No in vitro effects of fatty acids on glucose uptake, lipolysis or insulin signaling in rat adipocytes.
Elevated plasma levels of free fatty acids (FFA) can produce insulin resistance in skeletal muscle tissue and liver and, together with alterations in beta-cell function, this has been referred to as lipotoxicity. This study explores the effects of FFAs on insulin action in rat adipocytes. Cells were incubated 4 or 24 h with or without an unsaturated FFA, oleate or a saturated FFA, palmitate (0.6 and 1.5 mM, respectively). After the culture period, cells were washed and insulin effects on glucose uptake and lipolysis as well as cellular content of insulin signaling proteins (IRS-1, PI3-kinase, PKB and phosphorylated PKB) and the insulin regulated glucose transporter GLUT4 were measured. No significant differences were found in basal or insulin-stimulated glucose uptake in FFA-treated cells compared to control cells, regardless of fatty acid concentration or incubation period. Moreover, there were no significant alterations in the expression of IRS-1, PI3-kinase, PKB and GLUT4 following FFA exposure. Insulin's ability to stimulate PKB phosphorylation was also left intact. Nor did we find any alterations following FFA exposure in basal or cAMP-stimulated lipolysis or in the ability of insulin to inhibit lipolysis. The results indicate that oleate or palmitate does not directly influence insulin action to stimulate glucose uptake and inhibit lipolysis in rat fat cells. Thus, lipotoxicity does not seem to occur in the fat tissue itself.


Articulation points in complex networks.
An articulation point in a network is a node whose removal disconnects the network. Those nodes play key roles in ensuring connectivity of many real-world networks, from infrastructure networks to protein interaction networks and terrorist communication networks. Despite their fundamental importance, a general framework of studying articulation points in complex networks is lacking. Here we develop analytical tools to study key issues pertinent to articulation points, such as the expected number of them and the network vulnerability against their removal, in an arbitrary complex network. We find that a greedy articulation point removal process provides us a different perspective on the organizational principles of complex networks. Moreover, this process results in a rich phase diagram with two fundamentally different types of percolation transitions. Our results shed light on the design of more resilient infrastructure networks and the effective destruction of terrorist communication networks.


The incidence of unprovoked seizures and occurrence of neurodevelopmental comorbidities in children at the time of their first epileptic seizure and during the subsequent six months.
To evaluate the incidence of unprovoked seizures in children and the prevalence of related neurodevelopmental comorbidities at the time of the presumed first seizure and six months thereafter. The medical records of all children (0-18 years of age) seeking medical attention as the result of a first unprovoked seizure between September 1, 2001 and December 31, 2006, and registered in the population-based Stockholm Incidence Registry of Epilepsy (SIRE) were reviewed. Neurodevelopmental comorbidities were evaluated on the basis of the medical records from this first visit and from other healthcare during the following six months. The incidence of unprovoked seizures was between 30 and 204/100,000 person years (n=766) in the different age groups. It was highest among the youngest children and lowest among the 18-year-olds with small gender differences. The most common neurodevelopment comorbidities were developmental delay (22%, CI: 19-25%), speech/language and learning difficulties (23%, CI: 20-26%) and intellectual disability (16%, CI: 13-18%). The types of neurodevelopmental comorbidity varied by age at the time of seizure onset, with cerebral palsy being more common among the 0-5-year-olds, attention deficits among the 6-16-year-olds, and autism and psychiatric diagnosis among the older children. An associated neurodevelopmental comorbidity was more common among those experiencing recurrent than single seizures during follow-up six months from the index seizure (42% versus 66%). In 68% (CI: 64-71%) of the children there was no known or suspected neurodevelopmental comorbidity. The incidence of unprovoked, non-febrile seizures among 0-18-year-olds included in the SIRE was 67/100,000 person-years. Neurodevelopmental comorbidities were common already at the time of onset of the seizure disorder, indicating that neither seizure treatment nor seizures were the underlying cause of other neurodevelopmental symptoms in these patients during the period studied.


Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: implications for enzyme-directed bioreductive drug development.
Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot be predicted on the basis of DTD activity. Measurement of MMC metabolism by tumor homogenates on the other hand may provide a better indicator of tumor response, and further studies are required to determine whether this approach has real clinical potential in terms of individualizing patient chemotherapy.


Late miocene tidal deposits in the amazonian foreland basin.
Late Miocene tidal sediments of Acre, Brazilian Amazonia, were deposited in an embayment or interior seaway located in the sub-Andean zone. This late Tertiary embayment system may once have connected the Caribbean with the South Atlantic. The tidal coasts of the embayment-seaway have provided an avenue for the earliest waif (over water) dispersal phases of the great American biotic interchange in the late Miocene. The subsequent change from semimarine to terrestrial environments is of value in assessing the importance of earlier hypotheses on the evolution of the westem Amazonian landscape and gives insight into the formation of several observed biogeographic patterns, especially of aquatic biota.


Restricted expression of an early myeloid and monocytic cell surface antigen defined by monoclonal antibody M195.
A mouse monoclonal IgG2a antibody, M195, with reactivity restricted to early myeloid cells, acute non-lymphoid leukemia cells (ANLL), and monocytic cells is described. The antibody was derived from a mouse immunized with live human leukemic myeloblasts. Specificity of binding of mAb M195 was determined by protein-A red blood cell rosetting assays, immunoabsorption, radioimmunoassays with iodine-125 labeled M195 IgG and F(Ab)'2, and complement cytotoxicity with live human cells and cell lines representing a broad range of lineages and tissues. Antigen expression was restricted to myeloid and monocytic leukemia cell lines and a fraction of mature adherent monocytes. Mature myeloid cells, T and B cells, erythrocytes, and platelets were negative. The antigen was not expressed on adult human tissues in immunoperoxidase and immunofluorescence assays. Blocking antigen was not found in the serum of patients with ANLL. Ten thousand sites per cell were expressed on myeloid or monocytic leukemia cell lines and 5000 sites per cell on mature monocytes. M195 IgG bound to its antigen target with an avidity of 3 x 10(9) liters/mol and induced rapid modulation of the antigen. M195 IgG was able to effectively kill cells with rabbit or guinea pig complement, but not human complement. The antibody did not mediate antibody dependent cellular cytotoxicity. The molecular nature of the target antigen remains unknown but it appears to be carried on the CD33 protein p67. Because of its restricted distribution on myelomonocytic cells, mAb M195 may be useful in studying myeloid differentiation, in the clinical diagnosis of ANLL, in purging of bone marrow of ANLL, and/or in monoclonal antibody therapy in vivo.


Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia.
High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.


IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression.
IFN regulatory factor 8 (IRF8) is a transcription factor that was originally identified in myeloid cells and has been shown to be essential for differentiation and function of hemopoietic cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of the granulocytic and monocytic lineages that progress into a phenotype resembling human chronic myelogenous leukemia. In human patients with chronic myelogenous leukemia, IRF8 transcript levels are frequently diminished. Therefore, IRF8 is a key regulator of myeloid tumor development. In this study, we report that IRF8 is a critical regulator of apoptosis in nonhemopoietic tumor cells. Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells. Both constitutively expressed and IFN-gamma-activated IRF8 were involved in regulation of apoptosis. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN-gamma-initiated induction of STAT1 phosphorylation, which in turn, blocked IFN-gamma-induced Fas up-regulation. Interestingly, the constitutively expressed IRF8 was also essential for TNF-alpha sensitization of Fas-mediated apoptosis because disruption of IRF8 function also inhibited TNF-alpha-sensitized and Fas-mediated apoptosis. Taken together, our data suggest that IRF8 is an essential mediator of Fas-mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas expression in nonhemopoietic tumor cells.


Piecemeal deglutition and dysphagia limit in normal subjects and in patients with swallowing disorders.
Before the advanced evaluation of deglutition and selection of a treatment method, objective screening methods are necessary for patients with dysphagia. In this study a new electroclinical test was established to evaluate patients with dysphagia. This test is based on determining piecemeal deglutition; which is a physiological phenomenon occurring when a bolus of a large volume is divided into two or more parts which are swallowed successively. The combined electrophysiological and mechanical method used to record laryngeal movements detected by a piezoelectric transducer, and activities of the related submental integrated EMG (SM-EMG)-and sometimes the cricopharyngeal muscle of the upper oesophageal sphincter (CP-EMG)-were performed during swallowing. Thirty normal subjects and 66 patients with overt dysphagia of neurogenic origin were investigated after detailed clinical evaluation. Twenty patients with a potential risk of dysphagia, but who were normal clinically at the time of investigation, were also evaluated to determine the specificity of the test. All subjects were instructed to swallow doses of water, gradually increasing in quantity from 1 ml to 20 ml, and any recurrence of the signals related to swallowing within the eight seconds was accepted as a sign of dysphagia limit. In normal subjects as well as in the patients without dysphagia, piecemeal deglutition was never seen with less than 20 ml water. This volume was therefore accepted as the lower limit of piecemeal deglutition. In patients with dysphagia, dysphagia limits were significantly lower than those of normal subjects. The method is a highly specific and sensitive test for the objective evaluation of oropharyngeal dysphagia even in patients with suspected dysphagia of neurogenic origin. It can also be safely and simply applied in any EMG laboratory.


