Hydrogenophaga soli sp. nov., isolated from rice field soil.
A novel Gram-stain-negative bacterial strain, designated strain S10T, was isolated from soil collected in a rice field in Goyang, South Korea. Cells of strain S10T were strictly aerobic, motile and rod-shaped. Colonies were round, convex, smooth and white. The strain grew optimally at 37 °C, pH 7.0 and 0 % (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene sequence of strain S10T revealed that the bacterium belongs to the family Comamonadaceae and is related to members of the genus Hydrogenophaga, with Hydrogenophaga caeni EMB71T being its closest relative (97.9 % sequence similarity). The DNA G+C content of strain S10T was 68.2 mol%. Strain S10T contained phosphatidylethanolamine and diphosphatidylglycerol as the major polar lipids. The major fatty acids were C16 : 0 and summed feature 3 (C16 : 1ω7c and/or iso-C15 : 0 2-OH). The predominant respiratory quinone was ubiquinone Q-8. DNA-DNA hybridization values of strain S10T with Hydrogenophaga caeni KCTC 12613T, Hydrogenophaga atypica DSM 15342T and Hydrogenophaga defluvii DSM 15341T were 16.1±4.8, 49.0±3.2 and 21.9±8.8 %, respectively. Based on phylogenetic distinctiveness, DNA-DNA hybridization and specific physiological and biochemical characteristics, strain S10T (=KCTC 52520T=JCM 31711T) is classified as a novel species of the genus Hydrogenophaga, for which the name Hydrogenophagasoli sp. nov. is proposed.


Genotype of CDC73 germline mutation determines risk of parathyroid cancer.
Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.


Poppr: an R package for genetic analysis of populations with clonal, partially clonal, and/or sexual reproduction.
Many microbial, fungal, or oomcyete populations violate assumptions for population genetic analysis because these populations are clonal, admixed, partially clonal, and/or sexual. Furthermore, few tools exist that are specifically designed for analyzing data from clonal populations, making analysis difficult and haphazard. We developed the R package poppr providing unique tools for analysis of data from admixed, clonal, mixed, and/or sexual populations. Currently, poppr can be used for dominant/codominant and haploid/diploid genetic data. Data can be imported from several formats including GenAlEx formatted text files and can be analyzed on a user-defined hierarchy that includes unlimited levels of subpopulation structure and clone censoring. New functions include calculation of Bruvo's distance for microsatellites, batch-analysis of the index of association with several indices of genotypic diversity, and graphing including dendrograms with bootstrap support and minimum spanning networks. While functions for genotypic diversity and clone censoring are specific for clonal populations, several functions found in poppr are also valuable to analysis of any populations. A manual with documentation and examples is provided. Poppr is open source and major releases are available on CRAN: http://cran.r-project.org/package=poppr. More supporting documentation and tutorials can be found under 'resources' at: http://grunwaldlab.cgrb.oregonstate.edu/.


'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation.
The Gardos channel is a Ca2+ sensitive, K+ selective channel present in several tissues including RBCs, where it is involved in cell volume regulation. Recently, mutations at two different aminoacid residues in KCNN4 have been reported in patients with hereditary xerocytosis. We identified by whole exome sequencing a new family with two members affected by chronic hemolytic anemia carrying mutation R352H in the KCNN4 gene. No additional mutations in genes encoding for RBCs cytoskeletal, membrane or channel proteins were detected. We performed functional studies on patients' RBCs to evaluate the effects of R352H mutation on the cellular properties and eventually on the clinical phenotype. Gardos channel hyperactivation was demonstrated in circulating erythrocytes and erythroblasts differentiated ex-vivo from peripheral CD34+ cells. Pathological alterations in the function of multiple ion transport systems were observed, suggesting the presence of compensatory effects ultimately preventing cellular dehydration in patient's RBCs; moreover, flow cytometry and confocal fluorescence live-cell imaging showed Ca2+ overload in the RBCs of both patients and hypersensitivity of Ca2+ uptake by RBCs to swelling. Altogether these findings suggest that the 'Gardos channelopathy' is a complex pathology, to some extent different from the common hereditary xerocytosis.


Gene relics in the genome of the yeast Saccharomyces cerevisiae.
There is increasing evidence that DNA duplication is a common and ongoing process that plays a major role in molecular evolution of genomes and that a large fraction of the duplicated gene copies becomes non-functional by accumulation of deleterious mutations. In order to describe this phenomenon, we systematically searched the 6404 intergenic regions (IRs) of the genome of Saccharomyces cerevisiae for traces of coding sequences presenting degenerated but still recognizable sequence similarity with active open reading frames (5823 annotated ORFs). We detected a total of 124 anciently coding regions, or "gene relics", showing similarity to a total of 149 distinct active ORFs. This set of relics shows a continuum of sequence degeneration from those whose sequence is slightly altered compared to the functional ORF (classically defined as pseudogenes), to those that contains so many deleterious mutations, as to reach the limit of recognition. Gene relics are more concentrated in the subtelomeric regions of the chromosomes, reflecting the high plasticity of these regions. The presence of relics also revealed ancestral duplication events of chromosomal segments that were previously undetected. Some of these segments are intermingled with the more easily recognizable ancestral blocks of duplication, indicating successive duplication events. We present a compilation of all the data available, leading to a total of 278 pseudogenes in the genome of S. cerevisiae.


Gelatinases (MMP2 and MMP9) in swine antral follicle.
Follicular growth is allowed by extracellular matrix remodeling and vascular network development. Since matrix metalloproteinases (MMPs) play a crucial role in both of these processes, the aim of the present study was to evaluate the expression of gelatinases MMP2 and MMP9 in swine ovarian follicle (theca and granulosa compartments) during its development. Moreover, we measured gelatinase activities into follicular fluids (FF). Our data demonstrate for the first time that MMP2 and MMP9 are expressed in swine ovarian follicle both in theca and granulosa layers; moreover we show that the expression of both gelatinases increases in theca while decreases in granulosa during follicle growth. Additionally, MMP2 activity has been detected in FF. The spatial pattern of expression of gelatinases in swine follicle suggests a differential role during physiological ovarian events.


Anticonvulsant Activity of Extracts of Plectranthus barbatus Leaves in Mice.
Plectranthus barbatus is a medicinal plant used to treat a wide range of disorders including seizure. However, the anticonvulsant activity of this plant has not been studied in depth. We therefore sought to evaluate the anticonvulsant activity of a hydroalcoholic extract of P. barbatus leaves on seizures induced by strychnine sulphate (2.0 mg/kg) and pilocarpine (600 mg/kg) in mice. The extract was administered orally at 1, 10, 30, and 100 mg/kg. We report that the P. barbatus extract had marked anticonvulsant activity against strychnine-induced convulsions, but was quite ineffective against pilocarpine-induced convulsions. Further experiments will be required to identify the active molecules(s) and their mechanism(s) of action.


Polarized notum activation at wounds inhibits Wnt function to promote planarian head regeneration.
Regeneration requires initiation of programs tailored to the identity of missing parts. Head-versus-tail regeneration in planarians presents a paradigm for study of this phenomenon. After injury, Wnt signaling promotes tail regeneration. We report that wounding elicits expression of the Wnt inhibitor notum preferentially at anterior-facing wounds. This expression asymmetry occurs at essentially any wound, even if the anterior pole is intact. Inhibition of notum with RNA interference (RNAi) causes regeneration of an anterior-facing tail instead of a head, and double-RNAi experiments indicate that notum inhibits Wnt signaling to promote head regeneration. notum expression is itself controlled by Wnt signaling, suggesting that regulation of feedback inhibition controls the binary head-tail regeneration outcome. We conclude that local detection of wound orientation with respect to tissue axes results in distinct signaling environments that initiate appropriate regeneration responses.


Evaluation of Secondhand Smoke Using PM2.5 and Observations in a Random Stratified Sample in Hospitality Venues from 12 Cities.
Turkey passed a law banning smoking in all indoor public places in 2008. In response to the indoor smoking restriction, many smokers may have relocated to outdoor areas of venues. The aim of this study was to evaluate air pollution related to SHS exposure in indoor and outdoor areas of hospitality venues in 12 cities in Turkey. In this cross-sectional study, we evaluated hospitality venues in 12 cities in Turkey. In each visited venue, we evaluated a pre-specified number of study locations such as the outdoor area of the main entrance, indoor areas, and patios or other outdoor dining areas, completely or partially covered with window walls. We measured particulate matter 2.5 (PM2.5) in those areas. The fieldworkers visited 72 randomly selected hospitality venues and measured PM2.5 concentrations in 165 different locations (indoor, outdoor, and patios) of those venues. Overall, 2573 people were observed, 909 of them smoking. The median (IQR) PM2.5 concentrations were 95 (39-229) μg/m3 indoors, 25 (13-48) μg/m3 outdoors, and 31 μg/m3 (16-62) in the patios (p < 0.001). After adjustment, each additional smoker was associated with a 2% increase in PM2.5 concentrations in patio air (GMR (95% CI): 1.02 (1.00, 1.05), and a 4% increase in indoor air (GMR (95% CI): 1.04 (1.02, 1.05). There were unhealthy levels of smoking-caused PM2.5 concentrations, not only indoors, but also in the patios of hospitality venues. Legislative efforts to expand the smoke-free legislation to outdoor areas adjacent to indoor public places and an action plan to increase compliance with the smoke-free policy are urgently needed in Turkey.


