Genomic analysis of the causative agents of coccidiosis in domestic chickens.
Global production of chickens has trebled in the past two decades and they are now the most important source of dietary animal protein worldwide. Chickens are subject to many infectious diseases that reduce their performance and productivity. Coccidiosis, caused by apicomplexan protozoa of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens, which reveal the full extent of previously described repeat-rich and repeat-poor regions and show that these parasites possess the most repeat-rich proteomes ever described. Furthermore, while no other apicomplexan has been found to possess retrotransposons, Eimeria is home to a family of chromoviruses. Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding.


Isocitrate dehydrogenase from the hyperthermophile Aeropyrum pernix: X-ray structure analysis of a ternary enzyme-substrate complex and thermal stability.
Isocitrate dehydrogenase from Aeropyrum pernix (ApIDH) is a homodimeric enzyme that belongs to the beta-decarboxylating dehydrogenase family and is the most thermostable IDH identified. It catalyzes the NADP+ and metal-dependent oxidative decarboxylation of isocitrate to alpha-ketoglutarate. We have solved the crystal structures of a native ApIDH at 2.2 A, a pseudo-native ApIDH at 2.1 A, and of ApIDH in complex with NADP+, Ca2+ and d-isocitrate at 2.3 A. The pseudo-native ApIDH is in complex with etheno-NADP+ which was located at the surface instead of in the active site revealing a novel adenine-nucleotide binding site in ApIDH. The native and the pseudo-native ApIDHs were found in an open conformation, whereas one of the subunits of the ternary complex was closed upon substrate binding. The closed subunit showed a domain rotation of 19 degrees compared to the open subunit. The binding of isocitrate in the closed subunit was identical with that of the binary complex of porcine mitochondrial IDH, whereas the binding of NADP+ was similar to that of the ternary complex of IDH from Escherichiacoli. The reaction mechanism is likely to be conserved in the different IDHs. A proton relay chain involving at least five solvent molecules, the 5'-phosphate group of the nicotinamide-ribose and a coupled lysine-tyrosine pair in the active site, is postulated as essential in both the initial and the final steps of the catalytic reaction of IDH. ApIDH was found to be highly homologous to the mesophilic IDHs and was subjected to a comparative analysis in order to find differences that could explain the large difference in thermostability. Mutational studies revealed that a disulfide bond at the N terminus and a seven-membered inter-domain ionic network at the surface are major determinants for the higher thermostability of ApIDH compared to EcIDH. Furthermore, the total number of ion pairs was dramatically higher in ApIDH compared to the mesophilic IDHs if a cutoff of 4.2 A was used. A calculated net charge of only +1 compared to -19 and -25 in EcIDH and BsIDH, respectively, suggested a high degree of electrostatic optimization, which is known to be an important determinant for increased thermostability.


Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation.
Activation of the transcription factor Nrf2 regulates expression of phase II enzymes and other adaptive responses to electrophile and oxidant stress. Nrf2 concentrations are regulated by the thiol-rich sensor protein Keap1, which is an adaptor protein for Cul3-dependent ubiquitination and degradation of Nrf2. However, the links between site specificity of Keap1 modification by electrophiles and mechanisms of Nrf2 activation are poorly understood. We studied the actions of the prototypical Nrf2 inducer tert-butylhydroquinone (tBHQ) and two biotin-tagged, thiol-reactive electrophiles, N-iodoacetyl-N-biotinylhexylenediamine (IAB) and 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido)butane (BMCC). Both IAB and tBHQ induced antioxidant response element (ARE)-directed green fluorescent protein (GFP) expression in ARE/thymidine kinase GFP HepG2 cells, and both initiated nuclear Nrf2 accumulation and induction of heme oxygenase 1 in HEK293 cells. In contrast, BMCC produced none of these effects. Liquid chromatography tandem mass spectrometry (MS-MS) analysis of human Keap1 modified by IAB or BMCC in vitro indicated that IAB adduction occurred primarily in the central linker domain, whereas BMCC modified other Keap1 domains. Treatment of FLAG-Keap1-transfected HEK293 with the Nrf2-activating compounds IAB and tBHQ generated high molecular weight Keap1 forms, which were identified as K-48-linked polyubiquitin conjugates by immunoblotting and liquid chromatography MS-MS. Keap1 polyubiquitination coincided with Nrf2 stabilization and nuclear accumulation. In contrast, BMCC did not induce Keap1 polyubiquitination. Our results suggest that Nrf2 activation is regulated through the polyubiquitination of Keap1, which in turn is triggered by specific patterns of electrophile modification of the Keap1 central linker domain. These results suggest that Keap1 adduction triggers a switching of Cul3-dependent ubiquitination from Nrf2 to Keap1, leading to Nrf2 activation.


Plasma alkylresorcinol concentrations correlate with whole grain wheat and rye intake and show moderate reproducibility over a 2- to 3-month period in free-living Swedish adults.
Plasma alkylresorcinols (AR) are useful as dietary biomarkers of wheat and rye whole grain (WG) during interventions but need to be validated in free-living populations. This study estimated the medium-term reproducibility and relative validity of plasma AR as biomarkers of WG and cereal fiber intake. Seventy-two Swedish adults kept 3-d weighed food records on 2 occasions 2-3 mo apart. Of these men and women, 51 provided a fasting blood sample at the end of each occasion. In addition, 18 participants provided 3 fasting and 3 nonfasting samples for 3 consecutive days on the first and second occasions, respectively. Dietary and blood variables did not differ between the 2 occasions. Nonfasting plasma total AR concentration [210 nmol/L (95% CI: 140, 314)] was higher than fasting [99 nmol/L (95% CI: 72, 137)] (P < 0.0001). Mean WG intake was 70 ± 61 g/d (41% from rye) and the intra-class correlation coefficient was 0.44 (95% CI: 0.26, 0.63) for total WG intake and 0.47 (95% CI: 0.27, 0.67) for the fasting plasma total AR concentration, suggesting moderate reproducibility. Fasting plasma total AR moderately correlated with WG rye + wheat (r(s) = 0.53; P < 0.001) and cereal fiber intake (r(s) = 0.32; P < 0.05) when using mean values from both occasions. This suggests that plasma AR concentration in fasting samples can be used as a biomarker of rye + wheat WG intake in free-living populations with a high and consistent WG intake.


DNA methylation patterns associated with oxidative stress in an ageing population.
Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values <0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.


A practical tissue sampling method using ordinary paper for molecular detection of infectious bursal disease virus RNA by RT-PCR.
A practical sampling method for bursal tissue using ordinary paper for molecular diagnosis of infectious bursal disease (IBD) was established. IBD virus-infected bursa was directly smeared on chromatography paper, filter paper, or stationery copy paper and was then fixed with absolute ethanol, Tris-HCl-saturated phenol, or phenol:chloroform:isoamyl alcohol (25:24:1). Flinders Technology Associates (FTA) card, which is designed for the collection of biological samples for molecular detection, was also used. After storage at 37 C for up to 30 days, total RNA directly extracted from the tissue fixed on the papers and FTA card were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) for detection of IBD virus (IBDV) RNA. In addition, the ability of each chemical used in the fixation and the FTA card to inactivate IBDV was evaluated. Regardless of the paper quality, storage period, and fixation method, IBDV RNA was consistently detected in all of the samples. IBDV in the bursal tissue was inactivated with phenol but not with ethanol or the unknown chemicals in FTA card. These results show that ordinary papers sustain the viral RNA, as does FTA card, but phenol fixation is superior to FTA card in inactivating IBDV. The new sampling method using ordinary paper with phenol fixation is safe, inexpensive, simple, and easy, and is thus suitable for conducting a global survey of IBD even where laboratory resources are limited. This practical method should contribute to the control of IBD worldwide.


Adaptive recognition by nucleic acid aptamers.
Nucleic acid molecules play crucial roles in diverse biological processes including the storage, transport, processing, and expression of the genetic information. Nucleic acid aptamers are selected in vitro from libraries containing random sequences of up to a few hundred nucleotides. Selection is based on the ability to bind ligand molecules with high affinity and specificity. Three-dimensional structures have been determined at high resolution for a number of aptamers in complex with their cognate ligands. Structures of aptamer complexes reveal the key molecular interactions conferring specificity to the aptamer-ligand association, including the precise stacking of flat moieties, specific hydrogen bonding, and molecular shape complementarity. These basic principles of discriminatory molecular interactions in aptamer complexes parallel recognition events central to many cellular processes involving nucleic acids.


