Functional brain network modularity captures inter- and intra-individual variation in working memory capacity.
Cognitive abilities, such as working memory, differ among people; however, individuals also vary in their own day-to-day cognitive performance. One potential source of cognitive variability may be fluctuations in the functional organization of neural systems. The degree to which the organization of these functional networks is optimized may relate to the effective cognitive functioning of the individual. Here we specifically examine how changes in the organization of large-scale networks measured via resting state functional connectivity MRI and graph theory track changes in working memory capacity. Twenty-two participants performed a test of working memory capacity and then underwent resting-state fMRI. Seventeen subjects repeated the protocol three weeks later. We applied graph theoretic techniques to measure network organization on 34 brain regions of interest (ROI). Network modularity, which measures the level of integration and segregation across sub-networks, and small-worldness, which measures global network connection efficiency, both predicted individual differences in memory capacity; however, only modularity predicted intra-individual variation across the two sessions. Partial correlations controlling for the component of working memory that was stable across sessions revealed that modularity was almost entirely associated with the variability of working memory at each session. Analyses of specific sub-networks and individual circuits were unable to consistently account for working memory capacity variability. The results suggest that the intrinsic functional organization of an a priori defined cognitive control network measured at rest provides substantial information about actual cognitive performance. The association of network modularity to the variability in an individual's working memory capacity suggests that the organization of this network into high connectivity within modules and sparse connections between modules may reflect effective signaling across brain regions, perhaps through the modulation of signal or the suppression of the propagation of noise.


Population-based study of birth prevalence and factors associated with cleft lip and/or palate in Taiwan 2002-2009.
Facial cleft deformities, including cleft lip with or without cleft palate (CL/P) and cleft palate (CP), are common congenital birth anomalies, especially in Asia. This study aimed to analyze the prevalence of CL/P and CP and to identify associated factors in Taiwan. This population-based epidemiological study retrospectively analyzed birth data obtained from the Department of Health in Taiwan for years 2002-2009. Frequency distribution, percentages and related predictors were investigated, and findings were presented by types of cleft deformities. Logistic regression analysis was performed to identify factors associated with cleft deformities. Overall prevalence of cleft deformities among 1,705,192 births was 0.1% for CL/P and 0.04% for CP over the 8-year study period. Higher prevalence of CL/P or CP was observed with multiple pregnancies, being male for CL/P, being female for CP, gestational age ≤37 weeks and lower birth weight (<1.5 kg). Both CL/P and CP were significantly associated with gestational age <37 weeks and birth weight<1.5 kg (all P <0.0001). CL/P was significantly associated with multiple parities (P = 0.0004-0.002). Male newborns and female newborns were significantly associated with CL/P and CP, respectively (both P<0.0001). Overall prevalence for congenital cleft deformities in study subjects was 0.1%, in keeping with high rates in Asia. Results suggest the need for awareness and early identification of those at high risk for cleft deformities, including newborns with gestational age <37 weeks, weighing <1.5 kg at birth and women with multiple parities, as a potential strategy to counter long-term adverse effects on speech and language in this population.


Wheat streak mosaic virus in Australia: Relationship to Isolates from the Pacific Northwest of the USA and Its Dispersion Via Seed Transmission.
Wheat streak mosaic virus (WSMV) was found for the first time in Australia in 2002. It subsequently was found widely dispersed around the continent and was shown to be seedborne in wheat. The coat protein (CP) gene sequences of nine WSMV isolates from eastern and southwestern Australia are reported, one obtained directly from infected wheat seed, three from seedlings grown from infected wheat seed, and five from infected wheat plant samples. These sequences were compared with those of 66 WSMV CP sequences, including eight previously sequenced Australian isolates. All 17 Australian sequences formed a closely knit monophyletic cluster as part of the D1 subclade of WSMV previously only reported from the Pacific Northwest of the United States. The close phylogenetic relationships of these sequences indicate that the Australian outbreak arose from a single incursion, the source of which appears to be the Pacific Northwest. Three Australian CP sequences were identical, one from the location of the post-entry quarantine facility at Tamworth, New South Wales, and two from seed that had originally been propagated at that facility. These three sequences were closest to the Pacific Northwest sequences and differed from them by as little as eight nucleotides (0.76%). The sequence of a third seedborne isolate originally from the same source differed from the other two seedborne isolates by two nucleotides, indicating that the immigrant WSMV population may have been variable. The other Australian sequences differed from the three identical ones by only one to four nucleotides. The phylogenetic pattern and small number of nucleotide differences between individual isolates from different geographic locations fit the scenario that the virus was introduced once in seed of wheat breeding material, multiplied where it was introduced, and then was dispersed over long distances around the Australian continent along standard distribution routes for wheat breeding lines, germ plasm, and crop seed. These conclusions provide a cautionary tale indicating the importance of effective monitoring of imported plant materials for exotic virus diseases during post-entry quarantine.


Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.
Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.


Serious adverse event rates and reoperation after arthroscopic shoulder surgery: population based cohort study.
To provide clinicians and patients with accurate risk estimates of serious adverse events after common elective shoulder arthroscopic procedures, including reoperation within one year. Population based cohort study. Hospital Episode Statistics for NHS England, including civil registration mortality data from the Office for National Statistics. 288 250 arthroscopic shoulder procedures performed in 261 248 patients aged ≥16 years between 1 April 2009 and 31 March 2017. Elective procedures were grouped into subacromial decompression, rotator cuff repair, acromioclavicular joint excision, glenohumeral stabilisation, and frozen shoulder release. The primary outcomes were rates of serious adverse events (mortality, pulmonary embolism, pneumonia, myocardial infarction, acute kidney injury, stroke, and urinary tract infection) requiring inpatient care within 90 days post-surgery. Secondary outcomes were specific adverse event rates at 90 days, and reoperations (including for deep infection) within one year. The overall rate of complications within 90 days after arthroscopic shoulder surgery (including reoperation) was low at 1.2% (95% confidence interval 1.2% to 1.3%), with one in 81 patients at risk, and varied according to type of procedure, from 0.6% (0.5% to 0.8%) for glenohumeral stabilisation to 1.7% (1.5% to 1.8%) for frozen shoulder release. After adjustment for age, comorbidities, and sex, no effect of procedure type was observed. Pneumonia was the most common adverse event (0.3%, 0.3% to 0.4%), with one in 303 patients at risk. Pulmonary embolic events were rare, at 0.1% (0.1% to 0.1%), with one in 1428 patients at risk. At one year, the overall rate for reoperation was 3.8% (3.8% to 3.9%), with one in 26 patients at risk, ranging from 2.7% (2.5% to 3.0%) for glenohumeral stabilisation to 5.7% (5.4% to 6.1%) for frozen shoulder release. The overall rate of further surgery for deep infection was low, at 0.1% (0.1% to 0.1%), with one in 1111 patients at risk, but was higher after rotator cuff repair (0.2%, 0.2% to 0.2%), with one in 526 patients at risk. Over the study period the number of arthroscopic shoulder procedures increased, except for subacromial decompression, which decreased. The findings of this study suggest that risks of serious adverse events associated with common shoulder arthroscopy procedures are low. Nevertheless, serious complications do occur, and include the risk of reoperation in one in 26 patients within one year. Clinical. gov NCT03573765.


Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray.
To identify new diagnostic markers and drug targets for pancreatic cancer, we compared the gene expression patterns of pancreatic cancer cell lines growing in tissue culture with those of normal pancreas using cDNA microarray analysis. Fluorescently (cyanine 5) labeled cDNA probes, made individually from mRNA samples of nine pancreatic cell lines, were each combined with fluorescently (cyanine 3) labeled universal reference mRNA. The mixed probes of each sample were then hybridized with 5760 cDNA arrays (5289 unique cDNA sequences) printed on individual microscope slides. Fluorescently (cyanine 5) labeled normal pancreas mRNA was also compared with the same universal reference mRNA reference pool. The expression ratios of neoplastic versus normal pancreas cells were then calculated by multiplying the ratio of cancer versus the universal reference mRNA and the ratio of the universal reference mRNA cell versus normal pancreas. For 5289 different genes interrogated by the arrays, 30 of them showed an expression ratio 2 SD from the mean in at least three of the nine pancreatic cell lines studied. To confirm the expression profiles of these genes, quantitative reverse transcription-PCR and Northern blot were carried out for 25 of the overexpressed genes. To verify the overexpression in patient samples, two of the overexpressed genes, c-Myc and Rad51, were selected to undergo analysis by reverse transcription-PCR in frozen tumor tissues and by immunostaining in paraffin-embedded tissue section microarrays. The results of these experiments are in agreement with the microarray data. Potential up-regulated targets of note from this study include urokinase-type plasminogen activator receptor, serine/threonine kinase 15, thioredoxin reductase, and CDC28 protein kinase 2, as well as several others.


