Paucity and preferential suppression of transgenes in late replication domains of the D. melanogaster genome.
Eukaryotic genomes are organized in extended domains with distinct features intimately linking genome structure, replication pattern and chromatin state. Recently we identified a set of long late replicating euchromatic regions that are underreplicated in salivary gland polytene chromosomes of D. melanogaster. Here we demonstrate that these underreplicated regions (URs) have a low density of P-element and piggyBac insertions compared to the genome average or neighboring regions. In contrast, Minos-based transposons show no paucity in URs but have a strong bias to testis-specific genes. We estimated the suppression level in 2,852 stocks carrying a single P-element by analysis of eye color determined by the mini-white marker gene and demonstrate that the proportion of suppressed transgenes in URs is more than three times higher than in the flanking regions or the genomic average. The suppressed transgenes reside in intergenic, genic or promoter regions of the annotated genes. We speculate that the low insertion frequency of P-elements and piggyBacs in URs partially results from suppression of transgenes that potentially could prevent identification of transgenes due to complete suppression of the marker gene. In a similar manner, the proportion of suppressed transgenes is higher in loci replicating late or very late in Kc cells and these loci have a lower density of P-elements and piggyBac insertions. In transgenes with two marker genes suppression of mini-white gene in eye coincides with suppression of yellow gene in bristles. Our results suggest that the late replication domains have a high inactivation potential apparently linked to the silenced or closed chromatin state in these regions, and that such inactivation potential is largely maintained in different tissues.


The expression levels of the human papillomavirus type 16 E7 correlate with its transforming potential.
The transforming potential of the human papillomavirus (HPV) type 16 has been defined largely in the E7, E6, and E5 oncoproteins, with the major transforming capability residing in the E7 gene. In this paper, we found that in cooperation with the activated ras, the HPV16 E7 gene when expressed in a retroviral vector could fully transform baby rat kidney (BRK) cells in transfections, whereas the same construct could only immortalize the BRK cells following retroviral infection. This inability to transform correlated with the low levels of E7 gene RNA expression in the viral infected cells, which harbor a lower number of copies of the E7 gene constructs. Cotransfection of the expression vector FV2E7, which gives high levels of E7 gene expression, and activated ras lead to rapid and efficient morphological transformation of BRK cells which grew easily in soft agar and induced large tumors in athymic nude mice. In contrast, cotransfections of the expression vector FV1E7, which gives lower levels of E7 gene expression, produced much lower numbers of transformed colonies which took longer to form, showed a retarded growth on soft agar, and induced smaller tumors in nude mice. Under these conditions, colonies of immortalized, but morphologically untransformed cells formed in large numbers. These results indicate that the transforming potential is directly correlated to the expression levels of the oncoprotein and that a threshold level of the E7 oncoprotein may be required before the cells can be fully transformed. This supports the hypothesis that the transformation processes include at least two separate and continuous steps which first lead to immortalization and then to metastasis, in agreement with the clinical progression of genital tumors from benign to malignancy. Such a progression may involve enhanced expression of the oncoproteins.


Three-dimensional direct visualization of silica dispersion in polymer-based composites.
The uniform dispersion of silica fillers or other neutral fillers in the polymer matrix is significant for fabricating high-performance polymer-based composites. However, there is a long-standing challenge to provide a comprehensive, wide-area and real 3D distribution map to achieve direct visualization for the dispersion state of neutral silica. Herein, we propose a novel strategy for modifying silica fillers with commercial fluorophores to form fluorescent fillers in a standard manner. Through fluorescence imaging technology, we successfully observed the 2D-planar and 3D-spatial dispersion states of silica fillers in the polymer matrix. This success not only provides a visualized evaluation method for the spatial dispersion of an oxide filler, but also offers great potential in the further establishment of industrialized standards for the polymer-based composite industry.


Protective antigens against enterotoxigenic Escherichia coli O101:K99,F41 in the infant mouse diarrhea model.
Protective antigens present in whole cells of bovine enterotoxigenic Escherichia coli strains were tested in an infant mouse diarrhea model. Reduction of mortality rates of infant mice suckling vaccinated mothers was measured 1, 2, and 5 days after oral challenge with strain B41 (O101:K99,F41:H-). Vaccines consisted of strains of serogroup O101, O9, O8, or O20 and of variants bearing or not bearing antigens K99 and F41. K99 and F41 expressions were checked by slide agglutination with K99 and F41 antisera and by mannose-resistant microhemagglutination with horse, sheep, and guinea pig erythrocytes. Absence of production of K99 antibodies following hyperimmunization with K99-negative variants was established in rabbit antisera. Strains bearing K99 alone induced less protection of infant mice 5 days after challenge than strains bearing F41 alone or both K99 and F41. Absence of expression of K99 in the vaccinal strains resulted in either a slight decrease (strains bearing additional F41) or complete abolishment (strains bearing K99 alone) of protection. Failure of F41 synthesis by O101 strains or variants resulted in no protection 5 days after challenge. F41 probably also supplied most of the protection induced by the O9 strain. When negative for both K99 and F41, strains of serogroup O101 still provided protection 1 and 2 days after challenge. This protection was also induced by strain H510a, the reference for O101 antigen. Thus, O antigen contributed to the best vaccinal protection, in addition to K99 and F41.


Spatiotemporally coherent motion direction perception occurs even for spatiotemporal reversal of motion sequence.
Thus far, it has been pointed out that motion representation is completed in motion trajectory, and that motion representation interferes with a single physical input at a specific time and space in the motion trajectory. However, it has not been fully investigated whether the internal motion representation could interact with multiple physical inputs across time and space in motion trajectory. Thus, the current research investigated whether spatiotemporally coherent motion perception could be established in a situation involving the spatiotemporal reversal of motion sequences. In a five-point motion display, we found that the motion direction perception of the last two stimuli containing the spatiotemporal reversal was consistent with three preceding stimuli. This failure to perceive motion direction reversal occurred when the shapes of motion trajectory (to upper or lower) were randomly changed. Moreover, we confirmed that one preceding stimulus (three-point motion) was sufficient to produce the failure to perceive motion direction reversal, and the effect of the prior stimuli saturated when the preceding sequence contained two or more stimuli. These findings suggest that the flexible internal motion representation mechanisms reorganize the spatiotemporal irregularities in motion trajectory and establish spatiotemporally coherent motion perceptions.


Does numeracy correlate with measures of health literacy in the emergency department?
The objective was to quantify the correlation between general numeracy and health literacy in an emergency department (ED) setting. This was a prospective cross-sectional convenience sample study of adult patients in an urban, academic ED with 97,000 annual visits. General numeracy was evaluated using four validated questions and health literacy using three commonly used validated screening tools (Short Test of Functional Health Literacy in Adults [S-TOFHLA], Rapid Estimate of Adult Literacy in Medicine-Revised [REALM-R], and the Newest Vital Sign [NVS]). Scores were dichotomized for health literacy tests to limited (low or marginal) versus adequate health literacy, and the proportion of patients answering all numeracy questions correctly was calculated with the mean proportion of correct responses in these groups. The correlation between numeracy scores and scores on the health literacy screening tools was evaluated using Spearman's correlation. A total of 446 patients were enrolled. Performance on questions evaluating general numeracy was universally poor. Only 18 patients (4%) answered all numeracy questions correctly, 88 patients (20%) answered zero questions correctly, and overall the median number of correct answers was one (interquartile range [IQR] = 1 to 2). Among patients with limited health literacy (LHL) by any of the three screening tools used, the mean number of correct numeracy answers was approximately half that of patients with adequate health literacy. However, even among those with adequate health literacy, the average number of correct answers to numeracy questions ranged from 1.6 to 2.4 depending on the screening test used. When dichotomized into those who answered ≤50% versus >50% of numeracy questions correctly, there was a significant difference between those with LHL and those who scored ≤50% on numeracy. Health literacy screening results were correlated with general numeracy in the low to moderate range: S-TOFHLA rs = 0.428 (p < 0.0001); REALM, rs = 0.400 (p < 0.0001); and NVS, rs = 0.498 (p < 0.0001). Correlations between measures of general numeracy and measures of health literacy are in the low to moderate range. Performance on numeracy testing was nearly universally poor, even among patients performing well on health literacy screens, with a substantial proportion of the latter patients unable to answer half of the numeracy items correctly. Insofar as numeracy is considered a subset of health literacy, these results suggest that commonly used health literacy screening tools in ED-based studies inadequately evaluate and overestimate numeracy. This suggests the potential need for separate numeracy screening when these skills are important for health outcomes of interest. Providers should be sensitive to potential numeracy deficits among those who may otherwise have normal health literacy.