Ah receptor in mice genetically "nonresponsive" for cytochrome P4501A1 induction: cytosolic Ah receptor, transformation to the nuclear binding state, and induction of aryl hydrocarbon hydroxylase by halogenated and nonhalogenated aromatic hydrocarbons in embryonic tissues and cells.
The aromatic hydrocarbon (Ah) receptor mediates induction of cytochrome P4501A1 and associated aryl hydrocarbon hydroxylase (AHH) activity in tissues or cells exposed to polycyclic aromatic hydrocarbons. Strains of mice designated "nonresponsive" do not show increased hepatic AHH activity when exposed in vivo to nonhalogenated aromatic hydrocarbons such as 3-methylcholanthrene, benz[a]anthracene (BA), or benzo[a]pyrene and have reduced sensitivity to halogenated inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, with a modified assay, we detected Ah receptor in hepatic cytosols from adult nonresponsive mice [Mol. Pharmacol. 35:823-830 (1989)]; the receptor was present in reduced amount, and the apparent affinity for TCDD was lower than in hepatic cytosol from responsive C57BL/6J mice. Using the same assay procedure, we now report detection of Ah receptor in cytosols prepared from embryonic tissue and from cultured embryo cells of both responsive (C57BL/6J) and nonresponsive mice (DBA/2J, AKR/J, and SWR/J). Cytosolic receptor in embryonic cells from nonresponsive as well as responsive strains was detectable both with [3H]TCDD and with [3H]3-methylcholanthrene. In addition, the receptor-ligand complex could be extracted from nuclei of embryo cells exposed to [3H]TCDD in culture. AHH activity was induced in embryo cell cultures incubated with either TCDD or BA. The EC50 values for AHH induction were virtually identical in cell cultures from nonresponsive (DBA/2J) and responsive (C57BL/6J) strains, using either TCDD or BA as the inducer. Moreover, the affinity with which [3H]TCDD bound to cytosolic Ah receptor was much more similar in cytosols from cell cultures from the two strains than in cytosols prepared from adult liver. Thus, embryonic cell cultures differ in at least three respects from the adult liver, as follows: (i) Ah receptor can be detected with [3H]3-methylcholanthrene in embryonic cell cytosols but not in cytosols from adult liver; (ii) the degree of difference between nonresponsive and responsive strains in the affinity with which [3H]TCDD binds to receptor is only about 2-fold in cytosol from embryonic cells, whereas it is almost 10-fold in adult liver; and (iii) induction of AHH activity (by either TCDD or by the nonhalogenated inducer BA) shows no significant difference between strains in embryonic cell culture, whereas there is at least a 15-fold difference in responsiveness between C57BL/6J and DBA/2J mice in adult liver in vivo. The mechanistic reason for the diminished degree of difference between responsive and nonresponsive mice during embryonic cell culture (compared with adult tissues) is not yet known.


Understanding the extent and impact of Indigenous road trauma.
While transport-related injuries represent a leading cause of death for all Australians, several disparities exist between Indigenous and non-Indigenous populations. Compared to non-Indigenous Australians, Indigenous Australians are more than twice as likely to have a transport-related fatal injury, with fatality risk remaining high with age while declining among the non-Indigenous community. Few studies and appropriate databases exist to elucidate the causes and solutions to this over-representation. This paper presents a summary of known risk factors, discusses the impact of road injury at multiple levels and suggests steps towards addressing this significant public health problem.


Development and validation of a physical model to investigate the biomechanics of infant head impact.
Head injury in childhood is the single most common cause of death or permanent disability from injury. However, despite its frequency and significance, there is little understanding of the response of a child's head to injurious loading. This is a significant limitation when making early diagnoses, informing clinical and/or forensic management or injury prevention strategies. With respect to impact vulnerability, current understanding is predominantly based on a few post-mortem-human-surrogate (PMHS) experiments. Researchers, out of experimental necessity, typically derive acceleration data, currently an established measure for head impact vulnerability, by calculation. Impact force is divided by the head mass, to produce a "global approximation", a single-generalised head response acceleration value. A need exists for a new experimental methodology, which can provide specific regional or localised response data. A surrogate infant head, was created from high resolution computer tomography scans with properties closely matched to tissue response data and validated against PMHS head impact acceleration data. The skull was 3D-printed from co-polymer materials. The brain, represented as a lumped mass, comprised of an injected gelatin/water mix. High-Speed Digital-Image-Correlation optically measured linear and angular velocities and accelerations, strains and strain rates. The "global approximation" was challenged by comparison with regional and local acceleration data. During impacts, perpendicular (at 90°) to a surface, regional and local accelerations were up to three times greater than the concomitant "global" accelerations. Differential acceleration patterns were very sensitive to impact location. Suture and fontanelle regions demonstrated ten times more strain (103%/s) than bone, resulting in skull deformations similar in magnitude to those observed during child birth, but at much higher rates. Surprisingly, perpendicular impacts produced significantly greater rotational velocities and accelerations, which are closer to current published injury thresholds than expected, seemingly as a result of deformational changes to the complex skull geometry. The methodology has proven a significant new step in characterising and understanding infant head injury mechanics.


Controls and Adaptive Management of Nitrification in Agricultural Soils.
Agriculture is responsible for over half of the input of reactive nitrogen (N) to terrestrial systems; however improving N availability remains the primary management technique to increase crop yields in most regions. In the majority of agricultural soils, ammonium is rapidly converted to nitrate by nitrification, which increases the mobility of N through the soil matrix, strongly influencing N retention in the system. Decreasing nitrification through management is desirable to decrease N losses and increase N fertilizer use efficiency. We review the controlling factors on the rate and extent of nitrification in agricultural soils from temperate regions including substrate supply, environmental conditions, abundance and diversity of nitrifiers and plant and microbial interactions with nitrifiers. Approaches to the management of nitrification include those that control ammonium substrate availability and those that inhibit nitrifiers directly. Strategies for controlling ammonium substrate availability include timing of fertilization to coincide with rapid plant update, formulation of fertilizers for slow release or with inhibitors, keeping plant growing continuously to assimilate N, and intensify internal N cycling (immobilization). Another effective strategy is to inhibit nitrifiers directly with either synthetic or biological nitrification inhibitors. Commercial nitrification inhibitors are effective but their use is complicated by a changing climate and by organic management requirements. The interactions of the nitrifying organisms with plants or microbes producing biological nitrification inhibitors is a promising approach but just beginning to be critically examined. Climate smart agriculture will need to carefully consider optimized seasonal timing for these strategies to remain effective management tools.


Analysis of the interaction between the eukaryotic chaperonin CCT and its substrates actin and tubulin.
Two mechanisms have thus far been characterized for the assistance by chaperonins of the folding of other proteins. The first and best described is that of the prokaryotic chaperonin GroEL, which interacts with a large spectrum of proteins. GroEL uses a nonspecific mechanism by which any conformation of practically any unfolded polypeptide interacts with it through exposed, hydrophobic residues. ATP binding liberates the substrate in the GroEL cavity where it is given a chance to fold. A second mechanism has been described for the eukaryotic chaperonin CCT, which interacts mainly with the cytoskeletal proteins actin and tubulin. Cryoelectron microscopy and biochemical studies have revealed that both of these proteins interact with CCT in quasi-native, defined conformations. Here we have performed a detailed study of the docking of the actin and tubulin molecules extracted from their corresponding CCT:substrate complexes obtained from cryoelectron microscopy and image processing to localize certain regions in actin and tubulin that are involved in the interaction with CCT. These regions of actin and tubulin, which are not present in their prokaryotic counterparts FtsA and FtsZ, are involved in the polymerization of the two cytoskeletal proteins. These findings suggest coevolution of CCT with actin and tubulin in order to counteract the folding problems associated with the generation in these two cytoskeletal protein families of new domains involved in their polymerization.


Alpha, beta and gamma T-cell receptor genes: rearrangements correlate with haematological phenotype in T cell leukaemias.
We have studied the arrangement of the alpha, beta and gamma T cell receptor (TCR) genes in 27 patients with T cell lymphoproliferative disorders. Nine patients had acute lymphoblastic leukaemia (T-ALL), nine patients had prolymphocytic leukaemia (PLL), six patients presented with a T-CLL/T-lymphocytosis syndrome, two patients had Sezary syndrome (SS) and one patient had HTLV-I positive T-cell leukaemia/lymphoma (ATLL). alpha TCR gene rearrangement could be demonstrated by the use of three available probes in only one case. By contrast, both beta and gamma TCR gene rearrangement could be demonstrated by Southern blot analysis of DNA samples digested with appropriate restriction enzymes in the majority of cases. In general, when rearrangements were present they involved both alleles. The proportion of rearranged chromosomes was lower in T-ALL than in other forms of T-cell leukaemia and it was lower in cases with the CD4-/CD8+ phenotype than in those with a CD4+/CD8- phenotype. In three out of 34 cases of B-cell leukaemia the TCR beta-gene but not the TCR gamma-gene was rearranged, just as in two out of 26 cases of T-cell leukaemia the immunoglobulin (Ig) heavy chain but not the light chain genes were rearranged. These data suggest that development of the machinery required for gene rearrangement may precede commitment to B or T cell lineage. The use of this technique is especially useful for the classification of cases of ALL in which the cells are negative with respect to most current phenotypic markers and in cases of T cell lymphocytosis in which the finding of a gene rearrangement identifies a monoclonal cell population.


