The effects of smoking and hypertensive disorders on fetal growth.
It is well known that smoking and pregnancy induced hypertension (PIH) are associated with decreased fetal growth. It has been reported that in preeclampsia the fetal growth deficit attributable to smoking is higher, which has been contradicted in other studies. We therefore evaluated the effects on fetal growth of early- and late onset PIH and chronic hypertension and how cigarette smoking modify these effects. We also quantified the proportion of small for gestational age (SGA) cases attributable to PIH, chronic hypertension, and smoking. Population-based study based on record of 215598 singleton pregnancies from the Medical Birth Registry of Norway. In severe preeclampsia, mild preeclampsia, transient hypertension, and normotension in term birth, odds ratios (ORs) of SGA in smokers compared with non-smokers were 1.4 (95% confidence interval 0.9, 2.2), 1.6 (1.3, 1.9), 2.3 (1.8, 3.1), and 2.0 (1.9, 2.1), respectively. For preterm births, corresponding ORs were 1.3 (0.9, 2.0), 1.8 (1.1, 3.0), 4.1 (1.9, 9.0), and 1.7 (1.4, 2.0), respectively. The effect of early onset PIH was stronger than that in term births, while the effect of smoking was equal in preterm and term newborns. Only in non-smokers who delivered at term, the rates of SGA significantly increased with the severity of PIH (ORs = 1.3 (1.1, 1.5), 1.8 (1.7, 2.0), and 2.5 (2.2, 3.0) for transient hypertension, mild-, and severe preeclampsia, respectively). The combined effects of smoking and hypertension were generally not synergistic. The effect of smoking was not stronger in women who had chronic hypertension. Nor were the effects of chronic hypertension stronger in smokers. PIH explained 21.9 and 2.5% of preterm and term cases of SGA, respectively, while smoking explained 12% of SGA cases. The effects of hypertensive disorder and smoking were generally not synergistic, which suggest that they may exert their main actions on separate sites or work through separate mechanisms within or outside the placenta. If smoking were eliminated in pregnant women, the number of SGA cases would be reduced by 12%.


Early Recognition of High Risk of Bipolar Disorder and Psychosis: An Overview of the ZInEP "Early Recognition" Study.
Early detection of persons with first signs of emerging psychosis is regarded as a promising strategy to reduce the burden of the disease. In recent years, there has been increasing interest in early detection of psychosis and bipolar disorders, with a clear need for sufficient sample sizes in prospective research. The underlying brain network disturbances in individuals at risk or with a prodrome are complex and yet not well known. This paper provides the rationale and design of a prospective longitudinal study focused on at-risk states of psychosis and bipolar disorder. The study is carried out within the context of the Zurich Program for Sustainable Development of Mental Health services (Zürcher Impulsprogramm zur Nachhaltigen Entwicklung der Psychiatrie). Persons at risk for psychosis or bipolar disorder between 13 and 35 years of age are examined by using a multi-level-approach (psychopathology, neuropsychology, genetics, electrophysiology, sociophysiology, magnetic resonance imaging, near-infrared spectroscopy). The included adolescents and young adults have four follow-ups at 6, 12, 24, and 36 months. This approach provides data for a better understanding of the relevant mechanisms involved in the onset of psychosis and bipolar disorder, which can serve as targets for future interventions. But for daily clinical practice a practicable "early recognition" approach is required. The results of this study will be useful to identify the strongest predictors and to delineate a prediction model.


The impact of p53 function on the metabolic activation of the carcinogenic air pollutant 3-nitrobenzanthrone and its metabolites 3-aminobenzanthrone and N-hydroxy-3-aminobenzanthrone in human cells.
The tumour suppressor p53, encoded by TP53, is a key player in a wide network of signalling pathways. We investigated its role in the bioactivation of the environmental carcinogen 3-nitrobenzanthrone (3-NBA)found in diesel exhaust and its metabolites 3-aminobenzanthrone (3-ABA) and N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) in a panel of isogenic human colorectal HCT116 cells differing only with respect to their TP53 status [i.e. TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+) or TP53(R248W/-)]. As a measure of metabolic competence, DNA adduct formation was determined using 32P-postlabelling. Wild-type (WT) p53 did not affect the bioactivation of 3-NBA; no difference in DNA adduct formation was observed in TP53(+/+), TP53(+/-) and TP53(-/-) cells. Bioactivation of both metabolites 3-ABA and N-OH-3-ABA on the other hand was WT-TP53 dependent. Lower 3-ABA- and N-OH-3-ABA-DNA adduct levels were found in TP53(+/-) and TP53(-/-) cells compared to TP53(+/+) cells, and p53's impact was attributed to differences in cytochrome P450 (CYP) 1A1 expression for 3-ABA whereas for N-OH-3-ABA, an impact of this tumour suppressor on sulphotransferase (SULT) 1A1/3 expression was detected. Mutant R248W-p53 protein function was similar to or exceeded the ability of WT-p53 in activating 3-NBA and its metabolites, measured as DNA adducts. However, identification of the xenobiotic-metabolising enzyme(s) (XMEs), through which mutant-p53 regulates these responses, proved difficult to decipher. For example, although both mutant cell lines exhibited higher CYP1A1 induction after 3-NBA treatment compared to TP53(+/+) cells, 3-NBA-derived DNA adduct levels were only higher in TP53(R248W/-) cells but not in TP53(R248W/+) cells. Our results show that p53's influence on carcinogen activation depends on the agent studied and thereby on the XMEs that mediate the bioactivation of that particular compound. The phenomenon of p53 regulating CYP1A1 expression in human cells is consistent with other recent findings; however, this is the first study highlighting the impact of p53 on sulphotransferase-mediated (i.e. SULT1A1) carcinogen metabolism in human cells.


Self-Control as Value-Based Choice.
Self-control is often conceived as a battle between "hot" impulsive processes and "cold" deliberative ones. Heeding the angel on one shoulder leads to success; following the demon on the other leads to failure. Self-control feels like a duality. What if that sensation is misleading, and, despite how they feel, self-control decisions are just like any other choice? We argue that self-control is a form of value-based choice wherein options are assigned a subjective value and a decision is made through a dynamic integration process. We articulate how a value-based choice model of self-control can capture its phenomenology and account for relevant behavioral and neuroscientific data. This conceptualization of self-control links divergent scientific approaches, allows for more robust and precise hypothesis testing, and suggests novel pathways to improve self-control.


Brain stem and inner ear abnormalities in children with auditory neuropathy spectrum disorder and cochlear nerve deficiency.
Cranial abnormalities, including CND, are common in children with ANSD. The purpose of this study was to assess whether CND is associated with brain or inner ear abnormalities in a cohort of children with ANSD. Two neuroradiologists retrospectively reviewed cranial MR imaging examinations in 103 children with ANSD. Brain, cochlear nerve, and temporal bone abnormalities were described and tabulated. Findings were stratified on the basis of the presence and laterality of CND, and differences in the presence of associated inner ear or intracranial abnormalities were assessed by using 2-tailed Fisher exact tests. CND was identified in 33.0% of children and 26.9% of ears with ANSD. Significantly more patients with bilateral CND had intracranial abnormalities than those with unilateral CND (60.0% versus 15.8%; P = .012). Forty percent of patients with bilateral CND, 0% of patients with unilateral CND, and 10.1% of those without CND demonstrated hindbrain malformations. Patients with bilateral CND were more likely to demonstrate hindbrain malformations than patients with normal nerves (P = .01) or unilateral CND (P = .004). Labyrinthine abnormalities were significantly more common in patients with bilateral CND than in those without CND (P ≤ .001). Cochlear anomalies were more common in patients with bilateral versus unilateral CND (P = .01). IAC and cochlear aperture stenosis were more common in those with unilateral and bilateral CND than those without CND (both P < .001). Cochlear and hindbrain abnormalities are significantly more common among patients with ANSD with bilateral CND compared with those with at least 1 intact cochlear nerve.


Generation and maintenance of tandemly repeated extrachromosomal plasmid DNA in Chlamydomonas chloroplasts.
Unusual chloroplast transformants of Chlamydomonas reinhardtii that contain 2000 copies of a mutant version of the chloroplast atpB gene, maintained as an extrachromosomal tandem repeat, have recently been described. In this paper studies have been undertaken to (i) address possible mechanisms for generating and maintaining the amplified DNA and (ii) determine whether it is possible to use chloroplast gene amplification to overexpress chloroplast or foreign genes. Data presented here indicate that high copy number transformants harbor characteristic rearrangements in both copies of the chloroplast genome large inverted repeat. These rearrangements appear to be a consequence of, or required for, maintenance of the amplified DNA. In an attempt to mimic the apparently autonomous replication of extrachromosomal DNA in the chloroplast, transformation was carried out with a plasmid that lacked homology with the chloroplast genome or with the same plasmid carrying a putative chloroplast DNA replication origin (oriA). Transformants were recovered only with the plasmid containing oriA, and all transformants contained an integrated plasmid copy at oriA, suggesting that establishment or maintenance of the extrachromosomal tandem repeat requires conditions that were not replicated in this experiment. To determine whether other genes could be maintained at high copy number in the chloroplast, plasmids carrying the wild-type atpB gene or the bacterial aadA gene were introduced into a high copy number transformant. Surprisingly, the copy number of the plasmid tandem repeat declined rapidly after the secondary transformation events, even when strong selective pressure for the introduced gene was applied. Thus, chloroplast transformation can either create or destabilize high copy number tandem repeats.


