Protective effects of increasing vitamin E and a doses on cisplatin-induced oxidative damage to kidney tissue in rats.
Cisplatin (DDP, cis-diamminedichloroplatinium II) is one of the most potent chemotherapeutic antitumor drugs, but is able to generate reactive oxygen species (ROS) and it also inhibits the activity of antioxidant enzymes in renal tissue. In the present study, we investigated the preventive effect of 100, 200 and 400 mg/kg b.w. doses of vitamin E (VE), and 25, 50, and 100 mg/kg b.w. doses of vitamin A (VA) combination on malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels and superoxide dismutase (SOD) activity in cisplatin-induced toxicity in rat kidneys. Our literature survey indicated a lack of any experimental study showing the beneficial effect of VA on cisplatin-induced MDA, NO, GSH and SOD changes. For this reason, we hoped that this study would provide a unique contribution in that respect. 59 Wistar rats (11 to replace prematurely lost animals) were used. 48 evaluable rats were divided into 8 groups (n = 6 in each group): control group, DDP alone (5 mg/kg b.w.) group, 3 VE combination treatment groups of VE100+DDP, VE200+DDP, and VE400+DDP, and 3 VA combination treatment groups of VA25+DDP, VA50+DDP, and VA100+DDP. Kidney MDA, GSH, NO levels and SOD activities were determined for the assessment of oxidant-antioxidant balance. While in the DDP group the tissue levels of MDA and NO were found to be significantly higher than in the control group, GSH levels and SOD activities were significantly lower. MDA and NO levels were found to be significantly lower and GSH levels and SOD activities significantly higher in the VE200+DDP and VE400+ DDP groups when compared with the DDP alone group. MDA and NO levels were found to be significantly lower in the VA50+DDP and VA100+DDP groups when compared with the DDP alone group. However, identical comparisons with the DDP alone group showed significantly higher GSH levels and SOD activities in the VA25+DDP, VA50+DDP, and VA100+DDP groups. Among the VE100+ DDP, VE200+DDP, and VE400+DDP groups, and VA25+ DDP, VA50+DDP, and VA100+DDP groups, MDA and NO levels decreased and GSH levels and SOD activities increased steadily and significantly as the doses of VE and VA increased. These vitamins would be effective in protecting against cisplatin-induced tissue damage in rat kidneys. It is possible that the toxic effect of cisplatin is somehow minimized by a compensatory mechanism involving VE and VA via induction of antioxidant enzyme activities following intraperitoneal injection of DDP.


Towards a general theory of the major cooperative evolutionary transitions.
Major Cooperative Evolutionary Transitions occur when smaller-scale entities cooperate together to give rise to larger-scale entities that evolve and adapt as coherent wholes. Key examples of cooperative transitions are the emergence of the complex eukaryote cell from communities of simpler cells, the transition from eukaryote cells to multicellular organisms, and the organization of humans into complex, modern societies. A number of attempts have been made to develop a general theory of the major cooperative transitions. This paper begins by critiquing key aspects of these previous attempts. Largely, these attempts comprise poorly-integrated collections of separate models that were each originally developed to explain particular transitions. In contrast, this paper sets out to identify processes that are common to all cooperative transitions. It develops an alternative theoretical framework known as Management Theory. This general framework suggests that all major cooperative transitions are the result of the emergence of powerful, evolvable 'managers' that derive benefit from using their power to organize smaller-scale entities into larger-scale cooperatives. Management Theory is a contribution to the development of a general, "all levels" understanding of major cooperative transitions that is capable of identifying those features that are level-specific, those that are common across levels and those that are involved in trends across levels.


Duplication (20p) in association with thyroid carcinoma.
We report on a girl with short stature, mental retardation, mutism, "coarse" facial appearance, and papillary-follicular thyroid carcinoma. She had dup(20p) derived from a paternal balanced translocation [(12p;20p)]. We speculate that the carcinoma in our patient may be related to the deletion of material from 12p resulting in absence of genetic material normally required for the suppression of thyroid tumorigenesis.


Musical Creativity and Depth of Implicit Knowledge: Spectral and Temporal Individualities in Improvisation.
It has been suggested that musical creativity is mainly formed by implicit knowledge. However, the types of spectro-temporal features and depth of the implicit knowledge forming individualities of improvisation are unknown. This study, using various-order Markov models on implicit statistical learning, investigated spectro-temporal statistics among musicians. The results suggested that lower-order models on implicit knowledge represented general characteristics shared among musicians, whereas higher-order models detected specific characteristics unique to each musician. Second, individuality may essentially be formed by pitch but not rhythm, whereas the rhythms may allow the individuality of pitches to strengthen. Third, time-course variation of musical creativity formed by implicit knowledge and uncertainty (i.e., entropy) may occur in a musician's lifetime. Individuality of improvisational creativity may be formed by deeper but not superficial implicit knowledge of pitches, and that the rhythms may allow the individuality of pitches to strengthen. Individualities of the creativity may shift over a musician's lifetime via experience and training.


Family planning practices and attitudes among former Soviet new immigrant women in Israel.
One hundred young new immigrant women from the former U.S.S.R. now living in Israel answered a detailed semi-open questionnaire regarding their knowledge, attitudes and behaviors in fertility and birth control issues. A collective family planning profile of these women is largely in line with that of the urban population of Slavonic U.S.S.R., combining early marriage, early and low fertility, the latter achieved by both abortion and contraception. Most respondents and their partners tried to prevent unwanted pregnancies, usually starting from traditional methods and switching over time to modern ones. An IUD remained most popular contraceptive among parous women, while use of the pill, very rare in the U.S.S.R., has almost doubled upon migration, mostly among younger women. Still, they kept some misleading ideas on the pros and cons of traditional versus modern methods, suggesting lack of adequate information also upon migration. Like their ex-compatriots, our women preferred to solve their birth control problems without external professional involvement. Contrary to the expected, free abortion ideology was not universally advocated by our respondents, and most were fully aware of abortion limitations in Israel. While rationally condemning abortion in both moral and health terms, most respondents still use it, this gap between beliefs and practice being indicative of their readiness to adopt efficient contraception. This switch occurs faster in women actively involved with host society via work or studies. Younger women were found to be more flexible and advanced in their family planning practices than were older ones, while almost no differences were related to education and origin within the U.S.S.R. This exploratory study suggests that any investment into promotion of healthy fertility control practices among new immigrants will be cost-effective in the near future.


MAP-kinase-activated protein kinase 2 expression and activity is induced after neuronal depolarization.
Mitogen-activated protein kinase-activated protein kinase (MK)2 is one of several downstream targets of p38 mitogen-activated protein kinase and has a well documented role in inflammation. Here, we describe a possible new function of MK2. We show that triggering depolarization by potassium chloride or increasing the cellular cAMP by forskolin treatment led to elevated levels of expression and activity of mouse MK2. In both treatments, the kinase inhibitor H89 completely prevented the up-regulation of MK2 at the transcript level. By the use of different cell lines we demonstrated that the induction of MK2 expression is characteristic of neuronal cells and is absent in fibroblasts, macrophages and kidney cells. In vivo, induction of a status epilepticus by systemic administration of the chemoconvulsant kainic acid resulted in markedly reduced neurodegeneration in the pyramidal layer of the hippocampus, dentate gyrus and hilus of MK2-deficient mice compared with wild-type mice. Together, our data suggest a possible role of MK2 in the cellular response after neuronal depolarization, in particular in excitotoxicity.


Genetically Inherited Obesity and High-Fat Diet-Induced Obesity Differentially Alter Spermatogenesis in Adult Male Rats.
Obesity is a multifactorial disorder with predominantly genetic and/or environmental causes. Our aim was to delineate effects of genetically inherited and high-fat diet-induced obesity on fertility and spermatogenesis using two Wistar rat models: genetically inherited obese (GIO) WNIN/Ob rats and diet-induced obese (DIO) rats, which received a high-fat diet. The terminal body weights were similar in both groups, but there was a significant difference in metabolic and hormone profiles between the groups. Fertility assessment revealed a significant decrease in the litter size due to increased pre- and postimplantation loss in the DIO group, whereas the rats in the GIO group were infertile due to lack of libido. Significantly decreased sperm counts were observed in the GIO group compared with the DIO group. Enumeration of testicular cells on the basis of ploidy and cell type-specific expression markers, to study the effect of obesity on spermatogenesis, demonstrated that the GIO and DIO states affected mitosis: spermatogonia and S-phase population were increased. However, distinctive effects were observed on meiosis and spermiogenesis in both the groups. Differential effects of GIO and DIO on fertility and spermatogenesis could be due to the significant difference in white adipose tissue accumulation between the groups and not due to high body weights. The differential effects of obesity suggest male obesity-induced infertility observed in humans could be a combination of genetic and environmental factors.


Association of the ecto-ATPase NTPDase2 with glial cells of the peripheral nervous system.
Cellular signaling via extracellular nucleotides appears to play a major role in the functioning of the peripheral nervous system. Information regarding the functional characterization of nucleotide P2 receptors or their expression pattern has been accumulating rapidly; however, very little is known regarding the distribution of ecto-nucleotidases in the periphery. The extracellular level of nucleotides is controlled by ecto-nucleotidases, whereby the three membrane-bound members of the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family are of special functional importance. Using enzyme histochemistry and immunostaining, we demonstrate that NTPDase2 is associated with nonmyelinating Schwann cells of the rat sciatic nerve, whereas NTPDase1 is restricted to blood vessel walls. NTPDase2 immunoreactivity was detected from embryonic day E18 onward, suggesting that immature Schwann cells express the enzyme. With the onset of myelination, NTPDase2 immunoreactivity remained associated solely with nonmyelinating Schwann cells. NTPDase2 was absent from perisynaptic Schwann cells but was associated with fibroblasts covering the endplate at some distance. In addition, NTPDase2 immunoreactivity was associated with the satellite glial cells in dorsal root ganglia and sympathetic ganglia, and with the enteric glia surrounding the cell bodies of ganglionic neurons of the myenteric and the submucous plexus. In contrast to NTPDase1, NTPDase2 preferentially hydrolyzes nucleoside triphosphates over nucleoside diphosphates and thus can act either in inactivating or in producing P2 receptor ligands. Our results suggest that NTPDase2 plays an important role in the control of nucleotide-mediated activation of peripheral neurons or glia and in the dialogue between these two cell types.