The Expression of CD14(+)CD16(+) Monocyte Subpopulation in Coronary Heart Disease Patients with Blood Stasis Syndrome.
Blood stasis syndrome (BSS), a comprehensive pathological state, is one of the traditional Chinese medicine syndromes of coronary heart disease (CHD). In our previous study, we investigated that Fc γ RIIIA (also called CD14(+)CD16(+) monocyte subpopulation) is one of the differentially expressed genes related to CHD patients and its possible role in the atherosclerotic formation and plaque rupture. However, whether or not the deregulation of CD14(+)CD16(+) monocyte subpopulation expression is implicated in the pathogenesis of CHD patients with BSS has not yet been elucidated. In this study, we found that there was no significant difference between CHD patients with BSS and non-BSS in CD14(+)CD16(+) monocyte subpopulation at gene level. Moreover, the protein level of CD14(+)CD16(+) monocyte subpopulation in CHD patients with BSS was increased significantly when compared to the CHD patients with non-BSS. Additionally, the level of inflammatory cytokines downstream of CD14(+)CD16(+) monocyte subpopulation such as TNF- α and IL-1 in sera was much higher in CHD patients with BSS than that in CHD patients with non-BSS. Taken together, these results indicated that CD14(+)CD16(+) monocyte subpopulation was implicated in the pathogenesis of CHD patients with BSS, which may be one of the bases of the essence of BSS investigation.


The BEST criteria improve sensitivity for detecting positive cultures in residual blood components cultured in suspected septic transfusion reactions.
Culturing residual blood components after suspected septic transfusion reactions guides management of patients and cocomponents. Current practice, accuracy of provider vital sign assessment, and performance of the AABB culture criteria are unknown. A multicenter international study was undertaken to investigate these issues and develop improved culture criteria. Retrospective data for all transfusion reactions resulting in residual blood component culture in 2016 were collected from participating hospitals. The performance of the AABB culture criteria were assessed for detection of positive culture results. Modifications to the AABB criteria including 1) recommending culturing in the setting of isolated high fevers, 2) defining hypotension and tachycardia using objective parameters, and 3) incorporating antipyretic use were tested to determine if modifications improved performance. Modifications associated with improvement were incorporate into the BEST criteria. The AABB and the BEST criteria were then tested against a data set enriched for positive culture results to determine which criteria were superior. Data were collected from 20 centers encompassing 779,143 transfusions, 3,187 reported transfusion reactions, and 1,104 cultured components. There was marked variation in reaction reporting and culturing rates (0.0%-100.0%). Of 35 total positive component cultures, only one of 35 (2.9%) had concordant patient cultures; 12 of 34 (35.3%) did not have patient cultures performed. The BEST criteria had better sensitivity for detection of a positive culture result compared to the AABB criteria (74% vs. 41%), although specificity decreased (45% vs. 65%). Compared to the AABB criteria, the BEST criteria have improved sensitivity for positive culture detection.


The efficacy of vaginal suppository based on myrtle in patients with cervicovaginal human papillomavirus infection: A randomized, double-blind, placebo trial.
Human papillomavirus (HPV) can be detected in most of cervical cancers. Due to antiviral, antimutagenic, and proapoptotic activities of myrtle, this study was designed to investigate the effect of a herbal suppository based on myrtle in cervicovaginal HPV infections. This study was performed as a double-blind randomized trial at the Clinic of Traditional Medicine in Mashhad University of Medical Sciences between 2016 and 2017. Sixty women, 18 to 50 years old, with cervicovaginal HPV infection, were included and randomly allocated to two groups. Sixty placebo or herbal vaginal suppositories were prescribed for 3 months (20 suppositories at each menstrual cycle). Each herbal vaginal suppository contained 10% of myrtle aqueous extract and 0.5% of myrtle essential oil. The HPV test and colposcopic findings were evaluated after treatment. There was no difference between two groups as regards lesion site, diagnosis time of disease, and HPV type before intervention (p ≥ 0.05). At the end of the study, the HPV test was negative in 92.6% and 62.6% of the intervention and placebo groups, respectively (p = 0.036). The change in cervical lesion size was 71.4% and 30.4% in the intervention and placebo groups, respectively, based on colposcopic findings (p = 0.015). It seems that herbal suppository can speed up virus clearance and can be effective in treating HPV infection.


A phenomenological order approach to the volume phase transition in microgel particles.
We proposed a model to describe the volume phase transition of microgel particles, based on constitutive relations that consider the mechano-chemical coupling of deformation and solvency processes, as well as the phenomenological cooperative effect of molecular orientation of solvatable segments in the particles. We regard a nematic-isotropic like transition and define a tensor order parameter allowing analysis of the collective behaviour of water solvation mechanisms based on the Landau-De Gennes theory for liquid crystal elastomers. A complementary approach to the energy balance density is obtained with the order parameter field considering the deformation by a continuum mechanics approximation; our approach aims to extend the comprehensive understanding of the elastic behaviour and water sorption related phenomena in microgel particles. With the proposed model, we reproduce the behaviour of swelling curves through a volume phase transition of thermosensitive microgel particles by assessing characteristic parameters belonging to particular physical properties. The parameters defined within the model such as elastic and solvency related constants and characteristic temperatures were obtained by fitting of a data set mimicking the experimentally observed swelling behaviour. The obtained values of the parameters were consistent with the discussed phenomenology which shows the importance of molecular ordering interpretation as a source to describe the volume phase transition in microgel particles.


An overview of telemedicine: the virtual gaze of health care in the next century.
This article considers the role of telemedicine in the production of biomedical health care using three specific theoretical constructs as lenses through which to examine this phenomenon: (1) Foucault's medical "gaze"; (2) the political economy of health; and (3) deterritorialization and multisite ethnography. This examination focuses first on the changing corporate structure of health care and changing political attitudes toward telemedicine. Second, it documents the current use of telemedicine in prisons, the military, and in cross-cultural settings. Third, it discusses responses to telemedicine of individual physicians, health care staff, and patients, finding that these responses are broadly conditioned by an individual's mode of articulation with biomedical institutions and that they are mediated by personal experience.


[Radiation sensitizers: with special reference to hypoxic cell sensitizers].
Recent advances in radiation chemistry and radiation biology have led to the combined use of radiosensitizing agents with radiation in the treatment of radioresistant tumors. Various chemicals, including cancerocidal drugs, are used, although radiation sensitizers are defined as drugs which can increase cellular radiosensitivity but have no direct cancerocidal effect. At least four classes of agents, pyrimidine analogues, hypoxic cell sensitizers, PLDR inhibitors and thiol-depleting agents, can modify radiosensitivity and have potential for differential sensitization. Pyrimidine analogues are incorporated into DNA in replicating tumor cells, and can sensitize these cells to radiation up to a factor of 3. Results of clinical trials of intra-arterial infusion of BUdR have not proved satisfactory, especially with regard to long-term survival, possibly because of the existence of non-replicating cells in the tumor. The latter two are still in the experimental stage of study. The radioresistance of hypoxic cells in tumor has been regarded as one of the limiting factors in the local control of cancer by radiation. Attempts to improve the situation involve high-LET radiation and combined use of chemicals, such as oxygen, prefluorochemicals and electron-affinic compounds, with low-LET radiation. Although some clinical trials in head and neck cancer and in cervical cancer have yielded positive results in patients treated using hyperbaric oxygen, attempts have been made to devise other methods, such as those using perfluorochemicals with normobaric oxygen, because of the technical difficulty involved with the former method. A more promising and easier method is the combined use of electron-affinic chemicals, which like oxygen can sensitize the hypoxic cells. Misonidazole (alpha 2-nitroimidazole derivative) was found to be an excellent sensitizer of this kind in cultured mammalian cells and in some rodent tumors. Several randomized clinical trials to determine its efficacy have been carried out on a word-wide scale, but most of them failed to demonstrate any beneficial effect, mainly because of the drug's neurotoxicity which limits its dose. After misonidazole, many researchers have made every effort to develop more efficient hypoxic cell sensitizers. The present state and future prospects of study were reviewed with special reference to studies currently being undertaken in Japan.


Immune response to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg.
Hepatitis B surface antigen (HBsAg) particles are composed of a major polypeptide, p25, and additional polypeptides of higher m.w., namely p33 and p39, are variably present. All three polypeptides share the 226 amino acid residues of the S region: p33 consists of the p25 sequence plus an NH2-terminal 55 residues (pre-S(2], and p39 consists of the p33 sequence plus an NH2-terminal 108-119 residues (pre-S(1). In previous studies we demonstrated the influence of two Ir genes on the humoral and cellular immune responses to the S region and identified nonresponder phenotypes (H-2f,s). Subsequent studies showed that the immune response to the pre-S(2) region was regulated by H-2-linked genes independently of the S region response, such that immunization of S region nonresponder, pre-(S2) region responder mice (H-2s) with HBsAg/p33 circumvented nonresponse to the S region. In the present study, we have extended this analysis to the pre-S(1) region of HBsAg, with the following results: 1) and pre-S(1) region is immunogenic at the T and B cell levels; 2) anti-pre-S(1) specific antibody production is regulated by H-2-linked genes and can be independent of anti-S and anti-pre-S(2) antibody production; 3) immunization of H-2f strains with HBsAg/p39 particles containing the pre-S(1) region can bypass nonresponsiveness to the S and pre-S(2) regions in terms of antibody production; 4) two synthetic peptides, p32-53 and p94-117, define murine and human antibody binding sites on the pre-S(1) region, and p1-21 and p12-32 define additional human antibody binding sites; 5) pre-S(1)-specific T cells can be elicited in S and pre-S(2) region nonresponder mice (H-2f) and provide functional T cell help for S-pre-S(2)-, and pre-S(1)-specific antibody production; and 6) a T cell recognition site in the pre-S(1) region, p12-32 was identified. These results are relevant to HBV vaccine development, and possibly to viral clearance mechanisms, since the higher m.w. polypeptides are preferentially expressed on intact virions.