Development and verification of the PAM50-based Prosigna breast cancer gene signature assay.
The four intrinsic subtypes of breast cancer, defined by differential expression of 50 genes (PAM50), have been shown to be predictive of risk of recurrence and benefit of hormonal therapy and chemotherapy. Here we describe the development of Prosigna™, a PAM50-based subtype classifier and risk model on the NanoString nCounter Dx Analysis System intended for decentralized testing in clinical laboratories. 514 formalin-fixed, paraffin-embedded (FFPE) breast cancer patient samples were used to train prototypical centroids for each of the intrinsic subtypes of breast cancer on the NanoString platform. Hierarchical cluster analysis of gene expression data was used to identify the prototypical centroids defined in previous PAM50 algorithm training exercises. 304 FFPE patient samples from a well annotated clinical cohort in the absence of adjuvant systemic therapy were then used to train a subtype-based risk model (i.e. Prosigna ROR score). 232 samples from a tamoxifen-treated patient cohort were used to verify the prognostic accuracy of the algorithm prior to initiating clinical validation studies. The gene expression profiles of each of the four Prosigna subtype centroids were consistent with those previously published using the PCR-based PAM50 method. Similar to previously published classifiers, tumor samples classified as Luminal A by Prosigna had the best prognosis compared to samples classified as one of the three higher-risk tumor subtypes. The Prosigna Risk of Recurrence (ROR) score model was verified to be significantly associated with prognosis as a continuous variable and to add significant information over both commonly available IHC markers and Adjuvant! Online. The results from the training and verification data sets show that the FDA-cleared and CE marked Prosigna test provides an accurate estimate of the risk of distant recurrence in hormone receptor positive breast cancer and is also capable of identifying a tumor's intrinsic subtype that is consistent with the previously published PCR-based PAM50 assay. Subsequent analytical and clinical validation studies confirm the clinical accuracy and technical precision of the Prosigna PAM50 assay in a decentralized setting.


Magnetic measurements of pulmonary contamination.
The magnitic determination of pulmonary contamination is based on the remanent magnetization of ferromagnetic contaminating particles. The remanent field of the externally magnetized particles is proportional to their amount and shows their distribution. Although only magnetizable particles are detected with this method, the amount of the inhaled ferromagnetic substance can be used when the total dust exposure of the worker is estimated. In this work five shipyard welders were studied. First the particles disposed to the lungs were externally magnetized and then their distribution was mapped with a sensitive magnetometer. The magnitudes of the remanent fields measured from the welders differed from the fields measured from controls by several orders of magnitude. The radiographic findings showed a good correlation with the magnetic measurements, and further experiments will prove whether this method can partly replace presently used radiological investigations.


Reducing warm ischaemia time during laparoscopic partial nephrectomy: a prospective comparison of two renal closure techniques.
To test the hypothesis that a modified technique for renal parenchymal closure during laparoscopic partial nephrectomy (LPN) enables a significant reduction in warm ischaemia (WIT). Perioperative factors including WIT were prospectively recorded during 40 consecutive LPNs performed by a single experienced laparoscopist. In the first 20 (controls), renal parenchyma was closed by conventional technique (haemostasis and closure of the collecting system with interrupted sutures, then closure of the renal parenchyma over a Surgicel bolster before unclamping the renal artery). In the second consecutive 20 patients (group 1), a modified closure technique was used, which involved earlier arterial unclamping after two (group 1a) or one (group 1b) running suture on the tumour bed. Vascularised renal parenchyma was then closed over a surgical bolster. All LPNs were performed successfully without conversion. WIT was significantly less in group 1 compared with the control group (27.2+/-5 min vs. 13.7+/-4 min, respectively; p<0.01). WIT was 16.8+/-3.6 vs. 10.3+/-1.2 min in groups 1a and 1b (p<0.01); no other significant differences were observed in perioperative factors. All specimens had negative tumour margins histologically. Major complications and haemoglobin reduction were lower in group 1 compared with the control group. The described technique is effective and allows a significant reduction of WIT, even in challenging cases, without increasing perioperative bleeding or morbidity. Its use therefore reduces the need for hypothermic techniques, and allows more time for careful tumour resection and renal reconstruction.


The function of glycine decarboxylase complex is optimized to maintain high photorespiratory flux via buffering of its reaction products.
Oxidation of glycine in photorespiratory pathway is the major flux through mitochondria of C3 plants in the light. It sustains increased intramitochondrial concentrations of NADH and NADPH, which are required to engage the internal rotenone-insensitive NAD(P)H dehydrogenases and the alternative oxidase. We discuss here possible mechanisms of high photorespiratory flux maintenance in mitochondria and suggest that it is fulfilled under conditions where the concentrations of glycine decarboxylase reaction products NADH and CO2 achieve an equilibrium provided by malate dehydrogenase and carbonic anhydrase, respectively. This results in the removal of these products from the glycine decarboxylase multienzyme active sites and in the maintenance of their concentrations at levels sufficiently low to prevent substrate inhibition of the reaction.


KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy.
Neuroendocrine (NE) cancers can cause significant patient morbidity. Besides surgery, there are no curative treatments for NE cancers and their metastases, emphasizing the need for the development of other forms of therapy. In this study, multifunctional unimolecular micelles were developed for targeted NE cancer therapy. The unimolecular micelles were formed by multi-arm star amphiphilic block copolymer poly(amidoamine)-poly(valerolactone)-poly(ethylene glycol) conjugated with KE108 peptide and Cy5 dye (abbreviated as PAMAM-PVL-PEG-KE108/Cy5). The unimolecular micelles with a spherical core-shell structure exhibited a uniform size distribution and excellent stability. The hydrophobic drug thailandepsin-A (TDP-A), a recently discovered HDAC inhibitor, was physically encapsulated into the hydrophobic core of the micelles. KE108 peptide, a somatostatin analog possessing high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), commonly overexpressed in NE cancer cells, was used for the first time as an NE cancer targeting ligand. KE108 exhibited superior targeting abilities compared to other common somatostatin analogs, such as octreotide, in NE cancer cell lines. The in vitro assays demonstrated that the TDP-A-loaded, KE108-targeted micelles exhibited the best capabilities in suppressing NE cancer cell growth. Moreover, the in vivo near-infrared fluorescence imaging on NE-tumor-bearing nude mice showed that KE108-conjugated micelles exhibited the greatest tumor accumulation due to their passive targeting and active targeting capabilities. Finally, TDP-A-loaded and KE108-conjugated micelles possessed the best anticancer efficacy without detectable systemic toxicity. Thus, these novel TDP-A-loaded and KE108-conjugated unimolecular micelles offer a promising approach for targeted NE cancer therapy.


Aspects for calculating local absorption with the rigorous coupled-wave method.
The calculation of local absorption is very important in the context of lithography and in photo-detector design. We present a rigorous method for calculating the local absorption in periodic structures. The computation depends primarily on the calculation of the electric field inside the structure. Since the standard definitions produce unsatisfactory results, we use a modified version of a method published by Lalanne [J. Modern Opt. 45, 1357 (1998)]. The results for these field definitions agree very accurately with results obtained by the law of conservation of energy. We present some examples which are typical for the application scenarios of lithography and detectors.


New Sepsis and Septic Shock Definitions: Clinical Implications and Controversies.
New sepsis definitions shift emphasis from the systemic inflammatory response syndrome to organ dysfunction, quantified using the Sequential Organ Failure Assessment (SOFA) score. The new definitions also propose Quick SOFA criteria to rapidly identify potentially infected patients at risk for poor outcomes. The diagnosis of septic shock requires vasopressor dependence and increased lactate levels. Strengths of these definitions include their simplicity and clear association with adverse outcomes. However, their utility in identifying patients with serious infections before frank sepsis ensues remains to be seen. This article reviews challenges in defining sepsis, strengths and weaknesses of the new definitions, and unresolved issues.


Music-based memory enhancement in Alzheimer's disease: promise and limitations.
In a previous study (Simmons-Stern, Budson & Ally, 2010), we found that patients with Alzheimer's disease (AD) better recognized visually presented lyrics when the lyrics were also sung rather than spoken at encoding. The present study sought to further investigate the effects of music on memory in patients with AD by making the content of the song lyrics relevant for the daily life of an older adult and by examining how musical encoding alters several different aspects of episodic memory. Patients with AD and healthy older adults studied visually presented novel song lyrics related to instrumental activities of daily living (IADL) that were accompanied by either a sung or a spoken recording. Overall, participants performed better on a memory test of general lyric content for lyrics that were studied sung as compared to spoken. However, on a memory test of specific lyric content, participants performed equally well for sung and spoken lyrics. We interpret these results in terms of a dual-process model of recognition memory such that the general content questions represent a familiarity-based representation that is preferentially sensitive to enhancement via music, while the specific content questions represent a recollection-based representation unaided by musical encoding. Additionally, in a test of basic recognition memory for the audio stimuli, patients with AD demonstrated equal discrimination for sung and spoken stimuli. We propose that the perceptual distinctiveness of musical stimuli enhanced metamemorial awareness in AD patients via a non-selective distinctiveness heuristic, thereby reducing false recognition while at the same time reducing true recognition and eliminating the mnemonic benefit of music. These results are discussed in the context of potential music-based memory enhancement interventions for the care of patients with AD.


Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system.
Low-grade follicular non-Hodgkin's lymphomas are characterized by the presence of a t(14;18) chromosomal translocation that results in deregulation of the B-cell lymphoma (Bcl-2) gene. Studies in cell lines and transgenic animal models have suggested that this results in the suppression of apoptotic cell death in germinal centers. B lymphocytes from normal germinal centers and lymph nodes infiltrated by follicular lymphoma were isolated by immunomagnetic depletion of cells bearing CD4, CD8, or slgD for study in vitro. Follicular lymphoma cells expressing Bcl-2 protein were shown to resist apoptosis after isolation, and could be induced to proliferate in a culture system previously described for the growth of normal B lymphocytes. By the use of a mouse fibroblast monolayer transfected with the CDw32 Fc receptor to present CD40 monoclonal antibody in the presence of interleukin-4, prolonged culture was possible. Karyotypic analysis of cultured lymphoma cells showed the t(14;18) translocation, with clonal identity confirmed by polymerase chain reaction amplification of the breakpoints and direct sequence analysis. These findings support the hypothesis that resistance to apoptosis is an influence on the initiation of follicular lymphoma, and provide a novel means of studying in vitro the intercellular reactions that may be important in progression of the disease.


Long-term exposure to low-level air pollution and incidence of chronic obstructive pulmonary disease: The ELAPSE project.
Air pollution has been suggested as a risk factor for chronic obstructive pulmonary disease (COPD), but evidence is sparse and inconsistent. We examined the association between long-term exposure to low-level air pollution and COPD incidence. Within the 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE) study, we pooled data from three cohorts, from Denmark and Sweden, with information on COPD hospital discharge diagnoses. Hybrid land use regression models were used to estimate annual mean concentrations of particulate matter with a diameter < 2.5 µm (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) in 2010 at participants' baseline residential addresses, which were analysed in relation to COPD incidence using Cox proportional hazards models. Of 98,058 participants, 4,928 developed COPD during 16.6 years mean follow-up. The adjusted hazard ratios (HRs) and 95% confidence intervals for associations with COPD incidence were 1.17 (1.06, 1.29) per 5 µg/m3 for PM2.5, 1.11 (1.06, 1.16) per 10 µg/m3 for NO2, and 1.11 (1.06, 1.15) per 0.5 10-5m-1 for BC. Associations persisted in subset participants with PM2.5 or NO2 levels below current EU and US limit values and WHO guidelines, with no evidence for a threshold. HRs for NO2 and BC remained unchanged in two-pollutant models with PM2.5, whereas the HR for PM2.5 was attenuated to unity with NO2 or BC. Long-term exposure to low-level air pollution is associated with the development of COPD, even below current EU and US limit values and possibly WHO guidelines. Traffic-related pollutants NO2 and BC may be the most relevant.


Towards integrated clinico-genomic models for personalized medicine: combining gene expression signatures and clinical factors in breast cancer outcomes prediction.
Genomic data, particularly genome-scale measures of gene expression derived from DNA microarray studies, has the potential for adding enormous information to the analysis of biological phenotypes. Perhaps the most successful application of this data has been in the characterization of human cancers, including the ability to predict clinical outcomes. Nevertheless, most analyses have used gene expression profiles to define broad group distinctions, similar to the use of traditional clinical risk factors. As a result, there remains considerable heterogeneity within the broadly defined groups and thus predictions fall short of providing accurate predictions for individual patients. One strategy to resolve this heterogeneity is to make use of multiple gene expression patterns that are more powerful in defining individual characteristics and predicting outcomes than any single gene expression pattern. Statistical tree-based classification systems provide a framework for assessing multiple patterns, that we term metagenes, selecting those that are most capable of resolving the biological heterogeneity. Moreover, this framework provides a mechanism to combine multiple forms of data, both genomic and clinical, to most effectively characterize individual patients and achieve the goal of personalized predictions of clinical outcomes.


Neural Functions Play Different Roles in Triple Negative Breast Cancer (TNBC) and non-TNBC.
Triple negative breast cancer (TNBC) represents the most malignant subtype of breast cancer, and yet our understanding about its unique biology remains elusive. We have conducted a comparative computational analysis of transcriptomic data of TNBC and non-TNBC (NTNBC) tissue samples from the TCGA database, focused on genes involved in neural functions. Our main discoveries are: (1) while both subtypes involve neural functions, TNBC has substantially more up-regulated neural genes than NTNBC, suggesting that TNBC is more complex than NTNBC; (2) non-neural functions related to cell-microenvironment interactions and intracellular damage processing are key inducers of the neural genes in both TNBC and NTNBC, but the inducer-responder relationships are different in the two cancer subtypes; (3) key neural functions such as neural crest formation are predicted to enhance adaptive immunity in TNBC while glia development, along with a few other neural functions, induce both innate and adaptive immunity in NTNBC. These results reveal key differences in the biology between the two cancer subtypes, particularly in terms of the roles that neural functions play. Our findings may open new doors for further investigation of the distinct biology of TNBC vs. NTNBC.


Rat lung response to PM2.5 exposure under different cold stresses.
Ambient particulate matters and temperature were reported to have additive effects over the respiratory disease hospital admissions and deaths. The purpose of this study is to discuss the interactive pulmonary toxicities of cold stress and fine particulate matter (PM2.5) exposure by estimating inflammation and oxidative stress responses. 48 Wistar male rats, matched by weight and age, were randomly assigned to six groups, which were treated with cold stress alone (0 °C, 10 °C, and 20 °C (Normal control)) and cold stresses plus PM2.5 exposures respectively. Cold stress alone groups were intratracheal instillation of 0.25 mL normal saline, while cold stress plus PM2.5 exposure groups were intratracheal instillation of 8 mg/0.25 mL PM2.5. These procedures were carried out for three times with an interval of 48 hours for each treatment. All rats were sacrificed after 48 hours of the third treatment. The bronchoalveolar lavage fluid (BALF) was collected for analyzing inflammatory cells and cytokines, and lung homogenate MDA was determined for oxidative stress estimation. Results showed higher level of total cell and neutrophil in the BALF of PM2.5 exposed groups (p < 0.05). Negative relationships between cold stress intensity and the level of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP) interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF were indicated in PM2.5 exposure groups. Exposure to cold stress alone caused significant increase of inflammatory cytokines and methane dicarboxylic aldehyde (MDA) and decline of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity only in 0 °C exposure group (p < 0.05). The two-way ANOVA found significant interactive effects between PM2.5 exposure and cold stress in the level of neutrophil, IL-6 and IL-8 and SOD activity (p < 0.05). These data demonstrated that inflammation and oxidative stress involved in the additive effect of PM2.5 exposure and cold stress on pulmonary toxicity, providing explanation for epidemiological studies on the health effect of ambient PM2.5 and cold stress.


Potentiometric monitoring of cobalt in beer sample by solid contact ion selective electrode.
A new solid contact cobalt selective electrode was constructed with 4-tert-butylthiacalix[4]arene as ionophore. The best performance was observed with the membrane having an ionophore/polyvinyl chloride/sodium tetraphenylborate/nitrophenyl octyl ether ratio of 3.5:33:1.5:62 (w/w; mg). The electrode, under steady-state conditions, exhibited a working concentration range of 1 × 10-1 - 1 × 10-6 mol/L with a near-Nernstian slope of 25.3 mV/decade and a detection limit of 3.5 × 10-7 mol/L. The electrode had a very short response time (<10 seconds) and good reproducibility at a working pH range of 4.0-6.5. The electrode was used for 4 months without any significant change in its sensitivity. The potentiometric performance of the electrode in partially nonaqueous medium [up to 20 % (v/v) alcohol] was found satisfactory. The performance of the prepared electrode for the analysis of beer samples using direct potentiometric method is very encouraging.


Racial disparities in family-provider interactions for pediatric asthma care.
Black and Latino children experience significantly worse asthma morbidity than their white peers for multifactorial reasons. This study investigated differences in family-provider interactions for pediatric asthma, based on race/ethnicity. This was a cross-sectional study of parent surveys of asthmatic children within the Population-Based Effectiveness in Asthma and Lung Diseases Network. Our study population comprised 647 parents with survey response data. Data on self-reported race/ethnicity of the child were collected from parents of the children with asthma. Outcomes studied were responses to the questions about family-provider interactions in the previous 12 months: (1) number of visits with asthma provider; (2) number of times provider reviewed asthma medications with patient/family; (3) review of a written asthma treatment plan with provider; and (4) preferences about making asthma decisions. In multivariate adjusted analyses controlling for asthma control and other co-morbidities, black children had fewer visits in the previous 12 months for asthma than white children: OR 0.63 (95% CI 0.40, 0.99). Additionally, black children were less likely to have a written asthma treatment plan given/reviewed by a provider than their white peers, OR 0.44 (95% CI 0.26, 0.75). There were no significant differences by race in preferences about asthma decision-making nor in the frequency of asthma medication review. Black children with asthma have fewer visits with their providers and are less likely to have a written asthma treatment plan than white children. Asthma providers could focus on improving these specific family-provider interactions in minority children.


