Ru-Based CO releasing molecules with azole ligands: interaction with proteins and the CO release mechanism disclosed by X-ray crystallography.
fac-[RuII(CO)3Cl2(N3-Imidazole)] (RuIIIM), fac-[RuII(CO)3Cl2(N3-methyl-imidazole)] (RuIIMIM) and fac-[RuII(CO)3Cl2(N3-methyl-benzimidazole)] (RuIIMBI) are three ruthenium based CO releasing molecules (Ru-CORMs) that are cytotoxic towards ovarian and colon carcinoma cell lines. Detailed structural information on the adducts formed upon reaction of RuIIIM and RuIIMIM with hen egg white lysozyme and of the three Ru-CORMs with bovine pancreatic ribonuclease is provided here by X-ray crystallography. Comparative analysis of seven crystal structures of these adducts allows one to delineate some general trends in the reactivity of these Ru-CORMs with proteins. Indeed, in all cases Ru-CORMs bind these model systems upon detachment of the azole ligand and concomitant coordination to a protein His or Asp residue. Apparently the three Ru-CORMs progressively dissociate losing azoles, chlorides, and one or two CO molecules. Data were compared with those reported in the literature for adducts of the same proteins with other Ru-CORMs and with in-solution data previously obtained on the same systems. These results are potentially useful for a better understanding of the chemistry, potential toxicity and mechanism of actions of these interesting Ru-CORMs and are helpful in defining the molecular mechanisms of CO release.


Acute right ventricular myocardial infarction.
Acute right ventricular myocardial infarction (RVMI) is observed in 30-50% of patients presenting with inferior wall myocardial infarction (MI) and, occasionally, with anterior wall MI. The clinical consequences vary from no hemodynamic compromise to severe hypotension and cardiogenic shock depending on the extent of RV ischemia. Areas covered: The pathophysiological mechanisms, diagnostic steps, and novel therapeutic approaches of acute RVMI are described. Expert commentary: Diagnosis of acute RVMI is based on physical examination, cardiac biomarkers, electrocardiography, and coronary angiography, whereas noninvasive imaging modalities (echocardiography, cardiac magnetic resonance imaging) play a complementary role. Early revascularization, percutaneous or pharmacological, represents key step in the management of RMVI. Maintenance of reasonable heart rate and atrioventricular synchrony is essential to sustain adequate cardiac output in these patients. When conventional treatment is not successful, mechanical circulatory support, including right ventricle assist devices, percutaneous cardiopulmonary support, and intra-aortic balloon pump, might be considered. The prognosis associated with RVMI is worse in the short term, compared to non-RVMI, but those patients who survive hospitalization have a relatively good long-term prognosis.


Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens.
The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: group A (170)ExDK(173) and group B (168)EIExD(172). (170)E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas (173)K and (168)E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vbeta in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vbeta in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.


Relevance of hydro-climatic change projection and monitoring for assessment of water cycle changes in the Arctic.
Rapid changes to the Arctic hydrological cycle challenge both our process understanding and our ability to find appropriate adaptation strategies. We have investigated the relevance and accuracy development of climate change projections for assessment of water cycle changes in major Arctic drainage basins. Results show relatively good agreement of climate model projections with observed temperature changes, but high model inaccuracy relative to available observation data for precipitation changes. Direct observations further show systematically larger (smaller) runoff than precipitation increases (decreases). This result is partly attributable to uncertainties and systematic bias in precipitation observations, but still indicates that some of the observed increase in Arctic river runoff is due to water storage changes, for example melting permafrost and/or groundwater storage changes, within the drainage basins. Such causes of runoff change affect sea level, in addition to ocean salinity, and inland water resources, ecosystems, and infrastructure. Process-based hydrological modeling and observations, which can resolve changes in evapotranspiration, and groundwater and permafrost storage at and below river basin scales, are needed in order to accurately interpret and translate climate-driven precipitation changes to changes in freshwater cycling and runoff. In contrast to this need, our results show that the density of Arctic runoff monitoring has become increasingly biased and less relevant by decreasing most and being lowest in river basins with the largest expected climatic changes.


Association between Smoking and Uveitis: Results from the Pacific Ocular Inflammation Study.
To assess whether cigarette smoking is associated with the development of uveitis in a population-based setting. Retrospective, population-based, case-control study. Patients aged ≥ 18 years who were seen at a Kaiser Permanente Hawaii clinic between January 1, 2006, and December 31, 2007. Analysis included 100 confirmed incident uveitis cases, 522 randomly selected controls from the general Kaiser Hawaii population, and 528 randomly selected controls from the Kaiser Hawaii ophthalmology clinic. International Classification of Diseases, 9th revision (ICD-9), diagnosis codes were used to identify possible uveitis cases. A uveitis fellowship-trained ophthalmologist then conducted individual chart review to confirm case status. Multivariate logistic regression models were used to evaluate the association between smoking and uveitis, adjusting for age, sex, race, and socioeconomic status. Development of uveitis. Current smokers had a 1.63 (95% confidence interval [CI], 0.88-3.00; P = 0.12) and 2.33 (95% CI, 1.22-4.45; P = 0.01) times greater odds of developing uveitis compared with those who never smoked using the general and ophthalmology control groups, respectively. The association was even stronger with noninfectious uveitis, which yielded odds ratios of 2.10 (95% CI, 1.10-3.99; P = 0.02) and 2.96 (95% CI, 1.52-5.77; P = 0.001) using the general and ophthalmology control groups, respectively. Cigarette smoking is significantly associated with new-onset uveitis within a population-based setting. The association was stronger for noninfectious uveitis. Given the well-established risks of smoking with regard to other inflammatory disorders, these results reaffirm the importance of encouraging patients to avoid or cease smoking.


Structure and function of Vps15 in the endosomal G protein signaling pathway.
G protein-coupled receptors mediate cellular responses to a wide variety of stimuli, including taste, light, and neurotransmitters. In the yeast Saccharomyces cerevisiae, activation of the pheromone pathway triggers events leading to mating. The view had long been held that the G protein-mediated signal occurs principally at the plasma membrane. Recently, it has been shown that the G protein alpha subunit Gpa1 can promote signaling at endosomes and requires two components of the sole phosphatidylinositol-3-kinase in yeast, Vps15 and Vps34. Vps15 contains multiple WD repeats and also binds to Gpa1 preferentially in the GDP-bound state; these observations led us to hypothesize that Vps15 may function as a G protein beta subunit at the endosome. Here we show an X-ray crystal structure of the Vps15 WD domain that reveals a seven-bladed propeller resembling that of typical Gbeta subunits. We show further that the WD domain is sufficient to bind Gpa1 as well as to Atg14, a potential Ggamma protein that exists in a complex with Vps15. The Vps15 kinase domain together with the intermediate domain (linking the kinase and WD domains) also contributes to Gpa1 binding and is necessary for Vps15 to sustain G protein signaling. These findings reveal that the Vps15 Gbeta-like domain serves as a scaffold to assemble Gpa1 and Atg14, whereas the kinase and intermediate domains are required for proper signaling at the endosome.


Reverse actin sliding triggers strong myosin binding that moves tropomyosin.
Actin/myosin interactions in vertebrate striated muscles are believed to be regulated by the "steric blocking" mechanism whereby the binding of calcium to the troponin complex allows tropomyosin (TM) to change position on actin, acting as a molecular switch that blocks or allows myosin heads to interact with actin. Movement of TM during activation is initiated by interaction of Ca(2+) with troponin, then completed by further displacement by strong binding cross-bridges. We report x-ray evidence that TM in insect flight muscle (IFM) moves in a manner consistent with the steric blocking mechanism. We find that both isometric contraction, at high [Ca(2+)], and stretch activation, at lower [Ca(2+)], develop similarly high x-ray intensities on the IFM fourth actin layer line because of TM movement, coinciding with x-ray signals of strong-binding cross-bridge attachment to helically favored "actin target zones." Vanadate (Vi), a phosphate analog that inhibits active cross-bridge cycling, abolishes all active force in IFM, allowing high [Ca(2+)] to elicit initial TM movement without cross-bridge attachment or other changes from relaxed structure. However, when stretched in high [Ca(2+)], Vi-"paralyzed" fibers produce force substantially above passive response at pCa approximately 9, concurrent with full conversion from resting to active x-ray pattern, including x-ray signals of cross-bridge strong-binding and TM movement. This argues that myosin heads can be recruited as strong-binding "brakes" by backward-sliding, calcium-activated thin filaments, and are as effective in moving TM as actively force-producing cross-bridges. Such recruitment of myosin as brakes may be the major mechanism resisting extension during lengthening contractions.


Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.
Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.


A developmental framework for dissected leaf formation in the Arabidopsis relative Cardamine hirsuta.
The developmental basis for the generation of divergent leaf forms is largely unknown. Here we investigate this problem by studying processes that distinguish development of two related species: Arabidopsis thaliana, which has simple leaves, and Cardamine hirsuta, which has dissected leaves with individual leaflets. Using genetics, expression studies and cell lineage tracing, we show that lateral leaflet formation in C. hirsuta requires the establishment of growth foci that form after leaf initiation. These growth foci are recruited at the leaf margin in response to activity maxima of auxin, a hormone that polarizes growth in diverse developmental contexts. Class I KNOTTED1-like homeobox (KNOX) proteins also promote leaflet initiation in C. hirsuta, and here we provide evidence that this action of KNOX proteins is contingent on the ability to organize auxin maxima via the PINFORMED1 (PIN1) auxin efflux transporter. Thus, differential deployment of a fundamental mechanism polarizing cellular growth contributed to the diversification of leaf form during evolution.


AMPA receptor potentiators for the treatment of CNS disorders.
Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.


Transdermal histamine in multiple sclerosis, part two: a proposed theoretical basis for its use.
This paper is the companion to an earlier publication, which discussed preliminary results of transdermal histamine use for ameliorating symptoms of both relapsing-remitting and progressive multiple sclerosis (MS). Here we include preliminary findings on the impairments of digestion and assimilation in MS patients seen in a private clinic. Although only a small number of patients was surveyed, an association was found between impaired gastric acid production, impaired protein hydrolysis, and subnormal plasma histidine levels in patients with MS. Impaired digestion might, therefore, impair the ability of MS patients to synthesize histamine. This paper discusses how impairment of histamine synthesis might lead to symptoms of MS, and conversely how exogenously administered histamine might alleviate symptoms. Various mechanisms of action are suggested, including: enhanced gastric acid and pancreatic enzyme secretion, augmentation of subnormal cerebral tissue levels of histamine, improved electrical function of demyelinated fibers, increased cerebral blood flow, suppression of aberrant autoimmune responses, and stimulation of remyelination. We also discuss the observed failure of digestive function in MS and point out that pathological changes which parallel CNS findings have been found in the enteric nervous system (ENS) of patients with Parkinson's disease. Similar parallels might exist between the CNS and ENS in multiple sclerosis.


A mathematical model for the mating-induced prolactin rhythm of female rats.
For the first 10 days of pregnancy and the first 12 days of pseudopregnancy, the secretion of prolactin (PRL) from pituitary lactotrophs is rhythmic, with two surges/day. This rhythm can also be triggered by bolus injection of oxytocin (OT). We describe a mathematical model for the initiation, maintenance, and termination of the OT-induced PRL rhythm. In our model, the mechanism for this circadian rhythm is mutual interaction between lactotrophs and neuroendocrine dopamine (DA) neurons. This rhythm is, under normal lighting conditions, entrained by the suprachiasmatic nucleus (SCN) but persists in the absence of input from the SCN. We postulate that OT injection triggers the rhythm by activating a population of bistable hypothalamic neurons that innervate and inhibit DA neurons. The bistable nature of these neurons allows them to act as a memory device, maintaining the rhythm long after OT has been cleared from the blood. The mechanism for this memory device and the arguments supporting it are detailed with computer simulations. Finally, we consider potential targets for a rhythm-terminating factor and make predictions that may be used to determine which mechanism is operational in terminating the OT- or mating-induced PRL rhythm.


Effect of Gelatin-Stabilized Copper Nanoparticles on Catalytic Reduction of Methylene Blue.
The synthesis of copper nanoparticles was carried out with gelatin as a stabilizer by reducing CuSO4.5H2O ions using hydrazine. Ascorbic acid and aqueous NaOH were also used as an antioxidant and pH controller, respectively. The effects of NaOH, hydrazine, and concentration of gelatin as stabilizer were studied. The synthesized copper nanoparticles were characterized by UV-vis spectroscopy, XRD, zeta potential measurements, FTIR, EDX, FESEM, and TEM. The formation of CuNPs@Gelatin is initially confirmed by UV-vis spectroscopic analysis with the characteristic band at 583 nm. XRD and TEM reports revealed that CuNPs@Gelatin (0.75 wt.%) is highly crystalline and spherical in shape with optimum average size of 4.21 ± 0.95 nm. FTIR studies indicated the presence of amide group on the surface of the CuNPs indicating the stability of CuNPs which is further supported by zeta potential measurements with the negative optimum value of -37.90 ± 0.6 mV. The CuNPs@G4 showed a good catalytic activity against methylene blue (MB) reduction using NaBH4 as a reducing agent in an aqueous solution. The best enhanced properties of CuNPs@G4 were found for the 0.75 wt.% gelatin concentration. Thermodynamic parameters (ΔH and ΔS) indicate that under the studied temperature, the reduction of MB by CuNPs@G4 is not feasible and had endothermic in nature.


Toward Large-Scale Continuous EDA: A Random Matrix Theory Perspective.
Estimations of distribution algorithms (EDAs) are a major branch of evolutionary algorithms (EA) with some unique advantages in principle. They are able to take advantage of correlation structure to drive the search more efficiently, and they are able to provide insights about the structure of the search space. However, model building in high dimensions is extremely challenging, and as a result existing EDAs may become less attractive in large-scale problems because of the associated large computational requirements. Large-scale continuous global optimisation is key to many modern-day real-world problems. Scaling up EAs to large-scale problems has become one of the biggest challenges of the field. This paper pins down some fundamental roots of the problem and makes a start at developing a new and generic framework to yield effective and efficient EDA-type algorithms for large-scale continuous global optimisation problems. Our concept is to introduce an ensemble of random projections to low dimensions of the set of fittest search points as a basis for developing a new and generic divide-and-conquer methodology. Our ideas are rooted in the theory of random projections developed in theoretical computer science, and in developing and analysing our framework we exploit some recent results in nonasymptotic random matrix theory.


Linking community profiles, gene expression and N-removal in anammox bioreactors treating municipal anaerobic digestion reject water.
Anaerobic ammonium oxidation (anammox) requires 60% less oxygen and no external organic carbon compared to conventional biological nitrogen removal (BNR). Nevertheless, full-scale installations of anammox are uncommon, primarily owing to the lack of well-established process monitoring and control strategies that result in stable anammox reactor performance. The overarching goal of this study was to develop and apply molecular biomarkers that link microbial community structure and activity to anammox process performance in a bioreactor fed with actual anaerobic digestion centrate from a full-scale operational wastewater treatment facility. Over long-term operation, Candidatus "Brocadia sp. 40" emerged as the dominant anammox population present in the reactor. There was good correspondence between reactor nitrogen removal performance and anammox bacterial concentrations. During the period of reactor operation, there was also a marked shift in biomass morphology from discrete cells to granular aggregates, which was paralleled by a shift also to more stable nitrogen removal and the succession and establishment of bacteria related to the Chlorobi/Bacteroidetes superfamily. Based on batch assays, hydrazine oxidoreductase (hzo) expression and concentrations of the 16S-23S rRNA intergenic spacer region (ISR) were good quantitative biomarkers of oxygen- and nitrite-mediated inhibition. When applied to a continuous anammox reactor, both molecular biomarkers show promise as monitoring tools for "predicting" reactor performance.