A comprehensive global genotype-phenotype database for rare diseases.
The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ®) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool for identifying new disease genes through the correlation of novel genetic variants with specific, well-defined phenotypes.


Retinoid X receptor-selective ligands produce malformations in Xenopus embryos.
Retinoids exert pleiotropic effects on the development of vertebrates through the action of retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the effect of synthetic retinoids selective for RXR and RAR on the development of Xenopus and zebrafish embryos. In Xenopus, both ligands selective for RAR and RXR caused striking malformations along the anterior-posterior axis, whereas in zebrafish only ligands specific for RAR caused embryonic malformations. In Xenopus, RAR- and RXR-selective ligands regulated the expression of the Xlim-1, gsc, and HoxA1 genes similarly as all-trans-retinoic acid. Nevertheless, RXR-selective ligands activated only an RXR responsive reporter but not an RAR responsive reporter introduced by microinjection into the Xenopus embryo, consistent with our failure to detect conversion of an RXR-selective ligand to different derivatives in the embryo. These results suggest that Xenopus embryos possess a unique response pathway in which liganded RXR can control gene expression. Our observations further illustrate the divergence in retinoid responsiveness between different vertebrate species.


Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a highly virulent malignancy with no effective treatment, thus requiring innovative and effective targeted therapies. The oncogene astrocyte-elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis and profoundly downregulates insulin-like growth factor-binding protein-7 (IGFBP7). The present study focuses on analyzing potential tumor suppressor functions of IGFBP7 in HCC and the relevance of IGFBP7 downregulation in mediating AEG-1 function. IGFBP7 expression was detected by immunohistochemistry in HCC tissue microarray and real-time PCR and ELISA in human HCC cell lines. Dual FISH was done to detect LOH at IGFBP7 locus. Stable IGFBP7-overexpressing clones were established in the background of AEG-1-overexpressing human HCC cells and were analyzed for in vitro proliferation and senescence and in vivo tumorigenesis and angiogenesis. IGFBP7 expression is significantly downregulated in human HCC samples and cell lines compared with normal liver and hepatocytes, respectively, and inversely correlates with the stages and grades of HCC. Genomic deletion of IGFBP7 was identified in 26% of patients with HCC. Forced overexpression of IGFBP7 in AEG-1-overexpressing HCC cells inhibited in vitro growth and induced senescence, and profoundly suppressed in vivo growth in nude mice that might be an end result of inhibition of angiogenesis by IGFBP7. The present findings provide evidence that IGFBP7 functions as a novel putative tumor suppressor for HCC and establish the corollary that IGFBP7 downregulation can effectively modify AEG-1 function. Accordingly, targeted overexpression of IGFBP7 might be a potential novel therapy for HCC.


Expression and characterization of truncated human heme oxygenase (hHO-1) and a fusion protein of hHO-1 with human cytochrome P450 reductase.
A human heme oxygenase (hHO-1) gene without the sequence coding for the last 23 amino acids has been expressed in Escherichia coli behind the pho A promoter. The truncated enzyme is obtained in high yields as a soluble, catalytically-active protein, making it available for the first time for detailed mechanistic studies. The purified, truncated hHO-1/heme complex is spectroscopically indistinguishable from that of the rat enzyme and converts heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase. A self-sufficient heme oxygenase system has been obtained by fusing the truncated hHO-1 gene to the gene for human cytochrome P450 reductase without the sequence coding for the 20 amino acid membrane binding domain. Expression of the fusion protein in pCWori+ yields a protein that only requires NADPH for catalytic turnover. The failure of exogenous cytochrome P450 reductase to stimulate turnover and the insensitivity of the catalytic rate toward changes in ionic strength establish that electrons are transferred intramolecularly between the reductase and heme oxygenase domains of the fusion protein. The Vmax for the fusion protein is 2.5 times higher than that for the reconstituted system. Therefore, either the covalent tether does not interfere with normal docking and electron transfer between the flavin and heme domains or alternative but equally efficient electron transfer pathways are available that do not require specific docking.


Psychiatric and Behavioural Problems in Children and Adolescents with Epilepsy.
To investigate the psychiatric and behavioural symptoms in children and adolescents with epilepsy. Patients with epilepsy and aged 4 to 16 years were recruited from a medical centre in Azerbaijan during January 2012 to December 2013. A community sample was drawn from 3 schools as the comparison group. The Strengths and Difficulties Questionnaire (SDQ) was administered to parents of both patients with epilepsy and children in the comparison group. The total difficulties score and the scores for each subscale were compared between the 2 groups. Additionally, scores between different groups of epileptic patients were compared. A total of 409 patients with epilepsy and 515 children in the comparison group were recruited. Those with epilepsy had a significantly higher mean total difficulties score and mean difficulties subscale scores (p < 0.001). In epileptic children with severe mental or physical disabilities, prosocial behaviour scores were significantly lower than those in the comparison group. The proportion of children with a total difficulties score in the abnormal range was higher in the epilepsy group than in the comparison group (53.1% vs. 15.7%; p < 0.001). Children with symptomatic epilepsy showed a higher total difficulties score than those with idiopathic epilepsy (p < 0.05). Children with epilepsy have a higher rate of psychiatric and behavioural symptoms. These rates are even higher in children with symptomatic epilepsy.


Topological changes in the transmembrane domains of hepatitis C virus envelope glycoproteins.
Hepatitis C virus proteins are synthesized as a polyprotein cleaved by a signal peptidase and viral proteases. The behaviour of internal signal sequences at the C-terminus of the transmembrane domains of hepatitis C virus envelope proteins E1 and E2 is essential for the topology of downstream polypeptides. We determined the topology of these transmembrane domains before and after signal sequence cleavage by tagging E1 and E2 with epitopes and by analysing their accessibility in selectively permeabilized cells. We showed that, after cleavage by signal peptidase in the endoplasmic reticulum, the C-terminal orientation of these transmembrane domains changed from luminal to cytosolic. The dynamic behaviour of these transmembrane domains is unique and it is linked to their multifunctionality. By reorienting their C-terminus toward the cytosol and being part of a transmembrane domain, the signal sequences at the C-terminus of E1 and E2 contribute to new functions: (i) membrane anchoring; (ii) E1E2 heterodimerization; and (iii) endoplasmic reticulum retention.


Humoral immune responses in Gambians to Pfs16, an immunodominant, Plasmodium falciparum integral membrane protein.
Naturally acquired humoral immune responses to Pfs16, an integral membrane protein expressed in Plasmodium falciparum gametocytes and sporozoites, were investigated in The Gambia. A high prevalence of antibodies to this molecule was detected by peptide ELISA. Ninety-three per cent of the people taking part in a survey at the end of the rainy season (November) had serum antibodies to one or more synthetic peptides spanning the sequence: 88% reacted with one particular peptide sequence (IMLIILSGIVGFKVK) whereas only one out of ten non-Gambians (taking anti-malarial prophylaxis with no history of infection) reacted with the peptide. Epitope mapping with mouse MoAbs has shown that this peptide is located on a part of the molecule differing from immunodominant regions of the molecule identified in a previous study in Papua New Guinea.


Urinary diversion.
A consensus conference convened by the World Health Organization (WHO) and the Société Internationale d'Urologie (SIU) met to critically review reports of urinary diversion. The world literature on urinary diversion was identified through a Medline search. Evidence-based recommendations for urinary diversion were prepared with reference to a 4-point scale. Many level 3 and 4 citations, but very few level 2 and no level 1, were noted. This outcome supported the clinical practice pattern. Findings of >300 reviewed citations are summarized. Published reports on urinary diversion rely heavily on expert opinion and single-institution retrospective case series: (1) The frequency distribution of urinary diversions performed by the authors of this report in >7000 patients with cystectomy reflects the current status of urinary diversion after cystectomy for bladder cancer: neobladder, 47%; conduit, 33%; anal diversion, 10%; continent cutaneous diversion, 8%; incontinent cutaneous diversion, 2%; and others, 0.1%. (2) No randomized controlled studies have investigated quality of life (QOL) after radical cystectomy. Such studies are desirable but are probably difficult to conduct. Published evidence does not support an advantage of one type of reconstruction over the others with regard to QOL. An important proposed reason for this is that patients are subjected preoperatively to method-to-patient matching, and thus are prepared for disadvantages associated with different methods. (3) Simple end-to-side, freely refluxing ureterointestinal anastomosis to an afferent limb of a low-pressure orthotopic reconstruction, in combination with regular voiding and close follow-up, is the procedure that results in the lowest overall complication rate. The potential benefit of "conventional" antireflux procedures in combination with orthotopic reconstruction seems outweighed by the higher complication and reoperation rates. The need to prevent reflux in a continent cutaneous reservoir is not significantly debated, and this should be done. (4) Most reconstructive surgeons have abandoned the continent Kock ileal reservoir largely because of the significant complication rate associated with the intussuscepted nipple valve.


Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo.
Fortilin, a 172-amino-acid polypeptide present both in the cytosol and nucleus, possesses potent anti-apoptotic activity. Although fortilin is known to bind Ca2+, the biochemistry and biological significance of such an interaction remains unknown. In the present study we report that fortilin must bind Ca2+ in order to protect cells against Ca2+-dependent apoptosis. Using a standard Ca2+-overlay assay, we first validated that full-length fortilin binds Ca2+ and showed that the N-terminus (amino acids 1-72) is required for its Ca2+-binding. We then used flow dialysis and CD spectropolarimetry assays to demonstrate that fortilin binds Ca2+ with a dissociation constant (Kd) of approx. 10 mM and that the binding of fortilin to Ca2+ induces a significant change in the secondary structure of fortilin. In order to evaluate the impact of the binding of fortilin to Ca2+ in vivo, we measured intracellular Ca2+ levels upon thapsigargin challenge and found that the lack of fortilin in the cell results in the exaggerated elevation of intracellular Ca2+ in the cell. We then tested various point mutants of fortilin for their Ca2+ binding and identified fortilin(E58A/E60A) to be a double-point mutant of fortilin lacking the ability of Ca2+-binding. We then found that wild-type fortilin, but not fortilin(E58A/E60A), protected cells against thapsigargin-induced apoptosis, suggesting that the binding of fortilin to Ca2+ is required for fortilin to protect cells against Ca2+-dependent apoptosis. Together, these results suggest that fortilin is an intracellular Ca2+ scavenger, protecting cells against Ca2+-dependent apoptosis by binding and sequestering Ca2+ from the downstream Ca2+-dependent apoptotic pathways.


Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the Digital Pathology Association.
In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber-security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Highly thermally stable and robust enantiopure zirconium NNN-scorpionates for the controlled ring-opening polymerization of rac-lactide.
A series of enantiopure alkoxide and thioalkoxide zirconium derivatives [Zr(ER)3(κ3-R,R-fbpza)] (1-6) (E = O, R = CHMe21, CHMeEt 2, CH2SiMe33, 2,6-C6H3Me24, 4-tBuPh 5; E = S, R = 4-tBuPh 6) has been prepared for use as thermally stable and robust initiators in the ROP of rac-lactide. The compounds were prepared by alcoholysis or thioalcoholysis of the tris(amide) precursor [Zr(NMe2)3(κ3-R,R-fbpza)] [R,R-fbpzaH = N-p-fluorophenyl-(1R)-1-[(1R)-6,6-dimethylbicyclo[3.1.1]-2-hepten-2-yl]-2,2-bis(3,5-dimethylpyrazol-1-yl)ethylamine] with ROH and ArEH (E = O, S) in a 1 : 3 molar ratio. The structures of the different compounds were determined by spectroscopic methods and, in addition, the X-ray crystal structure of 6 was also established. Interestingly, the tris(amide) precursor and complexes 2, 5, and 6 act as single-site living initiators for the well-controlled ring-opening polymerization of rac-lactide both in solution and in the melt. These processes produce polymers with medium molecular weights in good agreement with theoretical values and with narrow dispersity ranges. The activity of all initiators increased markedly with temperature and, more importantly, complex 2 exhibits the highest activity reported to date for a group 4-based initiator in the ROP of rac-LA under the industrially preferred melt and solvent-free conditions. Surprisingly, complex 2 is still highly active in the melt when using an unpurified monomer and it shows an unprecedented tolerance to water and impurities (49% conv., 15 min, 130 °C). Microstructural analysis of the poly(rac-lactide)s revealed a moderate heteroactivity in solution, with a Ps value of up to 0.70.


Molecular assessment of genetic diversity in mung bean germplasm.
RAPD profiles were used to identify the extent of diversity among 54 accessions of mung bean that included both improved and local land races. Out of the 40 primers screened, seven primers generated 174 amplification products with an average of 24.85 bands per primer. The RAPD profiles were analysed for Jaccard's similarity coefficients that was found to be in the range from 0 to 0.48, indicating the presence of wide range of genetic diversity at molecular level. Cluster analysis was carried out based on distances (1-similarity coefficient) using neighbour-joining method in Free Tree package. The dendrogram resolved all the accessions into two major clusters, I (with 11 accessions) and II (with 43 accessions). However, the cluster was further divided into four subclusters (II A with six, II B with nine, II C with 15 and II D with 13 accessions). The distribution of the accessions in different clusters and subclusters appears to be related to their performance in field conditions for 10 morphological traits that were scored. This study indicated that the RAPD profiles provide an easy and simple technique for preliminary genetic diversity assessment of mung bean accessions that may reflect morphological trait differences among them.


Effect of different running modes on the morphological, biochemical, and mechanical properties of articular cartilage.
Mechanical loading plays an important role not solely in cartilage development, but also in cartilage degeneration. Its adaptation behavior to mechanical loading has not been clearly delineated. The aim of the study was to examine the effect of different running modes (with different muscle contraction types) on morphological, biochemical, and mechanical properties of articular cartilage in the knee of growing rats. Thirty-six female Sprague-Dawley rats were randomly assigned into a nonactive age-matched control (AMC), level (LEVEL), and 20° downhill (DOWN) running group (n = 12 each). Running groups were trained on a treadmill for 30 min/day, 5 days/week for 6 weeks. Immunohistochemical staining and analysis of expression for collagen II, collagen IX, cartilage oligomeric matrix protein (COMP), and matrilin-3, histomorphometry of femoral cartilage height and femoral COMP staining height, and indentation testing of tibial articular cartilage were performed. Rats subjected to downhill running showed a significantly (P = 0.015) higher COMP staining height and a tendentially (P = 0.084) higher cartilage height in the high-weight bearing area of femoral articular cartilage. Cartilage thickness, mechanical properties, and expression of cartilage network proteins in tibial cartilage remained unaffected by different running modes. Our data suggest that joint loading induced by eccentric muscle contractions during downhill running may lead to a site-specific adaptation.


Community Perspectives on Access to and Availability of Healthy Food in Rural, Low-Resource, Latino Communities.
Attention has focused on the food environment as a result of the growing concern with obesity rates among Latinos in rural areas. Researchers have observed associations between a lack of physical access to affordable produce in areas where supermarkets and grocery stores are limited and poor dietary intake and obesity; these associations are high in rural, low-resource neighborhoods with a high population of Latino residents. We aimed to engage residents of low-resource, Latino-majority neighborhoods in discussions of food access in a rural yet agricultural community setting, which is typically described as a "food desert." We used a mixed-methods approach and conducted 3 focus groups (n = 20) and in-depth interviews (n = 59) and surveys (n = 79) with residents of a rural yet agricultural community. We used thematic analysis to explore residents' perceptions of access to healthy foods. Residents (n = 79; mean age, 41.6 y; 72% female; 79% Latino; 53% Spanish-speaking) reported that dollar and discount stores in this agricultural area provided access to produce; however, produce at retail stores was less affordable than produce at nonretail outlets such as fruit and vegetable stands. Gifts and trades of fruits and vegetables from neighbors and community organizations supplied no-cost or low-cost healthy foods. Residents' suggestions to improve food access centered on lowering the cost of produce in existing retail outlets and seeking out nonretail outlets. Our findings contribute to understanding of the food environment in low-resource, rural yet agricultural areas. Although such areas are characterized as "food deserts," residents identified nonretail outlets as a viable source of affordable produce, while indicating that the cost of retail produce was a concern. Innovative policy solutions to increase healthy food consumption must focus on affordability as well as accessibility, and consider alternate, nonretail food outlets in agricultural areas.


api, A novel Medicago truncatula symbiotic mutant impaired in nodule primordium invasion.
Genetic approaches have proved to be extremely useful in dissecting the complex nitrogen-fixing Rhizobium-legume endosymbiotic association. Here we describe a novel Medicago truncatula mutant called api, whose primary phenotype is the blockage of rhizobial infection just prior to nodule primordium invasion, leading to the formation of large infection pockets within the cortex of noninvaded root outgrowths. The mutant api originally was identified as a double symbiotic mutant associated with a new allele (nip-3) of the NIP/LATD gene, following the screening of an ethylmethane sulphonate-mutagenized population. Detailed characterization of the segregating single api mutant showed that rhizobial infection is also defective at the earlier stage of infection thread (IT) initiation in root hairs, as well as later during IT growth in the small percentage of nodules which overcome the primordium invasion block. Neither modulating ethylene biosynthesis (with L-alpha-(2-aminoethoxyvinylglycine or 1-aminocyclopropane-1-carboxylic acid) nor reducing ethylene sensitivity in a skl genetic background alters the basic api phenotype, suggesting that API function is not closely linked to ethylene metabolism or signaling. Genetic mapping places the API gene on the upper arm of the M. truncatula linkage group 4, and epistasis analyses show that API functions downstream of BIT1/ERN1 and LIN and upstream of NIP/LATD and the DNF genes.


A retrospective analysis of pedicle screws in contact with the great vessels.
Pedicle screws placed in the thoracic, lumbar, and sacral spine occasionally come in contact with the aorta, vena cava, or iliac vessels. When such screws are seen on postoperative imaging in an asymptomatic patient, the surgeon must decide whether it is riskier to revise the screw or to observe it. The authors hypothesized that the incidence of screw placement causing perioperative vessel injury is low and, further, that screws placed in contact with major vessels do not always result in vessel injury. A retrospective review of the operative records of 182 consecutive patients undergoing thoracic, lumbar, and lumbosacral pedicle screw fusion was performed to determine the frequency of intraoperative vessel injury. Postoperative imaging for 107 patients was available to determine the incidence of screws in contact with major vessels. Charts were examined to determine if any adverse sequelae had resulted from malpositioned screws. Patient outcomes were documented. There were no intraoperative vessel injuries or deaths in 182 consecutive operations. One hundred seven patients with available postoperative films had 680 pedicle screws placed between T-3 and the sacrum during 115 operations. No patient had arterial screw penetration or deformation on postoperative imaging. Thirty-three of the 680 inserted screws were in contact with a major vessel on routine postoperative imaging. The contacted vessels included the aorta (4 cases), the iliac artery (7 cases), and the iliac veins (22 cases). Patients were followed up until death or November 2009, for a mean follow-up of 44 months (median 44 months, range 5-109 months). None of the patients with vessel contact was noted to suffer symptoms or sequelae as a result of vessel contact. Radiographic follow-up as long as 50 months after surgery revealed no detectable vessel abnormality at the contacted site. Placing pedicle screws in contact with major vessels is a known risk of spinal surgery. The risk of repositioning a screw in contact with a major vessel but causing no symptoms must be weighed against the relative risk of leaving it in place.