Adipose saturation reduces lipotoxic systemic inflammation and explains the obesity paradox.
Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context of dietary patterns of the countries from which the studies originated. Increased severity was noted in leaner populations with a higher proportion of unsaturated fat intake. In mice, greater hydrolysis of unsaturated visceral triglyceride caused worse organ failure during pancreatitis, even when the mice were leaner than those having saturated triglyceride. Saturation interfered with triglyceride's interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox.


Predicting antiretroviral drug resistance from the latest or the cumulative genotype.
This study evaluates the added benefit when estimating antiretroviral drug resistance of combining all available resistance test results in a cumulative genotype relative to using the latest genotype alone. The prevalence of resistance and genotypic sensitivity scores (GSS) predicted by the latest and the cumulative genotype, together with virological outcomes after the latest genotype, were measured in treatment-experienced patients who underwent ≥2 resistance tests in 1999-2008. Comparing the latest with the cumulative genotype in 227 patients, 4 (1.7%) versus 0 (0.0%) showed no major resistance mutations, whereas 74 (32.6%) versus 46 (20.3%), 88 (38.8%) versus 76 (33.5%) and 61 (26.9%) versus 105 (46.3%) showed single-class, dual-class and triple-class resistance mutations, respectively. The median (IQR) number of fully or partially active drugs was 6 (5-6) versus 5 (4-6) for the nucleoside/nucleotide reverse transcriptase inhibitors, 3 (1-3) versus 1 (1-3) for the non-nucleoside reverse transcriptase inhibitors and 7 (7-7) versus 7 (7-7) for the protease inhibitors, respectively. Among 163 patients who started a new regimen after the latest genotype, both the latest and the cumulative GSS were predictive of early (≤24 weeks) virological responses. The GSS decreased by median 1 unit (IQR 0.5-1.0) in the cumulative genotype and larger differences relative to the latest genotype corresponded to smaller decreases in viral load. The cumulative genotype offers a more comprehensive evaluation of the burden of resistance. This approach can guide small but appreciable improvements in the selection of antiretroviral regimens for treatment-experienced patients.


Awareness and interest in intrauterine contraceptive device use among HIV-positive women in Cape Town, South Africa.
To assess awareness of and interest in intrauterine contraceptive device (IUCD) use among HIV-positive women in Cape Town, South Africa. Cross-sectional survey. HIV-positive women aged 18 through 45 years presenting for care at a primary health care clinic in Cape Town, South Africa participated in this study. Consented participants completed a staff-administered questionnaire in a private setting. Descriptive statistics were generated. Comparisons between demographic and reproductive health-related variables and IUCD awareness and interest were performed with multiple logistic regression. Analyses for IUCD interest excluded women with prior surgical sterilization. Of 277 HIV-positive women, 37% were aware of the IUCD; awareness was independently associated with greater age (adjusted odds ratio (AOR)=1.15, 95%; confidence interval (CI): 1.10-1.20) and not switching contraceptive methods in the last year (AOR=2.45, 95% CI: 1.03-5.83). Following an IUCD information session, 86% of women (n=206/240) were interested in IUCD use. IUCD interest was inversely associated with age (AOR=0.91, 95% CI: 0.86-0.97) and marginally positively associated with current menstrual bleeding pattern complaints (AOR=2.14, 95% CI: 0.98-4.68). Despite low levels of method awareness, HIV-positive women in this setting are frequently interested in IUCD use, indicating need for programming to expand method access.


Tumor re-growth, case outcome, and tumor scoring systems in rehabilitated green turtles with fibropapillomatosis.
Fibropapillomatosis (FP) is an infectious, neoplastic disease of major concern in sea turtle rehabilitation facilities. Rehabilitating sea turtles that undergo tumor removal surgery often have tumor regrowth and may experience mortality. We evaluated tumor score, removal, and regrowth in rehabilitating green sea turtles with FP in 4 rehabilitation facilities in the southeastern USA during 2009-2017. Of 756 cases, 312 (41%) underwent tumor removal surgery, 155 (50%) of those had tumor regrowth within an average of 46 ± 45 d, and 85 (27%) had multiple (>1) regrowth events. Of 756 turtles with FP, 563 (75%) did not survive after admission into a rehabilitation facility, including 283 (37%) that were euthanized and 280 that died without euthanasia (37%), and 193 survived, including 186 (25%) released and 7 (1%) placed in permanent captive care. Tumor removal surgery increased the odds of tumor regrowth but also enhanced survivorship, whereas tumor regrowth was not a significant predictor of case outcome. Three FP tumor scoring systems were used to assign tumor scores to 449 cases, and differing results emphasize that tumor scoring systems should be applied to the situations and/or location(s) for which they were intended. FP tumor score was not a significant predictor for the event or extent of FP tumor regrowth after surgical excision. Under current rehabilitation regimes, outcomes of rehabilitation for tumored turtles have a low probability of success. The results of this study may be used to help guide clinical decision-making and determine prognoses for rehabilitating sea turtles with FP.


Double Tension Adjustments with Novel Modification on Tension-Free Vaginal Tape.
To evaluate the results of novel modifications on tension- free vaginal tape (TVT) for the treatment of women with stress urinary incontinence (SUI). Sixteen female patients (average age 49.29 years, range: 31-78) who underwent anti-incontinence surgery to correct their SUI in the period between June 2010 and August 2014 were included in the study. In situ anterior vaginal wall sling was prepared, and monofilament polypropylene tape passed below the in situ-sling and standard TVT procedure was performed. Both ends of the mesh in the suprapubic region were labeled with Vicryl sutures and left outside the wound. The middle of the mesh in the vaginal region were labeled with similar suture and left outside the vagina. Foley catheter was removed on the third postoperative day. The average period of follow-up was 8 months (range: 5-17). All patients benefited from the surgery; 15 (94%) of them completely cured and one patient clinically improved. Urinary retention was observed in one patient where the tension of the tape was reduced using adjustment sutures. No vaginal mesh erosion was detected during the gynecological examination postoperatively. No significant post-voiding residue was detected after catheter removal. This technique gives feasible option to adjust the tension of the mesh in the early post-operative period in case of urinary retention. Presence of intervening in situ sling reduces the risk of vaginal erosions. Long-term success is expected because dislocation of the mid-urethral sling is less likely.


Gambling among Swedish youth: Predictors and prevalence among 15- and 17-year-old students.
Gambling among adolescents is a growing public health concern in Sweden as in many other countries. Excessive gambling has been found to be associated with a wide range of negative consequences such as financial problems, strained relationships, criminal behaviour, depression, and an elevated risk for suicide. Research suggests a link between alcohol consumption and gambling, particularly among male gamblers. There are nevertheless gaps in the available knowledge pertaining to school-aged students in Sweden. The purpose of this study is to investigate predictors of gambling and frequent gambling among Swedish students in Grade 9 and Grade 11 (ages 15 and 17 years). Data on gambling and alcohol consumption were obtained from the Swedish Council on Information and Other Drugs yearly school surveys (n = 4763) in Grade 9 and Grade 11 (n = 3720). Poisson regression models have been applied to estimate the association between less frequent and frequent gambling with the predictors of gender, family and school satisfaction, school situation, and alcohol and drug use. Gambling among Swedish students is a highly gendered activity: boys gamble more and more frequently than girls. Having consumed alcohol was associated with both less frequent and more frequent gambling among Grade 9 students while controlling for other variables. In Grade 9, heavy episodic drinking was only associated with less frequent gambling, not with frequent gambling. Among Grade 11 students, both alcohol consumption and heavy episodic drinking was associated with less frequent gambling but heavy episodic drinking was only associated with frequent gambling. Moreover, drug use was associated with less frequent gambling in Grade 11. Skipping classes was the only school factor that was found to be associated with less frequent gambling (Grade 11). Such factors as family satisfaction and two measurements of economic situation were not associated with gambling at all.


Stabilization and swelling of hagfish slime mucin vesicles.
When agitated, Atlantic hagfish (Myxine glutinosa) produce large quantities of slime that consists of hydrated bundles of protein filaments and membrane-bound mucin vesicles from numerous slime glands. When the slime exudate contacts seawater, the thread bundles unravel and the mucin vesicles swell and rupture. Little is known about the mechanisms of vesicle rupture in seawater and stabilization within the gland, although it is believed that the vesicle membrane is permeable to most ions except polyvalent anions. We hypothesized that the most abundant compounds within the slime gland exudate have a stabilizing effect on the mucin vesicles. To test this hypothesis, we measured the chemical composition of the fluid component of hagfish slime exudate and conducted functional assays with these solutes to test their ability to keep the vesicles in a condensed state. We found K(+) concentrations that were elevated relative to plasma, and Na(+), Cl(-) and Ca(2+) concentrations that were considerably lower. Our analysis also revealed high levels of methylamines such as trimethylamine oxide (TMAO), betaine and dimethylglycine, which had a combined concentration of 388 mmol l(-1) in the glandular fluid. In vitro rupture assays demonstrated that both TMAO and betaine had a significant effect on rupture, but neither was capable of completely abolishing mucin swelling and rupture, even at high concentrations. This suggests that some other mechanism such as the chemical microenvironment within gland mucous cells, or hydrostatic pressure is responsible for stabilization of the vesicles within the gland.