Association between circulating CD39+CD8+ T cells pre-chemoradiotherapy and prognosis in patients with nasopharyngeal carcinoma.
The mortality rate among patients with nasopharyngeal carcinoma (NPC) has improved significantly with the advent of chemoradiotherapy strategies. However, distant metastasis remains problematic. Tumor-specific reactivity in cancer patients has been detected exclusively in CD39+ T cells, particularly in CD39+CD103+ T cells. Circulating cancer-specific T cells are important for protecting against metastasis. This study aimed to evaluate the predictive value of circulating CD39+CD8+ T cells for metastasis in patients with NPC. We performed a cross-sectional, longitudinal study of 55 patients with newly diagnosed NPC of stage III-IVa. All patients were initially treated with standard combined chemoradiotherapy. Blood samples were obtained from 24 patients before and at 1 month and 6 months after treatment. T cell expression of CD39 and CD103, together with the markers of T cell exhaustion programmed death-1 (PD-1)/T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and markers of cell differentiation CD27/CC-chemokine receptor 7/CD45RA, was examined by flow cytometry. The Wilcoxon rank-sum test analysis was used to analyze the differences between two groups. Kaplan-Meier analysis was used for analysis of progression-free survival (PFS). The expression of circulating CD39+CD8+ and CD39+CD103+ CD8+ T cells was significantly higher in patients without distant metastasis (CD39+CD8+: 6.52% [1.24%, 12.58%] vs. 2.41% [0.58%, 5.31%], Z=-2.073, P=0.038 and CD39+CD103+CD8+: 0.72% [0.26%, 2.05%] vs. 0.26% [0.12%, 0.64%], Z=-2.313, P = 0.021). Most CD39+ T cells did not express PD-1 or Tim-3. Patients with high expression of CD39+CD103+CD8+ T cells had better PFS than patients with low expression (log rank value = 4.854, P = 0.028). CD39+CD8+ T cells were significantly elevated at 1-month post-treatment (10.02% [0.98%, 17.42%] vs. 5.91% [0.61%, 10.23%], Z = -2.943, P = 0.003). The percentage of advanced differentiated CD8+ T cells also increased at 1-month post-treatment compared with pre-treatment (33.10% [21.60%, 43.05%] vs. 21.00% [11.65%, 43.00%], Z = -2.155, P = 0.031). There was a significant correlation between elevated CD39+CD8+ T cells and increased effector memory T cells (intermediate stage: r = 0.469, P = 0.031; advanced stage: r = 0.508, P = 0.019). CD39+CD8+ circulating T cells have preserved effector function, contributing to an improved prognosis and a reduced risk of metastasis among NPC patients. These cells may thus be a useful predictive marker for a better prognosis in patients with NPC.


The presence of residual gold nanoparticles in samples interferes with the RT-qPCR assay used for gene expression profiling.
RT-qPCR is routinely used in expression profiling of toxicity pathway genes. However, genetic and molecular level studies used to determine, understand and clarify potential risks of engineered nanomaterials (ENMs) are still incomplete. Concerns regarding possible interference caused by intracellular ENMs during analyses have been raised. The aim of this study was to verify a qPCR procedure for gene expression assays, which can be used in toxicity and exposure assessments. Amplification of ten reference genes was performed to test the expression stability. A preliminary study was performed on RNA from BEAS-2B cells that had been treated with AuNPs. Also, a reference total RNA standard from ten cell lines was spiked with various amounts of the same AuNP. This treatment mimics exposure assessment studies, where assay-interference may be caused by intracellular residual ENMs still being present in the biological samples (during and after isolation/purification procedures). Both types of RNA samples were reverse transcribed and then amplified by qPCR. The qPCR-related software and statistical programs used included BestKeeper, NormFinder, REST and qBase+. These results proved that using standard qPCR analysis and statistical programs should not be the only procedure applied to verify the assay for gene expression assessment related to ENMs. A comparison of SYBR Green to EVA Green was discussed, in addition to a comparison to the latest reports regarding the influence of ENM thermal conductivity, surface interactions with ENMs, effects of ENM size and charge, as well as, the limit of detection in a qPCR assay. AuNPs have the potential to interfere with the assay mechanism of RT-qPCR, thus, assay verification is required for AuNP-related gene expression studies used to evaluate toxicity. It is recommended to use HSP90 and YWHAZ as reference genes, i.e. these were the most stable in our study, irrespective of the source of the RNA, or, the point at which the AuNPs interacted with the assay. This report describes steps that can be utilised to generate a suitable method for gene expression studies associated with toxicity testing of various ENMs. For example, RNA standards that have been spiked with known amounts of ENMs should be run in conjunction with the unknown samples, in order to verify any RT-qPCR assay and determine the degree of error.


Cytochrome p450-dependent lipid metabolism in preovulatory follicles.
Estrogen biosynthesis and proteolysis are both important processes involved in ovarian follicular development, which may be influenced by cytochrome P450 (CYP)-dependent fatty acid metabolites. However, CYP-dependent lipid metabolism has not been characterized with respect to follicular maturation in vivo. Therefore, follicular fluid was collected in the hours before and after the LH surge in pigs, and concentrations of epoxy, hydroxy, and dihydroxy lipids were measured by liquid chromatography tandem mass spectrometry. Arachidonate oxidation and epoxyeicosatrienoic acid hydrolysis to dihydroxyeicosatrienoic acids (DHETs) were also assessed in thecal and granulosa tissue fractions, and the expression of CYP epoxygenases was evaluated by immunoblots using available antisera. To evaluate soluble epoxide hydrolase (sEH) expression, the porcine sEH was cloned from ovarian tissue, expressed and purified for antibody generation. The follicular fluid oxylipin concentrations ranged from 1-150 nm depending on the compound and estrous stage. The follicular fluid concentrations of CYP-dependent oxylipins increased at estrus, as did sEH expression; however, significant changes in epoxides were not observed, and the 11,12-DHET peak was delayed. The ratio of 14,15-DHET:11,12-DHET across all samples correlated with the log of follicular fluid estradiol concentrations (P < 0.01). Epoxygenase activities were similar in theca and granulosa, varying little with follicular development, whereas the decline of a single CYP2J isoform at ovulation was observed by immunoblots. The sEH activity was higher in granulosa than in theca. Finally, the dynamic changes in follicular CYP-dependent arachidonic acid metabolites and their modulatory function in vascular models suggest roles for these metabolites in follicular maturation, which may include regulation of estradiol biosynthesis and preovulatory remodeling of the follicular wall that should be fully explored in future studies.


Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse.
Although the antidepressant bupropion is prescribed to aid in smoking cessation, little is known concerning its mechanisms of action in this regard. One factor that might influence quit success is nicotine tolerance, which could promote high levels of nicotine intake in order to maintain nicotine's subjective effects (thereby making attempts to reduce smoking more difficult). To explore whether bupropion and its active hydroxymetabolite modulate nicotine tolerance, mice were injected for 14 days with saline or nicotine. On Day 14, animals received saline, (2S,3S)-hydroxybupropion, or bupropion at different doses. On Day 15, mice were assayed on test day for nicotine-induced analgesia and hypothermia. Animals chronically injected with saline + nicotine developed tolerance to nicotine's effects in both assays. Administration of bupropion and (2S,3S)-hydroxybupropion dose-dependently reversed chronic nicotine tolerance. These results indicate that bupropion's ability to promote smoking cessation may be partly due to its attenuation of nicotine tolerance since both measured responses of nicotine (antinociception and hypothermia) are mediated to a large extent by neuronal α4β2* nicotine receptors.


Precision Interface Engineering of an Atomic Layer in Bulk Bi2Te3 Alloys for High Thermoelectric Performance.
Grafting nanotechnology on thermoelectric materials leads to significant advances in their performance. Creation of structural defects including nano-inclusion and interfaces via nanostructuring achieves higher thermoelectric efficiencies. However, it is still challenging to optimize the nanostructure via conventional fabrication techniques. The thermal instability of nanostructures remains an issue in the reproducibility of fabrication processes and long-term stability during operation. This work presents a versatile strategy to create numerous interfaces in a thermoelectric material via an atomic-layer deposition (ALD) technique. An extremely thin ZnO layer was conformally formed via ALD over the Bi0.4Sb1.6Te3 powders, and numerous heterogeneous interfaces were generated from the formation of Bi0.4Sb1.6Te3-ZnO core-shell structures even after high-temperature sintering. The incorporation of ALD-grown ZnO into the Bi0.4Sb1.6Te3 matrix blocks phonon propagation and also provides tunability in electronic carrier density via impurity doping at the heterogeneous grain boundaries. The exquisite control in the ALD cycles provides a high thermoelectric performance of zT = 1.50 ± 0.15 (at 329-360 K). Specifically, ALD is an industry compatible technique that allows uniform and conformal coating over large quantities of powders. The study is promising in terms of the mass production of nanostructured thermoelectric materials with considerable improvements in performance via an industry compatible and reproducible route.


Zinc: the brain's dark horse.
Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.


Self-care behavior when suffering from the common cold and health-related quality of life in individuals attending an annual checkup in Japan: a cross-sectional study.
The World Health Organization and several governments encourage medical self-care (including self-medication) for minor illnesses. Accordingly, the factors that influence self-care have received research attention, with socioeconomic status identified as one such predictor. Although studies have examined the relationship between socioeconomic status and quality of life (QOL) in patients suffering from respiratory allergies or chronic illnesses, the relationship between QOL and self-care behavior for the common cold, the most common illness seen in primary care, has not been examined. Therefore, we investigated the relationship between QOL and self-care behavior in individuals suffering from the common cold. We distributed questionnaires to 499 people who attended an annual public health checkup in Kasama city, Japan. Valid questionnaires were received from 398 participants (mean age = 59.0, SD = 15.8, range = 24-87 years; 61.4 % women). The materials included a question relating to typical actions taken when treating a common cold (self-care or visiting a health clinic), demographics, and the Short Form-8™ (SF-8™)-an 8-item survey that assesses health-related quality of life (HRQOL). The association of care action and HRQOL were investigated using Mann-Whitney U tests with a significance level of p < 0.05. The mean scores for the Physical Functioning, Role-Physical, Bodily Pain, Social Functioning, Role-Emotional, and Physical Component Summary score of the SF-8™ were significantly higher among the self-care group than the group that preferred visiting a clinic. HRQOL among individuals who engage in self-care when treating the common cold was observed to be significantly higher than among individuals who preferred to attend a health clinic. It is unclear whether self-care behavior affects QOL, or whether QOL affects self-care behavior; however, this finding highlights the importance of the relationship between QOL and self-care behavior. Additional studies should be conducted in order to investigate the direction of causality between self-care behaviors and QOL further.


