Peak Width of Skeletonized Mean Diffusivity as a Marker of Diffuse Cerebrovascular Damage.
The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. 145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer's disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH. PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes. PSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden.


The effect of delta-9-tetrahydrocannabinol on herpes simplex virus replication.
Both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) failed, in an identical fashion to replicate and produce extensive c.p.e. in human cell monolayer cultures which were exposed (8 h before infection, at infection, or 8 h p.i.) to various concentrations of delta-9-tetrahydrocannabinol. Similar results were obtained with a plaque assay utilizing confluent monkey cells. Possible mechanisms for this antiviral activity are discussed.


Surface forces measurements of spin-coated cellulose thin films with different crystallinity.
A systematic study of the surface forces between a cellulose sphere and cellulose thin films of varying crystallinity has been conducted as a function of ionic strength and pH. Semicrystalline cellulose II surfaces and amorphous cellulose films were prepared by spin-coating of the precursor cellulose solutions onto oxidized silicon wafers before regeneration in water. Crystalline cellulose I surfaces were prepared by spin-coating wafers with aqueous suspensions of sulfate-stabilized cellulose I nanocrystals. These preparation methods produced thin, smooth films suitable for surface forces measurements. The interaction with the cellulose I was monotonically repulsive at pH 3.5, 5.8, and 8.5 and at 0.1, 1, and 10 mM ionic strengths. This was attributed to the presence of strongly ionizable sulfur-containing groups on the cellulose nanocrystal surfaces. The amorphous film typically showed a steric interaction up to 100 nm away from the interface that was independent of the solution conditions. A range of surface forces were successfully measured on the semicrystalline cellulose II films; attractive and repulsive regimes were observed, depending on pH and ionic strength, and were interpreted in terms of van der Waals and electrostatic interactions. Clearly, the forces acting near cellulose surfaces are very dependent on the way the cellulose surface has been prepared.


Use of Postdischarge Emergency Medical Services to Reduce Hospital Readmissions: Does It Work and Is It Economically Feasible?
A new model of community health delivery has utilized emergency medical services (EMS) to manage care transitions and provide chronic care services in patients' homes. The authors performed a retrospective, case-controlled analysis of a quality improvement project that examined whether an EMS home visit to recently discharged inpatients from the zip code where EMS provides services can reduce 30-day unscheduled ED visits and hospital readmissions. Additionally, the financial impact from the perspective of the community-based EMS provider and the community hospital from which patients were discharged was examined. A total of 53 patients and 53 controls were matched on the following variables: readmission risk score, age, sex, insurance status, and case management intervention. Patients who received the intervention had a 44% relative reduction of 30-day ED visits (17% vs 24.5%, P = 0.3381) and a 28.4% relative reduction in 30-day readmissions (18.9% vs 26.4%, P = 0.3532) but neither achieved statistical significance. The intervention cost to EMS was $1937; the intervention led to a $3626 profit for the hospital compared to a loss of $9915 for the control group. Use of local EMS providers may lead to enhanced health care and financial outcomes for community hospitals but the study was underpowered to make a definitive conclusion. However, the results may allow health systems to assess whether collaboration with local EMS providers can improve outcomes at a lower cost.


Role of prokaryotic biomasses and activities in carbon and phosphorus cycles at a coastal, thermohaline front and in offshore waters (Gulf of Manfredonia, Southern Adriatic Sea).
The Western areas of the Adriatic Sea are subjected to inputs of inorganic nutrients and organic matter that can modify the trophic status of the waters and consequently, the microbiological processes involved in the carbon and phosphorus biogeochemical cycles, particularly in shallow coastal environments. To explore this topic, a survey was carried out during the spring of 2003 in a particular hydrodynamic area of the Gulf of Manfredonia, where the potential (P) and real (R) rates of four different microbial exoenzymatic activities (EEA) (α [αG] and ß glucosidases [ßG], leucine aminopeptidase [LAP], and alkaline phosphatase [AP]) as well as the P and R rates of prokaryotic heterotrophic production (PHP), AP as well as the P and R rates of PHP, primary production (PPnet), the prokaryotic and phototrophic stocks and basic hydrological parameters were examined. Three different water masses were found, with a thermohaline front (THF) being detected between the warmer and less saline coastal waters and colder and saltier offshore Adriatic waters. Under the general oligotrophic conditions of the entire Gulf, a decreasing gradient from the coastal toward the offshore areas was detected, with PHP, PPnet, stocks and EEA (αG, ßG, AP) being directly correlated with the temperature and inversely correlated with the salinity, whereas opposite relationships were observed for LAP activity. No enhancement of microbiological activities or stocks was observed at the THF. The use of P or R rates of microbiological activities, which decrease particularly for EEA, could result in discrepancies in interpreting the efficiency of several metabolic processes.


Pulse-Field capillary electrophoresis of repeat-primed PCR amplicons for analysis of large repeats in Spinocerebellar Ataxia Type 10.
Large expansions of microsatellite DNA cause several neurological diseases. In Spinocerebellar ataxia type 10 (SCA10), the repeat interruptions change disease phenotype; an (ATTCC)n or a (ATCCT)n/(ATCCC)n interruption within the (ATTCT)n repeat is associated with the robust phenotype of ataxia and epilepsy while mostly pure (ATTCT)n may have reduced penetrance. Large repeat expansions of SCA10, and many other microsatellite expansions, can exceed 10,000 base pairs (bp) in size. Conventional next generation sequencing (NGS) technologies are ineffective in determining internal sequence contents or size of these expanded repeats. Using repeat primed PCR (RP-PCR) in conjunction with a high-sensitivity pulsed-field capillary electrophoresis fragment analyzer (FEMTO-Pulse, Agilent, Santa Clara, CA) (RP-FEMTO hereafter), we successfully determined sequence content of large expansion repeats in genomic DNA of SCA10 patients and transformed yeast artificial chromosomes containing SCA10 repeats. This RP-FEMTO is a simple and economical methodology which could complement emerging NGS for very long sequence reads such as Single Molecule, Real-Time (SMRT) and nanopore sequencing technologies.


[Quantitative assessment of risks for coronary heart diseases in urban residents in Sichuan].
To set a quantitative criteria for determining risk for coronary heart disease (CHD) so that potential risk of an individual dying from CHD can be identified and to lay a foundation for predicting individual risk of CHD. Data of case-control and cohort studies published during 1978 to 2002, as well as data of surveillance of behavior exposure in Sichuan province, were collected by retrieval of literatures. Pooled odds ratios (OR) and relative risks (RR) of all risk factors for CHD were estimated using various statistical models with software for meta-analysis, and attributable risk fractions of varied levels of risk factors could be converted. A risk score conversion table (quantitative criteria for assessment) of main risk factors for CHD were developed for men and women aged 15 - 69 at an interval of five years, including smoking, passive smoking, hypertension, high blood cholesterol level, body mass index, lack of physical activity, alcohol drinking, past history of diabetes, and family history of CHD and hypertension. Individuals with all these risk factors had a risk score beyond 1.00, and risk score for those without them was equal to or below 1.00, which would increase with rise in one's risk level. Estimation of risk of dying from CHD was based on risk score conversion table of risk factors for CHD, which could be used to predict individual potential risk of dying from CHD in the following 10 years. It lays a foundation for health education to persuade people to change their unhealthy lifestyles and behaviors, and could be used in community health services.


The clinical implications of the World Health Organization's classification of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic clonal stem cell diseases characterized by dysplastic morphological features with a varying percentage of leukemic blasts and clinical bone marrow failure. The French-American-British (FAB) system served as the gold standard of MDS classification for more than two decades. The World Health Organization (WHO) classification, built on the backbone of the FAB classification, is an attempt to further improve the prognostic value of MDS classification as well as to establish its clinical utility as a tool to select different treatments. In this article we highlight the major differences between the FAB classification and the WHO MDS classification. We discuss in more details the experience of using the new WHO classification since its publications and review the studies that tried to either validate the prognostic value of the new classification or apply it to predict clinical responses to various treatments.


Circumcision and meatotomy.
The indications for and complications of neonatal circumcision are presented in this article, along with a discussion of meatal stenosis. Suggested methods for performing office-based meatotomy and in-nursery circumcision are outlined.


Amino acid changes at positions 173 and 187 in the human T-cell leukemia virus type 1 surface glycoprotein induce specific neutralizing antibodies.
The nucleotide sequence of human T-cell leukemia virus type 1 (HTLV-1) is highly conserved, most strains sharing at least 95% sequence identity. This sequence conservation is also found in the viral env gene, which codes for the two envelope glycoproteins that play a major role in the induction of a protective immune response against the virus. However, recent reports have indicated that some variations in env sequences may induce incomplete cross-reactivity between HTLV-1 strains. To identify the amino acid changes that might be involved in the antigenicity of neutralizable epitopes, we constructed expression vectors coding for the envelope glycoproteins of two HTLV-1 isolates (2060 and 2072) which induced human antibodies with different neutralization patterns. The amino acid sequences of the envelope glycoproteins differed at four positions. Vectors coding for chimeric or point-mutated envelope proteins were derived from 2060 and 2072 HTLV-1 env genes. Syncytium formation induced by the wild-type or mutated envelope proteins was inhibited by human sera with different neutralizing specificities. We thus identified two amino acid changes, I173-->V and A187-->T, that play an important role in the antigenicity of neutralizable epitopes located in this region of the surface envelope glycoprotein.