[A case study of the Community Health Agents Program in Uruburetama, Ceará (Brazil)].
The program of community health agents institutionalized by the Department of Health in 1991 was the first strategy of its kind on national scale to bring attention to improving health in Brazil. In Ceará, this program exists since 1986. The aim of this study is to identify and discuss the practices of health agents within the community. Interactions between a specific group of 19 infants in their first year of life from August 2004 to August 2005 and community health agents were followed and examined through individual interviews, focus groups, and field observations to gain a greater understanding of the common practices and the obstacles faced by these health agents. The study took place in Uruburetama, Ceará. Fifteen agents were the main source of information of this study. By looking at the analytical category of the health agent as an educator, it was empirically identified that they have an insufficient knowledge of the root causes and consequences of the social-economic determinants; and that the health practices themes and information are taken out of context of reality. This study points out the need to reinforce the training of health agents and, more importantly, strengthen their action as health educators in the community.


Estimating the onset of spring from a complex phenology database: trade-offs across geographic scales.
Phenology is an important indicator of ecological response to climate change. Yet, phenological responses are highly variable among species and biogeographic regions. Recent monitoring initiatives have generated large phenological datasets comprised of observations from both professionals and volunteers. Because the observation frequency is often variable, there is uncertainty associated with estimating the timing of phenological activity. "Status monitoring" is an approach that focuses on recording observations throughout the full development of life cycle stages rather than only first dates in order to quantify uncertainty in generating phenological metrics, such as onset dates or duration. However, methods for using status data and calculating phenological metrics are not standardized. To understand how data selection criteria affect onset estimates of springtime leaf-out, we used status-based monitoring data curated by the USA National Phenology Network for 11 deciduous tree species in the eastern USA between 2009 and 2013. We asked, (1) How are estimates of the date of leaf-out onset, at the site and regional levels, influenced by different data selection criteria and methods for calculating onset, and (2) at the regional level, how does the timing of leaf-out relate to springtime minimum temperatures across latitudes and species? Results indicate that, to answer research questions at site to landscape levels, data users may need to apply more restrictive data selection criteria to increase confidence in calculating phenological metrics. However, when answering questions at the regional level, such as when investigating spatiotemporal patterns across a latitudinal gradient, there is low risk of acquiring erroneous results by maximizing sample size when using status-derived phenological data.


Anchoring mechanisms for LFA-3 cell adhesion glycoprotein at membrane surface.
The manner in which a membrane protein is anchored to the lipid bilayer may have a profound influence on its function. Most cell surface membrane proteins are anchored by a membrane-spanning segment(s) of the polypeptide chain, but another type of anchor has been described for several proteins: a phosphatidyl inositol glycan moiety, attached to the protein C terminus. This type of linkage has been identified on membrane proteins involved in adhesion and transmembrane signalling and could be important in the execution of these functions. We report here that an immunologically important adhesion glycoprotein, lymphocyte function-associated antigen 3 (LFA-3), can be anchored to the membrane by both types of mechanism. These two distinct cell-surface forms of LFA-3 are derived from different biosynthetic precursors. The existence of a phosphatidyl-inositol-linked and a transmembrane anchored form of LFA-3 has important implications for adhesion and transmembrane signalling by LFA-3.


Boundary spanning by nurse managers: effects of managers' characteristics and scope of responsibility on teamwork.
Increasing role complexity has intensified the work of managers in supporting healthcare teams. This study examined the influence of front-line managers' characteristics and scope of responsibility on teamwork. Scope of responsibility considers the breadth of the manager's role. A descriptive, correlational design was used to collect cross-sectional survey and administrative data in four acute care hospitals. A convenience sample of 754 staff completed the Relational Coordination Scale as a measure of teamwork that focuses on the quality of communication and relationships. Nurses (73.9%), allied health professionals (14.7%) and unregulated staff (11.7%) worked in 54 clinical areas, clustered under 30 front-line managers. Data were analyzed using hierarchical linear modelling. Leadership practices, clinical support roles and compressed operational hours had positive effects on teamwork. Numbers of non-direct report staff and areas assigned had negative effects on teamwork. Teamwork did not vary by span, managerial experience, worked hours, occupational diversity or proportion of full-time employees. Large, acute care teaching hospitals can enable managers to foster teamwork by enhancing managers' leadership practices, redesigning the flow or reporting structure for non-direct reports, optimizing managerial hours relative to operational hours, allocating clinical support roles, reducing number of areas assigned and, potentially, introducing co-manager models.


The Studer orthotopic neobladder: long-term (more than 10 years) functional outcomes, urodynamic features, and complications.
Radical cystectomy and urinary diversion are the standard treatment for invasive bladder cancer. We analyzed the long-term (>10 years postoperatively) functional outcomes, complications, and urodynamic findings in a single center series of patients who underwent cystectomy and a Studer ileal neobladder substitution. A retrospective chart review of 108 Studer pouches constructed during 1990 and 2011 was performed. Data were analyzed in terms of long-term (>10 years) outcomes. Complications, incontinence, voiding difficulties, upper urinary tract changes, overall satisfaction, and urodynamic findings of the reservoir were obtained. We evaluated 19 out of 50 patients who had lived for over 10 years postoperatively. Another 31 patients were not traced: 7 patients died following recurrence, 15 died due to exacerbation of a comorbidity, and 9 patients were lost to follow-up. Concerning complications, 6 patients had an atrophied kidney, 5 patients had moderate hydronephrosis, 5 patients had chronic recurrence of pylelonephritis, and 2 patients had voiding difficulty because of bladder neck stricture due to clean intermittent catheterization. One patient underwent an operation due to intestinal obstruction. Seven patients had incontinence; all 7 patients showed intermittently at night and 2 patients even in waking hours. Maximum bladder capacity was 484.1±119.2 mL, maximum flow rate was 13.6±9.7 mL/sec, and post-void residual urine volume was 146.8±82.7 mL. Long-term outcomes with the Studer orthotopic ileal neobladder have an acceptable complication rate and good functional results. However, potential adverse outcomes such as renal deterioration, dysfunctional voiding should also be considered.


New strategies in colorectal cancer: biomarkers of response to epidermal growth factor receptor monoclonal antibodies and potential therapeutic targets in phosphoinositide 3-kinase and mitogen-activated protein kinase pathways.
Initial experience with the epidermal growth factor receptor monoclonal antibodies (EGFR MoAb) in unselected patients with metastatic colorectal cancer (mCRC) showed that most of the treated patients did not derive therapeutic benefit. This outcome has driven the search for biomarkers for this population. Recent advances have further shown the heterogeneous nature of this disease with multiple interlinked pathways being implicated. Two such pathways downstream to the EGFR, mitogen-activated protein kinase (MAPK) and (phosphoinositide 3-kinase) PI3K, have gained increasing attention and become targets for development of novel biomarkers and therapeutic agents. Here, we highlight recent progress.


Nursing Competencies for Multiple Modalities of Connected Health Technologies.
An overview of the rapid and diverse number developments in health information technologies (HIT) in recent years are described in this chapter and the move towards more integrated and connected health is described. The evolution of HIT is described as it has increased in complexity, diversity, connectivity, and more recently, the move towards multiple modalities. Examples of developments in various settings are represented from clinical settings, at home, and in low-resource settings. The implications of the move towards multiple modalities for nursing competencies and the move towards personalized and connected health are discussed, highlighting important areas for consideration and development in the future.


Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling.
Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK-SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre-mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76-dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.


Conscientiousness in the classroom: a process explanation.
Although the research literature has established that Conscientiousness predicts task performance across a variety of achievement contexts (e.g., ; ), comparatively less is known about the processes that underlie these relations. To the latter end, the current research examines effortful strategies and achievement goals as mediating factors that might explain why people with higher levels of Conscientiousness are predicted to reach higher levels of academic performance. In a longitudinal study, 347 college students completed measures of personality and achievement goals at the beginning of the class, followed by measures of effortful strategies multiple times throughout the semester. Results support the hypothesis that effortful strategies mediate the association between Conscientiousness and academic performance. Moreover, the statistical effects of Conscientiousness were generally independent of achievement goals, but a small portion of the effect was mediated through approach, not avoidance, achievement goals. These results highlight the importance of examining mediating processes between personality and outcomes, and in the case of Conscientiousness, our results suggest that effortful strategies might serve as a useful target for performance-enhancing interventions.


Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice.
Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the alpha-synuclein (alphaSYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of alphaSYN protein fibrils. Moreover, alphaSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]alphaSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)-[A30P]alphaSYN transgenic mice further developed age-dependent, specific neuritic/terminal alphaSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-[A30P]alphaSYN mice. Thus, alphaSYN becomes phosphorylated in distinct parts of the brain in this alpha-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.


Horizontal propagation of visual activity in the synaptic integration field of area 17 neurons.
The receptive field of a visual neuron is classically defined as the region of space (or retina) where a visual stimulus evokes a change in its firing activity. At the cortical level, a challenging issue concerns the roles of feedforward, local recurrent, intracortical, and cortico-cortical feedback connectivity in receptive field properties. Intracellular recordings in cat area 17 showed that the visually evoked synaptic integration field extends over a much larger area than that established on the basis of spike activity. Synaptic depolarizing responses to stimuli flashed at increasing distances from the center of the receptive field decreased in strength, whereas their onset latency increased. These findings suggest that subthreshold responses in the unresponsive region surrounding the classical discharge field result from the integration of visual activation waves spread by slowly conducting horizontal axons within primary visual cortex.


Comparative transcriptome analysis of Arabidopsis thaliana infested by diamond back moth (Plutella xylostella) larvae reveals signatures of stress response, secondary metabolism, and signalling.
Plants are exposed to attack from a large variety of herbivores. Feeding insects can induce substantial changes of the host plant transcriptome. Arabidopsis thaliana has been established as a relevant system for the discovery of genes associated with response to herbivory, including genes for specialized (i.e. secondary) metabolism as well as genes involved in plant-insect defence signalling. Using a 70-mer oligonucleotide microarray covering 26,090 gene-specific elements, we monitored changes of the Arabidopsis leaf transcriptome in response to feeding by diamond back moth (DBM; Plutella xylostella) larvae. Analysis of samples from a time course of one hour to 24 hours following onset of DBM feeding revealed almost three thousand (2,881) array elements (including 2,671 genes with AGI annotations) that were differentially expressed (>2-fold; p[t-test] < 0.05) of which 1,686 also changed more than twofold in expression between at least two time points of the time course with p(ANOVA) < 0.05. While the majority of these transcripts were up-regulated within 8 h upon onset of insect feeding relative to untreated controls, cluster analysis identified several distinct temporal patterns of transcriptome changes. Many of the DBM-induced genes fall into ontology groups annotated as stress response, secondary metabolism and signalling. Among DBM-induced genes associated with plant signal molecules or phytohormones, genes associated with octadecanoid signalling were clearly overrepresented. We identified a substantial number of differentially expressed genes associated with signal transduction in response to DBM feeding, and we compared there expression profiles with those of previously reported transcriptome responses induced by other insect herbivores, specifically Pieris rapae, Frankliniella occidentalis, Bemisia tabaci,Myzus persicae, and Brevicoryne brassicae. Arabidopsis responds to feeding DBM larvae with a drastic reprogramming of the transcriptome, which has considerable overlap with the response induced by other insect herbivores. Based on a meta-analysis of microarray data we identified groups of transcription factors that are either affected by multiple forms of biotic or abiotic stress including DBM feeding or, alternatively, were responsive to DBM herbivory but not to most other forms of stress.


Health alliance for prudent prescribing and yield of antibiotics in a patient-centred perspective (HAPPY PATIENT): a before-and-after intervention and implementation study protocol.
Excessive and inappropriate use of antibiotics is the most important driver of antimicrobial resistance. The aim of the HAPPY PATIENT project is to evaluate the adaptation of European Union (EU) recommendations on the prudent use of antimicrobials in human health by evaluating the impact of a multifaceted intervention targeting different categories of healthcare professionals (HCPs) on common community-acquired infectious diseases, especially respiratory and urinary tract infections. HAPPY PATIENT was initiated in January 2021 and is planned to end in December 2023. The partners of this project include 15 organizations from 9 countries. Diverse HCPs (doctors, nurses, pharmacists, and pharmacy technicians) will be audited by the Audit Project Odense (APO) method before and after an intervention in four different settings: general practice, out of hours services, nursing homes and community pharmacies in four high antibiotic prescribing countries (France, Poland, Greece, and Spain) and one low prescribing country (Lithuania). About 25 individuals from each professional group will be recruited in each country, who will register at least 25 patients with community-acquired infections during each audit period. Shortly before the second registration participants will undertake a multifaceted intervention and will receive the results from the first registration to allow the identification of possible quality problems. At these meetings participants will receive training courses on enhancement of communication skills, dissemination of clinical guidelines with recommendations for diagnosis and treatment, posters for the waiting rooms, and leaflets for patients. The results of the second registration will be compared with those obtained in the first audit. HAPPY PATIENT is an EU-funded project aimed at contributing to the battle against antibiotic resistance through improvement of the quality of management of common community-acquired infections based on interventions by different types of HCPs. It is hypothesized that the use of multifaceted strategies combining active intervention will be effective in reducing inappropriate prescribing and dispensing of antibiotics. EU Health programmes project database https://webgate.ec.europa.eu/chafea_pdb/health/projects/900024/summary ; date of registration: 1 January 2021.


Susceptibility of Candida albicans and Enterococcus faecalis to Chitosan, Chlorhexidine gluconate and their combination in vitro.
The aim of the present study was to analyse the sustain release of Chlorhexidine with Chitosan and to investigate the antimicrobial activity of 2% Chlorhexidine gel, 2% Chitosan gel and their combination against Candida albicans and Enterococcus faecalis. Sustain release of Chlorhexidine with Chitosan was determined using UV spectrophotometer. Then the inoculae of these organisms were used to make the lawn culture on sabouraud's dextrose agar and blood agar plates. Wells were prepared in these lawn cultures and filled with 2% Chlorhexidine gel, 2% Chitosan gel and their combination. The agar plates were incubated overnight at 37 degrees C and the zone of inhibition was examined after 48 h. Release of Chlorhexidine with Chitosan was better than plain Chlorhexidine release. Combination of Chlorhexidine and Chitosan showed maximum inhibitory zone for C. albicans (25.2 mm) and E. faecalis (26.0 mm). Plain Chlorhexidine gel showed intermediate inhibitory zone for C. albicans (20.6 mm) and E. faecalis (21.4 mm) and plain Chitosan gel showed minimum inhibitory zone for C. albicans (16.6 mm) and E. faecalis (11.0 mm). Carbopol which served as control did not have any antimicrobial effect. The present study suggests that 2% Chlorhexidine gel in combination with 2% Chitosan gel has the highest antimicrobial effect against C. albicans and E. faecalis compared with 2% Chlorhexidine gel or 2% Chitosan gel alone.


[18F]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus.
2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [18F]FDG uptake in adipose tissue (AT). This study consisted of an in vivo clinical part and an ex vivo mechanistic part. In the clinical part, [18F]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54-66] years, HbA1c [6.3 ± 0.4 %], HOMA-IR 5.1[3.1-8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients were ex vivo incubated with [18F]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68+ macrophage infiltration and GLUT4 protein expression in AT. In vivo VAT [18F]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = - 0.32, p = 0.034), and positively related to adiponectin plasma levels (r = 0.43, p = 0.003). Ex vivo [18F]FDG uptake in VAT was not related to CD68+ macrophage infiltration, and IL-1ß and IL-6 mRNA expression levels. Ex vivo VAT [18F]FDG uptake was positively related to GLUT4 (r = 0.83, p = 0.042), inversely to GLUT3 (r = - 0.83, p = 0.042) and not related to GLUT1 mRNA expression levels. In vivo [18F]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR. Ex vivo [18F]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [18F]FDG uptake as a marker for AT inflammation.


Regulation of epithelial-mesenchymal transition in breast cancer cells by cell contact and adhesion.
Epithelial-mesenchymal transition (EMT) is a physiological program that is activated during cancer cell invasion and metastasis. We show here that EMT-related processes are linked to a broad and conserved program of transcriptional alterations that are influenced by cell contact and adhesion. Using cultured human breast cancer and mouse mammary epithelial cells, we find that reduced cell density, conditions under which cell contact is reduced, leads to reduced expression of genes associated with mammary epithelial cell differentiation and increased expression of genes associated with breast cancer. We further find that treatment of cells with matrix metalloproteinase-3 (MMP-3), an inducer of EMT, interrupts a defined subset of cell contact-regulated genes, including genes encoding a variety of RNA splicing proteins known to regulate the expression of Rac1b, an activated splice isoform of Rac1 known to be a key mediator of MMP-3-induced EMT in breast, lung, and pancreas. These results provide new insights into how MMPs act in cancer progression and how loss of cell-cell interactions is a key step in the earliest stages of cancer development.