Enzymatic and chemical treatment limits on the controlled solubilization of brewers' spent grain.
The enzymatic hydrolysis of brewers' spent grain (BSG) has been investigated through treatment with commercial carbohydrases and proteases. Resultant residues were then chemically fractionated and delignified. Enzymatic treatments released 25-30% of the BSG mass and yielded precursors suitable for subsequent conversion to potentially value-added products. Controlled chemical fractionation selectively solubilized arabinoxylan but with no differences apparent due to prior enzyme treatment. The loss of non-polysaccharide components during alkali treatment suggests the presence of a high proportion of alkali-soluble lignin. Further delignification of the alkali-insoluble residues and further chemical fractionation released the remaining hemicellulose, to yield a residue which was >90% cellulose. Further knowledge of the properties and interaction between BSG polymers will facilitate an improved enzyme-assisted total deconstruction of BSG and hence the exploitation of its biomass.


Effects of chronic iodine excess in a cohort of long-term American workers in West Africa.
A cross-sectional survey of 102 Peace Corps volunteers in Niger, West Africa, in 1998 had previously demonstrated a high rate of thyroid dysfunction and goiter attributable to excess iodine from their water filters. The Peace Corps volunteers were followed-up a mean of 30 wk after they ceased using iodine-based water filtration systems. Goiter was present in 44% of subjects during excess iodine ingestion and in 30% after removal of excess iodine. Mean serum iodine decreased from 293 micro g/liter during excess iodine ingestion to 84 micro g/liter after cessation of excess iodine. Mean total serum T(4) values increased from 100.4 to 113.3 nmol/liter (7.8 to 8.8 micro g/dl). Mean serum free T(4) increased from 32.2 to 34.7 pmol/liter (2.5 to 2.7 ng/dl). Mean serum TSH decreased from 4.9 to 1.8 mU/liter. Mean serum thyroid peroxidase antibody levels decreased from 33,000 to 22,000 IU/liter (33 to 22 IU/ml). We found that during prolonged excess iodine exposure there were marked increases in serum total iodine concentrations, and the prevalence of goiter, elevated serum TSH values, and elevated serum thyroid peroxidase antibody values increased. The prevalence of all abnormalities decreased after removal of excess iodine from the drinking water system.


Racial differences in medication switching and concomitant prescriptions in the treatment of bipolar disorder.
This study examined whether the practices of switching between classes of medications and prescription of concomitant medications differed between black and non-black patients with bipolar disorders. In a retrospective cohort design, data from 1998 to 2004 for patients with diagnoses of bipolar disorders were obtained from a large claims database. Information was obtained on the number of prescriptions for four classes of medications (anticonvulsants, mood stabilizers, and first- and second-generation antipsychotics) as well as on medication switching (between drug classes), concomitant prescriptions, resource use, and outcomes (an emergency department visit or a hospitalization). Logistic models assessed the relationship between outcomes and switching or concomitant prescriptions. The study population consisted of 1,113 adults who received at least one prescription from the four drug classes. Medication switching or concomitant prescriptions were documented for more than one-third of patients (36.6 percent). A significantly greater proportion of black patients received two or more medications from different drug classes (41.1 compared with 34.7 percent). The number of prescriptions was lower for black patients than for non-black patients. Patients for whom switching or concomitant prescriptions were documented were significantly more likely to have an emergency department visit or a hospitalization, and race was a significant predictor of these outcomes. The prevalence of polypharmacy-medication switching and concomitant prescriptions-was high among patients with bipolar disorder, with a higher prevalence among black patients. Patients who experienced switching or concomitant prescriptions were more likely to visit the emergency department or to be hospitalized.


Assertive community treatment: development of the team, selection of clients, and impact on length of hospital stay.
Mental health services have been criticized for the lack of focus and response to people suffering from a serious mental illness (SMI). Assertive community treatment (ACT) offers the potential for greater partnership working between the user and provider of mental health services. The author describes one approach in developing ACT in the UK. Four criteria were developed to identify the most appropriate service users for ACT: those with SMI, illness instability, illness disability and risk to self or others. Fifty-five clients were identified using these criteria and tracked for their length of hospital stay and frequency of admission 2 years before acceptance to an ACT team and for 12 months after. Duration of hospital stay was unchanged although both the frequency and total numbers of bed days were reduced.


Occurrences of antibodies against Streptococcus pneumoniae, Haemophilus influenzae and Branhamella catarrhalis in middle ear effusion and serum during the course of acute otitis media.
The occurrence of IgG, IgM and IgA class antibodies against a type-specific capsular polysaccharide of Streptococcus pneumoniae (Pn) and against a whole cell antigen of Haemophilus influenzae (Hi) and Branhamella catarrhalis (Br) was studied using the ELISA method on middle ear effusion (MEE) samples of 85 patients and paired serum samples of 40 patients during the course of acute otitis media (AOM). Although specific antibodies to all of these three bacteria appeared in MEE during the course of an AOM episode, antibodies against the infecting bacteria of that particular AOM episode were more often prominent. The antibodies were also detectable in the MEE without simultaneous presence in the serum. The middle ear infection was prolonged more often if specific antibodies to the infecting bacterium could not be detected in the MEE obtained at the beginning of the AOM attack. The present study indicates that AOM caused by Pn, Hi or Br may induce both a systemic and a local production of specific antibodies against the causative organisms during the course of otitis media. The occurrence of such antibodies in MEE seems to play a major role in the resolution of AOM.


Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model.
Theories of medically unexplained illness based on the concepts of dissociation, conversion, and somatization are summarized. Evidence cited in support of these theories is described and the conceptual strengths and shortcomings of each approach are considered. It is argued that each of these approaches adds to the understanding of unexplained illness but that none is able to provide a comprehensive explanation of the phenomenon. An integrative conceptual model of unexplained illness based on cognitive psychological principles is then presented. This model attempts to combine existing theoretical approaches within a single explanatory framework, extending previous theory by explaining how compelling symptoms can exist in the absence of organic pathology. The clinical and empirical implications of the model are then considered.


Electrostatic Potential Distribution for Spheroidal Surfaces in Symmetric Electrolyte Solutions
The electrostatic potential distribution for a charged spheroidal surface immersed in a symmetric electrolyte solution is derived. Such surfaces simulate a wide class of dispersed entities. Two types of boundary condition at the solid surface are considered, constant surface potential and constant amount of surface charges; both conductive and nonconductive surfaces are examined for the latter. The present analysis extends the conventional one-dimensional treatment on simple geometries to a two-dimensional space. A perturbation method is adopted to solve the governing Poisson-Boltzmann equation for the case of thin to moderately thick double layers. The classic results for planar and spherical surfaces can be recovered as special cases of the present analysis. The basic thermodynamic properties of the system under consideration, such as Helmholtz free energy, entropy, and surface excess, are derived. We show that using an equivalent sphere to approximate a spheroid can lead to an appreciable deviation in the prediction of the Helmholtz free energy. For a thin double layer, assuming a planar geometry will underestimate the Helmholtz free energy. Copyright 1997Academic Press


Treatment-resistant schizophrenia: reviewing the options and identifying the way forward.
Between 20% and 40% of schizophrenic patients are thought to be resistant to conventional antipsychotic therapy, although this may be an underestimate of the scale of the problem. The causes of nonresponsiveness are likely to be multifactorial, and there have been reported associations between refractoriness and neuropsychological impairment, negative symptoms, and abnormal brain morphology. For some patients, treatment resistance may in fact represent an intrinsic part of the schizophrenic illness. Treating the refractory patient should begin with a full, preferably multidisciplinary, review of diagnosis, symptoms, and side effects. Although an increased dose of a conventional antipsychotic agent can be effective for some patients, consideration should be given to reducing the dose and combining treatment with psychosocial management, or switching to one of the newer atypical antipsychotics.


Mechanisms of molecular recognition of tRNAs by aminoacyl-tRNA synthetases.
Interactions of Escherichia coli isoleucyl- and glutamyl-tRNA synthetases and their cognate tRNAs were analyzed by phosphate-alkylation mapping with N-nitroso-N-ethylurea and/or by 1H-NMR analysis. When E. coli tRNA(Ile) was bound with isoleucyl-tRNA synthetase, many of the phosphate groups in the anticodon loop and stem and in the D-stem were protected from alkylation. This result is consistent with that of analysis of imino proton resonances due to the secondary and tertiary base pairs. These analyses also suggested that the L-shaped tertiary structure of tRNA(Ile) is distorted upon complex formation with IleRS because of disruption of some tertiary base pairs. In the case of E. coli tRNA(Glu), several phosphate groups in the D-stem and the variable loop were significantly protected by the cognate synthetase. These results indicate that the two tRNAs, unlike other tRNAs studied so far, have some of the "identity determinants" in the D-stem and/or in the anticodon stem.


Energy Harvest from Organics Degradation by Two-Dimensional K+-Intercalated Manganese Oxide.
Pollution treatment, a problem our world is being deeply puzzled by, has required large amounts of energy during enrichment and degradation. However, some pollutants, for instance organics in wastewater, could offer an energy supply but instead are wasted. Here we report an energy harvesting galvanic cell, built by using a Pt foil as an anode and 2D K+-intercalated MnO2 as a cathode, which combines both dye degradation in wastewater and energy harvesting during the degradation process. Owing to the galvanic effect, this cell could accelerate the degradation rate and indicate the progress of degradation. Different kinds of organics could be degraded and produce energy in this cell with a stable open-circuit voltage (0.45 V). Magnification and imitation of this strategy offer a new chance to harvest waste energy in other exothermic reactions.