The Aspergillus nidulans signalling mucin MsbA regulates starvation responses, adhesion and affects cellulase secretion in response to environmental cues.
In the heterogeneous semi-solid environment naturally occupied by lignocellulolytic fungi the majority of nutrients are locked away as insoluble plant biomass. Hence, lignocellulolytic fungi must actively search for, and attach to, a desirable source of nutrients. During growth on lignocellulose a period of carbon deprivation provokes carbon catabolite derepression and scavenging hydrolase secretion. Subsequently, starvation and/or contact sensing was hypothesized to play a role in lignocellulose attachment and degradation. In Aspergillus nidulans the extracellular signalling mucin, MsbA, influences growth under nutrient-poor conditions including lignocellulose. Cellulase secretion and activity was affected by MsbA via a mechanism that was independent of cellulase transcription. MsbA modulated both the cell wall integrity and filamentous growth MAPK pathways influencing adhesion, biofilm formation and secretion. The constitutive activation of MsbA subsequently enhanced cellulase activity by increasing the secretion of the cellobiohydrolase, CbhA, while improved substrate attachment and may contribute to an enhanced starvation response. Starvation and/or contact sensing therefore represents a new dimension to the already multifaceted regulation of cellulase activity.


[Atmospheric asbestos pollution in the urban environment: Milan, Casale Monferrato, Brescia, Ancona, Bologna and Florence].
The atmospheric concentrations of asbestos fibres were measured in 6 towns by long term sampling of air (3 weeks) and by counting at TEM both long and short fibres. Chrisotile and amphiboles were separately counted. For each town high traffic, low traffic and no traffic zones were considered as well as industrial areas and areas with possible and probable sources of asbestos pollution. For Milano the seasonal variations in atmospheric concentrations of asbestos fibres were also recorded in a central square. The maximum concentrations of total fibres was found in Milano (251.7 fibres/liter) and the minimum in Bologna (0.3 fibres/liter). Chrisotile and ultrashort fibres are the most frequent component of the atmospheric pollution. The fibre counts to which people is exposed are far below the levels at which it has been possible to detect risks in industry: however the possibility of a synergism between asbestos and other pollutants with consequent increase of the total carcinogenic potential of the polluted atmosphere cannot be ruled out. The control of the most active sources of asbestos dispersion must be considered in a correct balance between costs and social benefits.


Convenient new chemical actinometer based on aqueous acetone, 2-propanol, and carbon tetrachloride.
A convenient new chemical actinometer was developed to measure the spectral output of laboratory ultraviolet (UV) light sources over the wavelength range of 260-330 nm. It can also be used to measure solar UV irradiance (< or =325 nm). The actinometer is based on the photoreduction of aqueous carbon tetrachloride (CT) to chloroform (CF) in the presence of acetone (the chromophore) and 2-propanol (the reductant). In all cases, CT disappearance (and CF formation) followed zero-order kinetics over 95% of the reaction. The slope of the linear decay curve forms the basis of the new actinometer, which was calibrated using ferrioxalate actinometry. Quantum yields were measured at 10 nm intervals and were found to be uniform throughout the range of 260-300 nm. As expected, quantum yields gradually decreased to zero asthe wavelength was increased from 300 to 340 nm. The high quantum yields (approximately 150), low sensitivityto room light, and the straightforward determination of [CT] and [CF] by gas chromatography offer significant advantages over some other chemical actinometers, which might require the preparation and purification of light-sensitive compounds in a darkened environment and long exposure times.


Alternative Splicing: Expanding Diversity in Major ABC and SLC Drug Transporters.
Alternative splicing is an important mechanism of genetic regulation enhancing diversity and complexity of the transcriptome and proteome from the finite number of genes. Many reported cases demonstrate that alternative splicing events can lead to changes in the expression/function of proteins during disease development and progression. For pharmacogenes that can influence drug disposition and response, the role of alternative splicing has begun to receive increasing attention as an under-explored source of variable drug response. Here, we provide an overview of alternative spliced variants reported for the major drug transporters of SLC and ABC families with their possible implications in disease and drug therapy. As more comprehensive analyses on the abundance and functional outcomes of variably spliced isoforms of major drug transporters become available, it will be possible to utilize the obtained knowledge as novel therapeutic targets for tailored treatment strategies.


An IkappaB homolog encoded by African swine fever virus provides a novel mechanism for downregulation of proinflammatory cytokine responses in host macrophages.
Cytokines stimulate inflammatory defenses against viral infections. In order to evade host defenses, viruses have developed strategies to counteract antiviral cytokines. African swine fever virus (ASFV) is a large, double-stranded DNA virus that infects macrophages. This study demonstrates that ASFV effectively inhibited phorbol myristic acid-induced synthesis of antiviral, proinflammatory cytokines alpha interferon, tumor necrosis factor alpha, and interleukin-8 in infected macrophages as assessed by enzyme-linked immunosorbent assay and reverse transcriptase PCR. In contrast, levels of mRNA and protein for transforming growth factor beta, an anti-inflammatory cytokine, were increased by ASFV infection, suggesting that ASFV-induced inhibition of cytokine synthesis may be limited to cytokines activated by NFkappaB. An interleukin-8 promoter, containing an NFkappaB enhancer site, driving expression of a luciferase reporter gene was used to show that NFkappaB-dependent transcription was inhibited by the virus and by a cloned ASFV gene, A238L. This gene encodes a protein with homology to IkappaB, the inhibitor of NFkappaB. Electrophoretic mobility shift assay showed that cells expressing the A238L gene inhibited NFkappaB binding to DNA. These results suggest that the A238L gene product interacts with NFkappaB to prevent transcription and downregulate proinflammatory cytokine production. This novel viral evasion strategy encoded in a single IkappaB-like protein may be capable of inhibiting most macrophage NFkappaB-dependent antiviral mechanisms and may provide insights into how ASFV causes a fatal hemorrhagic disease of domestic pigs and a persistent infection in the African warthog, which is its natural permissive host.


Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis.
The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes1. Although T cells are the predominant TIL population2, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.


Effects of AgRP inhibition on energy balance and metabolism in rodent models.
Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance.


Coevolution and divergence in the Joshua tree/yucca moth mutualism.
Theory suggests that coevolution drives diversification in obligate pollination mutualism, but it has been difficult to disentangle the effects of coevolution from other factors. We test the hypothesis that differential selection by two sister species of pollinating yucca moths (Tegeticula spp.) drove divergence between two varieties of the Joshua tree (Yucca brevifolia) by comparing measures of differentiation in floral and vegetative features. We show that floral features associated with pollination evolved more rapidly than vegetative features extrinsic to the interaction and that a key floral feature involved in the mutualism is more differentiated than any other and matches equivalent differences in the morphology of the pollinating moths. A phylogenetically based, ancestral states reconstruction shows that differences in moth morphology arose in the time since they first became associated with Joshua trees. These results suggest that coevolution, rather than extrinsic environmental factors, has driven divergence in this obligate pollination mutualism.


Implementation of Project Students Are Sun Safe (SASS) in Rural High Schools Along the Arizona-Mexico Border.
The incidence of skin cancer is raising in Hispanics/Latinos, which is a concern for Hispanics/Latinos living in Arizona, a state with a high amount of ultraviolet radiation exposure. There is a dearth of research on skin cancer prevention education for Hispanic/Latino adolescents in high school. Using a community-based participatory research (CBPR) framework, academic and community partners conducted a project to adapt an existing efficacious skin cancer prevention program, Project Students are Sun Safe (SASS) and the current SASS online training model, for dissemination to predominantly Hispanic/Latino students attending high schools in rural southeastern Arizona, located along the Arizona-Mexico border. We assessed the feasibility of training some of these students as peer educators (n = 16) to implement the "Border SASS" lesson to their peers in high school classrooms (n = 198). Border SASS training and the classroom lesson were feasible for, and highly acceptable to, peer educators and classroom students. These students significantly improved skin cancer prevention knowledge scores and self-reported skin cancer prevention behaviors over a 3- to 4-month period post training and the intervention implementation. Here we report on the following: (1) academic-community partnership and adaptation of the SASS training model for rural Hispanic high school students, (2) training of the high school peer educators, (3) administration of the SASS lesson by the trained peer educators to high school students, and (4) further evaluation of peer educator training and classroom student outcomes.


STAT3-Induced Upregulation of lncRNA CASC9 Promotes the Progression of Bladder Cancer by Interacting with EZH2 and Affecting the Expression of PTEN.
Long non-coding RNA (lncRNA) cancer susceptibility candidate 9 (CASC9) has been reported to play a vital role in tumorigenesis. This study explored the biological role of CASC9 and its regulation mechanism in bladder cancer (BC). Gene expression was evaluated using quantitative reverse transcription polymerase chain reaction and Western blot. The functional role of CASC9 in BC was studied using Cell Counting Kit-8, colony formation assay, scratch wound healing assay, transwell invasion assay, and xenograft tumor assay. In addition, the mechanism of CASC9 function in BC was determined using RNA immunoprecipitation assay and chromatin immunoprecipitation assay. CASC9 was upregulated in BC tissues and cell lines, and correlated with the staging and metastasis in BC. Knockdown of CASC9 inhibited the proliferation, migration, and invasion of BC cells. Similarly, silencing of CASC9 inhibited tumor growth in vivo. Signal transducer and activator of transcription 3 (STAT3) was upregulated in BC tissues and cell lines, and positively correlated with CASC9 in BC tissues. Moreover, CASC9 was shown to be regulated by STAT3 in BC cells. Furthermore, CASC9 regulated phosphatase and tensin homolog (PTEN) expression by interacting with enhancer of zeste homolog 2 (EZH2). More significantly, CASC9 silencing-mediated inhibition of BC progression was partly reversed by EZH2 overexpression or PTEN inhibition. Upregulation of CASC9 induced by STAT3 promoted the progression of BC by interacting with EZH2 and affecting the expression of PTEN, representing a novel regulatory mechanism for BC progression.