Preparation and application of a novel molecularly imprinted solid-phase microextraction monolith for selective enrichment of cholecystokinin neuropeptides in human cerebrospinal fluid.
A novel molecularly imprinted polymer (MIP) monolith for highly selective extraction of cholecystokinin (CCK) neuropeptides was prepared in a micropipette tip. The MIPs were synthesized by epitope imprinting technique and the polymerization conditions were investigated and optimized. The synthesized MIPs were characterized by infrared spectroscopy, elemental analyzer and scanning electron microscope. A molecularly imprinted solid-phase microextraction (MI-μ-SPE) method was developed for the extraction of CCK neuropeptides in aqueous solutions. The parameters affecting MI-μ-SPE were optimized. The results indicated that this MIP monolith exhibited specific recognition capability and high enrichment efficiency for CCK neuropeptides. In addition, it showed excellent reusability. This MIP monolith was used for desalting and enrichment of CCK4, CCK5 and CCK8 from human cerebrospinal fluid prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, and the results show that this MIP monolith can be a useful tool for effective purification and highly selective enrichment of multiple homologous CCK neuropeptides in cerebrospinal fluid simultaneously. By employing MI-μ-SPE combined with HPLC-ESI-MS/MS analysis, endogenous CCK4 in human cerebrospinal fluid was quantified.


Hyperbaric oxygen therapy for radiation-induced haemorrhagic cystitis.
To assess the efficacy of hyperbaric oxygen (HBO) for treating haemorrhagic cystitis. From February 1997 to April 2004, seven patients with radiation-induced haemorrhagic cystitis were treated with HBO; they received a mean (range) of 30 (18-57) HBO treatments and the follow-up was 24 (3-53) months. The haematuria resolved completely in all seven patients shortly after treatment; one had an improvement but died from complications relating to cancer shortly after completing treatment, and two had recurrence of gross haematuria. They were re-treated with HBO until the haematuria resolved. Radiation-induced haemorrhagic cystitis can be treated successfully with HBO primarily or after failure of standard regimens. This method was well tolerated even in patients debilitated by advanced cancer and blood loss. Long-term remission is possible in most patients, and re-treatment effectively manages recurrent bleeding.


Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas.
Pediatric and young adult central nervous system (CNS) germinomas have favorable cure rates. However, long-term follow-up data are limited because of the rarity of this tumor. We report the long-term overall survival (OS) and causes of late mortality for these patients. Data between 1973 and 2005 from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Kaplan Meier survival analysis was performed on 5-year survivors of childhood CNS germinomatous germ cell tumors (GGCTs) and nongerminomatous germ cell tumors (NGGCTs). Standardized mortality ratios (SMRs) were calculated using US population data to compare observed versus expected all-cause death and death from stroke. Cumulative incidence was calculated using a competing risk model. Four hundred five GGCTs and 94 NGGCTs cases were eligible. OS at 20 and 30 years for GGCTs was 84.1% and 61.9%, respectively, and was 86.7% for NGGCTs at both time points. Five-year survivors of GGCTs and NGGCTs experienced a 10-fold increase in mortality risk compared with their peers (SMR, 10.41; 95% confidence interval [CI], 7.71-13.76 vs SMR, 10.39;95% CI, 4.83-19.73, respectively). Five-year survivors GGCTs also experienced a nearly 59-fold increase in risk of death from stroke (SMR, 58.93; 95% CI, 18.72-142.10). At 25 years, the cumulative incidence of death due to cancer and subsequent malignancy was 16% and 6.0%, respectively. Although CNS germinomas have favorable cure rates, late recurrences, subsequent malignancies, and stroke significantly affect long-term survival. Close attention to long-term follow-up with assessment of stroke risk factors is recommended.


The 70 kDa heat shock protein assists during the repair of chilling injury in the insect, Pyrrhocoris apterus.
The Pyrrhocoris apterus (Insecta: Heteroptera) adults attain high levels of cold tolerance during their overwintering diapause. Non-diapause reproducing adults, however, lack the capacity to express a whole array of cold-tolerance adaptations and show relatively low survival when exposed to sub-zero temperatures. We assessed the competence of non-diapause males of P. apterus for responding to heat- and cold-stresses by up-regulation of 70 kDa heat shock proteins (Hsps) and the role of Hsps during repair of heat- and cold-induced injury. The fragments of P. apterus homologues of Hsp70 inducible (PaHsp70) and cognate forms (PaHsc70) were cloned and sequenced. The abundance of mRNA transcripts for the inducible form (qPCR) and corresponding protein (Western blotting) were significantly up-regulated in response to high and low temperature stimuli. In the cognate form, mRNA was slightly up-regulated in response to both stressors but very low or no up-regulation of protein was apparent after heat- or cold-stress, respectively. Injection of 695 bp-long Pahsp70 dsRNA (RNAi) caused drastic suppression of the heat- and cold-stress-induced Pahsp70 mRNA response and the up-regulation of corresponding protein was practically eliminated. Our RNAi predictably prevented recovery from heat shock and, in addition, negatively influenced repair of chilling injuries caused by cold stress. Cold tolerance increased when the insects were first exposed to a mild heat shock, in order to trigger the up-regulation of PaHsp70, and subsequently exposed to cold stress. Our results suggest that accumulation of PaHsp70 belongs to a complex cold tolerance adaptation in the insect Pyrrhocoris apterus.


Summarizing and correcting the GC content bias in high-throughput sequencing.
GC content bias describes the dependence between fragment count (read coverage) and GC content found in Illumina sequencing data. This bias can dominate the signal of interest for analyses that focus on measuring fragment abundance within a genome, such as copy number estimation (DNA-seq). The bias is not consistent between samples; and there is no consensus as to the best methods to remove it in a single sample. We analyze regularities in the GC bias patterns, and find a compact description for this unimodal curve family. It is the GC content of the full DNA fragment, not only the sequenced read, that most influences fragment count. This GC effect is unimodal: both GC-rich fragments and AT-rich fragments are underrepresented in the sequencing results. This empirical evidence strengthens the hypothesis that PCR is the most important cause of the GC bias. We propose a model that produces predictions at the base pair level, allowing strand-specific GC-effect correction regardless of the downstream smoothing or binning. These GC modeling considerations can inform other high-throughput sequencing analyses such as ChIP-seq and RNA-seq.


Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors.
Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37-year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by fluorescence in situ hybridization. There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by fluorescence in situ hybridization in 4/6 (67%) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNA sequencing. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36 to 74 y; M:F=4:3). The histologic spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors).


Functional characterization of human Kindlin-2 core promoter identifies a key role of SP1 in Kindlin-2 transcriptional regulation.
Kindlin-2 is a recently identified FERM and PH domain containing integrin interacting protein. Kindlin-2 is ubiquitously expressed in normal tissues. So far, much effort has been spent exploring the functional aspects of Kindlin-2. However, the transcriptional regulation of Kindlin-2 has not yet been investigated. In this study we identified and functionally characterized the promoter of the human Kindlin-2 gene. We show that the core promoter of Kindlin-2 is a 39 base pair long GC rich fragment located -122/-83 upstream of the Kindlin-2 transcription start site. Functional characterization of this core promoter region by both in silico as well as in vitro/in vivo analysis shows that the transcription factor SP1 plays an important role in regulation of Kindlin-2 expression.


Clinical practice guidelines for the management of metastatic colorectal cancer: a consensus statement of the Hellenic Society of Medical Oncologists (HeSMO).
There is discrepancy and failure to adhere to current international guidelines for the management of metastatic colorectal cancer (CRC) in hospitals in Greece and Cyprus. The aim of the present document is to provide a consensus on the multidisciplinary management of metastastic CRC, considering both special characteristics of our Healthcare System and international guidelines. Following discussion and online communication among the members of an executive team chosen by the Hellenic Society of Medical Oncology (HeSMO), a consensus for metastastic CRC disease was developed. Statements were subjected to the Delphi methodology on two voting rounds by invited multidisciplinary international experts on CRC. Statements reaching level of agreement by ≥80% were considered as having achieved large consensus, whereas statements reaching 60-80% moderate consensus. One hundred and nine statements were developed. Ninety experts voted for those statements. The median rate of abstain per statement was 18.5% (range: 0-54%). In the end of the process, all statements achieved a large consensus. The importance of centralization, care by a multidisciplinary team, adherence to guidelines, and personalization is emphasized. R0 resection is the only intervention that may offer substantial improvement in the oncological outcomes.


The apolipoprotein B messenger RNA editing enzyme.
The editing of apolipoprotein (apo)B messenger RNA (mRNA) involves a novel C to U modification, which creates an in-frame stop-translation codon, thereby generating the carboxyl-terminal of apoB48. The 27 kDa catalytic subunit of the editing enzyme has been cloned and established to be a zinc-containing cytidine deaminase. The catalytic subunit is guided to the editing site by a second targeting subunit or subunits. A candidate for the targeting subunit is a 60 kDa protein that can be UV crosslinked to the sequence UGAU, which is part of a motif downstream of the editing site that is essential for editing.