Postprandial concentrations of free and conjugated bile acids down the length of the normal human small intestine.
Small intestinal samples were obtained by intubation from multiple sites along the small intestine in 11 subjects with no known gastrointestinal disease eating a normal diet and at laparotomy in a further three subjects. Free (unconjugated) bile acids were consistently demonstrated in ileal samples, and occasionally in lower jejunal samples, by thin-layer chromatography, supplemented in some cases by gas/liquid chromatography and by infrared spectroscopy. The free bile acid concentration, measured enzymically following thin-layer chromatography, reached a maximum (1 mM) in the lower ileum, where it represented half the total bile acid concentration. Following ampicillin, the concentration of free bile acids decreased markedly, suggesting that they resulted from bacterial deconjugation; at the same time the total bile acid concentration increased, suggesting impaired absorption due to the reduced concentration of the more rapidly absorbed free bile acids. Our results indicate that the presence of free bile acids in lower jejunal and ileal samples is a normal finding, and cannot be taken as evidence of abnormal bacterial overgrowth. They also suggest that bacterial deconjugation at these sites may be a factor contributing to the remarkable efficiency of bile salt reabsorption.


Infection of the brown alga Ectocarpus siliculosus by the oomycete Eurychasma dicksonii induces oxidative stress and halogen metabolism.
Pathogens are increasingly being recognized as key evolutionary and ecological drivers in marine ecosystems. Defence mechanisms of seaweeds, however, have mostly been investigated by mimicking infection using elicitors. We have established an experimental pathosystem between the genome brown model seaweed Ectocarpus siliculosus and the oomycete Eurychasma dicksonii as a powerful new tool to investigate algal responses to infection. Using proteomics, we identified 21 algal proteins differentially accumulated in response to Eu. dicksonii infection. These include classical algal stress response proteins such as a manganese superoxide dismutase, heat shock proteins 70 and a vanadium bromoperoxidase. Transcriptional profiling by qPCR confirmed the induction of the latter during infection. The accumulation of hydrogen peroxide was observed at different infection stages via histochemical staining. Inhibitor studies confirmed that the main source of hydrogen peroxide is superoxide converted by superoxide dismutase. Our data give an unprecedented global overview of brown algal responses to pathogen infection, and highlight the importance of oxidative stress and halogen metabolism in these interactions. This suggests overlapping defence pathways with herbivores and abiotic stresses. We also identify previously unreported actors, in particular a Rad23 and a plastid-lipid-associated protein, providing novel insights into the infection and defence processes in brown algae.


Online self-management interventions for chronically ill patients: cognitive impairment and technology issues.
As the fraction of the population with chronic diseases continues to grow, methods and/or technologies must be found to help the chronically ill to take more responsibility to self-manage their illnesses. Internet based and/or mobile support for disease self-management interventions have often proved effective, but patients with chronic illnesses may have co-occurring cognitive impairment, making it more difficult for them to cope with technologies. Many older patients are also not familiar with technologies or they may have cognitive disabilities or dementia that reduce their ability to self-manage their healthcare. On-line solutions to the needs of chronically ill patients must be investigated and acted upon with care in an integrated manner, since resources invested in these solutions will be lost if patients do not adopt and continue to use them successfully. To review the capabilities of online and mobile support for self-management of chronic illnesses, and the impacts that age and disease-related issues have on these interventions, including cognitive impairment and lack of access or familiarity with Internet or mobile technologies. This study includes a review of the co-occurrence of cognitive impairment with chronic diseases, and discusses how cognitive impairment, dyadic caregiver patient support, patient efficacy with technology, and smart home technologies can impact the effectiveness and sustainability of online support for disease self-management. Disease self-management interventions (SMIs) using online patient centered support can often enable patients to manage their own chronic illnesses. However, our findings show that cognitive impairment often co-occurs in patients with chronic disease. This, along with age-related increases in multiple chronic illnesses and lack of technology efficacy, can be obstacles to Internet and mobile support for chronic disease self-management. Patients with chronic diseases may have greater than expected difficulties in using Internet and mobile technologies for disease self-management, often due to cognitive impairment or unfamiliarity with technology. Approaches to dealing with such barriers include suitable integration of solutions involving patient-caregiver dyads, better design of online applications, careful attention to technology adoption and sustainability, and smart home technologies.


Nutritional manipulation of primate retinas, II: effects of age, n-3 fatty acids, lutein, and zeaxanthin on retinal pigment epithelium.
To study the effects of age and of n-3 fatty acids, lutein, and zeaxanthin on the retinal pigment epithelium (RPE). Rhesus monkeys (age range, 7-17 years; n = 18) were fed xanthophyll-free semipurified diets from birth. The diets had either low or adequate amounts of n-3 fatty acids. Six monkeys remained xanthophyll-free until death. Six received supplements of pure lutein and six of pure zeaxanthin for 6 to 24 months. The central retina was serially sectioned, and the number of RPE cells were counted in an 8-microm strip along the vertical meridian. Cell counts were compared with data from control monkeys (n = 15) fed a standard laboratory diet. Foveal and parafoveal RPE cell densities increased with age. Xanthophyll-free monkeys had a dip in the RPE cell density profile at the foveal center, rather than the normal peak. After supplementation with xanthophylls, the RPE profile of animals low in n-3 fatty acids no longer had a dip at the foveal center but became asymmetric, with higher densities in the inferior retina. In animals with adequate n-3 fatty acid levels, xanthophyll supplementation did not restore the foveal peak, and resulted in an asymmetric profile with higher densities in the superior retina. RPE cells are sensitive to the absence of macular pigment. Supplemental xanthophylls interact with n-3 fatty acid levels to produce asymmetries in the RPE profile. Xanthophylls and n-3 fatty acids are essential for the development and/or maintenance of a normal distribution of RPE cells.


Thinking big by thinking small: advances in mechanobiology across the length scales.
The field of mechanobiology provides an integrative understanding of biology and engineering principles. Mechanical forces are now well-established to provide a physical stimulus to help maintain normal tissue function, yet little is understood as to how forces experienced at various length scales influence cell behaviour and tissue function. In this Research Highlight, we describe recent technical innovations that have enabled advanced insight into the cellular microenvironment across a range of length scales.


Impact of prehospital hypothermia on transfusion requirements and outcomes.
Prehospital hypothermia (PH) is known to increase mortality following traumatic injury. PH relationship with transfusion requirements has not been documented. The purpose of this investigation was to analyze the impact of PH on blood product requirements and subsequent outcomes. The Los Angeles County Trauma System Database was queried for all patients admitted between 2005 and 2009. Demographics, physiologic parameters, and transfusion requirements were obtained and dichotomized by admission temperatures with a core temperature of less than 36.5 °C considered hypothermic. Multivariate analysis was performed to determine factors contributing to transfusion requirements and to derive adjusted odds ratios (AORs) for mortality and rates of adult respiratory distress syndrome and pneumonia. A total of 21,023 patients were analyzed in our study with 44.6% presenting with PH. Hypothermic patients required 26% more fluid resuscitation (p < 0.001) in the emergency department and 17% more total blood products (p < 0.001) than those who were admitted with a normal temperature. There was a trend toward an increase in emergency department transfusion (8%, p = 0.06). PH was independently associated with the need for a transfusion (AOR, 1.1; p = 0.047), increased mortality (AOR, 2.0; p < 0.01), as well as incidence of adult respiratory distress syndrome (AOR, 1.8; p < 0.05) and pneumonia (AOR, 2.6; p < 0.01). PH is associated with increased transfusion and fluid requirements and subsequently worse outcomes. Interventions that correct hypothermia may decrease transfusion requirements and improve outcomes. Prospective studies investigating correction of hypothermia in trauma patients are warranted. Prognostic/epidemiologic study, level III.