Rational surface design for molecular dynamics simulations of porous polymer adsorbent media.
The construction and use of nonflat agarose surfaces in a simulation box, together with the employment of criteria for the immobilization of a set of dextran polymer chains on the nonflat agarose surfaces whose mathematical physics is compatible with that of the criteria used for the immobilization of the same set of dextran polymer chains on flat agarose surfaces, are shown to generate, through the use of molecular dynamics simulations whose simulation box has linear dimensions along the lateral directions that are the same when flat and nonflat agarose surfaces are used, dextran porous polymer structures whose pore sizes at the outermost surface and in the vicinity of the outermost surface of the porous medium can be controlled by an indirect manner through the variation of the parameters that characterize the nonflat surface. The use of a nonflat surface for the generation of desired large pores requires only a small or modest increase in the number of solvent molecules in the simulation box, while the use of a flat surface for the construction of the same desired large pores requires significant increases in the size of the linear dimensions of the flat surface. This increases so substantially the number of solvent molecules that the computational loads become intractable. The results in this work show that through the use of nonflat surfaces porous dextran polymer layers having pores of desired sizes can be effectively constructed, and this approach could be used for the design and construction of polymer-based porous adsorbent media that could effectively facilitate the transport and adsorption of an adsorbate biomolecule of interest that must be separated from a mixture of components. A useful definition about the properties that a porous polymer structure must have in order to become, for an adsorbate biomolecule of interest of known molecular size, a useful adsorbent medium, is presented and is used to (1) evaluate the porous polymer structures generated through the employment of different nonflat surface models and (2) determine and select the nonflat surface model from a set of nonflat surface models that is effective in producing promising porous structures. Then a procedure is presented by which a set of porous polymer media is generated through the use of the selected nonflat surface model, and the desired porous structure from this set is determined and could be considered to be used for the transport and immobilization of the selected affinity groups/ligands and the subsequent transport and adsorption of the desired to be separated adsorbate.


Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase.
Dendritic cells are antigen-presenting cells that play an essential role in linking the innate and adaptive immune systems. Much research has focused on the signaling pathways triggered upon infection of dendritic cells by various pathogens. The high level of activity in the field makes it desirable to have a pathway-based resource to access the information in the literature. Current pathway diagrams lack either comprehensiveness, or an open-access editorial interface. Hence, there is a need for a dependable, expertly curated knowledgebase that integrates this information into a map of signaling networks. We have built a detailed diagram of the dendritic cell signaling network, with the goal of providing researchers with a valuable resource and a facile method for community input. Network construction has relied on comprehensive review of the literature and regular updates. The diagram includes detailed depictions of pathways activated downstream of different pathogen recognition receptors such as Toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors and nucleotide-binding oligomerization domain-like receptors. Initially assembled using CellDesigner software, it provides an annotated graphical representation of interactions stored in Systems Biology Mark-up Language. The network, which comprises 249 nodes and 213 edges, has been web-published through the Biological Pathway Publisher software suite. Nodes are annotated with PubMed references and gene-related information, and linked to a public wiki, providing a discussion forum for updates and corrections. To gain more insight into regulatory patterns of dendritic cell signaling, we analyzed the network using graph-theory methods: bifan, feedforward and multi-input convergence motifs were enriched. This emphasis on activating control mechanisms is consonant with a network that subserves persistent and coordinated responses to pathogen detection. This map represents a navigable aid for presenting a consensus view of the current knowledge on dendritic cell signaling that can be continuously improved through contributions of research community experts. Because the map is available in a machine readable format, it can be edited and may assist researchers in data analysis. Furthermore, the availability of a comprehensive knowledgebase might help further research in this area such as vaccine development. The dendritic cell signaling knowledgebase is accessible at http://tsb.mssm.edu/pathwayPublisher/DC_pathway/DC_pathway_index.html.


Muscle CD31(-) CD45(-) side population cells promote muscle regeneration by stimulating proliferation and migration of myoblasts.
CD31(-) CD45(-) side population (SP) cells are a minor SP subfraction that have mesenchymal stem cell-like properties in uninjured skeletal muscle but that can expand on muscle injury. To clarify the role of these SP cells in muscle regeneration, we injected green fluorescent protein (GFP)-positive myoblasts with or without CD31(-) CD45(-) SP cells into the tibialis anterior muscles of immunodeficient NOD/scid mice or dystrophin-deficient mdx mice. More GFP-positive fibers were formed after co-transplantation than after transplantation of GFP-positive myoblasts alone in both mdx and NOD/scid muscles. Moreover, grafted myoblasts were more widely distributed after co-transplantation than after transplantation of myoblasts alone. Immunohistochemistry with anti-phosphorylated histone H3 antibody revealed that CD31(-) CD45(-) SP cells stimulated cell division of co-grafted myoblasts. Genome-wide gene expression analyses showed that these SP cells specifically express a variety of extracellular matrix proteins, membrane proteins, and cytokines. We also found that they express high levels of matrix metalloproteinase-2 mRNA and gelatinase activity. Furthermore, matrix metalloproteinase-2 derived from CD31(-) CD45(-) SP cells promoted migration of myoblasts in vivo. Our results suggest that CD31(-) CD45(-) SP cells support muscle regeneration by promoting proliferation and migration of myoblasts. Future studies to further define the molecular and cellular mechanisms of muscle regeneration will aid in the development of cell therapies for muscular dystrophy.


Function and localization of the Arabidopsis thaliana diacylglycerol acyltransferase DGAT2 expressed in yeast.
Diacylglycerol acyltransferases (DGATs) catalyze the final and only committed step of triacylglycerol synthesis. DGAT activity is rate limiting for triacylglycerol accumulation in mammals, plants and microbes. DGATs belong to three different evolutionary classes. In Arabidopsis thaliana, DGAT1, encoded by At2g19450, is the major DGAT enzyme involved in triacylglycerol accumulation in seeds. Until recently, the function of DGAT2 (At3g51520) has remained elusive. Previous attempts to characterize its enzymatic function by heterologous expression in yeast were unsuccessful. In the present report we demonstrate that expression of a codon-optimized version of the DGAT2 gene is able to restore neutral lipid accumulation in the Saccharomyces cerevisiae mutant strain (H1246), which is defective in triacylglycerol biosynthesis. Heterologous expression of codon-optimized DGAT2 and DGAT1 induced the biogenesis of subcellular lipid droplets containing triacylglycerols and squalene. Both DGAT proteins were found to be associated with these lipid droplets. The fatty acid composition was affected by the nature of the acyltransferase expressed. DGAT2 preferentially incorporated C16:1 fatty acids whereas DGAT1 displayed preference for C16:0, strongly suggesting that these enzymes have contrasting substrate specificities.


Metabolic imaging of myocardial triglyceride content: reproducibility of 1H MR spectroscopy with respiratory navigator gating in volunteers.
Institutional review board approval and informed consent were obtained. The purpose of the study was to prospectively compare spectral resolution and reproducibility of hydrogen 1 (1H) magnetic resonance (MR) spectroscopy, with and without respiratory motion compensation based on navigator echoes, in the assessment of myocardial triglyceride content in the human heart. In 20 volunteers (14 men, six women; mean age+/-standard error, 31 years+/-2.8 [range, 19-60 years]; body mass index, 19-30 kg/m2) without history of cardiovascular disease, 1H MR spectroscopy of the myocardium was performed at rest, with and without respiratory motion compensation. Unsuppressed water signal linewidth changed from 11.9 Hz to 10.7 Hz (P<.001) with the use of the navigator, which indicated better spectral resolution. The navigator improved the intraclass correlation coefficient for the assessment of myocardial triglyceride content from 0.32 to 0.81. Therefore, the authors believe that respiratory motion correction is essential for reproducible assessment of myocardial triglycerides.


Quantifying biological integrity by taxonomic completeness: its utility in regional and global assessments.
Water resources managers and conservation biologists need reliable, quantitative, and directly comparable methods for assessing the biological integrity of the world's aquatic ecosystems. Large-scale assessments are constrained by the lack of consistency in the indicators used to assess biological integrity and our current inability to translate between indicators. In theory, assessments based on estimates of taxonomic completeness, i.e., the proportion of expected taxa that were observed (observed/expected, O/E) are directly comparable to one another and should therefore allow regionally and globally consistent summaries of the biological integrity of freshwater ecosystems. However, we know little about the true comparability of O/E assessments derived from different data sets or how well O/E assessments perform relative to other indicators in use. I compared the performance (precision, bias, and sensitivity to stressors) of O/E assessments based on five different data sets with the performance of the indicators previously applied to these data (three multimetric indices, a biotic index, and a hybrid method used by the state of Maine). Analyses were based on data collected from U.S. stream ecosystems in North Carolina, the Mid-Atlantic Highlands, Maine, and Ohio. O/E assessments resulted in very similar estimates of mean regional conditions compared with most other indicators once these indicators' values were standardized relative to reference-site means. However, other indicators tended to be biased estimators of O/E, a consequence of differences in their response to natural environmental gradients and sensitivity to stressors. These results imply that, in some cases, it may be possible to compare assessments derived from different indicators by standardizing their values (a statistical approach to data harmonization). In situations where it is difficult to standardize or otherwise harmonize two or more indicators, O/E values can easily be derived from existing raw sample data. With some caveats, O/E should provide more directly comparable assessments of biological integrity across regions than is possible by harmonizing values of a mix of indicators.


Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo.
Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in granulocyte-macrophage progenitors, and highest among a novel CD34+CD38+CD123hiTim-3hi subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells. A novel Wnt/β-catenin signaling modulator, C82, and nilotinib synergistically killed KBM5T315I and TKI-resistant primary BC-CML cells with or without BCR-ABL kinase mutations even under leukemia/MSC co-culture conditions. Silencing of β-catenin by short interfering RNA restored sensitivity of primary BCR-ABLT315I/E255V BC-CML cells to nilotinib. Combining the C82 pro-drug, PRI-724, with nilotinib significantly prolonged the survival of NOD/SCID/IL2Rγ null mice injected with primary BCR-ABLT315I/E255V BC-CML cells. The combined treatment selectively targeted CML progenitors and inhibited CD44, c-Myc, survivin, p-CRKL and p-STAT5 expression. In addition, pretreating primary BC-CML cells with C82, or the combination, but not with nilotinib alone, significantly impaired their engraftment potential in NOD/SCID/IL2Rγ-null-3/GM/SF mice and significantly prolonged survival. Our data suggest potential benefit of concomitant β-catenin and Bcr-Abl inhibition to prevent or overcome Bcr-Abl kinase-dependent or -independent TKI resistance in BC-CML.


Quality control of the private veterinary profession in The Netherlands.
It was as early as the 19th Century when attempts were first made to organise the veterinary profession in The Netherlands into a professional association. Since then, the Royal Veterinary Association of The Netherlands has developed into an organisation which fully promotes the interests of the profession. From the beginning, the issues of professional standards and veterinary legislation were given high priority, and codes of conduct were established with the aim of improving the quality of professional veterinary practice. Having some form of independent regulatory body has always been important for maintaining these professional standards, even if history has taught us that establishing such independent testing and sanctioning facilities is a laborious process that requires perseverance and patience. By organising the control of animal diseases and promoting public health (e.g. meat inspection), the veterinary profession has always had a key role to play in the food production industry, and quality control programmes that monitor the food production chain now make use of veterinary surgeons tested by external organisations. To avoid any semblance of a conflict of interest, a new organisational structure has been developed recently: the Veterinary Quality Organisation (VKO: Veterinair Kwaliteits Orgaan). The VKO maintains the register of qualified veterinarians, upholds standards and organises the independent quality control of the profession.


Bi-directional relation between effort‒reward imbalance and risk of neck-shoulder pain: assessment of mediation through depressive symptoms using occupational longitudinal data.
Objectives Bi-directional associations between perceived effort‒reward imbalance (ERI) at work and neck-shoulder pain have been reported. There is also evidence of associations between ERI and depressive symptoms, and between depressive symptoms and pain while the links between ERI, depressive symptoms and pain have not been tested. We aimed to assess whether depressive symptoms mediate the association between ERI and neck-shoulder pain, as well as the association between neck-shoulder pain and ERI. Methods We used prospective data from three consecutive surveys of the Swedish Longitudinal Occupational Survey of Health (SLOSH) study. ERI was assessed with a short version of the ERI questionnaire, and pain was defined as having had neck-shoulder pain that affected daily life during the past three months. Depressive symptoms were assessed with a continuous scale based on six-items of the (Hopkins) Symptom Checklist. Counterfactual mediation analyses were applied using exposure measures from 2010/2012 (T1), depressive symptoms from 2012/2014 (T2), and outcomes from 2014/2016 (T3), and including only those free of outcome at T1 and T2 (N=2876‒3239). Results ERI was associated with a higher risk of neck-shoulder pain [risk ratio (RR) for total effect 1.22, 95% confidence interval (CI) 1.00-1.48] and 41% of this total effect was mediated through depressive symptoms. Corresponding RR for association between neck-shoulder pain and ERI was 1.34 (95% CI 1.09-1.64), but the mediating role of depressive symptoms was less consistent. Conclusions Depressive symptoms appear to be an intermediate factor in the relationship between ERI and neck-shoulder pain.


A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response.
At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor. This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after. Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment. Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.


Beta-mecaptoethanol suppresses inflammation and induces adipogenic differentiation in 3T3-F442A murine preadipocytes.
Preadipocytes are present in adipose tissues throughout adult life that can proliferate and differentiate into mature adipocytes in response to environmental cues. Abnormal increase in adipocyte number or size leads to fat tissue expansion. However, it is now recognized that adipocyte hypertrophy is a greater risk factor for metabolic syndrome whereas fat tissue that continues to produce newer and smaller fat cells through preadipocyte differentiation is "metabolically healthy". Because adipocyte hypertrophy is often associated with increased oxidant stress and low grade inflammation, both are linked to disturbed cellular redox, we tested how preadipocyte differentiation may be regulated by beta-mercaptoethanol (BME), a pharmacological redox regulator and radical scavenger, using murine 3T3-F442A preadipocytes as the cell model. Effects of BME on adipogenesis were measured by microphotography, real-time PCR, and Western analysis. Our data demonstrated that preadipocyte differentiation could be regulated by extracellular BME. At an optimal concentration, BME enhanced expression of adipogenic gene markers and lipid accumulation. This effect was associated with BME-mediated down-regulation of inflammatory cytokine expression during early differentiation. BME also attenuated TNFalpha-induced activation of NFkappaB in differentiating preadipocytes and partially restored TNFalpha-mediated suppression on adipogenesis. Using a non-adipogenic HEK293 cell line transfected with luciferase reporter genes, we demonstrated that BME reduced basal and TNFalpha-induced NFkappaB activity and increased basal and ciglitazone-induced PPARgamma activity; both may contribute to the pro-adipogenic effect of BME in differentiating F442A preadipocytes.


Gonococcal ribosomes as skin test antigens. I. Preliminary tests of sensitivity and specificity.
Ribosomes isolated from N. gonorrhoeae and N. meningitidis were used as skin test antigens in guinea-pigs which had been previously sensitized with killed Neisseria cells in incomplete Freund adjuvant. Intradermal injection of ribosomes from skin test dose N. gonorrhoeae into the skin of animals sensitized to the homologous organism was characterized by a specificity based upon ribosomal skin test dose 50's (STD50) sensitivity which was at least five-fold greater than that of the animals sensitized to the heterologous organism. The sensitized guinea-pigs had lost their skin-test reactivity within 3 months of the cessation of immunization but regained it immediately on reimmunization. The results of this model system indicate that gonococcal ribosomes may be used as antigens in skin testing or other testing modes in gonorrhoea.


Virtual reality training for stroke rehabilitation.
To evaluate the effectiveness of a 2-D virtual reality (2DVR) programme in the training of people with stroke on how to access and use the station facilities of the Mass Transit Railway (MTR). A flat-screen 2DVR based training programme and a corresponding, typical psycho-educational programme with video modelling were developed for comparison through a research design that involved a randomised control group pre-test and post-test. Twenty and sixteen subjects respectively received 10 training sessions using the 2DVR strategy and a video-based psycho-educational programme. An additional 22 subjects formed the control group. They were assessed by using a behavioural checklist of MTR skills and a newly validated MTR self-efficacy scale. The subjects of both training groups showed a significant improvement in their knowledge, skills and self-efficacy in using the MTR (p<0.01), whereas, the MTR skills and self-efficacy of the control group remained stable over a four-week interval. Though both training programmes were effective in training the patients with stroke, they demonstrated differential improvements in MTR skills and related self-efficacy. Additional studies are recommended to identify the most effective training procedures for maintaining these skills and the best transfer ratio in the training of VR-based community living skills of people with stroke.