Construction of human activity-based phosphorylation networks.
The landscape of human phosphorylation networks has not been systematically explored, representing vast, unchartered territories within cellular signaling networks. Although a large number of in vivo phosphorylated residues have been identified by mass spectrometry (MS)-based approaches, assigning the upstream kinases to these residues requires biochemical analysis of kinase-substrate relationships (KSRs). Here, we developed a new strategy, called CEASAR, based on functional protein microarrays and bioinformatics to experimentally identify substrates for 289 unique kinases, resulting in 3656 high-quality KSRs. We then generated consensus phosphorylation motifs for each of the kinases and integrated this information, along with information about in vivo phosphorylation sites determined by MS, to construct a high-resolution map of phosphorylation networks that connects 230 kinases to 2591 in vivo phosphorylation sites in 652 substrates. The value of this data set is demonstrated through the discovery of a new role for PKA downstream of Btk (Bruton's tyrosine kinase) during B-cell receptor signaling. Overall, these studies provide global insights into kinase-mediated signaling pathways and promise to advance our understanding of cellular signaling processes in humans.


Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration.
Pluripotent cells in the embryo can generate all cell types, but lineage-restricted cells are generally thought to replenish adult tissues. Planarians are flatworms and regenerate from tiny body fragments, a process requiring a population of proliferating cells (neoblasts). Whether regeneration is accomplished by pluripotent cells or by the collective activity of multiple lineage-restricted cell types is unknown. We used ionizing radiation and single-cell transplantation to identify neoblasts that can form large descendant-cell colonies in vivo. These clonogenic neoblasts (cNeoblasts) produce cells that differentiate into neuronal, intestinal, and other known postmitotic cell types and are distributed throughout the body. Single transplanted cNeoblasts restored regeneration in lethally irradiated hosts. We conclude that broadly distributed, adult pluripotent stem cells underlie the remarkable regenerative abilities of planarians.


RKB: a Semantic Web knowledge base for RNA.
Increasingly sophisticated knowledge about RNA structure and function requires an inclusive knowledge representation that facilitates the integration of independently -generated information arising from such efforts as genome sequencing projects, microarray analyses, structure determination and RNA SELEX experiments. While RNAML, an XML-based representation, has been proposed as an exchange format for a select subset of information, it lacks domain-specific semantics that are essential for answering questions that require expert knowledge. Here, we describe an RNA knowledge base (RKB) for structure-based knowledge using RDF/OWL Semantic Web technologies. RKB extends a number of ontologies and contains basic terminology for nucleic acid composition along with context/model-specific structural features such as sugar conformations, base pairings and base stackings. RKB (available at http://semanticscience.org/projects/rkb) is populated with PDB entries and MC-Annotate structural annotation. We show queries to the RKB using description logic reasoning, thus opening the door to question answering over independently-published RNA knowledge using Semantic Web technologies.


Sexually-transmitted/founder HIV-1 cannot be directly predicted from plasma or PBMC-derived viral quasispecies in the transmitting partner.
Characterization of HIV-1 sequences in newly infected individuals is important for elucidating the mechanisms of viral sexual transmission. We report the identification of transmitted/founder viruses in eight pairs of HIV-1 sexually-infected patients enrolled at the time of primary infection ("recipients") and their transmitting partners ("donors"). Using a single genome-amplification approach, we compared quasispecies in donors and recipients on the basis of 316 and 376 C2V5 env sequences amplified from plasma viral RNA and PBMC-associated DNA, respectively. Both DNA and RNA sequences indicated very homogeneous viral populations in all recipients, suggesting transmission of a single variant, even in cases of recent sexually transmitted infections (STIs) in donors (n = 2) or recipients (n = 3). In all pairs, the transmitted/founder virus was derived from an infrequent variant population within the blood of the donor. The donor variant sequences most closely related to the recipient sequences were found in plasma samples in 3/8 cases and/or in PBMC samples in 6/8 cases. Although donors were exclusively (n = 4) or predominantly (n = 4) infected by CCR5-tropic (R5) strains, two recipients were infected with highly homogeneous CXCR4/dual-mixed-tropic (X4/DM) viral populations, identified in both DNA and RNA. The proportion of X4/DM quasispecies in donors was higher in cases of X4/DM than R5 HIV transmission (16.7-22.0% versus 0-2.6%), suggesting that X4/DM transmission may be associated with a threshold population of X4/DM circulating quasispecies in donors. These suggest that a severe genetic bottleneck occurs during subtype B HIV-1 heterosexual and homosexual transmission. Sexually-transmitted/founder virus cannot be directly predicted by analysis of the donor's quasispecies in plasma and/or PBMC. Additional studies are required to fully understand the traits that confer the capacity to transmit and establish infection, and determine the role of concomitant STIs in mitigating the genetic bottleneck in mucosal HIV transmission.


Hypertension control in ambulatory care patients with diabetes.
Hypertension (HTN) control among diabetics is essential to preventing macrovascular complications. We investigated correlates of HTN control among a national sample of 1313 patients with diabetes receiving care in ambulatory care settings. The current study employed extant data from the 2008 National Ambulatory Care Survey. Multivariate logistic regression analyses were employed to examine the relationship between HTN control and candidate covariates, including race, income, provider, and facility characteristics, and patient demographic and health status indicators among patients with diabetes receiving care in ambulatory care facilities. Approximately 28.7% of patients achieved HTN control at the level of 130/80 mm Hg and 57.0% at 140/90 mm Hg. Patients seen at physician offices or academic medical center/hospital settings had greater probability of HTN control compared with outpatient departments and community health centers. Patients seen in academic medical centers or other hospital settings had the greatest probability of control (47.9% at 130/80 mm Hg and 70% at 140/90 mm Hg, P < .0001). Despite being more likely to be on antihypertensive medications, black patients with diabetes had the lowest probability of HTN control at the level of 140/90 mm Hg (41.1%) or 130/80 mm Hg (19.0%) compared with other race/ethnic groups (P < .0001). Patients with diabetes seen in diverse primary care settings had a low probability of having blood pressure (BP) controlled to the recommended levels. Care setting-specific policies may prove useful in improving BP control. Continued attention is still warranted for racial and ethnic disparities in HTN control.


A novel mechanism of aluminum-induced cell death involving vacuolar processing enzyme and vacuolar collapse in tobacco cell line BY-2.
The role of vacuole in the cell death mechanism induced by aluminum (Al) was investigated in tobacco (Nicotiana tabacum L.) cell line BY-2. Cells at logarithmic phase of growth were treated without (control) or with Al (up to 150 μM) in a treatment medium containing CaCl2, sucrose and 2-(N-morpholino) ethanesulfonic acid (MES) buffer (pH 5.0). After 18 h treatment, both the integrity of the plasma membrane (estimated by Evans blue uptake) and growth capacity (estimated by post-Al treatment growth in nutrient medium) were decreased, while the activity of vacuolar processing enzyme (VPE) was increased, in the Al dose-dependent manner. The activity of the vacuole (estimated by neutral red uptake) was slightly increased at 50 μM then decreased with an increase in Al concentration. Direct observation of morphological changes of vacuole in a transgenic BY-2 expressing GFP-AtVam3p fusion protein localized on tonoplast indicated Al-induced collapse of vacuole. Time-course experiments indicated that both an increase in VPE activity and a loss of growth capacity were clearly observed at 6 h of the treatment time, prior to the loss of plasma membrane integrity. The presence of Ac-YVAD-CHO (an inhibitor effective to VPE) during Al treatment suppressed a loss of plasma membrane integrity. The expression of VPE genes (VPE-1a, VPE-1b) were significantly enhanced by Al treatment. Taken together, we conclude that an enhancement of VPE activity by Al is controlled at transcriptional level, and is a key factor leading to a loss of integrity of the plasma membrane and a loss of growth capacity.


Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.
Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).


Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment.
Lymphocyte homing is mediated by specific interaction between L-selectin on lymphocytes and the carbohydrate ligand 6-sulfo sialyl Lewis X on high endothelial venules. Here we generated mice lacking both core 1 extension and core 2 branching enzymes to assess the functions of O-glycan-borne L-selectin ligands in vivo. Mutant mice maintained robust lymphocyte homing, yet they lacked O-glycan L-selectin ligands. Biochemical analyses identified a class of N-glycans bearing the 6-sulfo sialyl Lewis X L-selectin ligand in high endothelial venules. These N-glycans supported the binding of L-selectin to high endothelial venules in vitro and contributed in vivo to O-glycan-independent lymphocyte homing in wild-type and mutant mice. Our results demonstrate the critical function of N-glycan-linked 6-sulfo sialyl Lewis X in L-selectin-dependent lymphocyte homing and recruitment.