Antiplatelet or anticoagulant therapy after coronary artery bypass surgery. A meta-analysis of clinical trials.
To determine the efficacy of antiplatelet or anti-coagulant therapy in preventing graft occlusions after coronary artery bypass surgery. Studies published from 1966 to 1988 were identified through a computerized search using MEDLINE, by searching the bibliographies of all identified articles, and by consulting with the cardiologists and cardiothoracic surgeons in the Veterans Administration Cooperative Study Group on Antiplatelet Therapy After Coronary Artery Bypass Surgery. All studies selected were randomized, controlled clinical trials comparing at least one active drug with a placebo or nonplacebo control group. Key data were extracted from each article, including the percentage of patients in each treatment group with one or more grafts occluded, the percentage of patients with completed postoperative catheterizations, timing of postoperative catheterization, and timing of start of treatment. These data were easily obtained from each article and did not require multiple observers. All studies had positive treatment-effect sizes in favor of active treatment, although some studies did not achieve statistical significance. A meta-analysis combining all treatment effects clearly shows that active treatment is beneficial (overall effect size = 0.30; CI, 0.21 to 0.38). Efficacy improves with early initiation of treatment. Early initiation of antiplatelet or anticoagulant drugs reduces the incidence of graft occlusions after coronary artery bypass surgery.


Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9.
Elevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9(-/-) genotype. These activities arise from the role of NEDD9 in assembling complexes and supporting activity of cancer signaling proteins, including FAK, Src, Shc, and AKT, and would support evaluation of NEDD9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9(-/-) tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9(+/+) cells in anchorage-independent growth, in growth on three-dimensional matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9(-/-) cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9(-/-) cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9(-/-) cells persistently have low levels of Src activation and are hypersensitive to the Src kinase inhibitor dasatinib. These studies identify NEDD9 as a complex modulator of different aspects of mammary tumor growth.


Between knowing and doing person-centredness: A qualitative examination of health professionals' perceptions of roles in self-management support.
Self-management is a contemporary model of chronic condition care that places expectations on, and roles for, both patients and health professionals. Health professionals are expected to form partnerships with their patients, and patients are expected to be active participants in their own care. In these new roles, control and responsibility for self-management are shared between people with chronic conditions and their health professionals. We still have limited knowledge about how these new roles are enacted in self-management support. In this article, we examine how health professionals perceive the roles of patients and professionals in chronic condition self-management, drawing on Bourdieu's concepts of field, doxa and capital. In this qualitative study, 32 in-depth interviews were conducted with 11 health professionals in Sydney, Australia. Data were analysed thematically. Three themes were derived. First, there was incongruence between how participants characterised and enacted their roles. Second, participants compartmentalised clinical and non-clinical aspects of self-management support. Finally, the roles of health professionals entwined with emotions and judgements of patienthood revealed that the provision of self-management support was linked to a fit between individuals' cultural health capital and the expectations governing the field. We argue that 'taken for granted' assumptions about self-management and self-management support must be challenged to mitigate negative social representations and unrealistic expectations placed on patients and health professionals, particularly those patients with less capital, who are more marginalised within clinical interactions.


"I can also serve as an inspiration": a qualitative study of the TB&Me blogging experience and its role in MDR-TB treatment.
In 2011, Médecins Sans Frontières (MSF) established a blogging project, "TB&Me," to enable patients with multidrug-resistant tuberculosis (MDR-TB) to share their experiences. By September 2012, 13 MDR-TB patients had blogged, either directly or with assistance, from the UK, Australia, Philippines, Swaziland, Central African Republic, Uganda, South Africa, India, and Armenia. Due to the lack of research on the potential for social media to support MDR-TB treatment and the innovative nature of the blog, we decided to conduct a qualitative study to examine patient and staff experiences. Our aim was to identify potential risks and benefits associated with blogging to enable us to determine whether social media had a role to play in supporting patients with MDR-TB. Participants were identified and selected purposively. TB&Me bloggers, project staff, MSF headquarters staff involved with TB and WHO European Region TB policy advisors were invited to participate in a semi-structured interview. Twenty interviews were conducted (five with bloggers). Data analysis drew upon principles of grounded theory, with constant comparison of data, cases and categories, and attention to deviant cases. We found that the TB&Me blog was associated with identified health benefits, with no reported instances of harm. There were three main findings: blogging was reported as useful for adherence to DR-TB treatment and supportive of the treatment-taking process by all bloggers and project staff; blogging provided support to patients (peer support, shared experience and reduction in isolation); and the blog was perceived as giving patients strength and voice. The TB&Me blog was seen to be associated with positive identified health and emotional benefits. Component 5 of the Stop TB Global Plan highlights the importance of empowering TB patients and communities. Blogging could be a useful tool to help achieve that ambition.


Sleeping beauty transposon-mediated gene therapy for prolonged expression.
The Sleeping Beauty (SB) transposon system represents a new vector for non-viral gene transfer that melds advantages of viruses and other forms of naked DNA transfer. The transposon itself is comprised of two inverted terminal repeats of about 340 base pairs each. The SB system directs precise transfer of specific constructs from a donor plasmid into a mammalian chromosome. The excision of the transposon from a donor plasmid and integration into a chromosomal site is mediated by Sleeping Beauty transposase, which can be delivered to cells vita its gene or its mRNA. As a result of its integration in chromosomes, and its lack of viral sequences that are often detected by poorly understood cellular defense mechanisms, a gene in a chromosomally integrated transposon can be expressed over the lifetime of a cell. SB transposons integrate nearly randomly into chromosomes at TA-dinucleotide base pairs although the sequences flanking the TAs can influence the probability of integration at a given site. Although random integration of vectors into human genomes is often thought to raise significant safety issues, evidence to date does not indicate that random insertions of SB transposons represent risks that are equal to those of viral vectors. Here we review the activities of the SB system in mice used as a model for human gene therapy, methods of delivery of the SB system, and its efficacy in ameliorating disorders that model human disease.


Identification of Nearctic black flies using DNA barcodes (Diptera: Simuliidae).
DNA barcoding has gained increased recognition as a molecular tool for species identification in various groups of organisms. In this preliminary study, we tested the efficacy of a 615-bp fragment of the cytochrome c oxidase I (COI) as a DNA barcode in the medically important family Simuliidae, or black flies. A total of 65 (25%) morphologically distinct species and sibling species in species complexes of the 255 recognized Nearctic black fly species were used to create a preliminary barcode profile for the family. Genetic divergence among congeners averaged 14.93% (range 2.83-15.33%), whereas intraspecific genetic divergence between morphologically distinct species averaged 0.72% (range 0-3.84%). DNA barcodes correctly identified nearly 100% of the morphologically distinct species (87% of the total sampled taxa), whereas in species complexes (13% of the sampled taxa) maximum values of divergence were comparatively higher (max. 4.58-6.5%), indicating cryptic diversity. The existence of sibling species in Prosimulium travisi and P. neomacropyga was also demonstrated, thus confirming previous cytological evidence about the existence of such cryptic diversity in these two taxa. We conclude that DNA barcoding is an effective method for species identification and discovery of cryptic diversity in black flies.


Network stratification analysis for identifying function-specific network layers.
A major challenge of systems biology is to capture the rewiring of biological functions (e.g. signaling pathways) in a molecular network. To address this problem, we proposed a novel computational framework, namely network stratification analysis (NetSA), to stratify the whole biological network into various function-specific network layers corresponding to particular functions (e.g. KEGG pathways), which transform the network analysis from the gene level to the functional level by integrating expression data, the gene/protein network and gene ontology information altogether. The application of NetSA in yeast and its comparison with a traditional network-partition both suggest that NetSA can more effectively reveal functional implications of network rewiring and extract significant phenotype-related biological processes. Furthermore, for time-series or stage-wise data, the function-specific network layer obtained by NetSA is also shown to be able to characterize the disease progression in a dynamic manner. In particular, when applying NetSA to hepatocellular carcinoma and type 1 diabetes, we can derive functional spectra regarding the progression of the disease, and capture active biological functions (i.e. active pathways) in different disease stages. The additional comparison between NetSA and SPIA illustrates again that NetSA could discover more complete biological functions during disease progression. Overall, NetSA provides a general framework to stratify a network into various layers of function-specific sub-networks, which can not only analyze a biological network on the functional level but also investigate gene rewiring patterns in biological processes.