Reduced numbers of CD8+ T cells and B cell-expression of Leu-8 antigen in peripheral blood of patients with primary biliary cirrhosis.
The presence of Leu-8 antigen, the human homologue of the murine MEL-14 peripheral lymph node homing receptor, defines subsets of peripheral blood mononuclear cells (PBMC) with different functions. Since it has been suggested that abnormal function of Leu-8 subsets may contribute to the immunopathogenesis of primary biliary cirrhosis (PBC), this study was undertaken to define whether abnormal expression of the Leu-8 antigen occurs in this disease. We studied 25 PBC patients, 12 with other chronic liver diseases, and 21 normal controls. PBMC were tested by direct immunofluorescence using monoclonal antibodies and flow cytometry. In PBC the proportion of PBMC that were CD4+ was normal; in contrast, the proportion that were CD8+ was decreased (p < 0.01). A negative correlation was found between absolute numbers of CD8+ T cells and total serum bilirubin levels (r = -0.50, p < 0.05). The distribution of Leu-8 antigen on T cells was normal; however, the proportion of PBMC that were B cells was increased (p < 0.01) and the fraction of these that were Leu-8 negative was also increased (p < 0.01). The expression of antigens of activation on B cells was similar to that for normal controls. These findings suggest that in peripheral blood of PBC patients reduced numbers of T cells may occur due to a selective intrahepatic sequestration of CD8+ T cells, and that the decreased expression of Leu-8 antigen by B cells may be associated with their participation in autoimmune processes.


Development of a spiritual screening tool for children and adolescents.
A chaplain's ability to provide care where it is most needed depends upon some method of pastoral triage. Screening for spiritual needs of children and adolescents has been a largely neglected area. A Delphi panel developed elements to be included in a tool to screen 10-18 year olds' spiritual needs and resources. The Delphi panelists were informed of survey results of school-aged children and adolescents' opinions on spiritual issues important to them if they were hospitalized. A case study of the tool's use was conducted with a convenient sample of children and adolescents. Subsequent pilot use of the tool by five pediatric chaplains demonstrated the tool's utility in identifying patients' spiritual issues, ability to serve as a springboard to deeper discussion, and as a basis for initiating discussion of spiritual concerns with other disciplines on the healthcare team. Feedback indicates the potential clinical usefulness of this tool for hospitalized children and adolescents.


Temporal patterns of discomfort reported by plasterers over a five-day workweek.
Plastering activities can involve exposure to Work-Related Musculoskeletal Disorder (WRMSD) risk factors that are an intrinsic part of a plasterer's daily work. Exposure can be assessed by recording perceptions of symptoms of discomfort during work. To record a sample of plasterers' self-reported perceptions of discomfort to identify temporal patterns and to investigate whether work-break patterns and some task demands influence the intensity levels of their discomfort. Eighteen experienced plasterers indicated their level of perceived discomfort for 10 body-parts four times a day for five consecutive workdays using a Body Part Discomfort Survey (BPDS) containing a body map, Visual Analogue Discomfort Scales (VADS) and questionnaires to provide information about their working activities over the duration of the assessment. Plasterers experienced discomfort in all body parts assessed with symptoms increasing over the working day and week and declining after periods of rest i.e. after lunch and overnight. Task activities and standing platforms used influenced the patterns of discomfort intensity. Plasterers in this group experience greater physical strain with infrequent work/break patterns, or when carrying out the same activity or using a single standing platform for prolonged periods.


Requirements for innate immune pathways in environmentally induced autoimmunity.
There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.


Sequences, structural models, and cellular localization of the actin-related proteins Arp2 and Arp3 from Acanthamoeba.
We cloned and sequenced the two actin-related proteins (Arps) present in the profilin-binding complex of Acanthamoeba (Machesky, L. M., S. J. Atkinson, C. Ampe, J. Vandekerckhove, and T. D. Pollard. 1994, J. Cell Biol. 127:107-115). The sequence of Arp2 is more similar to other Arp2s than to actin, while the sequence of Arp3 is more similar to other Arp3s than to actin. Phylogenetic analysis of all known Arps demonstrates that most group into three major families, which are likely to be shared across all eukaryotic phyla. Together with conventional actins, the Arps form a larger family distinct from structurally related ATPases such as Hsp70's and sugar kinases. Atomic models of the Arps based on their sequences and the structure of actin provide some clues about function. Both Arps have atoms appropriately placed to bind ATP and divalent cation. Arp2, but not Arp3, has a conserved profilin-binding site. Neither Arp has the residues required to copolymerize with actin, but an Arp heterodimer present in the profilin-binding complex might serve as a pointed end nucleus for actin polymerization. Both Acanthamoeba Arps are soluble in cell homogenates, and both are concentrated in the cortex of Acanthamoeba. The cellular concentrations are 1.9 microM Arp2 and 5.1 microM Arp3, substoichiometric to actin (200 microM) but comparable to many actin-binding proteins.


Leptin induces a novel form of NMDA receptor-dependent long-term depression.
It is becoming apparent that the hormone leptin plays an important role in modulating hippocampal function. Indeed, leptin enhances NMDA receptor activation and promotes hippocampal long-term potentiation (LTP). Furthermore, obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Here we demonstrate that under conditions of enhanced excitability (evoked in Mg2+-free medium or following blockade of GABA(A) receptors), leptin induces a novel form of long-term depression (LTD) in area CA1 of the hippocampus. Leptin-induced LTD was markedly attenuated in the presence of D-(-)-2-Amino-5-Phosphonopentanoic acid (D-AP5), suggesting that it is dependent on the synaptic activation of NMDA receptors. In addition, low-frequency stimulus-evoked LTD occluded the effects of leptin. In contrast, metabotropic glutamate receptors (mGluRs) did not contribute to leptin-induced LTD as mGluR antagonists failed to either prevent or reverse this process. The signalling mechanisms underlying leptin-induced LTD were independent of the Ras-Raf-mitogen-activated protein kinase signalling pathway, but were markedly enhanced following inhibition of either phosphoinositide 3-kinase or protein phosphatases 1 and 2A. These data indicate that under conditions of enhanced excitability, leptin induces a novel form of homosynaptic LTD, which further underscores the proposed key role for this hormone in modulating NMDA receptor-dependent hippocampal synaptic plasticity.


Reliability and validity of the transport and physical activity questionnaire (TPAQ) for assessing physical activity behaviour.
No current validated survey instrument allows a comprehensive assessment of both physical activity and travel behaviours for use in interdisciplinary research on walking and cycling. This study reports on the test-retest reliability and validity of physical activity measures in the transport and physical activity questionnaire (TPAQ). The TPAQ assesses time spent in different domains of physical activity and using different modes of transport for five journey purposes. Test-retest reliability of eight physical activity summary variables was assessed using intra-class correlation coefficients (ICC) and Kappa scores for continuous and categorical variables respectively. In a separate study, the validity of three survey-reported physical activity summary variables was assessed by computing Spearman correlation coefficients using accelerometer-derived reference measures. The Bland-Altman technique was used to determine the absolute validity of survey-reported time spent in moderate-to-vigorous physical activity (MVPA). In the reliability study, ICC for time spent in different domains of physical activity ranged from fair to substantial for walking for transport (ICC = 0.59), cycling for transport (ICC = 0.61), walking for recreation (ICC = 0.48), cycling for recreation (ICC = 0.35), moderate leisure-time physical activity (ICC = 0.47), vigorous leisure-time physical activity (ICC = 0.63), and total physical activity (ICC = 0.56). The proportion of participants estimated to meet physical activity guidelines showed acceptable reliability (k = 0.60). In the validity study, comparison of survey-reported and accelerometer-derived time spent in physical activity showed strong agreement for vigorous physical activity (r = 0.72, p<0.001), fair but non-significant agreement for moderate physical activity (r = 0.24, p = 0.09) and fair agreement for MVPA (r = 0.27, p = 0.05). Bland-Altman analysis showed a mean overestimation of MVPA of 87.6 min/week (p = 0.02) (95% limits of agreement -447.1 to +622.3 min/week). The TPAQ provides a more comprehensive assessment of physical activity and travel behaviours and may be suitable for wider use. Its physical activity summary measures have comparable reliability and validity to those of similar existing questionnaires.


Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction.
The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Eμ-tTA/tetO-MYC T-cell acute lymphoblastic leukemia, some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express either transgenic or endogenous Myc, albeit in many cases at levels below those in the original tumor, suggesting that tumors continue to be addicted to MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator, resulting in expression of the MYC transgene even in the presence of doxycycline. Some of the remaining recurring tumors expressed high levels of endogenous Myc, which was associated with a genomic rearrangement of the endogenous Myc locus or activation of Notch1. By gene expression profiling, we confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis, confirming that these tumors remain oncogene addicted. These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene.


The effects of skin colour distribution and topography cues on the perception of female facial age and health.
According to evolutionary psychology, the preference for some facial characteristics reflects adaptations for mate choice because they signal aspects of mate quality. Although morphological features such as facial symmetry and sexually dimorphic traits have been studied extensively in recent years, little is known about skin condition in this context. The preferences for young and healthy looking skin could offer an explanation as to why women place such an importance on the condition of their skin and its refinement through e.g., cosmetic products. Recent research showed that facial skin colour distribution significantly influences the perception of age and attractiveness of female faces, independent of skin surface topography cues. However, the relative effect of skin colour distribution and topography cues on age and health perception remains to be investigated. We present data showing that both skin colour distribution and skin surface topography cues not only significantly influence the perception of female facial age and health but also convey differential information with regard to the strength of these effects. Our data indicate that skin surface topography cues account for a large proportion of variation in facial age perception, whereas skin colour distribution seems to be a stronger health cue.