Role of cGAS-STING in colorectal cancer: A new window for treatment strategies.
Colorectal cancer (CRC) is a common and deadly form of cancer, leading to the need for new therapeutic targets and strategies for treatment. Recent studies have shown the cGAS-STING pathway to be a promising target for cancer therapy. The cGAS-STING pathway is a part of the innate immune system and serves to identify DNA damage and viral infection, promoting an immune response. Activation of this pathway leads to the production of immune mediators, such as type I interferons, that activate immune cells to attack cancer cells. Research has identified the cGAS-STING pathway as a frequently dysregulated component in CRC, promoting tumor growth and metastasis, or leading to chronic inflammation and tissue damage. The modulation of this pathway presents a potential therapeutic approach, either activating or inhibiting the pathway to enhance the immune response and prevent inflammation, respectively. Developing drugs that can modulate the cGAS-STING pathway offers promise for improving treatment outcomes for CRC patients. The present review explores recent research on the role of cGAS-STING in CRC and highlights the potential therapeutic benefits of targeting this pathway.


The complex of Arl2-GTP and PDE delta: from structure to function.
Arf-like (Arl) proteins are close relatives of the Arf regulators of vesicular transport, but their function is unknown. Here, we present the crystal structure of full-length Arl2-GTP in complex with its effector PDE delta solved in two crystal forms (Protein Data Bank codes 1KSG, 1KSH and 1KSJ). Arl2 shows a dramatic conformational change from the GDP-bound form, which suggests that it is reversibly membrane associated. PDE delta is structurally closely related to RhoGDI and contains a deep empty hydrophobic pocket. Further experiments show that H-Ras, Rheb, Rho6 and G alpha(i1) interact with PDE delta and that, at least for H-Ras, the intact C-terminus is required. We suggest PDE delta to be a specific soluble transport factor for certain prenylated proteins and Arl2-GTP a regulator of PDE delta-mediated transport.


Origin and extent of resistance to fipronil in the German cockroach, Blattella germanica (L.) (Dictyoptera: Blattellidae).
Fipronil, a phenylpyrazole insecticide, was made available in 1999 in bait formulations for use against the German cockroach, Blattella germanica (L.). We have investigated resistance to fipronil in the descendants of cockroaches collected just before, or contemporaneously with, the introduction of fipronil baits. Cockroaches were obtained in two types of settings: homes that either had or had not been serviced by a pest management professional while occupied by their current residents. Thorough inspections by us turned up no evidence that fipronil had been used in any of the homes, and in addition, no residents claimed to have used baits containing fipronil. Resistance to fipronil was detected by topically dosing adult males with the LC99 of fipronil, the value of which was determined in a dose-response assay with males of an insecticide-susceptible strain. Fewer than 99 of 100 males of all field-collected strains died within 72 h of being treated. Moreover, substantial numbers of males survived doses three and 10-fold greater than the LC99. Regression analysis showed that 67% of the variation in the percentage of males that died after being treated with fipronil was explained by a linear relationship with the percentage that died after being treated with dieldrin. Therefore, it appears that resistance to fipronil in German cockroaches--whose ancestors had never been exposed to it--is attributable to enduring resistance to the cyclodienes, which were formerly used for cockroach control and have a similar mode of action as fipronil. Lastly, we found that insects resistant to topically administered fipronil were likewise resistant, and to a similar degree, to ingested fipronil.


Xlr1 is involved in the transcriptional control of the pentose catabolic pathway, but not hemi-cellulolytic enzymes in Magnaporthe oryzae.
Magnaporthe oryzae is a fungal plant pathogen of many grasses including rice. Since arabinoxylan is one of the major components of the plant cell wall of grasses, M. oryzae is likely to degrade this polysaccharide for supporting its growth in infected leaves. D-Xylose is released from arabinoxylan by fungal depolymerising enzymes and catabolized through the pentose pathway. The expression of genes involved in these pathways is under control of the transcriptional activator XlnR/Xlr1, conserved among filamentous ascomycetes. In this study, we identified M. oryzae genes involved in the pentose catabolic pathway (PCP) and their function during infection, including the XlnR homolog, XLR1, through the phenotypic analysis of targeted null mutants. Growth of the Δxlr1 strain was reduced on D-xylose and xylan, but unaffected on L-arabinose and arabinan. A strong reduction of PCP gene expression was observed in the Δxlr1 strain on D-xylose and L-arabinose. However, there was no significant difference in xylanolytic and cellulolytic enzyme activities between the Δxlr1 mutant and the reference strain. These data demonstrate that XLR1 encodes the transcriptional activator of the PCP in M. oryzae, but does not appear to play a role in the regulation of the (hemi-) cellulolytic system in this fungus. This indicates only partial similarity in function between Xlr1 and A. niger XlnR. The deletion mutant of D-xylulose kinase encoding gene (XKI1) is clearly unable to grow on either D-xylose or L-arabinose and showed reduced growth on xylitol, L-arabitol and xylan. Δxki1 displayed an interesting molecular phenotype as it over-expressed other PCP genes as well as genes encoding (hemi-) cellulolytic enzymes. However, neither Δxlr1 nor Δxki1 showed significant differences in their pathogeny on rice and barley compared to the wild type, suggesting that D-xylose catabolism is not required for fungal growth in infected leaves.


Learning to Eat: Behavioral and Psychological Aspects.
Because infants are totally dependent upon parents (or other caregivers) for care and sustenance, parents' feeding practices are a key feature of the family environments in which infants and young children learn about food and eating. Feeding practices include not only what the child is fed, but also the how, when, why and how much of feeding. Extensive evidence indicates that parenting behavior influences a variety of child outcomes, including cognitive and socioemotional development, as well as the development of self-regulatory skills. The focus of this chapter is on what is known about how parenting, particularly feeding practices, influences the early development of several aspects of children's eating behavior, including the acquisition of food preferences, self-regulatory skills, children's reactivity to food cues, satiety responsiveness and 'picky eating'. It is argued that traditional feeding practices, which evolved to protect children from environmental threats and ensure adequate intake in the context of food scarcity, can be maladaptive in current environments. An evidence base is needed to inform public policy to reduce early obesity risk in current environments, where too much palatable food is a major threat to child health. Results of recent research provides evidence that promoting responsive feeding practices can alter the development of eating behavior, sleep patterns and early self-regulatory skills, as well as reduce early obesity risk.


A systematic review of the evidence on the effect of parental communication about health and health behaviours on children's health and wellbeing.
Parents report feeling unsure how best to talk with their children about sensitive health topics and may avoid such conversations; yet if children have questions or concerns about their health, talking to a parent could enhance their health and wellbeing. We investigated the effects of parental communications about health and health behaviours on children's health and wellbeing, and explored what strategies can encourage parents to communicate about health. We conducted a systematic review and narrative synthesis of research published between January 2008 and April 2020 from five databases. Of 14,007 articles identified, 16 met inclusion criteria focusing on five topics: diet and weight (n = 5), body image (n = 2), sexual health (n = 7), physical activity (n = 1) and bullying (n = 1). Positive child outcomes were associated with positive general parent-child communication characterised by warmth, openness and allowing children choice. Conversely, hostility, negative and inconsistent messaging were associated with poorer outcomes. Interventions to increase parent-child communication could be classified as providing single directive messages, media campaigns or intensive support. Single messages increased communication frequency; media campaigns and intensive interventions showed mixed outcomes. No differences in outcomes were found according to child's gender or socio-economic status. Generally, parents were less confident in initiating, rather than continuing, conversations and were more likely to initiate conversations when they felt they had good topic knowledge. While the relatively small, diverse sample limits the strength of these findings, this review provides provisional support for approaches to promote positive parent-child communication about health that are associated with better child health and wellbeing.


The eidochromatic transform for color-image coding.
We introduce the eidochromatic transform as a tool for improved lossy coding of color images. Many current image-coding formats (such as JPEG 2000) utilize both a color-component transform (relating values of different image components at a single location) and a wavelet or other spatial transform (relating values of a single-image component at proximate, but different image locations). The eidochromatic transform further reduces redundancy by relating image values simultaneously across color components and in the two spatial dimensions. Our approach is to introduce an additional transform step following the color-component and spatial transforms. In tests, this step reduced the overall static entropy of the chrominance components of quantized transformed images by up to 40% or more. Combined with JPEG 2000's modeling and coding method, the eidochromatic transform was found to reduce the size of lossily coded color images by up to 27% overall.


Use of functional employment testing to facilitate safe job placement.
Functional testing has evolved to a new sophistication, and is currently used in a variety of situations to assist the employer and physician in safely placing an individual at the job site. The functional capacity evaluation can be employed in several ways, not only to place individuals safely in jobs, but also to monitor their progress throughout recovery from an injury or illness and aid in the establishment of vocational counseling and planning. Many legal issues now alter employer techniques for hiring and assigning people to jobs. This state of affairs places increasing importance on functional testing.