Big Data Challenges of High-Dimensional Continuous-Time Mean-Variance Portfolio Selection and a Remedy.
Investors interested in the global financial market must analyze financial securities internationally. Making an optimal global investment decision involves processing a huge amount of data for a high-dimensional portfolio. This article investigates the big data challenges of two mean-variance optimal portfolios: continuous-time precommitment and constant-rebalancing strategies. We show that both optimized portfolios implemented with the traditional sample estimates converge to the worst performing portfolio when the portfolio size becomes large. The crux of the problem is the estimation error accumulated from the huge dimension of stock data. We then propose a linear programming optimal (LPO) portfolio framework, which applies a constrained ℓ1 minimization to the theoretical optimal control to mitigate the risk associated with the dimensionality issue. The resulting portfolio becomes a sparse portfolio that selects stocks with a data-driven procedure and hence offers a stable mean-variance portfolio in practice. When the number of observations becomes large, the LPO portfolio converges to the oracle optimal portfolio, which is free of estimation error, even though the number of stocks grows faster than the number of observations. Our numerical and empirical studies demonstrate the superiority of the proposed approach.


Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making.
Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.


Microbial Extracellular Polymeric Substances (EPSs) in Ocean Systems.
Microbial cells (i.e., bacteria, archaea, microeukaryotes) in oceans secrete a diverse array of large molecules, collectively called extracellular polymeric substances (EPSs) or simply exopolymers. These secretions facilitate attachment to surfaces that lead to the formation of structured 'biofilm' communities. In open-water environments, they also lead to formation of organic colloids, and larger aggregations of cells, called 'marine snow.' Secretion of EPS is now recognized as a fundamental microbial adaptation, occurring under many environmental conditions, and one that influences many ocean processes. This relatively recent realization has revolutionized our understanding of microbial impacts on ocean systems. EPS occur in a range of molecular sizes, conformations and physical/chemical properties, and polysaccharides, proteins, lipids, and even nucleic acids are actively secreted components. Interestingly, however, the physical ultrastructure of how individual EPS interact with each other is poorly understood. Together, the EPS matrix molecules form a three-dimensional architecture from which cells may localize extracellular activities and conduct cooperative/antagonistic interactions that cannot be accomplished efficiently by free-living cells. EPS alter optical signatures of sediments and seawater, and are involved in biogeomineral precipitation and the construction of microbial macrostructures, and horizontal-transfers of genetic information. In the water-column, they contribute to the formation of marine snow, transparent exopolymer particles (TEPs), sea-surface microlayer biofilm, and marine oil snow. Excessive production of EPS occurs during later-stages of phytoplankton blooms as an excess metabolic by product and releases a carbon pool that transitions among dissolved-, colloidal-, and gel-states. Some EPS are highly labile carbon forms, while other forms appear quite refractory to degradation. Emerging studies suggest that EPS contribute to efficient trophic-transfer of environmental contaminants, and may provide a protective refugia for pathogenic cells within marine systems; one that enhances their survival/persistence. Finally, these secretions are prominent in 'extreme' environments ranging from sea-ice communities to hypersaline systems to the high-temperatures/pressures of hydrothermal-vent systems. This overview summarizes some of the roles of exopolymer in oceans.


Structural and functional consequences of the replacement of proximal residues Cys(172) and Cys(192) in the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase from Chlamydomonas reinhardtii.
Proximal Cys(172) and Cys(192) in the large subunit of the photosynthetic enzyme Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase; EC 184.108.40.206) are evolutionarily conserved among cyanobacteria, algae and higher plants. Mutation of Cys(172) has been shown to affect the redox properties of Rubisco in vitro and to delay the degradation of the enzyme in vivo under stress conditions. Here, we report the effect of the replacement of Cys(172) and Cys(192) by serine on the catalytic properties, thermostability and three-dimensional structure of Chlamydomonas reinhardtii Rubisco. The most striking effect of the C172S substitution was an 11% increase in the specificity factor when compared with the wild-type enzyme. The specificity factor of C192S Rubisco was not altered. The V(c) (V(max) for carboxylation) was similar to that of wild-type Rubisco in the case of the C172S enzyme, but approx. 30% lower for the C192S Rubisco. In contrast, the K(m) for CO(2) and O(2) was similar for C192S and wild-type enzymes, but distinctly higher (approximately double) for the C172S enzyme. C172S Rubisco showed a critical denaturation temperature approx. 2 degrees C lower than wild-type Rubisco and a distinctly higher denaturation rate at 55 degrees C, whereas C192S Rubisco was only slightly more sensitive to temperature denaturation than the wild-type enzyme. X-ray crystal structures reveal that the C172S mutation causes a shift of the main-chain backbone atoms of beta-strand 1 of the alpha/beta-barrel affecting a number of amino acid side chains. This may cause the exceptional catalytic features of C172S. In contrast, the C192S mutation does not produce similar structural perturbations.


Everolimus Use for Intolerance or Failure of Baseline Immunosuppression in Adult Heart and Lung Transplantation.
BACKGROUND Everolimus can be utilized after heart or lung transplantation to reduce calcineurin inhibitor associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection, cardiac allograft vasculopathy, and bronchiolitis obliterans syndrome. MATERIAL AND METHODS A single-center, retrospective cohort study was conducted including 51 adult heart transplant patients (n=32) and lung transplant patients (n=19) started on everolimus due to immunosuppressive therapy intolerance or failure, between 2010 and 2017. Everolimus indication, response, efficacy, and tolerability were assessed. RESULTS Everolimus was most commonly initiated due to leukopenia/neutropenia (n=17, 33%) or renal dysfunction (n=13, 25%). Leukopenia/neutropenia resolved in 76% of patients (13 out of 17 patients). Renal function (GFR) increased 7.4 mL/min from baseline to 3 months after everolimus initiation (P=0.011). The most common adverse effects were edema (n=23, 45%) and hyperlipidemia (n=25, 49%). A high discontinuation rate was observed (n=21, 41%), mostly from edema. CONCLUSIONS Everolimus might be beneficial in heart and lung transplant patients with leukopenia or neutropenia and lead to modest, short-term renal function improvement. Patient selection is crucial because adverse effects frequently lead to everolimus discontinuation.


Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation.
Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.