Anti-apoptotic effect of clusterin on cisplatin-induced cell death of retinoblastoma cells.
Clusterin is a cytoprotective chaperone protein that is known to protect various retinal cells. It was also reported to be overexpressed in several types of malignant tumors, whose chemoresistance correlates with the expression of clusterin. Herein, we investigated the effect of clusterin on cisplatin-induced cell death of retinoblastoma cells. Firstly, evaluation of clusterin expression demonstrated that it was highly expressed in human retinoblastoma tissues and cell lines (SNUOT-Rb1 and Y79) particularly in the area between viable cells around vessels and necrotic zones in the relatively avascular area in human retinoblastoma tissues. Furthermore, the effects of cisplatin on retinoblastoma cells were evaluated. Cisplatin (1 µg/ml) significantly affected cell viability of SNUOT-Rb1 cells by inducing caspase-3-dependent apoptosis. Notably, the cell death due to cisplatin was prevented by 5 µg/ml of clusterin administered 4 h prior to cisplatin treatment by inhibiting cisplatin-induced apoptosis. Furthermore, overexpression of clusterin exerted its anti-apoptotic effect on cisplatin-induced apoptosis, and effectively prevented cisplatin-induced cell death. These data suggest that clusterin, found to be expressed in human retinoblastoma, may exert anti-apoptotic effects on cisplatin-induced apoptosis and prevent cell death. Therefore, clusterin can contribute to cisplatin resistance of retinoblastoma.


Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. Wortmannin is not a specific inhibitor of phosphatidylinositol 3-kinase.
Wortmannin and its structural analogue demethoxyviridin (DMV) have been reported to be specific inhibitors of phosphatidylinositol 3-kinase activity. Here we report that these compounds are not as selective as assumed and demonstrate inhibition of bombesin-stimulated phospholipase A2 activity by both wortmannin and DMV with an IC50 (2 nM) which is slightly more potent than the inhibition of insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate generation in these cells (approximately 10nM). While it has not been possible to fully block in vitro phospholipase A2 activity with wortmannin, inhibition cannot be a consequence of inhibition of PI 3-kinase activity since bombesin fails to generate 3-phosphorylated lipids in the intact cell. Therefore, while wortmannin is indeed a PI 3-kinase inhibitor, it is not as specific as previously reported, and experimental conclusions based solely on its use should be treated with caution.


Role of child neurologists and neurodevelopmentalists in the diagnosis of cerebral palsy: A survey study.
To contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care. The optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group). CNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present. Given its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.


In vitro nephrotoxicity and anticancer potency of newly synthesized cadmium complexes.
Complexes based on heavy metals have great potential for the treatment of a wide variety of cancers but their use is often limited due to toxic side effects. Here we describe the synthesis of two new cadmium complexes using N(4)-phenyl-2-formylpyridine thiosemicarbazone (L1) and 5-aminotetrazole (L2) as organic ligands and the evaluation of their anti-cancer and nephrotoxic potential in vitro. The complexes were characterized by Single-crystal X-ray data diffraction, 1HNMR, FT-IR, LC/MS spectrometry and CHN elemental analysis. Next, cytotoxicity of these cadmium complexes was evaluated in several cancer cell lines, including MCF-7 (breast), Caco-2 (colorectal) and cisplatin-resistant A549 (lung) cancer cell lines, as well as in conditionally-immortalized renal proximal tubule epithelial cell lines for evaluating nephrotoxicity compared to cisplatin. We found that both compounds were toxic to the cancer cell lines in a cell-cycle dependent manner and induced caspase-mediated apoptosis and caspase-independent cell death. Nephrotoxicity of these compounds was compared to cisplatin, a known nephrotoxic drug, in vitro. Our results demonstrate that compound {2}, but not compound {1}, exerts increased cytotoxicity in MCF-7 and A549 cell lines, combined with reduced nephrotoxic potential compared to cisplatin. Together these data make compound {2} a likely candidate for further development in cancer treatment.


The interpectoral fascia flap.
Despite the great number of pedicled and free flaps that are available for defect and contour repair, the number of fascia flaps with an axial blood supply are sparse. Such flaps with their gliding function are mandatory, whenever coverage with very thin, well-vascularized tissue is necessary. To the currently established fascia flaps, (the temporoparietal fascia flap, the radial forearm fascia flap, the lateral arm fascia flap, and the serratus anterior fascia flap), we want to add a new fascia flap, the interpectoral fascia flap. We dissected the interpectoral fascia flap from 20 cadavers. In each of the 40 hemichests, the trunk of the thoracoacromial vessels was selectively injected with red polyurethane and the tissue containing the pectoral branches was separated from the overlying pectoralis major muscle and converted into an independent fascia flap. The maximum flap length was 13.5 cm and the maximum breadth was 10.3 cm. The length of the vascular pedicle before entering the flap was 3.9 cm +/- 1.4 cm with a range of 1.5-6.8 cm. Concerning the arc of rotation, all 40 flaps reached the posterior axillary fold, and 29 flaps (73%) reached the mandibular border. This new fascia flap has applications as pedicled and as free flap. The pedicled flap is used in the neck region, in the axillary region and as gliding tissue between the nipple-areola complex and the pectoralis major muscle. The usage of the fascia flap as a free flap has similar characteristics as the other fascia flaps.


Precambrian age of the Boston basin: new evidence from microfossils.
A Vendian (Late Proterozoic Z) age has been determined for the Boston Basin by comparison of a microflora from the Cambridge Argillite with other late Precambrian assemblages. The microfossils, which include Bavlinella cf. faveolata, are preserved as petrifactions in pyrite. This age designation for the sedimentary rocks of the Boston Basin should allow for the reinterpretation of the structure of the basin and its regional correlations.


Epidemiology of nosocomial acquisition of Candida lusitaniae.
Candida species are important nosocomial pathogens; however, little is known about the epidemiology of Candida lusitaniae, an organism frequently resistant to amphotericin B. We evaluated 98 patients admitted to the bone marrow transplant and medical intensive care units of a tertiary-care hospital. Each patient with C. lusitaniae was matched with control patients. Restriction fragment analysis of DNA was used to determine strain relatedness. Seven patients (7.1%) with C. lusitaniae were identified; five acquired C. lusitaniae after admission to the study unit. All isolates were susceptible to amphotericin B. There were no differences between patients and controls with regard to duration of stay in the study unit, antibiotic administration, antifungal therapy, immunosuppressive therapy, catheter use, or underlying disease. Temporal and geographic clustering of five patients with identical strains occurred. No common source was identified. Restriction fragment analysis revealed a total of eight strains, and five patients shared one strain type. These results demonstrate exogenous acquisition of C. lusitaniae. The mechanism of acquisition is probably indirect contact transmission between patients.


[Aortic atheroma: not a sensitive indicators for coronary artery disease in patients with mitral valve disease].
Aortic atheroma detected by transoesophageal echocardiography has been reported to be a good prognostic marker for coronary disease on angiography. The value of this detection in valvular heart disease would be to avoid preoperative coronary angiography in asymptomatic patients. The aim of this study was to assess the prognostic value of aortic atheroma in a population with a low prevalence of coronary artery disease in whom transoesophageal echocardiography was systematically performed. In addition, calcification of the aortic knuckle, a marker of atherosclerosis, was analysed by simple chest X-ray. One hundred and ninety two patients (103 men, 89 women; mean age: 63.1 +/- 15 years), operated for mitral valve replacement, underwent transoesophageal echocardiography, angiography, within 6 months, and chest X-ray. The cardiovascular risk factors, presence of aortic atherome, angiographic coronary artery disease and aortic calcification were studied. Aortic atheroma was observed in 72 patients (37.5%), usually in the descending thoracic aorta (73.6%). Coronary stenosis was observed in 36 patients (18.7%). On univariate analysis, aortic atherome predicted coronary stenosis with a sensitivity of 53%, specificity of 66% and positive predictive value of 26% and negative predictive value of 86%, compared with chest X-ray: 71%, 65%, 33% and 90%, respectively. In multivariate analysis, only hypercholesterolaemia, smoking and age predicted the presence of coronary artery disease. The presence of aortic atheroma was not predictive (p = 0.3). The authors conclude that aortic atheroma does not predict the presence of coronary artery disease in a patient population with mitral valve disease and a low prevalence of coronary artery disease. Simple chest X-ray has almost the same diagnostic value. The association of these two investigations does not give sufficient negative predictive values to avoid coronary angiography.