Glycemic control and oxidative stress markers and their relationship with the thioredoxin interacting protein (TXNIP) gene in type 2 diabetic patients.
To investigate the relationship between oxidative stress and biochemical parameters and the expression of TXNIP, IL-6, IL-1β and TNF-α in peripheral mononuclear cells (PMCs) from type-2 diabetic patients. We studied 60 males: 20 normal-weight type- 2 diabetic patients (NW), 20 obese diabetic patients (OB) and 20 controls (C). Biochemical and oxidative stress parameters were evaluated. PMCs were isolated and total RNA was extracted in order to determine the expression of TXNIP, IL-6, IL-1β and TNF-α by qRT-PCR. OB had higher weight, BMI and abdominal circumference (One way ANOVA, p<0.0001). NW had higher fasting glycemia (One way ANOVA, p=0.0034) however OB had higher HbA1c (One way ANOVA, p<0.0001). OB also had higher hsCRP (One way ANOVA, p=0.0158). TBARS and AGES were elevated in both NW and OB (One way ANOVA, p<0.0001 and p=0.0008, respectively). Compared to OB and C participants, the expression of TXNIP was significantly higher in NW (Kruskal Wallis, p=0.0074); IL-1β, IL-6 and TNF-α transcripts were higher in NW and OB (Kruskal Wallis, p<0.0001, for all). In NW patients, the expression of TXNIP was positively correlated with fasting glycemia and AGES and negatively correlated with HOMA-β (r=0.72; r=0.59; r=-0.44, respectively, for all p<0.05), in OB there was correlation only with 8-Isoprostanes (r=0.42, p=0.046). Our results suggest that fasting glycemic control, independent of adiposity and nutritional status, represents a risk factor for β-cell dysfunction, increases oxidative stress markers and it is related with an elevation of TXNIP expression.


Gold nanostructures: a class of multifunctional materials for biomedical applications.
Gold nanostructures have proven to be a versatile platform for a broad range of biomedical applications, with potential use in numerous areas including: diagnostics and sensing, in vitro and in vivo imaging, and therapeutic techniques. These applications are possible because of the highly favorable properties of gold nanostructures, many of which can be tailored for specific applications. In the first part of this tutorial review, we will discuss the most critical properties of gold nanostructures for biomedical applications: surface chemistry, localized surface plasmon resonance (LSPR), and morphology. In the second part of the review, we will discuss how these properties can be harnessed for a selection of biomedical applications, aiming to give the reader an overview of general strategies as well as highlight some recent advances in this field.


Naturally occurring Ngn2 promoter activators from Butea superba.
Neurogenin2 (Ngn2), an activator-type bHLH transcriptional factor, promotes differentiation of neural stem cells into neurons by transcription of pro-neural genes. To find neural stem cell accelerators from the extract library of natural resources, we used a two-step screening including a Ngn2 promoter reporter gene screening and differentiation assay screening of neural stem cells. A reporter gene assay that can detect Ngn2 promoter activity by luciferase expression was constructed using C3H10T1/2 cells. Using this primary cell-based screening, Butea superba was found to include Ngn2 promoter activators from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 18 natural products, including pterocarpans and isoflavonoids. Dehydromaackiain (1), formononetin (6), ()-variabilin (13), ()-medicarpin (14), rothindin (17) and ononin (18) showed 1.8–2.8 times higher Ngn2 promoter activity at 5 mM compared with control. Of active natural compounds, 30-methoxydaidzein (3) showed promotion of neurite outgrowth of C17.2 in a secondary screen. 30-Methoxydaidzein (3) increased mRNA expression of pro-neural transcriptional factors (Ngn2, Ngn1, NeuroD2), a mature neuron-specific enzyme GAD1 and a pro-neural neurotrophic growth factor neurotrophin 3 (NT3) in C17.2 neural stem cells.


Investigation of the interactions between methadone and elvitegravir-cobicistat in subjects receiving chronic methadone maintenance.
Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.


Epidemiologic characteristics of dental caries: relation of DMFT and DMFS to proportion of children with DMF teeth.
The relation of the age-specific mean DMFT and mean DMFS to the age-specific proportion of children with DMF teeth has been studied using the original data of Knutson and data of a recent Finnish material. When studying the relationship between the mean DMFT (x) and the proportion of children with DMF teeth (y), three models of regression were compared. For low caries populations, a specific correction exponential curve y = 1-abx seemed to fit caries data somewhat better than the other models. The relationship between the mean DMFS (x) and the proportion of children with DMF teeth (y) could be expressed by a curvilinear model y = e[b(lnx) + a]; this applied to low caries populations (y approximately less than 0.7) as well, but the unexplained residual variation was about 6%.


Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases: An International Survey of >1000 Radiation Oncologists.
Stereotactic body radiotherapy (SBRT) is often used to treat patients with oligometastases (OM). Yet, patterns of SBRT practice for OM are unknown. Therefore, we surveyed radiation oncologists internationally, to understand how and when SBRT is used for OM. A 25-question survey was distributed to radiation oncologists. Respondents using SBRT for OM were asked how long they have been treating OM, number of patients treated, organs treated, primary reason for use, doses used, and future intentions. Respondents not using SBRT for OM were asked reasons why SBRT was not used and intentions for future adoption. Data were analyzed anonymously. We received 1007 surveys from 43 countries. Eighty-three percent began using SBRT after 2005 and greater than one third after 2010. Eighty-four percent cited perceived treatment response/durability as the primary reason for using SBRT in OM patients. Commonly treated organs were lung (90%), liver (75%), and spine (70%). SBRT dose/fractionation schemes varied widely. Most would offer a second course to new OM. Nearly all (99%) planned to continue and 66% planned to increase SBRT for OM. Of those not using SBRT, 59% plan to start soon. The most common reason for not using SBRT was lack of clinical efficacy (48%) or lack of necessary image guidance equipment (34%). Radiation oncologists are increasingly using SBRT for OM. The main reason for not using SBRT for OM is a perceived lack of evidence demonstrating clinical advantages. These data strengthen the need for robust prospective clinical trials (ongoing and in development) to demonstrate clinical efficacy given the widespread adoption of SBRT for OM.


Just give me hope: lived experiences of Medicaid patients with advanced cancer.
The purpose of this phenomenological exploration was to describe the lived experiences of persons diagnosed with advanced cancer who receive Medicaid. Themes emerged from the transcribed interviews of 10 participants in accordance with the cancer trajectory. Before diagnosis, participants were uninsured or underinsured and had more severe symptoms prior to late diagnosis. Upon diagnosis, they desired hopeful, respectful communication and experienced strong emotional reactions. There was also an abrupt change in the use of health care resources. During cancer treatment, they experienced social isolation from family and friends while receiving strong psychosocial support from the health care team. Throughout the cancer trajectory, they focused on living, reclaiming normalcy, and expressed resiliency and spirituality. Findings support the need to recognize the "fighting spirit" of patients regardless of prognosis or socioeconomic status; the impact of hopeful, respectful communication; and the value of oncology social work assistance when navigating the cancer experience. Lack of health care coverage prior to severe symptoms prevented earlier diagnosis and contributed to poor physical outcomes. Medicaid eligibility enabled these patients to receive quality health care and focus on living beyond cancer.


Evaluation of machine learning methodology for the prediction of healthcare resource utilization and healthcare costs in patients with critical limb ischemia-is preventive and personalized approach on the horizon?
Critical limb ischemia (CLI) is a severe stage of peripheral arterial disease and has a substantial disease and economic burden not only to patients and families, but also to the society and healthcare systems. We aim to develop a personalized prediction model that utilizes baseline patient characteristics prior to CLI diagnosis to predict subsequent 1-year all-cause hospitalizations and total annual healthcare cost, using a novel Bayesian machine learning platform, Reverse Engineering Forward Simulation™ (REFS™), to support a paradigm shift from reactive healthcare to Predictive Preventive and Personalized Medicine (PPPM)-driven healthcare. Patients ≥ 50 years with CLI plus clinical activity for a 6-month pre-index and a 12-month post-index period or death during the post-index period were included in this retrospective cohort of the linked Optum-Humedica databases. REFS™ built an ensemble of 256 predictive models to identify predictors of all-cause hospitalizations and total annual all-cause healthcare costs during the 12-month post-index interval. The mean age of 3189 eligible patients was 71.9 years. The most common CLI-related comorbidities were hypertension (79.5%), dyslipidemia (61.4%), coronary atherosclerosis and other heart disease (42.3%), and type 2 diabetes (39.2%). Post-index CLI-related healthcare utilization included inpatient services (14.6%) and ≥ 1 outpatient visits (32.1%). Median annual all-cause and CLI-related costs per patient were $30,514 and $2196, respectively. REFS™ identified diagnosis of skin and subcutaneous tissue infections, cellulitis and abscess, use of nonselective beta-blockers, other aftercare, and osteoarthritis as high confidence predictors of all-cause hospitalizations. The leading predictors for total all-cause costs included region of residence and comorbid health conditions including other diseases of kidney and ureters, blindness of vision defects, chronic ulcer of skin, and chronic ulcer of leg or foot. REFS™ identified baseline predictors of subsequent healthcare resource utilization and costs in CLI patients. Machine learning and model-based, data-driven medicine may complement physicians' evidence-based medical services. These findings also support the PPPM framework that a paradigm shift from post-diagnosis disease care to early management of comorbidities and targeted prevention is warranted to deliver a cost-effective medical services and desirable healthcare economy.


[Comparison of PIM and SOFA scoring systems for mortality risk prognosis in critically ill children with sepsis].
The task of the study was the comparison of 2 scoring systems SOFA and PIM for mortality risk assessment in intensive care units. SOFA score is evaluated on admission and thereafter 72 and 120 h until ICU discharge in Children's Central Clinical Hospital from 2001 to 2005 years. Total 200 patients were studied. Mean age was 234.5+/-14.5. Mortality rate was 54 (27%). 89 (44.5%) were females and 111 (55.5%) were mails. Mechanical ventilation was performed in 72 (36%) patients. Septic shock was developed in 39 (19.5%) cases. Diagnose was confirmed by bacteriology in 68 (34%) cases. Higher score was in 93 (46.5%) cases, middle scores in 94 (47%) cases and low in 13 (6.5%) cases at the first day of admission. After 72 h. higher score was in 33 (16.5%) cases, middle in 113 (56.5%) cases and low in 54 (27.5%) cases. By evaluation with PIM--Higher score was in 58 (29%) cases, middle scores in 51 (25.5%) cases and low in 91 (45.5%) cases at the first day of admission. There is a correlation between the SOFA and PIM scores and paediatric mortality. Sofa scores predict mortality in ICU better then PIM scoring system. Kendall's tau of SOFA 0.64+/-0.3. Kendall's tau of PIM 0.45+/-0.2. Sofa scores is an excellent tool to describe the extent of organ dysfunction in critically ill patients.