CALCIUM AND INORGANIC PHOSPHORUS IN THE BLOOD OF RABBITS : I. RESULTS OF REPEATED AND PROLONGED OBSERVATIONS ON NORMAL RABBITS.
It will be seen at once that the mean values obtained for calcium are higher than most of those recorded in the literature, and that the values for inorganic phosphorus are perhaps lower. It is well to bear in mind, however, that the significance that may be attached to any series of determinations of calcium and inorganic phosphorus in the blood of animals depends largely upon the conditions under which the determinations are made. As is well known, there are many factors that may affect the values obtained, including inherent differences in the animal material and the method of analysis used as well as the particular procedure employed in carrying out a given method. When all other conditions are uniform, irregularities in the handling of the blood after it is drawn will give rise to surprisingly large differences in the results for both calcium and inorganic phosphorus, as permitting blood to stand tends to decrease calcium values and to increase those for inorganic phosphorus. It seems desirable, therefore, to emphasize the fact that the results recorded above are to be viewed as results obtained under certain definitely prescribed conditions which differ in several important respects from those governing determinations made by other workers in this field. Moreover, it is to be noted that the conditions varied to some extent with each of the 4 groups of animals comprising this series. For example, there was a small but definite age difference. The animals of Groups I and II were older and more mature than those of Groups III and IV at the beginning of the experiments, and this initial difference was increased by the extension of the experiments on Groups I and II over a longer period of time, so that the observations made on these animals not only included data for a more advanced age, but represented a mean age considerably above that of the observations made on the animals of Groups III and IV. There was a similar difference of experimental conditions between Groups III and IV, while the observations on Group II differed from those on Group I in that no blood analyses were made on the animals of Group II for 2 months after they were placed under observation. These particular features of the experiments are mentioned because an examination of the text-figures will show that a line of cleavage between Groups I and II on the one hand, and III and IV on the other, is traceable through all of the distribution curves and to some extent in the tabulated results. With the combined values as the axis of distribution, Groups I and II invariably hang together, or swing to one side, while Groups III and IV swing to the other. Moreover, the extreme positions are usually represented by Groups II and IV. Whether these peculiarities of the results are in reality attributable to the conditions mentioned or to some other cause, such as the length of cage life (2), or the particular period covered by the observations, the suggested relation is sufficient to indicate the extent to which even slight differences in experimental conditions may affect the results obtained for blood calcium and inorganic phosphorus. The values obtained for calcium may be regarded as showing a fairly close agreement (Tables I and II and Text-fig. 1). The extreme difference between the means for the 4 groups of animals is only 0.5 mg. or approximately 3.00 per cent of the mean for the combined groups. Still, the small absolute difference between the means for Groups I and IV is nearly 6 times its probable error and, hence, cannot be disregarded. The most important feature of these results is, however, the range of normal variation. The distribution curves (Text-fig. 1) show a remarkably close agreement in the frequency with which values of a given magnitude occurred and an unusually symmetrical distribution of all values. The coefficients of variation are comparatively small (7.09 to 8.9 per cent), but values anywhere between 14.0 and 16.0 mg. of calcium per 100 cc. of serum occurred with great frequency, while figures as low as 13.5 or as high as 17.5 mg. (Table II) were by no means rare; and the extreme limits of observation indicate a potential difference in the calcium content of the blood of normal rabbits of as much as 100 per cent. Inorganic phosphorus was found to be subject to much wider variation than calcium (Tables III and IV and Text-fig. 2). The coefficient of variation is approximately twice that for calcium (17.29 and 8.01 respectively), while the group means for phosphorus show a difference of 0.85 mg. per 100 cc. of serum. This difference is small in absolute value, but is nearly 20.0 per cent of the mean for all groups and is 15 times its probable error. It is safe to assume, therefore, that the values obtained indicate an actual difference in the inorganic phosphorus in the blood of the several groups of animals. This conclusion is borne out by the distribution frequencies (Table IV and Text-fig. 2) which show that the values obtained for Groups I and II lie at a distinctly lower level than those for Groups III and IV; the difference between modal classes is, in fact, of the same order as that shown by the means. The limits of probable variation as determined by the standard deviation of the combined results are 3.73 and 5.29 mg. per 100 cc. of serum, but one-third of all values lie outside of these limits, while the extreme limits of normal are sufficiently wide to include values that may differ by as much as 200.0 or even 300.0 per cent. From the values obtained for calcium and inorganic phosphorus, the relation existing between the two substances may be measured in a number of ways. The ratio of the calcium to the phosphorus and the product of the amounts of the two substances have received the greatest attention. In addition to these values, we have computed values for the sum and for the ratio of the product to the sum, and also for the sum of the calcium-phophorus ratio and the product-sum ratio. The value for the sum of the calcium and inorganic phosphorus in the serum is determined largely by the calcium, but as it is also affected by the phosphorus, one might expect that the constancy of the value as compared with that of calcium would be diminished unless the variations in the two substances were so related as to neutralize each other. As is well known, there is an apparent tendency in this direction and in these experiments it was found that on the whole the values for the sum showed less variation (coefficients 6.42 and 8.01 per cent) and were more uniformly distributed than those for calcium (Tables V and VI and Text-fig. 3). It is true that differences between groups were distinctly greater than in the case of calcium, but the agreement is sufficiently close to give evidence of a tendency to the maintenance of an inverse relation between serum calcium and inorganic phosphorus. Values for the product of calcium and inorganic phosphorus emphasize the phosphorus factor rather than the calcium, reversing the conditions that obtain in the case of the sum. A consideration of the product values given in Tables VII and VIII and Text-fig. 4 show that, while the order of variation is essentially the same as that of inorganic phosphorus (coefficients 17.09 and 17.29 per cent respectively), the distribution of values is more uniform. This may be attributable to the occurrence of coordinate variations in calcium and inorganic phosphorus. The situation presented by the values obtained for the ratio of calcium to inorganic phosphorus is somewhat surprising in that the ratio between the two substances proves to be less constant than the absolute amounts of either substance (Tables IX and X and Text-fig. 5). There are considerable differences between the standard values for individual groups of animals, and the distribution frequencies are inclined to be irregular. Moreover, all groups show a large standard deviation and correspondingly high coefficients of variation, but combining the results for the 4 groups of animals gives a fairly uniform and symmetrical distribution, a striking feature of which is the high frequency with which values occur over the entire range of standard variation, that is, from ratios of 2.85 to 4.29. It thus appears that, despite the evidence of a tendency to the observance of an inverse relation between the calcium and inorganic phosphorus in the blood, the ratio of one substance to the other is by no means constant. By using the product and the sum as a basis of expressing the relation between calcium and inorganic phosphorus, the form of the relation is ???


Detection of early colorectal cancer development in the azoxymethane rat carcinogenesis model with Fourier domain low coherence interferometry.
Fourier domain low coherence interferometry (fLCI) is an emerging optical technique used to quantitatively assess cell nuclear morphology in tissue as a means of detecting early cancer development. In this work, we use the azoxymethane rat carcinogenesis model, a well characterized and established model for colon cancer research, to demonstrate the ability of fLCI to distinguish between normal and preneoplastic ex-vivo colon tissue. The results show highly statistically significant differences between the measured cell nuclear diameters of normal and azoxymethane-treated tissues, thus providing strong evidence that fLCI may be a powerful tool for non-invasive, quantitative detection of early changes associated with colorectal cancer development.


Time-dependent evolution of tissue markers by MALDI-MS imaging.
We have used MALDI-MS imaging (MALDI-MSI) to monitor the time dependent appearance and loss of signals when tissue slices are brought rapidly to room temperature for short to medium periods of time. Sections from mouse brain were cut in a cryostat microtome, placed on a MALDI target and allowed to warm to room temperature for 30 s to 3 h. Sections were then refrozen, fixed by ethanol treatment and analysed by MALDI-MSI. The intensity of a range of markers were seen to vary across the time course, both increasing and decreasing, with the intensity of some markers changing significantly within 30 s and markers also showed tissue location specific evolution. The markers resulting from this autolysis were compared directly to those that evolved in a comparable 16 h on-tissue trypsin digest, and the markers that evolved in the two studies were seen to be substantially different. These changes offer an important additional level of location-dependent information for mapping changes and seeking disease-dependent biomarkers in the tissue. They also indicate that considerable care is required to allow comparison of biomarkers between MALDI-MSI experiments and also has implications for the standard practice of thaw-mounting multiple tissue sections onto MALDI-MS targets.


Sonochemical reaction to control the near-infrared photoluminescence properties of single-walled carbon nanotubes.
The effect of ultrasonic irradiation on the optical properties of single-walled carbon nanotubes (SWNTs) was investigated. Upon sonication in D2O in the presence of sodium dodecylbenzene sulfonate (SDBS) under air, red-shifted photoluminescence (PL) peaks at ∼1043 and ∼1118 nm were observed from the aqueous suspensions of (6,4) and (6,5)SWNTs, accompanied by a decrease in the intensity of the intrinsic PL peaks. Upon sonication with SDBS under an Ar atmosphere, the rate of spectral change increased with the sonication time and new PL peaks emerged at 1043, 1118, and 1221 nm. Meanwhile, upon the addition of 1-butanol, the PL peaks emerged only at 1043 nm and 1118 nm, while the emergence of the peak at 1221 nm was inhibited. On the other hand, a suspension with highly dispersed SWNTs was obtained upon sonication in the presence of sodium cholate without any change in the intrinsic optical properties of SWNTs. These experimental results reveal that the PL characteristics of SWNTs can be controlled by controlling the sonication conditions such as the type of surfactant used, the concentration of SWNTs, reaction environment, and the presence of an inhibitor such as 1-butanol.


Family Caregiver and Provider Perspectives on Inclusive Care: Aligning Needs and Expectations.
Home-based and community-based health care for individuals with complex medical conditions is often provided by family caregivers. Yet caregivers often are not meaningfully included in interactions with clinical health care teams. Inclusive care means inviting the caregiver to participate in shared decision-making and treatment planning. For aging or medically vulnerable adults, caregiver inclusion is an important facet of patient-centered care. We apply a mixed-methods approach using a survey (n=50) and semistructured interview data (n=13) from a national sample of caregivers of veterans and semistructured interview data from (n=24) providers from 3 Veterans Affairs regional networks. We elicited data from caregivers about their experiences with inclusive care and how providers communicate with them and assess their capacity. We juxtaposed these data with provider perspectives to see where there was alignment. We determined that caregivers play important roles in trust-building, communications management, implementation of care plans at home or in the community, and improving the care of care recipients-while maintaining a balance between competing tensions. Our findings suggest that expanding inclusive care could improve care quality and health outcomes of individuals with complex health care needs. Further, our findings bolster recent policy efforts at the federal and state levels to increase recognition of caregivers as key members of the health care team.


Menthol cigarettes and the public health standard: a systematic review.
Although menthol was not banned under the Tobacco Control Act, the law made it clear that this did not prevent the Food and Drug Administration from issuing a product standard to ban menthol to protect public health. The purpose of this review was to update the evidence synthesis regarding the role of menthol in initiation, dependence and cessation. A systematic review of the peer-reviewed literature on menthol cigarettes via a PubMed search through May 9, 2017. The National Cancer Institute's Bibliography of Literature on Menthol and Tobacco and the FDA's 2011 report and 2013 addendum were reviewed for additional publications. Included articles addressing initiation, dependence, and cessation were synthesized based on study design and quality, consistency of evidence across populations and over time, coherence of findings across studies, and plausibility of the findings. Eighty-two studies on menthol cigarette initiation (n = 46), dependence (n = 14), and cessation (n = 34) were included. Large, representative studies show an association between menthol and youth smoking that is consistent in magnitude and direction. One longitudinal and eight cross-sectional studies demonstrate that menthol smokers report increased nicotine dependence compared to non-menthol smokers. Ten studies support the temporal relationship between menthol and reduced smoking cessation, as they measure cessation success at follow-up. The strength and consistency of the associations in these studies support that the removal of menthol from cigarettes is likely to reduce youth smoking initiation, improve smoking cessation outcomes in adult smokers, and in turn, benefit public health.