DNA mutational differences in cytological specimens from pancreatic cancer and cholangiocarcinoma.
Preoperative distinction between pancreatic cancer (PC) and extrahepatic cholangiocarcinoma (CC) is desirable due to diverging management options, and to optimize enrollment into neoadjuvant trials. A single-center retrospective study of patients with PC or CC was undertaken. Four blinded pathologists reviewed all cases and reached a consensus diagnosis (PC or CC). Microdissection-based multiple microsatellite loss analysis and direct sequencing of K-ras oncogene was performed and compared for PC and CC. Of 33 cases studied (17 males; 16 PC, 17 CC; 10 with primary sclerosing cholangitis), a K-ras mutation was present in 14/16 (87.5%) PC and 1/17 (5.9%) CC cases (p < 0.001), sensitivity and specificity were 87.5 and 94%, respectively. The mean fractional mutational rate was higher in PC (0.51; 95% CI 0.45-0.58) compared to CC (0.34; 95% CI 0.28-0.39, p < 0.001). The presence of a K-ras mutation in cytology specimens distinguishes PC from CC in this study. and IAP.


Association of the chaperone glucose-regulated protein 58 (GRP58/ER-60/ERp57) with Stat3 in cytosol and plasma membrane complexes.
Glucose-regulated protein 58 (GRP58/ER-60/ERp57), best known as a chaperone in the endoplasmic reticulum lumen, was previously identified by us as one of several accessory proteins in the S100 cytosol fraction of human hepatoma Hep3B cells that was differentially coshifted by anti-Stat3 antibody in an antibody-subtracted differential protein display assay. In the present study, the association between GRP58 and Stat3 in different cytoplasmic compartments was evaluated using cross-immunoprecipitation and cell-fractionation techniques. In the S100 cytosol fraction, three different anti-GRP58 polyclonal antibodies (pAb) cross-immunoprecipitated Stat3 (but not Stat1), and, conversely, anti-Stat3 pAb cross-immunoprecipitated GRP58. Both cytosolic Stat3 and GRP58 eluted during Superose-6 gel-filtration chromatography in complexes of size 200-400 kDa (statosome I), and anti-Stat3 pAb cross-immunoprecipitated GRp58 from these FPLC elution fractions. Using differential sedimentation and density equilibrium flotation methods, Stat3 and GRP58 were observed to be coassociated with cytoplasmic membranes enriched for the plasma membrane marker 5' nucleotidase but not with those containing the endoplasmic reticulum marker BiP/GRP78. The Stat3 and GRP58-containing plasma membrane fraction also contained Stat1, Stat5b, and gp130. Stat activation by orthovanadate caused the accumulation of PY-Stat3 in the GRP58-containing plasma membrane fraction. However, this PY-Stat3 was DNA-binding deficient. Likewise, excess exogenous recombinant human GRP58 prepared using a baculovirus expression system preferentially inhibited Stat3 DNA-binding activity in the S100 cytosol, suggesting that GRP58 may sequester activated Stat3. The new data confirm the association between GRP58 and Stat3 in cytosolic 200-400-kDa statosome I complexes and show that both GRP58 and Stat family members coassociate in the plasma membrane compartment. We suggest that the chaperone GRP58 may regulate signaling by sequestering inactive and activated Stat3.


Transrepression of AP-1 by nuclear receptors in Drosophila.
Mammalian cell culture studies have shown that several members of the nuclear receptor super family such as glucocorticoid receptor, retinoic acid receptor and thyroid hormone receptor can repress the activity of AP-1 proteins by a mechanism that does not require the nuclear receptor to bind to DNA directly, but that is otherwise poorly understood. Several aspects of nuclear receptor function are believed to rely on this inhibitory mechanism, which is referred to as transrepression. This study presents evidence that nuclear receptor-mediated transrepression of AP-1 occurs in Drosophila melanogaster. In two different developmental situations, embryonic dorsal closure and wing development, several nuclear receptors, including Seven up, Tailless, and Eagle antagonize AP-1. The inhibitory interactions with nuclear receptors are integrated with other modes of AP-1 regulation, such as mitogen-activated protein kinase signaling. A potential role of nuclear receptors in setting a threshold of AP-1 activity required for the manifestation of a cellular response is discussed.


Rehabilitation for adults with severe mental illness and substance use disorders. A clinical trial.
Faced with many patients with comorbid severe mental illness and substance use disorders, a university-affiliated, inner-city community mental health center and a psychosocial rehabilitation center initiated this clinical trial assessing a program to care for these patients. Fifty-four patients, age 18 to 40, with either schizophrenia or major affective disorder and a substance use disorder were randomly assigned to usual community mental health center and rehabilitation services with or without an innovative group and intensive case management program. One-year follow-ups detected no significant advantages on patient outcomes for adding the innovative program to usual services. Failure to engage patients in the experimental program posed a major and enduring barrier to treatment, despite intensive case management. Future efforts must give greater consideration to effective engagement techniques and patients' readiness for active treatment.


Stories and Challenges of Genome Wide Association Studies in Livestock - A Review.
Undoubtedly livestock is one of the major contributors to the economy of any country. The economic value of livestock includes meat, dairy products, fiber, fertilizer etc. Understanding and identifying the associations of quantitative trait loci (QTL) with the economically important traits is believed to substantially benefit the livestock industry. The past two decades have seen a flurry of interest in mapping the QTL associated with traits of economic importance on the genome. With the availability of single nucleotide polymorphism chip of various densities it is possible to identify regions, QTL and genes on the genome that explain the association and its effect on the phenotype under consideration. Remarkable advancement has been seen in genome wide association studies (GWAS) since its inception till the present day. In this review we describe the progress and challenges of GWAS in various livestock species.


Transcatheter closure of multiple paravalvular leaks by a transapical approach under echocardiographic guidance: A case report.
A patient who underwent mechanical aortic and mitral valve replacement developed three paravalvular leaks 10 months later. We located the tracks by puncturing the apex cordis under transoesophageal echocardiography guidance alone and puncturing the femoral artery guided by fluoroscopy. Three paravalvular leaks were occluded with a hybridization method simultaneously. The patient was followed up for 24 months and maintained a good condition. Multiple paravalvular leaks after double valve replacement can be occluded in patients by the use of different approaches under echocardiographic guidance alone.


Juvenile idiopathic arthritis: the paediatric perspective.
Paediatric rheumatology is a relatively new specialty that has developed rapidly over the last 30 years. There have been major advances, which have included improvements in the classification and management of juvenile idiopathic arthritis (JIA). The former has led to enhanced international collaboration with disease registries, multicentre research and the development of new therapeutic agents. This has resulted in improved disease control and remission induction in many. There is, however, still significant morbidity associated with JIA during childhood, adolescence and adulthood, and challenges for the future include early identification of those with a poorer prognosis, appropriate administration of safe therapies and optimizing outcomes as young people move through adolescence into adulthood.


Cancer epigenomics.
Research in cancer epigenomics is driven by the development of novel technologies and the utilization of model organisms ranging from yeasts to plants to vertebrates. For decades, the search for cancer genes has focused on genetic defects that were used as tags for identification of these genes. With the realization that epigenetic modifications, most importantly DNA methylation events, are frequently involved in transcriptional changes in both tumor suppressor genes and oncogenes, techniques have been developed that support the identification of novel cancer genes altered by DNA methylation alone or in combination with genetic events. Recent data demonstrate that, in addition to DNA methylation, chromatin modifications are also involved in gene regulation. We are now beginning to understand this interesting interplay between chromatin modifications, DNA methylation and gene regulation. This review will summarize our current knowledge of DNA methylation and histone modification in normal cells, introduce emerging concepts that show the intimate link between DNA methylation and chromatin modifications, and highlight recent advancements in our understanding of aberrant DNA methylation, with special emphasis on genome-wide hypermethylation.


Molybdenum-Sulfur Bond: Electronic Structure of Low-Lying States of MoS.
The molybdenum-sulfur bond plays an important role in many processes such as nitrogen-fixation, and it is found as a building block in layered materials such as MoS2, known for its various shapes and morphologies. Here, we present an accurate theoretical and experimental investigation of the chemical bonding and the electronic structure of 20 low-lying states of the MoS molecule. Multireference and coupled cluster methodologies, namely, MRCISD, MRCISD + Q, RCCSD(T), and RCCSD[T], were employed in conjunction with basis sets up to aug-cc-pwCV5Z-PP/aug-cc-pwCV5Z for the study of these states. We note the significance of including the inner 4s24p6 electrons of Mo and 2s22p6 of S in the correlated space to obtain accurate results. Experimentally, the predissociation threshold of MoS was measured using resonant two-photon ionization spectroscopy, allowing for a precise measurement of the bond dissociation energy. Our extrapolated computational D0 value for the ground state is 3.936 eV, in excellent agreement with our experimental measurement of 3.932 ± 0.004 eV. The largest calculated adiabatic D0 (5.74 eV) and the largest dipole moment (6.50 D) were found for the 5Σ+ state, where a triple bond is formed. Finally, the connection of the chemical bonding of the isolated MoS species to the relevant solid, MoS2, is emphasized. The low-lying septet states of the diatomic molecule are involved in the material as a building block, explaining the stability and the variety of the shapes and morphologies of the material.


Magnetic PiezoBOTs: a microrobotic approach for targeted amyloid protein dissociation.
Piezoelectric nanomaterials have become increasingly popular in the field of biomedical applications due to their high biocompatibility and ultrasound-mediated piezocatalytic properties. In addition, the ability of these nanomaterials to disaggregate amyloid proteins, which are responsible for a range of diseases resulting from the accumulation of these proteins in body tissues and organs, has recently gained considerable attention. However, the use of nanoparticles in biomedicine poses significant challenges, including targeting and uncontrolled aggregation. To address these limitations, our study proposes to load these functional nanomaterials on a multifunctional mobile microrobot (PiezoBOT). This microrobot is designed by coating magnetic and piezoelectric barium titanate nanoparticles on helical biotemplates, allowing for the combination of magnetic navigation and ultrasound-mediated piezoelectric effects to target amyloid disaggregation. Our findings demonstrate that acoustically actuated PiezoBOTs can effectively reduce the size of aggregated amyloid proteins by over 80% in less than 10 minutes by shortening and dissociating constituent amyloid fibrils. Moreover, the PiezoBOTs can be easily magnetically manipulated to actuate the piezocatalytic nanoparticles to specific amyloidosis-affected tissues or organs, minimizing side effects. These biocompatible PiezoBOTs offer a promising non-invasive therapeutic approach for amyloidosis diseases by targeting and breaking down protein aggregates at specific organ or tissue sites.


