Isolated Abducens Palsy as the First Presenting Sign of Multiple Sclerosis.
While brain stem involvement in multiple sclerosis (MS) is relatively common, isolated cranial nerve palsies are rare, especially when they represent the initial presenting sign of a new diagnosis of MS. This report describes a patient with no prior history of MS whose sole presenting sign was an isolated abducens palsy. An enhancing pontine lesion was found on MRI which correlated with his abducens palsy, and additional nonactive lesions on MRI led to a diagnosis of MS. This case demonstrates the importance of considering MS as part of the differential diagnosis of patients with isolated cranial nerve palsies.


High-Performance Hydrogen Storage Nanoparticles Inside Hierarchical Porous Carbon Nanofibers with Stable Cycling.
An effective route based on space-confined chemical reaction to synthesize uniform Li2Mg(NH)2 nanoparticles is reported. The hierarchical pores inside the one-dimensional carbon nanofibers (CNFs), induced by the creation of well-dispersed Li3N, serve as intelligent nanoreactors for the reaction of Li3N with Mg-containing precursors, resulting in the formation of uniformly discrete Li2Mg(NH)2 nanoparticles. The nanostructured Li2Mg(NH)2 particles inside the CNFs are capable of complete hydrogenation and dehydrogenation at a temperature as low as 105 °C with the suppression of ammonia release. Furthermore, by virtue of the nanosize effects and space-confinement by the porous carbon scaffold, no degradation was observed after 50 de/rehydrogenation cycles at a temperature as low as 130 °C for the as-prepared Li2Mg(NH)2 nanoparticles, indicating excellent reversibility. Moreover, the theoretical calculations demonstrate that the reduction in particle size could significantly enhance the H2 sorption of Li2Mg(NH)2 by decreasing the relative activation energy barrier, which agrees well with our experimental results. This method could represent an effective, general strategy for synthesizing nanoparticles of complex hydrides with stable reversibility and excellent hydrogen storage performance.


The influence of strategic encoding on false memory in patients with mild cognitive impairment and Alzheimer's disease dementia.
Patients with Alzheimer's disease (AD) dementia exhibit high rates of memory distortions in addition to their impairments in episodic memory. Several investigations have demonstrated that when healthy individuals (young and old) engaged in an encoding strategy that emphasized the uniqueness of study items (an item-specific encoding strategy), they were able to improve their discrimination between old items and unstudied critical lure items in a false memory task. In the present study we examined if patients with AD could also improve their memory discrimination when engaging in an item-specific encoding strategy. Healthy older adult controls, patients with mild cognitive impairment (MCI) due to AD, and patients with mild AD dementia were asked to study lists of categorized words. In the Item-Specific condition, participants were asked to provide a unique detail or personal experience with each study item. In the Relational condition, they were asked to determine how each item in the list was related to the others. To assess the influence of both strategies, recall and recognition memory tests were administered. Overall, both patient groups exhibited poorer memory in both recall and recognition tests compared to controls. In terms of recognition, healthy older controls and patients with MCI due to AD exhibited improved memory discrimination in the Item-Specific condition compared to the Relational condition, whereas patients with AD dementia did not. We speculate that patients with MCI due to AD use intact frontal networks to effectively engage in this strategy.


Age-Related Success with Elective Single versus Double Blastocyst Transfer.
Background. Although the optimal outcome of assisted reproductive technology (ART) is a healthy singleton pregnancy, the rate of twin gestation from ART in women over the age of 35 is persistently high. Methods/Findings. We compared clinical pregnancy rates (PRs), ongoing pregnancy/live birth rates, and multiple gestation rates (MGRs) in 108 women who chose elective single blastocyst transfer (eSBT) to 415 women who chose elective double blastocyst transfer (eDBT) at a hospital-based IVF center. There was no significant difference in PR between eSBT and eDBT (57.4% versus 50.2%, P = 0.47) nor between eSBT and eDBT within each age group: <35, 35-37, 38-40, and >40. The risk of multiple gestations, however, was greatly increased between eSBT and eDBT (1.6 versus 32.4%, P < 0.00005), and this difference did not vary across age groups. Conclusion(s). Women undergoing eDBT are at uniformly high risk of multiple gestation regardless of age. eSBT appears to significantly lower the risk of multiple gestation without compromising PR.


Expression and purification of human diacylglycerol kinase α from baculovirus-infected insect cells for structural studies.
Diacylglycerol kinases (DGKs) are lipid kinases that modulate the levels of lipid second messengers, diacylglycerol and phosphatidic acid. Recently, increasing attention has been paid to its α isozyme (DGKα) as a potential target for cancer immunotherapy. DGKα consists of the N-terminal regulatory domains including EF-hand motifs and C1 domains, and the C-terminal catalytic domain (DGKα-CD). To date, however, no structures of mammalian DGKs including their CDs have yet been reported, impeding our understanding on the catalytic mechanism of DGKs and the rational structure-based drug design. Here we attempted to produce DGKα-CD or a full-length DGKα using bacterial and baculovirus-insect cell expression system for structural studies. While several DGKα-CD constructs produced using both bacterial and insect cells formed insoluble or soluble aggregates, the full-length DGKα expressed in insect cells remained soluble and was purified to near homogeneity as a monomer with yields (1.3 mg/mL per one L cell culture) feasible for protein crystallization. Following enzymatic characterization showed that the purified DGKα is in fully functional state. We further demonstrated that the purified enzyme could be concentrated without any significant aggregation, and characterized its secondary structure by circular dichroism. Taken together, these results suggest that the presence of N-terminal regulatory domains suppress protein aggregation likely via their intramolecular interactions with DGKα-CD, and demonstrate that the baculovirus-insect cell expression of the full-length form of DGKα, not DGKα-CD alone, represents a promising approach to produce protein sample for structural studies of DGKα. Thus, our study will encourage future efforts to determine the crystal structure of DGK, which has not been determined since it was first identified in 1959.


Intraneuronal ApoE in human visual cortical areas reflects the staging of Alzheimer disease pathology.
Alzheimer disease (AD) is marked by progressive loss of cortical neurons with associated cognitive decline. Multiple genetic and environmental factors likely contribute to this progressive loss. Such genetic factors include the polymorphic locus (APOE) that encodes apolipoprotein E (apoE). In order to investigate a possible correspondence between cellular localization of apoE and the neuropathology of AD, we examined the distribution of apoE-immunoreactive neurons in visual cortical areas with different apparent susceptibility to AD neuropathology (areas 17-primary sensory, 18-secondary sensory, and inferior temporal-association cortex) at different stages of AD pathology as described by Braak and Braak. We found that intraneuronal apoE was present at all these stages, however, only in visual cortical regions known to be vulnerable to AD. In the late stages, the laminar distribution of apoE-immunoreactivity matched the distribution of other markers of AD pathology, especially modified tau. These data support previous findings that intraneuronal apoE in neocortex is common in aged, nondemented controls and demonstrate that it may be more common in regions at risk for AD pathology. Thus, intraneuronal accumulation of apoE may be an attribute of cortical neurons that are more vulnerable to age-related injury with the presence of apoE antedating the classical indices of late-onset AD pathology.


Perineal resuturing versus conservative treatment for dehisced perineal wounds and episiotomies: a systematic review and meta-analysis.
Perineal wound dehiscence is associated with complications, such as infections, perineal pain, dyspareunia, and altered sexual function, that severely affects women's health. Currently, few studies have examined secondary repair of first- and second-degree perineal wound dehiscence and episiotomies, and there is currently no consensus on the optimal treatment option for dehisced perineal wounds. The objective was to evaluate whether resuturing or conservative treatment of first- and second-degree dehisced perineal wounds and episiotomies is the optimal treatment modality in terms of postoperative healing time and other secondary outcomes. A systematic literature search was carried out using PubMed, Embase, and Cochrane databases. All included studies were evaluated using the SIGN methodology checklist, with the purpose of assessing the study quality. Three randomized controlled trials were included. Only two small sample-sized studies presented data regarding healing time for both the resuturing and the conservative treatment groups. However, no significant difference was found between the two groups at 4-6 weeks' healing time (RR 1.16, 95% CI 0.53-2.52). One study found that women being resutured experienced a significantly reduced healing time and higher satisfaction with the appearance of the wound healing at 3 months compared with the conservative treatment group. We found no significant differences in the healing time between the resuturing group and the conservative treatment group. However, the sample sizes of the studies were small. A well-designed, large, and prospective randomized controlled trial is needed to evaluate the optimal treatment modality for dehisced perineal wounds.


Direct hydrothermal synthesis of amine-functionalized cubic hematite (C-Fe2O3) and sonochemical deposition of nanosized Au for its application as a visible-light photocatalyst.
Cubic-shaped hematite (C-Fe2O3) functionalized with amine groups was directly prepared via one-pot hydrothermal reaction of Fe3+ with 1,12-diaminododecane (DA-12) in aqueous solution (50% ethanol). Herein, DA-12 (as a Lewis acid) promoted the aggregation of α-FeOOH nanorods with Lewis base sites, leading to the rapid recrystallization and conversion into uniform C-Fe2O3. C-Fe2O3 was subsequently deposited with nanosized Au via sonochemical reduction of 1.0 wt% HAuCl4 (0.1-0.8 mL), hereafter referred to as Au-deposited C-Fe2O3 (C-Fe2O3@Au). X-ray diffraction patterns of C-Fe2O3@Au confirmed the hexagonal crystalline phases of hematite and crystalline Au (111) and showed a weak broad band attributed to the amorphous carbon of DA-12. C-Fe2O3@Au was tested as a visible-light photocatalyst towards the degradation of methylene blue (MB) dye. C-Fe2O3@Au (0.1-0.4 mL of 1.0 wt% HAuCl4) exhibited 6-8 times higher photocatalytic activity than the Au-free counterpart (C-Fe2O3). The enhanced photocatalysis was mainly attributed to the improved separation efficiency of photo-excited charge carriers, i.e., the facilitated transport of electrons from the conduction band to the lower lying Fermi level of Au. However, the photocatalytic activity of C-Fe2O3@Au (0.8 mL of 1.0 wt% HAuCl4) was decreased probably due to the reduction of active sites for MB adsorption by the high coverage of the Au layer. The combined hydrothermal and sonochemical methods provided the direct synthetic route to cubic-shaped hematite decorated with nanosized Au and surface amine functionality as a promising visible-light photocatalyst.