Effects of Probiotic Supplementation on Selected Parameters of Blood Prooxidant-Antioxidant Balance in Elite Athletes: A Double-Blind Randomized Placebo-Controlled Study.
A randomized, double-blind, placebo-controlled study was conducted, in order to evaluate if Lactobacillus helveticus Lafti® L10 (Lallemand Health Solutions, Montreal, Canada) supplementation during three months could influence oxidative markers in the population of elite athletes: triathletes, cyclists and endurance athletes. Twenty-two elite athletes were randomized to either placebo (n = 12) or probiotic (n = 10) groups. The probiotic group received 2x1010 colony forming units of Lafti® L10. Before and after the supplementation serum samples were collected. Markers of oxidative stress and anti-oxidative defense: superoxide dismutase (SOD), paraoxonase (PON), advanced oxidation protein products (AOPP), malondialdehyde (MDA), total antioxidant status, total oxidant status, pro-oxidant-antioxidant balance, oxidative stress index, bilirubin, uric acid and albumin were determined in serum. Parameters of lipid status, as well as susceptibility to copper-induced oxidation of LDL particles in vitro were also determined. There was a significant interaction effect for MDA (p = 0.039), with a decrease in MDA in the probiotic group only (p = 0.049). There was a significant interaction effect for AOPP (p = 0.037), with a significant decrease in the probiotic group (p = 0.045). Interaction effect for SOD was approaching to formal significance (p = 0.108) and the post-hoc test showed a significant decrease in the probiotic group (p = 0.041) only. A significant correlation between AOPP and SOD (p = 0.012, r = -0.40) was found in the probiotic group at the end of the study. PON1 activity was decreased in both the probiotic (p = 0.032) and placebo group (p = 0.035). No significant changes in the remainder of the evaluated parameters were noted. In conclusion, probiotic strain Lafti® L10 exerts certain antioxidant potential, but further research is needed.


Relation between the estimated glomerular filtration rate and pulse wave velocity in Japanese.
We investigated the link between renal function as evaluated by estimated glomerular filtration rate (eGFR) and pulse wave velocity (PWV) in Japanese without medications. A total of 1,244 Japanese subjects, aged 20-79 years, were recruited in a cross-sectional clinical investigation study. They received no medications. eGFR was calculated using serum creatinine (Cr), age and sex. Peripheral arterial stiffness was evaluated by brachial-ankle PWV (baPWV). eGFR and baPWV were significantly correlated with age. eGFR was negatively correlated with baPWV (men: r=-0.308, p<0.0001, women: r=-0.293, p<0.0001). Twenty-six men (5.6%) and 35 women (4.5%) were diagnosed as reduced eGFR (eGFR <60 mL/min/1.73 m(2)). We compared clinical parameters between subjects with reduced eGFR (Group R) and without such reduction (Group N). baPWV in Group R was significantly higher than that in Group N even after adjusting for age. In women, systolic blood pressure in Group R was also significantly higher than that in Group N. eGFR was closely associated with peripheral arterial stiffness in Japanese.


Nurse-led case management in the National Health Service: bridging clinical and social worlds.
To understand the effects of Nurse Case Managers (NCMs) working in primary care in the English National Health Service (NHS) from multiple perspectives and how this new role impacts on social workers, this paper reports and discusses findings from a multi-level study of the role of NCMs working in primary care in the English NHS. Case management as understood by the NHS is equivalent to key-worker type care management as understood by social workers. However, English health and social services are separately organised with different organisational principles; health services are free at the time of need, whereas social services are means-tested and access is restricted. The study included reviews of evaluations and policy, a national survey of nurse case management in Primary Care Trusts (PCTs) and case studies in three purposively selected PCTs. The views and experiences of patients were collected through face-to-face and telephone interviews with 51 older people and their carers, and these experiences are illustrated. In this paper, we further draw on data reporting the views of NCMs and stakeholders from other disciplines and services. The opinions of older people receiving nurse case management reveal the value of high intensity support to individuals with major health and social needs. The NCMs' clinical expertise, the improved continuity of care they provided and the psychosocial support they offered, were all emphasised by older people or their carers. NCMs substituted for social workers in some cases, when the older person would not have been eligible for publicly funded social care or had declined it. In other cases, they supplemented social services by identifying unmet needs. In a third category of cases, they may have curtailed social services' involvement by preventing hospital admission and social services' involvement as a consequence. The implications of this from the viewpoint of other study participants are discussed.


Factors related to academic success among nursing students: a descriptive correlational research study.
The current rise in employment is improving forecasts for the future supply of registered nurses; however sizeable shortages are still projected. With the intention of improving academic success in nursing students, related factors need to be better understood. The purpose of the correlational study was to describe the relationship between emotional intelligence, psychological empowerment, resilience, spiritual well-being, and academic success in undergraduate and graduate nursing students. A descriptive correlational design was utilized. The study was set in a private Catholic university. There were 124 participants. There were 59% undergraduate and 41% graduate students. Background data, in addition to the Spreitzer Psychological Empowerment Scale, the Wagnild and Young Resilience Scale, and the Spiritual Well-Being Scale and the Mayer-Salovey-Caruso Emotional Intelligence Test, was collected from students who met study criteria. In a combined sample, academic success was correlated with overall spiritual well-being, empowerment and resilience. Although academic success was not correlated with overall emotional intelligence, it was correlated with the emotional intelligence branch four (managing emotions) score. When undergraduate and graduate students were considered separately, only one correlation was found to be significantly related to academic success in the undergraduate sample, namely, emotional intelligence branch one (perceiving emotions). When examining the data from just graduate level nurses, significant relationships were found between total emotional intelligence with academic success, resilience with academic success, and psychological empowerment with academic success. The significant relationship between psychological empowerment, resilience, spiritual well-being and academic success in this study supports the statements in the literature that these concepts may play an important role in persistence through the challenges of nursing education. Research is needed to examine if strategies to enhance empowerment, resilience, and spiritual well-being can increase academic success in a test-retest design.


Renal rupture following extracorporeal shockwave lithotripsy.
A 41-year-old woman presented to the emergency department with a chief complaint of hematuria three days status post extracorporeal shockwave lithotripsy. The patient described a three-day history of worsening left-sided abdominal pain immediately following the procedure. She denied any fever, chills, changes in bowel habits, hematochezia, increased urinary frequency, urinary urgency, or dysuria. Physical exam revealed tenderness to palpation in the left upper quadrant, left flank and periumbilical region with mild guarding. Laboratory studies revealed an anemic patient with downward trending hematocrit (red blood cell count of 3.41 10(6)/μL, hemoglobin of 10.6 g/dL, and a hematocrit of 31.3% down from 43% a week and a half prior). Urinalysis revealed red and cloudy urine with 3+ leukocytes. A chest radiograph was unremarkable. A computed tomography of the chest, abdomen, and pelvis showed a laceration to the lateral aspect of the mid left kidney with a hematoma measuring 3.2 cm in thickness (Figure). The patient was subsequently admitted to the hospital for monitoring and discharged on day nine.


Vulnerability as a function of individual and group resources in cumulative risk assessment.
The field of risk assessment has focused on protecting the health of individual people or populations of wildlife from single risks, mostly from chemical exposure. The U.S. Environmental Protection Agency recently began to address multiple risks to communities in the "Framework for Cumulative Risk Assessment" [EPA/630/P02/001F. Washington DC:Risk Assessment Forum, U.S. Environmental Protection Agency (2003)]. Simultaneously, several reports concluded that some individuals and groups are more vulnerable to environmental risks than the general population. However, vulnerability has received little specific attention in the risk assessment literature. Our objective is to examine the issue of vulnerability in cumulative risk assessment and present a conceptual framework rather than a comprehensive review of the literature. In this article we consider similarities between ecologic and human communities and the factors that make communities vulnerable to environmental risks. The literature provides substantial evidence on single environmental factors and simple conditions that increase vulnerability or reduce resilience for humans and ecologic systems. This observation is especially true for individual people and populations of wildlife. Little research directly addresses the topic of vulnerability in cumulative risk situations, especially at the community level. The community level of organization has not been adequately considered as an end point in either human or ecologic risk assessment. Furthermore, current information on human risk does not completely explain the level of response in cumulative risk conditions. Ecologic risk situations are similarly more complex and unpredictable for cases of cumulative risk. Psychosocial conditions and responses are the principal missing element for humans. We propose a model for including psychologic and social factors as an integral component of cumulative risk assessment.


Are heterotrophic and silica-rich eukaryotic microbes an important part of the lichen symbiosis?
We speculate that heterotrophic and/or silica-rich eukaryotic microorganisms maybe an important part of the lichen symbiosis. None of the very few studies of heterotrophic protists associated with lichens have considered the possibility that they may be of functional significance in the lichen symbiosis. Here we start to develop, currently speculative, theoretical ideas about their potential significance. For example, all the protist taxa identified in lichens we sampled in Ohio USA depend on silica for growth and construction of their cell walls, this could suggest that silica-rich lichen symbionts may be significant in the biogeochemistry of the lichen symbiosis. We also present arguments suggesting a role for protists in nitrogen cycling within lichen thalli and a potential role in controlling bacterial populations associated with lichens. In this necessarily speculative paper we highlight areas for future research and how newer technologies may be useful for understanding the full suite of organisms involved in the lichen symbiosis.


The spectrum of mutations for CADASIL diagnosis.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations of the Notch3 gene at the chromosome locus 19p13. The clinical spectrum includes recurrent ischaemic episodes, cognitive deficits, migraine and psychiatric disorders. The histopathological hallmark of CADASIL is accumulation of electron dense granules (GOM) in the media of arterioles. MRI reveals extensive cerebral white matter lesions and subcortical infarcts. CADASIL was initially thought to be a rare disorder, but increasing numbers of families have been identified; therefore, it is likely that CADASIL is still largely underdiagnosed. Here we report an update on mutations of the Notch3 gene and some information on the pathogenesis of the disease.