Developing a protocol based on the Brazilian Dietary Guidelines for individual dietary advice in the primary healthcare: theoretical and methodological bases.
To describe the methodology of development of a protocol for application of the Brazilian Dietary Guidelines by primary healthcare professionals in individual dietary advice. A five-step approach was followed: (1) format definition; (2) definition of the instrument for assessment of individuals' food consumption; (3) Dietary Guidelines' content extraction; (4) protocol content development; (5) content and face validity. An example from Brazil was displayed with the development of a protocol to guide healthcare professional decision-making when providing nutrition advice based on the Brazilian Dietary Guidelines. The instrument of the Brazilian Nutrition Surveillance System (SISVAN) was chosen to the food consumption assessment, which contains questions about the consumption of seven healthy or unhealthy food groups and one question about eating modes. The Guidelines' content extraction process led to the identification of recommendations related to the food consumption markers assessed by the SISVAN questionnaire. Then, a protocol was developed in a flowchart format, in which the professional's conduct is guided by the answer given to each question of the SISVAN instrument. For each 'non-compliant' answer (unhealthy eating practice), the professional is instructed how to provide recommendations and identify obstacles. Lastly, experts and healthcare professionals highlighted pertinence, clarity and usability of the protocol. This study provides the blueprint for the phase-wise development of protocols of application of the Dietary Guidelines and may contribute to promote healthier eating and ending malnutrition in all its forms.


Suppression of B-cell proliferation to lipopolysaccharide is mediated through induction of the nitric oxide pathway by tumor necrosis factor-alpha in mice with acute graft-versus-host disease.
Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as important effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (slg+) B cells was observed in GVHD spleens isolated 2 weeks after transplant. However, proliferation of these cells in response to LPS was suppressed by more than 35-fold. Activated GVHD splenocytes secreted large amounts of TNF-alpha and NO in culture. Neutralization of TNF-alpha with anti-TNF-alpha antibody (Ab) both abrogated NO production and restored LPS-induced proliferation of B cells to levels found in non-GVHD control mice. The specific inhibition of NO synthesis with LG-monomethyl-arginine (NMMA) restored splenocyte responses but did not significantly reduce TNF-alpha levels, showing that TNF-alpha per se did not cause immunosuppression. These data show that, during GVHD, induction of the NO pathway is an important mechanism that mediates B-cell hyporesponsiveness to LPS and that this pathway is induced by TNF-alpha.


Evaluation of risk for incident hypertension using glomerular filtration rate in the normotensive general population.
The present study tested the hypothesis that glomerular filtration rate can predict the onset of hypertension in individuals with normal blood pressure in the general population. Normotensive individuals (n = 7684) who visited our hospital for a routine physical examination were enrolled in the study (4907 men; mean age 52.1 ± 11.1 years) and were followed up with the endpoint being the development of hypertension. The relationship between estimated glomerular filtration rate at baseline and the incidence of hypertension was evaluated. During the follow-up period (median 4.0 years; actual follow-up 30 624 person-years), hypertension developed in 2031 participants (66.3 per 1000 person-years). After adjustment for possible risk factors, the hazard ratio of incident hypertension (first tertile as reference) in the second and third tertiles was 1.03 (95% confidence interval 0.92-1.16) and 1.40 (95% confidence interval 1.26-1.57), respectively. Multivariate Cox proportional hazard regression analysis, in which estimated glomerular filtration rate was taken as a continuous variable and adjustments were made for known risk factors, also indicated that baseline estimated glomerular filtration rate independently predicted the onset of hypertension (P < 0.0001). Furthermore, multiple regression analysis revealed that a longitudinal increase in SBP was significantly associated with baseline estimated glomerular filtration rate after adjustment for known risk factors (P < 0.01). Estimated glomerular filtration rate in normotensive individuals is a good predictor of the onset of hypertension in the general population.


Regulation of the level of epidermal growth factor by oestrogen in the submandibular gland of female mice.
The concentration of epidermal growth factor (EGF) in the submandibular gland of immature female mice (less than 6 weeks old) was low, ranging from 0.07 to 0.17 pmol (0.4 to 1.0 ng)/mg wet wt, but increasing to 7.61 pmol/mg wet wt by 8 weeks of age. It remained relatively constant up to 24 weeks of age, but thereafter the glandular EGF concentration increased again during the post-reproductive period to reach 62.9 pmol/mg wet wt. In contrast, the glandular EGF content in male mice increased greatly during the first 17 weeks of age to about 310 pmol/mg wet wt, and thereafter remained relatively constant up to 48 weeks of age. Ovariectomy of mature virgin mice markedly increased the glandular concentration of EGF to about 74.4 pmol/mg wet wt 4 weeks after the operation. This increase was suppressed by oestradiol-17 beta administered to ovariectomized mice at a dose of 1 microgram/mouse per day but not by 1 mg progesterone. Histological studies indicated that granular convoluted tubular cells that produced EGF in the submandibular gland were much less abundant in 12-week-old female and in oestrogen-treated ovariectomized mature mice than in 40-week-old female and ovariectomized mature mice. We conclude that oestrogen suppresses the concentration of EGF in the submandibular gland of female mice.


Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection.
Chronic oxidative stress has been linked to the neurodegenerative changes characteristic of Parkinson's disease, particularly alpha-synuclein accumulation and aggregation. However, it remains contentious whether these alpha-synuclein changes are cytotoxic or neuroprotective. The current study utilised long-term primary neural culture techniques with antioxidant free media to study the cellular response to chronic oxidative stress. Cells maintained in antioxidant free media were exquisitely more vulnerable to acute exposure to hydrogen peroxide, yet exposure of up to 10 days in antioxidant free media did not lead to morphological alterations in neurones or glia. However, a subpopulation of neurones demonstrated a significant increase in the level of alpha-synuclein expressed within the cell body and at synaptic sites. This subset of neurones was also more resistant to apoptotic changes following exposure to antioxidant free media relative to other neurones. These data indicate that increased alpha-synuclein content is associated with neuroprotection from relatively low levels of oxidative stress.


Baseline Plasma Metabotype Correlates With Direct-Acting Antiviral Therapy Nonresponse for HCV in HIV-HCV Coinfected Patients.
Introduction: With the advent of direct-acting antiviral (DAA) therapy for HCV, the cure is achieved at similar rates among HIV-HCV coinfected patients as in HCV mono-infected patients. The present study evaluates host plasma metabolites as putative indicators in predicting the treatment response in baseline HIV-HCV patients. Methods: Non-cirrhotic HIV-HCV (N = 43) coinfected patients were treated with sofosbuvir and daclatasvir for 12 weeks. Plasma metabolite profiling of pre- and post-therapy was analyzed in 20/43 patients. Of the 20 selected, 10 (50%) attained the sustained viral response [(SVR) (responders)] as defined by the absence of HCV RNA at 12 weeks after the treatment, and 10 (50%) did not attain the cure for HCV (nonresponders). Results: A total of 563 features were annotated (metabolomic/spectral databases). Before therapy, 39 metabolites differentiated (FC ±1.5, p < 0.05) nonresponders from responders. Of these, 20 upregulated and 19 downregulated were associated with tryptophan metabolism, nicotinamide metabolism, and others. Post therapy, 62 plasma metabolites (12 upregulated and 50 downregulated, FC±1.5, p < 0.05) differentiated nonresponders from responders and highlighted a significant increase in the steroid and histidine metabolism and significant decrease in tryptophan metabolism and ascorbate and pyruvate metabolism in the nonresponders. Based on random forest and multivariate linear regression analysis, the baseline level of N-acetylspermidine (FC > 2, AUC = 0.940, Bfactor = -0.267) and 2-acetolactate (FC > 2, AUC = 0.880, Bfactor = -0.713) significantly differentiated between nonresponders from responders in HIV-HCV coinfected patients and was able to predict the failure of treatment response. Conclusion: Increased baseline levels of N-acetylspermidine and 2-acetolactate levels are associated with the likeliness of failure to attain the cure for HCV in HIV-HCV coinfected patients.


The use of intraallelic variability for testing neutrality and estimating population growth rate.
To better understand the forces affecting individual alleles, we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci (the intraallelic variability). We model three types of intraallelic variability: (a) the number of nonrecombinants at a linked biallelic marker locus, (b) the length of a conserved haplotype, and (c) the number of mutations at a linked marker locus. If the population growth rate is known, the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency. If the population growth rate is unknown but neutrality can be assumed, the joint distribution provides the likelihood of the growth rate and leads to a maximum-likelihood estimate. We apply the method to data from published data sets for four loci in humans. We conclude that the Delta32 allele at CCR5 and a disease-associated allele at MLH1 arose recently and have been subject to strong selection. Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0.027 per generation with a support interval of (0.017-0.037). Four of the relatively common alleles at CFTR also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers.


Catheter-based renal denervation for treatment of resistant hypertension.
Hypertension is a common disease associated with important cardiovascular complications. Persistent blood pressure of 140/90 or higher despite combined use of a reninangiotensin system blocker, calcium channel blocker and a diuretic at highest tolerated doses constitutes resistant hypertension. Excess sympathetic activity plays an important pathogenic role in resistant hypertension in addition to contributing to the development of metabolic problems, in particular diabetes. Reduction of renal sympathetic activity by percutaneous catheter-based radiofrequency ablation via the renal arteries has been shown in several studies to decrease blood pressure in patients with resistant hypertension, and importantly is largely free of significant complications. However, longer term follow-up is required to confirm both long-term safety and efficacy.