Efficacy of Ceftriaxone, Cefepime, Doxycycline, Ciprofloxacin, and Combination Therapy for Vibrio vulnificus Foodborne Septicemia.
Foodborne Vibrio vulnificus infections are associated with higher rates of sepsis and mortality than wound infections; however, antibiotic efficacy studies have not been performed in foodborne infection models. The efficacies of ceftriaxone, cefepime, doxycycline, ciprofloxacin, and combination therapy were assessed in V. vulnificus intestinal infection in mice in order to model foodborne infections. In accordance with prior studies of cefotaxime, cefepime was synergistic with doxycycline and ciprofloxacin in vitro; combination therapy significantly decreased bacterial growth, by ≥2 log10 units, from that with antibiotic monotherapy (P < 0.01). In vivo, survival rates in the ceftriaxone (50%), doxycycline (79%), and ciprofloxacin (80%) groups were significantly higher than those in the control group (0%) (P < 0.0001). Survival was significantly higher with ceftriaxone-doxycycline (91%) or ceftriaxone-ciprofloxacin (100%) therapy than with ceftriaxone (50%) (P ≤ 0.05). Survival with cefepime-doxycycline (96%) or cefepime-ciprofloxacin (90%) therapy was significantly higher than that with cefepime alone (20%) (P < 0.001). There was no difference in survival between the combination therapy groups. Thus, we conclude that combination therapy was the most effective treatment for foodborne V. vulnificus septicemia. In a septic patient with a recent ingestion of raw seafood, cefepime in combination with doxycycline or ciprofloxacin should be initiated for coverage of resistant Gram-negative organisms and V. vulnificus pending a microbiological diagnosis. Once a diagnosis of foodborne V. vulnificus septicemia is established, treatment can safely transition to ceftriaxone in combination with doxycycline or ciprofloxacin.


Development and comparison of strain specific gag and pol real-time PCR assays for the detection of Visna/maedi virus.
The aim of this study was the development of gag and pol dual labelled probe real-time PCR and RT PCR assays to quantify the proviral load and the transcripts of the British Visna/maedi virus EV1 strain. Primers and probes were chosen based on the consensus sequences of gag and pol clones representative of EV1 genetic variants. Both PCRs had a detection limit of 3 copies of target gene, with a linearity over 6 orders of magnitude. The performances of the two PCRs in vivo were evaluated and compared on a panel of DNAs extracted from blood of sheep infected experimentally with EV1. The pol assay detected in most cases lower numbers of viral molecules than gag assay, yielding some false negative results. The gag real-time RT PCR had a detection limit of 100 RNA molecules with a linearity over 5 orders of magnitude. This did not result in a lower performance of the RT PCR compared to the PCR in cells permissive for virus replication, which contain higher numbers of viral transcripts than proviral genomes. The real-time assays developed in this study, particularly the gag assay, provide a sensitive tool which can be used to quantify the viral load in experimental infections.


High-grade B cell lymphoma, unclassifiable, with blastoid features: an unusual morphological subgroup associated frequently with BCL2 and/or MYC gene rearrangements and a poor prognosis.
A subset of B cell lymphomas with blastoid features do not fit either as B lymphoblastic lymphoma/leukaemia or blastoid mantle cell lymphoma. Their classification is challenging, even with complete clinicopathological and genetic information. At a haematopathology workshop, experts had suggested the term 'high-grade B cell lymphoma, unclassifiable, with blastoid features', and recommended further studies. We describe the clinicopathological, immunophenotypic and cytogenetic findings of 24 high-grade B cell lymphomas, unclassifiable, with blastoid features. Fifteen patients presented de novo and seven patients had a history of lymphoma. Twenty patients (83%) presented with nodal disease. All tumours expressed pan-B cell antigens and 17 (89%) of 19 tumours assessed had a germinal centre B cell immunophenotype. Ten (63%) of 16 tumours assessed by fluorescence in-situ hybridization (FISH) had MYC rearrangement, 13 of 18 (72%) carried IGH-BCL2 and nine of 15 (60%) had both (double-hit lymphoma). The median overall survival was 1.1 years. Using 2008 World Health Organization criteria, 15 cases were classified as B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma, and nine as DLBCL, small centroblastic variant. High-grade B cell lymphomas, unclassifiable, with blastoid features are clinically aggressive with poor survival. Most neoplasms have a germinal centre B cell phenotype. MYC rearrangements and IGH-BCL2 are common, and ~60% are double-hit lymphomas.


Transarticular external fixation versus deltoid ligament repair in treating SER IV ankle fractures: a comparative study.
The topic that whether the injured deltoid ligament should be repaired when associated with ankle joint fractures is still discussed. The objective of this study was to compare the clinical effect of open reduction and internal fixation (ORIF) with deltoid ligament repair (DLR) or transarticular external fixation (TEF) in treating supination-external rotation type IV (SER IV) ankle fractures. Between January 2012 and December 2015, 43 patients were diagnosed as SER IV ankle fractures, 20 underwent ORIF and transarticular external fixation (TEF) without DLR (group 1), 23 were treated with ORIF and DLR (group 2). The pre- and post-operative radiographic examination were performed, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the visual analog scale (VAS), the Medical Outcomes Short Form 36-item questionnaire score (SF-36), and the ankle range of motion (ROM) were used for functional evaluation. In both groups, the three scores improved significantly after surgery, but there was no significant difference between the two groups. At 6 weeks after surgery, patients in group 2 had better ankle ROM than group 1 (29.35 ± 2.033 vs. 40.35 ± 3.550, P < 0.001), but there was no difference at 12 months postoperatively. No cases of bone nonunion or post-traumatic arthritic changes were seen during the follow-up. Patients in group 1 required a shorter time to achieve fracture union than patients in group 2. ORIF with TIF is an optional strategy to manage SER IV ankle fractures as it achieves comparable functional results to ORIF with DLR. It also allows patients to start relatively earlier weight-bearing and may promote fracture union.


Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.
In addition to increased DNA-strand exchange, a cytogenetic feature of cells lacking the RecQ-like BLM helicase is a tendency for telomeres to associate. We also report additional cellular and biochemical evidence for the role of BLM in telomere maintenance. BLM co-localizes and complexes with the telomere repeat protein TRF2 in cells that employ the recombination-mediated mechanism of telomere lengthening known as ALT (alternative lengthening of telomeres). BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur. Additionally, TRF1 and TRF2 interact directly with BLM and regulate BLM unwinding activity in vitro. Whereas TRF2 stimulates BLM unwinding of telomeric and non-telomeric substrates, TRF1 inhibits BLM unwinding of telomeric substrates only. Finally, TRF2 stimulates BLM unwinding with equimolar concentrations of TRF1, but not when TRF1 is added in molar excess. These data suggest a function for BLM in recombination-mediated telomere lengthening and support a model for the coordinated regulation of BLM activity at telomeres by TRF1 and TRF2.


Brief report: decoding representations: how children with autism understand drawings.
Young typically developing children can reason about abstract depictions if they know the intention of the artist. Children with autism spectrum disorder (ASD), who are notably impaired in social, 'intention monitoring' domains, may have great difficulty in decoding vague representations. In Experiment 1, children with ASD are unable to use another person's eye gaze as a cue for figuring out what an abstract picture represents. In contrast, when the participants themselves are the artists (Experiment 2), children with ASD are equally proficient as controls at identifying their own perceptually identical pictures (e.g. lollipop and balloon) after a delay, based upon what they intended them to be. Results are discussed in terms of intention and understanding of visual representation in autism.


A threonine stabilizes the NiC and NiR catalytic intermediates of [NiFe]-hydrogenase.
The heterodimeric [NiFe] hydrogenase from Desulfovibrio fructosovorans catalyzes the reversible oxidation of H2 into protons and electrons. The catalytic intermediates have been attributed to forms of the active site (NiSI, NiR, and NiC) detected using spectroscopic methods under potentiometric but non-catalytic conditions. Here, we produced variants by replacing the conserved Thr-18 residue in the small subunit with Ser, Val, Gln, Gly, or Asp, and we analyzed the effects of these mutations on the kinetic (H2 oxidation, H2 production, and H/D exchange), spectroscopic (IR, EPR), and structural properties of the enzyme. The mutations disrupt the H-bond network in the crystals and have a strong effect on H2 oxidation and H2 production turnover rates. However, the absence of correlation between activity and rate of H/D exchange in the series of variants suggests that the alcoholic group of Thr-18 is not necessarily a proton relay. Instead, the correlation between H2 oxidation and production activity and the detection of the NiC species in reduced samples confirms that NiC is a catalytic intermediate and suggests that Thr-18 is important to stabilize the local protein structure of the active site ensuring fast NiSI-NiC-NiR interconversions during H2 oxidation/production.


Carriage of methicillin-resistant Staphylococcus aureus, ceftazidime-resistant Gram-negative bacilli, and vancomycin-resistant enterococci before and after intensive care unit admission.
To measure patients' risk for acquiring antibiotic-resistant microorganisms associated with intensive care unit admission. Prospective, observational study. Ten public hospitals including one university medical center. Consecutive patients admitted to ten intensive care units. Serial patient surveillance cultures were screened for vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA), ceftazidime-resistant Gram-negative bacilli (CR-GNB), Acute Physiology and Chronic Health Evaluation II score, and antibiotic and medical device exposures. A total of 1,697 patient admissions in ten intensive care units were enrolled. The overall carriage rate of antibiotic-resistant bacteria at intensive care unit entry was 12.1% for MRSA, 14% for CR-GNB and 4.7% for both. At discharge from the intensive care unit, new carriage of MRSA, CR-GNB, and both was found in 11.1%, 14.2%, and 2.4% of the patients, respectively. The acquisition rates in the individual units correlated highly and positively with proportion of patients with carriage at intensive care unit entry for both MRSA (n = 10, Pearson's r =.89, p < 0.001) and CR-GNB (n = 10, Pearson's r =.92, p < 0.001). By logistic regression, severity of illness (odds ratio, 1.4), length of stay (odds ratio, 1.7), use of penicillins (odds ratio, 1.9), and number of antibiotics (odds ratio, 1.2) and medical devices (odds ratio, 1.2) were independently associated with intensive care unit acquisition of MRSA. In comparison, variables independently associated with intensive care unit acquisition of CR-GNB were Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.5), number of antibiotics (odds ratio, 1.1), and artificial airway (odds ratio, 1.5). These data suggest that hospitalization in the intensive care unit introduces significant risk to patients in terms of transmission of MRSA and/or CR-GNB. This risk seems to be influenced strongly by the proportion of patients with colonization at intensive care unit admission and is associated with severity of illness, length of stay, and exposures to antibiotics and medical devices.