Prevalence and Characteristics of Hepatitis B Virus (HBV) Coinfection among HIV-Positive Women in South Africa and Botswana.
There is progressive concern about the evolving burden of morbidity and mortality caused by coinfection with HIV-1 and hepatitis B virus (HBV) in sub-Saharan Africa, but the epidemiology and impact of this problem are not well defined. We therefore set out to assimilate more information about the nature of HBV/HIV coinfection in this region by undertaking a retrospective observational study of southern African adult women. We used samples from previously recruited HIV-1 positive women attending antenatal clinics in three settings in South Africa and Botswana (n = 950) and added a small cohort of HIV-negative antenatal South African women for comparison (n = 72). We tested for HBsAg and followed up HBsAg-positive samples by testing for HBeAg, HBV DNA, HBV genotype, presence of drug-resistance associated mutations (RAMs) and HDV. We identified HBsAg in 72 individuals (7% of the whole cohort), of whom 27% were HBeAg-positive, and the majority HBV genotypes A1 and A2. We did not detect any HDV coinfection. HBV prevalence was significantly different between geographically distinct cohorts, but did not differ according to HIV status. Among adults from South Africa, HBV/HIV coinfected patients had lower CD4+ T cell counts compared to those with HIV-monoinfection (p = 0.02), but this finding was not replicated in the cohort from Botswana. Overall, these data provide a snapshot of the coinfection problem at the heart of the HIV/HBV co-epidemic, and are important to inform public health policy, resource allocation, education, surveillance and clinical care.


Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells.
The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), inhibit the growth of human breast cancer cells in animal models and cell lines, but the mechanism by which this occurs is not well understood. In order to explore possible mechanisms for the modulation of breast cancer cell growth by omega-3 fatty acids, we examined the effects of EPA and DHA on the human breast cancer cell line MDA-MB-231. Omega-3 fatty acids (a combination of EPA and DHA) inhibited the growth of MDA-MB-231 cells by 30-40% (p<0.05) in both the presence and absence of linoleic acid, an essential omega-6 fatty acid. When provided individually, DHA was more potent than EPA in inhibiting the growth of MDA-MB-231 cells (p<0.05). EPA and DHA treatment decreased tumor cell proliferation (p<0.05), as estimated by decreased [methyl-(3)H]-thymidine uptake and expression of proliferation-associated proteins (proliferating cell nuclear antigen, PCNA, and proliferation-related kinase, PRK). In addition, EPA and DHA induced apoptosis, as indicated by a loss of mitochondrial membrane potential, increased caspase activity and increased DNA fragmentation (p<0.05). Cells incubated with omega-3 fatty acids demonstrated decreased Akt phosphorylation, as well as NFkappaB DNA binding activity (p<0.05). The results of this study indicate that omega-3 fatty acids decrease cell proliferation and induce apoptotic cell death in human breast cancer cells, possibly by decreasing signal transduction through the Akt/NFkappaB cell survival pathway.


Numerical model for tomographic image formation in transmission x-ray microscopy.
We present a numerical image-formation model for investigating the influence of partial coherence, sample thickness and depth-of-focus on the accuracy of tomographic reconstructions in transmission x-ray microscopes. The model combines wave propagation through the object by finite difference techniques with Fourier methods. We include a ray-tracing model to analyse the origin of detrimental stray light in zone plate-based x-ray microscopes. These models allow optimization of x-ray microscopy systems for quantitative tomographic imaging of thick objects. Results show that both the depth-of-focus and the reconstructed local absorption coefficient are highly dependent on the degree of coherence of the optical system.


Mycoplasma pneumoniae in adult community-acquired pneumonia increases matrix metalloproteinase-9 serum level and induces its gene expression in peripheral blood mononuclear cells.
The objective of this study was to assess the concentration of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) in peripheral circulation and their mRNA expression in peripheral blood mononuclear cells (PBMCs) in patients with CAP caused by M. pneumoniae. We prospectively analyzed MMPs in 40 hospitalized patients with M. pneumoniae CAP on admission, and in the convalescent phase. Twenty healthy men were used as controls. Quantitative real-time PCR and ELISA tests were used. MMP-9 mRNA expression in PBMCs was increased in the acute phase of illness compared to the control group as well as in convalescent phase in which case it was statistically significant (Mann-Whitney; p=0.028). The same was found for MMP-9 plasma levels (Mann-Whitney test; p<0.001; p=0.001). Circulating MMP-2 concentration in acute patients was significantly lower than in the control group and convalescent phase (Mann-Whitney test; p=0.012; p=0.001), while no MMP-2 mRNA expression was found in PBMCs. The plasma level of MMP-9 correlated with leukocyte count in peripheral circulation (r=0.67, p<0.001). We conclude that M. pneumoniae in adult CAP induces activity of MMP-9 in peripheral blood circulation.


Transcriptome analyses of the Giardia lamblia life cycle.
We quantified mRNA abundance from 10 stages in the Giardia lamblia life cycle in vitro using Serial Analysis of Gene Expression (SAGE). 163 abundant transcripts were expressed constitutively. 71 transcripts were upregulated specifically during excystation and 42 during encystation. Nonetheless, the transcriptomes of cysts and trophozoites showed major differences. SAGE detected co-expressed clusters of 284 transcripts differentially expressed in cysts and excyzoites and 287 transcripts in vegetative trophozoites and encysting cells. All clusters included known genes and pathways as well as proteins unique to Giardia or diplomonads. SAGE analysis of the Giardia life cycle identified a number of kinases, phosphatases, and DNA replication proteins involved in excystation and encystation, which could be important for examining the roles of cell signaling in giardial differentiation. Overall, these data pave the way for directed gene discovery and a better understanding of the biology of G. lamblia.


Wettability of graphene: from influencing factors and reversible conversions to potential applications.
As a member of the carbon material family, graphene has long been the focus of research on account of its abundant excellent properties. Nevertheless, many previous research works have attached much importance to its mechanical capacity and electrical properties, and not to its surface wetting properties with respect to water. In this review, a series of methods are put forward for characterization of the water contact angle of graphene, such as experimental measurements, classic molecular dynamics simulations, and formula calculations. A series of factors that affect the wettability of graphene, including defects, controllable atmosphere, doping, and electric field, are also discussed in detail, and have rarely have been covered in other review articles before. Finally, with the developments of smart surfaces, a reversible wettability variation of graphene from hydrophobic to hydrophilic is important in the presence of external stimulation and is discussed in detail herein. It is anticipated that graphene could serve as a tunable wettability coating for further developments in electronic devices and brings a new perspective to the construction of smart material surfaces.


General practitioners, primary care and support for carers in England: can training make a difference?
As a part of the national carers' strategy, the Department of Health commissioned six pilot workshops spread across England for General Practitioners (GPs) and other primary healthcare workers. The six workshops were held during September and October 2009, arranged by the Royal College of General Practitioners and planned in consultation with the Princess Royal Trust for Carers. The workshops were delivered by one of two GPs and by a carer. The Department of Health commissioned an evaluation of the workshop programme. This paper reports on the attitudes towards and knowledge of carers by GPs and other primary care workers, such as community matrons, practice nurses, healthcare assistants, practice managers and receptionists. It also tracks changes over time from the questionnaire responses pre- and post-workshop and 3 months later in the GPs' and other primary care workers' response to carers. Prior to the workshops, GPs and other primary care workers saw primary care as having a significant role in directly assisting carers, especially with emotional support and in signposting to other services. However, there was a lack of knowledge about issues facing carers, limited confidence in assisting carers and few services within the primary care teams directly focussed on carers. The workshops were regarded positively by those who attended, and the evaluation found that there was a positive impact with GPs and other primary care workers reporting specific actions they had taken post-workshop to assist carers, greater confidence and awareness in working with carers, and increased knowledge about carers. The paper concludes by recommending how the pilot programme might be rolled out more widely.


General anesthetics sensitize the capsaicin receptor transient receptor potential V1.
General anesthetics (GAs) are central nervous system depressants that render patients unresponsive to external stimuli. In contrast, many of these agents are also known to stimulate peripheral sensory nerves, raising the possibility that they may exacerbate tissue inflammation. We have found that pungent GAs excite sensory neurons by directly activating the transient receptor potential (TRP) A1 ion channel. Here, we show that GAs also sensitize the capsaicin receptor TRPV1, a key ion channel expressed in nociceptive neurons. Clinically relevant concentrations of isoflurane, sevoflurane, enflurane, and desflurane sensitize TRPV1 to capsaicin and protons and reduce the threshold for heat activation. Furthermore, isoflurane directly activates TRPV1 after stimulation of protein kinase C. Likewise, isoflurane excites TRPV1 and sensory neurons during concomitant application of bradykinin, a key inflammatory mediator formed during tissue injury. Thus, GAs can enhance the activation of TRPV1 that occurs during surgically induced tissue damage. These results support the hypothesis that some GAs, through direct actions at TRP channels, increase postsurgical pain and inflammation.