Vitamin E supplementation, cereal feed type and consumer sensory perceptions of poultry meat quality.
Lipid oxidation leads to meat spoilage and has been reported to cause adverse changes in the flavour and texture of poultry meat. Vitamin E has been found to be effective in delaying lipid oxidation. The aim of this study was to determine whether the vitamin E supplementation of chicken feed influences the consumers' perception of the quality of chicken meat under normal display and storage conditions. Untrained consumers (n 32) evaluated cooked breast meat from chickens (both corn fed and wheat fed) supplemented with 75,250 or 500 mg/kg vitamin E and after storage at 4 degrees C for 4 and 7 d. Factorial analysis found an interaction between vitamin E treatment and storage day upon the perceived juiciness (P=0.023) and tenderness (P=0.041) of the chicken meat. Perceptions of quality relative to vitamin E level were more evident on day 4 than day 7. When the two cereal types were compared, the time-related sub-group effects were observed only in meat from corn-fed chickens supplemented with either 75 or 250 mg/kg, which was perceived to be juicier (P=0.018) and more tender (P=0.020) than that supplemented at the 500 mg/kg level. These results imply that the two lower concentrations of vitamin E have some advantages over 500 mg/kg, but for optimal consumer acceptance of corn-fed chicken meat, we suggest that 250 mg/kg vitamin E should be added to corn-fed poultry feed. There was no evidence to suggest any advantages in changing the current amount of vitamin E (75 mg/kg) used to rear wheat-fed birds.


New Properties of a Bioinspired Pyridine Benzimidazole Compound as a Novel Differential Staining Agent for Endoplasmic Reticulum and Golgi Apparatus in Fluorescence Live Cell Imaging.
In this study, we explored new properties of the bioinspired pyridine benzimidazole compound B2 (2,4-di-tert-butyl-6-(3H-imidazo[4,5-c]pyridine-2-yl)phenol) regarding its potential use as a differential biomarker. For that, we performed 1D 1HNMR (TOCSY), UV-Vis absorption spectra in different organic solvents, voltammetry profile (including a scan-rate study), and TD-DFT calculations that including NBO analyses, to provide valuable information about B2 structure and luminescence. In our study, we found that the B2 structure is highly stable, where the presence of an intramolecular hydrogen bond (IHB) seems to have a crucial role in the stability of luminescence, and its emission can be assigned as fluorescence. In fact, we found that the relatively large Stokes Shift observed for B2 (around 175 nm) may be attributed to the stability of the B2 geometry and the strength of its IHB. On the other hand, we determined that B2 is biocompatible by cytotoxicity experiments in HeLa cells, an epithelial cell line. Furthermore, in cellular assays we found that B2 could be internalized by passive diffusion in absence of artificial permeabilization at short incubation times (15 min to 30 min). Fluorescence microscopy studies confirmed that B2 accumulates in the endoplasmic reticulum (ER) and Golgi apparatus, two organelles involved in the secretory pathway. Finally, we determined that B2 exhibited no noticeable blinking or bleaching after 1 h of continuous exposure. Thus, B2 provides a biocompatible, rapid, simple, and efficient way to fluorescently label particular organelles, producing similar results to that obtained with other well-established but more complex methods.


Physical activity in recurrent colon cancer: Cancer and Leukemia Group B/SWOG 80702 (Alliance).
One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET-h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests. Compared with patients expending <3.0 MET-h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET-h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42-0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%-69.2%) with <3.0 MET-h/week of physical activity and 72.2% (95% CI, 63.1%-79.6%) with ≥18 MET-h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2-20.8 percentage points). Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.


Tumor gene expression profiling in women with breast cancer. Test category: prognostic.
Differences in the expression of specific genes within breast tumors have been associated with risk of recurrence after treatment. Most women with Stage I or II node-negative breast cancer (especially when estrogen-receptor positive and treated with tamoxifen) remain disease-free at 10 years. Information on risk of recurrence could help identify women most likely to benefit from chemotherapy. Several clinically available gene expression profiles (GEP) provide "recurrence risk scores" that are intended to supplement information used by clinicians and patients in treatment decision-making.


Neurogranin: immunocytochemical localization of a brain-specific protein kinase C substrate.
The developmental expression and the cellular localization of neurogranin (formerly designated p17), a brain-specific protein kinase C (PKC) substrate, were investigated. The developmental expression of neurogranin was studied by immunoblotting of rat brain and neuronal cell-culture extracts using neurogranin polyclonal antibodies. Neurogranin synthesis was found to be developmentally regulated, with no expression in the embryonic and neonatal period and an abrupt increase between 2 and 3 weeks of age. By immunohistochemistry, neurogranin was found essentially in the adult rat telencephalon, specifically located in the cell bodies and dendritic processes of neurons of the cerebral cortex, hippocampus, striatum, and a few other discreet areas. Neurogranin immunoreactivity was nearly absent in the thalamus, cerebellum, and brain stem. The late developmental expression and the dendritic localization of neurogranin in neurons are 2 features that also characterize the type I PKC isozyme. The specific localization of the protein in integrative areas of the rat brain suggests a highly specialized function of neurogranin in the CNS. A possible role for neurogranin in the transduction of the PKC activation signals at the postsynaptic level is suggested.


Experimental mycobacteriosis in striped bass Morone saxatilis.
Striped bass Morone saxatilis were infected intraperitoneally with approximately 10(5) Mycobacterium marinum, M. shottsii sp. nov., or M. gordonae. Infected fish were maintained in a flow-through freshwater system at 18 to 21 degrees C, and were examined histologically and bacteriologically at 2, 4, 6, 8, 17, 26, 36 and 45 wk post-infection (p.i.). M. marinum caused acute peritonitis, followed by extensive granuloma development in the mesenteries, spleen and anterior kidney. Granulomas in these tissues underwent a temporal progression of distinct morphological stages, culminating in well-circumscribed lesions surrounded by normal or healing tissue. Mycobacteria were cultured in high numbers from splenic tissue at all times p.i. Standard Ziehl-Neelsen staining, however, did not demonstrate acid-fast rods in most early inflammatory foci and granulomas. Large numbers of acid-fast rods were present in granulomas beginning at 8 wk p.i. Between 26 and 45 wk p.i., reactivation of disease was observed in some fish, with disintegration of granulomas, renewed inflammation, and elevated splenic bacterial densities approaching 10(9) colony-forming units g(-1). Infection with M. shottsii or M. gordonae did not produce severe pathology. Mild peritonitis was followed by granuloma formation in the mesenteries, but, with 1 exception, granulomas were not observed in the spleen or anterior kidney. M. shottsii and M. gordonae both established persistent infections in the spleen, but were present at densities at least 2 orders of magnitude less than M. marinum at all time points observed. Granulomas in the mesenteries of M. shottsii- and M. gordonae-infected fish resolved over time, and no reactivation of disease was observed.


Graph theory network function in Parkinson's disease assessed with electroencephalography.
To determine what differences exist in graph theory network measures derived from electroencephalography (EEG), between Parkinson's disease (PD) patients who are cognitively normal (PD-CN) and matched healthy controls; and between PD-CN and PD dementia (PD-D). EEG recordings were analyzed via graph theory network analysis to quantify changes in global efficiency and local integration. This included minimal spanning tree analysis. T-tests and correlations were used to assess differences between groups and assess the relationship with cognitive performance. Network measures showed increased local integration across all frequency bands between control and PD-CN; in contrast, decreased local integration occurred in PD-D when compared to PD-CN in the alpha1 frequency band. Differences found in PD-MCI mirrored PD-D. Correlations were found between network measures and assessments of global cognitive performance in PD. Our results reveal distinct patterns of band and network measure type alteration and breakdown for PD, as well as with cognitive decline in PD. These patterns suggest specific ways that interaction between cortical areas becomes abnormal and contributes to PD symptoms at various stages. Graph theory analysis by EEG suggests that network alteration and breakdown are robust attributes of PD cortical dysfunction pathophysiology.


A mire of highly subjective and ineffective voluntary guidelines: tobacco industry efforts to thwart tobacco control in Malaysia.
To describe tobacco industry efforts in Malaysia to thwart government efforts to regulate tobacco promotion and health warnings. Systematic keyword and opportunistic website searches of formerly private tobacco industry internal documents made available through the Master Settlement Agreement and secondary websites; relevant information from news articles and financial reports. Commencing in the 1970s, the industry began to systematically thwart government tobacco control. Guidelines were successfully promoted in the place of legislation for over two decades. Even when the government succeeded in implementing regulations such as health warnings and advertising bans they were compromised and acted effectively to retard further progress for years to come. Counter-measures to delay or thwart government efforts to regulate tobacco were initiated by the industry. Though not unique to Malaysia, the main difference lies in the degree to which strategies were used to successfully counter stringent tobacco control measures between 1970 and 1995.


Anion exchange kinetics of nanodimensional layered metal hydroxides: use of isoconversional analysis.
Anion exchange reactions of nanodimensional layered metal hydroxide compounds are utilized to create materials with targeted physical and chemical properties and also as a means for controlled release of intercalated anions. The kinetics of this important class of reaction are generally characterized by model-based approaches. In this work, a different approach based on isothermal, isoconversional analysis was utilized to determine effective activation energies with respect to extent of reaction. Two different layered metal hydroxide materials were chosen for reaction with chloride anions, using a temperature range of 30-60 °C. The concentrations of anions released into solution and the changes in polycrystalline solid phases were evaluated using model-based (Avrami-Erofe'ev nucleation-growth model) and model-free (integral isoconversional) methods. The results demonstrate the utility of the isoconversional approach for identifying when fitting to a single model is not appropriate, particularly for characterizing the temperature dependence of the reaction kinetics.