Outcome of and prognostic indicators for dogs and cats with pneumoperitoneum and no history of penetrating trauma: 54 cases (1988-2002).
To determine the outcome of and prognostic indicators for dogs and cats with pneumoperitoneum and no history of penetrating trauma. Retrospective study. 43 dogs and 11 cats. Medical records of dogs and cats with radiographic evidence of pneumoperitoneum and no history of penetrating trauma were reviewed. Information collected included signalment, previous medical problems, initial complaint, duration of illness, physical examination findings, radiographic findings, laboratory abnormalities, abdominocentesis results, bacterial culture results, concurrent diseases, hospitalization time, and outcome. Abdominal radiographs were reviewed, and radiographic severity of pneumoperitoneum was classified. For those animals that underwent exploratory laparotomy, time from admission to surgery and results of histologic examination of biopsy specimens were recorded. 24 (44%) animals survived and were discharged from the hospital, but none of the variables examined was associated with whether animals survived. Rupture of the gastrointestinal tract was the cause of pneumoperitoneum in 40 animals. However, cause and location of gastrointestinal tract rupture was not associated with whether animals survived. Twenty-three of 40 (58%) animals that underwent exploratory laparotomy survived, compared with only 1 of 14 animals that did not undergo surgery. Results suggest that pneumoperitoneum in dogs and cats without any history of penetrating trauma is most commonly associated with rupture of the gastrointestinal tract and requires immediate surgical intervention. Even when appropriate treatment is instituted, the shortterm prognosis is only fair.


Administration of Flumazenil in a Patient with Acute Abamectin Intoxication: Case Report and Review of the Literature.
Abamectin is used in several countries as a type of macrocyclic lactone insecticide to control nematodes and other pests in livestock and agriculture. This medicine, used for animals and crops, would be highly toxic to human if a person has intentional poisoning. We report a case of a 47-year old man who was admitted to the hospital after ingestion of a large dose of abamectin on purpose, and who rapidly recovered consciousness after administration of flumazenil. Although flumazenil is not the antidote of abamectin, we may hypothesize that it could reduce recovery time and shorten expenditures in hospital. This is the first report that focusses on a specific treatment which could possibly accelerate recovery of consciousness for patients with abamectin intoxication.


A dinuclear ruthenium(ii) phototherapeutic that targets duplex and quadruplex DNA.
With the aim of developing a sensitizer for photodynamic therapy, a previously reported luminescent dinuclear complex that functions as a DNA probe in live cells was modified to produce a new iso-structural derivative containing RuII(TAP)2 fragments (TAP = 1,4,5,8-tetraazaphenanthrene). The structure of the new complex has been confirmed by a variety of techniques including single crystal X-ray analysis. Unlike its parent, the new complex displays Ru → L-based 3MLCT emission in both MeCN and water. Results from electrochemical studies and emission quenching experiments involving guanosine monophosphate are consistent with an excited state located on a TAP moiety. This hypothesis is further supported by detailed DFT calculations, which take into account solvent effects on excited state dynamics. Cell-free steady-state and time-resolved optical studies on the interaction of the new complex with duplex and quadruplex DNA show that the complex binds with high affinity to both structures and indicate that its photoexcited state is also quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products. Like the parent complex, this new compound is taken up by live cells where it primarily localizes within the nucleus and displays low cytotoxicity in the absence of light. However, in complete contrast to [{RuII(phen)2}2(tpphz)]4+, the new complex is therapeutically activated by light to become highly phototoxic toward malignant human melanoma cell lines showing that it is a promising lead for the treatment of this recalcitrant cancer.


Predictors and consequences of food neophobia and pickiness in young girls.
Vegetable intake among children is well below recommended levels. We assessed whether food neophobia and pickiness contribute to low vegetable intake in school-aged girls and if there are distinct predictors for neophobia and pickiness. Children with food neophobia are reluctant to eat new foods whereas picky children resist eating many familiar foods. Design/subjects Participants were 192 7-year-old girls and their parents, recruited for a study of girls' nutrition and development. We examined relationships between food neophobia and pickiness and assessed whether these variables predicted girls' vegetable consumption and predictors of food neophobia and pickiness. The data were analyzed using a two-step process. First, we used a two-way analysis of variance to assess whether girls who scored high or low on food neophobia and pickiness measures had different levels of vegetable consumption. We used multiple regression analysis to determine predictors of food neophobia and pickiness in the girls. Girls with both food neophobia and pickiness consumed fewer vegetables (1.1+/-0.1) than girls with neither neophobia nor pickiness (1.6+/-0.1). Neophobia and pickiness were modestly related in this sample, but had different predictors. Girls with food neophobia were more anxious and had mothers with food neophobia. Picky girls had mothers with less variety in their vegetable intake (r=-0.22) and mothers who perceived their family to have little time to eat healthful foods (r=0.36). In addition, picky eaters were breastfed for fewer than 6 months (r=-0.25). Pickiness was predicted primarily by environmental or experiential factors subject to changes; neophobia was predicted by more enduring and dispositional factors. Because food neophobia and pickiness negatively influence vegetable intake, intervention strategies to increase vegetable intake should focus on predictors of neophobia and pickiness, especially those subject to change.


Biochar and enhanced phosphate capture: Mapping mechanisms to functional properties.
A multi-technique analysis was performed on a range of biochar materials derived from secondary organic resources and aimed at sustainable recovery and re-use of wastewater phosphorus (P). Our purpose was to identify mechanisms of P capture in biochar and thereby inform its future optimisation as a sustainable P fertiliser. The biochar feedstock comprised pellets of anaerobically digested sewage sludge (PAD) or pellets of the same blended in the ratio 9:1 with ochre sourced from minewater treatment (POCAD), components which have limited alternative economic value. In the present study the feedstocks were pyrolysed at two highest treatment temperatures of 450 and 550 °C. Each of the resulting biochars were repeatedly exposed to a 20 mg l-1 PO4-P solution, to produce a parallel set of P-exposed biochars. Biochar exterior and/or interior surfaces were quantitatively characterised using laser-ablation (LA)-ICP-MS, X-ray diffraction, X-ray photo-electron spectroscopy (XPS) and scanning electron microscopy coupled with energy dispersive X-ray. The results highlighted the general importance of Fe minerals in P capture. XPS analysis of POCAD550 indicated lower oxidation state Fe2p3 bonding compared to POCAD450, and LA-ICP-MS indicated stronger covariation of Fe and S, even after P exposure. This suggests that low-solubility Fe/S compounds are formed during pyrolysis, are affected by process parameters and impact on P capture. Other data suggested capture roles for aluminium, calcium and silicon. Overall, our analyses suggest that a range of mechanisms for P capture are concurrently active in biochar. We highlighted the potential to manipulate these through choice of form and composition of feedstock as well as pyrolysis processing, so that biochar may be increasingly tailored towards specific functionality.


A pig model of the human gastrointestinal tract.
Easy access to next generation sequencing has enabled the rapid analysis of complex microbial populations. To take full advantage of these technologies, animal models enabling the manipulation of human microbiomes and the study of the impact of such perturbations on the host are needed. To this aim we are developing experimentally tractable and clinically relevant pig models of the human adult and infant gastro-intestinal tract. The intestine of germ-free piglets was populated with human adult or infant fecal microbial populations, and the piglets were maintained on solid or milk diet, respectively. Amplicons of 16S rRNA V6 region were deep-sequenced to monitor to what extent the transplanted human microbiomes changed in the pig. Within 24 h of transfer of human fecal microbiome to pigs, bacterial microbiomes rich in Proteobacteria emerged. These populations evolved toward a more diverse composition rich in Bacteroidetes and Firmicutes. In the experiment where infant microbiome was used, the phylogenetic composition of the transplanted bacterial population converged toward that of the human inoculum. A majority of sequences belonged to a relatively small number of operational taxonomic units, whereas at the other end of the abundance spectrum, a large number of rare and transient OTUs were detected. Analysis of fecal and colonic microbiomes originating from the same animal indicate that feces closely replicate the colonic microbiome. We conclude that the pig intestine can be colonized with human fecal microbiomes to generate a realistic model of the human GI tract.


Health and Sustainability in Public Meals-An Explorative Review.
The world is facing a number of challenges related to food consumption. These are, on the one hand, health effects and, on the other hand, the environmental impact of food production. Radical changes are needed to achieve a sustainable and healthy food production and consumption. Public and institutional meals play a vital role in promoting health and sustainability, since they are responsible for a significant part of food consumption, as well as their "normative influence" on peoples' food habits. The aim of this paper is to provide an explorative review of the scientific literature, focusing on European research including both concepts of health and sustainability in studies of public meals. Of >3000 papers, 20 were found to satisfy these criteria and were thus included in the review. The results showed that schools and hospitals are the most dominant arenas where both health and sustainability have been addressed. Three different approaches in combining health and sustainability have been found, these are: "Health as embracing sustainability", "Sustainability as embracing health" and "Health and sustainability as separate concepts". However, a clear motivation for addressing both health and sustainability is most often missing.


Lipid profile, plasma apolipoproteins, and risk of a first myocardial infarction among Asians: an analysis from the INTERHEART Study.
This study sought to determine the prevalence of lipid and lipoprotein abnormalities and their association with the risk of a first acute myocardial infarction (AMI) among Asians. Patterns of lipid abnormalities among Asians and their relative impact on cardiovascular risk have not been well characterized. In a case-control study, 65 centers in Asia recruited 5,731 cases of a first AMI and 6,459 control subjects. Plasma levels of lipids and apolipoproteins in the different Asian subgroups (South Asians, Chinese, Southeast Asians, and Japanese) were determined and correlated with the risk of AMI. Among both cases and controls, mean low-density lipoprotein cholesterol (LDL-C) levels were about 10 mg/dl lower in Asians compared with non-Asians. A greater proportion of Asian cases and controls had LDL-C </=100 mg/dl (25.5% and 32.3% in Asians vs. 19.4% and 25.3% in non-Asians, respectively). High-density lipoprotein cholesterol (HDL-C) levels were slightly lower among Asians compared with non-Asians. There was a preponderance of people with low HDL-C among South Asians (South Asia vs. rest of Asia: cases 82.3% vs. 57.4%; controls 81% vs. 51.6%; p < 0.0001 for both comparisons). However, despite these differences in absolute levels, the risk of AMI associated with increases in LDL-C and decreases in HDL-C was similar for Asians and non-Asians. Among South Asians, changes in apolipoprotein (Apo)A1 predicted risk better than HDL-C. ApoB/ApoA1 showed the strongest association with the risk of AMI. The preserved association of LDL-C with risk of AMI among Asians, despite the lower baseline levels, suggests the need to rethink treatment thresholds and targets in this population. The low HDL-C level among South Asians requires further study and targeted intervention.


Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1).
This article represents the first evidence that the renal secretion of the commonly used drug, digoxin, is mediated by P-glycoprotein. In this study, it was demonstrated that digoxin is a substrate of P-glycoprotein, and the mechanism of a clinically important drug interaction, such as digoxin-quinidine, was elucidated. Human P-glycoprotein was expressed on the apical membrane of the porcine kidney epithelial cell line, LLC-PK1 by transfecting with human MDR1 cDNA. The expression and function of P-glycoprotein were confirmed by Southern and Western blotting, RNase protection assay, immunostaining and transporting activity for vinblastine. The transepithelial transport of [3H]digoxin was measured across the cell monolayers grown on microporous polycarbonate membrane filters. The transfectant cells exhibited markedly greater basal-to-apical transport and less apical-to-basal transport than the host cells, and the former was 8-fold greater than the latter. The augmented transepithelial transport resulted from the increased efflux from cells to apical side. This oriented transport was inhibited by the presence of 20 microM vinblastine, quinidine or verapamil. The rate of efflux to the apical side was 2-fold greater than that to the basal side. Quinidine inhibited the efflux to the apical side but did not affect transport into the basal side. These findings demonstrate that digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney other than organic cation and anion transport systems, and suggest a molecular mechanism for the renal tubular secretion of digoxin as well as clinically important digoxin-quinidine interaction via P-glycoprotein.


Nonlinear spatial summation and the contrast gain control of cat retinal ganglion cells.
1. We studied how responses to visual stimuli at spatially separated locations were combined by cat retinal ganglion cells. 2. The temporal signal which modulated the stimuli was a sum of sinusoids. Fourier analysis of the ganglion cell impulse train yielded first order responses at the modulation frequencies, and second order responses at sums and differences of the input frequencies. 3. Spatial stimuli were spots in the centre and periphery of the cell's receptive field. Four conditions of stimulation were used: centre alone, periphery alone, centre and periphery in phase, centre and periphery out of phase. 4. The effective first order response of the centre was defined as the response due to centre stimulation in the presence of periphery stimulation, but independent of the relative phases of the two regions. Likewise, the effective first order response of the periphery was defined as the response due to periphery in the presence of centre stimulation, but independent of the relative phases of the two regions. These effective responses may be calculated by addition and subtraction of the measured responses to the combined stimuli. 5. There was a consistent difference between the first order frequency kernal of the effective centre and the first order kernel of the centre alone. The amplitudes of the effective centre responses were diminished at low frequencies of modulation compared to the isolated centre responses. Also, the phase of the effective centre's response to high frequencies was advanced. Such non-linear interaction occurred in all ganglion cells, X or Y, but the effects were larger in Y cells. 6. In addition to spatially uniform stimuli in the periphery, spatial grating patterns were also used. These peripheral gratings affected the first order kernal of the centre even though the peripheral gratings produced no first order responses by themselves. 7. The temporal properties of the non-linear interaction of centre and periphery were probed by modulation in the periphery with single sinusoids. The most effective temporal frequencies for producing non-linear summation were: (a) 4-15 Hz when all the visual stimuli were spatially uniform, (b) 2-8 Hz when spatial grating patterns were used in the periphery. 8. The characteristics of non-linear spatial summation observed in these experiments are explained by the properties of the contrast gain control mechanism which we have previously postulated.


Clinical Practice Guidelines on the Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention in Saudi Arabia.
Cervical cancer is the third most common gynecological malignancy in Saudi women with an estimated incidence rate of 1.9 cases per 100 000 women-years. More than 40% of cervical cancer cases are diagnosed at advanced stages due to lack of a routine screening program in Saudi Arabia. Thus, national guidelines for routine screening and treatment of precancerous cervical lesions are needed. The Saudi Centre for Evidence-Based Healthcare invited a panel of local experts and partnered them with a team from McMaster University in Canada for methodological support, to develop national clinical practice guidelines on the screening and treatment of precancerous lesions for cervical cancer. After the panel identified key clinical questions, the McMaster University working group updated existing systematic reviews that had been used for the 2013 WHO Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Recommendations were based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Those recommendations took into account the available evidence, patient values and preferences, and resource use in the Saudi context. The panel provided recommendations on two major issues: screening for precancerous lesions (cervical intraepithelial neoplasia 2 & 3) and treatment of those lesions to prevent cervical cancer in women who tested positive after screening. The Saudi expert panel recommends using the HPV DNA test followed by colposcopy or cytology (Pap test) followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. The panel recommends cryotherapy or loop excision electrosurgery procedure (LEEP) over cold knife cone biopsy to treat women at risk of cervical cancer that tests positive for CIN2+. Universal screening for precancerous cervical dysplasia in women in Saudi Arabia is recommended using HPV testing and or cytology. Either cryotherapy or LEEP are preferred for treatment. National studies on cervical cancer screening modalities and treatment of precancerous cervical lesions, including HPV prevalence and its association with cervical cancer, are scarce.


NHLBI workshop: respiratory medicine-related research training for adult and pediatric fellows.
The pulmonary physician-scientist has a special niche to generate basic research findings and apply them to a clinical disease and perhaps impact its medical care. The availability of new high throughput-based scientific technologies in the "omics era" has made this an opportune time for physician scientists to prepare and embark on an academic career in respiratory disease research. However, maintaining an adequate flow through the research pipeline of physician-scientist investigators studying respiratory system diseases is currently a challenge. There may not be a sufficient workforce emerging to capitalize on current research opportunities. The National Heart, Lung, and Blood Institute (NHLBI) organized a workshop to assess ways to attract and properly train advanced fellows to pursue research careers in adult and pediatric lung diseases. Participants included representatives from the various pulmonary training programs, respiratory-related professional societies, and NHLBI staff. Deliberation centered on present barriers that might affect interest in pursuing research training, devising better incentives to attract more trainees, and how current research support offered by the NHLBI and the Professional Societies (in partnership with Industry and Patient Support groups) might be better coordinated and optimized to ensure a continued pipeline of pulmonary investigators. Major recommendations offered are: (1) Attract trainees to pulmonary/critical care medicine-based research careers by increasing research exposure and opportunities for high school, college, and medical students. (2) Increase awareness of the outstanding physician-scientist role models in the lung community for trainees. (3) Facilitate mechanisms by which the lung community (NHLBI, professional societies, and partners) can better support and bridge senior fellows as they transition from Institutional Training Grants (T32) to Career Series (K) awards in their early faculty career development.


Fast computation of finite-time Lyapunov exponent fields for unsteady flows.
This paper presents new efficient methods for computing finite-time Lyapunov exponent (FTLE) fields in unsteady flows. The methods approximate the particle flow map, eliminating redundant particle integrations in neighboring flow map calculations. Two classes of flow map approximations are investigated based on composition of intermediate flow maps; unidirectional approximation constructs a time-T map by composing a number of smaller time-h maps, while bidirectional approximation constructs a flow map by composing both positive- and negative-time maps. The unidirectional method is shown to be fast and accurate, although it is memory intensive. The bidirectional method is also fast and uses significantly less memory; however, it is prone to error which is large in regions where the opposite-time FTLE field is large, rendering it unusable. The algorithms are implemented and compared on three example fluid flows: a double gyre, a low Reynolds number pitching flat plate, and an unsteady ABC flow.


Three-dimensional co-culture models to study prostate cancer growth, progression, and metastasis to bone.
Cancer-stromal interaction results in the co-evolution of both the cancer cells and the surrounding host stromal cells. As a consequence of this interaction, cancer cells acquire increased malignant potential and stromal cells become more inductive. In this review we suggest that cancer-stromal interaction can best be investigated by three-dimensional (3D) co-culture models with the results validated by clinical specimens. We showed that 3D culture promoted bone formation in vitro, and explored for the first time, with the help of the astronauts of the Space Shuttle Columbia, the co-culture of human prostate cancer and bone cells to further understand the interactions between these cells. Continued exploration of cancer growth under 3D conditions will rapidly lead to new discoveries and ultimately to improvements in the treatment of men with hormonal refractory prostate cancer.