Effect of sulfated beta-cyclodextrin, a water soluble cycloamylose, on the promotion and/or inhibition of angiogenesis.
Previous studies have reported that sulfated b b-cyclodextrin, a naturally occurring cycloamylose built up from six to eight glucopyranose units, when administered alone promotes angiogenesis, but administered with an angiostatic steroid inhibits angiogenesis in the cick embryo bioassay. In our experiments sulfated b b-cyclodextrin has been shown to possess many properties unrelated to its classical functions in the promotion and inhibition of angiogenesis that were not previously described. We studied the angiogenic and angiostatic properties of b b-cyclodextrin in a subcutaneous plastic sponge model in mice. We realized two set of experiments. In each set mice were randomized into five groups (n= 5 mice). The first group was treated with sulfated b b-cyclodextrin (200 ng), the second group was treated with sulfated b b-cyclodextrin (2000 ng), the third group received unsubstituted b b-cyclodextrin (2000 ng), the fourth group was treated with sulfated b b-cyclodextrin (20000 ng) and the last group was used as a control group. In all groups compounds were administered intraperitoneally 4 days after subcutaneous implantation of a sterile polyvinyl sponge on day 0, controls were not treated. Cyclodextrin administered alone at low drug concentration (200 ng) promoted angiogenesis and increased the development of venules in the sponge matrix. However, cyclodextrin administered at high drug concentration (2000 and 20 000 ng) reduced the vessel index in the sponge and areas of microhemorrhages were observed. From our results we propose that b b-cyclodextrin contains both a promoter and an inhibitor of angiogenesis and that the activation of both is drug concentration dependent.


[Membrane-bound sialoglycoproteins of the rat liver as affected by the combined action of benz(a)pyrene and sulfur dioxide].
Simultaneous effect of benz(a)pyrene and sulphurous gas was accompanied by distinct alteration in metabolism of sialoglycoproteins in liver tissue; at the time N-acetylneuraminic acid was redistributed in liver subcellular organelles (mitochondria, lysosomes and endoplasmic reticulum) as well as cytochromes P-450 and b5 were induced in liver microsomes. The alterations observed appear to play a definite role in manifestation of the unfavourable effect in combined action of the carcinogen and chemical contaminations of environments.


White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study.
Maturation of brain white matter pathways is an important factor in cognitive, behavioral, emotional and motor development during childhood and adolescence. In this study, we investigate white matter maturation as reflected by changes in anisotropy and white matter density with age. Thirty-four children and adolescents aged 6-19 years received diffusion-weighted magnetic resonance imaging scans. Among these, 30 children and adolescents also received high-resolution T1-weighed anatomical scans. A linear regression model was used to correlate fractional anisotropy (FA) values with age on a voxel-by-voxel basis. Within the regions that showed significant FA changes with age, a post hoc analysis was performed to investigate white matter density changes. With increasing age, FA values increased in prefrontal regions, in the internal capsule as well as in basal ganglia and thalamic pathways, the ventral visual pathways, and the corpus callosum. The posterior limb of the internal capsule, intrathalamic connections, and the corpus callosum showed the most significant overlaps between white matter density and FA changes with age. This study demonstrates that during childhood and adolescence, white matter anisotropy changes in brain regions that are important for attention, motor skills, cognitive ability, and memory. This typical developmental trajectory may be altered in individuals with disorders of development, cognition and behavior.


Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume.
Postoperative liver failure is a life-threatening complication after hepatic resection. Because of recent advances in liver surgery technique and a more stringent patient selection, mortality after hepatic resection has steadily decreased, but its incidence still ranges from 10% to 20%. The factors linked to postoperative liver failure in major hepatic resection in the modern era should be reevaluated. Of 80 patients with viral markers (hepatitis C viral antibody or hepatitis B surface antigen) who underwent major hepatic resections (no less than bisegmentectomies) for hepatocellular carcinoma between 1990 and 1996, 7 patients (8.8%) died of postoperative liver failure within 6 months after hepatectomy. The cause of liver failure was analyzed based on both the preoperative data and the intraoperative findings. In addition, since all the patients who died of liver failure underwent a right hepatic lobectomy, a further data analysis was also done in 47 patients who underwent a right lobectomy of the liver. A volumetric analysis by CT was then done to evaluate the remnant liver volume. Between the patients with liver failure and those without liver failure who underwent a right lobectomy, there were no significant differences in preoperative data or intraoperative findings. Volumetric analysis revealed that the remnant liver volume of patients who died of liver failure was significantly smaller than that of patients who lived (p = 0.008). The incidence of liver failure in patients with a remnant liver volume of less than 250 mL/m2 was 7 of 20 (38%), while it was 0 of 27 in patients with a liver volume of no less than 250 mL/m2 (p = 0.0012). The only significant risk factor for liver failure in patients with a remnant liver volume of less than 250 mL/m2 was diabetes mellitus (p = 0.0072). The expected remnant liver volume appears to be a good predictor for liver failure in patients who undergo a right lobectomy of the liver. In patients with diabetes mellitus and an expected remnant liver volume of less than 250 mL/m2, a major hepatectomy should be avoided. Careful patient selection based on volumetric analysis in major hepatectomy cases could help prevent the occurrence of postoperative liver failure.


Role and significance of plasma citrulline in the early phase after small bowel transplantation in pigs.
A reliable serological marker of acute cellular rejection (ACR) after small bowel transplantation (SBTx) is still missing. Plasma citrulline level (PCL) reflects the functional integrity of intestinal mucosa which is partially lost during ACR. The aim of our study was to investigate the role of PCL as marker of ACR after SBTx. Eighteen German landrace pigs were used and divided into three groups. Group 1 (G1), autologous SBTx (n = 4) as control; group 2 (G2), allogeneic SBTx without immunosuppression (IS) (n = 7) and group 3 (G3), allogeneic SBTx with IS (n = 7). IS consisted of tacrolimus and steroids without induction treatment. Observation period was 14 days. Mucosal biopsies were obtained intraoperatively and daily using a Thiry-Vella loop. ACR was differentiated into indeterminate, mild, moderate and severe using a standardized grading schema. PCL was measured daily. An ACR onset occurred generally from postoperative day 4 both in G2 and G3 as mild form and developed differently in the two groups: moderate to severe in G2 and indeterminate to mild in G3. A significant decline of PCL occurred only in cases of moderate and severe ACR, but not in cases of indeterminate and mild ACR. The PCL failed as a marker in the early diagnosis of ACR and became reliable only when advanced mucosal damage was present.


[Female tuberculosis morbidity and mortality in the Sverdlovsk Region].
In 2000 to 2006, the female proportion increased in the structure of tuberculosis morbidity from 21.4 to 30.1% and in that tuberculosis mortality from 13.1 to 21.4% in the Sverdlovsk Region. Female tuberculosis morbidity increased mainly at the age of 25-34 years (by 50.9%) and 35-44 years (by 66.0%) and tuberculosis mortality by 2.7 times and 42.1%, respectively. The increase was due to the proportion of socially poor unemployed women. Pregnancy and lactation worsened the course of tuberculosis resulting in death in 1.3% of young women. Of the greatest importance was a patient's poor social status: only 6% of the women with tuberculosis leading to death were employed; 2.8% were dying. A portion of those who died from tuberculosis were drug addicts (5.4%) and HIV infected (12.3%).


Ultrasound Imaging is a Valid Method of Measuring the Cross-Sectional Area of the Quadratus Femoris Muscle.
Atrophy of the stabilizing muscles of the hip, such as quadratus femoris (QF), may predispose the hip joint to dysfunction. Ultrasound imaging (USI) has been shown to be a valid and reliable method of measuring the size of several hip muscles, but QF size has not been investigated. The objectives of this study were to establish the criterion validity of USI against the "gold standard" magnetic resonance imaging (MRI) for measuring the QF cross-sectional area (CSA) and to investigate intra-rater reliability of USI. Eleven current or retired professional ballet dancers (six women, five men) volunteered for USI of their QF within 1 week of MRI. The mean CSAs of QF were compared between the two imaging modalities, and the mean USI CSAs from two different trials were compared. Mean CSA with MRI (4.8 cm(2), ± 1.54) was significantly larger than mean CSA with USI (4.29 cm(2) ± 1.56; t = 5.82; p < 0.001), and the mean difference was 0.41 cm² (9%). However, the measures were highly correlated for intra-class reliability (r = 0.96, p < 0.001), and intra-class correlation coefficients (ICC) demonstrated excellent agreement (ICC = 0.90; 95% confidence interval [CI]: 0.20 -0.97) and consistency of measures (ICC = 0.96; 95% CI: 0.90- 0.98). Intra-rater reliability of measuring QF with USI was excellent between two trials (ICC = 0.98; 95% CI: 0.96- 0.99). The minimal detectable change at a 95% CI (MDC95) was 0.38 cm(2) (9.5%). It is concluded that USI is a valid and reliable measure of QF muscle size and can be used to measure QF CSA in a research or clinical setting.