Molecular signatures for Bacillus species: demarcation of the Bacillus subtilis and Bacillus cereus clades in molecular terms and proposal to limit the placement of new species into the genus Bacillus.
The genus Bacillus is a phylogenetically incoherent taxon with members of the group lacking a common evolutionary history. Comprising aerobic and anaerobic spore-forming bacteria, no characteristics are known that can distinguish species of this genus from other similar endospore-forming genera. With the availability of complete genomic data from over 30 different species from this group, we have constructed detailed phylogenetic trees to determine the relationships among Bacillus and other closely related taxa. Additionally, we have performed comparative genomic analysis for the determination of molecular markers, in the form of conserved signature indels (CSIs), to assist in the understanding of relationships among species of the genus Bacillus in molecular terms. Based on the analysis, we report here the identification of 11 and 6 CSIs that clearly differentiate a 'Bacillus subtilis clade' and a 'Bacillus cereus clade', respectively, from all other species of the genus Bacillus. No molecular markers were identified that supported a larger clade within this genus. The subtilis and the cereus clades were also the largest observed monophyletic groupings among species from the genus Bacillus in the phylogenetic trees based on 16S rRNA gene sequences and those based upon concatenated sequences for 20 conserved proteins. Thus, the relationships observed among these groups of species through CSIs are independently well supported by phylogenetic analysis. The molecular markers identified in this study provide a reliable means for the reorganization of the currently polyphyletic genus Bacillus into a more evolutionarily consistent set of groups. It is recommended that the genus Bacillus sensu stricto should comprise only the monophyletic subtilis clade that is demarcated by the identified CSIs, with B. subtilis as its type species. Members of the adjoining cereus clade (referred to as the Cereus clade of bacilli), although they are distinct from the subtilis clade, will also retain the Bacillus genus name as they contain several clinically important species, and their transfer into a new genus could have serious consequences. However, all other species that are currently part of the genus Bacillus and not part of these two clades should be eventually transferred to other genera. We also propose that all novel species of the genus Bacillus must meet minimal requirements, foremost among which is that the branching of the prospective species with the Bacillus sensu stricto clade or the Cereus clade of bacilli should be strongly supported by 16S rRNA gene sequence trees or trees based upon concatenated protein sequences. Additionally, the presence of one or more of the CSIs that are specific for these clades may be used to confirm molecularly the placement of the species into these clades. The identified CSIs, in addition to their usefulness for taxonomic and diagnostic purposes, also provide novel probes for genetic and biochemical studies of these bacteria.


Alcohol misuse among elderly psychiatric patients: a pilot study.
The aim of this pilot study was to ascertain the frequency of alcohol misuse among the elderly (> 65) psychiatric referrals. Consecutive referrals to a suburban elderly psychiatric team were screened for alcohol misuse by using the CAGE questionnaire as a part of psychiatric assessment. Gamma-glutanyl transpeptidase (GGT) was measured in those showing evidence of alcohol misuse. Frequency of alcohol misuse in the elderly was found to be low. Alcohol misuse was associated with raised GGT, depression, being divorced/ widowed and living alone.


Bayesian estimation of gene constraint from an evolutionary model with gene features.
Measures of selective constraint on genes have been used for many applications including clinical interpretation of rare coding variants, disease gene discovery, and studies of genome evolution. However, widely-used metrics are severely underpowered at detecting constraint for the shortest ~25% of genes, potentially causing important pathogenic mutations to be overlooked. We developed a framework combining a population genetics model with machine learning on gene features to enable accurate inference of an interpretable constraint metric, shet. Our estimates outperform existing metrics for prioritizing genes important for cell essentiality, human disease, and other phenotypes, especially for short genes. Our new estimates of selective constraint should have wide utility for characterizing genes relevant to human disease. Finally, our inference framework, GeneBayes, provides a flexible platform that can improve estimation of many gene-level properties, such as rare variant burden or gene expression differences.


Accelerated Epi-On Versus Standard Epi-Off Corneal Collagen Cross-Linking for Progressive Keratoconus in Pediatric Patients.
To evaluate and compare the effectiveness and safety of accelerated transepithelial (A-epi-on) corneal collagen cross-linking (CXL) with standard CXL (epi-off) for children with progressive keratoconus. Prospective, cohort study including 61 eyes of 51 patients younger than 18 years with progressive keratoconus at Oftalmosalud Instituto de Ojos, Lima, Peru. A-epi-on CXL was performed for 36 eyes using 30 minutes of impregnation (0.25% riboflavin, 1.0% phosphate hydroxypropyl methylcellulose, 0.007% benzalkonium chloride) and 5 minutes of irradiation (18 mW/cm). Epi-off CXL was performed for 25 eyes using 30 minutes of impregnation (riboflavin 0.1% solution plus 20% dextran 500) and 30 minutes of irradiation (3 mW/cm). Scheimpflug imaging parameters were evaluated preoperatively and at 6 and 12 months postoperatively. Mean uncorrected visual acuity improvement was 0.12 logarithm of the minimum angle of resolution (logMAR) for both groups (P = 0.09 for A-epi-on and P = 0.16 for Epi-off). Mean improvements in the best-corrected visual acuity were 0.09 logMAR (P = 0.05) and 0.06 logMAR (P = 0.05) at 12 months postoperatively for the A-epi-on group and the epi-off group, respectively. Mean maximum keratometry changes were +0.1 D (P = 0.62) and -0.94 D (P = 0.11) for the A-epi-on group and the epi-off group, respectively, at 12 months postoperatively. There were no significant differences between groups regarding changes in pachymetry and posterior elevation values (P > 0.05). Keratoconus progression was observed in 5.6% and 12% of eyes in the A-epi-on group and the epi-off group, respectively. Accelerated epi-on CXL and standard epi-off CXL are safe and effective for stopping the progression of keratoconus at 12 months postoperatively.


[Diarrhoea and fever in chemotherapy patients due to listeriosis].
We present two patients with colorectal carcinoma who were admitted with fever and diarrhoea during treatment with chemotherapy. Blood cultures taken from both patients revealed an infection with Listeria monocytogenes. A contaminated ice cream was probably the source of infection in one patient. The other patient died of the listeriosis. Patients with diminished cellular immunity are at risk of invasive listeriosis. Listeriosis has a high mortality rate in this group of patients. Intravenous penicillin or ampicillin for 4 to 6 weeks is the first choice of antibiotic treatment. These antibiotics can be combined with an aminoglycoside or trimethoprim-sulfamethoxazole for a synergistic effect. To prevent invasive listeriosis we recommend strict dietary advice to all patients with diminished cellular immunity.


Evaluating Ultra-widefield Imaging Utility in the Detection of Treatment-requiring Peripheral Retinal Tears and Holes.
To determine the utility of Ultra-widefield (UWF) imaging in detecting pathologic peripheral retinal tears and holes. This was a retrospective, observational study. One-hundred and ninety-eight eyes of 198 patients diagnosed with acute posterior vitreous detachment were included. Eyes were divided into two groups: 89 eyes with peripheral retinal holes and tears treated with laser retinopexy (treatment group) and 109 control eyes. Patients underwent UWF imaging and indirect ophthalmoscopy with scleral depression. UWF images from both groups were reviewed by two blinded graders and then compared to funduscopic exam and medical records. UWF imaging identified 60 of the 89 eyes (sensitivity of 67.4%) found to have treatment-requiring peripheral retinal lesions and 107 of the 109 control eyes (specificity of 98.2%).The distribution of misses based on octant location did reach statistical significance (p=0.004). Lesions anterior to the equator were more likely to be missed (21/41 eyes, 51.2%) compared to those located posterior to the equator (4/20 eyes, 25.0%) and at the equator (4/28, 14.3%), p=0.002. The combined discordance rate between graders in the entire cohort was 12.1% (24/198 eyes) yielding an inter-rater agreement of 87.9%. UWF imaging showed a moderate sensitivity and high specificity in detecting treatment requiring retinal tears and holes, with high inter-rater agreement. Given there is only a moderate sensitivity in identifying treatment requiring retinal tears and holes, UWF imaging can assist with clinical exam, but a 360-degree scleral depressed exam should remain the gold standard.


Anticancer effect of Saussurea lappa extract via dual control of apoptosis and autophagy in prostate cancer cells.
To demonstrate the mechanisms of the curative effect of Saussurea lappa ethanol extract (SLE) against prostate cancer, we evaluated the effect of SLE on the induction of apoptosis and autophagy and investigated whether SLE-induced autophagy exerts a pro-survival or pro-apoptotic effect in lymph node carcinoma of the prostate (LNCaP) prostate cancer cells. SLE was prepared using 100% ethanol and added to LNCaP cells for 24 hours. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell apoptosis was evaluated by Tali assay. The expression of apoptosis-related mRNA and proteins was analyzed by quantitative real-time RT-PCR and western blotting. SLE treatment decreased the viability of LNCaP cells and increased Bax expression while suppressing the expression of pro-caspases-8/9/3, PARP, Bid, and Bcl-2, thereby inducing apoptosis in LNCaP cells. Cell proliferation related proteins, including p-Akt, androgen receptor, and prostate-specific antigen, were suppressed by SLE treatment. SLE also induced autophagy in LNCaP cells, and inhibition of autophagy enhanced the apoptosis induced by SLE treatment. These results suggest that SLE exerts anticancer effects through the induction of both cellular apoptosis and autophagy, and apoptotic cell death can be facilitated by blocking autophagy in SLE-treated LNCaP cells. Therefore, SLE might be a potential anticancer agent for the treatment of prostate cancer.