Dyslexics' faster decay of implicit memory for sounds and words is manifested in their shorter neural adaptation.
Dyslexia is a prevalent reading disability whose underlying mechanisms are still disputed. We studied the neural mechanisms underlying dyslexia using a simple frequency-discrimination task. Though participants were asked to compare the two tones in each trial, implicit memory of previous trials affected their responses. We hypothesized that implicit memory decays faster among dyslexics. We tested this by increasing the temporal intervals between consecutive trials, and by measuring the behavioral impact and ERP responses from the auditory cortex. Dyslexics showed a faster decay of implicit memory effects on both measures, with similar time constants. Finally, faster decay of implicit memory also characterized the impact of sound regularities in benefitting dyslexics' oral reading rate. Their benefit decreased faster as a function of the time interval from the previous reading of the same non-word. We propose that dyslexics' shorter neural adaptation paradoxically accounts for their longer reading times, since it reduces their temporal window of integration of past stimuli, resulting in noisier and less reliable predictions for both simple and complex stimuli. Less reliable predictions limit their acquisition of reading expertise.


Differential expression of neuregulin-1 isoforms and downregulation of erbin are associated with Erb B2 receptor activation in diabetic peripheral neuropathy.
Aberrant neuron/glia interactions can contribute to a variety of neurodegenerative diseases and we have previously demonstrated that enhanced activation of Erb B2, which is a member of the epidermal growth factor receptor (EGFR) family, can contribute to the development of diabetic peripheral neuropathy (DPN). In peripheral nerves, Erb B receptors are activated by various members of the neuregulin-1 (NRG1) family including NRG1 Type I, NRG1 Type II and NRG1 Type III to regulate Schwann cell (SC) growth, migration, differentiation and dedifferentiation. Alternatively, Erb B2 activity can be negatively regulated by association with the Erb B2-interacting protein, erbin. Since the effect of diabetes on the expression of NRG1 isoforms and erbin in peripheral nerve are unknown, the current study determined whether changes in NRG1 isoforms and erbin may be associated with altered Erb B2 signaling in DPN. Swiss Webster mice were rendered diabetic with streptozotocin (STZ) and after 12 weeks of diabetes, treated with erlotinib, an inhibitor of Erb B2 activation. Inhibition of Erb B2 signaling partially reversed several pathophysiologic aspects of DPN including a pronounced sensory hypoalgesia, nerve conduction velocity deficits and the decrease in epidermal nerve fiber innervation. We also observed a decrease of NRG1 Type III but an increase of NRG1 Type I level in diabetic sural nerves at early stage of diabetes. With disease progression, we detected reduced erbin expression and enhanced MAPK pathway activity in diabetic mice. Inhibition of Erb B2 receptor suppressed MAPK pathway activity in treated-diabetic sural nerves. These results support that hyperglycemia may impair NRG1/Erb B2 signaling by disrupting the balance between NRG1 isoforms, decreasing the expression of erbin and correspondingly activating the MAPK pathway. Together, imbalanced NRG1 isoforms and downregulated erbin may contribute to the dysregulation of Erb B2 signaling in the development of DPN.


Intrinsic constraint of asymmetry acting as a control parameter on rapid, rhythmic bimanual coordination: a study of professional drummers and nondrummers.
Expert musicians show experience-dependent reduced asymmetry in the structure of motor-related brain areas and in the maximum tapping frequency between the hands. Therefore we hypothesized that a reduced hand-skill asymmetry is strongly related to rapid and rhythmical bimanual coordination and developed a dynamical model including a symmetry-breaking parameter Δω, for human bimanual coordination. We conducted unimanual and bimanual drumming experiments to test the following model predictions. 1) The asymmetry in the maximum tapping frequency is more pronounced in nondrummers than that in drummers. If so, 2) a larger number of phase wanderings (i.e., succession of taps by the same hand), 3) larger SD of the relative phase between the hands (SD ), and 4) larger deviation of mean relative phase (mean ) from 180° would be observed in nondrummers than that in professional drummers during antiphase bimanual drumming at the maximum speed. In a unimanual tapping task, the asymmetry in maximum tapping frequency of nondrummers was more pronounced than that of professional drummers. In a bimanual coordination task, phase wanderings were observed only in nondrummers and SD of the nondrummers is significantly larger than that of professional drummers. On the other hand, there was no significant difference between the mean of the two groups. All these observations were successfully reproduced by changing Δω, which corresponded to the asymmetry in the maximum tapping frequency. These results support the hypothesis indicating that the prominent bimanual coordination pattern emerges spontaneously after a nonspecific change in Δω or symmetry restoration of the nonlinear dynamical systems.


High- and Low-Load Resistance Training: Interpretation and Practical Application of Current Research Findings.
Our current state of knowledge regarding the load (lighter or heavier) lifted in resistance training programmes that will result in 'optimal' strength and hypertrophic adaptations is unclear. Despite this, position stands and recommendations are made based on, we propose, limited evidence to lift heavier weights. Here we discuss the state of evidence on the impact of load and how it, as a single variable, stimulates adaptations to take place and whether evidence for recommending heavier loads is available, well-defined, currently correctly interpreted or has been overlooked. Areas of discussion include electromyography amplitude, in vivo and in vitro methods of measuring hypertrophy, and motor schema and skill acquisition. The present piece clarifies to trainers and trainees the impact of these variables by discussing interpretation of synchronous and sequential motor unit recruitment and revisiting the size principle, poor agreement between whole-muscle cross-sectional area (CSA) and biopsy-determined changes in myofibril CSA, and neural adaptations around task specificity. Our opinion is that the practical implications of being able to self-select external load include reducing the need for specific facility memberships, motivating older persons or those who might be less confident using heavy loads, and allowing people to undertake home- or field-based resistance training intervention strategies that might ultimately improve exercise adherence.


Realizing a desired family size: when should couples start?
Until what age can couples wait to start a family without compromising their chances of realizing the desired number of children? The latest female age at which a couple should start trying to become pregnant strongly depends on the importance attached to achieving a desired family size and on whether or not IVF is an acceptable option in case no natural pregnancy occurs. It is well established that the treatment-independent and treatment-dependent chances of pregnancy decline with female age. However, research on the effect of age has focused on the chance of a first pregnancy and not on realizing more than one child. An established computer simulation model of fertility, updated with recent IVF success rates, was used to simulate a cohort of 10 000 couples in order to assess the chances of realizing a one-, two- or three-child family, for different female ages at which the couple starts trying to conceive. The model uses treatment-independent pregnancy chances and pregnancy chances after IVF/ICSI. In order to focus the discussion, we single out three levels of importance that couples could attach to realizing a desired family size: (i) Very important (equated with aiming for at least a 90% success chance). (ii) Important but not at all costs (equated with a 75% success chance) (iii) Good to have children, but a life without children is also fine (equated with a 50% success chance). In order to have a chance of at least 90% to realize a one-child family, couples should start trying to conceive when the female partner is 35 years of age or younger, in case IVF is an acceptable option. For two children, the latest starting age is 31 years, and for three children 28 years. Without IVF, couples should start no later than age 32 years for a one-child family, at 27 years for a two-child family, and at 23 years for three children. When couples accept 75% or lower chances of family completion, they can start 4-11 years later. The results appeared to be robust for plausible changes in model assumptions. Our conclusions would have been more persuasive if derived directly from large-scale prospective studies. An evidence-based simulation study (as we did) is the next best option. We recommend that the simulations should be updated every 5-10 years with new evidence because, owing to improvements in IVF technology, the assumptions on IVF success chances in particular run the risk of becoming outdated. Information on the chance of family completion at different starting ages is important for prospective parents in planning their family, for preconception counselling, for inclusion in educational courses in human biology, and for increasing public awareness on human reproductive possibilities and limitations. No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.