Genomic basis for early-life mortality in sharpsnout seabream.
Mortality at early life stages of fishes is common in nature and can be shaped by stochastic and selective processes. Selective mortality has rarely been assessed in natural conditions but can now be studied by combining genomic data with information on different life stages that realates to fitness. Here we investigate selective mortality between settlers and six-month survivors of the sharpsnout seabream by genotype-phenotype/environmental association studies in three localities along a geographic gradient. We gathered information on 105 individuals at 85,031 SNPs, obtained from individual based 2b-RAD libraries, as well as 9 phenotypic and environmental variables derived from individual otolith readings. We found common signals across localities for potential selection, such as lower survival rates for individuals hatching earlier, growing faster and experiencing higher temperatures during their planktonic phase. We identified 122 loci with parallel significant association to phenotypic and environmental variables. Importantly, one of these loci mapped to the exonic region of the il20rb, a gene involved in immune response, in the phylogenetically closest reference genome, showing parallel frequency changes in non-synonymous mutations in the three studied populations. Further temporal assessments are needed to understand how polymorphisms that are key to selective mortality are maintained.


Dentoskeletal effects of the Bite-Jumping Appliance and the Twin-Block Appliance in the treatment of skeletal Class II malocclusion: a randomized controlled trial.
The current parallel group, randomized controlled trial aimed to compare the dentoalveolar and skeletal changes resulting from treatment using two popular functional appliances: the Bite-Jumping Appliance (BJA) and the Twin-Block Appliance (TBA). This study is designed as a parallel-group, randomized controlled trial. Patients were screened from the patients who were seeking treatment at the Department of Orthodontics, Al-Baath University. Eligibility criteria included skeletal Class II division 1 malocclusion resulting from the retrusion of the mandible. A computer-generated randomization list was used to randomly divide the patients into two equal groups to be treated with either the BJA or the TBA. Blinding was applicable for outcome assessment only. Forty-four patients (22 male and 22 female) aged 10.2-13.5 years were randomized in a 1:1 ratio to either the BJA or the TBA groups, and four patients were lost to follow-up (two from each group). Lateral cephalometric radiographs were obtained before treatment and after 12 months of active appliance therapy. Inter-group differences were evaluated with two-sample t-tests, and intra-group differences were assessed with paired-sample t-tests at the P <0.05 level. Forty patients (20 in each group) were available for the statistical analysis. Baseline characteristics were similar between groups. Similar changes were observed in the sagittal plane, including a significant increase in the SNB angle. No significant changes were observed in the maxilla. The lower incisors were significantly proclined, and the upper incisors significantly retruded. In the vertical plane, BJA induced mandibular clockwise rotation, and the SN:MP angle increased by 2.14 ± 2.97° (P = 0.002). Conversely, no significant changes took place in this angle in the TBA group 0.75 ± 2.37° (P = 0.096). Similarly, Jarabak ratio decreased significantly in the BJA group by -1.78 ± 0.85% (P = 0.002) and increased significantly in the TBA group by 1.26 ± 0.76% (P = 0.032), with significant differences between the two groups (P ≤ 0.001). No serious harm was observed. A limitation of this research is a lack of an untreated control group. However, the resulting differences between the two groups can be attributed to the appliance differences, which fulfil the aim of the current research. Each of the two appliances is recommended for the functional treatment of skeletal Class II malocclusion resulting from the retrusion of the mandible. The BJA is recommended when clockwise rotation is desired, whereas the TBA is recommended to inhibit vertical development. This trial was registered at the Department of Orthodontics, Al-Baath University, Number 16, on 6/25/2012. The protocol was not published before trial commencement. No funding or conflict of interest to be declared.


Case Report: Bilateral diaphragmatic dysfunction due to Borrelia Burgdorferi.
In this case report we describe a rare case of bilateral diaphragmatic dysfunction due to Lyme disease. A 62-years-old male presented to the hospital because of flu-like symptoms. During initial evaluation a bilateral diaphragmatic weakness with orthopnea and nocturnal hypoventilation was observed, without a known aetiology. Bilateral diaphragmatic paralysis was confirmed by fluoroscopy with a positive sniff test. The patient was referred to our centre for chronic non-invasive nocturnal ventilation (cNPPV). Subsequent investigations revealed evidence of anti- Borrelia seroactivity in EIA-IgG and IgG-blot, suggesting a recent infection with Lyme disease, and resulted in a 4-week treatment with oral doxycycline. The symptoms of nocturnal hypoventilation were successfully improved with cNPPV. However, our patient still shows impaired diaphragmatic function but he is no longer fully dependent on nocturnal ventilatory support. Lyme disease should be considered in the differential diagnosis of diaphragmatic dysfunction. It is a tick-borne illness caused by one of the three pathogenic species of the spirochete Borrelia burgdorferi, present in Europe. A delay in recognizing the symptoms can negatively affect the success of treatment. Non-invasive mechanical ventilation (NIV) is considered a treatment option for patients with diaphragmatic paralysis.


A comparative study between real-time PCR and loop-mediated isothermal amplification to detect carbapenemase and/or ESBL genes in Enterobacteriaceae directly from bronchoalveolar lavage fluid samples.
To evaluate and compare the efficacy of real-time PCR (Xpert Carba-R) and loop-mediated isothermal amplification (Eazyplex® SuperBug CRE) for detecting carbapenemase carriage in Enterobacteriaceae directly from bronchoalveolar lavage (BAL). Negative BAL samples were spiked with 21 well-characterized carbapenemase-producing Enterobacteriaceae strains to a final concentration of 102-104 cfu/mL. Xpert Carba-R (Cepheid, Sunnyvale, CA, USA), which detects five targets (blaKPC, blaNDM, blaVIM, blaOXA-48 and blaIMP-1), and the Eazyplex® SuperBug CRE system (Amplex-Diagnostics GmbH, Germany), which detects seven genes (blaKPC, blaNDM, blaVIM, blaOXA-48, blaOXA-181, blaCTXM-1 and blaCTXM-9), were evaluated for the detection of these genes directly from BAL samples. Xpert Carba-R showed 100% agreement with carbapenemase characterization by PCR and sequencing for all final bacteria concentrations. Eazyplex® SuperBug CRE showed 100%, 80% and 27% agreement with PCR and sequencing when testing 104, 103 and 102 cfu/mL, respectively. False negative results for Eazyplex® SuperBug CRE matched the highest cycle threshold values for Xpert Carba-R. Hands-on time for both assays was about 15 min, but Eazyplex® SuperBug CRE results were available within 30 min, whereas Xpert Carba-R took around 50 min. We here describe the successful use of two commercial diagnostic tests, Xpert Carba-R and Eazyplex® SuperBug CRE, to detect bacterial carbapenem resistance genes directly in lower respiratory tract samples. Our results could be used as proof-of-concept data for validation of these tests for this indication.


MicroRNA-127 post-transcriptionally downregulates Sept7 and suppresses cell growth in hepatocellular carcinoma cells.
Hepatocellular carcinoma is one of the most common cancers worldwide. It has been suggested that microRNAs, a class of small regulatory RNAs, are associated with tumorigenesis by targeting the mRNAs of hundreds of genes that modulate a variety of biological processes, including cellular differentiation, apoptosis, metabolism, and proliferation. we analyzed the expression levels of mir-127 in 33 HCC and non-cancerous tissues using qRT-PCR. MiR-127 is downregulated in 69.7% of HCC tissues compared with adjacent normal tissues, but its expression level is not correlated with the TNM stage, AFP level, or age. In vitro, miR-127 can arrest Huh7 at the G2/M phase and inhibit Huh7 cell proliferation. In an in vivo xenograft model, the overexpression of miR-127 can inhibit Huh7 cell tumorigenicity. The luciferase reporter and western blot results confirm that miR-127 downregulates Sept7 expression by targeting its 3'UTR. Furthermore, the knockdown of Sept7 has the same effect on cell proliferation as the overexpression of miR-127 in Huh7 cells. miR-127 plays a tumor-suppressor role and can serve as a potential diagnostic biomarker for HCC.


Impact of introduction of 20-week ultrasound scan on prevalence and fetal and neonatal outcomes in cases of selected severe congenital heart defects in The Netherlands.
To evaluate in a population-based cohort the effect of the introduction of the 20-week ultrasound scan in 2007 on the time of diagnosis, pregnancy outcome and total prevalence and liveborn prevalence of cases with selected congenital heart defects (CHDs) in The Netherlands. We included children and fetuses diagnosed with selected severe CHD, born in the 11-year period from 2001 to 2011. Two groups of CHD were defined: those associated with an abnormal four-chamber view at ultrasound (Group 1), and those associated with a normal four-chamber view at ultrasound (Group 2). The time of diagnosis, pregnancy outcome and total liveborn prevalence were compared for both groups over two 5-year periods, before and after the introduction of the 20-week ultrasound scan. Trends in total and liveborn prevalence were examined over 2001 to 2011. Information was collected on 269 children and fetuses. After the introduction of the 20-week ultrasound scan, the prenatal detection rate of CHDs increased in both groups (Group 1, 34.6% in 2001-2005 vs 84.8% in 2007-2011 (P < 0.001); Group 2, 14.3% in 2001-2005 vs 29.6% in 2007-2011 (P = 0.037)). The rate of termination of pregnancy (TOP) increased significantly only for Group 1 (15.4% vs 51.5% (P < 0.001)). The total prevalence of CHD in Group 1 increased over time from 2.9 per 10 000 births in 2001 to 6.4 per 10 000 births in 2011 (P = 0.016). The liveborn prevalence did not show a trend over time. For Group 2, no trends in total or liveborn prevalence could be detected over time. Since the implementation of the routine 20-week ultrasound scan in The Netherlands, prenatal detection rate of selected severe CHDs increased significantly. Improved prenatal detection was accompanied by a more than three-fold increase in TOP, although only in those CHDs with an abnormal four-chamber view at prenatal ultrasound.