Timing of the occurrence of pulmonary embolism in trauma patients.
To determine how soon after trauma pulmonary embolism (PE) occurs and if there is an association between the duration of this interval and mortality. Retrospective case series. All patients admitted to our trauma service with established PE based on high probability findings on ventilation perfusion scan, positive results on a pulmonary arteriogram, or autopsy from July 1, 1990, to September 30, 1995. Time interval between injury and PE. Level I university trauma center. Of 18,255 trauma patients identified, 63 met our criteria for PE (30 using a pulmonary arteriogram; 26, a ventilation perfusion scan; and 7, autopsy). Four patients (6%) had a documented PE on day 1 following injury. Mortality was not correlated with the interval between injury and PE. Of the 63 patients, 58 (92%) had 1 or more established risk factors for thromboembolism. The ratio of PaO2 to fraction of inspired oxygen was the only factor predictive of mortality (P = .02, logistic regression analysis). Pulmonary embolism occurs in the immediate period following injury. Aggressive workup in patients with signs consistent with PE should be instituted promptly. Trauma patients who have at least 1 risk factor for thromboembolism should receive prophylaxis as soon after injury as possible.


Taxonomic vocabularies in medicine: the intention of usage determines different established structures.
This paper deals with the reasons for distinguishing taxonomic vocabularies for standardizing terminology according to their different dedicated purposes. Different kinds of vocabularies are defined and then characterized using criteria like purposes, semiotic bases, principles for establishing hierarchical relations, mechanisms for guaranteeing reproducibility, and underlying representation formats. Furthermore, the kinds of taxonomic vocabularies worked out so far are named by preferred terms and assigned to proper places within the whole context of medical routine and research. Finally, it is argued that there must be a careful distinction between a conceptual level on one hand and a purpose-dependent non-conceptual level on the other. Unfortunately, both levels are crucially intertwined in existing vocabularies. Efforts on conceptually linking the vocabularies can help to share and re-use information evolving from different sources due to their common conceptual core. However, one must be aware of the effects resulting from special structural features on a non-conceptual level.


Intracellular and interstitial expression of Helicobacter pylori virulence genes in gastric precancerous intestinal metaplasia and adenocarcinoma.
Gastric intestinal metaplasia (IM) and gastric cancer are associated with Helicobacter pylori, but the bacterium often is undetectable in these lesions. To unravel this apparent paradox, IM, H. pylori presence, and the expression of H. pylori virulence genes were quantified concurrently using histologic testing, in situ hybridization, and immunohistochemistry. H. pylori was detected inside metaplastic, dysplastic, and neoplastic epithelial cells, and cagA and babA2 expression was colocalized. Importantly, expression of cagA was significantly higher in patients with IM and adenocarcinoma than in control subjects. The preneoplastic "acidic" MUC2 mucin was detected only in the presence of H. pylori, and MUC2 expression was higher in patients with IM, dysplasia, and cancer. These novel findings are compatible with the hypothesis that all stages of gastric carcinogenesis are fostered by persistent intracellular expression of H. pylori virulence genes, especially cagA inside MUC2-producing precancerous gastric cells and pleomorphic cancer cells.


Mechanisms accelerating muscle atrophy in catabolic diseases.
In summary, muscle protein loss in uremia is related to activation of the ubiquitin-proteasome proteolytic system to degrade muscle proteins. This response invariably includes increased transcription of genes encoding components of this pathway, suggesting that these illnesses stimulate a program of catabolism. Signals that could activate muscle protein degradation by this system in CRF include metabolic acidosis, impaired response to insulin and high circulating levels of cytokines. The activation mechanism also involves glucocorticoids which are necessary but not sufficient to activate protein degradation in muscle.


Maturation of b lymphocytes in rates. III. Two subpopulations of memory B cells in the thoracic duct lymph differ by size, turnover rate, and surface immunoglobulin.
We examined the ability of large and small thoracic duct cells obtained from Lewis rats primed to DNP to restore the adoptive secondary anti-DNP response in irradiated syngeneic hosts given an excess of T helper cells. The large cells were four to five times more active on a per cell basis than were the small cells. However, the large cells constitute only 7 to 8% of the thoracic duct cells and, therefore, make a minor contribution to the restorative activity of the unfractionated cells. Pretreatment of thoracic duct cell donors with high specific activity 3H-TdR for 48 hr before cannulation markedly reduced the memory B cell activity of the large cells, but had little effect on that of small cells. In addition, the activity of the large cells diminished with time after primary immunization, but that of the small cells remained stable. Immunofluorescent staining of the large and small cells for surface IgM and IgG, and subsequent sorting on the fluorescence-activated cell sorter (FA CS), showed that surface IgM was present on large memory B cells, and that IgG was present on small memory B cells. The experimental results suggest that two subpopulations of memory B cells in the thoracic duct lymph differ by size, rate of turnover, persistence after primary immunization, and class of surface IgG.


Breastfeeding experiences of mothers from disadvantaged groups: a review.
Despite the World Health Organization promoting breastfeeding as the optimal feeding method for infants, the breastfeeding initiation rates within these disadvantaged groups' remains low. It is important to identify the factors that prevent these groups from initiating and establishing successful breastfeeding. This review aims to identify the breastfeeding experiences of teenage mothers and mothers from low income groups. Qualitative research papers were identified using electronic and manual searches by following a systematic methodology. Nine relevant articles were critically analysed using a qualitative Critical Appraisal Skills Programme tool. Coding of the nine papers generated six themes. The benefits of breastfeeding known to these mothers were often superseded by the perceived barriers of breastfeeding, while the decision to breastfeed was frequently influenced by their social support network and prior exposure to breastfeeding. Disadvantaged mothers may require extra input and support to overcome any problems associated with breastfeeding. Developing healthcare professionals' capabilities to educate these disadvantaged groups, their social networks and the public about breastfeeding is crucial if it is to become established within our society.


Ontology-based Brucella vaccine literature indexing and systematic analysis of gene-vaccine association network.
Vaccine literature indexing is poorly performed in PubMed due to limited hierarchy of Medical Subject Headings (MeSH) annotation in the vaccine field. Vaccine Ontology (VO) is a community-based biomedical ontology that represents various vaccines and their relations. SciMiner is an in-house literature mining system that supports literature indexing and gene name tagging. We hypothesize that application of VO in SciMiner will aid vaccine literature indexing and mining of vaccine-gene interaction networks. As a test case, we have examined vaccines for Brucella, the causative agent of brucellosis in humans and animals. The VO-based SciMiner (VO-SciMiner) was developed to incorporate a total of 67 Brucella vaccine terms. A set of rules for term expansion of VO terms were learned from training data, consisting of 90 biomedical articles related to Brucella vaccine terms. VO-SciMiner demonstrated high recall (91%) and precision (99%) from testing a separate set of 100 manually selected biomedical articles. VO-SciMiner indexing exhibited superior performance in retrieving Brucella vaccine-related papers over that obtained with MeSH-based PubMed literature search. For example, a VO-SciMiner search of "live attenuated Brucella vaccine" returned 922 hits as of April 20, 2011, while a PubMed search of the same query resulted in only 74 hits. Using the abstracts of 14,947 Brucella-related papers, VO-SciMiner identified 140 Brucella genes associated with Brucella vaccines. These genes included known protective antigens, virulence factors, and genes closely related to Brucella vaccines. These VO-interacting Brucella genes were significantly over-represented in biological functional categories, including metabolite transport and metabolism, replication and repair, cell wall biogenesis, intracellular trafficking and secretion, posttranslational modification, and chaperones. Furthermore, a comprehensive interaction network of Brucella vaccines and genes were identified. The asserted and inferred VO hierarchies provide semantic support for inferring novel knowledge of association of vaccines and genes from the retrieved data. New hypotheses were generated based on this analysis approach. VO-SciMiner can be used to improve the efficiency for PubMed searching in the vaccine domain.


Thoracic and abdominal outgrowths in early pterygotes: a clue to the common ancestor of winged insects?
One of the fundamental questions in insect evolution is the origin of their wings and primary function of ancestral wing precursors. Recent phylogenomic and comparative morphological studies broadly support a terrestrial ancestor of pterygotes, but an aquatic or semiaquatic ancestor cannot be ruled out. Here new features of the branchial system of palaeodictyopteran larvae of several different instars of Katosaxoniapteron brauneri gen. et sp. nov. (Eugereonoidea) from the late Carboniferous collected at Piesberg (Germany) are described, which consist of delicate dorsolateral and lamellate caudal abdominal gills that support an aquatic or at least semiaquatic lifestyle for these insects. Moreover, the similar form and surface microstructures on the lateral abdominal outgrowths and thoracic wing pads indicate that paired serial outgrowths on segments of both tagmata presumably functioned as ancestral type of gills resembling a protopterygote model. This is consistent with the hypothesis that the wing sheaths of later stage damselfly larvae in hypoxic conditions have a respiratory role similar to abdominal tracheal gills. Hence, the primary function and driving force for the evolution of the precursors of wing pads and their abdominal homologues could be respiration.


Detection of Methicillin Resistance and Various Virulence Factors in Staphylococcus aureus Strains Isolated from Nasal Carriers.
Staphylococus aureus can be found as a commensal on skin and nasal flora or it may cause local and invasive infections. S. aureus has a large number of virulence factors. To investigate the methicillin resistance and frequency of various virulence factors in S. aureus nasal isolates. Descriptive study. Nasal samples collected from university students were cultured in media. S. aureus was identified by conventional methods and the Staphyloslide latex test (Becton Dickinson, Sparks, USA). Antibiotic susceptibility tests were conducted, and the methicillin resistance was determined. The mecA, nuc, pvl and staphylococcal toxin genes were examined by polymerase chain reaction (PCR). S. aureus was isolated in 104 of 600 (17.3%) nasal samples. In total, 101 (97.1%) S. aureus isolates were methicillin-sensitive and the remaining 3 (2.9%) were methicillin-resistant. Furthermore, all but five isolates carried at least one staphylococcal enterotoxin gene, with seg being predominant. The tst and eta genes were determined in 29 (27.9%), and 3 (2.9%) isolates, respectively. None of the S. aureus isolates harbored see, etb, and pvl genes. A moderate rate of S. aureus carriage and low frequency of MRSA were detected in healthy students. S. aureus isolates had a high prevalence of staphylococcal enterotoxin genes and the tst gene. In this study, a large number of virulence factors were examined in S. aureus nasal isolates, and the data obtained from this study can be used for monitoring the prevalence of virulence genes in S. aureus strains isolated from nasal carriers.