Impact of child and informant gender on parent and teacher ratings of attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) rating scales typically provide normative tables arranged according to child age, child gender, and type of informant, which facilitates addressing the fifth edition of the Diagnostic and Statistical Manual of Mental Health Disorders developmental deviance requirement for diagnosing ADHD. Missing, however, is any consideration of the gender of the informant. The purpose of this paper was to conduct an exploratory examination of informant gender via secondary analyses of a large data set used to standardize the ADHD Rating Scale-5. Two (informant gender) by two (child gender) ANOVAs were conducted separately for parents and teachers using inattention (IN) symptoms, hyperactive-impulsive (HI) symptoms, the total impairment score related to IN, and the total impairment score for HI as dependent variables. Results showed that female parents rated male children significantly higher on both IN symptoms and impairment related to IN than did male parents. Female teacher ratings were also significantly higher than male teacher ratings for male children in terms of HI symptoms and with respect to impairment ratings related to both HI and IN. A significantly higher percentage of female parents (7.7%) identified male children as being at risk for ADHD relative to male parents (4.1%). This same pattern emerged for female teachers (11.9%) versus male teachers (5.3%). Such results suggest that informant gender may play a clinically meaningful role in assessing ADHD in children and adolescents, which is consistent with the developmental literature addressing gender stereotypes in children. Future research is needed to determine whether similar informant gender differences exist in other rating scale measures of ADHD. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm.
Ciprofloxacin use may be associated with adverse aortic events. However, the mechanism underlying the effect of ciprofloxacin on the progression of thoracic aortic aneurysm (TAA) is not well understood. Using an in vitro microphysiological model, we treated human aortic smooth muscle cells (HASMCs) derived from patients with bicuspid aortic valve- or tricuspid aortic valve-associated (BAV- or TAV-associated) TAAs with ciprofloxacin. TAA C57BL/6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time PCR, Western blotting, and RNA sequencing showed that ciprofloxacin exposure was associated with a downregulated contractile phenotype, an upregulated inflammatory reaction, and extracellular matrix (ECM) degradation in the normal HASMCs derived from the nondiseased aorta. Ciprofloxacin induced mitochondrial dysfunction in the HASMCs and further increased apoptosis by activating the ERK1/2 and P38 mitogen-activated protein kinase pathways. These adverse effects appeared to be more severe in the HASMCs derived from BAV- and TAV-associated TAAs than in the normal HASMCs when the ciprofloxacin concentration exceeded 100 μg/mL. In the aortic walls of the TAA-induced mice, ECM degradation and apoptosis were aggravated after ciprofloxacin exposure. Therefore, ciprofloxacin should be used with caution in patients with BAV- or TAV-associated TAAs.


Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer.
We have investigated the DNA substrate specificity of BACH1 (BRCA1-associated C-terminal helicase). The importance of various DNA structural elements for efficient unwinding by purified recombinant BACH1 helicase was examined. The results indicated that BACH1 preferentially binds and unwinds a forked duplex substrate compared with a duplex flanked by only one single-stranded DNA (ssDNA) tail. In support of its DNA substrate preference, helicase sequestration studies revealed that BACH1 can be preferentially trapped by forked duplex molecules. BACH1 helicase requires a minimal 5 ' ssDNA tail of 15 nucleotides for unwinding of conventional duplex DNA substrates; however, the enzyme is able to catalytically release the third strand of the homologous recombination intermediate D-loop structure irrespective of DNA tail status. In contrast, BACH1 completely fails to unwind a synthetic Holliday junction structure. Moreover, BACH1 requires nucleic acid continuity in the 5 ' ssDNA tail of the forked duplex substrate within six nucleotides of the ssDNA-dsDNA junction to initiate efficiently DNA unwinding. These studies provide the first detailed information on the DNA substrate specificity of BACH1 helicase and provide insight to the types of DNA structures the enzyme is likely to act upon to perform its functions in DNA repair or recombination.


Introduction to the AFDC program. Aid to Families with Dependent Children.
This journal issue discusses the policy challenges of helping parents move from welfare to work. As a foundation, this introductory article explains the federal-state program of cash assistance called Aid to Families with Dependent Children (AFDC), to which the term welfare refers in most of these articles. While a number of other social programs are sometimes included under the umbrella of welfare-such as the Supplemental Security Income program for the disabled, food stamps, and Medicaid-the program that has drawn the most public scrutiny and negative attention, and the centerpiece of the 1996 welfare reform legislation, is AFDC. This article explains the basic structure of the AFDC program, including eligibility criteria and benefits; discusses the characteristics of families that have received AFDC; describes trends in the program's size and cost from the 1970s to 1996; and indicates the major ways in which the block grant established in the 1996 welfare reform legislation compares to the AFDC program that it replaced.


Examining the association of smoking with work productivity and associated costs in Japan.
Smoking is associated with significant health and economic burden globally, including an increased risk of many leading causes of mortality and significant impairments in work productivity. This burden is attenuated by successful tobacco cessation, including reduced risk of disease and improved productivity. The current study aimed to show the benefits of smoking cessation for workplace productivity and decreased costs associated with loss of work impairment. The data source was the 2011 Japan National Health and Wellness Survey (n = 30,000). Respondents aged 20-64 were used in the analyses (n = 23,738) and were categorized into: current smokers, former smokers, and never smokers. Generalized linear models controlling for demographics and health characteristics examined the relationship of smoking status with the Work Productivity and Activity Impairment questionnaire (WPAI-GH) endpoints, as well as estimated indirect costs. Current smokers reported the greatest overall work impairment, including absenteeism (i.e. work time missed) and presenteeism (i.e. impairment while at work); however, after controlling for covariates, there were no significant differences between former smokers and never smokers on overall work impairment. Current smokers and former smokers had greater activity impairment (i.e. impairment in daily activities) than never smokers. Current smokers reported the highest indirect costs (i.e. costs associated with work impairment); however, after controlling for covariates, there were no significant differences between former smokers and never smokers on indirect costs. Smoking exerts a large health and economic burden; however, smoking cessation attenuates this burden. The current study provides important further evidence of this association, with former smokers appearing statistically indistinguishable from never smokers in terms of work productivity loss and associated indirect costs among a large representative sample of Japanese workers. This report highlights the workplace benefits of smoking cessation across productivity markers and cost-savings.


Vertical T cell immunodominance and epitope entropy determine HIV-1 escape.
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell-mediated in vivo control of HIV-1. Primary HIV-1-specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or "vertical" immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.


Metabolic Network-Based Identification and Prioritization of Anticancer Targets Based on Expression Data in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with high mortality worldwide. Unfortunately, the large heterogeneity of this disease makes it difficult to develop effective treatment strategies. Cellular network analyses have been employed to study heterogeneity in cancer, and to identify potential therapeutic targets. However, the existing approaches do not consider metabolic growth requirements, i.e., biological network functionality, to rank candidate targets while preventing toxicity to non-cancerous tissues. Here, we developed an algorithm to overcome these issues based on integration of gene expression data, genome-scale metabolic models, network controllability, and dispensability, as well as toxicity analysis. This method thus predicts and ranks potential anticancer non-toxic controlling metabolite and gene targets. Our algorithm encompasses both objective-driven and-independent tasks, and uses network topology to finally rank the predicted therapeutic targets. We employed this algorithm to the analysis of transcriptomic data for 50 HCC patients with both cancerous and non-cancerous samples. We identified several potential targets that would prevent cell growth, including 74 anticancer metabolites, and 3 gene targets (PRKACA, PGS1, and CRLS1). The predicted anticancer metabolites showed good agreement with existing FDA-approved cancer drugs, and the 3 genes were experimentally validated by performing experiments in HepG2 and Hep3B liver cancer cell lines. Our observations indicate that our novel approach successfully identifies therapeutic targets for effective treatment of cancer. This approach may also be applied to any cancer type that has tumor and non-tumor gene or protein expression data.