Proteomic analysis of the mouse liver mitochondrial inner membrane.
Mitochondria play a crucial role in cellular homeostasis, which justifies the increasing interest in mapping the different components of these organelles. Here we have focused our study on the identification of proteins of the mitochondrial inner membrane (MIM). This membrane is of particular interest because, besides the well known components of the respiratory chain complexes, it contains several ion channels and many carrier proteins that certainly play a key role in mitochondrial function and, therefore, deserve to be identified at the molecular level. To achieve this goal we have used a novel approach combining the use of highly purified mouse liver mitochondrial inner membranes, extraction of membrane proteins with organic acid, and two-dimensional liquid chromatography coupled to tandem mass spectrometry. This procedure allowed us to identify 182 proteins that are involved in several biochemical processes, such as the electron transport machinery, the protein import machinery, protein synthesis, lipid metabolism, and ion or substrate transport. The full range of isoelectric point (3.9-12.5), molecular mass (6-527 kDa), and hydrophobicity values (up to 16 transmembrane predicted domains) were represented. In addition, of the 182 proteins found, 20 were unknown or had never previously been associated with the MIM. Overexpression of some of these proteins in mammalian cells confirmed their mitochondrial localization and resulted in severe remodeling of the mitochondrial network. This study provides the first proteome of the MIM and provides a basis for a more detailed study of the newly characterized proteins of this membrane.


Stem cells increase in numbers in perinecrotic areas in human renal cancer.
Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis-associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4-coexpressing cells derived from the two responder xenograft models were used for in vitro studies. In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4-coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4-coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers.


[Immune System in Patients with Head and Neck Carcinoma].
The insight into the biological nature of head and neck squamous cell carcinoma has evolved significantly in the last few years. Tobacco use and alcohol consumption are proven risk factors of head and neck squamous cell carcinoma. Cancer patients possessing such a tumor are generally elderly, mostly in fifth or sixth decade of life. In addition, significant association of head and neck squamous cell carcinoma with infection by human papillomavirus (HPV) was proven. HPV is now considered to be one of the most important risk factors, particularly for oropharyngeal carcinoma. HPV positive tumors of oropharynx are associated with significantly better prognosis. Experimental and clinical data indicate that HPV positive and HPV negative tumors can be considered as two different entities and it has not been clarified which factors are crucial for better prognosis of HPV positive tumors. The character of immune reaction, which contributes to distinct prognosis, may be one of the important factors. This review summarizes current knowledge concerning various aspects of antitumor immune responses in HPV positive and HPV negative tumors. Recent studies have shown that a broad repertoire of tumor infiltrating HPV specific T-cells is detectable in almost all patients with HPV positive tumors. Despite this, there is a development of tumor, which may be facilitated by abnormalities in antigen processing, T-cell dysfunction or prevalence of immunosuppressive cells. Nonetheless, the immunologic profile of HPV positive vs. HPV negative head and neck squamous cell carcinoma is associated with better outcome, and HPV specific immune response is suggested to play an essential role in the better response to conventional therapy of HPV positive patients. We also discuss HPV specific antitumor immunotherapy approaches, which are now tested in clinical trials.


Optogenetic Monitoring of Synaptic Activity with Genetically Encoded Voltage Indicators.
The age of genetically encoded voltage indicators (GEVIs) has matured to the point that changes in membrane potential can now be observed optically in vivo. Improving the signal size and speed of these voltage sensors has been the primary driving forces during this maturation process. As a result, there is a wide range of probes using different voltage detecting mechanisms and fluorescent reporters. As the use of these probes transitions from optically reporting membrane potential in single, cultured cells to imaging populations of cells in slice and/or in vivo, a new challenge emerges-optically resolving the different types of neuronal activity. While improvements in speed and signal size are still needed, optimizing the voltage range and the subcellular expression (i.e., soma only) of the probe are becoming more important. In this review, we will examine the ability of recently developed probes to report synaptic activity in slice and in vivo. The voltage-sensing fluorescent protein (VSFP) family of voltage sensors, ArcLight, ASAP-1, and the rhodopsin family of probes are all good at reporting changes in membrane potential, but all have difficulty distinguishing subthreshold depolarizations from action potentials and detecting neuronal inhibition when imaging populations of cells. Finally, we will offer a few possible ways to improve the optical resolution of the various types of neuronal activities.


The cost of expecting events in the wrong sensory modality.
We examined the effects of modality expectancy on human performance. Participants judged azimuth (left vs. right location) for an unpredictable sequence of auditory, visual, and tactile targets. In some blocks, equal numbers of targets were presented in each modality. In others, the majority (75%) of the targets were presented in just one expected modality. Reaction times (RTs) for targets in an unexpected modality were slower than when that modality was expected or when no expectancy applied. RT costs associated with shifting attention from the tactile modality were greater than those for shifts from either audition or vision. Any RT benefits for the most likely modality were due to priming from an event in the same modality on the previous trial, not to the expectancy per se. These results show that stimulus-driven and expectancy-driven effects must be distinguished in studies of attending to different sensory modalities.


An evolutionary dynamics model adapted to eusocial insects.
This study aims to better understand the evolutionary processes allowing species coexistence in eusocial insect communities. We develop a mathematical model that applies adaptive dynamics theory to the evolutionary dynamics of eusocial insects, focusing on the colony as the unit of selection. The model links long-term evolutionary processes to ecological interactions among colonies and seasonal worker production within the colony. Colony population dynamics is defined by both worker production and colony reproduction. Random mutations occur in strategies, and mutant colonies enter the community. The interactions of colonies at the ecological timescale drive the evolution of strategies at the evolutionary timescale by natural selection. This model is used to study two specific traits in ants: worker body size and the degree of collective foraging. For both traits, trade-offs in competitive ability and other fitness components allows to determine conditions in which selection becomes disruptive. Our results illustrate that asymmetric competition underpins diversity in ant communities.


Adverse drug reactions causing admission to a paediatric hospital.
To obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health. Prospective observational study. A large tertiary children's hospital providing general and specialty care in the UK. All acute paediatric admissions over a one year period. Any medication taken in the two weeks prior to admission. Occurrence of adverse drug reaction. 240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia. Adverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed.


Effect of aluminum sulfate on litter composition and ammonia emission in a single flock of broilers up to 42 days of age.
New alternatives are necessary if the environmental impact linked to intensive poultry production is to be reduced, and different litter handling methods should be explored. Among these, acidifying amendments added to poultry litters has been suggested as a management practice to help reduce the potential environmental effect involved in multiple flock cycles. There have been several studies on the use of aluminum sulfate (alum) and its benefits, but almost no data are available under farm conditions in Europe. An experiment with Ross 308 broilers from 1 to 42 days of age was conducted to evaluate the effect of alum on litter composition, the solubility of some mineral elements and NH3 emission during a single flock-rearing period in commercial houses located in southeast Spain. Broilers were placed on clean wood shavings in four commercial houses, containing 20 000 broilers each. Before filling, alum was applied at a rate of 0.25 kg/m2 to the wood shavings of two poultry houses, whereas the remaining two were used as control. Litter from each poultry house was sampled every 3 to 5 days. Ammonia emissions from the poultry houses were monitored from 37 to 42 days of age. In comparison with the control group, alum treatment significantly reduced the pH level of the litter (P < 0.001) with an average difference of 1.32 ± 0.24 units. Alum-treated litter showed, on average, a higher electrical conductivity than the control litter (5.52 v. 3.63 dS/m). The dry matter (DM) and total N and P contents did not show differences between the treatments (P > 0.05). Regarding the NH4 +-N content, alum-treated litter showed a higher value than the untreated litter, with an average difference of 0.16 ± 0.07% (on a DM basis). On average, alum-treated litter had lower water-soluble P, Zn and Cu contents than the untreated litter. Alum noticeably reduced the in-house ammonia concentration (P < 0.001), with an average of 4.8 ppm at 42 days of age (62.9% lower than the control), and ammonia emissions from 37 to 42 days of age were significantly reduced by the alum treatment (P < 0.001), representing a reduction of 73.3%. The lower pH values might have reduced ammonia volatilization from the litter, with a corresponding positive effect on the building environment and poultry health. For these reasons, litter amendment with alum could be recommended as a way of reducing the pollution potential of European broiler facilities during a single flock cycle.


Two new species of erect Bryozoa (Gymnolaemata: Cheilostomata) and the application of non-destructive imaging methods for quantitative taxonomy.
Two new species of cheilostome Bryozoa are described from continental-slope habitats off Mauritania, including canyon and cold-water coral (mound) habitats. Internal structures of both species were visualised and quantified using microcomputed tomographic (micro-CT) methods. Cellaria bafouri n. sp. is characterised by the arrangement of zooids in alternating longitudinal rows, a smooth cryptocyst, and the presence of an ooecial plate with denticles. Smittina imragueni n. sp. exhibits many similarities with Smittina cervicornis (Pallas, 1766), but differs especially in the shape and orientation of the suboral avicularium. Observations on Smittina imragueni and material labelled as Smittina cervicornis suggest that the latter represents a species group, members of which have not yet been discriminated, possibly because of high intracolony variation and marked astogenetic changes in surface morphology. Both new species are known only from the habitats where they were collected, probably reflecting the paucity of bryozoan sampling from this geographic area and depth range. Both species are able to tolerate low oxygen concentration, which is assumed to be compensated by the high nutrient supply off Mauritania. The application of micro-CT for the semiautomatic quantification of zooidal skeletal characters was successfully tested. We were able to automatically distinguish individual zooidal cavities and acquire corresponding morphological datasets. Comparing the obtained results with conventional SEM measurements allowed ascertaining the reliability of this new method. The employment of micro-CT allows the observation and quantification of previously unseen characters that can be used in describing and differentiating species that were previously indistinguishable. Furthermore, this method might help elucidate processes of colony growth and the function of individual zooids during this process.


Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains.
The molecular size of the plasma LDL (low density lipoprotein) receptor synthesized by cultured fibroblasts from a patient with the internalization-defective form of familial hypercholesterolemia (FH 274) was smaller by 10,000 daltons than the size of the normal LDL receptor. The segment of the gene encoding the truncated portion of the FH 274 receptor was cloned into bacteriophage lambda. Comparison of the nucleotide sequences of the normal and FH 274 genes revealed a 5-kilobase deletion, which eliminated the exons encoding the membrane-spanning region and the carboxyl terminal cytoplasmic domain of the receptor. The deletion appeared to be caused by a novel intrastrand recombination between two repetitive sequences of the Alu family that were oriented in opposite directions. The truncated receptors lack membrane-spanning regions and cytoplasmic domains; they are largely secreted into the culture medium, but a small fraction remains adherent to the cell surface. The surface-adherent receptors bind LDL, but they are unable to cluster in coated pits, thus explaining the internalization-defective phenotype.


Collagen inhibitory peptide R1R2 mediates vascular remodeling by decreasing inflammation and smooth muscle cell activation.
The extracellular matrix (ECM) is a major constituent of the vessel wall. In addition to providing a structural scaffold, the ECM controls numerous cellular functions in both physiologic and pathologic settings. Vascular remodeling occurs after injury and is characterized by endothelial cell activation, inflammatory cell infiltration, phenotypic modulation of smooth muscle cells (SMCs), and augmented deposition of collagen-rich ECM. R1R2, a peptide derived from the bacterial adhesin SFS, with sequence homology to collagen, is known to inhibit collagen type I deposition in vitro by inhibiting the binding of fibronectin to collagen. However, the inhibitory effects of R1R2 during vascular remodeling have not been explored. We periadventitially delivered R1R2 to carotid arteries using pluronic gel in a vascular remodeling mouse model induced by blood flow cessation, and evaluated its effects on intima-media thickening, ECM deposition, SMC activation, and inflammatory cell infiltration. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening compared to the control groups. R1R2 treatment also decreased collagen type I deposition in the vessel wall, and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by ∼ 78%. This decrease was accompanied by decreased VCAM-1 and ICAM-1 expression. Our in vitro studies revealed that R1R2 attenuated SMC proliferation and migration, and also decreased monocyte adhesion and transendothelial migration through endothelial cells. Together, these data suggest that R1R2 attenuates vascular remodeling responses by decreasing inflammation and by modulating SMC proliferation and migration, and suggest that the R1R2 peptide may have therapeutic potential in treating occlusive vascular diseases.


BSE in Northern Ireland: epidemiological patterns past, present and future.
By 30 January 1998, there had been 170,259 confirmed cases of BSE in Great Britain (GB), 1766 confirmed cases in Northern Ireland (NI) (2 January 1998), and 276 confirmed cases in the Republic of Ireland (31 January 1998). Analysis of the epidemiological patterns in the NI epidemic reveals significant clustering of cases in herds and counties. The observed clustering of cases within herds results in lower per capita incidence of BSE in previously unaffected herds, providing support for the introduction of a certified herd scheme in NI. By fitting a backcalculation model to the case data, we can estimate the number of animals infected with the aetiological agent of BSE and project the number of future cases. We predict that the epidemic will decline rapidly, with approximately 99 cases (95% confidence interval 30,504) occurring in the five year period 1997-2001.


Continuing education for primary health care nurse practitioners in Ontario, Canada.
The Council of Ontario University Programs in Nursing offers a nine-university, consortium-based primary health care nurse practitioner education program and on-line continuing education courses for primary health care nurse practitioners. Our study sought to determine the continuing education needs of primary health care nurse practitioners across Ontario, how best to meet these needs, and the barriers they face in completing continuing education. Surveys were completed by 83 (40%) of 209 learners who had participated in continuing education offered by the Council of Ontario University Programs in Nursing between 2004 and 2007. While 83% (n=50) of nurse practitioners surveyed indicated that continuing education was extremely important to them, they also identified barriers to engaging in continuing education offerings including; time intensity of the courses, difficulty taking time off work, family obligations, finances and fatigue. The most common reason for withdrawal from a continuing education offering was the difficulty of balancing work and study demands. Continuing education opportunities are important to Ontario primary health care nurse practitioners, and on-line continuing education offerings have been well received, but in order to be taken up by their target audience they must be relevant, readily accessible, flexible, affordable and offered over brief, intense periods of time using technology that is easy to use and Internet sites that are easily navigated.


Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs.
Dishevelled (DVL) is an essential component of the Wnt signaling cascades. Function of DVL is controlled by phosphorylation but the molecular details are missing. DVL3 contains 131 serines and threonines whose phosphorylation generates complex barcodes underlying diverse DVL3 functions. In order to dissect the role of DVL phosphorylation we analyzed the phosphorylation of human DVL3 induced by previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and newly identified (TTBK2, Aurora A) DVL kinases. Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on immunoprecipitates from HEK293T cells was used to identify and quantify phosphorylation of DVL3 protein induced by 8 kinases. Functional characterization was performed by in-cell analysis of phospho-mimicking/non-phosphorylatable DVL3 mutants and supported by FRET assays and NMR spectroscopy. We used quantitative mass spectrometry and calculated site occupancies and quantified phosphorylation of > 80 residues. Functional validation demonstrated the importance of CK1ε-induced phosphorylation of S268 and S311 for Wnt-3a-induced β-catenin activation. S630-643 cluster phosphorylation by CK1, NEK2 or TTBK2 is essential for even subcellular distribution of DVL3 when induced by CK1 and TTBK2 but not by NEK2. Further investigation showed that NEK2 utilizes a different mechanism to promote even localization of DVL3. NEK2 triggered phosphorylation of PDZ domain at S263 and S280 prevents binding of DVL C-terminus to PDZ and promotes an open conformation of DVL3 that is more prone to even subcellular localization. We identify unique phosphorylation barcodes associated with DVL function. Our data provide an example of functional synergy between phosphorylation in structured domains and unstructured IDRs that together dictate the biological outcome. Video Abtract.


Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.
There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.


Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome.
Liposomal drugs accumulate only in perivascular regions in tumors after i.v. injection. Thus, they cannot kill tumor cells in deeper tissue layers. To circumvent this problem, we investigated effects of doxorubicin (DOX) encapsulated in a lysolecithin-containing thermosensitive liposome (LTSL) on tumor microcirculation because damaging microvessels would stop nutrient supply to deeper tumor cells. We used LTSL-DOX in combination with hyperthermia to treat a human squamous carcinoma xenograft (FaDu) implanted in dorsal skinfold chambers in nude mice. Before the treatment, the RBC velocity in tumors was 0.428 +/- 0.037 mm/s and the microvascular density was 3.93 +/- 0.44 mm/mm(2). At 24 hours after the treatment, they were reduced to 0.003 +/- 0.003 mm/s and 0.86 +/- 0.27 mm/mm(2), respectively. The same treatment, however, caused only 32% decrease in the RBC velocity and no apparent change in microvascular networks in normal s.c. tissues over the same period. LTSL and LTSL-DOX alone had no effect on tumor microcirculation, and LTSL plus hyperthermia caused only a transient decrease in the RBC velocity in tumors. At 24 hours after treatments, tumor microcirculation in all these control experiments was insignificantly different from that before the treatments. We also examined apoptosis of cells in tumors at different time points after LTSL-DOX plus hyperthermia treatment and observed few apoptotic cells in tumor microvessels. In conclusion, the rapid release of DOX during hyperthermia could make the drug to shutdown tumor blood flow while have only minor effects on normal microcirculation in s.c. tissues.