The effect of etching techniques on cement penetration into dentinal tubules on fiber post cementation.
A combination of self-etch and additional etch techniques as pre-cementation procedures for fiber post restoration was reported able to increase the bonding of adhesive material. This research aimed to determine the effects of different etching techniques on resin cement penetration into dentinal tubules. Thirty-two endodontic treated premolars were prepared for 10 mm fiber posts and were divided into two groups (n = 16). Group one was treated with self-etch only, and the second was treated with a combination of self-etch and additional etching. The fiber posts were cemented using fluorescent rhodamine B 0.1%-colored resin cement. The samples were cut to a 2 mm thickness in the middle third of the root and were evaluated with confocal laser scanning microscopy (CLSM). Statistical analysis measurements were analyzed by an independent t-test and Pearson correlation test. There were statistically different in densities hybrid layer and resin tag penetration lengths. Statistically strong linear positive correlations between the hybrid layer density and resin tag penetration length in both groups were also observed. Hybrid layer density (9.68 μm), resin tag penetration depth (32.51 μm) in the self-etch group with additional etching were higher than in the other group. The Pearson correlation test results between hybrid bond density and resin tag penetration depth in the self-etch treatment group showed a value of r = 0.634 and p-value = 0.008 and in the etching group self-treatment with additional etching a value of r = 0.516 and p-value = 0.041 (p ≤ 0.05). There is a statistically significant positive correlation or linear relationship between hybrid bond density and the penetration depth of resin tags in both treatment groups: the thicker the hybrid layer density, the deeper the penetration of the resin tags. This phenomenon may increase mechanical strength regarding stronger binding of resin cement to a tooth's substrate.


Combined adaptiveness of specific motor cortical ensembles underlies learning.
Learning motor skills entails adaptation of neural computations that can generate or modify associations between sensations and actions. Indeed, humans can use different strategies when adapting to dynamic loads depending on available sensory feedback. Here, we examined how neural activity in motor cortex was modified when monkeys made arm reaches to a visual target and locally adapted to curl force field with or without visual trajectory feedback. We found that firing rates of a large subpopulation of cells were consistently modulated depending on the distance of their preferred direction from the learned movement direction. The newly acquired activity followed a cosine-like function, with maximal increase in directions that opposed the perturbing force and decrease in opposite directions. As a result, the combined neuronal activity generated an adapted population vector. The results suggest that this could be achieved without changing the tuning properties of the cells. This population directional signal was however altered in the absence of visual feedback; while the cosine pattern of modulation was maintained, the population distributions of modulated cells differed across feedback consistent with the different trajectory shapes. Finally, we predicted generalization patterns of force-field learning based on the cosine-like modulation. These conformed to reported features of generalization in humans, suggesting that the generalization function was related to the observed rate modulations in the motor cortex. Overall, the findings suggest that the new combined activation of neuronal ensembles could underlie the change in the internal model of movement dynamics in a way that depends on available sensory feedback and chosen strategy.


Fabricating low cost and high performance elastomer lenses using hanging droplets.
Existing methods for low cost lenses using parallel mold stamping and high temperature reflow requires complex engineering controls to produce high quality lenses. These manufacturing techniques rely on expensive equipment. In this paper, we propose a low cost (< $ 0.01 per pc) flexible moldless lens fabrication method based on curing a hanging transparent polydimethylsiloxane (PDMS) elastomer droplet on a curved substrate. Additional deposition of hanging droplets in the same manner led to a substantial increase in the lens curvature and concomitant decrease in the focal length of the PDMS lenses down to ~2 mm. The shortest focal length lenses were shown to collimate light from a bare light emitting diode (LED) and image microscopic structures down to around 4 µm with 160x magnification. Our hanging droplet lens fabrication technique heralds a new paradigm in the manufacture of low cost, high performance optical lenses for the masses. Using these lenses, we were able to transform an ordinary commercial smartphone camera into a low-cost digital dermascope (60x magnification) that can readily visualize microscopic structures on skin such as sweat pores.


Does Estimated Pulse Wave Velocity Add Prognostic Information?: MORGAM Prospective Cohort Project.
The Reference Values for Arterial Stiffness Collaboration has derived an equation using age and mean blood pressure to estimated pulse wave velocity (ePWV), which predicted cardiovascular events independently of Systematic COoronary Risk Evaluation (SCORE) and Framingham Risk Score. The study aim was to investigate the independent association between ePWV and clinical outcomes in 107 599 apparently healthy subjects (53% men) aged 19 to 97 years from the MORGAM Project who were included between 1982 and 2002 in 38 cohorts from 11 countries. Using multiple Cox-regression analyses, the predictive value of ePWV was calculated adjusting for country of inclusion and either SCORE, Framingham Risk Score, or traditional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, body mass index [BMI], total and high-density lipoprotein cholesterol). Cardiovascular mortality consisted of fatal stroke, fatal myocardial infarction, or coronary death, and the composite cardiovascular end point consisted of stroke, myocardial infarction, or coronary death. Model discrimination was assessed using Harrell's C-statistic. Adjusting for country and logSCORE or Framingham Risk Score, ePWV was associated with all-cause mortality (hazard ratio, 1.23 [95% CI 1.20-1.25] per m/s or 1.32 [1.29-1.34]), cardiovascular mortality (1.26 [1.21-1.32] or 1.35 [1.31-1.40]), and composite cardiovascular end point (1.19 [1.16-1.22] or 1.23 [1.20-1.25]; all P<0.001). However, after adjusting for traditional cardiovascular risk factors, ePWV was only associated with all-cause mortality (1.15 [1.08-1.22], P<0.001) and not with cardiovascular mortality (0.97 [0.91-1.03]) nor composite cardiovascular end point (1.10 [0.97-1.26]). The areas under the last 3 receiver operator characteristic curves remained unchanged when adding ePWV. Elevated ePWV was associated with subsequent mortality and cardiovascular morbidity independently of systematic coronary risk evaluation and Framingham Risk Score but not independently of traditional cardiovascular risk factors.


An acetylation mimicking mutation, K274Q, in tau imparts neurotoxicity by enhancing tau aggregation and inhibiting tubulin polymerization.
In Alzheimer's disease, tau is predominantly acetylated at K174, K274, K280, and K281 residues. The acetylation of K274-tau is linked with memory loss and dementia. In this study, we have examined the molecular mechanism of the toxicity of acetylated K274-tau. We incorporated an acetylation mimicking mutation at K274 (K→Q) residue of tau. The mutation (K274Q) strongly reduced the ability of tau to bind to tubulin and also to polymerize tubulin while K274R mutation did not reduce the ability of tau either to bind or polymerize tubulin. In addition, K274Q-tau displayed a higher aggregation propensity than wild-type tau as evident from thioflavin S fluorescence, tryptophan fluorescence, and electron microscopic images. Furthermore, dynamic light scattering, atomic force microscopy, and dot blot analysis using an oligomer-specific antibody suggested that K274Q mutation enhanced the oligomerization of tau. The K274Q mutation also strongly decreased the critical concentration for the liquid-liquid phase separation of tau. The oligomeric forms of K274Q-tau were found to be more toxic than wild tau to neuroblastoma cells. Using circular dichroism and fluorescence spectroscopy, we provide evidence indicating that the acetylation mimicking mutation (K274Q) induced conformational changes in tau. The results suggested that the acetylation of tau at 274 residues can increase tau aggregation and enhance the cytotoxicity of tau oligomers.


Phosphatidylinositol-4-phosphate kinase from rat brain. Activation by polyamines and inhibition by phosphatidylinositol 4,5-bisphosphate.
Phosphatidylinositol-4-phosphate (PtdIns-P) kinase was purified approximately 30-fold from rat brain cytosol. No contaminating activity of PtdIns kinase or of phosphomonoesterase and phospholipase C using PtdIns-P or PtdIns-P2 as substrate could be detected in the enzyme preparation. The PtdIns-P kinase activity was severalfold higher when PtdIns-P/PtdEtn vesicles rather than PtdIns-P alone were used as substrate. This might be due to increased accessibility of the enzyme for the vesicular substrate, further indicated by the lower activity obtained when PtdCho or PtdIns, phospholipids with bulky head groups, was also present in the vesicles. The product PtdIns-P2 was a competitive inhibitor with respect to PtdIns-P and 50% inhibition of enzyme activity was observed at the same product concentration regardless of whether the substrate-product mixture was presented in vesicular or micellar form, or the substrate and product were added in separate vesicles. The polyamines spermine and spermidine enhanced PtdIns-P kinase activity severalfold. Spermine also caused a shift in the MgCl2 saturation curve from sigmoidal to hyperbolic, lowering the Mg2+ concentration required for optimum kinase activity to the physiological range. Myelin basic protein enhanced the enzyme activity when PtdIns-P/PtdEtn vesicles were used as substrate, whereas it was inhibitory when PtdIns-P was added alone. The possible role of polyamines and the product PtdIns-P2 in the regulation of PtdIns-P kinase activity is discussed.