Geographic coincidence of richness, mass, conservation value, and response to climate of U.S. land birds.
Distributional patterns across the United States of five avian community breeding-season characteristics--community biomass, richness, constituent species' vulnerability to extirpation, percentage of constituent species' global abundance present in the community (conservation index, CI), and the community's position along the ecological gradient underlying species composition (principal curve ordination score, PC--were described, their covariation was analyzed, and projected effects of climate change on the characteristics and their covariation were modeled. Higher values of biomass, richness, and CI were generally preferred from a conservation perspective. However, higher values of these characteristics often did not coincide geographically; thus regions of the United States would differ in their value for conservation depending on which characteristic was chosen for setting conservation priorities. For instance, correlation patterns between characteristics differed among Landscape Conservation Cooperatives. Among the five characteristics, community richness and the ecological gradient underlying community composition (PC) had the highest correlations with longitude, with richness declining from east to west across the contiguous United States. The ecological gradient underlying composition exhibited a demarcation near the 100th meridian, separating the contiguous United States grossly into two similar-sized avian ecological provinces. The combined score (CS), a measure of species' threat of decline or extirpation, exhibited the strongest latitudinal pattern, declining from south to north. Over -75% of the lower United States, projected changes in June temperature and precipitation to year 2080 were associated with decreased averaged values of richness, biomass, and CI, implying decreased conservation value for birds. The two ecological provinces demarcated near the 100th meridian diverged from each other, with projected changes in June temperatures and precipitation from the year 2000 to 2080 suggesting increased ecological dissimilarity between the eastern and western halves of the lower United States with changing climate. Anticipated climate-related changes in the five characteristics by 2080 were more weakly correlated with latitude or longitude then the responses themselves, indicating less distinct geographic patterns of characteristic change than in the characteristics themselves. Climate changes projected for 2080 included geographic shifts in avian biomass, CS, and PC values, a moderate overall decline in CI, and general decline in species richness per site.


Design and implementation of real-time software radio for anti-interference GPS/WAAS sensors.
Adaptive antenna array processing is widely known to provide significant anti-interference capabilities within a Global Navigation Satellite Systems (GNSS) receiver. A main challenge in the quest for such receiver architecture has always been the computational/processing requirements. Even more demanding would be to try and incorporate the flexibility of the Software-Defined Radio (SDR) design philosophy in such an implementation. This paper documents a feasible approach to a real-time SDR implementation of a beam-steered GNSS receiver and validates its performance. This research implements a real-time software receiver on a widely-available x86-based multi-core microprocessor to process four-element antenna array data streams sampled with 16-bit resolution. The software receiver is capable of 12 channels all-in-view Controlled Reception Pattern Antenna (CRPA) array processing capable of rejecting multiple interferers. Single Instruction Multiple Data (SIMD) instructions assembly coding and multithreaded programming, the key to such an implementation to reduce computational complexity, are fully documented within the paper. In conventional antenna array systems, receivers use the geometry of antennas and cable lengths known in advance. The documented CRPA implementation is architected to operate without extensive set-up and pre-calibration and leverages Space-Time Adaptive Processing (STAP) to provide adaptation in both the frequency and space domains. The validation component of the paper demonstrates that the developed software receiver operates in real time with live Global Positioning System (GPS) and Wide Area Augmentation System (WAAS) L1 C/A code signal. Further, interference rejection capabilities of the implementation are also demonstrated using multiple synthetic interferers which are added to the live data stream.


Modified PEHPS medium as an alternative for the in vitro culture of Giardia lamblia.
Commercial culture media present interlot variations in biological activity. We have previously designed a homemade and economic culture medium, PEHPS medium, for the axenic cultivation of Entamoeba histolytica and Trichomonas vaginalis. Trophozoites of amoebae and trichomonads grow well in this medium. Furthermore, the medium is stable for several months when stored frozen or refrigerated. The objective of this work was to modify PEHPS medium to support the in vitro growth of Giardia lamblia. Inocula of 5 × 10(3) trophozoites/mL of G. lamblia were incubated at 36.5°C in modified PEHPS or TYI-S-33 medium. Then, the growths of the three Giardia strains in both media were compared. The logarithmic growth phase lasted 72 h; the mean yield of the strains ranged from 10.06 to 11.43 × 10(5) Giardia trophozoites/mL, and the range of duplication time in the three strains was from 5.67 to 6.06 in modified PEHPS medium. These growth characteristics were not significantly different from those obtained with TYI-S-33 medium. We conclude that modified PEHPS medium might be used for the axenic cultivation of G. lamblia.


Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense breast tissue. A systematic review.
Mammographic screening alone will miss a certain fraction of malignancies, as evidenced by retrospective reviews of mammograms following a subsequent screening. Mammographic breast density is a marker for increased breast cancer risk and is associated with a higher risk of interval breast cancer, i.e. cancer detected between screening tests. The purpose of this review is to estimate risks and benefits of supplemental breast ultrasound in women with negative mammographic screening with dense breast tissue. A systematic search and review of studies involving mammography and breast ultrasound for screening of breast cancer was conducted. The search was performed for the period 1/2000-8/2008 within the data source of PubMed, DARE, and Cochrane databases. Inclusion and exclusion criteria were determined prospectively, and the Oxford evidence classification system for diagnostic studies was used for evidence level. The parameters biopsy rate, positive predictive value (PPV) for biopsy, cancer yield for breast ultrasound alone, and carcinoma detection rate by breast density were extracted or constructed. The systematic search identified no randomized controlled trials or systematic reviews, six cohort studies of intermediate level of evidence (3b) were found. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR); mean tumor size for those identified was 9.9 mm, 90% with negative lymph node status. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Biopsy rates were in the range 2.3%-4.7%, with PPV of 8.4-13.7% for those biopsied due to positive ultrasound, or about one third of the PPV of biopsies due to mammography. The study populations included wide age ranges, and the application to women age 50-69 years as proposed for mammographic screening could result in less striking benefit. Further validation studies should employ a uniform assessment system such as BI-RADS and report not only PPV, but also negative predictive value, sensitivity and specificity. Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small, otherwise occult, breast cancers. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate.


∆ DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis.
Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. We have previously shown that ∆DNMT3B is the predominantly expressed form of DNMT3B. In this study, we found that most of the lung cancer cell lines tested predominantly expressed DNMT3B isoforms without exons 21, 22 or both 21 and 22 (a region corresponding to the enzymatic domain of DNMT3B) termed DNMT3B/∆DNMT3B-del. In normal bronchial epithelial cells, DNMT3B/ΔDNMT3B and DNMT3B/∆DNMT3B-del displayed equal levels of expression. In contrast, in patients with non-small cell lung cancer NSCLC), 111 (93%) of the 119 tumors predominantly expressed DNMT3B/ΔDNMT3B-del, including 47 (39%) tumors with no detectable DNMT3B/∆DNMT3B. Using a transgenic mouse model, we further demonstrated the biological impact of ∆DNMT3B4-del, the ∆DNMT3B-del isoform most abundantly expressed in NSCLC, in global DNA methylation patterns and lung tumorigenesis. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation patterns during lung tumorigenesis and suggest that ∆DNMT3B4-del may be a target for lung cancer prevention.


DNA familial binding profiles made easy: comparison of various motif alignment and clustering strategies.
Transcription factor (TF) proteins recognize a small number of DNA sequences with high specificity and control the expression of neighbouring genes. The evolution of TF binding preference has been the subject of a number of recent studies, in which generalized binding profiles have been introduced and used to improve the prediction of new target sites. Generalized profiles are generated by aligning and merging the individual profiles of related TFs. However, the distance metrics and alignment algorithms used to compare the binding profiles have not yet been fully explored or optimized. As a result, binding profiles depend on TF structural information and sometimes may ignore important distinctions between subfamilies. Prediction of the identity or the structural class of a protein that binds to a given DNA pattern will enhance the analysis of microarray and ChIP-chip data where frequently multiple putative targets of usually unknown TFs are predicted. Various comparison metrics and alignment algorithms are evaluated (a total of 105 combinations). We find that local alignments are generally better than global alignments at detecting eukaryotic DNA motif similarities, especially when combined with the sum of squared distances or Pearson's correlation coefficient comparison metrics. In addition, multiple-alignment strategies for binding profiles and tree-building methods are tested for their efficiency in constructing generalized binding models. A new method for automatic determination of the optimal number of clusters is developed and applied in the construction of a new set of familial binding profiles which improves upon TF classification accuracy. A software tool, STAMP, is developed to host all tested methods and make them publicly available. This work provides a high quality reference set of familial binding profiles and the first comprehensive platform for analysis of DNA profiles. Detecting similarities between DNA motifs is a key step in the comparative study of transcriptional regulation, and the work presented here will form the basis for tool and method development for future transcriptional modeling studies.