Structural and functional study of the GlnB22-insulin mutant responsible for maturity-onset diabetes of the young.
The insulin gene mutation c.137G>A (R46Q), which changes an arginine at the B22 position of the mature hormone to glutamine, causes the monogenic diabetes variant maturity-onset diabetes of the young (MODY). In MODY patients, this mutation is heterozygous, and both mutant and wild-type (WT) human insulin are produced simultaneously. However, the patients often depend on administration of exogenous insulin. In this study, we chemically synthesized the MODY mutant [GlnB22]-insulin and characterized its biological and structural properties. The chemical synthesis of this insulin analogue revealed that its folding ability is severely impaired. In vitro and in vivo tests showed that its binding affinity and biological activity are reduced (both approximately 20% that of human insulin). Comparison of the solution structure of [GlnB22]-insulin with the solution structure of native human insulin revealed that the most significant structural effect of the mutation is distortion of the B20-B23 β-turn, leading to liberation of the B chain C-terminus from the protein core. The distortion of the B20-B23 β-turn is caused by the extended conformational freedom of the GlnB22 side chain, which is no longer anchored in a hydrogen bonding network like the native ArgB22. The partially disordered [GlnB22]-insulin structure appears to be one reason for the reduced binding potency of this mutant and may also be responsible for its low folding efficiency in vivo. The altered orientation and flexibility of the B20-B23 β-turn may interfere with the formation of disulfide bonds in proinsulin bearing the R46Q (GlnB22) mutation. This may also have a negative effect on the WT proinsulin simultaneously biosynthesized in β-cells and therefore play a major role in the development of MODY in patients producing [GlnB22]-insulin.


Quality Improvement Measures for Increasing the Colorectal Cancer Screening Rates at a Community Health Center.
Direct recommendation from health care professionals has been shown to generally increase colorectal cancer screening rates in the United States. However, data for rural, underserved communities are limited. To increase colorectal cancer screening rates at a rural community health center (CHC) by increasing health care professionals' awareness of patients' screening eligibility. Participants were health care professionals at a CHC treating patients eligible for colorectal cancer screening (defined as patients aged 50-74 years who visited the CHC between February 24, 2014, and March 15, 2014, and whose electronic medical records [EMRs] had no recording of colorectal cancer screening). For a 3-week period, these participants added electronic reminders to eligible patients' EMRs. Data reports for the screening rates of each participant, in addition to the overall CHC, were generated 4 weeks after the study period and compared with screening rates in 2013. Five health care professionals volunteered to participate. No statistically significant difference was found in screening rates of participants compared with overall clinic rates between the 2013 (P=.639) and 2014 (P=.583) sample dates. No statistically significant difference was found in the overall CHC screening rates (P=.052), which were 47.69% and 40.84% in 2013 and 2014, respectively. During the study period, 99 eligible patients were seen. An incidental finding revealed a substantial EMR flaw in uniform data system reporting measures: self-reported colorectal cancer screenings by patients, without official documentation provided, were documented in an EMR section that is not retrieved during uniform data system reporting. No associated change in colorectal cancer screening rates was found at the CHC after increasing participants' awareness of patients' screening eligibility using electronic flagging. However, colorectal cancer screening results cannot be reported with certainty given that incidental documentation and data collection discrepancies were found.


Ligamentous Lisfranc joint injuries: a biomechanical comparison of dorsal plate and transarticular screw fixation.
The current treatment of displaced ligamentous injuries of the tarsometatarsal (TMT) joints is open reduction and rigid fixation using transarticular screws. This technique causes further articular surface damage that theoretically may increase the risk of arthritis. Should the screws break, hardware removal is difficult. An alternative method that avoids these potential complications is rigid fixation using dorsal plates. The displacement between the first metatarsal and medial cuneiform, the second metatarsal and intermediate cuneiform, the first and second metatarsal bases, and the medial cuneiform and second metatarsal base were measured in 10 matched pairs of fresh-frozen cadaver lower extremities in the unloaded and loaded condition. After sectioning the Lisfranc and TMT joint ligaments, measurements were repeated in the loaded condition. The first and second TMT joints of the right feet were fixed with transarticular 3.5-mm cortical screws while those of the left feet with were fixed with dorsal 2.7-mm 1/4 tubular plates. Measurements were then repeated in the unloaded and loaded condition. After ligament sectioning, significantly increased first and second TMT joint subluxation with loading was seen. No significant difference was noted with direct comparison between plates and screws with respect to ability to realign the first and second TMT joints and to maintain TMT joint alignment during loading. The amount of articular surface destruction caused by one 3.5-mm screw was 2.0 +/- 0.7% for the medial cuneiform, 2.6 +/- 0.5% for the first metatarsal, 3.6 +/- 1.2% for the intermediate cuneiform, and 3.6 +/- 1.0% for the second metatarsal. The model reliably produced displacement of the first and second TMT joints consistent with a ligamentous Lisfranc injury. Transarticular screws and dorsal plates showed similar ability to reduce the first and second TMT joints after TMT and Lisfranc ligament transection and to resist TMT joint displacement with weightbearing load. Dorsal plating may be an alternative to transarticular screws in the treatment of displaced Lisfranc injuries.


Dimethylarginine dimethylaminohydrolase-1 contributes to exercise-induced cardiac angiogenesis in mice.
Dimethylarginine dimethylaminohydrolase-1 (DDAH1) maintains nitric oxide (NO) bioavailability by degrading asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). It has been well established that DDAH1 and exercise play crucial roles in promoting cardiac angiogenesis under pathological conditions. However, the role of DDAH1 in exercise-induced cardiac angiogenesis remains unclear. In this study, we focused on the change in DDAH1 in response to moderate exercise and the underlying mechanism of exercise-induced cardiac angiogenesis. Eight-week-old male DDAH1 global knockout (KO) mice and DDAH1flox/flox mice (wild-type) were randomly divided into sedentary groups (control) and swimming groups (exercise). After eight weeks of swimming at five days per week, all the mice were anesthetized and sacrificed. Histological examination and Western blot analysis were performed. There were low levels of myocardial capillaries in DDAH1 KO mice under control and exercise conditions. Notably, exercise elevated DDAH1 protein expression, as observed by Western blot analysis. The common cardiac angiogenesis biomarkers vascular endothelial growth factor (VEGF) and Caveolin-1 were increased during exercise. A significant difference in VEGF was observed between the DDAH1 KO and wild-type groups. Similarly, increased Caveolin-1 expression was abrogated in DDAH1 KO mice. Furthermore, we tested the R-Ras/AKT/GSK3β signaling pathway to study the underlying molecular mechanism. DDAH1 may regulate the R-Ras/AKT/GSK3β pathway due to distinct protein changes in this pathway in the DDAH1 KO and wild-type groups. Our findings suggest that DDAH1 plays an important role in exercise-induced cardiac angiogenesis by regulating the R-Ras/AKT/GSK3βsignaling pathway.


Addressing Children's Needs in Disasters: A Regional Pediatric Tabletop Exercise.
Preparing and responding to the needs of children during public health emergencies continues to be challenging. The purpose of this study was to assess the usefulness of a tabletop exercise in initiating pediatric preparedness strategies and assessing the impact of the exercise on participants' understanding of and confidence in their roles during pediatric public health emergencies. A tabletop exercise was developed to simulate a public health emergency scenario involving smallpox in a child, with subsequent spread to multiple states. During the exercise, participants discussed and developed communication, collaboration, and medical countermeasure strategies to enhance pediatric public health preparedness. Exercise evaluation was designed to assess participants' knowledge gained and level of confidence surrounding pediatric public health emergencies. In total, 22 participants identified over 100 communication and collaboration strategies to promote pediatric public health preparedness during the exercise and found that the most beneficial aspect during the exercise was the partnership between pediatricians and public health officials. Participants' knowledge and level of confidence surrounding a pediatric public health emergency increased after the exercise. The tabletop exercise was effective in identifying strategies to improve pediatric public health preparedness as well as enhancing participants' knowledge and confidence surrounding a potential pediatric public health emergency. (Disaster Med Public Health Preparedness. 2018;12:582-586).


A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats.
Events during early life can affect reproductive and metabolic functions in adulthood. We evaluated the programming effects of a single early postnatal estradiol injection (within 3h after birth) in female rats. We assessed ovarian and parametrial adipose tissue morphology, evaluated gene expression related to follicular development and adipose tissue metabolism, and developed a non-invasive volumetric estimation of parametrial adipose tissue by magnetic resonance imaging. Estradiol reduced ovarian weight, increased antral follicle size and number of atretic antral follicles, and decreased theca interna thickness in atretic antral follicles. Adult estradiol-injected rats also had malformed vaginal openings and lacked corpora lutea, confirming anovulation. Estradiol markedly reduced parametrial adipose tissue mass. Adipocyte size was unchanged, suggesting reduced adipocyte number. Parametrial adipose tissue lipoprotein lipase activity was increased. In ovaries, estradiol increased mRNA expression of adiponectin, complement component 3, estrogen receptor α, and glucose transporter 3 and 4; in parametrial adipose tissue, expression of complement component 3 was increased, expression of estrogen receptor α was decreased, and expression of leptin, lipoprotein lipase, and hormone-sensitive lipase was unaffected. These findings suggest that early postnatal estradiol exposure of female rats result in long-lasting effects on the ovary and parametrial adipose tissue at adult age.