Patient isolation measures for infants with candida colonization or infection for preventing or reducing transmission of candida in neonatal units.
Candida is one of the most common nosocomial infections in the intensive care setting worldwide and is associated with increased healthcare costs. In neonates, candida infection is associated with high mortality and morbidity. Candida is transmitted by direct and indirect contact. Routine infection control measures that include standard precautions are routinely employed to prevent spread of nosocomial infections. Patient isolation measures, i.e. single room isolation or cohorting, are usually recommended for infections spread by contact. To determine the effect of patient isolation measures (single room isolation and/or cohorting) for infants with candida colonization or infection as an adjunct to routine infection control measures on the transmission of candida to other infants in the neonatal unit. Relevant trials in any language were searched in the following databases in Jan 2007: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2006), MEDLINE (1966 - Jan 2007) and PREMEDLINE, EMBASE (1980 - Jan 2007), CINAHL (1982 - Jan 2007). Proceedings of the Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and the European Society for Pediatric Research (1987 - Jan 2007) were also searched in Jan 2007. Authors or other experts were contacted for more information on relevant published or unpublished trials. Additional searches were also made in the reference lists of relevant journal articles and in the reviewer's personal files. Types of studies: Cluster randomized trials (where clusters may be defined by hospital, ward, or other subunits of the hospital). Neonatal units caring for infants colonized or infected with candida. Types of interventions: A policy of patient isolation measures (single room isolation or cohorting of infants with candida colonization or infection) compared to routine isolation measures. The standard methods of the Cochrane Neonatal Review Group (CNRG) were to be used to identify studies and to assess the methodological quality of eligible trials. The statistical package (RevMan 4.2) provided by the Cochrane Collaboration was to be used. In cluster-randomized trials, if the unit of analysis of the trial was the cluster (not individuals) and analysis took into account the correlation between clusters, the inverse variance method was to be used for meta-analysis. If this was not the case, a narrative synthesis was to be made without meta-analysis. Infection rates and colonization rates were to be expressed as rate ratios for each trial and if appropriate for meta-analysis, the generic inverse variance method in RevMan was to be used. No eligible trials were identified. The review found no evidence to either support or refute the use of patient isolation measures (single room isolation or cohorting) in neonates with candida colonization or infection. Despite the evidence for transmission of candida by direct or indirect contact and evidence of cross-infection by health care workers, no standard policy of patient isolation measures beyond routine infection control measures exists in the neonatal unit. There is an urgent need to research the role of patient isolation measures for preventing transmission of candida in the neonatal unit. Cluster randomized trials involving multiple units or hospitals with randomized allocation of one type of patient isolation measure or the other (i.e. single room isolation or cohorting) with careful consideration for determining an appropriate sample size and analysis would be the most appropriate method to research this intervention.


Regulation of estrogen receptor-alpha gene expression by epidermal growth factor.
The role of epidermal growth factor (EGF) in the regulation of estrogen receptor-alpha (ER-alpha) gene expression in the human breast cancer cell line MCF-7 was investigated. Treatment of cells with 0.4 ng/ml EGF resulted in an approximately 60% decrease in ER-alpha protein concentration by 6 h and the amount of receptor remained suppressed for 24 h. Ligand binding assays demonstrated that the decrease in ER-alpha protein corresponded to a similar decrease (approximately 50%) in estradiol binding sites. Although EGF treatment resulted in a decrease in the number of binding sites, it had no effect on the binding affinity of ER-alpha. The dissociation constant of the estradiol-ER-alpha complex in the presence or absence of EGF was the same (K(d)=2.3x10(-)(10) M in control cells versus K(d)=1.98x10(-)(10) M in EGF-treated cells). The decrease in ER-alpha protein concentration paralleled a decrease in the steady-state amount of ER-alpha mRNA. By 9 h there was an approximately 60% decrease in ER-alpha mRNA. The amount of ER-alpha mRNA remained suppressed for 48 h. Transcription run-on experiments demonstrated that there was a decrease of approximately 70% in ER-alpha gene transcription upon EGF treatment, suggesting that the mechanism by which EGF regulates ER-alpha gene expression is transcriptional. In addition to regulating the amount of ER-alpha, EGF affected the activity of the receptor. At high concentrations, EGF induced progesterone receptor. Estradiol and high concentrations of EGF had an additive effect on progesterone receptor. In contrast to high concentrations, low concentrations of EGF had no effect on progesterone receptor and blocked estradiol induction. The effects of EGF on ER-alpha expression were inhibited by tyrophostins and wortmannin, suggesting that the effects of the growth factor are mediated by the EGF receptor and protein kinase B. When the cells were placed in serum-free medium and then treated with EGF, there was no effect on ER-alpha protein concentration or activity. However, increasing concentrations of serum restored the effects of EGF on ER-alpha, suggesting that an additional serum factor was required for the EGF-mediated effect on the decrease in ER-alpha protein concentration.


New genetic approach to detecting individuals of rare and endangered species.
Many rare and endangered species are difficult to locate, observe, and study. Consequently, many individuals, breeding pairs, and even populations of such species could remain undetected. Genetic markers can potentially be used to detect the existence of undiscovered individuals and populations, and we propose a method to do so that requires 3 conditions. First, sampling of the known population(s) of the target species must be comprehensive. Second, the species must display a reasonable level of philopatry and genetic structuring. Third, individuals must be able to be caught outside of breeding locations (e.g., at courtship or feeding areas, in flight), and the level of recapture must be reasonably high. We applied our method to the Chatham Island Taiko (Pterodroma magentae), one of the world's most endangered seabirds. We sequenced the Taiko mitochondrial cytochrome b gene and both copies of a fragment of the duplicated domain I of the control region. Twenty-one haplotypes were revealed, including 4 (19%) not found in birds at known burrows. These results suggest there are more burrow groups yet to be located. The species is a pelagic gadfly petrel that inhabits land only in the breeding season during which it is nocturnal and nests in burrows. Taiko burrows are situated in dense forest in a remote area of Chatham Island, and are consequently difficult to locate and study. It is important that all Taiko burrows be discovered to enable monitoring and protection of the birds from exotic predators.


Comparison of Wrist- and Hip-Worn Activity Monitors When Meeting Step Guidelines.
Physical activity (PA) guidelines aimed at accumulating 10,000 steps per day have become increasingly common with the advent of wristband PA monitors. However, accumulated steps measured with wristband PA monitors may not be equal to steps measured with validated, hip-worn pedometers. Consequently, evaluating and developing guidelines for step counts using wristband PA monitors for the general population is needed. We compared step counts accumulated with hip-worn pedometers with those accumulated with wrist-worn activity monitors during 1) treadmill exercise, 2) treadmill walking, and 3) activities of daily living (ADL) to determine their accuracy in meeting step count guidelines (ie, 10,000 steps/d). Eighty-six adults (aged 18-65 y; body mass index, 19-45 kg/m2) completed 30 minutes of treadmill exercise while simultaneously using a hip-worn pedometer and wrist-worn PA monitor. Remaining steps needed to reach 10,000 steps (ie, 10,000 steps minus the number of pedometer steps recorded from treadmill exercise = remainder) were completed via treadmill walking or ADL. Steps were recorded for both devices after treadmill exercise, treadmill walking, and ADL for both devices. Fewer steps were accumulated via wrist-worn PA monitors than via hip-worn pedometers during treadmill exercise (3,552 [SD, 63] steps vs 3,790 [SD, 55] steps, P < .01) and treadmill walking (5,877 [SD, 83] steps vs 6,243 [SD, 49] steps, P < .01). More steps were accumulated via wrist-worn PA monitors than hip-worn pedometers during ADL (7,695 [SD, 207] steps vs 6,309 [SD, 57] steps, P < .01). Consequently, total steps were significantly higher for wristband PA monitors than hip-worn pedometers (11,247 [SD, 210] steps vs 10,099 [SD, 39] steps; P < .01). The widely used 10,000-step recommendation may not be accurate for all users of all activity monitors, given the discrepancy in daily step count among wrist-worn and hip-worn devices. Having a more accurate indication of number of steps taken per day based on the device used could have positive effects on health.


Database-Driven Spatially Resolved Lipidomics Highlights Heterogeneous Metabolic Alterations in Type 2 Diabetic Mice.
Spatially resolved lipidomics is pivotal for detecting and interpreting lipidomes within spatial contexts using the mass spectrometry imaging (MSI) technique. However, comprehensive and efficient lipid identification in MSI remains challenging. Herein, we introduce a high-coverage, database-driven approach combined with air-flow-assisted desorption electrospray ionization (AFADESI)-MSI to generate spatial lipid profiles across whole-body mice. Using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), we identified 2868 unique lipids in the serum and various organs of mice. Subsequently, we systematically evaluated the distinct ionization properties of the lipids between LC-MS and MSI and created a detailed MSI database containing 14 123 ions. This method enabled the visualization of aberrant fatty acid and phospholipid metabolism across organs in a diabetic mouse model. As a powerful extension incorporated into the MSIannotator tool, our strategy facilitates the rapid and accurate annotation of lipids, providing new research avenues for probing spatially resolved heterogeneous metabolic changes in response to diseases.