Direct and indirect effects of predators on the dominant invertebrates of two freshwater littoral communities.
Two congeneric damselfly species, Enallagma traviatum and E. aspersum, dominate the littoral macroinvertebrates of Bays Mountain Lake and of the adjacent fish-free Ecology Pond, respectively (northeastern Tennessee, USA). Extending previous experimental studies, we test seven hypotheses concerning the role of fish (bluegill sunfish, Lepomis macrochirus) and larvaldragonfly (Anax junius) predation, competitive effects on damselflies, and the interaction between competition and predation, in determining invertebrate dominance in these communities. Three types of experiments were conducted: an enclosure experiment within Ecology Pond, an outdoor replicated tub experiment, and a laboratory behavior experiment. The in-situ enclosure experiment showed that E. traviatum larvae were more susceptible to Anax predation than were E. aspersum larvae; a tendency toward greater vulnerability to fish of E. aspersum compared with E. traviatum was not statistically significant. The outdoor tub experiment confirmed both of these trends with statistically significant results. In the tubs, both predators inhibited feeding of both zygopterans (as indicated by reduced fecal mass), particularly for E. aspersum in the presence of fish. This effect appears to have been primarily indirect, mediated through exploitation of the zooplankton. We also detected competitive effects of E. traviatum on E. aspersum: E. traviatum reduced the emergence and increased the exposure above the substrate of E. aspersum. In the absence of predators, E. traviatum inhibited feeding of E. aspersum via interference. In the laboratory behavior experiment, predators inhibited crawling by E. aspersum. E. aspersum was more exposed than was E. traviatum; it swam and crawled more than did E. traviatum, considerably increasing these movements at night. Over all, E. traviatum consistently appeared to be the more cryptic of the two species, and E. aspersum appeared to be much more active. Our results suggest an explanation for the clear difference in structure between communities like Bays Mountain Lake and Ecology Pond: predaceous fish eliminate large invertebrate predators and shift the community toward cryptic forms at relatively low densities, reflecting the effects of both predation and exploitation competition. In the absence of fish, large invertebrate predators are less able to deplete littoral invertebrates but may favor the more active forms, perhaps because these are better able to avoid invertebrate predators.


Effect of spa therapy with saline balneotherapy on oxidant/antioxidant status in patients with rheumatoid arthritis: a single-blind randomized controlled trial.
Oxidative stress has been shown to play a contributory role in the pathogenesis of rheumatoid arthritis (RA). Recent studies have provided evidence for antioxidant properties of spa therapy. The purpose of this study is to investigate whether spa therapy with saline balneotherapy has any influence on the oxidant/antioxidant status in patients with RA and to assess clinical effects of spa therapy. In this investigator-blind randomized controlled trial, we randomly assigned 50 patients in a 1:1 ratio to spa therapy plus standard drug treatment (spa group) or standard drug treatment alone (control group). Spa group followed a 2-week course of spa therapy regimen consisting of a total of 12 balneotherapy sessions in a thermal mineral water pool at 36-37 °C for 20 min every day except Sunday. All clinical and biochemical parameters were assessed at baseline and after spa therapy (2 weeks). The clinical parameters were pain intensity, patient global assessment, physician global assessment, Health Assessment Questionnaire disability index (HAQ-DI), Disease Activity Score for 28-joints based on erythrocyte sedimentation rate (DAS28-4[ESR]). Oxidative status parameters were malondialdehyde (MDA), nonenzymatic superoxide radical scavenger activity (NSSA), antioxidant potential (AOP), and superoxide dismutase (SOD). The NSSA levels were increased significantly in the spa group (p = 0.003) but not in the control group (p = 0.509); and there was a trend in favor of spa therapy for improvements in NSSA levels compared to control (p = 0.091). Significant clinical improvement was found in the spa group compared to the control in terms of patient global assessment (p = 0.011), physician global assessment (p = 0.043), function (HAQ-DI) (p = 0.037), disease activity (DAS28-4[ESR]) (0.044) and swollen joint count (0.009), and a trend toward improvement in pain scores (0.057). Spa therapy with saline balneotherapy exerts antioxidant effect in patients with RA as reflected by the increase in NSSA levels after spa therapy; whether this antioxidant effect contributes to the clinical improvements observed remains to be verified.


Lung cancer in humans is not associated with lifetime total alcohol consumption or with genetic variation in alcohol dehydrogenase 3 (ADH3).
Although there is clear evidence that smoking is the primary risk factor for lung cancer, not all variation in disease risk is understood. There is some evidence that alcohol may contribute to risk. We examined lifetime and recent (12-24 mo previous) alcohol consumption in relation to risk of lung cancer in a case-control study in western New York. In addition we examined the alcohol dehydrogenase 3 (ADH3) genotype in relation to lung cancer risk; ADH3 is rate limiting in alcohol metabolism and has a functional polymorphism. We interviewed incident, primary, histologically confirmed lung cancer cases (n = 111) in two counties. Controls were randomly selected from among those residing in the counties, frequency-matched to cases for age and race (n = 1546). Lifetime and recent total alcohol and beverage-specific alcohol consumption as well as relevant confounders were assessed by interview. ADH3 genotype was evaluated by a PCR-restriction fragment length polymorphism assay. Because of the small sample size, power was limited and CI were wide. Residual confounding by smoking remains a concern. Although we found a significant trend for increased risk for beer consumption in the recent period (odds ratio 1.67, 95% CI 0.96-2.92, P for trend = 0.05), chance cannot be ruled out as an explanation. We found no evidence of risk related to lifetime alcohol consumption nor evidence that alcohol dehydrogenase genotype modifies risk related to alcohol and lung cancer.


Radiative cooling of H3O+ and its deuterated isotopologues.
In conjunction with ab initio potential energy and dipole moment surfaces for the electronic ground state, we have made a theoretical study of the radiative lifetimes for the hydronium ion H3O+ and its deuterated isotopologues. We compute the ro-vibrational energy levels and their associated wavefunctions together with Einstein coefficients for electric dipole transitions. A detailed analysis of the stability of the ro-vibrational states has been carried out and the longest-living states of the hydronium ions have been identified. We report estimated radiative lifetimes and cooling functions for temperatures <200 K. A number of long-living meta-stable states are identified, capable of population trapping.


Ultra-compact 32-channel drop filter with 100 GHz spacing.
We demonstrated 32-channel drop filters with 100 GHz spacing consisting of arrayed nanocavities and a waveguide in a photonic crystal silicon slab. Changing the lattice constant of the nanocavities on the subnanometer scale successfully controlled the drop wavelengths at 100 GHz spacing in the wavelength range between 1510 and 1550 nm. The device size was as small as 15 μm × 270 μm, and the variation in drop wavelengths was less than 0.3 nm in terms of standard deviation. We also present a movie showing the operation of the drop filter, demonstrating that the arrayed nanocavities have the potential for developing ultracompact 100 GHz spaced filters in a dense wavelength division multiplexing system.


Complete Genome Sequences of Two Methicillin-Susceptible Staphylococcus aureus Clinical Strains Closely Related to Community-Associated Methicillin-Resistant S. aureus USA300.
Predominant community-associated methicillin-resistant Staphylococcus aureus strain USA300 is believed to have originated from an ancestral methicillin-susceptible strain, although the details of that evolution remain unknown. To help understand the emergence of this highly successful strain, we sequenced the genomes of two methicillin-susceptible Staphylococcus aureus clinical strains that are very closely related to USA300.


Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.
Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR-/-) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR-/- mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR-/- MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.


UHPLC: The Greening Face of Liquid Chromatography.
Pharmaceutical analysis based on chromatographic separation is an important part of studies aimed at developing routine quality analysis of drugs. High-performance liquid chromatography (HPLC) is one of the main analytical techniques recommended for drug analysis. Although it meets many criteria vital for analysis, it is time-consuming and uses a relatively high amount of organic solvents compared to other analytical techniques. Recently, Ultra-high-performance liquid chromatography (UHPLC) has been frequently proposed as an alternative to HPLC, which means introducing an environment-friendly approach to drug analysis achieved by reducing the consumption of solvents. It also offers greater chromatographic resolution and higher sensitivity as well as requiring less time due to faster analysis. This review focuses on the basics of UHPLC, compares that technique with HPLC and discusses the possibilities of applying UHPLC for the analysis of different pharmaceuticals and biopharmaceuticals.


"You can't touch this": Delivery of inpatient neuropsychological assessment in the era of COVID-19 and beyond.
Objective: The COVID-19 pandemic is a global health crisis that has created sudden and unique challenges within the field of clinical neuropsychology. Adapting neuropsychology services using teleneuropsychology models (e.g. video or telephone assessments) may not always be a viable option for all providers and settings. Based on the existing teleneuropsychology literature, we propose a "contactless" evidence-based inpatient test battery to be used for in-person assessments amenable to physical distancing. Method: In addition to the proposed test battery, we suggest a decision-making workflow process to help readers determine the appropriateness of the proposed methods given their patients' needs. Considerations for special populations (i.e. seniors, patients with brain injury, psychiatric patients), feedback, limitations of the proposed physical distancing approach, and future directions are also discussed. Conclusions: Our aim is that the suggested teleneuropsychology-informed battery and model may inform safe and practical neuropsychological inpatient assessments during the COVID-19 pandemic and other situations requiring contact precautions for infection prevention and control.


Nonspecific lipid-transfer protein genes expression in grape (Vitis sp.) cells in response to fungal elicitor treatments.
Nonspecific lipid transfer proteins (nsLTPs) are small, basic cystein-rich proteins believed to be involved in plant defense mechanisms. Three cDNAs coding nsLTPs from grape (Vitis vinifera sp.) were cloned by reverse-transcriptase-polymerase chain reaction (RT-PCR) and PCR. The expression of nsLTP genes was investigated in 41B-rootstock grape cell suspension, in response to various defense-related signal molecules. Ergosterol (a fungi-specific sterol) and a proteinaceous elicitor purified from Botrytis cinerea strongly and rapidly induced the accumulation of nsLTP mRNAs. Jasmonic acid, cholesterol, and sitosterol also promoted nsLTPs mRNA accumulation, although to a lesser extent, whereas salicylic acid had no effect. High performance liquid chromatography analysis indicated that the amounts of three LTP isoforms (previously named P1, P2, and P4) were increased by ergosterol. None of the four isoforms displayed any significant antifungal properties, with the exception of the P4 isoform, which reduced Botrytis mycelium growth in vitro, but only in calcium-free medium. The results are discussed in the context of plant-pathogen interactions.