Factors Affecting Community Pharmacist's Knowledge About Chronic Obstructive Pulmonary Disease (COPD) Management in China: A Cross-Sectional Survey Study.
Chronic obstructive pulmonary disease (COPD) has become a significant risk factor that threatens public health. Many studies have confirmed that the professional services for COPD patients by community pharmacists can improve comprehensive benefits. However, there's less research investigating the factors affecting community pharmacists' knowledge about COPD management. Therefore, this study aimed to investigate the knowledge of COPD among community pharmacists in China and analyze the factors affecting community pharmacist's knowledge about COPD management. This study employed a face-to-face, self-administered questionnaire survey targeting community pharmacists from three cities (Nanjing, Zhuhai, Qingyang) in China. Descriptive statistics, t-test and one-way ANOVA were used for data analysis. Out of the 794 pharmacists surveyed, 177 (22.3%) were completed and valid. The majority (91.0%) of participants had a positive attitude they were responsible for assisting patients to control the disease progression. Among 12 knowledge-related survey questions, only 34 (19.2%) pharmacists answered more than half of them correctly, showing that overall knowledge level of participants was generally low. The overall knowledge level was significantly (P < 0.05) associated with higher academic education, on-the-job training, and pharmacies selling drugs for treating COPD. Regarding medical knowledge, participants got higher accuracy rates at some questions as the symptoms of COPD and identifying the main causative factors but were weak in disease characteristics and guidelines for disease diagnosis. As for medication, participants had a certain understanding of different drugs for COPD and their adverse reactions. For non-drug treatment, participants could not entirely choose the best non-drug treatment for patients, while most of them recognize the importance of pulmonary rehabilitation. This research indicated that community pharmacists in China lacked sufficient knowledge about COPD management. It is necessary to improve university education, strengthen on-the-job training, adjust the social insurance system, and develop service guidelines for licensed pharmacists to support their professional services for COPD patients.


Overexpression of mitotic centromere-associated Kinesin stimulates microtubule detachment and confers resistance to paclitaxel.
Numerous studies have implicated mutations in tubulin or the overexpression of specific tubulin genes in resistance to microtubule-targeted drugs. Much less is known about the role of accessory proteins that modulate microtubule behavior in the genesis of drug resistance. Here, we examine mitotic centromere-associated kinesin (MCAK), a member of the kinesin family of microtubule motor proteins that has the ability to stimulate microtubule depolymerization, and show that overexpressing the protein confers resistance to paclitaxel and epothilone A, but increases sensitivity to colcemid. Cells transfected with FLAG-tagged MCAK cDNA using a tet-off-regulated expression system had a disrupted microtubule cytoskeleton and were able to survive a toxic concentration of paclitaxel in the absence, but not in the presence of tetracycline, showing that drug resistance was caused by ectopic MCAK production. Moreover, a population that was heterogeneous with respect to FLAG-MCAK expression became enriched with cells that produced the ectopic protein when it was placed under paclitaxel selection. Similar to previously isolated mutants with altered tubulin, paclitaxel resistant cells resulting from MCAK overexpression were found to have decreased microtubule polymer and a seven-fold increase in the frequency of microtubule detachment from centrosomes. These data are consistent with a model for paclitaxel resistance that is based on stability of the attachment of microtubules to their nucleating centers, and they implicate MCAK in the mechanism of microtubule detachment.


Management of patients with acute ST-segment elevation myocardial infarction in Russian hospitals adheres to international guidelines.
Russia has one of the highest cardiovascular mortality rates. Modernisation of the Russian health system has been accompanied by a substantial increase in uptake of percutaneous coronary intervention (PCI), which substantially reduces the risk of mortality in patients with acute ST-elevation myocardial infarction (STEMI). This paper aims to describe contemporary Hospital treatment of acute STEMI among patients in a range of hospitals in the Russian Federation. This study used data from a prospective observational cohort of 1128 suspected patients with myocardial infarction recruited in both PCI and non-PCI hospitals across 13 regions and multiple levels of the health system in Russia. The primary objective was to examine the use of reperfusion strategies in patients with STEMI. Among patients reaching PCI centres within 12 hours of symptom onset, the vast majority received angiography and PCI, regardless of age, sex and comorbidity, in line with current European Society of Cardiology guidelines. Patients reaching Russian hospitals are very likely to receive appropriate treatment, although performance varies. The best hospitals can serve as beacons of good practice as PCI facilities continue to expand across Russia where geography allows.


Power spectrum analysis of circadian oscillations of heart rate variability in patients with left ventricular dysfunction.
The physiological significance of diurnal fluctuations in heart rate variability (HRV) has not been established to a full extent. The aim of our investigation was to assess a new method of power spectrum analysis of circadian oscillations in HRV in patients with left ventricular systolic and diastolic dysfunction. Holter ECG monitoring and echocardiography were performed in 101 patients with coronary artery disease and arterial hypertension: 55 patients with systolic left ventricular dysfunction (LVD) and 46 patients with diastolic LVD, and also in 32 subjects of the control group. The original method of HRV assessment was based on spectrum analysis of time series of consecutive 5-minute measures of standard deviations of mean RR intervals. The study revealed oscillations of HRV with a periodicity of 12 hours and 80-120 minutes. Their amplitude was highest in the control group and lowest in patients with systolic LVD. Power spectrum analysis of circadian oscillations of heart rate variability reveals information about the character of LVD. Regular oscillations of time domain indices of HRV were observed in the patients with LVD and in the control group; their amplitude is highest in the control group and lowest in systolic LVD.


Generation of a reference transcriptome for evaluating rainbow trout responses to various stressors.
Fish under intensive culture conditions are exposed to a variety of acute and chronic stressors, including high rearing densities, sub-optimal water quality, and severe thermal fluctuations. Such stressors are inherent in aquaculture production and can induce physiological responses with adverse effects on traits important to producers and consumers, including those associated with growth, nutrition, reproduction, immune response, and fillet quality. Understanding and monitoring the biological mechanisms underlying stress responses will facilitate alleviating their negative effects through selective breeding and changes in management practices, resulting in improved animal welfare and production efficiency. Physiological responses to five treatments associated with stress were characterized by measuring plasma lysozyme activity, glucose, lactate, chloride, and cortisol concentrations, in addition to stress-associated transcripts by quantitative PCR. Results indicate that the fish had significant stressor-specific changes in their physiological conditions. Sequencing of a pooled normalized transcriptome library created from gill, brain, liver, spleen, kidney and muscle RNA of control and stressed fish produced 3,160,306 expressed sequence tags which were assembled and annotated. SNP discovery resulted in identification of ~58,000 putative single nucleotide polymorphisms including 24,479 which were predicted to fall within exons. Of these, 4907 were predicted to occupy the first position of a codon and 4110 the second, increasing the probability to impact amino acid sequence variation and potentially gene function. We have generated and characterized a reference transcriptome for rainbow trout that represents multiple tissues responding to multiple stressors common to aquaculture production environments. This resource compliments existing public transcriptome data and will facilitate approaches aiming to evaluate gene expression associated with stress in this species.


Cocaine detection in maternal and neonatal hair: implications to fetal toxicology.
Cocaine use during pregnancy is difficult to ascertain, and maternal reports are likely to be inaccurate. Presently, the dose-response characteristics between maternal cocaine use and fetal exposure and adverse effects are unknown. Clinically, some babies are harmed, whereas others are not adversely affected. Taking advantage of the fact that cocaine and its metabolite benzoylecgonine (BE) accumulate and can be detected months after exposure in maternal and neonatal hair, an analytical test for cocaine and BE was developed by the authors. The aim of this study was to describe the characteristics of maternal and neonatal hair cocaine as biomarkers of fetal exposure. Of nearly 10,000 cases, all mother-child pairs in whom at least one had cocaine and/or BE detected in hair were identified. The relationship between maternal and neonatal levels was studied. When available, these data were also compared with meconium levels of cocaine. Median cocaine concentration was 10-fold higher in hair of the mothers compared with the neonates (3.56 ng/mg vs 0.31 ng/mg of hair). Infants' cocaine in hair was positively correlated with maternal cocaine and BE in hair (r2 = 0.41 and r2 = 0.22, respectively, P < 0.001 for both correlations). Infants' BE was also correlated with maternal cocaine and BE concentrations in hair (r2 = 0.50 and r2 = 0.27, P < 0.001 for both correlations). Thirty-nine (40%) babies had negative cocaine and BE results despite their mothers being positive. Mothers whose infants were cocaine-positive had a median hair cocaine concentration of 7.34 ng/mg, significantly higher than those whose infants were negative (1.25 ng/mg). Maternal cocaine levels below 0.24 ng/mg may serve as a relative threshold for detectable fetal exposure during the third trimester of pregnancy. Fetal hair grows in the last trimester. Hence, a positive neonatal hair indicates maternal use after pregnancy became known, a strong indicator of maternal addiction. Transplacental exposure to cocaine of babies of addicted mothers is highly variable. The dose-response relationship of both cocaine and BE between maternal and neonatal hair suggests that the placenta protects some fetuses but not others. More research is needed to understand the mechanisms leading to placental defense against cocaine.


Wnt/Dkk negative feedback regulates sensory organ size in zebrafish.
Correct organ size must involve a balance between promotion and inhibition of cell proliferation. A mathematical model has been proposed in which an organ is assumed to produce its own growth activator as well as a growth inhibitor [1], but there is as yet no molecular evidence to support this model [2]. The mechanosensory organs of the fish lateral line system (neuromasts) are composed of a core of sensory hair cells surrounded by nonsensory support cells. Sensory cells are constantly replaced and are regenerated from surrounding nonsensory cells [3], while each organ retains the same size throughout life. Moreover, neuromasts also bud off new neuromasts, which stop growing when they reach the same size [4, 5]. Here, we show that the size of neuromasts is controlled by a balance between growth-promoting Wnt signaling activity in proliferation-competent cells and Wnt-inhibiting Dkk activity produced by differentiated sensory cells. This negative feedback loop from Dkk (secreted by differentiated cells) on Wnt-dependent cell proliferation (in surrounding cells) also acts during regeneration to achieve size constancy. This study establishes Wnt/Dkk as a novel mechanism to determine the final size of an organ.