Surface plasmon resonance measurements of plasma antibody avidity during primary and secondary responses to anthrax protective antigen.
Establishment of humoral immunity against pathogens is dependent on events that occur in the germinal center and the subsequent induction of high-affinity neutralizing antibodies. Quantitative assays that allow monitoring of affinity maturation and duration of antibody responses can provide useful information regarding the efficacy of vaccines and adjuvants. Using an anthrax protective antigen (rPA) and alum model antigen/adjuvant system, we describe a methodology for monitoring antigen-specific serum antibody concentration and avidity by surface plasmon resonance during primary and secondary immune responses. Our analyses showed that following a priming dose in mice, rPA-specific antibody concentration and avidity increases over time and reaches a maximal response in about six weeks, but gradually declines in the absence of antigenic boost. Germinal center reactions were observed early with maximal development achieved during the primary response, which coincided with peak antibody avidity responses to primary immunization. Boosting with antigen resulted in a rapid increase in rPA-specific antibody concentration and five-fold increase in avidity, which was not dependent on sustained GC development. The described methodology couples surface plasmon resonance-based plasma avidity measurements with germinal center analysis and provides a novel way to monitor humoral responses that can play a role in facilitating vaccine and adjuvant development.


Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism.
The purposes of this study were to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 (dup[15]) and autism and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p<0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% of idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p<0.04). The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.


A spatio-temporal approach to short-term prediction of visceral leishmaniasis diagnoses in India.
The elimination programme for visceral leishmaniasis (VL) in India has seen great progress, with total cases decreasing by over 80% since 2010 and many blocks now reporting zero cases from year to year. Prompt diagnosis and treatment is critical to continue progress and avoid epidemics in the increasingly susceptible population. Short-term forecasts could be used to highlight anomalies in incidence and support health service logistics. The model which best fits the data is not necessarily most useful for prediction, yet little empirical work has been done to investigate the balance between fit and predictive performance. We developed statistical models of monthly VL case counts at block level. By evaluating a set of randomly-generated models, we found that fit and one-month-ahead prediction were strongly correlated and that rolling updates to model parameters as data accrued were not crucial for accurate prediction. The final model incorporated auto-regression over four months, spatial correlation between neighbouring blocks, and seasonality. Ninety-four percent of 10-90% prediction intervals from this model captured the observed count during a 24-month test period. Comparison of one-, three- and four-month-ahead predictions from the final model fit demonstrated that a longer time horizon yielded only a small sacrifice in predictive power for the vast majority of blocks. The model developed is informed by routinely-collected surveillance data as it accumulates, and predictions are sufficiently accurate and precise to be useful. Such forecasts could, for example, be used to guide stock requirements for rapid diagnostic tests and drugs. More comprehensive data on factors thought to influence geographic variation in VL burden could be incorporated, and might better explain the heterogeneity between blocks and improve uniformity of predictive performance. Integration of the approach in the management of the VL programme would be an important step to ensuring continued successful control.


Do brain responses to emotional images and cigarette cues differ? An fMRI study in smokers.
Chronic smoking is thought to cause changes in brain reward systems that result in overvaluation of cigarette-related stimuli and undervaluation of natural rewards. We tested the hypotheses that, in smokers, brain circuits involved in emotional processing: (i) would be more active during exposure to cigarette-related than neutral pictures; and (ii) would be less active to pleasant compared with cigarette-related pictures, suggesting a devaluation of intrinsically pleasant stimuli. We obtained whole-brain blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data from 35 smokers during the presentation of pleasant (erotica and romance), unpleasant (mutilations and sad), neutral, and cigarette-related pictures. Whole-brain analyses showed significantly larger BOLD responses during presentation of cigarette-related pictures relative to neutral ones within the secondary visual areas, the cingulate gyrus, the frontal gyrus, the dorsal striatum, and the left insula. BOLD responses to erotic pictures exceeded responses to cigarette-related pictures in all clusters except the insula. Within the left insula we observed larger BOLD responses to cigarette-related pictures than to all other picture categories. By including intrinsically pleasant and unpleasant pictures in addition to neutral ones, we were able to conclude that the presentation of cigarette-related pictures activates brain areas supporting emotional processes, but we did not find evidence of overall reduced activation of the brain reward systems in the presence of intrinsically pleasant stimuli.


Solamargine triggers cellular necrosis selectively in different types of human melanoma cancer cells through extrinsic lysosomal mitochondrial death pathway.
Previous reports showed that the Steroidal Glycoalkaloid Solamargine inhibited proliferation of non-melanoma skin cancer cells. However, Solamargine was not tested systematically on different types of melanoma cells and was not simultaneously tested on normal cells either. In this study we aimed to investigate the effect of Solamargine and the mechanism involved in inhibiting the growth of different types of melanoma cells. Solamargine effect was tested on normal cells and on another three melanoma cell lines. Vertical growth phase metastatic and primary melanoma cell lines WM239 and WM115, respectively and the radial growth phase benign melanoma cells WM35 were used. The half inhibitory concentration IC50 of Solamargine was determined using Alamarblue assay. The cellular and subcellular changes were assessed using light and Transmission Electron Microscope, respectively. The percentage of cells undergoing apoptosis and necrosis were measured using Flow cytometry. The different protein expression was detected and measured using western blotting. The efficacy of Solamargine was determined by performing the clonogenic assay. The data collected was analyzed statistically on the means of the triplicate of at least three independent repeated experiments using one-way ANOVA test for parametric data and Kruskal-Wallis for non-parametric data. Differences were considered significant when the P values were less than 0.05. Hereby, we demonstrate that Solamargine rapidly, selectively and effectively inhibited the growth of metastatic and primary melanoma cells WM239 and WM115 respectively, with minimum effect on normal and benign WM35 cells. Solamargine caused cellular necrosis to the two malignant melanoma cell lines (WM115, WM239), by rapid induction of lysosomal membrane permeabilization as confirmed by cathepsin B upregulation which triggered the extrinsic mitochondrial death pathway represented by the release of cytochrome c and upregulation of TNFR1. Solamargine disrupted the intrinsic apoptosis pathway as revealed by the down regulation of hILP/XIAP, resulting in caspase-3 cleavage, upregulation of Bcl-xL, and Bcl2, and down regulation of Apaf-1 and Bax in WM115 and WM239 cells only. Solamargine showed high efficacy in vitro particularly against the vertical growth phase melanoma cells. Our findings suggest that Solamargine is a promising anti-malignant melanoma drug which warrants further attention.


Newly-Developed Positron Emission Mammography (PEM) Device for the Detection of Small Breast Cancer.
Positron emission mammography (PEM) has higher detection sensitivity for breast cancer compared with whole-body positron emission tomography (PET) due to higher spatial resolution. We have developed a new PEM device with high resolution over a wide field of view. This PEM device comprises novel scintillation crystals, praseodymium-doped lutetium aluminum garnet (Pr:LuAG). In the present study, the clinical use of the newly developed PEM for the detection of small breast cancer was compared with that of the conventional PET-computed tomography (PET/CT). Eighty-two patients with breast cancer less than 20 mm (UICC T1) participated in this study, including 23 patients with T1a or T1b breast cancer (less than 10 mm). Histologically-proved lesions were examined by PET/CT and PEM on the same day after injection of [18F]fluoro-2-deoxy-2-fluoro-D-glucose ([18F]FDG), a marker of glycolytic activity. The newly developed PEM showed better sensitivity of cancer detection compared with PET/CT especially in case of the small T1a or T1b lesions. Moreover, when the conventional PET/CT and new PEM were combined, the detection sensitivity with [18F]FDG molecular imaging for T1 (N = 82) and T1a plus T1b breast cancer (N = 23) were 90% and 70%, respectively. The uptake of [18F]FDG was proportional to the histological malignancy of breast cancer. Using the newly-developed PEM with [18F]FDG, we are able to identify and characterize exactly the small breast tumors less than 10 mm in combination with the conventional PET/CT. These data indicate that PEM and PET/CT are synergic and complementary for the detection of small breast cancer.


HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome.
Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1-related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC.


FASTmC: A Suite of Predictive Models for Nonreference-Based Estimations of DNA Methylation.
We describe a suite of predictive models, coined FAST(m)C, for nonreference, cost-effective exploration and comparative analysis of context-specific DNA methylation levels. Accurate estimations of true DNA methylation levels can be obtained from as few as several thousand short-reads generated from whole-genome bisulfite sequencing. These models make high-resolution time course or developmental and large diversity studies practical regardless of species, genome size, and availability of a reference genome.


Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.


'Quality in, quality out', a stepwise approach to EBM for rare diseases promoted by MEN1.
Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2-3 per 100.000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrollment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.


Production and comparison of high surface area bamboo derived active carbons.
High surface area activated carbons have been produced from the natural biomaterial bamboo, using phosphoric acid as the activating agent. The effects of phosphoric acid impregnation ratio, activation temperature, heating rate on the carbon surface area, porosity and mass yield are presented. Three of these bamboo derived active carbons, surface areas 1337, 1628 and 2123m(2)/g were assessed for their ability to adsorb Acid Red 18 dye from aqueous solution; these results were compared with three conventional adsorbents: activated carbon F400, bone char and peat. Isotherm data were analysed using Langmuir, Freundlich, Redlich-Peterson and Langmuir-Freundlich isotherms. Different isotherms provided the best fit correlations to the adsorption experimental data but the Langmuir-Freundlich equation provided the best overall correlation of data. The adsorption capacities of two of the selected bamboo derived carbons were much greater than the capacities of the other three adsorbents.


Time-dependent influence of the somatostatin analogue octreotide on the proliferation of rat astrocytes and glioma cells.
The somatostatin receptor subtype sst2 was visualized by immunostaining on cultivated rat astrocytes and C6 rat glioma cells. Octreotide, a metabolically stable sst2 agonist reduced [3H]thymidine incorporation into DNA of both cell types dose-dependently only after short-time application (2-5 h), after prolonged incubation (> 12 h) no antiproliferative effect was measurable. We conclude that sst2 receptors may be desensitized. Thus, desensitization might hinder application of octreotide to reduce glial tumour growth.


Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.
Comparative effectiveness data pertaining to competing colorectal cancer (CRC) screening tests do not exist but are necessary to guide clinical decision making and policy. To perform a comparative synthesis of clinical outcomes studies evaluating the effects of competing tests on CRC-related mortality. Traditional and network meta-analyses. Two reviewers identified studies evaluating the effect of guaiac-based fecal occult blood testing (gFOBT), flexible sigmoidoscopy (FS), or colonoscopy on CRC-related mortality. gFOBT, FS, colonoscopy. Traditional meta-analysis was performed to produce pooled estimates of the effect of each modality on CRC mortality. Bayesian network meta-analysis (NMA) was performed to indirectly compare the effectiveness of screening modalities. Multiple sensitivity analyses were performed. Traditional meta-analysis revealed that, compared with no intervention, colonoscopy reduced CRC-related mortality by 57% (relative risk [RR] 0.43; 95% confidence interval [CI], 0.33-0.58), whereas FS reduced CRC-related mortality by 40% (RR 0.60; 95% CI, 0.45-0.78), and gFOBT reduced CRC-related mortality by 18% (RR 0.82; 95% CI, 0.76-0.88). NMA demonstrated nonsignificant trends favoring colonoscopy over FS (RR 0.71; 95% CI, 0.45-1.11) and FS over gFOBT (RR 0.74; 95% CI, 0.51-1.09) for reducing CRC-related deaths. NMA-based simulations, however, revealed that colonoscopy has a 94% probability of being the most effective test for reducing CRC mortality and a 99% probability of being most effective when the analysis is restricted to screening studies. Randomized trials and observational studies were combined within the same analysis. Clinical outcomes studies demonstrate that gFOBT, FS, and colonoscopy are all effective in reducing CRC-related mortality. Network meta-analysis suggests that colonoscopy is the most effective test.


Human Bone Progenitor Cells for Clinical Application: What Kind of Immune Reaction Does Fetal Xenograft Tissue Trigger in Immunocompetent Rats?
The potential of human fetal bone cells for successful bone regeneration has been shown in vivo. In particular, it has been demonstrated that the seeding of these cells in porous poly-(l-lactic acid)/β-tricalcium phosphate scaffolds improved the bone formation compared to cell-free scaffolds in skulls of rats. However, even if the outcome is an improvement of bone formation, a thorough analysis concerning any immune responses, due to the implantation of a xenograft tissue, is not known. As the immune response and skeletal system relationship may contribute to either the success or failure of an implant, we were interested in evaluating the presence of any immune cells and specific reactions of human fetal cells (also called human bone progenitor cells) once implanted in femoral condyles of rats. For this purpose, (1) cell-free scaffolds, (2) human bone progenitor cells, or (3) osteogenic human bone progenitor cells within scaffolds were implanted over 3, 7, 14 days, and 12 weeks. The key finding is that human bone progenitor cells and osteogenic human bone progenitor cells do not trigger any particular specific immune reactions in immunocompetent rats but are noted to delay some bone formation.


Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia.
Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P < 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.


A psycho-education intervention for parents of adolescents with eating disorders: a randomized controlled trial.
This study evaluated the efficacy of a 2-hour psycho-education session combined with bi-weekly telephone support in increasing parent/caregiver knowledge about eating disorders, increasing self-efficacy by empowering parents to support their child's recovery, and decreasing the impact of eating disorder symptoms on the family. The intervention was targeted at parents/caregivers whose child was waiting to be assessed for an eating disorder. Participants included 51 parents/caregivers and 36 youths. The brief intervention successfully increased parent/caregiver knowledge of the illness, feelings of self-efficacy, and help-seeking behaviors. These findings are clinically useful as waiting lists are common in Canada.


Bioengineered nisin A derivatives with enhanced activity against both Gram positive and Gram negative pathogens.
Nisin is a bacteriocin widely utilized in more than 50 countries as a safe and natural antibacterial food preservative. It is the most extensively studied bacteriocin, having undergone decades of bioengineering with a view to improving function and physicochemical properties. The discovery of novel nisin variants with enhanced activity against clinical and foodborne pathogens has recently been described. We screened a randomized bank of nisin A producers and identified a variant with a serine to glycine change at position 29 (S29G), with enhanced efficacy against S. aureus SA113. Using a site-saturation mutagenesis approach we generated three more derivatives (S29A, S29D and S29E) with enhanced activity against a range of Gram positive drug resistant clinical, veterinary and food pathogens. In addition, a number of the nisin S29 derivatives displayed superior antimicrobial activity to nisin A when assessed against a range of Gram negative food-associated pathogens, including E. coli, Salmonella enterica serovar Typhimurium and Cronobacter sakazakii. This is the first report of derivatives of nisin, or indeed any lantibiotic, with enhanced antimicrobial activity against both Gram positive and Gram negative bacteria.


Qualitative analysis using Raman spectroscopy and chemometrics: a comprehensive model system for narcotics analysis.
The rapid, on-site identification of illicit narcotics, such as cocaine, is hindered by the diverse nature of the samples, which can contain a large variety of materials in a wide concentration range. This sample variance has a very strong influence on the analytical methodologies that can be utilized and in general prevents the widespread use of quantitative analysis of illicit narcotics on a routine basis. Raman spectroscopy, coupled with chemometric methods, can be used for in situ qualitative and quantitative analysis of illicit narcotics; however, careful consideration must be given to dealing with the extensive variety of sample types. To assess the efficacy of combining Raman spectroscopy and chemometrics for the identification of a target analyte under real-world conditions, a large-scale model sample system (633 samples) using a target (acetaminophen) mixed with a wide variety of excipients was created. Materials that exhibit problematic factors such as fluorescence, variable Raman scattering intensities, and extensive peak overlap were included to challenge the efficacy of chemometric data preprocessing and classification methods. In contrast to spectral matching analyte identification approaches, we have taken a chemometric classification model-based approach to account for the wide variances in spectral data. The first derivative of the Raman spectra from the fingerprint region (750-1900 cm(-1)) yielded the best classifications. Using a robust segmented cross-validation method, correct classification rates of better than ∼90% could be attained with regression-based classification, compared to ∼35% for SIMCA. This study demonstrates that even with very high degrees of sample variance, as evidenced by dramatic changes in Raman spectra, it is possible to obtain reasonably reliable identification using a combination of Raman spectroscopy and chemometrics. The model sample set can now be used to validate more advanced chemometric or machine learning algorithms being developed for the identification of analytes such as illicit narcotics.