Bayesian basket trial design with false-discovery rate control.
Recent advances in developing "tumor agnostic" oncology therapies have identified molecular targets that define patient subpopulations in a manner that supersedes conventional criteria for cancer classification. These successes have produced effective targeted therapies that are administered to patients regardless of their tumor histology. Trials have evolved as well with master protocol designs. By blending translational and clinical science, basket trials in particular are well-suited to investigate and develop targeted therapies among multiple cancer histologies. However, basket trials intrinsically involve more complex design decisions, including issues of multiple testing across baskets, and guidance for investigators is needed. The sensitivity of the multisource exchangeability model to prior specification under differing degrees of response heterogeneity is explored through simulation. Then, a multisource exchangeability model design that incorporates control of the false-discovery rate is presented and a simulation study compares the operating characteristics to a design where the family-wise error rate is controlled and to the frequentist approach of treating the baskets as independent. Simulations are based on the original design of a real-world clinical trial, the SUMMIT trial, which investigated Neratinib treatment for a variety of solid tumors. The methods studied here are specific to single-arm phase II trials with binary outcomes. Values of prior probability of exchangeability in the multisource exchangeability model between 0.1 and 0.3 provide the best trade-offs between gain in precision and bias, especially when per-basket sample size is below 30. Application of these calibration results to a re-analysis of the SUMMIT trial showed that the breast basket exceeded the null response rate with posterior probability of 0.999 while having low posterior probability of exchangeability with all other baskets. Simulations based on the design of the SUMMIT trial revealed that there is meaningful improvement in power even in baskets with small sample size when the false-discovery rate is controlled as opposed to the family-wise error rate. For example, when only the breast basket was active, with a sample size of 25, the power was 0.76 when the false-discovery rate was controlled at 0.05 but only 0.56 when the family-wise error rate was controlled at 0.05, indicating that impractical sample sizes for the phase II setting would be needed to achieve acceptable power while controlling the family-wise error rate in this setting of a trial with 10 baskets. Selection of the prior exchangeability probability based on calibration and incorporation of false-discovery rate control result in multisource exchangeability model designs with high power to detect promising treatments in the context of phase II basket trials.


Safety pharmacology and genotoxicity evaluation of AVI-4658.
Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations. Restoration of dystrophin by exon skipping was demonstrated with the phosphorodiamidate morpholino oligomers (PMO) class of splice-switching oligomers, in both mouse and dog disease models. The authors report the results of Good Laboratory Practice-compliant safety pharmacology and genotoxicity evaluations of AVI-4658, a PMO under clinical evaluation for DMD. In cynomolgus monkeys, no test article-related effects were seen on cardiovascular, respiratory, global neurological, renal, or liver parameters at the maximum feasible dose (320 mg/kg). Genotoxicity battery showed that AVI-4658 has no genotoxic potential at up to 5000 microg/mL in an in vitro mammalian chromosome aberration test and a bacterial reverse mutation assay. In the mouse bone marrow erythrocyte micronucleus test, a single intravenous injection up to 2000 mg/kg was generally well tolerated and resulted in no mutagenic potential. These results allowed initiation of systemic clinical trials in DMD patients in the United Kingdom.


Lack of role of TGF-beta 1 in decreased lymphoproliferative response in HIV-1 infection.
We investigated whether reduction of the phytohemagglutinin (PHA)-induced proliferative response of lymphocytes from HIV type-1 (HIV-1)-infected (HIV+) individuals could be explained by overproduction of transforming growth factor-beta 1 (TGF-beta 1), a strong inhibitor of T cell proliferation. PHA-stimulated PBMC from 40 HIV- and 42 HIV+ homosexual men from the Baltimore Center of the Multicenter AIDS Cohort Study (MACS) were studied using Northern blot analysis of expression of TGF-beta 1 mRNA and determining the effects of anti-TGF-beta 1 neutralizing antibody on PHA-induced proliferative responses. Compared to the HIV- donors, HIV+ donors did not show increased expression of TGF-beta 1 mRNA in unstimulated or PHA-stimulated PBMC. Furthermore, a neutralizing antibody to TGF-beta 1 did not reverse the decreased proliferative response of PBMC from HIV+ individuals to PHA or interleukin-2. These results indicate that TGF-beta 1 is not involved in T cell proliferation defects seen in HIV+ donors.


Virtual tissue engineering of the human atrium: modelling pharmacological actions on atrial arrhythmogenesis.
Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.


Outcomes of culprit versus multivessel PCI in patients with multivessel coronary artery disease presenting with ST-elevation myocardial infarction complicated by shock.
The optimal revascularization strategy in patients with multivessel coronary artery disease (MVCAD) who present with ST-elevation myocardial infarction (STEMI) and shock is undefined. We aimed to determine differences in survival among patients with MVCAD presenting with STEMI complicated by shock treated with percutaneous coronary intervention (PCI) of the infarct-related artery alone (culprit-only PCI) versus multivessel PCI (MVPCI). Patients with MVCAD and STEMI complicated by shock who underwent PCI between January 1, 2002 and May 31, 2010 were identified (n = 199). Differences in survival between patients undergoing culprit-only PCI versus MVPCI were assessed using a multiphase survival model and propensity matching. MVPCI was used in 22% of patients (n = 43). Patient characteristics were similar in the groups, although more patients treated with MVPCI met the National Cardiovascular Data Registry definition of shock. Death was higher in patients treated with MVPCI at 1 month (27% vs 46%) and 8 years (65% vs 75%; P=.04). The early risk of death was higher in the patients treated with MVPCI when compared to patients treated with culprit-only PCI (coefficient: 0.66 ± 0.25; P=.009), but not the late risk of death (coefficient: -0.18 ± 0.58; P=.70). However, in a propensity-matched cohort (n = 64), there were no differences in the risk of death over the early (coefficient: 0.50 ± 0.37; P=.16) or late phase (P>.90). Patients undergoing MVPCI for STEMI-related shock are clinically different than those treated with culprit PCI only; however, after risk adjustment both groups have similar short- and long-term outcomes. Prospective studies are needed to determine the optimal revascularization strategy in this high-risk population.


Dimension-specific intertrial priming effects are task-specific: evidence for multiple weighting systems.
Feature singleton search is faster when the target-defining dimension repeats across consecutive trials than when it changes (Found & Müller, 1996). However, this dimension repetition benefit (DRB) has also been demonstrated for the tasks with no search component (Mortier, Theeuwes, & Starreveld, 2005). If DRBs in the search and non-search tasks have the same origin, significant DRBs across trials of different tasks should rise. Two different tasks varied either in a predictable manner (Experiment 1) or randomly (Experiment 2) across trials. In detection task, search displays containing either color or orientation singletons were used. Discrimination task required identification of either color or orientation of a single presented item (non-search display). In Experiment 3, participants performed only the discrimination task, while the search and non-search displays varied randomly. There were significant DRBs for both tasks when the task repeated but not when the task changed (Experiments 1 and 2). DRBs were significant both when the display type repeated and when it changed (Experiment 3). Overall, the findings can be well explained by assuming multiple, independent dimension-weighting systems generating DRBs in different tasks.


Power and sample size determination for noninferiority trials using an exact method.
Noninferiority studies are frequently conducted to justify the development of new drugs and vaccines that have been shown to offer better safety profiles, easier administration, or lower cost while maintaining similar efficacy as compared to the standard treatment. Recently, exact methods have been developed to address the concern that existing asymptotic methods for analyzing and planning noninferiority may fail because of small sample size or because of skewed or sparse data structure. In this paper, we explore the use of exact methods in determining sample size and power for noninferiority studies that focus on the difference of two proportions. The methodology for sample size and power calculations is developed based on an exact unconditional test of noninferiority. We illustrate this exact method using a clinical trial example in childhood nephroblastoma and briefly discuss the optimal sample-size allocation strategy. This exact unconditional method performs very well in various scenarios and compares favorably to its asymptotic counterpart in terms of sensitivity. Therefore, it is a very desirable tool for planning noninferiority trials, especially in situations where asymptotic methods are likely to fail.


Predicting toxicity-related docetaxel discontinuation and overall survival in metastatic castration-resistant prostate cancer: a pooled analysis of open phase 3 clinical trial data.
Docetaxel is widely used in metastatic castration-resistant prostate cancer (mCRPC), however its optimal use remains unclear in the current treatment landscape. Biomarkers to predict Docetaxel toxicity may help optimize treatment selection. We aimed to create a predictive model for toxicity-related Docetaxel discontinuation (TRDD). Through Project Data Sphere, we accessed individual patient data from the control arms of three frontline mCRPC trials: ASCENT2, VENICE, and MAINSAIL. The inclusion criteria for these trials were all similar and included patients with chemotherapy-naïve mCRPC. The primary outcome was occurrence of TRDD. A competing risks regression (CRR) was used to predict TRDD, after accounting for the occurrence of competing events (death or progression). The output of the model was used as the dependent variable on a classification and regression tree (CART) to identify risk groups for TRDD. Overall, 1568 patients were considered. Pooled CI of TRDD was 19% after accounting for competing events (death: 474; progression: 59) within 12 months of starting treatment. To build a risk calculator we relied on a CRR that ultimately included age, ECOG performance status, AST, bilirubin, use of analgesics, and presence of diabetes and chronic kidney disease. The CART analysis identified three risk groups that were named: low (model-derived TRDD risk ≤24%), intermediate (25-64%), and high (≥65%) risk group. In each risk group, probability of TRDD during treatment was 14%, 58%, and 79%, and median OS was 24 months, 20 months, and 13 months, respectively (p < 0.001). Treatment selection in mCRPC remains a challenge. Our model can help clinicians balance Docetaxel toxicity and efficacy. The three risk categories that we identified correlated with OS and this is particularly useful for an optimal shared decision-making process.


Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats.
The protective effects of hesperidin against hypercholesterolemia and fatty liver were examined in male Wistar rats fed a high-cholesterol diet for 12 weeks. Compared with a standard diet, a high-cholesterol diet not only increased body weights, liver weights, and serum concentration of cholesterol, but also induced the fatty degeneration (steatosis) of liver. Hesperidin (0.08%) reduced levels of hepatic steatosis, adipose tissue and liver weights (P < 0.05), serum total cholesterol and retinol binding protein (RBP) 4 concentrations (P < 0.05) in rats fed with high-cholesterol diet, while reduction in low-density lipoprotein cholesterol levels and triglyceride concentrations was not significant. It also attenuated the marked changes in mRNA expression of lipid metabolism-related proteins: RBP, heart fatty acid-binding protein (H-FABP), and cutaneous fatty acid-binding protein (C-FABP), in liver and adipose tissue. According to the results of gas chromatography, serum concentrations of total cholesterol and biomarkers of cholesterol synthesis (lathosterol) and absorption (campesterol, β-sitosterol) were lower, and concentrations of cholesterol in feces were higher in the rats given hesperidin (P < 0.05). Hesperidin may improve hypercholesterolemia and fatty liver by inhibiting both the synthesis and absorption of cholesterol and regulating the expression of mRNA for RBP, C-FABP, and H-FABP.


The down syndrome behavioral phenotype: implications for practice and research in occupational therapy.
ABSTRACT Down syndrome (DS) is the most common chromosomal cause of intellectual disability. The genetic causes of DS are associated with characteristic outcomes, such as relative strengths in visual-spatial skills and relative challenges in motor planning. This profile of outcomes, called the DS behavioral phenotype, may be a critical tool for intervention planning and research in this population. In this article, aspects of the DS behavioral phenotype potentially relevant to occupational therapy practice are reviewed. Implications and challenges for etiology-informed research and practice are discussed.


Response to netakimab in radiographic axial spondyloarthritis patients with different baseline C-reactive protein, sacroiliitis evaluated by MRI and peripheral joint involvement status: a post-hoc analysis of the ASTERA study.
Netakimab is a humanised camelid-derived monoclonal antibody targeting interleukin-17A. Here, we report the results of post-hoc analysis of the ASTERA phase 3 study (NCT03447704, February 27, 2018) in patients with active radiographic axial spondyloarthritis (r-axSpA) grouped by baseline C-reactive protein (CRP), baseline sacroiliac joint (SIJ) inflammation through magnetic resonance imaging (MRI) or presence of peripheral arthritis (PA). In this double-blinded, multicentre, randomised, placebo-controlled, phase 3 ASTERA study, 228 adult patients with active r-axSpA received 120 mg of subcutaneous netakimab or placebo at weeks 0, 1, 2, and thereafter every other week. For the subanalysis, 16-week data of 114 netakimab-treated patients with the available baseline CRP and SIJ MRI were grouped by normal (<5 mg/L) or abnormal (≥5 mg/L) CRP, by the grade of sacroiliitis (SI) based on the SPARCC MRI score <2 (MRI-SI-) or ≥2 (MRI-SI+), or by the presence of PA. ASAS-recommended activity, spinal mobility, and function endpoints for r-axSpA were analysed. At week 16, an improvement in all the outcomes was similar for MRI-SI- and MRI-SI+ patients, except for a change in ASspi-MRI-a which was significantly greater in MRI-SI+. Netakimab was effective regardless of baseline CRP and PA. For patients with CRP ≥5 mg/L, a more pronounced decline in r-axSpA activity was observed with a trend towards the most prominent improvement in ASDAS-CRP and BASDAI for patients with CRP >20 mg/L. Subcutaneous netakimab is effective in patients with r-axSpA irrespective of baseline CRP and inflammation on SIJ MRI. The benefit in patients with high CRP (>20 mg/L) was more pronounced.


Can the Expiratory Disproportion Index Distinguish PVFMD from Subglottic Stenosis in Obese Patients?
Expiratory disproportion index (EDI) is the ratio of forced expiratory volume in 1 second (FEV1) divided by peak expiratory flow rate (PEFR) multiplied by 100. Prominent EDI (>50) values can differentiate subglottic stenosis (SGS) from paradoxical vocal fold movement disorder (PVFMD), but this has not been verified when considering body habitus. We hypothesize that the predictive value of elevated EDI in differentiating SGS from PVFMD will be lower in obese patients than non-obese patients. Patients ≥ 18 years old with recorded PFT values, BMI, and airway imaging were reviewed retrospectively from 01/2011 to 10/2018. EDI was recorded for 4 cohorts: non-obese/SGS, non-obese/ PVFMD, obese/SGS, and obese/ PVFMD, to determine the mean EDI and the sensitivity/specificity of an elevated EDI. Mean EDI values were 69.32 and 48.38 in the non-obese SGS and PVFMD groups, respectively (P < .01). They were 58.89 and 47.67 in the obese SGS and PVFMD groups, respectively (P < .05). At a threshold of >50, EDI had a sensitivity of 90.0% and specificity of 51.6% in differentiating between SGS and PVFMD cases in non-obese patients and 51.6% and 63.6% in obese patients. Prior literature has established that EDI can distinguish SGS from PVFMD in the general population. Our results show that the mean EDI values were significantly different in both cohorts, but an elevated EDI was not as sensitive at identifying SGS cases in obese patients. This suggests that the EDI should be used with caution in obese patients and should not be relied upon to rule out SGS. 3.


Analysis of differences between conditioned and control reflex series in EMG recordings.
Two methods are presented for the data analysis of signals derived by subtracting conditioned from control reflex data in full-wave rectified and averaged electromyographic (EMG) signals. The first method uses the ratios of the mean amplitudes and standard errors of the mean (S.E.M.s) (i.e. Student's t values) of a series of data points in such a difference signal, and deals with the detection of latencies of reflex components which are susceptible to a conditioning stimulus or experimental situation. The second method applies a modified cumulative sum (CUSUM) technique to full-wave rectified difference signals. This modified CUSUM technique determines the magnitude of the effects of the conditioning situation above that expected due to chance fluctuations, taking into account the effect of reflex modulations on such chance fluctuations in a post-stimulus period. The modified CUSUM technique proved particularly useful when various subtle but consistent, opposing changes occurred sequentially in the conditioned series thus yielding a complicated pattern of effects in a difference signal, with a low signal-to-noise ratio.


Characterization of the ARR15 and ARR16 response regulators with special reference to the cytokinin signaling pathway mediated by the AHK4 histidine kinase in roots of Arabidopsis thaliana.
The cytokinin receptor AHK4 histidine kinase, identified in Arabidopsis thaliana, presumably acts in concert with downstream components, such as histidine-containing phosphotransfer (HPt) factors (AHPs) and response regulators (ARRs). In this respect, we characterized a loss-of-function mutant of the AHK4 gene, named cre1-1, which showed a reduced cell number within the vascular tissues in roots. Among the 10 type-A ARR members, the expression of ARR15 and ARR16 in roots was specifically and markedly reduced in cre1-1, suggesting a link between these response regulators and the AHK4-mediated signal transduction in roots. The results for transgenic plants expressing promoter::GUS or promoter::LUC fusion genes showed that both the ARR15 and the ARR16 gene products are accumulated upon cytokinin treatment in roots. The results of GFP-fusion experiments with onion epidermal cells further showed that ARR15 was found in the nucleus, and ARR16 mainly in the cytoplasm. Together, it was suggested that ARR15 and ARR16 are distinctly implicated in the presumed AHK4-mediated signaling pathway in roots.


Research: promoting positive attitudes through education.
This paper outlines a study which was undertaken to explore the relationship between nurses' attitudes towards research and their educational experience. A Likert-type attitude questionnaire, using statements derived from themes emerging within the literature, was used prior to, and following, 61 students' learning experiences on research modules at diploma and degree levels. Teaching and learning strategies adopted within the modules focused on overcoming some of the main barriers to utilization of research findings identified within the literature. The results obtained identified a significant shift towards more positive attitudes to research following the modules. The conclusions exhort nurse educators to not only include research into curricula, but also to reflect on the teaching and learning strategies adopted.


Preparation, Physicochemical Properties, and Transfection Activities of Tartaric Acid-Based Cationic Lipids as Effective Nonviral Gene Delivery Vectors.
In this work two novel cationic lipids using natural tartaric acid as linking backbone were synthesized. These cationic lipids were simply constructed by tartaric acid backbone using head group 6-aminocaproic acid and saturated hydrocarbon chains dodecanol (T-C12-AH) or hexadecanol (T-C16-AH). The physicochemical properties, gel electrophoresis, transfection activities, and cytotoxicity of cationic liposomes were tested. The optimum formulation for T-C12-AH and T-C16-AH was at cationic lipid/dioleoylphosphatidylethanolamine (DOPE) molar ratio of 1 : 0.5 and 1 : 2, respectively, and N/P charge molar ratio of 1 : 1 and 1 : 1, respectively. Under optimized conditions, T-C12-AH and T-C16-AH showed effective gene transfection capabilities, superior or comparable to that of commercially available transfecting reagent 3β-[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol) and N-[2,3-dioleoyloxypropyl]-N,N,N-trimethylammonium chloride (DOTAP). The results demonstrated that the two novel tartaric acid-based cationic lipids exhibited low toxicity and efficient transfection performance, offering an excellent prospect as nonviral vectors for gene delivery.


Mean mortality among Brazilian left- and right-handers: modification or selective elimination?
Many surveys report a higher incidence of left-handedness in younger than in older cohorts, and explanations for this phenomenon have centred around two rival hypotheses. The modification hypothesis attributes this trend to secular differences in the social tolerance of left-handed preferences, whereas the elimination hypothesis contends that left-handers have a shorter life-span than right-handers do, and hence are infrequent in the population above age 70. In order to evaluate these two hypotheses, data were collected on 513 decedents from kin informants. There were 465 right- and 48 left-handed decedents, including 18 switched sinistrals. Females lived significantly longer than males, and there was a nonsignficant survival advantage for left-handers. Switched left-handers were disproportionately represented among older compared to younger decedents, indicating an historical reduction of sanctions against left-handed writing. These results contradict the survival advantage for right-handers reported by Coren and Halpern (1991), providing evidence more favourable to a cultural conditioning explanation, rather than one emphasising selective mortality.