Cell morphology drives spatial patterning in microbial communities.
The clearest phenotypic characteristic of microbial cells is their shape, but we do not understand how cell shape affects the dense communities, known as biofilms, where many microbes live. Here, we use individual-based modeling to systematically vary cell shape and study its impact in simulated communities. We compete cells with different cell morphologies under a range of conditions and ask how shape affects the patterning and evolutionary fitness of cells within a community. Our models predict that cell shape will strongly influence the fate of a cell lineage: we describe a mechanism through which coccal (round) cells rise to the upper surface of a community, leading to a strong spatial structuring that can be critical for fitness. We test our predictions experimentally using strains of Escherichia coli that grow at a similar rate but differ in cell shape due to single amino acid changes in the actin homolog MreB. As predicted by our model, cell types strongly sort by shape, with round cells at the top of the colony and rod cells dominating the basal surface and edges. Our work suggests that cell morphology has a strong impact within microbial communities and may offer new ways to engineer the structure of synthetic communities.


Negative capacitance in multidomain ferroelectric superlattices.
The stability of spontaneous electrical polarization in ferroelectrics is fundamental to many of their current applications, which range from the simple electric cigarette lighter to non-volatile random access memories. Research on nanoscale ferroelectrics reveals that their behaviour is profoundly different from that in bulk ferroelectrics, which could lead to new phenomena with potential for future devices. As ferroelectrics become thinner, maintaining a stable polarization becomes increasingly challenging. On the other hand, intentionally destabilizing this polarization can cause the effective electric permittivity of a ferroelectric to become negative, enabling it to behave as a negative capacitance when integrated in a heterostructure. Negative capacitance has been proposed as a way of overcoming fundamental limitations on the power consumption of field-effect transistors. However, experimental demonstrations of this phenomenon remain contentious. The prevalent interpretations based on homogeneous polarization models are difficult to reconcile with the expected strong tendency for domain formation, but the effect of domains on negative capacitance has received little attention. Here we report negative capacitance in a model system of multidomain ferroelectric-dielectric superlattices across a wide range of temperatures, in both the ferroelectric and paraelectric phases. Using a phenomenological model, we show that domain-wall motion not only gives rise to negative permittivity, but can also enhance, rather than limit, its temperature range. Our first-principles-based atomistic simulations provide detailed microscopic insight into the origin of this phenomenon, identifying the dominant contribution of near-interface layers and paving the way for its future exploitation.


Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.
There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(-) strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.


Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway.
Telomerase is a specialized reverse transcriptase that extends telomeres of eukaryotic chromosomes. The catalytic core of human telomerase is composed of an RNA template known as hTER (human telomerase RNA) and a protein subunit named hTERT (human telomerase reverse transcriptase). We have been studying other functions of the telomerase besides its major role in telomere maintenance. In our previous work, we have demonstrated that the hTERT can functionally interact with a rabbit TER to regulate expression of other genes and also attenuate the induced apoptosis. Here we report that overexpression of hTERT in a human lens epithelial cell line accelerates growth of the transfected lens epithelial cells. Associated with the acceleration of cell growth, expression of p53, p21 and GCIP (Grap2 cyclin-D interacting protein) is downregulated in the hTERT-transfected cells. With the downregulation of p21 and GCIP, the retinoblastoma protein (RB) is completely hyperphosphorylated in the hTERT-transfected cells. As expected, in the presence of RB hyperphosphorylation, the E2F transactivity is upregulated. Inhibition of telomerase activity abolishes the observed growth acceleration and also the related molecular changes. Furthermore, expression of hTERT in telomerase-negative human lens epithelial cells derived from primary cultures also accelerates growth of the transfected cells. Taken together, our results suggest that hTERT, when overexpressed in human lens epithelial cells, accelerates cell growth rate through regulation of RB/E2F pathway and possibly other genes.


An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma.
Alveolar rhabdomyosarcoma (aRMS) is a very aggressive sarcoma of children and young adults. Our previous studies have shown that small molecule inhibition of Pdgfra is initially very effective in an aRMS mouse model. However, slowly evolving, acquired resistance to a narrow-spectrum kinase inhibitor (imatinib) was common. We identified Src family kinases (SFKs) to be potentiators of Pdgfra in murine aRMS primary cell cultures from mouse tumors with evolved resistance in vivo in comparison to untreated cultures. Treating the resistant primary cell cultures with a combination of Pdgfra and Src inhibitors had a strong additive effect on cell viability. In Pdgfra knockout tumors, however, the Src inhibitor had no effect on tumor cell viability. Sorafenib, whose targets include not only PDGFRA but also the Src downstream target Raf, was effective at inhibiting mouse and human tumor cell growth and halted progression of mouse aRMS tumors in vivo. These results suggest that an adaptive Src-Pdgfra-Raf-Mapk axis is relevant to PDGFRA inhibition in rhabdomyosarcoma.


Identification and assessment of students with disabilities.
Students with disabilities or suspected disabilities are evaluated by schools to determine whether they are eligible for special education services and, if eligible, to determine what services will be provided. In many states, the results of this evaluation also affect how much funding assistance the school will receive to meet the students' special needs. Special education classification is not uniform across states or regions. Students with identical characteristics can be diagnosed as disabled in one state but not in another and may be reclassified when they move across state or school district lines. Most disabilities with a clear medical basis are recognized by the child's physician or parents soon after birth or during the preschool years. In contrast, the majority of students with disabilities are initially referred for evaluation by their classroom teacher (or parents) because of severe and chronic achievement or behavioral problems. There is evidence that the prevalence of some disabilities varies by age, the high-incidence disabilities such as learning disabilities and speech-language disabilities occur primarily at the mild level, the mild disabilities exist on broad continua in which there are no clear demarcations between those who have and those who do not have the disability, and even "mild" disabilities may constitute formidable barriers to academic progress and significantly limit career opportunities. Problems with the current classification system include stigma to the child, low reliability, poor correlation between categorization and treatment, obsolete assumptions still in use in treatment, and disproportionate representation of minority students. Both African-American and Hispanic students are disproportionately represented in special education but in opposite directions. The disproportionately high number of African Americans in special education reflects the fact that more African-American students than white students are diagnosed with mild mental retardation. Though poverty, cultural bias, and inherent differences have been suggested as reasons for this disproportionate representation, there are no compelling data that fully explain the phenomenon. In most states, classification of a student as disabled leads to increased funding from the state to the school district. This article suggests a revised funding system that weights four factors (number of deficits, degree of discrepancy, complexity of intervention, and intensity of intervention) in a regression equation that would yield a total amount of dollars available to support the special education of a particular student.


Renal medullary captopril delivery lowers blood pressure in spontaneously hypertensive rats.
We examined the contribution of renal medullary function to the maintenance of hypertension in spontaneously hypertensive rats by infusing captopril chronically into the renal medullary interstitial space of uninephrectomized rats. Changes in cortical and medullary blood flow were determined using a newly developed optical fiber implantation technique for laser-Doppler flowmetry. Renal medullary interstitial infusion of captopril (5 mg/kg per day) selectively increased medullary blood flow by 40% without altering renal cortical blood flow throughout the 5 days of captopril delivery. In association with the selective increase of medullary perfusion, a significant natriuresis was observed on the second day of the drug infusion, and urine osmolality was significantly reduced during the first 3 days of captopril infusion. Mean arterial pressure was significantly decreased by 20 mm Hg during 5 days of captopril infusion, and the chronic renal function curve was shifted to a lower level of arterial pressure compared with the control values when 0.9% sodium chloride saline vehicle was infused. Intravenously infused captopril at 5 mg/kg per day did not alter mean arterial pressure, excluding the possibility that the hypotensive effect of medullary captopril infusion was due to recirculation. In summary, chronic reduction of the elevated renal medullary vascular tone by medullary interstitial infusion of captopril reset the steady-state renal function curve and lowered arterial pressure in spontaneously hypertensive rats.


Social interactions, emotion and sleep: A systematic review and research agenda.
Sleep and emotion are closely linked, however the effects of sleep on socio-emotional task performance have only recently been investigated. Sleep loss and insomnia have been found to affect emotional reactivity and social functioning, although results, taken together, are somewhat contradictory. Here we review this advancing literature, aiming to 1) systematically review the relevant literature on sleep and socio-emotional functioning, with reference to the extant literature on emotion and social interactions, 2) summarize results and outline ways in which emotion, social interactions, and sleep may interact, and 3) suggest key limitations and future directions for this field. From the reviewed literature, sleep deprivation is associated with diminished emotional expressivity and impaired emotion recognition, and this has particular relevance for social interactions. Sleep deprivation also increases emotional reactivity; results which are most apparent with neuro-imaging studies investigating amygdala activity and its prefrontal regulation. Evidence of emotional dysregulation in insomnia and poor sleep has also been reported. In general, limitations of this literature include how performance measures are linked to self-reports, and how results are linked to socio-emotional functioning. We conclude by suggesting some possible future directions for this field.