[Glucagon binding by isolated chick hepatocytes].
Studies have been made on the binding of 125I-glucagon by isolated chick hepatocytes. It was shown that pH and temperature dependence of the binding does not differ from that in rat hepatocytes. Optimum binding was observed at pH 7.6, the rate of binding being higher at 37 degrees C as compared to that at 20 degrees C, although the binding capacity increased with the decrease in the temperature. Unlabeled glucagon was able to compete with 125I-glucagon at the binding sites. Scatchard plot was found to be curvilinear revealing two classes of the binding sites with Kd values 10(-9) and 10(-7) M at temperatures 20 and 37 degrees C correspondingly. Earlier studies revealed in rats the binding sites of a sole class with Kd value 10(-9) M. Preincubation of cells with native glucagon results in changes of labeled glucagon binding, the effect being proportional to the concentration of native glucagon. Preincubation effect was observed at 37 degrees C, being absent at 20 degrees C; the effect was due to the decrease in the number of both high and low affinity binding sites. The presence of down-regulation of glucagon receptors in chick hepatocytes is suggested.


Increased hepatic expression of nitric oxide synthase type II in cirrhotic rats.
To determine the role and effect of nitric oxide synthase type II (NOSII) in cirrhotic rats. Expression of NOSII mRNA was detected by real time RT-PCR. The activity of nitric oxide synthase and serum levels of NO, systemic and portal hemodynamics and degrees of cirrhosis were measured with high sensitive methods. Chinese traditional medicine tetrandrine was used to treat cirrhotic rats and to evaluate the function of NO. Double-blind method was applied during the experiment. The concentration of NO and the activity of NOS were increased markedly at all stages of cirrhosis, and iNOSmRNA was greatly expressed. Meanwhile the portal-venous-pressure (PVP), and portal-venous-flow (PVF) were significantly increased. NO, NOS and iNOSmRNA were positively correlated to the quantity of hepatic fibrosis. Tetrandrine significantly inhibited NO production and the expression of iNOSmRNA. Increased hepatic expression of NOSII is one of the important causes of hepatic cirrhosis and portal hypertension.


Evidence for a posttranscriptional role of a TFIIICalpha-like protein in Chironomus tentans.
We have cloned and sequenced a cDNA that encodes for a nuclear protein of 238 kDa in the dipteran Chironomus tentans. This protein, that we call p2D10, is structurally similar to the alpha subunit of the general transcription factor TFIIIC. Using immunoelectron microscopy we have shown that a fraction of p2D10 is located at sites of transcription, which is consistent with a possible role of this protein in transcription initiation. We have also found that a large fraction of p2D10 is located in the nucleoplasm and in the nuclear pore complexes. Using gel filtration chromatography and coimmunoprecipitation methods, we have identified and characterized two p2D10-containing complexes that differ in molecular mass and composition. The heavy p2D10-containing complex contains at least one other component of the TFIIIC complex, TFIIIC-epsilon. Based on its molecular mass and composition, the heavy p2D10-containing complex may be the Pol III holoenzyme. The light p2D10-containing complex contains RNA together with at least two proteins that are thought to be involved in mRNA trafficking, RAE1 and hrp65. The observations reported here suggest that this new TFIIIC-alpha-like protein is involved in posttranscriptional steps of premRNA metabolism in Chironomus tentans.


Characterizing the Organohalogen Iceberg: Extractable, Multihalogen Mass Balance Determination in Municipal Wastewater Treatment Plant Sludge.
The large number and diversity of organohalogen compounds (OHCs) occurring in the environment poses a grand challenge to analytical chemists. Since no single targeted method can identify and quantify all OHCs, the size of the OHC "iceberg" may be underestimated. We sought to address this problem in municipal wastewater treatment plant (WWTP) sludge by quantifying the unidentified fraction of the OHC iceberg using targeted analyses of major OHCs together with measurements of total and extractable (organo)halogen (TX and EOX, respectively; where X = F, Cl, or Br). In addition to extensive method validation via spike/recovery and combustion efficiency experiments, TX and/or EOX were determined in reference materials (BCR-461 and NIST SRMs 2585 and 2781) for the first time. Application of the method to WWTP sludge revealed that chlorinated paraffins (CPs) accounted for most (∼92%) of the EOCl, while brominated flame retardants and per- and polyfluoroalkyl substances (PFAS) accounted for only 54% of the EOBr and 2% of the EOF, respectively. Moreover, unidentified EOF in nonpolar CP extracts points to the existence of organofluorine(s) with physical-chemical properties unlike those of target PFAS. This study represents the first multihalogen mass balance in WWTP sludge and offers a novel approach to prioritization of sample extracts for follow-up investigation.


Adenylate cyclase regulation in intact cultured myocardial cells.
To examine the coupling of cardiac cell-surface beta-adrenergic receptors to adenylate cyclase activation and contractile response, we studied this receptor-effector response system in monolayers of spontaneously contracting chick embryo ventricular cells under physiological conditions. The hydrophilic ligand 3H-CGP12177 identified uniformly high-agonist affinity beta-adrenergic receptors (isoproterenol KD = 15 +/- 9 nM). Isoproterenol-stimulated cyclic AMP (cAMP) accumulation with 50% effective concentration at (EC50) = 12.1 nM and augmented contractile response with EC50 = 6 nM under identical conditions. One micromolar isoproterenol induced receptor loss from the cell surface with t1/2 = 13.2 min; under identical conditions cAMP content declined with t1/2 = 13.5 min and contractile response with t1/2 = 20.7 min. After agonist removal cAMP response recovered with t1/2 = 15.7 min and receptors with t1/2 = 24.7 min. Sixty minutes after agonist removal there was recovery of 52% of maximal cAMP responsiveness and 82% of the initial number of receptors; receptor occupancy was associated with 78% of initial contractile response. Agonist affinity for cell-surface receptors was changed only modestly by agonist exposure. We conclude that for this system there is relatively close coupling between high-affinity receptors, adenylate cyclase stimulation, and contractile response.


The Adam family metalloprotease Kuzbanian regulates the cleavage of the roundabout receptor to control axon repulsion at the midline.
Slits and their Roundabout (Robo) receptors mediate repulsive axon guidance at the Drosophila ventral midline and in the vertebrate spinal cord. Slit is cleaved to produce fragments with distinct signaling properties. In a screen for genes involved in Slit-Robo repulsion, we have identified the Adam family metalloprotease Kuzbanian (Kuz). Kuz does not regulate midline repulsion through cleavage of Slit, nor is Slit cleavage essential for repulsion. Instead, Kuz acts in neurons to regulate repulsion and Kuz can cleave the Robo extracellular domain in Drosophila cells. Genetic rescue experiments using an uncleavable form of Robo show that this receptor does not maintain normal repellent activity. Finally, Kuz activity is required for Robo to recruit its downstream signaling partner, Son of sevenless (Sos). These observations support the model that Kuz-directed cleavage is important for Robo receptor activation.


The Emerging Role of Microbial Biofilm in Lyme Neuroborreliosis.
Lyme borreliosis (LB) is the most common tick-borne disease caused by the spirochete Borrelia burgdorferi in North America and Borrelia afzelii or Borrelia garinii in Europe and Asia, respectively. The infection affects multiple organ systems, including the skin, joints, and the nervous system. Lyme neuroborreliosis (LNB) is the most dangerous manifestation of Lyme disease, occurring in 10-15% of infected individuals. During the course of the infection, bacteria migrate through the host tissues altering the coagulation and fibrinolysis pathways and the immune response, reaching the central nervous system (CNS) within 2 weeks after the bite of an infected tick. The early treatment with oral antimicrobials is effective in the majority of patients with LNB. Nevertheless, persistent forms of LNB are relatively common, despite targeted antibiotic therapy. It has been observed that the antibiotic resistance and the reoccurrence of Lyme disease are associated with biofilm-like aggregates in B. burgdorferi, B. afzelii, and B. garinii, both in vitro and in vivo, allowing Borrelia spp. to resist to adverse environmental conditions. Indeed, the increased tolerance to antibiotics described in the persisting forms of Borrelia spp., is strongly reminiscent of biofilm growing bacteria, suggesting a possible role of biofilm aggregates in the development of the different manifestations of Lyme disease including LNB.


Concussion Management for Children Has Changed: New Pediatric Protocols Using the Latest Evidence.
Return to activity (RTA) and return to school (RTS) are important issues in pediatric concussion management. This study aims to update CanChild's 2015 RTA and RTS protocols, on the basis of empirical data and feedback collected from our recently completed prospective cohort study, focusing on concussed children and their caregivers; systematic review of evidence published since 2015; and consultation with concussion management experts. The new protocols highlight differences from the earlier versions, mainly, (1) symptom strata to allow quicker progression for those who recover most quickly; (2) a shortened rest period (24-48 hours) accompanied by symptom-guided activity; (3) the recommendation that children progress through the stages before they are symptom free, if symptoms have decreased and do not worsen with activity; (4) specific activity suggestions at each stage of the RTA protocol; (5) recommendations for the amount of time to spend per stage; and (6) integration of RTS and RTA.


Continuity of Care, Follow-Up Care, and Outcomes among Breast Cancer Survivors.
This retrospective cohort study examined the effects of care continuity on the utilization of follow-up services and outcome of breast cancer patients (stages I-III) in the post-treatment phase of care. Propensity score matching and generalized estimation equations were used in the analysis of data obtained from national longitudinal databases. The continuity of care index (COCI) was calculated separately for primary care physicians (PCP) and oncologists. Our results revealed that breast cancer survivors with a higher oncology COCI were more likely than those with a lower oncology COCI to use mammography or breast ultrasound during the follow-up period (OR = 1.26, 95% CI: 1.19-1.32; OR = 1.12, 95% CI: 1.06-1.18; respectively). In terms of health outcomes, a higher oncology COCI was associated with a lower likelihood of hospitalization (OR = 0.78, 95% CI: 0.71-0.85) and emergency department use (OR = 0.88, 95% CI: 0.82-0.95). A higher PCP COCI was also associated with a lower likelihood of hospitalization (OR = 0.77, 95% CI: 0.70-0.85) and emergency department use (OR = 0.75, 95% CI: 0.68-0.82). Overall, this study determined that ambulatory care continuity is positively associated with the likelihood of using recommended follow-up care services and negatively associated with adverse health events among breast cancer survivors.