Global patterns in predator-prey size relationships reveal size dependency of trophic transfer efficiency.
Predator-prey body size relationships influence food chain length, trophic structure, transfer efficiency, interaction strength, and the bioaccumulation of contaminants. Improved quantification of these relationships and their response to the environment is needed to parameterize food web models and describe food web structure and function. A compiled data set comprising 29582 records of individual prey eaten at 21 locations by individual predators that spanned 10 orders of magnitude in mass and lived in marine environments ranging from the poles to the tropics was used to investigate the influence of predator size and environment on predator and prey size relationships. Linear mixed effects models demonstrated that predator-prey mass ratios (PPMR) increased with predator mass. The amount of the increase varied among locations and predator species and individuals but was not significantly influenced by temperature, latitude, depth, or primary production. Increases in PPMR with predator mass implied nonlinear relationships between log body mass and trophic level and reductions in transfer efficiency with increasing body size. The results suggest that very general rules determine dominant trends in PPMR in diverse marine ecosystems, leading to the ubiquity of size-based trophic structuring and the consistency of observed relationships between the relative abundance of individuals and their body size.


The transcription factor GTF2IRD1 regulates the topology and function of photoreceptors by modulating photoreceptor gene expression across the retina.
The mechanisms that specify photoreceptor cell-fate determination, especially as regards to short-wave-sensitive (S) versus medium-wave-sensitive (M) cone identity, and maintain their nature and function, are not fully understood. Here we report the importance of general transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1) in maintaining M cone cell identity and function as well as rod function. In the mouse, GTF2IRD1 is expressed in cell-fate determined photoreceptors at postnatal day 10. GTF2IRD1 binds to enhancer and promoter regions in the mouse rhodopsin, M- and S-opsin genes, but regulates their expression differentially. Through interaction with the transcription factors CRX and thyroid hormone receptor β 2, it enhances M-opsin expression, whereas it suppresses S-opsin expression; and with CRX and NRL, it enhances rhodopsin expression. In an apparent paradox, although GTF2IRD1 is widely expressed in multiple cell types across the retina, knock-out of GTF2IRD1 alters the retinal expression of only a limited number of annotated genes. Interestingly, however, the null mutation leads to altered topology of cone opsin expression in the retina, with aberrant S-opsin overexpression and M-opsin underexpression in M cones. Gtf2ird1-null mice also demonstrate abnormal M cone and rod electrophysiological responses. These findings suggest an important role for GTF2IRD1 in regulating the level and topology of rod and cone gene expression, and in maintaining normal retinal function.


Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.
Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.


G4Killer web application: a tool to design G-quadruplex mutations.
G-quadruplexes (G4) are important regulatory non-B DNA structures with therapeutic potential. A tool for rational design of mutations leading to decreased propensity for G4 formation should be useful in studying G4 functions. Although tools exist for G4 prediction, no easily accessible tool for the rational design of G4 mutations has been available. We developed a web-based tool termed G4Killer that is based on the G4Hunter algorithm. This new tool is a platform-independent and user-friendly application to design mutations crippling G4 propensity in a parsimonious way (i.e., keeping the primary sequence as close as possible to the original one). The tool is integrated into our DNA analyzer server and allows for generating mutated DNA sequences having the desired lowered G4Hunter score with minimal mutation steps. The G4Killer web tool can be accessed at: http://bioinformatics.ibp.cz. Supplementary data are available at Bioinformatics online.


Analysis of creep strain during tensile fatigue of cortical bone.
During fatigue tests of cortical bone specimens, at the unload portion of the cycle (zero stress) non-zero strains occur and progressively accumulate as the test progresses. This non-zero strain is hypothesised to be mostly, if not entirely, describable as creep. This work examines the rate of accumulation of this strain and quantifies its stress dependency. A published relationship determined from creep tests of cortical bone (Journal of Biomechanics 21 (1988) 623) is combined with knowledge of the stress history during fatigue testing to derive an expression for the amount of creep strain in fatigue tests. Fatigue tests on 31 bone samples from four individuals showed strong correlations between creep strain rate and both stress and "normalised stress" (sigma/E) during tensile fatigue testing (0-T). Combined results were good (r(2)=0.78) and differences between the various individuals, in particular, vanished when effects were examined against normalised stress values. Constants of the regression showed equivalence to constants derived in creep tests. The universality of the results, with respect to four different individuals of both sexes, shows great promise for use in computational models of fatigue in bone structures.


Malignant (Diffuse) Mesothelioma in Patients With Hematologic Malignancies: A Clinicopathologic Study of 45 Cases.
Ionizing radiation has a role in the development of malignant mesothelioma, in several epidemiologic studies, including patients with hematologic malignancies. To study the clinicopathologic characteristics of patients with malignant mesothelioma and hematologic malignancies with and without a history of radiotherapy. From a database of approximately 3600 patients with malignant mesothelioma, we identified 45 patients (1%) who also had hematologic malignancies. We examined clinicopathologic features and noted whether the patient had received radiotherapy for malignancy, comparing those with and those without such exposure. Among the 45 cases, 18 (40%) had Hodgkin lymphoma, 15 (33%) had non-Hodgkin lymphoma, 10 (4%) had chronic lymphocytic leukemia, and 2 (22%) had chronic myelogenous leukemia; 20 patients (44%) had a history of radiotherapy, and 23 (51%) did not. Most patients with Hodgkin lymphoma (16 of 18; 90.0%) received radiation, whereas none of the patients with leukemia (0 of 12) and only 20% (3 of 15) of the patients with non-Hodgkin lymphoma did so. Patients without radiation were older than patients who received radiotherapy (median, 73 versus 54 years, respectively; P < .001), had a shorter interval from diagnosis of hematologic malignancy to that of mesothelioma (median, 2 versus 24 years, respectively; P < .001), and had a shorter survival period (median, 6.0 versus 14.0 months, respectively; P = .02). Epithelial mesotheliomas were proportionately more common in patients with a history of radiotherapy. Patients with mesothelioma and hematologic malignancies with a history of radiation tended to be younger, had a longer interval from diagnosis of hematologic malignancy to that of mesothelioma, had a longer survival period, and were more likely to have the epithelial variant compared with patients without radiotherapy.


Factor analysis of the children's sleep habits questionnaire among preschool children with autism spectrum disorder.
Sleep problems are prevalent among young children with autism spectrum disorders (ASD). The Children's Sleep Habits Questionnaire (CSHQ) is commonly used for assessment, but there are outstanding questions regarding its optimal measurement model. To examine the factor structure of the CSHQ in preschool children with ASD, and relationships between CSHQ factors and children's emotional, cognitive, and behavioral dysregulation. Participants included 4- to 5-year-olds with ASD (n = 281). Confirmatory factor analysis was used to examine whether two previously reported CSHQ factor structures provided adequate fit to the sample data. Exploratory Factor Analysis (EFA) was used examine alternative models. Regression analyses were used to examine how CSHQ factor scores explained variance in dysregulation symptoms, measured by the Child Behavior Checklist. Previously reported factor models in children with ASD were not confirmed, but a novel five-factor model identified using EFA provided excellent fit to the sample data. Sleep factors were generally not correlated with autism symptoms but were associated with aggression, anxiety/depression and attention problems, with evidence of specificity in these relationships. The proposed CSHQ five-factor model may be useful in future studies of sleep problems in young children with ASD.


Erythropoietin in cardiorenal anemia syndrome.
Incidents of heart and renal failure (HF, RF) together, are increasing in our country and all over the world, so a great attention has been dedicated to this problem recently. These diseases together have shown bad results because of the process of accelerated arteriosclerosis, structural changes of myocardium, oxidative stress, inflammation, increased activities of sympathetic nervous system (SNS), increased activities of a renin-angiotensin-aldosterone system (RAAS) (1). These factors are crucial in the development of patho-physiological process and consequential development of anemia, that together with heart and renal failure through interaction, cause serious disorder that we call the cardio-renal anemia syndrome (2). We examined effects of erythropoietin (Epoetin beta) at 90 (60 men and 30 women) pre-dialysed and dialysed patients with HF signs during a period of three years in individual dozes of 2000-6000 units subcutaneous (sc) weekly. Using computer S PLUS and SAS multiple variant analysis we have got correlations by Pearson. Epoetin beta significantly develops anemia parameters: number of erythrocytes (r=0.51779; p<0.0001), hemoglobin (r=0.38811; p<0.0002), MCV (r=0.59876; p<0.0001) at patients with HF. Positive effects are seen at NYHA class (r=0.59906; p<0.0001), on quality of life before and after prescribing medicine. Parameters of renal functions are improving: more urea (r =0.45557; p<0.0001) than creatinine (r=0.26397; p<0.00119) and potassium values K(+)) are not changed significantly (r=0.02060; p<0.8471). Epoetin beta has been useful in treatment of pre-dialysed and dialysed patients with HF and anemia by improving functional ability of myocardium and quality of life.