[Evidence based medicine for the gastroenterologist].
Evidence-based medicine (EBM) integrates the best available external evidence in the care of individual patients with the individual clinical expertise and the patient preferences. This method has been designed for use in daily clinical practice. We describe the rationale for EBM and its principles and application in this article. EBM enables gastroenterologists to update the knowledge required to provide patients with high quality medical care. EBM requires four steps: a) formulating a clinical question arising from a doubt concerning a patient; b) conducting an efficient literature search to answer this question; c) critically appraising this evidence using explicit methods to selected articles to determine the validity of their design and the clinical relevance of their results; and d) applying these results to the patient (taking into account their values and preferences and personal and social circumstances). In this paper, we explain the principles and basic concepts of EBM and their application to gastroenterology and we provide an extensive compilation of internet databases of valid information relevant to gastroenterologists. We also provide a selection of useful tools for self-directed learning of critical appraisal skills. Link updates can be accessed at the following URL: http://www.enlacesmedicos.com/e.htm


Axon guidance factor SLIT2 inhibits neural invasion and metastasis in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) metastasizes by neural, vascular, and local invasion routes, which limit patient survival. In nerves and vessels, SLIT2 and its ROBO receptors constitute repellent guidance cues that also direct epithelial branching. Thus, the SLIT2-ROBO system may represent a key pinch point to regulate PDAC spread. In this study, we examined the hypothesis that escaping from repellent SLIT2-ROBO signaling is essential to enable PDAC cells to appropriate their local stromal infrastructure for dissemination. Through immunohistochemical analysis, we detected SLIT2 receptors ROBO1 and ROBO4 on epithelia, nerves, and vessels in healthy pancreas and PDAC specimens, respectively. SLIT2 mRNA expression was reduced in PDAC compared with nontransformed pancreatic tissues and cell lines, suggesting a reduction in SLIT2-ROBO pathway activity in PDAC. In support of this interpretation, restoring the SLIT2 expression in SLIT2-deficient PDAC cells inhibited their bidirectional chemoattraction with neural cells, and more specifically, impaired unidirectional PDAC cell navigation along outgrowing neurites in models of neural invasion. Restoring autocrine/paracrine SLIT2 signaling was also sufficient to inhibit the directed motility of PDAC cells, but not their random movement. Conversely, RNA interference-mediated silencing of ROBO1 stimulated the motility of SLIT2-competent PDAC cells. Furthermore, culture supernatants from SLIT2-competent PDAC cells impaired migration of endothelial cells (human umbilical vein endothelial cells), whereas an N-terminal SLIT2 cleavage fragment stimulated such migration. In vivo investigations of pancreatic tumors with restored SLIT2 expression demonstrated reduced invasion, metastasis, and vascularization, with opposing effects produced by ROBO1 silencing in tumor cells or sequestration of endogenous SLIT2. Analysis of clinical specimens of PDAC showed that those with low SLIT2 mRNA expression exhibited a higher incidence and a higher fraction of tumor-infiltrated lymph nodes. Taken together, our findings argue that disrupting SLIT2-ROBO signaling in PDAC may enhance metastasis and predispose PDAC cells to neural invasion.


Negative Predictive Value of Human Papillomavirus Testing: Implications for Anal Cancer Screening in People Living with HIV/AIDS.
People living with HIV/AIDS (PLWHA) have an increased incidence of anal squamous cell carcinoma. Since high-risk human papillomavirus (hrHPV) is the primary cause, hrHPV DNA testing may play an important role in anal cancer screening. This study aims to determine the negative predictive value (NPV) of hrHPV testing in PLWHA as well as factors that may lead to false-negative results. Anal swabs were collected for cytology and Cobas® 4800 HPV test for 14 hrHPV types. Patients underwent concomitant high-resolution anoscopy (HRA) examination and biopsy. High-grade squamous intraepithelial lesions (HSIL, synonymous with anal intraepithelial neoplasia AIN2 and 3) detected in Cobas-negative patients were genotyped for 22 HPV types using BioPerfectus Multiplex Real-time PCR. 156 PLWHA tested negative for hrHPV on anal swab samples (i.e., Cobas-negative). HRA-guided biopsy detected HSIL/AIN3 in 13 patients (8%, NPV 92%), HSIL/AIN2 in 5 patients (3%), low-grade squamous intraepithelial lesions in 82 (LSIL, 53%), or benign findings in 56 (36%). No cancer was found. The HSIL group was similar to the LSIL/benign group regarding age, gender, race/ethnicity, clinical HIV parameters, cytological diagnoses, history of receptive anal sex, and smoking (p ≥ 0.02). Genotyping HSIL tissue derived from Cobas-negative patients revealed hrHPV (n=7), possibly carcinogenic HPV53, 67, 73, 82 (n=12), or absence of hrHPV (n=4). In this series, anal hrHPV DNA testing offered 92% NPV for PLWHA; in other words, a 8% risk of occult precancer remains for those who test hrHPV negative on anal swab samples.


MR imaging of Parkinson disease with spin-echo and gradient-echo sequences.
High-field MR with both spin-echo and gradient-echo sequences was performed in 21 patients with (idiopathic, drug-responsive) Parkinson disease. The use of gradient echoes allowed more sensitive detection than did spin echoes of susceptibility changes in the putamina and substantia nigra. No statistically significant difference in putaminal hypointensity on long TR/long TE spin-echo sequences or on T2*-weighted images using gradient-echo sequences was observed between Parkinson patients and controls. There was also no statistically significant difference in the frequency of restoration of the signal intensity of the substantia nigra between the two groups of patients. The width of the pars compacta of the substantia nigra in patients with Parkinson disease was 2.12 + 0.82 mm (mean +/- SD). This value in age- and gender-matched controls was 2.67 +/- 0.5. Comparing these two groups with an unpaired t test resulted in a p value less than or equal to .005. Our MR study with spin-echo and gradient-echo images in Parkinson and control patients was able to substantiate and elaborate on previously described MR features of Parkinson disease.


Nanoscale Manipulators: Review of Conceptual Designs Through Recent Patents.
Nanomanipulation techniques have gone through several phases to be used in scientific explorations not only to reveal more characteristics of nano, micro and mesoscopic phenomena but also to build functional nano-devices useful for specific applications. The nano-manipulator becomes a key instrument for technology bridging between sub-nano and mesoscale. The recent patents have exhibited integration of various functions in the nano-devices requiring sub-nanometer precision and highly stable manipulator with substantial pulling/pushing forces. This work reviews patents and works on conceptual designs of existing nanomanipulators with specific features. This includes design analysis leading to ultra-precision motion and stability with discussion of enabling technology. A novel integrated and numerically controlled instrument for nanomanipulation, visualization and inspection/characterization of materials at sub-nanoscale will be presented with a feature to keep the same datum for all operation and hence improve accuracy of samples. This paper has undertaken a review search in a structured examination of bibliographic databases for published and issued patents using a focused review keyword of nano-manipulation. The quality of selected patents was appraised using standard tools. The characteristics of screened patents were described, and a deductive qualitative content analysis methodology was applied to understand the modeling and testing of nanomachining process, the exact construction of nanostructure arrays and the inspection of devices with complex features. The paper encompassed forty patents. Fourteen patents exhibited the manipulation at the micro scale (MEMS manipulations), others outlined systems with sub-micron resolution and workspace range in mesoscale. Standard scale manipulation were described in 13 patents assuming only systems comprising positioning stages, arms and end-effectors where positioners are a few centimeters in size with workspace higher than one cm3. Finally, ten patents included in this review described the importance of end-effectors being extremely important in nanomanipulation as they do support the function defining the manipulation e.g. grippers, sprayers, Nano-tweezers. The findings of this patents review confirm the relevance of the nanomanipulation of objects in 3D system coupled with real time imaging having higher resolution in comparison with the standard manipulators including AFM, TEM, STM, SEM or NSOM. In terms of tooling, AFM cantilever tips, etched tungsten tips or tips with electron beam deposition can be used to manufacture or develop nanodevices e.g. nanowires in in-situ SEM. In handling and manipulating in ambient conditions, commercial microfabricated grippers although available, are less used compared to CNT nanotweezers. Nanomanipulation is currently enabled for nanoscale samples by on-chip operations using promising MEMS and NEMS devices to relatively large samples by the meso and standard scale nanomanipulators. Manipulation is comprehensive and requires multiple functions enabled by various types of end-effectors and probes actuated with high precision. Piezo actuators are at the moment of great performance. Nano and sub-nano samples require proper environment e.g, with electron microscopy to monitor and manipulate including testing, inspecting and fabricating and assembling.


Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.
Hypophosphatemia (Hyp) mice have defective regulation of 25(OH)D-1 alpha-hydroxylase activity in response to hypophosphatemia, hypocalcemia, and parathyroid hormone (PTH) administration. However, recent observations support the existence of anatomically distinct, independently regulated renal 1 alpha-hydroxylase systems in mammalian proximal convoluted and straight tubules. To more completely define the extent of the 1 alpha-hydroxylase regulatory defect in Hyp-mice, we compared enzyme maximum velocity in normal and mutants after infusion of calcitonin. Upon stimulation, renal 1 alpha-hydroxylase activity increased to similar levels in normal and Hyp-mouse renal homogenates. Moreover, time-course and dose-dependence studies revealed similar patterns of response in the animal models. Subsequently, we examined whether PTH and calcitonin stimulatory effects on enzyme activity are mediated through different mechanisms. In both animal models administration of PTH and calcitonin increased enzyme activity to levels greater than those obtained after maximal stimulation by either hormone alone, consistent with additive effects. These observations indicate that a calcitonin-sensitive component of 1 alpha-hydroxylase is not compromised in the X-linked hypophosphatemic syndrome.


[Can curcumin prevent the formation of Pseudomonas aeruginosa biofi lm on the surface of tympanostomy tubes?].
Formation of bacterial biofilm on the surface of tympanostomy tubes are held responsible in the pathogenesis of post-tympanostomy tube otorrhea. To prevent the formation of biofilm, various methods were employed and varying degrees of success have been achieved. In some recent studies curcumin, which is the fenolic form of Curcuma longa (turmeric), has been pointed out to have inhibitory effects on virulence factors of Pseudomonas aeruginosa. The aim of this study was to investigate whether the administration of curcumin is able to prevent the formation of P.aeruginosa biofilm on the surface of silicone tympanostomy tubes in vitro conditions. For this purpose, qualitative and quantitative analysis of P.aeruginosa biofilm created on the surface of the tympanostomy tubes were performed following a period of 48 hours incubation in microplate wells that contained decreasing concentrations of curcumin. For qualitative analysis, specimens were evaluated with an environmental scanning electron microscope for the existence of biofilm. For the quantitative analysis, bacteria attached to the tube surface was detached using a combination of vortexing and sonication. Following serial dilutions, the obtained solution was then inoculated on the sheep blood agar plates using calibrated loop, incubated for 24 hours and the colony forming unit (CFU) per mL were recorded. Environmental scanning electron microscope analysis revealed that 100 µg/mL of curcumin could prevent formation of the biofilm. Lower concentrations of curcumin could not prevent the biofilm formation. Qualitative analysis also revealed that when the concentrations of curcumin in the wells were decreased, the number of CFU/mL was increased significantly. Mean number of CFU in 100 µg/mL and 12.5 µg/mL groups were 35±7.07 and 650±494, respectively. Curcumin could prevent formation of P.aeruginosa biofilm on the surface of tympanostomy tubes in vitro with concentrations lower than the MIC value. The results of the present study show that local administration of curcumin may prevent suppurative otitis media following tympanostomy tube insertion, keep the patency of the tube and decrease the rate of treatment failure. In vivo studies are needed to support the in vitro anti-biofilm action of curcumin on tympanostomy tubes.


Calculating the dim light melatonin onset: the impact of threshold and sampling rate.
The dim light melatonin onset (DLMO) is the most reliable circadian phase marker in humans, but the cost of assaying samples is relatively high. Therefore, the authors examined differences between DLMOs calculated from hourly versus half-hourly sampling and differences between DLMOs calculated with two recommended thresholds (a fixed threshold of 3 pg/mL and a variable "3k" threshold equal to the mean plus two standard deviations of the first three low daytime points). The authors calculated these DLMOs from salivary dim light melatonin profiles collected from 122 individuals (64 women) at baseline. DLMOs derived from hourly sampling occurred on average only 6-8 min earlier than the DLMOs derived from half-hourly saliva sampling, and they were highly correlated with each other (r ≥ 0.89, p < .001). However, in up to 19% of cases the DLMO derived from hourly sampling was >30 min from the DLMO derived from half-hourly sampling. The 3 pg/mL threshold produced significantly less variable DLMOs than the 3k threshold. However, the 3k threshold was significantly lower than the 3 pg/mL threshold (p < .001). The DLMOs calculated with the 3k method were significantly earlier (by 22-24 min) than the DLMOs calculated with the 3 pg/mL threshold, regardless of sampling rate. These results suggest that in large research studies and clinical settings, the more affordable and practical option of hourly sampling is adequate for a reasonable estimate of circadian phase. Although the 3 pg/mL fixed threshold is less variable than the 3k threshold, it produces estimates of the DLMO that are further from the initial rise of melatonin.


Evaluation of relationship between sexual functions, depression and quality of life in patients with chronic kidney disease at predialysis stage.
The relation of chronic kidney disease (CKD) with metabolic, psychiatric and endocrinologic disorder is well-known. Depressive mood and sexual dysfunction are frequently observed as renal functions deteriorate. We aimed to analyze the relationship of sexual dysfunction, depressive mood and life quality in patients with CKD at predialysis stage. Fifty-three patients; 27 female and 26 male with CKD who had estimated glomerular filtration rate (eGFR) between 15 and 90 mL/min and followed up in the Nephrology Department, Bursa Sevket Yılmaz Education and Research Hospital, were enrolled. Age- and sex-matched 20 female and 20 male healthy control subjects were assigned to the control group. Detailed medical and sexual history was obtained by using Female Sexual Function Index (FSFI), Erectile Function International Evaluation Form (IEFF), Short form (SF) 36 Form and Beck Depression Questionnaire (BDI). Biochemical and hormonal parameters including urea, creatinine, uric acid, sedimentation rate, c-reactive protein, total testosterone, DHEA-S, FSH, LH, TSH, estradiol and prolactin were analyzed. Depression was observed in 12 male (46%) and 14 female (51%) patients. The frequency of depression among male patients and control subjects was similar, however, significantly higher in female patients than female controls (p=0.036). Physical function score, physical role score and pain score in SF 36 of entire patients were significantly lower than controls (p=0.0001, 0.0001, 0.001, respectively). The frequency of depression was similar between patients and controls (p>0.05). When SF 36 tests of male and female patients were compared, general health status, vitality and mental health status were significantly better in male patients (p=0.005, 0.016, 0.035, respectively). SF 36 scores of female patients were significantly lower than female controls (p=0.0001). The frequency of erectile dysfunction (ED) was similar between male patients (84%) and controls (75%) (p=0.62). On the other hand, sexual dysfunction was significantly higher in female patients when compared to female controls (92% vs. 30%; p=0.0001). We showed that sexual dysfunction and depression are more frequent among female patients with CKD at predialysis stage; however, it does not have significant impact on life quality. When life quality of female and male patients was compared, general health status, vitality and mental health status of female patients were poorer. We failed to demonstrate a relationship between sexual dysfunction and sex hormone level.


Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.
The translocation of fluorescently tagged PLC gamma and requirements for this process in cells stimulated with EGF were analyzed using real time fluorescence microscopy applied for the first time to monitor growth factor receptor--effector interactions. The translocation of PLC gamma to the plasma membrane required the functional Src homology 2 domains and was not affected by mutations in the pleckstrin homology domain or inhibition of phosphatidylinositol (PI) 3-kinase. An array of domains specific for PLC gamma isoforms was sufficient for this translocation. The dynamics of translocation to the plasma membrane and redistribution of PLC gamma, relative to localization of the EGF receptor and PI 4,5-biphosphate (PI 4,5-P(2)), were shown. Colocalization with the receptor was observed in the plasma membrane and in membrane ruffles where PI 4,5-P(2) substrate could also be visualized. At later times, internalization of PLC gamma, which could lead to separation from the substrate, was observed. The data support a direct binding of PLC gamma to the receptor as the main site of the plasma membrane recruitment. The presence of PLC gamma in membrane structures and its access to the substrate appear to be transient and are followed by a rapid incorporation into intracellular vesicles, leading to downregulation of the PLC activity.


PTEN deletion enhances the regenerative ability of adult corticospinal neurons.
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.