Regulation of petrobactin and bacillibactin biosynthesis in Bacillus anthracis under iron and oxygen variation.
Bacillus anthracis produces two catecholate siderophores, petrobactin and bacillibactin, under iron-limited conditions. Here, we investigate how variable iron and oxygen concentrations influence the biosynthetic output of both siderophores in B. anthracis. In addition, we describe the differential levels of transcription of select genes within the B. anthracis siderophore biosynthetic operons that are responsible for synthesis of petrobactin and bacillibactin, during variable growth conditions. Accumulation of bacillibactin in B. anthracis Sterne (34F(2)) and in a mutant lacking the major superoxide dismutase (ΔsodA1) was almost completely repressed by the addition of 20 µM of iron. In contrast, petrobactin synthesis in both strains continued up to 20 µM of iron. Accumulation of petrobactin and bacillibactin showed a slight increase with addition of low levels of paraquat-induced oxidative stress in wild type B. anthracis Sterne. Cultures grown with high aeration resulted in greater accumulation of petrobactin relative to low aeration cultures, and delayed the repressive effect of added iron. Conversely, iron-depleted cultures grown with low aeration resulted in increased levels of bacillibactin. No difference was found in overall superoxide dismutase (SOD) activity or transcriptional levels of the sodA1 and sodA2 genes between iron-depleted and iron-replete conditions at high or low aeration, suggesting that SOD regulation and iron metabolism are separate in B. anthracis. The highest transcription of the gene asbB, part of the petrobactin biosynthetic operon, occurred under iron-limitation with high aeration, but transcription was readily detectable even under iron-replete conditions and in low aeration. The gene dhbC, a member of the bacillibactin biosynthetic operon, was only transcribed under conditions of iron-depletion, regardless of growth aeration. These data suggest that bacillibactin regulation is highly sensitive to iron-concentration. In contrast, although regulation of petrobactin is less dependent on iron, it is likely subject to additional levels of regulation that may contribute to virulence of B. anthracis.


Gold-silver nanoclusters having dipicolinic acid imprinted nanoshell for Bacillus cereus spores recognition.
Molecular imprinted polymers (MIPs) as a recognition element for sensors are increasingly of interest and MIP nanoclusters have started to appear in the literature. In this study, we have proposed a novel thiol ligand-capping method with polymerizable methacryloylamidocysteine (MAC) attached to gold-silver nanoclusters, reminiscent of a self-assembled monolayer and have reconstructed surface shell by synthetic host polymers based on molecular imprinting method for recognition. In this method, methacryloyl iminodiacetic acid-chrome (MAIDA-Cr(III)) has been used as a new metal-chelating monomer via metal coordination-chelation interactions and dipicolinic acid (DPA) which is a main participant of Bacillus spores has been used as a template. Nanoshell sensors with templates give a cavity that is selective for DPA. The DPA can simultaneously chelate to Cr(III) metal ion and fit into the shape-selective cavity. Thus, the interaction between Cr(III) ion and free coordination spheres has an effect on the binding ability of the gold-silver nanoclusters nanosensor. The binding affinity of the DPA imprinted nanoclusters has been investigated by using the Langmuir and Scatchard methods and determined affinity constants (K(affinity)) were found as 18 x 10(6) mol L(-1) and 9 x 10(6) mol L(-1), respectively.


Optimizing PCR assays for DNA-based cancer diagnostics.
Somatically acquired DNA rearrangements are characteristic of many cancers. The use of these mutations as diagnostic markers is challenging, because tumor cells are frequently admixed with normal cells, particularly in early stage tumor samples, and thus the samples contain a high background of normal DNA. Detection is further confounded by the fact that the rearrangement boundaries are not conserved across individuals, and might vary over hundreds of kilobases. Here, we present an algorithm for designing polymerase chain reaction (PCR) primers and oligonucleotide probes to assay for these variant rearrangements. Specifically, the primers and probes tile the entire genomic region surrounding a rearrangement, so as to amplify the mutant DNA over a wide range of possible breakpoints and robustly assay for the amplified signal on an array. Our solution involves the design of a complex combinatorial optimization problem, and also includes a novel alternating multiplexing strategy that makes efficient detection possible. Simulations show that we can achieve near-optimal detection in many different cases, even when the regions are highly non-symmetric. Additionally, we prove that the suggested multiplexing strategy is optimal in breakpoint detection. We applied our technique to create a custom design to assay for genomic lesions in several cancer cell-lines associated with a disruption in the CDKN2A locus. The CDKN2A deletion has highly variable boundaries across many cancers. We successfully detect the breakpoint in all cell-lines, even when the region has undergone multiple rearrangements. These results point to the development of a successful protocol for early diagnosis and monitoring of cancer. For online Supplementary Material, see www.liebertonline.com.


The p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated T cell receptor/CD3/zeta complex.
The CD4 or CD8 co-receptors and the T cell receptor (TCR) are though to interact with the same antigen-presenting major histocompatibility complex molecule in a stable ternary complex. Therefore, the TCR and its co-receptor need to come into close proximity on the surface of the T cell. We have previously shown that the interaction of the p56lck SH2 domain with zeta-associated, tyrosine phosphorylated ZAP-70 and Syk kinases leads to an enhanced association of CD4 with TCR/CD3/zeta complex after CD3 stimulation of Jurkat cells. In this report, we analyzed whether a similar mechanism can mediate recruitment of the CD8 alpha alpha and CD8 alpha beta isoforms to the TCR. We demonstrate in vivo in association of CD8 alpha alpha/p56lck with the tyrosine kinase ZAP-70 after CD3 stimulation of Jurkat cells. A phosphopeptide competing in vitro for the binding of tyrosine phosphorylated proteins to the SH2 domain of p56lck specifically impedes the association of ZAP-70 with CD8 alpha alpha/p56lck without affecting the zeta/ZAP-70 interaction. The same peptide is able to compete for the activation-dependent association of the CD8 alpha alpha or CD8 alpha beta isoform with the TCR/CD3/zeta complex. Moreover, co-precipitation of the TCR with both CD8 isoforms was observed after CD3 stimulation. These findings strongly suggest that the p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated TCR/CD3/zeta complex.


Study on fracture behavior of molars based on three-dimensional high-precision computerized tomography scanning and numerical simulation.
A series of three-dimensional (3D) numerical simulations are conducted to investigate the gradual failure process of molars in this study. The real morphology and internal mesoscopic structure of a whole tooth are implemented into the numerical simulations through computerized tomography scanning, digital image processing, and 3D matrix mapping. The failure process of the whole tooth subject to compressions including crack initiation, crack propagation, and final failure pattern is reproduced using 3D realistic failure process analysis (RFPA3D) method. It is concluded that a series of microcracks are gradually initiated, nucleated, and subsequently interconnect to form macroscopic cracks when the teeth are under over-compressions. The propagation of the macroscopic cracks results in the formation of fracture surfaces and penetrating cracks, which are essential signs and manifestations of the tooth failure. Moreover, the simulations reveal that, the material heterogeneity is a critical factor that affects the mechanical properties and fracture modes of the teeth, which vary from crown fractures to crown-root fractures and root fractures depending on different homogeneity indices.


Contact optical nanolithography using nanoscale C-shaped apertures.
C-shaped ridge apertures are used in contact nanolithography to achieve nanometer scale resolution. Lithography results demonstrated that holes as small as 60 nm can be produced in the photoresist by illuminating the apertures with a 355 nm laser beam. Experiments are also performed using comparable square and rectangular apertures. Results show enhanced transmission and light concentration of C apertures compared to the apertures with regular shapes. Finite difference time domain simulations are used to design the apertures and explain the experimental results.


1H MRI phase thermometry in vivo in canine brain, muscle, and tumor tissue.
The temperature sensitivity of the chemical shift of water (approximately 0.01 ppm/degree C) provides a potential method to monitor temperature changes in vivo or in vitro through the changes in phase of a gradient-echo magnetic resonance (MR) image. This relation was studied at 1.5 T in gel materials and in vivo in canine brain and muscle tissue, heated with a radio frequency (rf) annular phased array hyperthermia antenna. The rf fields associated with heating (130 MHz) and imaging (64 MHz) were decoupled using bandpass filters providing isolation in excess of 100 dB, thus allowing simultaneous imaging and rf heating without deterioration of the MR image signal-to-noise ratio. In a gel, temperature sensitivity of the MR image phase was observed to be (4.41 +/- 0.02) phase degrees/degree C for Te = 20 ms, which allowed temperature changes of 0.22 degree C to be resolved for a 50-mm3 region in less than 10 s of data acquisition. In vivo, for Te = 20 ms, the temperature sensitivity was (3.2 +/- 0.1) phase degrees/degree C for brain tissue, (3.1 +/- 0.1) phase degrees/degree C for muscle, and (3.0 +/- 0.2) phase degrees/degree C for a muscle tumor (sarcoma), allowing temperature changes of 0.6 degree C to be resolved in a 16-mm3 volume in less than 10 s of data acquisition. We conclude that, while the technique is very sensitive to magnetic field inhomogeneity, stability, and subject motion, it appears to be useful for in vivo temperature change measurement.


Repeated Occupational Exposure to Low-level Blast in the Canadian Armed Forces: Effects on Hearing, Balance, and Ataxia.
Recently, there has been increasing concern about the adverse health effects of long-term occupational exposure to low-level blast in military personnel. Occupational blast exposure occurs routinely in garrison through use of armaments and controlled blast detonations. In the current study, we focused on a population of breaching instructors and range staff. Breaching is a tactical technique that is used to gain entry into closed spaces, often through the use of explosives. Initial measurements of blast overpressure collected during breaching courses found that up to 10% of the blasts for range staff and up to 32% of the blasts for instructors exceeded the recommended 3 psi exposure limit. Using a cross-sectional design, we used tests of balance, ataxia, and hearing to compare a sample of breachers (n = 19) to age-and sex-matched military controls (n = 19). There were no significant differences between the two groups on the balance and ataxia tests, although the average scores of both groups were lower than would be expected in a normative population. The prevalence of hearing loss was low in the breacher group (4 of 19), and hearing thresholds were not significantly different from the controls. However, the prevalence of self-reported tinnitus was significantly higher in the breacher group (12 of 19) compared with the controls (4 of 19), and all breachers who were identified as having hearing loss also reported tinnitus. Our results suggest that basic tests of balance, ataxia, and hearing on their own were not sensitive to the effects of long-term occupational exposure to low-level blast. Some of the blast exposure levels exceeded limits, and there was a significant association of exposure with tinnitus. Future studies should supplement with additional information including exposure history and functional hearing assessments. These findings should be considered in the design of future acute and longitudinal studies of low-level blast exposure.