Specific human cytotoxic T cells recognize B-cell lines persistently infected with respiratory syncytial virus.
The T-lymphocyte response to respiratory syncytial (RS) virus has been invoked to explain the bronchiolitis and pneumonia caused by RS virus in human infants. However, T cells also appear to play a role in protection against RS virus infection. Although RS virus-specific human lymphocytes have been demonstrated, neither the phenotype nor the function of the lymphocytes was characterized. We describe here the induction of anti-RS virus cytotoxic T lymphocytes, in both bulk culture and restimulated cell lines, from human peripheral blood. Infection of Epstein-Barr virus-transformed human B-cell lines with RS virus in vitro readily caused a persistent infection; these cells continued to synthesize RS viral proteins and secrete infectious RS virus 4 months after infection. The persistently infected cells were used both to restimulate cytotoxic-T-cell precursors and as targets for RS virus-specific cytotoxic T cells.


Mind the Information Gap: Quantifying the Courts' Role in Responding to Patient Harm, 1989 to 2013.
An empirical critique of Australia's medical indemnity crisis challenges assumptions about the role of the courts through determination of civil liability for medical negligence, occupational discipline and criminal liability. Courts were identified as a cause of a crisis in the 2000s that triggered extensive legislative reform of medical negligence law, absent adequate empirical data substantiating either criticisms of the courts or supporting the reforms. Changes to the occupational discipline framework for health practitioners were less controversial but have resulted in increasingly legalistic responses. Using a detailed longitudinal analysis across all jurisdictions this article examines the role of the courts in responding to patient harm across the relevant 25-year period encompassing these reforms, to determine whether the courts did cause the medical indemnity crisis, what effect the reforms had and what other roles the courts play in responding to patient harm.


Assessing the living and dead proportions of cold-water coral colonies: implications for deep-water Marine Protected Area monitoring in a changing ocean.
Coral growth patterns result from an interplay of coral biology and environmental conditions. In this study colony size and proportion of live and dead skeletons in the cold-water coral (CWC) Lophelia pertusa (Linnaeus, 1758) were measured using video footage from Remotely Operated Vehicle (ROV) transects conducted at the inshore Mingulay Reef Complex (MRC) and at the offshore PISCES site (Rockall Bank) in the NE Atlantic. The main goal of this paper was to explore the development of a simple method to quantify coral growth and its potential application as an assessment tool of the health of these remote habitats. Eighteen colonies were selected and whole colony and dead/living layer size were measured. Live to dead layer ratios for each colony were then determined and analysed. The age of each colony was estimated using previously published data. Our paper shows that: (1) two distinct morphotypes can be described: at the MRC, colonies displayed a 'cauliflower-shaped' morphotype whereas at the PISCES site, colonies presented a more flattened 'bush-shaped' morphotype; (2) living layer size was positively correlated with whole colony size; (3) live to dead layer ratio was negatively correlated to whole colony size; (4) live to dead layer ratio never exceeded 0.27. These results suggest that as a colony develops and its growth rate slows down, the proportion of living polyps in the colony decreases. Furthermore, at least 73% of L. pertusa colonies are composed of exposed dead coral skeleton, vulnerable to ocean acidification and the associated shallowing of the aragonite saturation horizon, with significant implications for future deep-sea reef framework integrity. The clear visual contrast between white/pale living and grey/dark dead portions of the colonies also gives a new way by which they can be visually monitored over time. The increased use of marine autonomous survey vehicles offers an important new platform from which such a surveying technique could be applied to monitor deep-water marine protected areas in the future.


Nutritional status alters saccharin intake and sweet receptor mRNA expression in rat taste buds.
Sweet taste usually signifies the presence of caloric food. It is commonly accepted that a close association exists among sweet taste perception, preference, and nutritional status. However, the mechanisms involved remain unknown. To investigate whether nutritional status affects the preference for palatable solutions and alters sweet taste receptor gene expression in rats, we measured saccharin intake and preference using a two-bottle preference test, and changes in body weight, plasma leptin levels, and gene expression for the sweet taste receptor in taste buds in high-fat diet-induced obese rats and chronically diet-restricted rats. We found that the consumption and preference ratios for 0.01 and 0.04 M saccharin were significantly lower in the high-fat diet-induced obese rats than in the normal diet rats, while the serum leptin levels were markedly increased in obese rats. Consistent with the changes in saccharin intake, the gene expression level of the sweet taste receptor T1R3 was significantly decreased in the high-fat diet-induced obese rats compared with the control rats. By contrast, the chronically diet-restricted rats showed remarkably enhanced consumption and preference for 0.04 M saccharin. The serum leptin concentration was decreased, and the gene expression of the leptin receptor was markedly increased in the taste buds. In conclusion, our results suggest that nutritional status alters saccharin preference and the expression of T1R3 in taste buds. These processes may be involved in the mechanisms underlying the modulation of peripheral sweet taste sensitivity, in which leptin plays a role.


Influence of data quality on computed Dutch hospital quality indicators: a case study in colorectal cancer surgery.
Our study aims to assess the influence of data quality on computed Dutch hospital quality indicators, and whether colorectal cancer surgery indicators can be computed reliably based on routinely recorded data from an electronic medical record (EMR). Cross-sectional study in a department of gastrointestinal oncology in a university hospital, in which a set of 10 indicators is computed (1) based on data abstracted manually for the national quality register Dutch Surgical Colorectal Audit (DSCA) as reference standard and (2) based on routinely collected data from an EMR. All 75 patients for whom data has been submitted to the DSCA for the reporting year 2011 and all 79 patients who underwent a resection of a primary colorectal carcinoma in 2011 according to structured data in the EMR were included. Comparison of results, investigating the causes for any differences based on data quality analysis. Main outcome measures are the computability of quality indicators, absolute percentages of indicator results, data quality in terms of availability in a structured format, completeness and correctness. All indicators were fully computable based on the DSCA dataset, but only three based on EMR data, two of which were percentages. For both percentages, the difference in proportions computed based on the two datasets was significant.All required data items were available in a structured format in the DSCA dataset. Their average completeness was 86%, while the average completeness of these items in the EMR was 50%. Their average correctness was 87%. Our study showed that data quality can significantly influence indicator results, and that our EMR data was not suitable to reliably compute quality indicators. EMRs should be designed in a way so that the data required for audits can be entered directly in a structured and coded format.


Enhanced photosynthetic activity in Spinacia oleracea by spectral modification with a photoluminescent light converting material.
The spectral conversion of incident sunlight by appropriate photoluminescent materials has been a widely studied issue for improving the efficiency of photovoltaic solar energy harvesting. By using phosphors with suitable excitation/emission properties, also the light conditions for plants can be adjusted to match the absorption spectra of chlorophyll dyes, in this way increasing the photosynthetic activity of the plant. Here, we report on the application of this principle to a high plant, Spinacia oleracea. We employ a calcium strontium sulfide phosphor doped with divalent europium (Ca0.4Sr0.6S:Eu(2+), CSSE) on a backlight conversion foil in photosynthesis experiments. We show that this phosphor can be used to effectively convert green to red light, centering at a wavelength of ~650 nm which overlaps the absorption peaks of chlorophyll a/b pigments. A measurement system was developed to monitor the photosynthetic activity, expressed as the CO2 assimilation rate of spinach leaves under various controlled light conditions. Results show that under identical external light supply which is rich in green photons, the CO2 assimilation rate can be enhanced by more than 25% when the actinic light is modified by the CSSE conversion foil as compared to a purely reflecting reference foil. These results show that the phosphor could be potentially applied to modify the solar spectrum by converting the green photons into photosynthetically active red photons for improved photosynthetic activity.


BAIAP2 is related to emotional modulation of human memory strength.
Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings. Here we combined a computational model-based analysis of memory-related processes with high density genetic information derived from a genome-wide study in healthy young adults. After identifying the best-fitting model for a verbal memory task and estimating the best-fitting individual cognitive parameters, we found a common variant in the gene encoding the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) that was related to the model parameter reflecting modulation of verbal memory strength by negative valence. We also observed an association between the same genetic variant and a similar emotional modulation phenotype in a different population performing a picture memory task. Furthermore, using functional neuroimaging we found robust genotype-dependent differences in activity of the parahippocampal cortex that were specifically related to successful memory encoding of negative versus neutral information. Finally, we analyzed cortical gene expression data of 193 deceased subjects and detected significant BAIAP2 genotype-dependent differences in BAIAP2 mRNA levels. Our findings suggest that model-based dissociation of specific cognitive parameters can improve the understanding of genetic underpinnings of human learning and memory.