Cognition in epilepsy patients with hypothalamic hamartomas.
Many patients with epilepsy caused by hypothalamic hamartomas (HHs) have cognitive impairments during the course of the disease or following neurosurgical treatment. The purpose of this study was to assess cognitive function in these patients, as well as factors influencing preoperative cognitive performance and cognitive outcome after neurosurgical treatment. Using the two largest and most detailed neuropsychology datasets on HH and epilepsy from two centers, we retrospectively report on cognitive functions in 48 patients with structural epilepsy due to HH (mean age ± standard deviation [SD] 20 ± 12 years, range 5-53 years, median 16 years; disease duration mean 17 ± 11 years). Intelligence, verbal learning and recall, and speed and executive functions (processing speed and cognitive flexibility) were assessed before and on average 19 (±11) months after surgery (interstitial radiosurgery: N = 22; neurosurgical resection/disconnection: N = 26). Prior to neurosurgical treatment, 52% of patients showed impaired executive and 62% showed reduced verbal memory functions. A trend for a detrimental effect of higher drug load on cognitive functioning was found. After neurosurgical treatment, intellectual functions for the entire cohort tended to increase. This correlated with improved seizure frequency and decreased number of antiepileptic drugs (AEDs). However, postoperative outcomes for individual patients were highly variable, with significant deteriorations in 17% (processing speed) to 34% (cognitive flexibility and verbal learning), and performance increases in 17% (intellectual functioning) up to 39% (processing speed) of the patients. Higher levels of presurgical performance were significant predictors of cognitive decline after surgery. These results are highly relevant for patient consultation and may help with therapeutic decisions.


Insulin-releasing and insulin-like activity of the traditional anti-diabetic plant Coriandrum sativum (coriander).
Coriandrum sativum (coriander) has been documented as a traditional treatment of diabetes. In the present study, coriander incorporated into the diet (62.5 g/kg) and drinking water (2.5 g/l, prepared by 15 min decoction) reduced hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of coriander (1 mg/ml) increased 2-deoxyglucose transport (1.6-fold), glucose oxidation (1.4-fold) and incorporation of glucose into glycogen (1.7-fold) of isolated murine abdominal muscle comparable with 10(-8) M-insulin. In acute 20 min tests, 0.25-10 mg/ml aqueous extract of coriander evoked a stepwise 1.3-5.7-fold stimulation of insulin secretion from a clonal B-cell line. This effect was abolished by 0.5 mM-diazoxide and prior exposure to extract did not alter subsequent stimulation of insulin secretion by 10 mM-L-alanine, thereby negating an effect due to detrimental cell damage. The effect of extract was potentiated by 16.7 mM-glucose and 10 mM-L-alanine but not by 1 mM-3-isobutyl-1-methylxanthine. Insulin secretion by hyperpolarized B-cells (16.7 mM-glucose, 25 mM-KCl) was further enhanced by the presence of extract. Activity of the extract was found to be heat stable, acetone soluble and unaltered by overnight exposure to acid (0.1 M-HCl) or dialysis to remove components with molecular mass < 2000 Da. Activity was reduced by overnight exposure to alkali (0.1 M-NaOH). Sequential extraction with solvents revealed insulin-releasing activity in hexane and water fractions indicating a possible cumulative effect of more than one extract constituent. These results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in Coriandrum sativum.


Pest categorisation of Nemorimyza maculosa.
The EFSA Panel on Plant Health performed a pest categorisation of Nemorimyza maculosa (Malloch) (Diptera: Agromyzidae) for the European Union (EU). N. maculosa is an oligophagous pest; cultivated hosts include Chrysanthemum, lettuce and other Asteraceae although there is little evidence of recent impacts. N. maculosa occurs widely in the Americas and is present on the island of Madeira (Portugal), where it is under official control. N. maculosa is not known to occur in mainland Portugal based on surveys. N. maculosa can have multiple overlapping generations per year. Eggs are inserted into the leaves of host plants. Developing larvae feed within leaves causing blotch mines. Pupation takes place in the soil or under debris on the ground. Immature stages on leafy host plant material such as Chrysanthemum cut flowers provide potential pathways for entry into the EU. Human-assisted movement of cut flowers, fresh leafy hosts for consumption and plants for planting with foliage are considered the main pathways for entry. Climatic conditions and the wide availability of cultivated and wild host plants provide conditions to support establishment in the EU in the open and in greenhouse. The extent of potential impacts on hosts such as ornamental Asteraceae and lettuce in the EU is uncertain. N. maculosa is regulated in the EU by Commission Implementing Regulation 2019/2072 (Annex IIA) where it appears using a synonym, Amauromyza maculosa. Within the Regulation, the import of soil or growing medium, from third countries other than Switzerland is regulated and therefore prevents the entry of N. maculosa pupae. All criteria assessed by EFSA above for consideration either as a potential union quarantine pest or as a potential regulated non-quarantine pest were met.


Conformational changes and ligand recognition of Escherichia coli D-xylose binding protein revealed.
ATP binding cassette transport systems account for most import of necessary nutrients in bacteria. The periplasmic binding component (or an equivalent membrane-anchored protein) is critical to recognizing cognate ligand and directing it to the appropriate membrane permease. Here we report the X-ray structures of D-xylose binding protein from Escherichia coli in ligand-free open form, ligand-bound open form, and ligand-bound closed form at 2.15 Å, 2.2 Å, and 2.2 Å resolutions, respectively. The ligand-bound open form is the first such structure to be reported at high resolution; the combination of the three different forms from the same protein furthermore gives unprecedented details concerning the conformational changes involved in binding protein function. As is typical of the structural family, the protein has two similar globular domains, which are connected by a three-stranded hinge region. The open liganded structure shows that xylose binds first to the C-terminal domain, with only very small conformational changes resulting. After a 34° closing motion, additional interactions are formed with the N-terminal domain; changes in this domain are larger and serve to make the structure more ordered near the ligand. An analysis of the interactions suggests why xylose is the preferred ligand. Furthermore, a comparison with the most closely related proteins in the structural family shows that the conformational changes are distinct in each type of binding protein, which may have implications for how the individual proteins act in concert with their respective membrane permeases.


How the Zundel (H5O2+) Potential Can Be Used to Predict the Proton Stretch and Bend Frequencies of Larger Protonated Water Clusters.
From a series of seminal experiments on the IR spectra of protonated water clusters and associated theoretical analyses, it is clear that the energies and spectral features of the proton stretch and bend modes are very sensitive functions of the cluster size. Here we show that this dynamic range can be understood by examining the sensitivity of these modes in the potential of the Zundel cation, H5O2+, as the separation of the two water monomers is varied. As this distance increases, the proton increasingly localizes on a monomer, and this is encoded in the IR spectrum of the proton vibrational modes. The quantitative predictions from this simple correlation are verified for the H7O3+ and H9O4+ clusters, for which new benchmark harmonic frequencies are reported. The predictions are also in good accord with trends seen experimentally and previous calculations for these and five other clusters, including H+(H2O)21.


The effects of diethylstilbestrol administration on rat kidney. Ultrastructural study.
To assess the histological and ultrastructural changes that can be induced by diethylstilbestrol (DES) on renal tissues using histological, immunohistochemical, and ultrastructural methods. Thirty adult male Wistar rats were divided into 3 groups (10 rats each): Group 1 - control; Group 2 - received DES at a dose of 60 ug/kg/day, dissolved in 0.1 ml corn oil for 20 days; and Group 3 - received the same dose of DES for 50 days by oral gavage. The renal tissues were studied histologically, immunohistochemically (using an anti-BCL2-associated X protein [BAX protein] antibody), and ultrastructurally. This study was carried out at the Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between December 2011 and December 2012. The DES administration for 50 days caused noticeable degeneration, and alteration of the morphology of the renal tissues in the form of damaged renal tubules with loss of the brush border of the proximal convoluted tubules and increased cellularity of the glomeruli. In addition, there was a significant increase in BAX protein expression based on immunoreactivity, and in renal tubules, as well as glomerular cells. These changes were less obvious after 20 days of treatment. Non-steroidal, synthetic estrogens showed harmful effects on the renal tissues and altered their morphology with an increased number of apoptotic cells, and these changes were duration dependent.


Neural network configuration and efficiency underlies individual differences in spatial orientation ability.
Spatial orientation is a complex cognitive process requiring the integration of information processed in a distributed system of brain regions. Current models on the neural basis of spatial orientation are based primarily on the functional role of single brain regions, with limited understanding of how interaction among these brain regions relates to behavior. In this study, we investigated two sources of variability in the neural networks that support spatial orientation--network configuration and efficiency--and assessed whether variability in these topological properties relates to individual differences in orientation accuracy. Participants with higher accuracy were shown to express greater activity in the right supramarginal gyrus, the right precentral cortex, and the left hippocampus, over and above a core network engaged by the whole group. Additionally, high-performing individuals had increased levels of global efficiency within a resting-state network composed of brain regions engaged during orientation and increased levels of node centrality in the right supramarginal gyrus, the right primary motor cortex, and the left hippocampus. These results indicate that individual differences in the configuration of task-related networks and their efficiency measured at rest relate to the ability to spatially orient. Our findings advance systems neuroscience models of orientation and navigation by providing insight into the role of functional integration in shaping orientation behavior.