3D reconstruction of carotid atherosclerotic plaque: comparison between spatial compound ultrasound models and anatomical models.
This study deals with the creation of 3D models that can work as a tool for discriminating between tissue and background in the development of tissue classification methods. Ten formalin-fixed atherosclerotic carotid plaques removed by endarterectomy were scanned with 3D multi-angle spatial compound ultrasound (US) and subsequently sliced and photographed to produce a 3D anatomical data set. Outlines in the ultrasound data were found by means of active contours and combined into 10 3D ultrasound models. The plaque regions of the anatomical photographs were outlined manually and then combined into 10 3D anatomical models. The volumes of the anatomical models correlated with the volume found by a water displacement method (r = 0.95), except for an offset. The models were compared in three ways. Visual inspection showed quite good agreement between the models. The volumes of the ultrasound models correlated with the volumes of the anatomical models (r = 0.93), again with an offset. Finally, the overlap between the anatomical models and the ultrasound models showed, on average, that the intersection comprised 90%(vol) of the anatomical models and 73%(vol) of the ultrasound models.


Estimating the Size of the U.S. Population at Risk of Severe Adverse Events from Replicating Smallpox Vaccine.
To quantify the population at risk of serious adverse reactions to replicating smallpox vaccine. Conditions known or suspected to carry risk were identified via Centers for Disease Control and Prevention planning documents, other federal publications, and peer-reviewed literature. Conditions identified were categorized as historically recognized risks or more recently recognized immunocompromised states that may pose risk. Major historical risk factors were as follows: eczema/atopic dermatitis, pregnancy, HIV, and primary immunodeficiency. More recently identified states were as follows: rheumatoid arthritis, inflammatory bowel disease, dialysis, bone marrow transplant recipients within 24 months post-transplant, solid-organ transplant recipients within 3 months post-transplant, age under 1 year, and systemic lupus erythematosus. The estimated prevalence or absolute number of affected individuals for each condition was ascertained from peer-reviewed studies, vital statistics, and registry databases. An estimated 48,121,280 to 50,028,045 individuals (15.2-15.8% of the U.S. population) are potentially contraindicated to replicating smallpox vaccine. This rises to 119,244,531 to 123,669,327 (37.4-38.8%) if household contacts are included. These figures are significant and larger than the only previously published study. Understanding this number allows for improved clinical utilization, equitable attention to the health needs of a vulnerable population, and strategic vaccine stockpiling.


The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex.
G protein-coupled receptors (GPCRs) mediate the majority of physiologic responses to hormones and neurotransmitters. However, many GPCRs exhibit varying degrees of agonist-independent G protein activation. This phenomenon is referred to as basal or constitutive activity. For many of these GPCRs, drugs classified as inverse agonists can suppress basal activity. There is a growing body of evidence that basal activity is physiologically relevant, and the ability of a drug to inhibit basal activity may influence its therapeutic properties. However, the molecular mechanism for basal activation and inhibition of basal activity by inverse agonists is poorly understood and difficult to study, because the basally active state is short-lived and represents a minor fraction of receptor conformations. Here, we investigate basal activation of the G protein Gs by the beta(2) adrenergic receptor (beta(2)AR) by using purified receptor reconstituted into recombinant HDL particles with a stoichiometric excess of Gs. The beta(2)AR is site-specifically labeled with a small, environmentally sensitive fluorophore enabling direct monitoring of agonist- and Gs-induced conformational changes. In the absence of an agonist, the beta(2)AR and Gs can be trapped in a complex by enzymatic depletion of guanine nucleotides. Formation of the complex is enhanced by the agonist isoproterenol, and it rapidly dissociates on exposure to concentrations of GTP and GDP found in the cytoplasm. The inverse agonist ICI prevents formation of the beta(2)AR-Gs complex, but has little effect on preformed complexes. These results provide insights into G protein-induced conformational changes in the beta(2)AR and the structural basis for ligand efficacy.


A zwitterionic near-infrared dye linked TrkC targeting agent for imaging metastatic breast cancer.
Much effort has been devoted to targeting agents for imaging and chemotherapy of tumors in cancer research, but there remain significant unmet needs in that area. We have reported a series of preclinical TrkC targeting agents for diagnoses and treatment of metastatic breast cancer; however, with respect to optical imaging, there are limitations to the agents already disclosed. In this work, a TrkC targeting fragment was equipped with a zwitterionic cyanine dye to give a near-infrared probe for in vivo imaging of metastatic breast tumors, with excitation and emission wavelengths of 760 and 780 nm, respectively, and facilitate the aqueous dissolution of the final design. To our delight, the newly developed probe maintained the specific targeting to TrkC+ 4T1 metastatic breast tumor cells as well as the TrkC+ metastatic breast tumor tissue. Upon injection into 4T1-tumor-bearing mice, the tumor was visualized in vivo and ex vivo through the fluorescence signal of the probe. These data seem to encourage further investigations toward developing a TrkC targeting agent for the diagnosis of metastatic breast tumors.


Reliability and Validity of the Activity Diversity Questionnaire for Older Adults in Japan.
Recent research has suggested that the breadth and evenness of activity and activity diversity contribute to health outcomes among older adults. However, few established assessment tools for activity diversity have been developed. This study developed an Activity Diversity Questionnaire (ADQ) for older adults through expert consultation and a preliminary survey among 18 community-dwelling older adults. The diversity score was calculated according to Shannon's entropy. In study 1, the intraclass correlation coefficients (ICC) of the diversity scores were determined for community-dwelling older adults (n = 30). In study 2, concurrent validity was tested with participants receiving comprehensive health checkups at the Itabashi ward in Japan in 2018 (n = 766). The correlation coefficients of the diversity scores were then calculated in reference to the Tokyo Metropolitan Institute of Gerontology Index of Competence and Japan Science and Technology Agency Index of Competence. The final version of the ADQ consisted of 20 total items with excellent test-retest reliability (ICC = 0.84) and moderate correlations with both the Tokyo Metropolitan Institute of Gerontology Index of Competence and Japan Science and Technology Agency Index of Competence (r = 0.48 and 0.60, respectively). The ADQ was developed through scientific procedures and revealed sufficient reliability and validity. As such, it is a scientifically validated tool for assessing activity diversity among older adults.


Importance of bacterial decomposition and carrion substrate to foraging brown treesnakes.
Brown treesnakes are an invasive species to the island of Guam that have caused extensive ecological and economic damage. Efforts to control the snake population have included trapping using live mouse lures, but for logistical and economic reasons a synthetic lure is needed. When searching for live food, brown treesnakes use both visual and odor cues. However, when searching for carrion, odor cues are sufficient. Attempts to develop synthetic lures based on chemical reconstruction of the complex carrion odor have not succeeded. We provide evidence that a microbial-substrate interaction is important for bait take by brown treesnakes. Microbial cultures taken from mouse carrion indicate that Enterobacter agglomerans is the predominant bacterium, and field tests suggest that this organism may be important to odor production that attracts brown treesnakes. This information may prove useful in the development of microbial-based biological reactors that could be formulated to produce a continuous stream of odor of sufficient complexity so as to be attractive to foraging snakes.


Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated.
Systemic and local immune deficiency is associated with cancer, and the role of M2 tumor-associated macrophages in this phenomenon is well recognized. However, the immune status of macrophages from peripheral compartments in tumor hosts is unclear. Peritoneal macrophages (PEM) are derived from circulating monocytes and recruited to the peritoneal cavity where they differentiate into macrophages. We have previously shown that PEMs from mice bearing D1-DMBA-3 mammary tumors (T-PEM) are deficient in inflammatory functions and that this impairment is associated with diminished expression of transcription factors nuclear factor kappaB and CAAT/enhancer-binding protein. We now provide evidence that T-PEMs display neither M1 nor M2 phenotypes, yet exhibit deficiencies in the expression of several inflammatory cytokines and various proinflammatory signaling pathways. Moreover, due to nuclear factor kappaB down-regulation, increased apoptosis was observed in T-PEMs. We report for the first time that macrophage depletion is associated with increased macrophage progenitors in bone marrow. Furthermore, T-PEMs have a lower expression of macrophage differentiation markers F4/80, CD68, CD115, and CD11b, whereas Gr-1 is up-regulated. Our results suggest that T-PEMs are less differentiated and represent a newly derived population from blood monocytes. Lastly, we show that transforming growth factor-beta and prostaglandin E(2), two immunosuppressive tumor-derived factors, may be involved in this phenomenon.