Syphilis: still with us, so watch out!
The number of syphilis cases has been increasing in the UK, partly because of localised outbreaks. The sharpest rises have been among men having sex with men, but the incidence among heterosexuals has also risen. Blood-test screening for syphilis is an important part of sexual health, and includes routine screening of pregnant women at the first antenatal visit. Prompt treatment with penicillin in the earlier stages can stop the progression of the disease. Unfortunately, public awareness of syphilis and its potentially serious consequences is low. It is important for health professionals to be alert for signs of the disease and to initiate tests if there is a likelihood that a patient has or is at risk for the disease.


Exclusive Ni-N4 Sites Realize Near-Unity CO Selectivity for Electrochemical CO2 Reduction.
Electrochemical reduction of carbon dioxide (CO2) to value-added carbon products is a promising approach to reduce CO2 levels and mitigate the energy crisis. However, poor product selectivity is still a major obstacle to the development of CO2 reduction. Here we demonstrate exclusive Ni-N4 sites through a topo-chemical transformation strategy, bringing unprecedentedly high activity and selectivity for CO2 reduction. Topo-chemical transformation by carbon layer coating successfully ensures preservation of the Ni-N4 structure to a maximum extent and avoids the agglomeration of Ni atoms to particles, providing abundant active sites for the catalytic reaction. The Ni-N4 structure exhibits excellent activity for electrochemical reduction of CO2 with particularly high selectivity, achieving high faradaic efficiency over 90% for CO in the potential range from -0.5 to -0.9 V and gives a maximum faradaic efficiency of 99% at -0.81 V with a current density of 28.6 mA cm-2. We anticipate exclusive catalytic sites will shed new light on the design of high-efficiency electrocatalysts for CO2 reduction.


Oversaturated part-based visual tracking via spatio-temporal context learning.
Partial occlusion is one of the key challenging factors in a robust visual tracking method. To solve this issue, part-based trackers are widely explored; most of them are computationally expensive and therefore infeasible for real-time applications. Context information around the target has been used in tracking, which was recently renewed by a spatio-temporal context (STC) tracker. The fast Fourier transform adopted in STC equips it with high efficiency. However, the global context used in STC alleviates the performance when dealing with occlusion. In this paper, we propose an oversaturated part-based tracker based on spatio-temporal context learning, which tracks objects based on selected parts with spatio-temporal context learning. Furthermore, a structural layout constraint and a novel model update strategy are utilized to enhance the tracker's anti-occlusion ability and to deal with other appearance changes effectively. Extensive experimental results demonstrate our tracker's superior robustness against the original STC and other state-of-art methods.


A simple mathematical model for Ebola in Africa.
We deal with the following question: Can the consumption of contaminated bush meat, the funeral practices and the environmental contamination explain the recurrence and persistence of Ebola virus disease outbreaks in Africa? We develop an SIR-type model which, incorporates both the direct and indirect transmissions in such a manner that there is a provision of Ebola viruses. We prove that the full model has one (endemic) equilibrium which is locally asymptotically stable whereas, it is globally asymptotically stable in the absence of the Ebola virus shedding in the environment. For the sub-model without the provision of Ebola viruses, the disease dies out or stabilizes globally at an endemic equilibrium. At the endemic level, the number of infectious is larger for the full model than for the sub-model without provision of Ebola viruses. We design a nonstandard finite difference scheme, which preserves the dynamics of the model. Numerical simulations are provided.


A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.
Patients with severe asthma have increased physiologically measured air trapping; however, a study using CT measures of air trapping has not been performed. This study was designed to address two hypotheses: (1) air trapping measured by multidetector CT (MDCT) quantitative methodology would be a predictor of a more severe asthma phenotype; and (2) historical, clinical, allergic, or inflammatory risk factors could be identified via multivariate analysis. MDCT scanning of a subset of Severe Asthma Research Program subjects was performed at functional residual capacity. Air trapping was defined as >or= 9.66% of the lung tissue < - 850 Hounsfield units (HU). Subjects classified as having air trapping were then compared to subjects without air trapping on clinical and demographic factors using both univariate and multivariate statistical analyses. Subjects with air trapping were significantly more likely to have a history of asthma-related hospitalizations, ICU visits, and/or mechanical ventilation. Duration of asthma (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.08 to 1.87), history of pneumonia (OR, 8.55; 95% CI, 2.07 to 35.26), high levels of airway neutrophils (OR, 8.67; 95% CI, 2.05 to 36.57), airflow obstruction (FEV(1)/FVC) [OR, 1.61; 95% CI, 1.21 to 2.14], and atopy (OR, 11.54; 95% CI, 1.97 to 67.70) were identified as independent risk factors associated with the air-trapping phenotype. Quantitative CT-determined air trapping in asthmatic subjects identifies a group of individuals at high risk for severe disease. Several independent risk factors for the presence of this phenotype were identified: perhaps most interestingly, history of pneumonia, neutrophilic inflammation, and atopy.


Adults with cerebral palsy benefit from participating in a strength training programme at a community gymnasium.
This study examined whether a community-based progressive resistance strength training programme could improve muscle strength and functional activity in a group of adults with cerebral palsy with high support needs. Using a single group pre-post clinical design, 10 adults (7 males, 3 females; mean age 47.8 SD 5.7 years) with cerebral palsy and high support needs completed 4 weeks of introduction and familiarization, followed by a 10-week progressive resistance strength training programme in a community gymnasium. Participants were measured for muscle strength, locomotion speed and timed sit-to-stand. After establishment of a stable baseline from weeks 2 to 5 with no systematic change and a high degree of association (r>0.86), participants increased leg strength by 22.0% (p=0.02), arm strength by 17.2% (p=0.01) and improved performance of sit-to-stand (p=0.02) during the 10-week strength training intervention. This study adds to the accumulating evidence that strength training can be beneficial for people with cerebral palsy by demonstrating benefits for adults with cerebral palsy and high support needs who are subject to decline in physical function associated with the ageing process.


Effect of Water Stress on Turgor Differences and C-Assimilate Movement in Phloem of Ecballium elaterium.
The effects of water stress on pressure differences and (14)C-assimilate translocation in sieve tubes of squirting cucumber Ecballium elaterium A. Rich were studied. Water stress was induced by transfer of plants from culture solution to a polyethylene glycol 6,000 solution having an osmotic potential of -18.2 atm. Sieve tube turgor, turgor differences between source and sink, and translocation rate were decreased. After 260 minutes of translocation, only 19% of the total fixed (14)CO(2) had moved out of the leaf, compared to the control value of 62% after the same period of time. The results suggest that water stress slows translocation by lowering sieve tube turgor differences, which are essential for the pressure flow mechanism of conduction.


Mechanistically Scoping Cell-Free and Cell-Dependent Artificial Scaffolds in Rebuilding Skeletal and Dental Hard Tissues.
Rebuilding mineralized tissues in skeletal and dental systems remains costly and challenging. Despite numerous demands and heavy clinical burden over the world, sources of autografts, allografts, and xenografts are far limited, along with massive risks including viral infections, ethic crisis, and so on. Per such dilemma, artificial scaffolds have emerged to provide efficient alternatives. To date, cell-free biomimetic mineralization (BM) and cell-dependent scaffolds have both demonstrated promising capabilities of regenerating mineralized tissues. However, BM and cell-dependent scaffolds have distinctive mechanisms for mineral genesis, which makes them methodically, synthetically, and functionally disparate. Herein, these two strategies in regenerative dentistry and orthopedics are systematically summarized at the level of mechanisms. For BM, methodological and theoretical advances are focused upon; and meanwhile, for cell-dependent scaffolds, it is demonstrated how scaffolds orchestrate osteogenic cell fate. The summary of the experimental advances and clinical progress will endow researchers with mechanistic understandings of artificial scaffolds in rebuilding hard tissues, by which better clinical choices and research directions may be approached.


Synthesis and characterization of completely delocalized mixed-valent dicopper complexes.
The multidentate ligands tris[(N'-tert-butylureayl)-N-ethyl)]amine (H(6)1) and 1-(tert-butylaminocarbonyl)-2,2-dimethylaminoethane (H(2)2) have been used to investigate the assembly and properties of complexes with Cu(1.5)Cu(1.5) units. The complexes [Cu(H(5)1)](2)(+) and [Cu(H2)](2)(+) have been isolated and structurally characterized by X-ray diffraction methods. [Cu(H(5)1)](2)(+) has a Cu(1.5)Cu(1.5) core, with each copper ion having square planar coordination geometry. The copper ions are linked through two mono-deprotonated urea ligands, which coordinate as mu-1,3-(kappaN:kappaO) ureate bridges to produce a Cu-Cu distance of 2.39 A. The remaining two urea arms of [H(5)1](-) form intramolecular hydrogen bonds, the result of which is to confine the Cu(1.5)Cu(1.5) unit within a pseudomacrocycle. The structure of [Cu(H2)](2)(+) lacks intramolecular hydrogen bonds and thus does not have a pseudomacrocyclic structure. However, the structural properties of the Cu(1.5)Cu(1.5) core in [Cu(H2)](2)(+) are nearly identical to those of [Cu(H(5)1)](2)(+). Both complexes exhibit rhombic EPR spectra at 77 K, which do not change upon cooling to 4 K. The optical spectra of [Cu(H(5)1)](2)(+) and [Cu(H2)](2)(+) are dominated by an intense band at approximately 700 nm. These spectral characteristics are consistent with [Cu(H(5)1)](2)(+) and [Cu(H2)](2)(+) being classified as fully delocalized (type III) mixed-valent species.