Toker cells of the nipple are commonly associated with underlying sebaceous glands but not with lactiferous ducts.
Toker cells are clear cells present in the squamous epithelium of the nipple of some women. In contrast to squamous epithelium, they are cytokeratin 7 (CK7) positive. The origin of these cells is not completely understood. It has been suggested that they may represent abortive glands or migratory ductal cells; and may be precursors of Paget's disease of the nipple. Our aim was to investigate the incidence and distribution of Toker cells and their relationship with lactiferous ducts. We examined nipple sections from 100 consecutive mastectomies performed at Charing Cross hospital. New sections were stained for CK7 using the immunoperoxidase technique. Toker cells were identified in 11 cases. They were always clustered within the squamous epithelium superficial to sebaceous glands with no relationship with lactiferous ducts. Two cases in the study had Paget's disease and these were not associated with underlying sebaceous glands. This study suggests that Toker cells are more likely to be developmentally related to sebaceous glands rather than lactiferous ducts. This raises doubts about the presence of a relationship between Toker cells and the common forms of Paget's disease, as the latter are commonly seen in association with ductal carcinoma in situ (DCIS) involving underlying lactiferous ducts. Toker cells, however, may be related to a less common form of Paget's disease which is not associated with underlying DCIS.


Structural color mechanism in the Papilio blumei butterfly.
The structural color found in biological systems has complicated nanostructure. It is very important to determine its color mechanism. In this study, the 2D photonic crystal structures of the Papilio blumei butterfly were constructed, and the corresponding reflectance spectra were simulated by the finite-difference time-domain method. The structural color of the butterfly depends on the incident angle of light, film thickness, film material (film refractive index), and the size of the air hole (effective refractive index). Analysis of simulations can help us understand the hue, brightness, and saturation of structural color on the butterfly wing. As a result, the analysis can help us fabricate expected structural color.


An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481--The Home INR Study (THINRS).
Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.


Antisocial personality--diagnosis or moral judgment?
Antisocial personality is a problem-filled diagnosis. Even when diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) II manual, it was replete with value laden terminology. DSM III makes repeated criminal behavior central and includes a list of other behaviors that do not always truly imply an antisocial personality. In order to test the possibility that factors other than those listed in the manual may often influence the diagnosis, the prevalence of required characteristics in patients diagnosed antisocial personality was compared with the prevalence of required characteristics in another personality disorder, schizoid personality. The study involved a hospitalized Veteran's Administration (VA) population, employing DSM II criteria, which was used by the VA at that time. The difference was statistically highly significant. Examination of the case histories suggests that dislike of the patients or negative moral judgments about their actions frequently were involved in making a diagnosis of antisocial personality. It is therefore crucial that moral judgments not be disguised as scientific ones, and the meaning of an antisocial personality diagnosis as utilized by clinicians needs to be seriously questioned.


An analysis of DNA ploidy pattern of hepatocellular carcinoma.
To determine whether a relationship exists between DNA ploidy and the prognosis of hepatocellular carcinoma (HCC), flow cytometric DNA analysis was performed in paraffin-embedded specimens obtained from 44 patients with HCC who underwent hepatectomy. There were 26 diploid (59%) and 18 aneuploid (41%) tumors. No correlation was shown between DNA ploidy pattern and patient age, sex, liver cirrhosis, hepatitis B virus antigen and serum alpha-fetoprotein level. The ploidy pattern had no significant correlation with the presence of vascular invasion or intrahepatic metastasis. Only Edmondson's grade was well correlated with the ploidy pattern. We noted a significant correlation between survival rates and the presence of vascular invasion or intrahepatic metastasis (p < 0.05). In contrast, no significant correlation was found between DNA ploidy pattern and the prognosis of HCC. The results of this study indicate that DNA ploidy pattern may not be a useful indicator for the prognosis of HCCs after hepatic resection, unlike the results of gastric and colon cancers.


Borreliosis Transmission from Ticks Associated with Desert Tortoise Burrows: Examples of Tick-Borne Relapsing Fever in the Mojave Desert.
Ticks transmit pathogens and parasitize wildlife in turn causing zoonotic diseases in many ecosystems. Argasid ticks, such as Ornithodoros spp., harbor and transmit Borrelia spp., resulting in tick-borne relapsing fever (TBRF) in people. In the western United States, TBRF is typically associated with the bite of an infected Ornithodoros hermsi tick found in habitats at high elevations (>1500 ft). This report describes the first TBRF cases in people in the Mojave Desert (Clark County, NV). Individuals documented in these case studies were exposed to Ornithodoros ticks during excavation of soil burrows associated with Mojave Desert tortoises (Gopherus agassizii), with bacteria from one of the human case's blood sample genetically matching to Borrelia turicatae as determined by quantitative PCR and sequencing. Our findings should serve as a precaution to individuals working with tortoises or animal burrows, or those in contact with Ornithodoros ticks in this region.


How can contemporary art contribute toward the development of social and cultural capital for people aged 64 and older.
This article focuses on how visiting contemporary art galleries and discussing the artwork in facilitated focus groups affected culturally inactive participants' social and cultural capital. The research is taken from a larger study that explored the contribution that visiting contemporary art galleries made to the well-being of people aged 64 and older. A total of 19 participants were given guided visits around 3 contemporary art galleries in the United Kingdom. Participants were drawn from categories identified as not already actively engaged in cultural activities (men, those with a limiting disability, people from minority ethnic backgrounds, those in lower socioeconomic groups and people living alone). Before and after each visit, focus group interviews were used to gage the impact of participation in the intervention in terms of subjective well-being. Follow-up interviews were held with participants and group leaders 2 years after the visits. Spontaneous reminiscence was a functional part of the discussion that facilitated shifts in participants' social and cultural capital. Participants developed bonding social capital with each other, bridging social capital with group leaders, and linking social capital with gallery staff and researchers. Participants' cultural capital developed in terms of an increase in knowledge and understanding of contemporary art. Understanding the interplay between social capital, cultural capital, and reminiscence has implications for programmers and policy makers trying to engage less culturally engaged participants in the arts. Developing bonding, bridging, and linking social capital and cultural capital through engagement with the arts may have implications for health, particularly among this demographic.


Epigenetic deregulation of genomic imprinting in humans: causal mechanisms and clinical implications.
Mammalian genes controlled by genomic imprinting play important roles in development and diverse postnatal processes. A growing number of congenital disorders have been linked to genomic imprinting. Each of these is caused by perturbed gene expression at one principal imprinted domain. Some imprinting disorders, including the Prader-Willi and Angelman syndromes, are caused almost exclusively by genetic mutations. In several others, including the Beckwith-Wiedemann and Silver-Russell growth syndromes, and transient neonatal diabetes mellitus, imprinted expression is perturbed mostly by epigenetic alterations at 'imprinting control regions' and at other specific regulatory sequences. In a minority of these patients, DNA methylation is altered at multiple imprinted loci, suggesting that common trans-acting factors are affected. Here, we review the epimutations involved in congenital imprinting disorders and the associated clinical features. Trans-acting factors known to be causally involved are discussed and other trans-acting factors that are potentially implicated are also presented.


Clinical characteristics of Dengue shock syndrome in Vietnamese children: a 10-year prospective study in a single hospital.
Dengue shock syndrome (DSS) is a severe manifestation of dengue virus infection that particularly affects children and young adults. Despite its increasing global importance, there are no prospective studies describing the clinical characteristics, management, or outcomes of DSS. We describe the findings at onset of shock and the clinical evolution until discharge or death, from a comprehensive prospective dataset of 1719 Vietnamese children with laboratory-confirmed DSS managed on a single intensive care unit between 1999 and 2009. The median age of patients was 10 years. Most cases had secondary immune responses, with only 6 clear primary infections, and all 4 dengue virus serotypes were represented during the 10-year study. Shock occurred commonly between days 4 and 6 of illness. Clinical signs and symptoms were generally consistent with empirical descriptions of DSS, although at presentation 153 (9%) were still febrile and almost one-third had no bleeding. Overall, 31 (2%) patients developed severe bleeding, primarily from the gastrointestinal tract, 26 of whom required blood transfusion. Only 8 patients died, although 123 of 1719 (7%) patients had unrecordable blood pressure at presentation and 417 of the remaining 1596 (26%) were hypotensive for age. The majority recovered well with standard crystalloid resuscitation or following a single colloid infusion. All cases were classified as severe dengue, while only 70% eventually fulfilled all 4 criteria for the 1997 World Health Organization classification of dengue hemorrhagic fever. With prompt intervention and assiduous clinical care by experienced staff, the outcome of this potentially fatal condition can be excellent.


Contemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US.
To provide a contemporary estimate of the prevalence and incidence of rheumatoid arthritis (RA) work disability and examine its permanence over time. Data were collected semiannually from 5,384 subjects with rheumatologist-diagnosed RA. We examined prevalence in subgroups formed by approximately 5-year disease duration intervals using data from subjects age < or =64 years who were employed at disease onset. Annual incidence was examined longitudinally among subjects who supplied data in 2003, 2004, or 2005, were employed at disease onset and in a year's first survey, and were age < or =63 years. For work disability permanence we used longitudinal data from all subjects who became work disabled and observed whether they later returned to work. Mean age of subjects was 52 years, 82% were female, 63% had more than a high school education, mean disease duration was 14 years, and mean Health Assessment Questionnaire score was 1.0. The prevalence of any premature work cessation was 23% in subjects with 1-3 years duration, 35% in those with 10 years, and 51% in those with > or =25 years RA duration. Arthritis-attributed work cessation was 14%, 29%, and 42%, respectively. Annual incidence of any premature work cessation was approximately 10% and arthritis-attributed work cessation incidence was approximately 6%. Thirty-nine percent of subjects who stopped working later returned to work. Work disability prevalence in this sample was high (35% within 10 years disease duration), but may represent a decline from the 50% prevalence reported in 1987. Annual incidence of work disability was higher than prior studies, but the return to work rate was also higher.


Locomotor behavior of wild orangutans (Pongo pygmaeus wurmbii) in disturbed peat swamp forest, Sabangau, Central Kalimantan, Indonesia.
This study examined the locomotor behavior of wild Bornean orangutans (P. p. wurmbii) in an area of disturbed peat swamp forest (Sabangau Catchment, Indonesia) in relation to the height in the canopy, age-sex class, behavior (feeding or traveling), and the number of supports used to bear body mass. Backward elimination log-linear modeling was employed to expose the main influences on orangutan locomotion. Our results showed that the most important distinctions with regard to locomotion were between suspensory and compressive, or, orthograde (vertical trunk) and pronograde (horizontal trunk) behavior. Whether orangutans were traveling or feeding had the most important influence on locomotion whereby compressive locomotion had a strong association with feeding, suspensory locomotion had a strong association with travel in the peripheral strata using multiple supports, whereas vertical climb/descent and oscillation showed a strong association with travel on single supports in the core stratum. In contrast to theoretical predictions on positional behavior and body size, age-sex category had a limited influence on locomotion. The study revealed that torso orthograde suspension dominates orangutan locomotion, concurring with previous studies in dipterocarp forest. But, orangutans in the Sabangau exhibited substantially higher frequencies of oscillatory locomotion than observed at other sites, suggesting this behavior confers particular benefits for traversing the highly compliant arboreal environment typical of disturbed peat swamp forest. In addition, torso pronograde suspensory locomotion was observed at much lower levels than in the Sumatran species. Together these results highlight the necessity for further examination of differences between species, which control for habitat.


Bixa orellana leaves extract inhibits bradykinin-induced inflammation through suppression of nitric oxide production.
The present study was conducted to assess the anti-inflammatory effect of a crude aqueous extract of Bixa orellana leaves (AEBO) and to examine the possible involvement of nitric oxide (NO) in its anti-inflammatory mechanism. The air-dried, powdered leaves were soaked in distilled water (1:20 w/v) at 50°C for 24 h and the supernatant obtained was freeze-dried (yield 8.5% w/w). The dosage was recorded as the mass of extract per kg b.w. of rats in all inflammatory assays (bradykinin-induced paw edema, peritoneal vascular permeability and NO assay). Pretreatment with AEBO for 4 consecutive days exhibited significant inhibitory activity against inflammatory models, the bradykinin-induced hind paw edema model and bradykinin-induced increased peritoneal vascular permeability at both doses in dose-dependent manner. In addition, AEBO was also found to significantly suppress the production of NO at doses of 50 and 150 mg/kg. This study provides scientific data to support the traditional use of B. orellana leaves in treating inflammation. Results from this study suggest that AEBO exerts anti-inflammatory effects. Part of this anti-inflammatory effect may be associated with its antibradykinin activity and may be related to a reduction of the NO production.


Effects of air pollution, land-use type, and maternal mental health on child development in the first two years of life in the Greater Taipei area.
Few studies have investigated the associations of child development with air pollution, land-use type, and maternal mental health simultaneously. Therefore, we evaluated the effect of exposure to air pollutants during several critical periods of life, with adjustment for land-use type and maternal mental status, on child development at 6, 12, and 24 months of age in the Greater Taipei area. Participants were selected from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014. Self-administered standardized questionnaires were used to collect information on sociodemographic factors, infant development and health, maternal mental status, etc. Air pollution levels in pre- and postnatal periods were estimated using a spatial interpolation technique (ordinary kriging) at children's residential addresses. Land-use types around participants' homes were evaluated using buffer analysis. We used multiple logistic regression analysis to examine the relationships between child development delay and environmental factors. In total, 228, 361, and 441 families completed child development forms at 6, 12, and 24 months of age, respectively. Our results indicated that prenatal exposure to particulate matter with aerodynamic diameter ≤10 μm and O3 and postnatal exposure to NO2 were negatively associated with child development. Traffic-related land-use types, gas stations, and power generation areas around participants' homes were also adversely correlated with child development. Moreover, poor maternal mental health was associated with child development delay. Prenatal exposure and postnatal exposure to air pollution were associated with development delay in children under 2 years of age, specifically those under 1 year of age, even after adjustment for land-use type and maternal mental status. Living environment is critical for the development of children under 2 years of age.


Spatiotemporal coherent control of lattice vibrational waves.
We achieved automated optical control over coherent lattice responses that were both time- and position-dependent across macroscopic length scales. In our experiments, spatiotemporal femtosecond pulse shaping was used to generate excitation light fields that were directed toward distinct regions of crystalline samples, producing terahertz-frequency lattice vibrational waves that emanated outward from their multiple origins at lightlike speeds. Interferences among the waves resulted in fully specified far-field responses, including tilted, focusing, or amplified wavefronts. Generation and coherent amplification of terahertz traveling waves and terahertz phased-array generation also were demonstrated.


Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression.
Although initiating mutations in the ret protooncogene have been found in familial and sporadic medullary thyroid carcinoma (MTC), the molecular events underlying subsequent tumor progression stages are unknown. We now report that changes in trk family neurotrophin receptor expression appear to be involved in both preneoplastic thyroid C cell hyperplasia and later tumor progression. Only a subset of normal C cells expresses trk family receptors, but, in C cell hyperplasia, the affected cells consistently express trkB, with variable expression of trkA and trkC. In later stages of gross MTC tumors, trkB expression was substantially reduced, while trkC expression was increased and often intense. In a cell culture model of MTC, exogenous trkB expression resulted in severely impaired tumorigenicity and was associated with 11-fold lower levels of the angiogenesis factor vascular endothelial growth factor. These results suggest that trk family receptor genes participate in MTC development and progression, and, in particular, that trkB may limit MTC tumor growth by inhibition of angiogenesis.


Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society.
The term interstitial lung abnormalities refers to specific CT findings that are potentially compatible with interstitial lung disease in patients without clinical suspicion of the disease. Interstitial lung abnormalities are increasingly recognised as a common feature on CT of the lung in older individuals, occurring in 4-9% of smokers and 2-7% of non-smokers. Identification of interstitial lung abnormalities will increase with implementation of lung cancer screening, along with increased use of CT for other diagnostic purposes. These abnormalities are associated with radiological progression, increased mortality, and the risk of complications from medical interventions, such as chemotherapy and surgery. Management requires distinguishing interstitial lung abnormalities that represent clinically significant interstitial lung disease from those that are subclinical. In particular, it is important to identify the subpleural fibrotic subtype, which is more likely to progress and to be associated with mortality. This multidisciplinary Position Paper by the Fleischner Society addresses important issues regarding interstitial lung abnormalities, including standardisation of the definition and terminology; predisposing risk factors; clinical outcomes; options for initial evaluation, monitoring, and management; the role of quantitative evaluation; and future research needs.


Ionic surface active compounds in atmospheric aerosols.
Surfactants in the atmosphere have several potential roles in atmospheric chemistry. They can form films on aqueous surfaces, which lowers the surface tension and possibly delays water evaporation and gaseous transportation across the aqueous interface. They can also increase the solubility of organic compounds in the aqueous phase. Recently, the decrease of surface tension in cloud growing droplets has been suggested as relevant to increases in the number of droplets of smaller size, potentially enhancing cloud albedo. Natural surfactants in the lung aid gas transfer and influence the dissolution rate of aerosol particles, so surfactants in atmospheric aerosols, once inhaled, may interact with pulmonary surfactants. Ambient aerosols were collected from the edge of Norwich, a small city in a largely agricultural region of England, and analysed for surfactants. Methylene blue, a conventional dye for detecting anionic surfactants, has been used as a colorimetric agent. The concentration of surfactants expressed as methylene blue active substances (MBAS) is in the range of 6-170 pmol m(-3)(air). A negative correlation with chloride aerosol indicates that these surfactants are probably not the well-known surfactants derived from marine spray. A more positive correlation with aerosol nitrate and gaseous NOx supports an association with more polluted inland air masses. The surfactants found in aerosols seem to be relatively strong acids, compared with weaker acids such as the long-chain carboxylic acids previously proposed as atmospheric surfactants. Surfactants from the oxidation of organic materials (perhaps vegetation- or soil-derived) seem a likely source of these substances in the atmosphere.