Vitrectomy for dense vitreous hemorrhage in infancy.
To report clinical data, including etiology and visual outcome, in newborns requiring vitrectomy for dense vitreous hemorrhage. In this retrospective case series, we surveyed subscribers to the American Association for Pediatric Ophthalmology and Strabismus ListServe regarding patients under their care. A total of 28 eyes of 21 patients were included. Most common etiologies were thrombocytopenia, shaken baby syndrome, and birth trauma. In 9 cases (12 eyes), the vitreous hemorrhage was idiopathic. Mean time between diagnosis and surgery was 1.4 months. Complications included strabismus, cataract, glaucoma, high myopia, and retinal detachment. Recognition visual acuities were available for 8 eyes: 20/25 (2 eyes), 20/30, 20/40 (2 eyes), 20/60 (2 eyes), and 20/100. One eye had no light perception. The etiologies encountered in our patients were similar to those reported previously. Visual outcomes were much worse in cases with retinal complications. Other patients had better visual outcomes. Despite potential surgical and postoperative complications, this series demonstrates favorable visual outcomes can be achieved following early vitrectomy in this setting.


The IDEFICS cohort: design, characteristics and participation in the baseline survey.
The European IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study was set up to determine the aetiology of overweight, obesity and related disorders in children, and to develop and evaluate a tailored primary prevention programme. This paper focuses on the aetiological element of the multicentre study, the measures and examinations, sociodemographic characteristics of the study sample and proportions of participation. Prospective cohort study with an embedded intervention study that started with a baseline survey in eight countries in 2007-2008. Baseline participants of the prospective cohort study were 16,224 children aged 2-9 years. Parents reported sociodemographic, behavioural, medical, nutritional and other lifestyle data for their children and families. Examinations of children included anthropometry, blood pressure, fitness, accelerometry, DNA from saliva and physiological markers in blood and urine. The built environment, sensory taste perception and other mechanisms of children's food choices and consumer behaviour were studied in subgroups. Between 1507 and 2567, children with a mean age of 6.0 years and an even sex distribution were recruited from each country. Of them, 82% lived in two-parent families. The distribution of standardised income levels differed by study sample, with low-income groups being strongly represented in Cyprus, Italy and Germany. At least one 24-h dietary recall was obtained for two-thirds of the children. Blood pressure and anthropometry were assessed in more than 90%. A 3-day accelerometry was performed in 46%, motor fitness was assessed in 41%, cardiorespiratory fitness in 35% and ∼11% participated in taste perception tests. The proportion of children donating venous blood, urine and saliva was 57, 86 and 88%, respectively. The IDEFICS cohort provides valuable data to investigate the interplay of social, environmental, genetic, physiological and behavioural factors in the development of major diet- and lifestyle-related disorders affecting children at present.


Sonographic monitoring of the treatment of developmental disturbances of the hip by the Pavlik harness.
This study was undertaken to verify the efficacy of the Pavlik harness in the treatment of developmental disturbances of the hip (DDH) when reduction and stabilization of the hip and conclusion of the treatment are monitored by sonography. With active mother participation, under direct supervision of one consistent orthopaedist, 547 patients (60 with 91 unstable hips; 196 with 232 dysplastic hips, types IIb, IIc, and D; and 291 with 376 dislocated hips types IIIa, IIIb, and IV), with an average age of 2.3 months were evaluated. The initial hip flexion in the harness was 60 degrees to 70 degrees, which was adjusted frequently until concentric hip reduction. Sonographic reduction was achieved in 89.7% of the hips in 2 weeks, in 8.3% in 3 weeks, and in 2% in 4 weeks. Sonographic hip stabilization was achieved in 87.4% in 4 weeks, in 9.8% in 5 weeks, and in 2.9% in 6 weeks. Soft tissue landmarks (the cartilaginous roof angle and capsule) were used for assessment of reduction and stabilization, but for conclusion of the treatment, bony roof angle was used as well. Fulltime harness treatment averaged 2.7 months for the whole group (1.4 months for unstable hips, 2.3 months for dysplastic hips, and 3 months for dislocated hips). The harness was abandoned in five patients, four because of mother noncompliance and one because of abdominal surgery. Other serious complications, including avascular necrosis (AVN), did not occur in this study. It was concluded that paying attention to the minute details of treatment with active engagement of the mother in the form of group therapy under direct and consistent supervision of one orthopaedist coupled with sonographic monitoring can ensure satisfactory outcome with a shorter period of treatment in a very high percentage of the cases.


Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression.
PCNA and esophagin have been implicated in the multistep process of carcinogenesis, but simultaneous characterization of these proteins in the early stages of esophageal neoplastic progression has yet to be undertaken. In morphologically normal esophageal epithelium, esophagin stains the granular layer cells, principally in their cell membrane portions. PCNA, in contrast, stains the nuclei of cells in the parabasal and basal layers. We examined 201 regions from 47 patients that represented different stages of esophageal neoplasia, comprising 34 areas of normal mucosa, 18 of dysplasia in squamous epithelium (DYS/SC), 39 squamous cell carcinoma (SCCA), 29 areas of Barrett's esophagus, 48 of Barrett's dysplasia (DYS/BAR) and 33 areas of adenocarcinoma (AC). The immunostaining patterns of esophagin and PCNA were evaluated and graded for level of expression. There was loss of esophagin expression in the high- and low-grade dysplasias compared to normal epithelia. In the squamous dysplasias, there was more intense staining (of esophagin) in the atypical nuclei and superficial squamous epithelial cells than in the basal cells. PCNA staining was increased in intensity in the high-grade dysplasias relative to normal basal layer cells. Combined analysis of esophagin and PCNA appears to reveal an inverse relationship between proliferation and differentiation during esophageal neoplastic progression. Moreover, this combined staining approach also offers promise for detecting esophageal cancer in early, precancerous stages.


Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry.
Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.


Monitoring Athlete Training Loads: Consensus Statement.
Monitoring the load placed on athletes in both training and competition has become a very hot topic in sport science. Both scientists and coaches routinely monitor training loads using multidisciplinary approaches, and the pursuit of the best methodologies to capture and interpret data has produced an exponential increase in empirical and applied research. Indeed, the field has developed with such speed in recent years that it has given rise to industries aimed at developing new and novel paradigms to allow us to precisely quantify the internal and external loads placed on athletes and to help protect them from injury and ill health. In February 2016, a conference on "Monitoring Athlete Training Loads-The Hows and the Whys" was convened in Doha, Qatar, which brought together experts from around the world to share their applied research and contemporary practices in this rapidly growing field and also to investigate where it may branch to in the future. This consensus statement brings together the key findings and recommendations from this conference in a shared conceptual framework for use by coaches, sport-science and -medicine staff, and other related professionals who have an interest in monitoring athlete training loads and serves to provide an outline on what athlete-load monitoring is and how it is being applied in research and practice, why load monitoring is important and what the underlying rationale and prospective goals of monitoring are, and where athlete-load monitoring is heading in the future.


A review of data in medical request and the patient questionnaire for magnetic resonance evaluation of silicone breast implants.
To analyze the quality and quantity of data in the questionnaires and in request forms for magnetic resonance imaging. This retrospective study was conducted with data from 300 medical records. The research used the following data from the questionnaires: patient age, reason for the magnetic resonance imaging, reason for placing the breast implant, report of any signs or symptoms, time elapsed since surgery to place the current breast implant, replacement implant surgery, chemotherapy, and/or radiation therapy treatments. From the magnetic resonance imaging request forms, information about the breast implant, the implant placement surgery, patient clinical information and ordering physician specialty were verified. The mean age of patients was 48.8 years, and the mean time elapsed since breast implant surgery was 5 years. A total of 60% of women in the sample were submitted to aesthetic surgery, while 23.7% were submitted to chemotherapy and/or radiation therapy. In the request forms, 23.7% of physicians added some piece of information about the patient, whereas 2.3% of them informed the type of implant and 5.2% informed about the surgery. The amount of information in the magnetic resonance imaging request forms is very limited, and this may hinder quality of radiological reports. Institutional and technological measures should be implemented to encourage the requesting physicians and radiologists to share information.


Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model.
Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.


An epidemiological study of child health and nutrition in a northern Swedish county. VII. A comparative study of general and dental health, food habits and socio-economic conditions in 4-year-old children.
A study of the general and dental health and the food habits of randomly selected 4-year-old Swedish urban children was performed. The results were compared with the findings of an investigation carried out four years earlier in the same area. In comparison with the earlier study no significant differences were found in haemoglobin values, packed red cell volume, microsedimentation rate and anthropometric measurements. The food habits had altered. A reduction in the frequency of between-meal consumption, particularly of sweets and soft drinks, as well as a reduction of the frequency of meat, fish and egg consumption was found. The children had an increased sandwich and milk consumption. The caries frequency was markedly reduced, which might be explained by the decreased between-meal consumption and an increased consumption of fluoride tablets. The food habits and the caries situation were generally influenced by the parents' socio-economic conditions, especially their educational level.