The immune system in children with malnutrition--a systematic review.
Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed. To review the scientific literature about immune function in children with malnutrition. A systematic literature search was done in PubMed, and additional articles identified in reference lists and by correspondence with experts in the field. The inclusion criteria were studies investigating immune parameters in children aged 1-60 months, in relation to malnutrition, defined as wasting, underweight, stunting, or oedematous malnutrition. The literature search yielded 3402 articles, of which 245 met the inclusion criteria. Most were published between 1970 and 1990, and only 33 after 2003. Malnutrition is associated with impaired gut-barrier function, reduced exocrine secretion of protective substances, and low levels of plasma complement. Lymphatic tissue, particularly the thymus, undergoes atrophy, and delayed-type hypersensitivity responses are reduced. Levels of antibodies produced after vaccination are reduced in severely malnourished children, but intact in moderate malnutrition. Cytokine patterns are skewed towards a Th2-response. Other immune parameters seem intact or elevated: leukocyte and lymphocyte counts are unaffected, and levels of immunoglobulins, particularly immunoglobulin A, are high. The acute phase response appears intact, and sometimes present in the absence of clinical infection. Limitations to the studies include their observational and often cross-sectional design and frequent confounding by infections in the children studied. The immunological alterations associated with malnutrition in children may contribute to increased mortality. However, the underlying mechanisms are still inadequately understood, as well as why different types of malnutrition are associated with different immunological alterations. Better designed prospective studies are needed, based on current understanding of immunology and with state-of-the-art methods.


The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP.
A recently described atypical myeloproliferative disorder is invariably associated with reciprocal translocations involving 8p11-12. The most common rearrangement is a t(8;13)(p11;q11-12). Here we determine that this translocation results in the fusion of the fibroblast growth factor receptor 1 gene (FGFR1), a member of the receptor tyrosine kinase family at 8p11, to a novel gene at 13q11-12 designated RAMP . The predicted RAMP protein exhibits strong homology to the product of a recently cloned candidate gene for X-linked mental retardation, DXS6673E . We also provide the first report of a novel, putative metal-binding motif, present as five tandem repeats in both RAMP and DXS6673E. RT-PCR detected only one of the two possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of RAMP become joined to the tyrosine kinase domain of FGFR1. Receptor tyrosine kinases are not commonly involved in the formation of tumour-specific fusion proteins. However, the previous reports of involvement of receptor tyrosine kinases in fusion proteins in non-Hodgkin's lymphoma, chronic myelomonocytic leukaemia and papillary thyroid carcinoma described similar rearrangements. By analogy with these, we propose that the RAMP-FGFR1 fusion product will contribute to progression of this myeloproliferative disorder by constitutive activation of tyrosine kinase function.


The impact of thunderstorm asthma on emergency department attendances across London during July 2013.
This study illustrates the potential of using emergency department attendance data, routinely accessed as part of a national syndromic surveillance system, to monitor the impact of thunderstorm asthma. The Emergency Department Syndromic Surveillance System (EDSSS) routinely monitors anonymised attendance data on a daily basis across a sentinel network of 35 emergency departments. Attendance data for asthma, wheeze and difficulty breathing are analysed on a daily basis. A statistically significant spike in asthma attendances in two EDSSS emergency departments in London was detected on 23 July 2013, coinciding with a series of large violent thunderstorms across southern England. There was also an increase in the reported severity of these attendances. This preliminary report illustrates the potential of the EDSSS to monitor the impact of thunderstorms on emergency department asthma attendances. Further work will focus on how this system can be used to quantify the impact on emergency departments, thus potentially improving resource planning and also adding to the thunderstorm asthma evidence-base.


Interaction of perceptual grouping and crossmodal temporal capture in tactile apparent-motion.
Previous studies have shown that in tasks requiring participants to report the direction of apparent motion, task-irrelevant mono-beeps can "capture" visual motion perception when the beeps occur temporally close to the visual stimuli. However, the contributions of the relative timing of multimodal events and the event structure, modulating uni- and/or crossmodal perceptual grouping, remain unclear. To examine this question and extend the investigation to the tactile modality, the current experiments presented tactile two-tap apparent-motion streams, with an SOA of 400 ms between successive, left-/right-hand middle-finger taps, accompanied by task-irrelevant, non-spatial auditory stimuli. The streams were shown for 90 seconds, and participants' task was to continuously report the perceived (left- or rightward) direction of tactile motion. In Experiment 1, each tactile stimulus was paired with an auditory beep, though odd-numbered taps were paired with an asynchronous beep, with audiotactile SOAs ranging from -75 ms to 75 ms. Perceived direction of tactile motion varied systematically with audiotactile SOA, indicative of a temporal-capture effect. In Experiment 2, two audiotactile SOAs--one short (75 ms), one long (325 ms)--were compared. The long-SOA condition preserved the crossmodal event structure (so the temporal-capture dynamics should have been similar to that in Experiment 1), but both beeps now occurred temporally close to the taps on one side (even-numbered taps). The two SOAs were found to produce opposite modulations of apparent motion, indicative of an influence of crossmodal grouping. In Experiment 3, only odd-numbered, but not even-numbered, taps were paired with auditory beeps. This abolished the temporal-capture effect and, instead, a dominant percept of apparent motion from the audiotactile side to the tactile-only side was observed independently of the SOA variation. These findings suggest that asymmetric crossmodal grouping leads to an attentional modulation of apparent motion, which inhibits crossmodal temporal-capture effects.


Pyruvate incubation enhances glycogen stores and sustains neuronal function during subsequent glucose deprivation.
The use of energy substrates, such as lactate and pyruvate, has been shown to improve synaptic function when administered during glucose deprivation. In the present study, we investigated whether prolonged incubation with monocarboxylate (pyruvate or lactate) prior rather than during glucose deprivation can also sustain synaptic and metabolic function. Pyruvate pre-incubation(3-4h) significantly prolonged (>25 min) the tolerance of rat hippocampal slices to delayed glucose deprivation compared to control and lactate pre-incubated slices, as revealed by field excitatory post synaptic potentials (fEPSPs); pre-incubation with pyruvate also reduced the marked decrease in NAD(P)H fluorescence resulting from glucose deprivation. Moreover, pyruvate exposure led to the enhancement of glycogen stores with time, compared to glucose alone (12 μmol/g tissue at 4h vs. 3.5 μmol/g tissue). Prolonged resistance to glucose deprivation following exogenous pyruvate incubation was prevented by glycogenolysis inhibitors, suggesting that enhanced glycogen mediates the delay in synaptic activity failure. The application of an adenosine A1 receptor antagonist enhanced glycogen utilization and prolonged the time to synaptic failure, further confirming this hypothesis of the importance of glycogen. Moreover, tissue levels of ATP were also significantly maintained during glucose deprivation in pyruvate pretreated slices compared to control and lactate. In summary, these experiments indicate that pyruvate exposure prior to glucose deprivation significantly increased the energy buffering capacity of hippocampal slices, particularly by enhancing internal glycogen stores, delaying synaptic failure during glucose deprivation by maintaining ATP levels, and minimizing the decrease in the levels of NAD(P)H.


Rosuvastatin can block pro-inflammatory actions of transgenic human C-reactive protein without reducing its circulating levels.
Statins have antiinflammatory effects and are known to decrease risk of cardiovascular events and to reduce serum levels of C-reactive protein (CRP), a widely studied biomarker and potential mediator of inflammation and heart disease. However, it is unclear whether statins can block pro-inflammatory effects of human CRP independent of their ability to reduce serum levels of human CRP. Here, we investigated whether rosuvastatin could block pro-inflammatory effects of human CRP without reducing circulating levels of human CRP. We studied the antiinflammatory effects of rosuvastatin in spontaneously hypertensive rats (SHR) transgenically expressing human CRP (CRP-transgenic SHR) and in nontransgenic SHR lacking human CRP (nontransgenic SHR). The CRP-transgenic SHR is characterized by increased serum levels of human CRP and inflammation. In the CRP-transgenic strain, we found that rosuvastatin treatment decreased circulating levels of inflammatory response markers IL6 and TNFα without decreasing circulating levels of human CRP. In contrast, in the nontransgenic strain lacking human CRP, rosuvastatin treatment had little or no effect on IL6 and TNFα levels. Rosuvastatin also reduced cardiac inflammation and oxidative tissue damage, reduced epididymal fat mass, and improved adipose tissue lipolysis much more in the CRP-transgenic strain than in the nontransgenic strain. Rosuvastatin can protect against pro-inflammatory effects of human CRP in a manner that is not dependent on achieving a reduction in circulating levels of human CRP.


Cyclic AMP-dependent osmoregulation of crp gene expression in Escherichia coli.
We have found that the cyclic AMP (cAMP) receptor protein (CRP)-cAMP regulatory complex in Escherichia coli is subject to osmoregulation at the level of crp gene expression. This osmoregulation was lost in a cya mutant strain but could be restored by external addition of cAMP, suggesting that the intracellular level of cAMP is a key factor in the osmoregulation of CRP. The ability of the cell to maintain optimal CRP activity was essential for the growth and survival of the bacteria under low-osmolarity conditions as shown by studies with different crp mutant alleles. A suppressor mutant with a novel amino acid substitution (L124R) in CRP showed restored growth at low osmolarity. CRP(L124R) was not activated by cAMP and was shown to be dominant negative over the wild type. Our findings suggest that the fine-tuning of the CRP activity may be critical for bacterial viability and adaptability to changing osmotic conditions.


PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice.
The strategies to protect against the disrupted blood-brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPARα agonist) or rosiglitazone (PPARγ agonist). In contrast, exposure to GW9662 (PPARγ antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1.


A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion.
Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.


Waking self-hypnosis efficacy in cognitive-behavioral treatment for pathological gambling: an effectiveness clinical assay.
Cognitive-behavioral therapy for pathological gambling has a long-term success rate of more than 50%. This study evaluated the effect of self-hypnosis in cognitive-behavioral treatment of pathological gamblers. Forty-nine participants were assigned to 2 groups. Both groups received a cognitive-behavioral protocol, and Group 1, the no-hypnosis group, received an 11-session intervention and Group 2, the hypnosis group, received 7 sessions that included self-hypnosis. Both groups were equal in gambling chronicity, frequency, intensity, change motivation, and problems derived from gambling. All participants reported significant improvement in gambling behavior and consequences at both treatment end and 6-month follow-up. Data show no differences between the interventions in abstinence, therapeutic compliance, fulfillment, and satisfaction. Results suggest that self-hypnosis reinforces treatment and can be a supportive technique for future brief interventions.