Endoscopic carpal tunnel release in Jamaica--seven years experience.
To assess the patient profile and outcome of treatment, by endoscopic release, of patients with carpal tunnel syndrome. A descriptive study was done using data from two sets of patients who had endoscopic carpal tunnel release in Jamaica from 2004 to 2006 and 2006 to 2010. The medical records of patients who had a diagnosis of carpal tunnel syndrome using symptoms, clinical signs and confirmation by nerve conduction test were reviewed. The data were analysed using SPSS and Micosoft Excel. A total of 68 patients with 75 cases of carpal tunnel syndrome were done. Fifty-two (76%) of these patients were females and about 50% were older than 41 years old. There were 61 (90%) unilateral cases. Of these, the majority of cases affected the right hand. All patients had improvement in symptoms after one week, required minimal analgesic use, had good compliance with rehabilitation and returned to work after about two weeks. There were three cases of pilar tenderness, two cases of transient paraesthesia in the index finger which resolved after three weeks. There were three failed cases from the first series which had to be converted to open carpal tunnel release. The complication rate was 6.7%. No serious complications occurred in the second series and all were treated successfully without interventional surgery. The rate of conversion to open release was 4%. Carpal tunnel affects mostly middle aged females and when treatment is done by endoscopic release, there is a fast resolution of symptoms and early return to work.


Heterogeneous expression of hydrocephalic phenotype in the hyh mice carrying a point mutation in alpha-SNAP.
The hyh mouse carrying a point mutation in the gene encoding for soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein alpha (alpha-SNAP) develops inherited hydrocephalus. The investigation was designed to study: (i) the clinical evolution of hyh mice; (ii) factors other than the alpha-SNAP mutation that may influence the expression of hydrocephalus; (iii) the neuropathological features underlying the different forms of clinical evolution. The study included 3017 mice, 22.4% of which were hydrocephalic. The neuropathological study was performed in 112 mice by use of light and electron microscopy. It was found that maternal- and sex-related factors are involved in the heterogeneous expression of hyh phenotype. The clinical evolution recorded throughout a 4-year period also revealed a heterogeneous expression of the hydrocephalic phenotype. Two subpopulations were distinguished: (i) 70% of mice underwent a rapidly progressive hydrocephalus and died during the first 2 months of life; they presented macrocephaly, extremely large expansion of the ventricles, equilibrium impairment and decreased motor activity. (ii) Mice with slowly progressive hydrocephalus (30%) survived for periods ranging between 2 months and 2 years. They had no or moderate macrocephaly; moderate ventricular dilatation and preserved general motor activity; they all presented spontaneous ventriculostomies communicating the ventricles with the subarachnoid space, indicating that such communications play a key role in the long survival of these mice. The hyh mutant represents an ideal animal model to investigate how do the brain "adapt" to a virtually life-lasting hydrocephalus.


Dynamics of ethyl cellulose nanoparticle self-assembly at the interface of a nematic liquid crystal droplet.
Design and fabrication of many next-generation liquid crystal (LC)-based devices rely on nematic LC domains in the form of drops or emulsions. In addition to surfactants, solid nanoparticles may be used to stabilize LC-in-water Pickering emulsions, possibly adding new dimensions to device functionality. In this work we quantitatively study the adsorption of ethyl cellulose (EC) nanoparticles, as a colloid model system, on the 4-cyano-4'-pentylbiphenyl (5CB)-water interface via a series of dynamic interfacial tension measurements. It is found that the planar alignment of 5CB molecules at the interface with water is unaffected by particle adsorption, but a significant reduction of the interfacial tension over time occurs. It is also found that adsorption of EC nanoparticles to the LC-water interface is irreversible and results in close hexagonal packing. This study demonstrates a systematic approach to quantitatively investigate the effect of nanoparticles on the stabilization of LC emulsions.


Model-driven design for the visual analysis of heterogeneous data.
As heterogeneous data from different sources are being increasingly linked, it becomes difficult for users to understand how the data are connected, to identify what means are suitable to analyze a given data set, or to find out how to proceed for a given analysis task. We target this challenge with a new model-driven design process that effectively codesigns aspects of data, view, analytics, and tasks. We achieve this by using the workflow of the analysis task as a trajectory through data, interactive views, and analytical processes. The benefits for the analysis session go well beyond the pure selection of appropriate data sets and range from providing orientation or even guidance along a preferred analysis path to a potential overall speedup, allowing data to be fetched ahead of time. We illustrate the design process for a biomedical use case that aims at determining a treatment plan for cancer patients from the visual analysis of a large, heterogeneous clinical data pool. As an example for how to apply the comprehensive design approach, we present Stack'n'flip, a sample implementation which tightly integrates visualizations of the actual data with a map of available data sets, views, and tasks, thus capturing and communicating the analytical workflow through the required data sets.


Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial.
Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.


Coronal microleakage of endodontically treated teeth with intracanal post exposed to fresh human saliva.
The aim of this study was to investigate the coronal microleakage of endodontically treated teeth prepared to receive an intracanal post and teeth with an intracanal post but without a prosthetic crown and exposed to contamination by fresh human saliva. A mechanical-chemical preparation following the step-back technique was carried out in 35 extracted single-rooted human teeth. The teeth were randomly divided into five groups: G1=root canals instrumented, obturated, and prepared to receive an intracanal post (N=10); G2=root canals with cemented posts but without coronal sealing (N=10); PC1=positive control root canals instrumented and open (N=5); PC2=positive control 2 root canals without instrumentation and open (N=5); and NC=negative control healthy teeth (N=5). The crowns were removed except for the control group of intact teeth. The root canals were obturated and sterilized with cobalt 60 gamma irradiation and were then adapted in an apparatus using a Brain Heart Infusion (BHI) medium and fresh human saliva for contamination. Microbial growth was indicated by the presence of turbidity in the BHI liquid medium. Data were submitted to the Kaplan-Meier Survival Analysis and the Holm-Sidak statistic method, which observed an index of 90% of microleakage in root canals after 24 hours for G1 and 70% of microleakage in samples at the end of 40 days for G2. The results show that root canals with an intracanal post but without a prosthetic crown can be recontaminated when exposed to fresh human saliva in a short period.


Evaluation of intervention reporting in published emergency medicine clinical trials.
The extent of intervention reporting in emergency medicine journals remains unclear. The primary objective is to assess overall completion of the Template for Intervention Description and Replication (TIDieR) checklist described in emergency medicine randomized clinical trials (RCTs). The secondary outcomes were to (1) compare reporting before and after TIDieR publication; (2) evaluate factors associated with intervention reporting. Our cross-sectional study used Google Scholar's metrics to identify seven emergency medicine journals; of which, we randomly sampled 300 articles. Using two PubMed searches, we extracted 150 RCTs before and after publications of TIDieR. Two investigators independently extracted data. The primary analysis to measure overall completion included descriptive statistics for each checklist item. Our secondary analysis used an interrupted time series analysis and generalized estimating equations to determine the effect of TIDieR publication on intervention reporting. Our initial search yielded 635 articles; from which, we randomly sampled 300 articles. We excluded 67 articles, leaving 233 for analysis. The mean number of TIDieR items reported was 5.4 (standard deviation = 1.18). Of the 233 trials, 42.9% provided information about materials, 67% provided intervention procedures, and 99.1% provided intervention delivery. The least reported items were intervention modifications (2.6%), intervention adherence assessment methods (3.4%), and intervention adherence assessment outcomes (2.2%). The completeness of intervention reporting is suboptimal in emergency medicine journals, necessitating improvement. The current state of adherence could be improved through the combined efforts of journal editors, major editorial organizations, and authors.


Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
Several anthropometric measures have been found to be associated with the risk of breast cancer. Current weight, body mass index, and adult weight gain appear to be predictors of postmenopausal breast cancer. These factors have been associated with a reduced risk of premenopausal breast cancer. We asked whether there is an association between changes in body weight and the risk of breast cancer in women who carry a mutation in either breast cancer susceptibility gene, BRCA1 or BRCA2. A matched case-control study was conducted in 1,073 pairs of women carrying a deleterious mutation in either BRCA1 (n = 797 pairs) or BRCA2 (n = 276 pairs). Women diagnosed with breast cancer were matched to control subjects by year of birth, mutation, country of residence, and history of ovarian cancer. Information about weight was derived from a questionnaire routinely administered to women who were carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between weight gain or loss and the risk of breast cancer, stratified by age at diagnosis or menopausal status. A loss of at least 10 pounds in the period from age 18 to 30 years was associated with a decreased risk of breast cancer between age 30 and 49 (odds ratio (OR) = 0.47; 95% confidence interval (CI) 0.28-0.79); weight gain during the same interval did not influence the overall risk. Among the subgroup of BRCA1 mutation carriers who had at least two children, weight gain of more than 10 pounds between age 18 and 30 was associated with an increased risk of breast cancer diagnosed between age 30 and 40 (OR = 1.44, 95% CI 1.01-2.04). Change in body weight later in life (at age 30 to 40) did not influence the risk of either premenopausal or postmenopausal breast cancer. The results from this study suggest that weight loss in early adult life (age 18 to 30) protects against early-onset BRCA-associated breast cancers. Weight gain should also be avoided, particularly among BRCA1 mutation carriers who elect to have at least two pregnancies.