaging, and they were more likely to receive a diagnosis code for sepsis, meningitis, or bronchiolitis. Neonates with PSW had lengths of stay and readmission rates similar to those with FSW but were more likely to undergo additional laboratory testing and imaging. Future studies including information about clinical severity and test results may provide additional insight into the variation in practice for this patient population.


Cyclosporine in psoriasis treatment. Inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor alpha/epidermal growth factor receptor pathways.
Cyclosporine, an immunosuppressive drug, is effective in the treatment of recalcitrant psoriasis. Previous work suggested that keratinocyte hyperproliferation and inflammation are linked in psoriasis and that immune mechanisms participate in the pathogenesis of psoriasis. Transforming growth factor (TGF) alpha may be an important regulatory factor of epidermal growth as overproduction of TGF-alpha is associated with epidermal hyperplasia in psoriatic plaques and epidermal growth factor receptors are overexpressed in psoriatic epithelium. In this study, the effects of cyclosporine on cultured human keratinocytes were examined. Cyclosporine specifically inhibited keratinocyte cell-cycle progression in the G1 phase without causing keratinocytes to terminally differentiate. Cyclosporine did not decrease the expression of TGF-alpha or epidermal growth factor receptors. These results suggest that the effects of cyclosporine on psoriatic skin are unrelated to direct effects on autocrine growth regulation of keratinocytes via TGF-alpha production or of epidermal growth factor receptor modulation.


Diabetes on demand and novel technologies.
To date, the use of technology for the management of diabetes represents a promising area of innovation that can dramatically change diabetics' lives. In the past decade, the use of diabetes devices has widely grown and looks to have partially improved diabetes management. The combination of cloud technology with real-expert intervention saves time and improves efficiency, as well as empowering the patient. The application of mathematical models applied to diabetes therapy could lead to significant improvement in life quality and challenge the burden of hypoglycaemia. Events where an individual needs support are instantly achieved, triggering outreach alerts via cloud and wireless connectivity, thereby improving patient compliance and reducing disease costs.