Free radicals hasten head and neck cancer risk: A study of total oxidant, total antioxidant, DNA damage, and histological grade.
Free radicals such as reactive oxygen species (ROS), which induce oxidative stress, are the main contributors to head and neck carcinogenesis (HNC). The present study was conducted with the aim to assess the oxidant/antioxidant status and DNA damage analysis in head and neck cancer/control patients. This prospective study was conducted on 60 patients with biopsy-proven HNC and 17 patients of head and neck disease (HND). The total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were determined by novel automatic colorimetric methods from tissue homogenate. DNA damage analysis was determined by single cell gel electrophoresis (SCGE). The mean age of the study cohort was 46.65 ± 14.84 years for HNC patients, while it was 49.41 ± 13.00 years for HND patients. There were no significant differences found between the two groups with respect to demographic presentation except tobacco addiction. The association between oxidative stress parameters and DNA damage analysis with study group revealed the following. (A) DNA damage - tissue homogenate TOS and OSI were significantly higher in HNC subjects than in HND (16.06 ± 1.78 AU vs 7.86 ± 5.97 AU, P < 0.001; 53.00 ± 40.61 vs 19.67 ± 21.90, P < 0.01; 7.221 ± 5.80 vs 2.40 ± 2.54, P < 0.01, respectively), while TAS was significantly decreased. (B) Aggressive histological features were identified, more commonly with higher TOS and lower TAS [probability (P) = 0.002, relative risk (RR) = 11.838, 95% confidence interval CI = 2.514-55.730 and P = 0.043, RR = 0.271, 95% CI = 0.077-0.960, respectively]. The increase in free radicals may be the event that led to the reduction of antioxidant status in HNC, thus explaining the oxidative damage of DNA and the severity of disease. Increased OSI represents a general mechanism in its pathogenesis.


A surface science approach to ultrafast electron transfer and solvation dynamics at interfaces.
Excess electrons in polar media, such as water or ice, are screened by reorientation of the surrounding molecular dipoles. This process of electron solvation is of vital importance for various fields of physical chemistry and biology as, for instance, in electrochemistry or photosynthesis. Generation of such excess electrons in bulk water involves either photoionization of solvent molecules or doping with e.g. alkali atoms, involving possibly perturbing interactions of the system with the parent-cation. Such effects are avoided when using a surface science approach to electron solvation: in the case of polar adsorbate layers on metal surfaces, the substrate acts as an electron source from where photoexcited carriers are injected into the adlayer. Besides the investigation of electron solvation at such interfaces, this approach allows for the investigation of heterogeneous electron transfer, as the excited solvated electron population continuously decays back to the metal substrate. In this manner, electron transfer and solvation processes are intimately connected at any polar adsorbate-metal interface. In this tutorial review, we discuss recent experiments on the ultrafast dynamics of photoinduced electron transfer and solvation processes at amorphous ice-metal interfaces. Femtosecond time-resolved two-photon photoelectron spectroscopy is employed as a direct probe of the electron dynamics, which enables the analysis of all elementary processes: the charge injection across the interface, the subsequent electron localization and solvation, and the dynamics of electron transfer back to the substrate. Using surface science techniques to grow and characterize various well-defined ice structures, we gain detailed insight into the correlation between adsorbate structure and electron solvation dynamics, the location (bulk versus surface) of the solvation site, and the role of the electronic structure of the underlying metal substrate on the electron transfer rate.


Faecal Microbiota Composition Varies between Patients with Breast Cancer and Healthy Women: A Comparative Case-Control Study.
The intestinal microbiota plays an essential role in many diseases, such as obesity, irritable bowel disease (IBD), and cancer. This study aimed to characterize the faecal microbiota from early-stage breast cancer (BC) patients and healthy controls. Faeces from newly diagnosed breast cancer patients, mainly for an invasive carcinoma of no specific type (HR+ and HER2-), before any therapeutic treatment and healthy controls were collected for metabarcoding analyses. We show that the Shannon index, used as an index of diversity, was statistically lower in the BC group compared to that of controls. This work highlights a reduction of microbial diversity, a relative enrichment in Firmicutes, as well as a depletion in Bacteroidetes in patients diagnosed with early BC compared to those of healthy women. A tendency towards a decreased relative abundance of Odoribacter sp., Butyricimonas sp., and Coprococcus sp. was observed. This preliminary study suggests that breast cancer patients may differ from healthy subjects in their intestinal bacterial composition.


Risk factors for cognitive impairment in amyotrophic lateral sclerosis: a systematic review and meta-analysis.
Cognitive impairment is a common, far-reaching but imperceptible manifestation in patients with amyotrophic lateral sclerosis (ALS). We aimed to identify the risk factors for cognitive impairment in ALS. We searched PubMed and EMBASE for cross-sectional, case-control and cohort studies that reported predictors of cognitive impairment in ALS. The obtained data were meta-analysed to generate overall ORs and 95% CIs. Twenty-seven eligible articles reporting on 6799 individuals were included out of 20 501 records. Nine predictors were identified: C9orf72 (OR 3.62, 95% CI 1.76 to 7.45), dysarthria (OR 2.25, 95% CI 1.20 to 4.22), family history of ALS (OR 1.76, 95% CI 1.18 to 2.61), predominant upper motor neuron (PUMN) phenotype (OR 1.73, 95% CI 1.09 to 2.73) and bulbar onset (OR 1.54, 95% CI 1.28 to 1.87) increased risk factors for cognitive impairment in ALS. ALS Functional Rating Scale-Revised scores, sex, age or education level were not significantly associated with cognitive impairment in ALS. In addition, C9orf72 (OR=5.94) and bulbar onset (OR=2.08) were strong predictors of ALS-frontotemporal dementia. Female sex conferred more susceptibility to executive cognitive impairment than male sex (OR=1.82). Patients with C9orf72 repeat expansion, dysarthria, family history of ALS, PUMN phenotype and bulbar onset had a high risk for cognitive impairment in ALS. These associations may contribute to understanding the heterogeneity of ALS. CRD42020201085.


[Kidney cancer (modern concepts of its histogenesis, nomenclature and classification)].
Using their own and literature data the authors recommend that malignant epithelial renal tumors be termed as "renal carcinoma" or "renal cell carcinoma". The term "hypernephroid carcinoma" which is of only historical importance may be used as a synonym of clear cell renal carcinoma. Designation of all forms of renal carcinoma by the general term "renal adenocarcinoma" does not reflect all the diversity of structure of malignant epithelial renal tumors. This term may be used only in those cases where the "glandular" structure of the tumor is adequately evident. Four main forms of renal carcinoma may be distinguished according to the predominant morphological characteristics: clear-cell, granular-cell spindle-cell (sarcoma-like), and glandular (adenocarcinoma proper). According to the authors' data, 41% of renal carcinomas are represented by mixed forms.


Hidden survival heterogeneity of three Common eider populations in response to climate fluctuations.
Understanding how individuals and populations respond to fluctuations in climatic conditions is critical to explain and anticipate changes in ecological systems. Most such studies focus on climate impacts on single populations without considering inter- and intra-population heterogeneity. However, comparing geographically dispersed populations limits the risk of faulty generalizations and helps to improve ecological and demographic models. We aimed to determine whether differences in migration tactics among and within populations would induce inter- or intra-population heterogeneity in survival in relation to winter climate fluctuations. Our study species was the Common eider (Somateria mollissima), a marine duck with a circumpolar distribution, which is strongly affected by climatic conditions during several phases of its annual cycle. Capture-mark-recapture data were collected in two arctic (northern Canada and Svalbard) and one subarctic (northern Norway) population over a period of 18, 15, and 29 years respectively. These three populations have different migration tactics and experience different winter climatic conditions. Using multi-event and mixture modelling, we assessed the association between adult female eider survival and winter conditions as measured by the North Atlantic Oscillation (NAO) index. We found that winter weather conditions affected the survival of female eiders from each of these three populations. However, different mechanisms seemed to be involved. Survival of the two migrating arctic populations was impacted directly by changes in the NAO, whereas the subarctic resident population was affected by the NAO with time lags of 2-3 years. Moreover, we found evidence for intra-population heterogeneity in the survival response to the winter NAO in the Canadian eider population, where individuals migrate to distinct wintering areas. Our results illustrate how individuals and populations of the same species can vary in their responses to climate variation. We suspect that the found variation in the survival response of birds to winter conditions is partly explained by differences in migration tactic. Detecting and accounting for inter- and intra-population heterogeneity will improve our predictions concerning the response of wildlife to global changes.


Inefficient stimulus processing at encoding affects formation of high-order general representation: A study on cross-modal word-stem completion task.
Priming is an implicit memory effect in which previous exposure to one stimulus influences the response to another stimulus. The main characteristic of priming is that it occurs without awareness. Priming takes place also when the physical attributes of previously studied and test stimuli do not match; in fact, it greatly refers to a general stimulus representation activated at encoding independently of the sensory modality engaged. Our aim was to evaluate whether, in a cross-modal word-stem completion task, negative priming scores could depend on inefficient word processing at study and therefore on an altered stimulus representation. Words were presented in the auditory modality, and word-stems to be completed in the visual modality. At study, we recorded auditory ERPs, and compared the P300 (attention/memory) and N400 (meaning processing) of individuals with positive and negative priming. Besides classical averaging-based ERPs analysis, we used an ICA-based method (ErpICASSO) to separate the potentials related to different processes contributing to ERPs. Classical analysis yielded significant difference between the two waves across the whole scalp. ErpICASSO allowed separating the novelty-related P3a and the top-down control-related P3b sub-components of P300. Specifically, in the component C3, the positive deflection identifiable as P3b, was significantly greater in the positive than in the negative priming group, while the late negative deflection corresponding to the parietal N400, was reduced in the positive priming group. In conclusion, inadequacy of specific processes at encoding, such as attention and/or meaning retrieval, could generate weak semantic representations, making words less accessible in subsequent implicit retrieval.