Creating an automated trigger for sepsis clinical decision support at emergency department triage using machine learning.
To demonstrate the incremental benefit of using free text data in addition to vital sign and demographic data to identify patients with suspected infection in the emergency department. This was a retrospective, observational cohort study performed at a tertiary academic teaching hospital. All consecutive ED patient visits between 12/17/08 and 2/17/13 were included. No patients were excluded. The primary outcome measure was infection diagnosed in the emergency department defined as a patient having an infection related ED ICD-9-CM discharge diagnosis. Patients were randomly allocated to train (64%), validate (20%), and test (16%) data sets. After preprocessing the free text using bigram and negation detection, we built four models to predict infection, incrementally adding vital signs, chief complaint, and free text nursing assessment. We used two different methods to represent free text: a bag of words model and a topic model. We then used a support vector machine to build the prediction model. We calculated the area under the receiver operating characteristic curve to compare the discriminatory power of each model. A total of 230,936 patient visits were included in the study. Approximately 14% of patients had the primary outcome of diagnosed infection. The area under the ROC curve (AUC) for the vitals model, which used only vital signs and demographic data, was 0.67 for the training data set, 0.67 for the validation data set, and 0.67 (95% CI 0.65-0.69) for the test data set. The AUC for the chief complaint model which also included demographic and vital sign data was 0.84 for the training data set, 0.83 for the validation data set, and 0.83 (95% CI 0.81-0.84) for the test data set. The best performing methods made use of all of the free text. In particular, the AUC for the bag-of-words model was 0.89 for training data set, 0.86 for the validation data set, and 0.86 (95% CI 0.85-0.87) for the test data set. The AUC for the topic model was 0.86 for the training data set, 0.86 for the validation data set, and 0.85 (95% CI 0.84-0.86) for the test data set. Compared to previous work that only used structured data such as vital signs and demographic information, utilizing free text drastically improves the discriminatory ability (increase in AUC from 0.67 to 0.86) of identifying infection.


Validating a biophysical dispersal model with the early life-history traits of common sole (Solea solea L.).
Larval dispersal and juvenile survival are crucial in determining variation in recruitment, stock size and adult distribution of commercially important fish. This study investigates the dispersal of early-life stages of common sole (Solea solea L.) in the southern North Sea, both empirically and through modeling. Age at different life-history events of juvenile flatfish sampled along the coasts of Belgium, the Netherlands and the United Kingdom in 2013, 2014 and 2016, was determined through the counting of daily growth rings in the otoliths. Juveniles captured between August and October were estimated to be on average 140 days old with an average pelagic larval duration of 34 days. The hatching period was estimated between early April and mid-May followed by arrival and settlement in the nurseries between May and mid-June. Growth rates were higher off the Belgian coast than in the other nursery areas, especially in 2013, possibly due to a post-settlement differentiation. Empirical pelagic larval duration and settlement distributions were compared with the Larvae&Co larval dispersal model, which combines local hydrodynamics in the North Sea with sole larval behavior. Yearly predicted and observed settlement matched partially, but the model estimated a longer pelagic phase. The observations fitted even better with the modelled average (1995-2015) distribution curves. Aberrant results for the small juvenile sole sampled along the UK coast in March 2016, led to the hypothesis of a winter disruption in the deposition of daily growth rings, potentially related to starvation and lower food availability. The similarities between measured and modelled distribution curves cross-validated both types of estimations and accredited daily ageing of juveniles as a useful method to calibrate biophysical models and to understand early-life history of fish, both important tools in support of efficient fisheries management strategies.


Molecular diagnosis of endemic and invasive mycoses: advances and challenges.
The diagnosis of endemic and invasive fungal disease remains challenging. Molecular techniques for identification of fungi now play a significant and growing role in clinical mycology and offer distinct advantages as they are faster, more sensitive and more specific. The aim of this mini-review is to provide an overview of the state of the art of molecular diagnosis of endemic and invasive fungal diseases, and to emphasize the challenges and current need for standardization of the different methods. The European Aspergillus PCR Initiative (EAPCRI) has made significant progress in developing a standard for Aspergillus polymerase chain reaction (PCR), but recognizes that the process will not be finished until clinical utility has been established in formal and extensive clinical trials. Similar efforts should be implemented for the diagnosis of the other mycoses in order to fully validate the current methods or reinforce the need to design new ones. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).


Obstructive sleep apnea syndrome: a child is not just a small adult.
Pediatric obstructive sleep apnea syndrome (OSAS), like adult OSAS, is characterized by intermittent upper airway collapse during sleep and is associated with anatomic and neuromuscular factors. However, the clinical manifestations, diagnostic criteria, and polysomnographic findings of OSAS in children are likely to be different from those in adults. The purpose of this study was to identify the characteristics that distinguish the clinical manifestations and polysomnographic findings of OSAS in children from those in adults. The study population consisted of 34 children (mean age, 7.6 years; range, 4 to 16 years) with OSAS and 33 adults (mean age, 40.1 years; range, 18 to 58 years) with OSAS. We compared various clinical manifestations, such as body mass index, tonsil size, severity of symptoms and signs, and polysomnographic data, between these groups. Obesity was more common among the adults, whereas tonsillar hypertrophy was more common among the children. There were significant differences between the groups in the severity of symptoms and signs, including witnessed apnea, daytime sleepiness, morning headache, memory reduction, and daytime fatigue. In the children with OSAS, slow-wave sleep was relatively well preserved, and respiratory events such as apnea and hypopnea occurred mainly during rapid eye movement sleep. The clinical manifestations and polysomnographic findings in children with OSAS differ from those in adults with OSAS.


Population trends of grassland birds in North America are linked to the prevalence of an agricultural epizootic in Europe.
Globalization of trade has dramatic socioeconomic effects, and, intuitively, significant ecological effects should follow. However, few quantitative examples exist of the interrelationship of globalization, socioeconomics, and ecological patterns. We present a striking illustration of a cascade in which bovine spongiform encephalopathy (BSE; "mad cow disease") outbreaks in Europe exerted pressure on global beef markets, subsequently affecting North American hayfields and grassland bird populations. We examined competing models, which linked the prevalence of BSE in five focal countries, volume of beef exports to those countries from North America, and the amount of hayfield harvested and the abundance of grassland birds in North America. We found that (i) imports from North America increased 1 y after BSE outbreaks; (ii) probably because fewer cattle remained, the hay harvest in North America was reduced 2 y after the outbreak; (iii) the reduced hay harvest yielded a positive response in grassland bird populations 3 y after the outbreak.


Cerium Oxide Nanoparticles Reduce Microglial Activation and Neurodegenerative Events in Light Damaged Retina.
The first target of any therapy for retinal neurodegeneration is to slow down the progression of the disease and to maintain visual function. Cerium oxide or ceria nanoparticles reduce oxidative stress, which is known to play a pivotal role in neurodegeneration. Our aim was to investigate whether cerium oxide nanoparticles were able to mitigate neurodegeneration including microglial activation and related inflammatory processes induced by exposure to high intensity light. Cerium oxide nanoparticles were injected intravitreally or intraveinously in albino Sprague-Dawley rats three weeks before exposing them to light damage of 1000 lux for 24 h. Electroretinographic recordings were performed a week after light damage. The progression of retinal degeneration was evaluated by measuring outer nuclear layer thickness and TUNEL staining to quantify photoreceptors death. Immunohistochemical analysis was used to evaluate retinal stress, neuroinflammatory cytokines and microglial activation. Only intravitreally injected ceria nanoparticles were detected at the level of photoreceptor outer segments 3 weeks after the light damage and electoretinographic recordings showed that ceria nanoparticles maintained visual response. Moreover, this treatment reduced neuronal death and "hot spot" extension preserving the outer nuclear layer morphology. It is noteworthy that in this work we demonstrated, for the first time, the ability of ceria nanoparticles to reduce microglial activation and their migration toward outer nuclear layer. All these evidences support ceria nanoparticles as a powerful therapeutic agent in retinal neurodegenerative processes.


Vibrational spectroscopy of biofluids for disease screening or diagnosis: translation from the laboratory to a clinical setting.
There remains a need for objective and cost-effective approaches capable of diagnosing early-stage disease in point-of-care clinical settings. Given an increasingly ageing population resulting in a rising prevalence of chronic diseases, the need for screening to facilitate the personalising of therapies to prevent or slow down pathology development will increase. Such a tool needs to be robust but simple enough to be implemented into clinical practice. There is interest in extracting biomarkers from biofluids (e.g., plasma or serum); techniques based on vibrational spectroscopy provide an option. Sample preparation is minimal, techniques involved are relatively low-cost, and data frameworks are available. This review explores the evidence supporting the applicability of vibrational spectroscopy to generate spectral biomarkers of disease in biofluids. We extend the inter-disciplinary nature of this approach to hypothesise a microfluidic platform that could allow such measurements. With an appropriate lightsource, such engineering could revolutionize screening in the 21(st) century.


Chemistry of constrained dioxocyclam ligands with Co(III): unusual examples of C-H and C-N bond cleavage.
The reactions between H(2)dc3 and Co(acac)(3) have been studied in the presence and absence of base. In the presence of base, a complex with an intramolecular Co-C bond, Co(dc3-C-(8))(H(2)O), 1, is formed, presumably through heterolytic C-H bond activation. An X-ray crystallographic study demonstrates the presence of a Co-C bond and shows that the diazacyclooctane (daco) subunit adopts the chair-boat conformation with respect to the metal. The cobalt-carbon bond induces strain in the macrocycle as demonstrated by bond angles significantly deviating from tetrahedral. The (13)C NMR resonance of the carbon atom bound to cobalt (-10.5 ppm) suggests significant ionic character in the cobalt-carbon bond. However, we were unable to cleave this bond in the presence of strong acid. In the absence of base, the reaction of Co(acac)(3) with H(2)dc3 resulted in C-N cleavage of the ligand and the formation of a complex of dioxocyclam, Co(dc)(acac), 2. This complex has subsequently been prepared in high yield by the reaction of Co(acac)(3) with dioxocyclam. An X-ray crystallographic study demonstrates that dioxocyclam adopts the heretofore unreported cis configuration, having folded along a N-Co-N axis that is perpendicular to the Co-acac plane.