Cross-cultural adaptation and measurement properties of the Arabic version of the Fall Efficacy Scale International.
To translate the Falls Efficacy Scale International (FES-I) into Arabic according to the World Health Organization`s (WHO) criteria and to evaluate the concurrent validity of the FES-I in persons living with balance and vestibular disorders. This cross-sectional descriptive study included 43 persons with balance and vestibular disorders presenting to an outpatient dizziness center at King Abdulaziz University Hospital, Riyadh, Kingdom of Saudi Arabia between June 2012 and May 2013. All participants completed the Arabic version of the FES-I and the Dizziness Handicap Inventory (DHI) during their assessment with the clinical audiologist. In addition, subjects completed the Dynamic Gait Index 4-item (DGI-4) gait test. An additional 55 control participants also completed the Arabic FES-I, the DGI-4, and the Arabic DHI. Forty-three participants with vestibular disorders (36 females, 7 males) with a mean age of 32 years (standard deviation (SD) 10 years, range 18-56 years) and 55 control participants (27 females, 28 males) with a mean age of 33, (SD-12), and age range of 18-78 participated. The correlation between the Arabic FES-I and the Arabic DHI was 0.75 in patients and 0.77 in control participants. The correlation between the Arabic FES-I and the DGI-4 was r=-0.30 (p=0.003). The Arabic FES-I has established concurrent validity and may be helpful for measuring an individual`s concern of falling in people with vestibular and balance disorders.


Caries experience of urban and rural children in Saudi Arabia.
Caries experience and restorative treatment needs often are reported to be higher in urban than rural areas in developing countries. The purpose of this study was to compare caries experience in 12- and 13-year-old children in urban and rural areas of Saudi Arabia, a young, oil-rich, developing country. A random sample of 1,873 schoolchildren aged 12-13 years from urban and adjoining rural areas of 10 administrative regions in the Kingdom of Saudi Arabia were examined for dental caries. Questionnaires also were administered to elicit information on the frequency of snacking as well as consumption of sweets and soft drinks. No statistically significant differences were found between urban and rural children in caries experience in permanent teeth (mean DMFT = 2.69 in urban areas; 2.65 in rural areas), frequency of snacking, or frequency of consumption of sweets and soft drinks. The percentage of DMFT found to be D was equally high (> 89%) in both urban and rural areas, indicating a high level of restorative treatment need. In Saudi Arabia, an economically prosperous developing country, exposure to cariogenic diet in urban and rural areas does not differ. Also, a difference in caries experience in urban and rural areas often reported for developing countries does not apply to Saudi Arabia.


Posttraining infusion of norepinephrine and corticotropin releasing factor into the bed nucleus of the stria terminalis enhanced retention in an inhibitory avoidance task.
The present study investigated whether the bed nucleus of the stria terminalis (BNST) is involved in formation and retrieval of affective memory. Male Wistar rats with cannulae bilaterally implanted into the BNST were trained on a one-trial step-through inhibitory avoidance task. Shortly after training they received bilateral intra-BNST infusion of lidocaine, various noradrenergic drugs, or corticotropin releasing factor (CRF). Results showed that posttraining intra-BNST infusion of lidocaine impaired retention. Posttraining intra-BNST infusion of norepinephrine or the alpha1 antagonist prazosin induced a dose- and time-dependent retention enhancement or deficit, respectively. The enhancing effect of norepinephrine was mimicked by the alpha1 agonist phenylephrine, and antagonized by prazosin at a non-impairing dose. Posttraining intra-BNST infusion of the alpha2 antagonist idazoxan or the beta antagonist propranolol failed to affect retention. Posttraining intra-BNST infusion of CRF also enhanced retention in a dose-dependent manner. Various drugs infused shortly before testing did not significantly influence locomotor activity and retention. These findings, taken together, suggest that the BNST is involved in memory formation processes for affective experience and norepinephrine released in the BNST acting via alpha1 receptors plays a critical role in this function.


Influence of Bleaching and Aging Procedures on Color and Whiteness of Dental Composites.
Bleaching can cause perceptible color changes on resin-based composite (RBC) restorations that may not be stable with aging. The objective of this study was to evaluate color stability and whiteness variations of RBCs after bleaching and aging procedures. Discs (10 mm in diameter and 1 mm thick) of shades A2 and A3 were fabricated from two RBCs (Filtek Z250 and Filtek Z350 XT) and divided into three subgroups (for each composite and shade) (n=5) as follows: control (no bleaching), at-home bleaching, and in-office bleaching. All specimens underwent an accelerated artificial aging up to 450 KJ/m2 and 900 KJ/m2 in an aging chamber (Suntest XXL+). A spectroradiometer (SpectraScan PR-670) was used to obtain CIE L*a*b* coordinates. CIEDE2000 color difference (ΔE00) and whiteness index for dentistry (WID) were used to evaluate color stability. Color and whiteness differences data were analyzed considering the 50:50% visual color difference thresholds (perceptibility [PT] and acceptability [AT]) and 50:50% whiteness thresholds (whiteness perceptibility [WPT] and whiteness acceptability [WAT]). Analysis of variance and Tukey tests (α=0.05) were used to statistically analyze the data. After bleaching, all specimens showed ΔE00 and ΔWID values below their corresponding acceptability thresholds (AT and WAT, respectively). After aging, L* and WID values decreased while b* values increased (p≤0.05), resulting in ΔE00 and ΔWID values above AT and WAT, respectively. Color changes after bleaching RBCs were clinically acceptable, while aging provoked clinically perceptible color changes.


Role of Sevoflurane on Natural Killer Group 2, Member D-Mediated Immune Response in Non-Small-Cell Lung Cancer: An In Vitro Study.
BACKGROUND The purpose of this study was to investigate the effects of sevoflurane on cancer immunosurveillance and metastasis in non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS NCI-H23 cells, a human NSCLC cell line, were incubated with or without sevoflurane at the concentrations of 0, 12.5, 25, 50, 100, and 200 μM for 6 h. Cell viability, the expression of natural killer group 2, member D ligands (NKG2D ligands: UL16-binding proteins 1-3 [ULBP1-3] and major histocompatibility complex class I chain-related molecules A/B [MICA/B]), the expression of matrix metalloproteinases (MMPs), NK cell-mediated cytotoxicity, and cancer cell migration were measured. RESULTS At 12.5, 25, 50, and 100 μM, sevoflurane increased the expression of NKG2D ligands (ULBP2-3 and MICA, ULBP1-3, ULBP1-3, and ULBP1, respectively). Sevoflurane decreased the expression of NKG2D ligands at 200 μM (MICA/B). NK cell-mediated lysis of NCI-H23 cells at 200 μM sevoflurane was significantly reduced compared with the control (P=0.025; target cell: effect cell=1: 10). Sevoflurane increased the expression of MMP-1, -2, and -9 and increased cell migration in NCI-H23 cells at 50, 100, and 200 μM (P=0.001, 0.035, and 0.039, respectively, compared with the control after 18 h of wound formation). CONCLUSIONS Sevoflurane could suppress NKG2D-mediated NK cell cytotoxicity and increased expression of MMPs and migration in NCI-H23 cells. Further research is needed to determine the effects of sevoflurane on cancer immunosurveillance and metastasis in NSCLC.


[The p22phox protein and the CYBA gene. Their function and associations with atherosclerosis-related diseases].
The significant amounts of reactive oxygen species (ROS), mainly superoxide anion (O2*-), are produced each day in the human body. ROS play many important and beneficial functions, but they can also contribute to the development of many diseases, including those with atherosclerotic background. Vascular and phagocytic NADPH oxidases are a multicomponent enzymatic complexes which are the main source of O2*- in the vasculature. The p22phox subunit plays an important role in the functioning of these enzymes and is encoded by the CYBA gene (cytochrome b-alpha). In recent years, it was shown the presence of multiple genetic polymorphisms in the CYBA gene, including variants: -930A>G, -852C>G, -675A>T, -536C>T, *24A>G, 521C>T and 214C>T. The functional and association studies were conducted in many research centers from around the world, as a result of these findings. The aim of the present study was to summarize of the available information on the CYBA gene, function of its polymorphisms and their associations with atherosclerosis-related diseases.


Posttraumatic stress symptoms and marital adjustment among Israeli combat veterans: The role of loneliness and attachment.
War trauma may foster ramifications for marital relationships. Veterans may feel that no one can understand them and thus impact their relationships. The current study aims to shed light on the role that posttraumatic stress symptoms (PTSS), loneliness, and attachment orientations may play in marital adjustment among combat veterans. Participants were 504 veterans who served in the Lebanon War in 1982. Analysis revealed that higher PTSS levels were related to lower marital adjustment and that the indirect path of this relation through loneliness was significant. Furthermore, attachment orientations moderated the direct link between PTSS and marital adjustment, but failed to moderate the indirect effect through loneliness. A sense of isolation should be addressed in therapy, as well as the interpersonal expectations of the veteran. (PsycINFO Database Record


Matters of the Heart: Advancing Psychological Perspectives on Cardiovascular Diseases.
Cardiovascular diseases (CVD) are the major cause of death in men and women in the United States. Type A behavior research was a starting point for psychological science's understanding of the development of CVD. Health psychology science has broadened its scope to consider other psychological constructs as potential risk factors, multilevel models and a life span approach, and new mechanistic pathways that could apply to a number of disease outcomes other than CVD.


The estimation of patients' views on organizational aspects of a general dental practice by general dental practitioners: a survey study.
Considering the changes in dental healthcare, such as the increasing assertiveness of patients, the introduction of new dental professionals, and regulated competition, it becomes more important that general dental practitioners (GDPs) take patients' views into account. The aim of the study was to compare patients' views on organizational aspects of general dental practices with those of GDPs and with GDPs' estimation of patients' views. In a survey study, patients and GDPs provided their views on organizational aspects of a general dental practice. In a second, separate survey, GDPs were invited to estimate patients' views on 22 organizational aspects of a general dental practice. For 4 of the 22 aspects, patients and GDPs had the same views, and GDPs estimated patients' views reasonably well: 'Dutch-speaking GDP', 'guarantee on treatment', 'treatment by the same GDP', and 'reminder of routine oral examination'. For 2 aspects ('quality assessment' and 'accessibility for disabled patients') patients and GDPs had the same standards, although the GDPs underestimated the patients' standards. Patients had higher standards than GDPs for 7 aspects and lower standards than GDPs for 8 aspects. On most aspects GDPs and patient have different views, except for social desirable aspects. Given the increasing assertiveness of patients, it is startling the GDP's estimated only half of the patients' views correctly. The findings of the study can assist GDPs in adapting their organizational services to better meet the preferences of their patients and to improve the communication towards patients.