Over prescription of antibiotics for adult pharyngitis is prevalent in developing countries but can be reduced using McIsaac modification of Centor scores: a cross-sectional study.
Although Group A beta hemolytic streptococcus (GABHS) can cause bacterial pharyngitis, the most common etiology is viral; despite this viral etiology, antibiotics are commonly prescribed for this infection in industrialized countries. We investigated the prevalence of GABHS in adult pharyngitis patients from lower socioeconomic settings in Karachi, Pakistan, how often antibiotics are prescribed for pharyngitis and if appropriate agents were used in a developing world setting. Finally, we wanted to see the usefulness of modified McIsaac scores in predicting positive cultures. Adult patients were recruited from three local hospital outpatient dispensaries (OPDs). All patients aged 14-65 years who were suspected of having bacterial pharyngitis had throat swabs taken. Laboratory results for GABHS pharyngitis were then compared with their prescriptions. Appropriateness (using the World Health Organization's definition) and type of antibiotic prescribed were assessed. Of 137 patients, 30 patients each were studied for scores of 0, 1, 2 and 3; 17 patients were studied for score 4. Although 6 (4.4%) patients were GABHS+, for a prevalence of 43.8 per 1000 population, antibiotics were prescribed to 135 patients (98.5%). Of these, only 11.1% received appropriate antibiotics while 88.9% received inappropriate antibiotics. Penicillins were prescribed most (34.1%), especially amoxicillin/clavulanate; followed by macrolides (31.1%), especially the second-generation agents, and fluoroquinolones (14.8%). McIsaac scores were found to be 100% sensitive and 68.7% specific, giving a positive predictive value (PPV) of 12.7% and a negative predictive value (NPV) of 100%. Antibiotics were prescribed irrationally to adult pharyngitis patients, as most cultures were negative for bacterial infection. McIsaac modification of Centor scores related directly to culture results. We would therefore highly recommend its use to help family physicians make treatment decisions for adult pharyngitis patients.


Clinical significance of respiratory compensation during exercise testing in cardiac patients.
Ventilation (VE) increases linearly with the increase of carbon dioxide output (VCO2) during cardiopulmonary exercise testing. VE-VCO2 slope rises in parallel with exercise intensity, reaches a turning point (called the RC point), then steepens because of respiratory compensation for lactic acidosis. While this RC point can be identified universally, it is undetectable in some patients. In this study we evaluated whether the respiratory compensation during exercise testing has clinical significance in cardiac patients. In total, 152 cardiac patients with a respiratory exchange ratio at peak exercise (peak R) of between 1.10 and 1.20 were enrolled. Cardiopulmonary parameters were compared between patients who manifested the RC point (n = 118) and those who did not (n = 34). The peak R did not significantly differ between these two groups. Compared to the patients without the RC point, those with the RC point had a higher oxygen uptake at peak exercise (peak VO2) (20.2 ± 5.3 vs 13.6 ± 3.4 mL/min/kg, p < 0.001), higher anaerobic threshold (AT) (12.4 ± 3.2 vs 9.2 ± 2.3 mL/min/kg, p < 0.001), and lower VE-VCO2 slope (31.7 ± 5.8 vs 37.8 ± 9.6, p = 0.001). Brain natriuretic peptide (BNP) tended to be lower in the patients with the RC point (175.4 ± 364.7 vs 327.9 ± 381.1 pg/mL, p = 0.067). Peak VO2, the marker of cardiopulmonary function, was found to be the independent predictor of the presence of the RC point. The present findings suggest that the phenomenon of respiratory compensation during heavy exercise indicates better cardiopulmonary function in cardiac patients within a prescribed range of effort.


Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.
hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.


Source of oxygen in the CO(2) produced in the bioluminescent oxidation of firefly luciferin.
Incorporation of (18)O into the CO(2) produced in the bioluminescent oxidation of firefly luciferin was studied. In H(2) (16)O medium with (18)O(2) gas, the product CO(2) contained up to 75% C(16)O(18)O, showing that one O of the product CO(2) arose from the O(2) that oxidized luciferin. This result is consistent with a dioxetane mechanism. Analysis of the mass spectral data of the CO(2) obtained in high-enrichment H(2) (18)O medium with (16)O(2) gas indicated the presence of about 20% contaminating CO(2), which contributes approximately 70% of the total incorporated (18)O. Thus the values of incorporated (18)O in H(2) (18)O medium with (16)O(2) gas have no significance in the present context. Data obtained with luciferases of the American firefly Photinus and Japanese firefly Luciola were similar.


Increasing the storage density of a page-based holographic data storage system by image upscaling using the PSF of the Nyquist aperture.
We introduce an image upscaling method that reduces bit errors caused by Nyquist apertures. Nyquist apertures used for higher storage densities generate optical aberrations and degrade the quality of the image that is recorded on the medium. Here, to correct the bit errors caused by the Nyquist aperture, an image upscaling method is used to restore the degraded image in the enhanced spatial frequency domain using its point spread function (PSF) as a restoration filter. The proposed method reduces the bit error rate (BER) significantly and hence allows higher storage densities.


Reversal of vecuronium with neostigmine: a comparison between male and female patients.
We investigated the differences between males and females in the reversal effect of neostigmine on neuromuscular blockade. Thirty male and 30 female patients undergoing elective general anesthesia were studied. Vecuronium was given in all patients anesthetized with nitrous oxide, oxygen, and sevoflurane. After the surgical procedure, when T1 (1st response in train-of-four (TOF))/control returned to 0.25, neostigmine 40 microg/kg in combination with atropine 20 microg/kg was given to antagonize residual neuromuscular blockade. Three, six, nine, 12, and 15 minutes after neostigmine reversal, T1/control or TOF ratio (T4/T1) did not significantly differ between the sexes. Also, 15 minutes after neostigmine administration, the number of patients in whom recovery from neuromuscular blockade was sufficient to guarantee good respiratory function, i.e., TOF ratio > 0.74, did not significantly differ between the sexes. In contrast, 15 minutes after neostigmine, the number of patients in whom recovery from neuromuscular blockade was adequate to ensure satisfactory recovery from neuromuscular blockade including the return of the faculty of sight, i.e., TOF ratio > 0.9, was significantly less in the males than in females (6 vs. 14, P = 0.028). In conclusion, 15 min after neostigmine, TOF ratio less often returns to a value of more than 0.9 in males than in females.


Long-term n-3 FA deficiency modifies peroxisome proliferator-activated receptor beta mRNA abundance in rat ocular tissues.
Peroxisomal proliferator-activated receptors (PPAR) are a FA-response system involved in diverse cellular responses. FA regulate PPAR activity and modulate PPAR mRNA abundance. Increasing evidence indicates that PUFA are required for optimal neuronal development and function. To gain insight into the mechanism for nutrition-induced impairment of neuronal development and function we investigated the effect of chronic n-3 FA deficiency on PPAR mRNA levels in rat brain and ocular tissues. Rats were fed for three generations a diet designed to reduce DHA levels in tissues, and the abundance of PPARalpha and PPARbeta transcripts was measured by hybridization with specific probes. Chronic consumption of the a-linolenic acid (LNA)-insufficient diet caused a remarkable modification in DHA content in membrane phospholipids. The results reported here indicate that PPARa mRNA levels did not exhibit significant variation in ocular, hepatic, or nervous tissues from rats fed the experimental diet. In contrast, PPARalpha mRNA normalized to beta-actin mRNA was 21% higher in ocular tissue from F3 generation rats consuming the LNA-deficient diet but was independent of diet in hepatic and nervous tissues. The absolute abundance of PPARbeta transcripts showed a 17% increase in ocular tissue from rats consuming the LNA-deficient diet (F3 generation). The biological significance of the reported changes in PPARbeta mRNA in ocular tissue remains to be determined.


Fertility Control: Reproductive Desires, Kin Work, and Women's Status in Contemporary India.
This article reappraises the link between fertility and women's status by examining changing means and meanings of reproduction in India. It is based on data gathered during and after 16 months of ethnographic fieldwork conducted between 2005 and 2007 in Lucknow, Uttar Pradesh, India, on social and cultural contexts of infertility. Lucknow is the capital city of Uttar Pradesh, India's most populous state. Historical views of population and fertility control in India and perspectives on the contemporary use of assisted reproductive technologies (ARTs) for practices such as surrogacy situate the ethnographic perspectives. Analysis of ARTs in practice complicates ideas of autonomy and choice in reproduction. Results show that these technologies allow women to challenge power relations within their marital families and pursue stigmatized forms of reproduction. However, they also offer new ways for families to continue and extend an old pattern of exerting control over women's reproductive potential.


MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons.
Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients' response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5-10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets.


Endogenous versus tumor-specific host response to breast carcinoma: a study of stromal response in synchronous breast primaries and biopsy site changes.
We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient. Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry. The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not. The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes.