Relationship between invasion of the periodontium by periodontal pathogens and periodontal disease: a systematic review.
Bacterial invasion of the periodontal tissues has been suggested as a relevant step in the etiopathogenesis of periodontal disease. However, its exact importance remains to be defined. The present systematic review assessed the scientific evidence concerning the relationship between the quality or quantity of periodontal microbiota in periodontal tissues and development of periodontal disease. The databases Medline-PubMed, Cochrane-CENTRAL, ISI Web of Knowledge and SCOPUS were searched, up to January 2014. Studies that reported evaluation of periodontal pathogens invasion on human tissues were selected. The screening of 440 title/abstracts elected 26 papers for full-text reading. Twenty three papers were subsequently excluded because of insufficient data or a study protocol not related to the objectives of this systematic review. All included studies were case-control studies that evaluated intracellular or adherent bacteria to epithelial cells from periodontal pockets versus healthy sulci. Study protocols presented heterogeneity regarding case and control definitions and methodological approaches for microbial identification. No consistent significant differences were found related to the presence/absence or proportion of specific periopathogens across the studies, as only one study found statistically significant differences regarding the presence of A. actinomycetemcomitans (p = 0.043), T. forsythia (P < 0.001), P. intermedia (P < 0.001), C. ochracea (P < 0.001) and C. rectus (P = 0.003) in epithelial cells from periodontal pockets vs. healthy sulci. All studies reported a larger unspecific bacterial load in or on the epithelial cells taken from a diseased site compared to a healthy sulcus. The current available data is of low to moderate quality and inconsistent mainly due to study design, poor reporting and methodological diversity. As so, there is insufficient evidence to support or exclude the invasion by periodontal pathogens as a key step in the etiopathogenesis of periodontal disease. Further research is needed.


Grunt variation in the oyster toadfish Opsanus tau: effect of size and sex.
As in insects, frogs and birds, vocal activity in fishes tends to be more developed in males than in females, and sonic swimbladder muscles may be sexually dimorphic, i.e., either larger in males or present only in males. Male oyster toadfish Opsanus tau L produce a long duration, tonal boatwhistle advertisement call, and both sexes grunt, a short duration more pulsatile agonistic call. Sonic muscles are present in both sexes but larger in males. We tested the hypothesis that males would call more than females by inducing grunts in toadfish of various sizes held in a net and determined incidence of calling and developmental changes in grunt parameters. A small number of fish were recorded twice to examine call repeatability. Both sexes were equally likely to grunt, and grunt parameters (sound pressure level (SPL), individual range in SPL, number of grunts, and fundamental frequency) were similar in both sexes. SPL increased with fish size before leveling off in fish >200 g, and fundamental frequency and other parameters did not change with fish size. Number of grunts in a train, grunt duration and inter-grunt interval were highly variable in fish recorded twice suggesting that grunt parameters reflect internal motivation rather than different messages. Grunt production may explain the presence of well-developed sonic muscles in females and suggests that females have an active but unexplored vocal life.


Purdue ionomics information management system. An integrated functional genomics platform.
The advent of high-throughput phenotyping technologies has created a deluge of information that is difficult to deal with without the appropriate data management tools. These data management tools should integrate defined workflow controls for genomic-scale data acquisition and validation, data storage and retrieval, and data analysis, indexed around the genomic information of the organism of interest. To maximize the impact of these large datasets, it is critical that they are rapidly disseminated to the broader research community, allowing open access for data mining and discovery. We describe here a system that incorporates such functionalities developed around the Purdue University high-throughput ionomics phenotyping platform. The Purdue Ionomics Information Management System (PiiMS) provides integrated workflow control, data storage, and analysis to facilitate high-throughput data acquisition, along with integrated tools for data search, retrieval, and visualization for hypothesis development. PiiMS is deployed as a World Wide Web-enabled system, allowing for integration of distributed workflow processes and open access to raw data for analysis by numerous laboratories. PiiMS currently contains data on shoot concentrations of P, Ca, K, Mg, Cu, Fe, Zn, Mn, Co, Ni, B, Se, Mo, Na, As, and Cd in over 60,000 shoot tissue samples of Arabidopsis (Arabidopsis thaliana), including ethyl methanesulfonate, fast-neutron and defined T-DNA mutants, and natural accession and populations of recombinant inbred lines from over 800 separate experiments, representing over 1,000,000 fully quantitative elemental concentrations. PiiMS is accessible at www.purdue.edu/dp/ionomics.


Recovery of Bacteria and Fungi From a Leg Wound.
Acute and chronic wound infections can both be encountered in the deployed setting. These wounds are often contaminated by bacteria and fungi derived from the external environment. In this article, we present the case of a wound infection simultaneously colonized by Enterobacter cloacae (a bacterial pathogen) and Trichosporon asahii (an unusual fungal pathogen). We describe the examination and treatment of the patient and review the distinguishing characteristics of each organism.


DEAD-box proteins from Escherichia coli exhibit multiple ATP-independent activities.
DEAD-box proteins (DBPs) are a widespread class of ATP-dependent RNA helicases that play a key role in unwinding RNA duplexes. In recent years, certain DBPs have also been found to exhibit activities that do not require ATP. To gain a better understanding of prokaryotic RNA metabolism, we investigated whether Escherichia coli DBPs harbor any ATP-independent activities. We show that each of the four E. coli DBPs tested in this study can accelerate the association of cRNA molecules, can stimulate strand displacement, and can function as an RNA chaperone without utilizing ATP. To the best of our knowledge, these prokaryotic DBPs constitute the first examples of proteins that harbor each of these three activities. The identification of these auxiliary functions indicates that the E. coli DBPs are versatile factors that possess significant RNA remodeling activity in addition to their canonical RNA helicase activity and might therefore participate in a greater variety of cellular processes than has been previously appreciated.


Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians.
The Joint Panel of the American Academy of Family Physicians and the American College of Physicians, in collaboration with the Johns Hopkins Evidence-based Practice Center, systematically reviewed the available evidence on the management of newly detected atrial fibrillation and developed recommendations for adult patients with first-detected atrial fibrillation. The recommendations do not apply to patients with postoperative or post-myocardial infarction atrial fibrillation, patients with class IV heart failure, patients already taking antiarrhythmic drugs, or patients with valvular disease. The target physician audience is internists and family physicians dedicated to primary care. The recommendations are as follows: RECOMMENDATION 1: Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with atrial fibrillation. Rhythm control has not been shown to be superior to rate control (with chronic anticoagulation) in reducing morbidity and mortality and may be inferior in some patient subgroups to rate control. Rhythm control is appropriate when based on other special considerations, such as patient symptoms, exercise tolerance, and patient preference. Grade: 2A. RECOMMENDATION 2: Patients with atrial fibrillation should receive chronic anticoagulation with adjusted-dose warfarin, unless they are at low risk of stroke or have a specific contraindication to the use of warfarin (thrombocytopenia, recent trauma or surgery, alcoholism). Grade: 1A. RECOMMENDATION 3: For patients with atrial fibrillation, the following drugs are recommended for their demonstrated efficacy in rate control during exercise and while at rest: atenolol, metoprolol, diltiazem, and verapamil (drugs listed alphabetically by class). Digoxin is only effective for rate control at rest and therefore should only be used as a second-line agent for rate control in atrial fibrillation. Grade: 1B. RECOMMENDATION 4: For those patients who elect to undergo acute cardioversion to achieve sinus rhythm in atrial fibrillation, both direct-current cardioversion (Grade: 1C+) and pharmacological conversion (Grade: 2A) are appropriate options. RECOMMENDATION 5: Both transesophageal echocardiography with short-term prior anticoagulation followed by early acute cardioversion (in the absence of intracardiac thrombus) with postcardioversion anticoagulation versus delayed cardioversion with pre- and postanticoagulation are appropriate management strategies for those patients who elect to undergo cardioversion. Grade: 2A. RECOMMENDATION 6: Most patients converted to sinus rhythm from atrial fibrillation should not be placed on rhythm maintenance therapy since the risks outweigh the benefits. In a selected group of patients whose quality of life is compromised by atrial fibrillation, the recommended pharmacologic agents for rhythm maintenance are amiodarone, disopyramide, propafenone, and sotalol (drugs listed in alphabetical order). The choice of agent predominantly depends on specific risk of side effects based on patient characteristics. Grade: 2A.


Genome-wide nucleosome mapping of Plasmodium falciparum reveals histone-rich coding and histone-poor intergenic regions and chromatin remodeling of core and subtelomeric genes.
Epigenetic modifications of histones and regulation of chromatin structure have been implicated in regulation of virulence gene families in P. falciparum. To better understand chromatin-mediated gene regulation, we used a high-density oligonucleotide microarray to map the position and enrichment of nucleosomes across the entire genome of P. falciparum at three time points of the intra-erythrocytic developmental cycle (IDC) in vitro. We used an unmodified histone H4 antibody for chromatin immunoprecipitation of nucleosome-bound DNA. We observed generally low nucleosomal occupancy of intergenic regions and higher occupancy of protein coding regions. In contract to the overall small fluctuation of nucleosomal occupancy in most coding regions throughout the IDC, subtelomeric genes encoding surface proteins such as var and rif, as well as some core chromosomal genes such as transcription factors, showed large changes in chromatin structure. Telomeres harbored a region with the highest nucleosomal occupancy of the genome and also exhibited large changes with higher nucleosomal occupancy at schizont stages. While many of these subtelomeric genes were previously shown to be modified by H3K9 trimethylation, we also identified some housekeeping genes in core chromosome regions that showed extensive changes in chromatin structure but do not contain this modification. tRNA and basal transcription factor genes showed low nucleosomal occupancy at all times, suggesting of an open chromatin structure that might be permissive for constitutively high levels of expression. Generally, nucleosomal occupancy was not correlated with the steady-state mRNA levels. Several var genes were exceptions: the var gene with the highest expression level showed the lowest nucleosomal occupancy, and selection of parasites for var2CSA expression resulted in lower nucleosomal occupancy at the var2CSA locus. We identified nucleosome-free regions in intergenic regions that may serve as transcription start sites or transcription factor binding sites. Using the nucleosomal occupancy data as the baseline, we further mapped the genome-wide enrichment of H3K9 acetylation and detected general enrichment of this mark in intergenic regions. These data on nucleosome enrichment changes add to our understanding of the influence of chromatin structure on the regulation of gene expression. Histones are generally enriched in coding regions, and relatively poor in intergenic regions. Histone enrichment patterns allow for identification of new putative gene-coding regions. Most genes do not show correlation between chromatin structure and steady-state mRNA levels, indicating the dominant roles of other regulatory mechanisms. We present a genome-wide nucleosomal occupancy map, which can be used as a reference for future experiments of histone modification mapping.


RNASeq in C. elegans Following Manganese Exposure.
Manganese is a metal that is required for optimal biological functioning of organisms. Absorption, cellular import and export, and excretion of manganese are all tightly regulated. While some genes involved in regulation, such as DMT-1 and ferroportin, are known, it is presumed that many more are involved and as yet unknown. Excessive exposure to manganese, usually in industrial settings such as mining or welding, can lead to neurotoxicity and a condition known as manganism that closely resembles Parkinson's disease. Elucidating transcriptional changes following manganese exposure could lead to the development of biomarkers for exposure. This unit presents a protocol for RNA sequencing in the worm Caenorhabditis elegans to assay for transcriptional changes following exposure to manganese. This protocol is adaptable to any environmental exposure in C. elegans. The protocol results in counts of gene transcripts in control versus exposed conditions and a ranked list of differentially expressed genes for further study.


Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models.
Gastric cancer is the second most common cause of cancer-related death worldwide. Although brain metastasis is a rare complication of gastric cancer, no standard therapy for gastric cancer brain metastasis has been established. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate such markers. A case-control study of patients newly diagnosed with gastric cancer who had developed brain metastasis during follow-up, was conducted. These patients were compared with patients who had advanced gastric cancer but no evidence of brain metastasis. Immunohistochemistry was used to analyze the expression of E-cadherin, N-cadherin, MSS1, claudin-3, claudin-4, Glut1, clusterin, ITGB4, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and p53. The expression of VEGF tended to be higher in the case group (33.3 vs. 0%, p=0.055). Median survival was significantly correlated with vascular invasion (12 vs. 33 months, p=0.008) and N-cadherin expression (36 vs. 12 months, p=0.027). We also investigated the effects of metformin in tumor-bearing mouse models. VEGF expression was decreased and E-cadherin increased in the metformin‑treated group when compared with the control group. The expression of the mesenchymal marker MMP9 was decreased in the metformin-treated group. Brain metastasis of advanced gastric cancer was associated with the expression of VEGF. Metformin treatment may be useful for modulating the metastatic capacity by reducing VEGF expression and blocking epithelial-to-mesenchymal transition.


Taming temptation: Visual perspective impacts consumption and willingness to pay for unhealthy foods.
While thinking about food is a ubiquitous facet of daily life, the perils of imaginary eating are well documented; food-related mental imagery elevates both cravings and consumption. Given the serious health issues that often arise from overeating and obesity, identifying strategies that can be used to combat the link between imagination and consumption is, therefore, of considerable theoretical and practical importance. Here we explored the possibility that a fundamental property of mental imagery-the visual perspective from which an event is viewed-may alter the appraisal of unhealthy foods. Specifically, because it is accompanied by attenuated sensorimotor activity, third-person (cf. first-person) imagery was expected to weaken the link between imagination and consumption. The results of 3 studies supported this prediction showing that third-person (cf. first-person) simulations decreased the mental representation, actual consumption, and willingness to pay for desirable items. Driving these effects was the natural reduction of sensory components furnished by third-person imagery. Together, these findings suggest that adoption of a third-person vantage point during mental imagery may be a viable and effective tactic for curbing consumption in everyday life.


Enhanced convective heat transfer using graphene dispersed nanofluids.
Nanofluids are having wide area of application in electronic and cooling industry. In the present work, hydrogen exfoliated graphene (HEG) dispersed deionized (DI) water, and ethylene glycol (EG) based nanofluids were developed. Further, thermal conductivity and heat transfer properties of these nanofluids were systematically investigated. HEG was synthesized by exfoliating graphite oxide in H2 atmosphere at 200°C. The nanofluids were prepared by dispersing functionalized HEG (f-HEG) in DI water and EG without the use of any surfactant. HEG and f-HEG were characterized by powder X-ray diffractometry, electron microscopy, Raman and FTIR spectroscopy. Thermal and electrical conductivities of f-HEG dispersed DI water and EG based nanofluids were measured for different volume fractions and at different temperatures. A 0.05% volume fraction of f-HEG dispersed DI water based nanofluid shows an enhancement in thermal conductivity of about 16% at 25°C and 75% at 50°C. The enhancement in Nusselts number for these nanofluids is more than that of thermal conductivity.


A survey of teaching and the use of clinical guidelines in accident and emergency departments.
To investigate organised teaching in accident and emergency (A&E) departments in England and Wales. A survey was carried out by postal questionnaire. Directed to senior house officers (SHOs), the questionnaire examined the nature and extent of departmental teaching, and measured the availability, suitability, and actual use made of guidelines. Of 231 questionnaires sent, 164 were returned (response rate 71%). The results show that most SHOs attended A&E induction courses at the beginning of their attachments, although the scope of these coursed varied widely. Most SHOs also received regular teaching, although the programmes were generally of less than 3 h in duration. The majority of respondents were well supported with written documentation in a variety of formats. However, a significant minority (29%) of SHOs requested more detailed clinical guidance, and these tended to be the respondents who received the most departmental teaching. More time could be allocated to structured teaching than at present, and greater use made of complementary educational methods such as practical skill teaching, case presentation, clinical audit, and involvement in journal clubs. More extensive departmental teaching should also be supported by making available more detailed and comprehensive clinical guidelines.


Genetic drift and rapid evolution of viviparity in insular fire salamanders (Salamandra salamandra).
Continental islands offer an excellent opportunity to investigate adaptive processes and to time microevolutionary changes that precede macroevolutionary events. We performed a population genetic study of the fire salamander (Salamandra salamandra), a species that displays unique intraspecific diversity of reproductive strategies, to address the microevolutionary processes leading to phenotypic and genetic differentiation of island, coastal and interior populations. We used eight microsatellite markers to estimate genetic diversity, population structure and demographic parameters in viviparous insular populations and ovoviviparous coastal and interior populations. Our results show considerable genetic differentiation (F(ST) range: 0.06-0.27), and no clear signs of gene flow among populations, except between the large and admixed interior populations. We find no support for island colonization by rafting or intentional/accidental anthropogenic introductions, indicating that rising sea levels were responsible for isolation of the island populations approximately 9000 years ago. Our study provides evidence of rapid genetic differentiation between island and coastal populations, and rapid evolution of viviparity driven by climatic selective pressures on island populations, geographic isolation with genetic drift, or a combination of these factors. Studies of these viviparous island populations in early stages of divergence help us better understand the microevolutionary processes involved in rapid phenotypic shifts.


The effect of emotional freedom techniques on stress biochemistry: a randomized controlled trial.
This study examined the changes in cortisol levels and psychological distress symptoms of 83 nonclinical subjects receiving a single hour long intervention. Subjects were randomly assigned to either an emotional freedom technique (EFT) group, a psychotherapy group receiving a supportive interviews (SI), or a no treatment (NT) group. Salivary cortisol assays were performed immediately before and 30 minutes after the intervention. Psychological distress symptoms were assessed using the symptom assessment-45. The EFT group showed statistically significant improvements in anxiety (-58.34%, p < 0.05), depression (-49.33%, p < 0.002), the overall severity of symptoms (-50.5%, p < 0.001), and symptom breadth (-41.93%, p < 0.001). The EFT group experienced a significant decrease in cortisol level (-24.39%; SE, 2.62) compared with the decrease observed in the SI (-14.25%; SE, 2.61) and NT (-14.44%; SE, 2.67) groups (p < 0.03). The decrease in cortisol levels in the EFT group mirrored the observed improvement in psychological distress.


Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases.
Receptor-mediated signal transduction requires the assembly of multimeric complexes of signalling proteins, and a number of conserved protein domains, such as the SH2, SH3 and PH domains, are involved in mediating protein-protein interactions in such complexes. The identification of binding partners for these domains has added considerably to our understanding of signal-transduction pathways, and the purpose of this work was to identify SH3-binding proteins in haematopoietic cells. We performed affinity-chromatography experiments with a panel of GST-SH3 fusion proteins (composed of glutathione-S-transferase appended to various SH3 domains) to search for SH3-binding proteins in a human megakaryocytic cell line. Protein microsequencing identified one of the SH3-binding proteins as WASp, the protein that is defective in Wiskott-Aldrich syndrome (WAS) and isolated X-linked thrombocytopenia. WASp bound preferentially in vitro to SH3 domains from c-Src family kinases, and analysis of proteins expressed in insect cells using a baculovirus vector demonstrated a specific interaction between WASp and the Fyn protein-tyrosine kinase. Finally, in vivo experiments showed that WASp and Fyn physically associate in human haematopoietic cells. Haematopoietic cells from individuals with WAS exhibit defects in cell morphology and signal transduction, including reduced proliferation and tyrosine phosphorylation in response to stimulatory factors. Members of the c Src family of protein-tyrosine kinases, including Fyn, are involved in a range of signalling pathways - such as those regulating cytoskeletal structure - in both haematopoietic and non-haematopoietic cells. Our data suggest that binding of Fyn to WASp may be a critical event in such signalling pathways in haematopoietic cells.


Highlight-shading relationship as a cue for the perception of translucent and transparent materials.
Natural surfaces, such as those of food and drink, have translucent properties. Translucent materials involve complex optics, such as sub-surface scattering and refraction, but humans can easily distinguish them from opaque materials. Here, we investigated image features that are diagnostic of the perceived translucency and transparency, focusing on the fact that variations in the opacity of a surface affect largely the non-specular component (shading pattern) of an image and little the specular component (highlights). In a simple rating experiment with computer-generated objects, we show that the non-specular image component tends to be blurred, faint, and even partially contrast-reversed for objects that appear more translucent or transparent. A subsequent experiment further demonstrated that manipulation of the contrast and blur of the non-specular image component dramatically alters the apparent translucency of an opaque object. The results support the notion that the spatial and contrast relationship between specular highlights and non-specular shading patterns is a robust cue for the perceived translucency and transparency of three-dimensional objects.


Local recurrence as immunoglobulin G4 (IgG4)-related disease 10 years after radiotherapy to ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue.
In 2000, a 48-year-old woman developed a left orbital mass with lacrimal gland involvement and then, in 2003, a right orbital mass with lacrimal gland involvement, both of which were diagnosed as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). She underwent 30 Gy external beam radiation to bilateral orbital lesions. The lymphoma cells in both lesions did not share the same clonality, as shown by amplification by polymerase chain reaction of the immunoglobulin heavy chain gene. Immunoglobulin light chain analysis by immunohistochemistry and messenger RNA in situ hybridization showed λ chain monotype in the left orbital lesion but κ chain monotype in the right orbital lesion. She developed recurrent left orbital mass with high uptake on fluorodeoxyglucose positron emission tomography fused with computed tomography in 2010, and excisional biopsy disclosed the formation of follicles and infiltration with immunoglobulin G4 (IgG4)-positive plasma cells mainly in interfollicular areas. The immunoglobulin light chain analysis showed the λ chain and κ chain bitype. With the immunohistopathological diagnosis of IgG4-related disease, the serum IgG4 level was found to show elevation at 376 mg/dL, and the patient chose observation. This is the first reported case of development of IgG4-related disease after bilataral orbital MALT lymphoma with external beam radiotherapy.


Body density of humpback whales (Megaptera novaengliae) in feeding aggregations estimated from hydrodynamic gliding performance.
Many baleen whales undertake annual fasting and feeding cycles, resulting in substantial changes in their body condition, an important factor affecting fitness. As a measure of lipid-store body condition, tissue density of a few deep diving marine mammals has been estimated using a hydrodynamic glide model of drag and buoyancy forces. Here, we applied the method to shallow-diving humpback whales (Megaptera novaeangliae) in North Atlantic and Antarctic feeding aggregations. High-resolution 3-axis acceleration, depth and speed data were collected from 24 whales. Measured values of acceleration during 5 s glides were fitted to a hydrodynamic glide model to estimate unknown parameters (tissue density, drag term and diving gas volume) in a Bayesian framework. Estimated species-average tissue density (1031.6 ± 2.1 kg m-3, ±95% credible interval) indicates that humpback whale tissue is typically negatively buoyant although there was a large inter-individual variation ranging from 1025.2 to 1043.1 kg m-3. The precision of the individual estimates was substantially finer than the variation across different individual whales, demonstrating a progressive decrease in tissue density throughout the feeding season and comparably high lipid-store in pregnant females. The drag term (CDAm-1) was estimated to be relatively high, indicating a large effect of lift-related induced drag for humpback whales. Our results show that tissue density of shallow diving baleen whales can be estimated using the hydrodynamic gliding model, although cross-validation with other techniques is an essential next step. This method for estimating body condition is likely to be broadly applicable across a range of aquatic animals and environments.


Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype.
The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have been shown to act on a wide range of tissue and cell types, both in the central nervous system and in the periphery. Two distinct receptors for VIP, the VIP receptor type 1 (VIPR1) and the VIP receptor type 2 (VIPR2), have recently been cloned, each of which binds PACAP and VIP with equal affinity. We report here the chromosomal mapping of the human and mouse VIPR2 genes by fluorescence in situ hybridization. The VIPR2 gene maps to the human chromosomal region 7q36.3 and to the F2 region of mouse chromosome 12. Our localization of the human gene places it in the region where the locus for the craniofacial defect holoprosencephaly type 3 (HPE3) maps. Further mapping experiments, carried out on cell lines derived from patients with HPE or HPE microforms and associated 7q deletions, have led us to redefine the distal extent of the HPE3 minimal critical region, originally characterized by Gurrieri et al. (1993, Nature Genet. 3: 247-251.) The VIPR2 gene lies within this new HPE3 minimal critical region. Our results suggest that deletion of the VIPR2 gene is not the sole factor responsible for the HPE3 phenotype. However, it is possible that monosomy at the VIPR2 locus may contribute to the phenotype observed in many cases of HPE3.


Neuronal fiber tracts connecting the brain and ventral nerve cord of the early Drosophila larva.
By using a combination of dye injections, clonal labeling, and molecular markers, we have reconstructed the axonal connections between brain and ventral nerve cord of the first-instar Drosophila larva. Out of the approximately 1,400 neurons that form the early larval brain hemisphere, less than 50 cells have axons descending into the ventral nerve cord. Descending neurons fall into four topologically defined clusters located in the anteromedial, anterolateral, dorsal, and basoposterior brain, respectively. The anterolateral cluster represents a lineage derived from a single neuroblast. Terminations of descending neurons are almost exclusively found in the anterior part of the ventral nerve cord, represented by the gnathal and thoracic neuromeres. This region also contains small numbers of neurons with axons ascending into the brain. Terminals of the ascending axons are found in the same basal brain regions that also contain descending neurons. We have mapped ascending and descending axons to the previously described scaffold of longitudinal fiber tracts that interconnect different neuromeres of the ventral nerve cord and the brain. This work provides a structural framework for functional and genetic studies addressing the control of Drosophila larval behavior by brain circuits.


Nursing home admission during the first year after hospitalization - the contribution of cognitive impairment.
The importance of cognitive and physical functioning for nursing home admission among medically hospitalized older patients is rarely studied in a one-year follow-up perspective. This study aims to explore the association between patient characteristics and nursing home admission within one year after hospitalization in persons 65 years or more. A one-year longitudinal study. We included 463 (234 women) persons aged 65 years or more from internal medical wards in a rural area of Norway. Cognitive function was assessed using the Mini Mental State Examination; physical and instrumental functional status was assessed using the physical self-maintenance scale and instrumental activities of daily living scale of Lawton and Brody. Comorbidity was measured with the Charlson index. Admission to nursing home within one year (yes versus no) was analyzed using logistic regression analysis and Cox proportional hazard regression analysis. The mean age of the sample was 80.5 (SD 7.4) years, mean Mini Mental State Examination score was 24.1 (SD 3.8) (maximum score is 30). In adjusted analysis participants with cognitive impairment (a Mini Mental State Examination score <25) or impaired physical functioning at baseline had higher risk of admission to nursing home within one year (OR 3.0, 95%CI 1.5-6.2 and OR 3.5, 95%CI 1.8-9.6, respectively). The time before admission was also associated with cognitive impairment and impaired physical functioning in the adjusted analysis (HR 2.6 95%CI 1.4-4.8 and HR 3.7, 95%CI 1.5-8.9, respectively). Impaired cognitive and physical functioning increased the risk for nursing home admission within one year after hospitalization. However, putative regressors, such as education and social network were not included in the analysis.


An ethnographic comparison of HIV risk behaviors among heroin and methamphetamine injectors.
Drug injection and other practices affecting the risk of human immunodeficiency virus (HIV) infection were studied among 154 heroin users and 45 methamphetamine users in San Antonio, Texas. Amphetamine users were younger, mostly white, and had less-severe drug dependence. Heroin users had significantly higher levels of needle risk, as indicated by frequency of injection, number of persons sharing equipment, and place of injection. Methamphetamine users tended to buy syringes in lots of 10 or more from pharmacies and to use a syringe less than 5 times before discarding it. Heroin users tended to buy 1 needle at a time from an illicit source and to use it more than 20 times. Of methamphetamine users, 71% had more than one sex partner, compared to 39% of heroin users. Partners of methamphetamine users were more likely to be drug injectors than were partners of heroin users. Fewer methamphetamine users reported a behavior change in response to the acquired immunodeficiency syndrome (AIDS) epidemic, and fewer had been contacted by AIDS Education/Outreach. We suggest that efforts to promote risk reduction among methamphetamine users be stepped up because this population has been underserved and because less-sweeping behavior changes are needed to reduce needle-related risks to acceptable levels.


Adaptive classification on brain-computer interfaces using reinforcement signals.
We introduce a probabilistic model that combines a classifier with an extra reinforcement signal (RS) encoding the probability of an erroneous feedback being delivered by the classifier. This representation computes the class probabilities given the task related features and the reinforcement signal. Using expectation maximization (EM) to estimate the parameter values under such a model shows that some existing adaptive classifiers are particular cases of such an EM algorithm. Further, we present a new algorithm for adaptive classification, which we call constrained means adaptive classifier, and show using EEG data and simulated RS that this classifier is able to significantly outperform state-of-the-art adaptive classifiers.


Nosocomial necrotising enterocolitis outbreaks: epidemiology and control measures.
Necrotising enterocolitis (NEC) is one of the most serious gastrointestinal diseases among newborns and it mainly affects those in intensive care units. The aetiology of the disease has been reported to be multifactorial and both sporadic cases and nosocomial outbreaks have occurred. In this report, we review 17 epidemics of NEC reported in the literature between 1973 and 1999. The number of confirmed cases ranged from 1 to 32 with an average of 10.5 confirmed cases. On average, 16.15% of cases required surgery (range 0-66.6%). The average mortality rate was 6.25% (range 0-87.5%). The mean age at disease onset was 9.5 days (range 6.6-29 days). Most of the infants had low birth weight (median weight 1,395 g; range 1,112-2,788 g, calculated on the reported mean weights). The main risk factors associated with NEC were: low birth weight, low gestational age, low Apgar score, perinatal complications, hyaline membrane disease, and umbilical catheterisation. The bacteria involved often included Enterobacteriaceae, particularly Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae type 3305573. The causative role of Clostridia in NEC is controversial. With regard to viral agents, coronarovirus, rotavirus and enterovirus, such as echovirus type 22, were isolated during some of the epidemics. The recommended control measures for NEC epidemics are those used for epidemics of other orofaecally transmitted infections. Understanding the epidemiology of necrotising enterocolitis is fundamental if adequate preventive control measures are to be developed and applied.


Preparation of titanium dioxide nanoparticles from electrocoagulated sludge using sacrificial titanium electrodes.
A comprehensive investigation of electrocoagulation using sacrificial titanium (Ti) electrodes in wastewater was carried out. The effects of specific process variables, such as initial pH, mixing, current density, initial organic loading, and ionic/electrolyte strength were first optimized to produce recyclable Ti-based sludge. The sludge was incinerated at 600 degrees C to produce functional TiO(2) photocatalyst. X-ray diffraction analysis revealed that TiO(2) produced at optimum electrocoagulation conditions was mostly anatase structure. The specific surface area of the synthesized TiO(2) photocatalyst was higher than that of the commercially available and widely used Degussa P-25 TiO(2). Furthermore, energy dispersive X-ray and X-ray photoelectron spectroscopy analyses showed that in additional to titanium and oxygen, this photocatalyst is also composed of carbon and phosphorus. These elements were mainly doped as a substitute site for the oxygen atom. Transmission electron microscopy images exhibited sharply edged nanorods, round nanoparticles, and nanotubes with nonuniform shapes showing some structural defects. Photodecomposition of gaseous acetaldehyde by this photocatalyst was also conducted under UV and visible light irradiation to study the photocatalytic properties of the doped TiO(2) photocatalyst. While no photocatalytic activity was observed under visible light irradiation, this doped TiO(2) photocatalyst exhibited high photocatalytic activity under UV light.


Pneumoperitoneum simulation based on mass-spring-damper models for laparoscopic surgical planning.
Laparoscopic surgery, which is one minimally invasive surgical technique that is now widely performed, is done by making a working space (pneumoperitoneum) by infusing carbon dioxide ([Formula: see text]) gas into the abdominal cavity. A virtual pneumoperitoneum method that simulates the abdominal wall and viscera motion by the pneumoperitoneum based on mass-spring-damper models (MSDMs) with mechanical properties is proposed. Our proposed method simulates the pneumoperitoneum based on MSDMs and Newton's equations of motion. The parameters of MSDMs are determined by the anatomical knowledge of the mechanical properties of human tissues. Virtual [Formula: see text] gas pressure is applied to the boundary surface of the abdominal cavity. The abdominal shapes after creation of the pneumoperitoneum are computed by solving the equations of motion. The mean position errors of our proposed method using 10 mmHg virtual gas pressure were [Formula: see text], and the position error of the previous method proposed by Kitasaka et al. was 35.6 mm. The differences in the errors were statistically significant ([Formula: see text], Student's [Formula: see text]-test). The position error of the proposed method was reduced from [Formula: see text] to [Formula: see text] using 30 mmHg virtual gas pressure. The proposed method simulated abdominal wall motion by infused gas pressure and generated deformed volumetric images from a preoperative volumetric image. Our method predicted abdominal wall deformation by just giving the [Formula: see text] gas pressure and the tissue properties. Measurement of the visceral displacement will be required to validate the visceral motion.


Prion propagation in a nerve conduit model containing segments devoid of axons.
Prions, the putative causative agents of transmissible spongiform encephalopathies, are neurotropic pathogens that spread to the central nervous system via synaptically linked neural conduits upon peripheral infection. Axons and their transport processes have been suggested as mediators of nerve-associated prion dissemination. However, the exact cellular components and molecular mechanisms underlying neural spread are unknown. This study used an established hamster scrapie model to pursue a novel experimental approach using nerve conduits containing segments devoid of neurites generated by incomplete nerve regeneration following Wallerian degeneration to probe the necessity of axons for the neural propagation of prions. For this purpose, animals were subjected to unilateral sciatic neurectomy 4 weeks before footpad inoculation with scrapie agent. The results showed that the regional nerve is the prime conduit for cerebral neuroinvasion and revealed, as evidenced by the accumulation of pathological prion protein PrP TSE, that prions can proceed along segments of peripheral neural projections without detectable axonal structures.


Unsuccessful percutaneous endoscopic lumbar discectomy: a single-center experience of 10,228 cases.
Percutaneous endoscopic lumbar discectomy (PELD) has remarkably evolved with successful results. Although PELD has gained popularity for the treatment of herniated disc (HD), the risk of surgical failure may be a major obstacle to performing PELD. We analyzed unsuccessful cases requiring reoperation. To find common causes of surgical failure and elucidate the limitations of the conventional PELD technique. A retrospective review was performed on all patients who had undergone PELD between January 2001 and December 2012. Unsuccessful PELD was defined as a case requiring reoperation within 6 weeks after primary surgery. Chart review was done, and preoperative, intraoperative, and postoperative radiographic reviews were performed. All unsuccessful PELD cases were classified according to the type of HD, location of herniation, extruded disc migration, working channel position, and intraoperative and postoperative findings. In 12 years, 10,228 patients had undergone PELD; 436 (4.3%) cases were unsuccessful. The causes were incomplete removal of HDs in 283 patients (2.8%), recurrence in 78 (0.8%), persistent pain even after complete HD removal in 41 (0.4%), and approach-related pain in 21 (0.2%). Incomplete removal of the HD was caused by inappropriate positioning (95 cases; 33.6%) of the working channel and occurred in central HDs (91 cases; 32.2%), migrated HDs (70 cases; 24.7%), and axillary type HDs (63 cases; 22.3%). Proper surgical indications and good working channel position are important for successful PELD. PELD techniques should be specifically designed to remove the disc fragments in various types of HD.


Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response.
Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models. A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab. We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS.


Photocatalytic application of nanosized CdS immobilized onto functionalized MWCNTs.
Nanosized semiconductor CdS immobilized onto modified multi-walled carbon nanotubes (MWCNTs) carrying poly(amidoamine) dendron units were visualized by HR-TEM. Evidently, spherical CdS nanoparticles 3-5 nm in diameter were identified. Moreover, EDX spectroscopy gave additional spectroscopic proof of the presence of CdS in the CdS-MWCNTs hybrid material. The photocatalytic activity of CdS-MWCNTs toward the decomposition of rhodamine B (RhB) was examined by monitoring spectral changes in the characteristic absorption band of RhB centred at 554 nm. The latter absorption band of RhB was found to continuously depress during visible light irradiation in the presence of CdS-MWCNTs, with faster kinetic rates as compared with the case when only reference CdS was present. The current result was rationalized in terms of efficient photoinduced electron-transfer from CdS to MWCNTs within the intrahybrid CdS-MWCNTs. In this frame, the suggested mechanism for the high and fast photocatalytic decomposition of RhB supports the accumulation of electrons in MWCNTs, which then react with molecular oxygen, thus reducing it to superoxide radical anion O2˙(-) responsible for the generation of the highly reactive species of HO˙ and HOO˙. The latter together with the holes generated in photoexcited CdS were responsible for the decomposition of RhB. Finally, the photocatalyst CdS-MWCNTs was recovered and efficiently reused for four consecutive catalytic cycles, thus highlighting its wider applicability in removing organic pollutants from water.


Effect of hearing aids on auditory function in infants with perinatal brain injury and severe hearing loss.
Approximately 2-4% of newborns with perinatal risk factors present with hearing loss. Our aim was to analyze the effect of hearing aid use on auditory function evaluated based on otoacoustic emissions (OAEs), auditory brain responses (ABRs) and auditory steady state responses (ASSRs) in infants with perinatal brain injury and profound hearing loss. A prospective, longitudinal study of auditory function in infants with profound hearing loss. Right side hearing before and after hearing aid use was compared with left side hearing (not stimulated and used as control). All infants were subjected to OAE, ABR and ASSR evaluations before and after hearing aid use. The average ABR threshold decreased from 90.0 to 80.0 dB (p = 0.003) after six months of hearing aid use. In the left ear, which was used as a control, the ABR threshold decreased from 94.6 to 87.6 dB, which was not significant (p>0.05). In addition, the ASSR threshold in the 4000-Hz frequency decreased from 89 dB to 72 dB (p = 0.013) after six months of right ear hearing aid use; the other frequencies in the right ear and all frequencies in the left ear did not show significant differences in any of the measured parameters (p>0.05). OAEs were absent in the baseline test and showed no changes after hearing aid use in the right ear (p>0.05). This study provides evidence that early hearing aid use decreases the hearing threshold in ABR and ASSR assessments with no functional modifications in the auditory receptor, as evaluated by OAEs.


Irisin may have a role in pubertal development and regulation of reproductive function in rats.
Physical exercise and body muscle/fat mass are known to affect the endocrine system, puberty onset and reproductive health. However, the potential effects of irisin, an adipo-myokine and exercise-induced hormone, have not yet been fully elucidated on reproductive maturation. Therefore, the present study aimed to determine the effects of irisin administration on pubertal maturation and reproductive system in female and male rats. Daily i.p. injection of irisin (100 ng/kg; from postnatal day 21 for about 10 weeks) delayed the ages at the vaginal opening (as an external index of puberty onset) and first estrus. Furthermore, continuous administration of irisin to female rats caused a significant decrease in serum follicle-stimulating hormone levels and an increase in serum luteinizing hormone and 17β-estradiol levels, as well as causing histopathological changes in the ovarian tissue. On the contrary, irisin administration to male rats did not modify the timing of puberty, as estimated by age at preputial separation. However, chronic exposure to irisin produced significant increases in serum luteinizing hormone and testosterone levels and also sperm concentration and seminiferous tubule diameter in male rats. In conclusion, irisin exposure has different effects on both pubertal maturation and reproductive system in female and male rats. The present findings reveal that chronic irisin exposure may lead to disorders in the female reproductive system and may have androgenic potential on the hypothalamic-pituitary-gonadal axis in males.


Antibacterial autophagy occurs at PI(3)P-enriched domains of the endoplasmic reticulum and requires Rab1 GTPase.
Autophagy mediates the degradation of cytoplasmic components in eukaryotic cells and plays a key role in immunity. The mechanism of autophagosome formation is not clear. Here we examined two potential membrane sources for antibacterial autophagy: the ER and mitochondria. DFCP1, a marker of specialized ER domains known as 'omegasomes,' associated with Salmonella-containing autophagosomes via its PtdIns(3)P and ER-binding domains, while a mitochondrial marker (cytochrome b5-GFP) did not. Rab1 also localized to autophagosomes, and its activity was required for autophagosome formation, clearance of protein aggregates and peroxisomes, and autophagy of Salmonella. Overexpression of Rab1 enhanced antibacterial autophagy. The role of Rab1 in antibacterial autophagy was independent of its role in ER-to-Golgi transport. Our data suggest that antibacterial autophagy occurs at omegasomes and reveal that the Rab1 GTPase plays a crucial role in mammalian autophagy.


Gene identification and substrate regulation provide insights into sulfur accumulation during bioleaching with the psychrotolerant acidophile Acidithiobacillus ferrivorans.
The psychrotolerant acidophile Acidithiobacillus ferrivorans has been identified from cold environments and has been shown to use ferrous iron and inorganic sulfur compounds as its energy sources. A bioinformatic evaluation presented in this study suggested that Acidithiobacillus ferrivorans utilized a ferrous iron oxidation pathway similar to that of the related species Acidithiobacillus ferrooxidans. However, the inorganic sulfur oxidation pathway was less clear, since the Acidithiobacillus ferrivorans genome contained genes from both Acidithiobacillus ferrooxidans and Acidithiobacillus caldus encoding enzymes whose assigned functions are redundant. Transcriptional analysis revealed that the petA1 and petB1 genes (implicated in ferrous iron oxidation) were downregulated upon growth on the inorganic sulfur compound tetrathionate but were on average 10.5-fold upregulated in the presence of ferrous iron. In contrast, expression of cyoB1 (involved in inorganic sulfur compound oxidation) was decreased 6.6-fold upon growth on ferrous iron alone. Competition assays between ferrous iron and tetrathionate with Acidithiobacillus ferrivorans SS3 precultured on chalcopyrite mineral showed a preference for ferrous iron oxidation over tetrathionate oxidation. Also, pure and mixed cultures of psychrotolerant acidophiles were utilized for the bioleaching of metal sulfide minerals in stirred tank reactors at 5 and 25°C in order to investigate the fate of ferrous iron and inorganic sulfur compounds. Solid sulfur accumulated in bioleaching cultures growing on a chalcopyrite concentrate. Sulfur accumulation halted mineral solubilization, but sulfur was oxidized after metal release had ceased. The data indicated that ferrous iron was preferentially oxidized during growth on chalcopyrite, a finding with important implications for biomining in cold environments.


Clinical and genetic correlates of growth differentiation factor 15 in the community.
Growth differentiation factor 15 (GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h(2) = 0.38; P = 2.5 × 10(-11)). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 × 10(-32) for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.


Computational imaging of aortic vasa vasorum and neovascularization in rabbits using contrast-enhanced intravascular ultrasound: Association with histological analysis.
Neoangiogenesis is pathophysiologically related to atherosclerotic plaque growth and vulnerability. We examined the in vivo performance of a computational method using contrast-enhanced intravascular ultrasound (CE-IVUS) to detect and quantify aortic wall neovascularization in rabbits. We also compared these findings with histological data. Nine rabbits were fed with a hyperlipidemic diet. IVUS image sequences were continuously recorded before and after the injection of a contrast agent. Mean enhancement of intensity of a region of interest (MEIR) was calculated using differential imaging algorithm. The percent difference of MEIR before and after the injection of microbubbles (d_MEIR) was used as an index of the density of plaque or/and adventitial neovascularization. Aortic segments were excised for histological analysis. CE-IVUS and histological analysis were performed in 11 arterial segments. MEIR was significantly increased (~20%) after microbubble injection (from 8.1±0.9 to 9.7±1.8, p=0.016). Segments with increased VV/neovessels in the tunica adventitia (histological scores 2 and 3) had significantly higher d_MEIR compared with segments with low presence of VV/neovessels (score 1); 40.5±22.9 vs. 8±14.6, p=0.024, respectively. It is possible to detect VV or neovessels in vivo using computational analysis of CE-IVUS images, which is in agreement with histological data. These findings may have critical implications on vulnerable plaque assessment and risk stratification.


Assessing individual-level needle and syringe coverage parameters and the measurement of coverage in Melbourne, Australia: methods and impacts.
To assess the structure of individual-level needle and syringe coverage measurement formula, and to estimate the impact of coverage-related behaviours/parameters (instances of syringe acquisition, total syringes acquired, peer-to-peer syringe distribution, injecting frequency) on overall coverage. Data are drawn from the Melbourne (Australia) injecting drug user cohort study, 2010-16. Data from 518 participants were analysed. We used correlations to explore the relationships between coverage parameters; pooled multiple-linear regression to estimate the effect of each parameter on coverage over time; and exploratory factor analysis to assess the relevance of each parameter within the coverage formula. A 1-unit increase in injecting frequency over time reduced coverage by 10.93 percentage points, almost twice as much as other coverage parameters. Factor analysis results indicated potential improvements to coverage formula structure. Our results suggest that reducing injecting frequency amongst people who inject drugs has the largest improvement in coverage levels, indicating harm reduction services should prioritize it. We also demonstrate that coverage measurement has been inconsistent to date. We sought to refine the method to assist in generating comparable research.


The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model.
Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined. The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF-alpha) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E2 and D2 in colon mucosa, as well as cyclooxygenase (COX)-1 and -2 and nuclear transcription factor NF-kappa B (NF-kappaB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions. Resveratrol (10 mg kg(-1) day(-1)) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF-alpha were significantly ameliorated. Resveratrol did not modify PGD2 levels but returned the decreased PGE2 values to basal levels and also reduced COX-2 and the NF-kappaB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS-induced apoptosis in colonic cells. In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE2 production to basal levels and stimulates apoptosis in colonic cells.


Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay.
Circulating cell-derived microparticles (MPs) have been implicated in several disease processes and elevated levels are found in many pathological conditions. The detection and accurate measurement of MPs, although attracting widespread interest, is hampered by a lack of standardisation. The aim of this study was to establish a reliable flow cytometric assay to measure distinct subtypes of MPs in disease and to identify any significant causes of variability in MP quantification. Circulating MPs within plasma were identified by their phenotype (platelet, endothelial, leukocyte and annexin-V positivity (AnnV+). The influence of key variables (i.e. time between venepuncture and centrifugation, washing steps, the number of centrifugation steps, freezing/long-term storage and temperature of thawing) on MP measurement were investigated. Increasing time between venepuncture and centrifugation leads to increased MP levels. Washing samples results in decreased AnnV+MPs (P=0.002) and platelet-derived MPs (PMPs) (P=0.002). Double centrifugation of MPs prior to freezing decreases numbers of AnnV+MPs (P=0.0004) and PMPs (P=0.0004). A single freeze thaw cycle of samples led to an increase in AnnV+MPs (P=0.0020) and PMPs (P=0.0039). Long-term storage of MP samples at -80° resulted in decreased MP levels. This study found that minor protocol changes significantly affected MP levels. This is one of the first studies attempting to standardise a method for obtaining and measuring circulating MPs. Standardisation will be essential for successful development of MP technologies, allowing direct comparison of results between studies and leading to a greater understanding of MPs in disease.


Bamboo extract reduces interleukin 6 (IL-6) overproduction under lipotoxic conditions through inhibiting the activation of NF-κB and AP-1 pathways.
Interleukin 6 (IL-6) is an inflammatory cytokine overexpressed in obese individuals that contributes to the development of diseases such as insulin resistance, type 2 diabetes, and cardiovascular disease. This study investigated the inhibitory effect of an extract from the bamboo Phyllostachys edulis (BEX) on lipotoxicity-induced over-production of IL-6 in metabolic cell lines. Palmitic acid (PA, 0.4mM) was used to induce lipotoxicity in murine C2C12, 3T3-L1, and Hepa6 cells. Both intra- and extra-cellular protein concentrations of IL-6 were measured in the three cell lines after PA treatment with or without the presence of BEX using cytometric bead assays. IL-6 mRNA levels were quantified using real-time PCR, and nuclear concentrations of c-fos, p50 and p65 proteins were measured using DNA-binding ELISA in 3T3-L1 cells. Lipotoxicity increased IL-6 protein concentration in both cytosol and media collected from myoblast and myotube C2C12, as well as preadipose and adipose 3T3-L1, and the presence of BEX (0.5%, v/v) effectively inhibited this overproduction. IL-6 protein expression in hepatic Hepa6 cells was less affected by lipotoxicity. BEX significantly ameliorated PA-induced upregulation of IL-6 mRNA, which correlated with a reduction in nuclear translocation of p50, p65, and c-fos proteins with the presence of BEX, indicating inhibition of NF-κB and AP-1 activation. In summary, BEX inhibits lipotoxicity-induced IL-6 overproduction in muscle and adipose cell lines through the NF-κB and AP-1 pathways, implicating a potential application of this natural product as a cost-effective anti-inflammation nutraceutical.


Utility of cell-free nucleic acid and circulating tumor cell analyses in prostate cancer.
Prostate cancer is characterized by bone metastases and difficulty of objectively measuring disease burden. In this context, cell-free circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) quantitation and genomic profiling afford the ability to noninvasively and serially monitor the tumor. Recent data suggest that ctDNA and CTC quantitation are prognostic for survival. Indeed, CTC enumeration using the CellSearch® platform is validated as a prognostic factor and warrants consideration as a stratification factor in randomized trials. Changes in quantities of CTCs using CellSearch also are prognostic and may be employed to detect a signal of activity of new agents. Molecular profiling of both CTCs and ctDNA for androgen receptor (AR) variants has been associated with outcomes in the setting of novel androgen inhibitors. Serial profiling to detect the evolution of new alterations may inform drug development and help develop precision medicine. The costs of these assays and the small quantities in which they are detectable in blood are a limitation, and novel platforms are required to address this challenge. The presence of multiple platforms to assay CTCs and ctDNA also warrants the consideration of a mechanism to allow comparison of data across platforms. Further validation and the continued development and standardization of these promising modalities will facilitate their adoption in the clinic.


Stroboscopic visual training improves information encoding in short-term memory.
The visual system has developed to transform an undifferentiated and continuous flow of information into discrete and manageable representations, and this ability rests primarily on the uninterrupted nature of the input. Here we explore the impact of altering how visual information is accumulated over time by assessing how intermittent vision influences memory retention. Previous work has shown that intermittent, or stroboscopic, visual training (i.e., practicing while only experiencing snapshots of vision) can enhance visual-motor control and visual cognition, yet many questions remain unanswered about the mechanisms that are altered. In the present study, we used a partial-report memory paradigm to assess the possible changes in visual memory following training under stroboscopic conditions. In Experiment 1, the memory task was completed before and immediately after a training phase, wherein participants engaged in physical activities (e.g., playing catch) while wearing either specialized stroboscopic eyewear or transparent control eyewear. In Experiment 2, an additional group of participants underwent the same stroboscopic protocol but were delayed 24 h between training and assessment, so as to measure retention. In comparison to the control group, both stroboscopic groups (immediate and delayed retest) revealed enhanced retention of information in short-term memory, leading to better recall at longer stimulus-to-cue delays (640-2,560 ms). These results demonstrate that training under stroboscopic conditions has the capacity to enhance some aspects of visual memory, that these faculties generalize beyond the specific tasks that were trained, and that trained improvements can be maintained for at least a day.


Collateral sensitivity to gemcitabine (2',2'-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines.
Multidrug resistance (MDR), characterized by a cross-resistance to many natural toxin-related compounds, may be caused either by overexpression of a drug efflux pump such as P-glycoprotein, (P-gP), multidrug resistance proteins MRP1-3, or BCRP/MXR or, in the case of DNA topoisomerase II active drugs, by a decrease in the enzymatic activity of the target molecule termed altered topoisomerase MDR (at-MDR). However, human small cell lung carcinoma (SCLC) cell lines showed a collateral sensitivity to 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) and 1-beta-D-arabinofuranosylcytosine (ara-C). H69/DAU, a daunorubicin (DAU)-resistant variant of H69 with a P-gP overexpression, and NYH/VM, a VM-26 (teniposide)-resistant variant of NYH with an at-MDR, were both 2-fold more sensitive to gemcitabine and 7- and 2-fold more sensitive to ara-C, respectively. MDR variants had a 4.3- and 2.0-fold increased activity of deoxycytidine kinase (dCK), respectively. dCK catalyzes the first rate-limiting activation step of both gemcitabine and ara-C. In addition, deoxycytidine deaminase, responsible for inactivation of dFdC and ara-C, was 9.0-fold lower in H69/DAU cells. The level of thymidine kinase 2, a mitochondrial enzyme that can also phosphorylate deoxycytidine and gemcitabine, was not significantly different between the variants. These differences most likely caused an increased accumulation of the active metabolites (dFdCTP, 2.1- and 1.6-fold in NYH/VM and H69/DAU cells, respectively) and of ara-CTP (1.3-fold in NYH/VM cells). Ara-CTP accumulation was not detectable in either H69 variant. The pools of all ribonucleoside and deoxyribonucleoside triphosphates were at least 3- to 4-fold higher in the NYH variants compared to the H69 variants; for dCTP and dGTP this difference was even larger. The higher ribonucleotide pools might explain the >10-fold higher accumulation of dFdCTP in NYH compared to H69 variants. Since dCTP is low, H69 cells might not need a high ara-CTP accumulation to inhibit DNA polymerase. This might be related to the lack of ara-CTP in H69 variants. In addition, the increased CTP, ATP, and UTP pools in the MDR variants might explain the increased ara-CTP and dFdCTP accumulation. In conclusion, the MDR variants of the human SCLC cell lines were collaterally sensitive due to an increased dCK activity, and consequently an increased ara-CTP and dFdCTP accumulation.


Impact and costs of incentives to reduce attrition in online trials: two randomized controlled trials.
Attrition from follow-up is a major methodological challenge in randomized trials. Incentives are known to improve response rates in cross-sectional postal and online surveys, yet few studies have investigated whether they can reduce attrition from follow-up in online trials, which are particularly vulnerable to low follow-up rates. Our objective was to determine the impact of incentives on follow-up rates in an online trial. Two randomized controlled trials were embedded in a large online trial of a Web-based intervention to reduce alcohol consumption (the Down Your Drink randomized controlled trial, DYD-RCT). Participants were those in the DYD pilot trial eligible for 3-month follow-up (study 1) and those eligible for 12-month follow-up in the DYD main trial (study 2). Participants in both studies were randomly allocated to receive an offer of an incentive or to receive no offer of an incentive. In study 1, participants in the incentive arm were randomly offered a £5 Amazon.co.uk gift voucher, a £5 charity donation to Cancer Research UK, or entry in a prize draw for £250. In study 2, participants in the incentive arm were offered a £10 Amazon.co.uk gift voucher. The primary outcome was the proportion of participants who completed follow-up questionnaires in the incentive arm(s) compared with the no incentive arm. In study 1 (n = 1226), there was no significant difference in response rates between those participants offered an incentive (175/615, 29%) and those with no offer (162/611, 27%) (difference = 2%, 95% confidence interval [CI] -3% to 7%). There was no significant difference in response rates among the three different incentives offered. In study 2 (n = 2591), response rates were 9% higher in the group offered an incentive (476/1296, 37%) than in the group not offered an incentive (364/1295, 28%) (difference = 9%, 95% CI 5% to 12%, P < .001). The incremental cost per extra successful follow-up in the incentive arm was £110 in study 1 and £52 in study 2. Whereas an offer of a £10 Amazon.co.uk gift voucher can increase follow-up rates in online trials, an offer of a lower incentive may not. The marginal costs involved require careful consideration. ISRCTN31070347; http://www.controlled-trials.com/ISRCTN31070347 (Archived by WebCite at http://www.webcitation.org/5wgr5pl3s).


A Comparison of the Effects of Different Types of Laryngoscope on the Cervical Motions: Randomized Clinical Trial.
The rate of cervical injury among all trauma patients is 3.1%. The most important point during intubation of those patients is not to increase the cervical injury. In this study, we hypothesize that there will be a minimal cervical extension during a laryngoscopy with the use of optical view laryngoscopes. Prospective, randomized clinical trial. One hundred and fifty adult patients with ASA physical status I to III were enrolled in our study. After routine anesthesia induction, we randomly assigned the patients into three groups according to the type of laryngoscope. Macintosh type, Truview EVO2(®) type and Airtraq® type laryngoscopes were used in Group DL (n=50), Group TW (n=50) and Group ATQ (n=50), respectively. After applying general anesthesia induction and mask ventilation, all of the patients were positioned in the neutral position. An inclinometer was placed on the forehead of the patients. Then, the extension angle during intubation and the Cormack-Lehane Score were measured and the time to intubation was recorded. One of the 50 patients in the DL Group, 2 of the 50 patients in the TW Group, and 4 of the 50 patients in the ATQ Group were excluded from the study because of the failure of intubation at defined times. The angle of cervical extension during laryngoscopy was found to be 27.24±6.71, 18.08±7.53, and 14.54±4.09 degrees in the Groups DL, TV and ATQ, respectively; these differences also had statistical significance (p=0.000). The duration of intubation was found to be 13.59±5.49, 23.60±15.23, and 29.80±13.82 seconds in Groups DL, TV and ATQ, respectively (p=0.000). A minimal cervical motion was obtained during tracheal intubation with the use of Truview EVO2® and Airtraq® types of laryngoscope compared with the Macintosh laryngoscope. (ClinicalTrials.gov Identifier: NCT02191904).


Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats.
A factor in the dose-dependent pharmacokinetics of ethyl 4-(3, 4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (TAK-603) in rats was shown to be due to the inhibition of metabolic clearance of unchanged TAK-603 by its major metabolite, M-I, in other words, product inhibition. The effect of M-I on the metabolic clearance of TAK-603 was studied using rats continuously infused i.v. with this metabolite at rates of 5.3 and 16.0 mg/h/kg. The total body clearance of TAK-603 was decreased remarkably in M-I-infused rats, and the decline of total body clearance depended on the steady-state plasma concentrations of M-I. The effect of M-I generated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile-cannulated rats after i.v. injection of 14C-labeled TAK-603 at doses of 1 and 15 mg/kg. Elimination rates of TAK-603 from rat plasma increased in the bile-cannulated rats in which systemic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in plasma concentration-time profiles, a kinetic model based on the product inhibition was developed for the bile-cannulated rats. A good agreement between calculated curves and the observed concentrations of both TAK-603 and M-I was found at 1 and 15 mg/kg, and the calculated curves were drawn using constant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmacokinetics of TAK-603 in rats.


Early detection of psychosis: positive effects on 5-year outcome.
During the last decades we have seen a new focus on early treatment of psychosis. Several reviews have shown that duration of untreated psychosis (DUP) is correlated to better outcome. However, it is still unknown whether early treatment will lead to a better long-term outcome. This study reports the effects of reducing DUP on 5-year course and outcome. During 1997-2000 a total of 281 consecutive patients aged >17 years with first episode non-affective psychosis were recruited, of which 192 participated in the 5-year follow-up. A comprehensive early detection (ED) programme with public information campaigns and low-threshold psychosis detection teams was established in one healthcare area (ED-area), but not in a comparable area (no-ED area). Both areas ran equivalent treatment programmes during the first 2 years and need-adapted treatment thereafter. At the start of treatment, ED-patients had shorter DUP and less symptoms than no-ED-patients. There were no significant differences in treatment (psychotherapy and medication) for the 5 years. Mixed-effects modelling showed better scores for the ED group on the Positive and Negative Syndrome Scale negative, depressive and cognitive factors and for global assessment of functioning for social functioning at 5-year follow-up. The ED group also had more contacts with friends. Regression analysis did not find that these differences could be explained by confounders. Early treatment had positive effects on clinical and functional status at 5-year follow-up in first episode psychosis.


Iron specificity of a biosensor based on fluorescent pyoverdin immobilized in sol-gel glass.
Two current technologies used in biosensor development are very promising: 1. The sol-gel process of making microporous glass at room temperature, and 2. Using a fluorescent compound that undergoes fluorescence quenching in response to a specific analyte. These technologies have been combined to produce an iron biosensor. To optimize the iron (II or III) specificity of an iron biosensor, pyoverdin (a fluorescent siderophore produced by Pseudomonas spp.) was immobilized in 3 formulations of porous sol-gel glass. The formulations, A, B, and C, varied in the amount of water added, resulting in respective R values (molar ratio of water:silicon) of 5.6, 8.2, and 10.8. Pyoverdin-doped sol-gel pellets were placed in a flow cell in a fluorometer and the fluorescence quenching was measured as pellets were exposed to 0.28 - 0.56 mM iron (II or III). After 10 minutes of exposure to iron, ferrous ion caused a small fluorescence quenching (89 - 97% of the initial fluorescence, over the range of iron tested) while ferric ion caused much greater quenching (65 - 88%). The most specific and linear response was observed for pyoverdin immobilized in sol-gel C. In contrast, a solution of pyoverdin (3.0 μM) exposed to iron (II or III) for 10 minutes showed an increase in fluorescence (101 - 114%) at low ferrous concentrations (0.45 - 2.18 μM) while exposure to all ferric ion concentrations (0.45 - 3.03 μM) caused quenching. In summary, the iron specificity of pyoverdin was improved by immobilizing it in sol-gel glass C.


Attentional bias in smokers: exposure to dynamic smoking cues in contemporary movies.
Research has shown that smokers have an attentional bias for pictorial smoking cues. The objective of the present study was to examine whether smokers also have an attentional bias for dynamic smoking cues in contemporary movies and therefore fixate more quickly, more often and for longer periods of time on dynamic smoking cues than non-smokers. By drawing upon established methods for assessing attentional biases for pictorial cues, we aimed to develop a new method for assessing attentional biases for dynamic smoking cues. We examined smokers' and non-smokers' eye movements while watching a movie clip by using eye-tracking technology. The sample consisted of 16 smoking and 17 non-smoking university students. Our results confirm the results of traditional pictorial attentional bias research. Smokers initially directed their gaze more quickly towards smoking-related cues (p = 0.01), focusing on them more often (p = 0.05) and for a longer duration (p = 0.01) compared with non-smokers. Thus, smoking cues in movies directly affect the attention of smokers. These findings indicate that the effects of dynamic smoking cues, in addition to other environmental smoking cues, need to be taken into account in smoking cessation therapies in order to increase successful smoking cessation and to prevent relapses.


Selectivity and affinity of triplex-forming oligonucleotides containing 2'-aminoethoxy-5-(3-aminoprop-1-ynyl)uridine for recognizing AT base pairs in duplex DNA.
We have used DNase I footprinting, fluorescence and ultraviolet (UV) melting experiments and circular dichroism to demonstrate that, in the parallel triplex binding motif, 2'-aminoethoxy-5-(3-aminoprop-1-ynyl)uridine (bis-amino-U, BAU) has very high affinity for AT relative to all other Watson-Crick base pairs in DNA. Complexes containing two or more substitutions with this nucleotide analogue are stable at pH 7.0, even though they contain several C.GC base triplets. These modified triplex-forming oligonucleotides retain exquisite sequence specificity, with enhanced discrimination against YR base pairs (especially CG). These properties make BAU a useful base analogue for the sequence-specific creation of stable triple helices at pH 7.0.


The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function.
We examined hematopoietic protein kinase 1 (HPK1), whose reliance on scaffold versus kinase functions for negative immune cell regulation is poorly understood and critical to its assessment as a viable drug target. We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, viral clearance and tumor growth inhibition were enhanced in HPK1.kd mice, accompanied by an increase in effector CD8 T cell function. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade. These results identify the importance of HPK1 kinase activity in the negative regulation of CD8 effector functions, implicating its potential as a cancer immunotherapy target.


Characterizing the weight-glycemia phenotypes of type 1 diabetes in youth and young adulthood.
Individuals with type 1 diabetes (T1D) present with diverse body weight status and degrees of glycemic control, which may warrant different treatment approaches. We sought to identify subgroups sharing phenotypes based on both weight and glycemia and compare characteristics across subgroups. Participants with T1D in the SEARCH study cohort (n=1817, 6.0-30.4 years) were seen at a follow-up visit >5 years after diagnosis. Hierarchical agglomerative clustering was used to group participants based on five measures summarizing the joint distribution of body mass index z-score (BMIz) and hemoglobin A1c (HbA1c) which were estimated by reinforcement learning tree predictions from 28 covariates. Interpretation of cluster weight status and glycemic control was based on mean BMIz and HbA1c, respectively. The sample was 49.5% female and 55.5% non-Hispanic white (NHW); mean±SD age=17.6±4.5 years, T1D duration=7.8±1.9 years, BMIz=0.61±0.94, and HbA1c=76±21 mmol/mol (9.1±1.9)%. Six weight-glycemia clusters were identified, including four normal weight, one overweight, and one subgroup with obesity. No cluster had a mean HbA1c <58 mmol/mol (7.5%). Cluster 1 (34.0%) was normal weight with the lowest HbA1c and comprised 85% NHW participants with the highest socioeconomic position, insulin pump use, dietary quality, and physical activity. Subgroups with very poor glycemic control (ie, ≥108 mmol/mol (≥12.0%); cluster 4, 4.4%, and cluster 5, 7.5%) and obesity (cluster 6, 15.4%) had a lower proportion of NHW youth, lower socioeconomic position, and reported decreased pump use and poorer health behaviors (overall p<0.01). The overweight subgroup with very poor glycemic control (cluster 5) showed the highest lipids and blood pressure (p<0.01). There are distinct subgroups of youth and young adults with T1D that share weight-glycemia phenotypes. Subgroups may benefit from tailored interventions addressing differences in clinical care, health behaviors, and underlying health inequity.


Towards matched pairs of porphyrin-Re(I) /(99m) Tc(I) conjugates that combine photodynamic activity with fluorescence and radio imaging.
We recently prepared two novel water soluble porphyrins bearing a single peripheral chelator, either diethylenetriamine (1) or bipyridyl (2), tethered to one meso position. The preparation of their conjugates with a fac-{(99m) Tc(CO)3 }(+) fragment and the potential of these resulting conjugates as fluorescence and radio imaging tools were also described. In this work, we focused on the corresponding non-radioactive analogues that bear the fac-{Re(CO)3 }(+) fragment (diethylenetriamine 3 and bipyridyl 4). We report on the uptake, in vitro PDT activity, and cellular localization of Re(I) conjugates 3 and 4 in comparison to the parent porphyrins 1 and 2. Compounds 1-4 have modest or negligible cytotoxicity in the dark against HeLa human cervical cancer cells but become remarkably cytotoxic after exposure to moderate doses of red visible light (590-700 nm). This phototoxicity was found to be directly proportional to the total light dose. Although the four compounds show distinct uptake patterns, they have comparable PDT activity. Confocal fluorescence measurements showed that porphyrin 1 and its Re(I) conjugate 3 have different cellular localization patterns in HeLa cells.


Active-to-Sedentary Behavior Transitions, Fatigability, and Physical Functioning in Older Adults.
With aging, daily physical activity (PA) becomes less frequent and more fragmented. Accumulation patterns of daily PA-including transitions from active-to-sedentary behaviors-may provide important insights into functional status in older, less active populations. Participants of the Baltimore Longitudinal Study of Aging (n = 680, 50% male, aged 27-94 years) completed a clinical assessment and wore an Actiheart accelerometer. Transitions between active and sedentary states were modeled as a probability (Active-to-Sedentary Transition Probability [ASTP]) defined as the reciprocal of the average PA bout duration. Cross-sectional associations between ASTP and gait speed (m/s), fatigability (rating-of-perceived-exertion [RPE]), 400 m time (seconds), and expanded short physical performance battery score were modeled using linear and logistic regression, adjusted for chronic conditions. Further analyses explored the utility of ASTP over-and-above total daily PA. In continuous models, each 0.10-unit higher ASTP was associated slower gait (β = -0.06 m/s, SE = 0.01), higher fatigability (β = 0.60 RPE, SE = 0.12), slower 400 m time (β = 16.31 s, SE = 2.70), and lower functioning (β = -0.13 expanded short physical performance battery score, SE = 0.03; p < .001). In categorical analyses, those in the highest tertile of ASTP were >2 times more likely to have high fatigability (rating of perceived exertion ≥10), slow 400 m time (>300 seconds) and reduced functional performance (expanded short physical performance battery score < 3.07) than those in the lowest tertile (p < .01). Further analyses demonstrated ASTP provided additional insight into functional outcomes beyond total daily PA. Fragmented daily PA-as measured by ASTP-is strongly linked with measures of health and functional status and may identify those at risk of high fatigability and reduced functional performance over and above traditional PA metrics.


Diabetes and stress hyperglycemia associated with myocardial infarctions at an urban municipal hospital: prevalence and effect on mortality.
Municipal hospitals in large cities provide care for patients from immigrant and mixed ethnic communities that are at high risk for diabetes. Both diabetes and stress hyperglycemia increase the risk of adverse outcome after myocardial infarctions, and the impact of stress hyperglycemia on the outcome of myocardial infarctions in this particular setting has not been previously studied. We therefore undertook a retrospective cohort study to determine the prevalence of diabetes and stress hyperglycemia in patients presenting to a university-affiliated Bronx municipal hospital with myocardial infarction, and the relationship of these conditions to the extent of coronary disease and mortality. We obtained data on 106 consecutive patients from July 1998 to April 1999 with a diagnosis-related group diagnosis of either myocardial infarction or acute coronary syndrome, in which myocardial infarction was confirmed by serum enzymes or characteristic electrocardiographic changes. Patients were followed until March 30, 2001. Measurements of clinical parameters and results of catheterization were obtained for all patients. Death rates were determined by laboratory database, direct patient contact, or data from National Death Index. Eighty percent of the cohort had either a diagnosis of diabetes (n = 45, 42% of cohort) or evidence of stress hyperglycemia (defined as serum glucose greater than 126 mg/dL at the time of admission without prior diagnosis of diabetes, n = 40, 38%). In-hospital mortality for patients with diabetes, stress hyperglycemia, or normal glucose was 20%, 15%, and 14%, respectively. Eighty-three percent of the cohort received beta blockers, and 61% of hospital survivors had catheterization. Left main or triple vessel disease was common in both patients with diabetes (52%) and patients with stress hyperglycemia (32%). Mortality at follow up (maximum follow up 3 years; mean follow up 19.6 months) was much higher in patients with either diabetes (42%) or stress hyperglycemia (52%) than normal subjects (24%). Kaplan-Meier analysis of the difference in mortality between patients with high glucose on admission and normal subjects was borderline significant (P = 0.06). Multivariate regression demonstrated that age (P = 0.020), increase in admission serum creatinine (P = 0.001), and reduction in either ejection fraction (P = 0.016) or admission systolic blood pressure (P = 0.005) were significant predictors of mortality. Glycemic status and sex were not independently associated with death after controlling for these other factors. These results show that the prevalence of both diabetes and stress hyperglycemia on presentation with myocardial infarction is strikingly high in this immigrant, mixed ethnic, urban population. Patients with diabetes and stress hyperglycemia had advanced disease on presentation and much higher mortality at 2 to 3 years than those with normal blood glucose. The mortality difference is the result of older age and more advanced disease rather than hyperglycemia per se.


Mental health care use in later life: results from a national survey of Canadians.
To estimate the proportion of older adults who have used mental health services in the past 12 months among those who meet the criteria for one or more Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, 12-month psychiatric disorders. We also examine the factors associated with mental health care use in this population. We used secondary data from the Canadian Community Health Survey: Mental Health and Well-Being (CCHS 1.2). We first estimated the proportion of adults aged 55 years and older who used a range of mental health services. Next, using logistic regression, we examined the relative contribution of predisposing, enabling, and need characteristics in predicting any service use in this population. Among the 12 792 adults aged 55 years and older in the CCHS 1.2, 513 (4.23%, 95% CI 3.89% to 4.95%) met the criteria for at least one 12-month DSM-IV disorder. Among these respondents, 37% (95% CI 31% to 43%) saw at least one type of mental health care provider in the past 12 months. Visits to a general health care provider for mental health reasons were most common, followed by specialist care. Only psychological distress was significantly and positively associated with using mental health care services. Over 60% of the older adults who met the criteria for a DSM-IV disorder were not using mental health care services. Social and demographic factors did not predict service use in this population.


Study design and protocol for a culturally adapted cognitive behavioral stress and self-management intervention for localized prostate cancer: The Encuentros de Salud study.
Almost 2.8 million men in the U.S. are living with prostate cancer (PC), accounting for 40% of all male cancer survivors. Men diagnosed with prostate cancer may experience chronic and debilitating treatment side effects, including sexual and urinary dysfunction, pain and fatigue. Side effects can be stressful and can also lead to poor psychosocial functioning. Prior trials reveal that group-based cognitive behavioral stress and self-management (CBSM) is effective in reducing stress and mitigating some of these symptoms, yet little is known about the effects of culturally-translated CBSM among Spanish-speaking men with PC. This manuscript describes the rationale and study design of a multi-site, randomized controlled trial to determine whether participation in a culturally adapted cognitive behavioral stress management (C-CBSM) intervention leads to significantly greater reductions in symptom burden and improvements in health-related quality of life relative to participation in a non-culturally adapted cognitive behavioral stress management (CBSM) intervention. Participants (N = 260) will be Spanish-speaking Hispanic/Latino men randomized to the standard, non-culturally adapted CBSM intervention (e.g., cognitive behavioral strategies, stress management, and health maintenance) or the culturally adapted C-CBSM intervention (e.g., content adapted to be compatible with Hispanic/Latino cultural patterns and belief systems, meanings, values and social context) for 10 weeks. Primary outcomes (i.e., disease-specific symptom burden and health-related quality of life) will be assessed across time. We hypothesize that a culturally adapted C-CBSM intervention will be more efficacious in reducing symptom burden and improving health-related quality of life among Hispanic/Latino men when compared to a non-culturally adapted CBSM intervention.


The effect of cigarette smoke on fertilization and pre-implantation development: assessment using animal models, clinical data, and stem cells.
Numerous studies have repeatedly shown that women who smoke experience problems establishing and maintaining pregnancies, and recent work has further demonstrated that the in utero effects of smoke may not be manifested until months or even years after birth. The purpose of this review is to examine the recent literature dealing with the effects of cigarette smoke on the earliest stages of human prenatal development. Studies in this area have included the use of animal models, patients undergoing in vitro fertilization, and embryonic stem cell models. Events leading to fertilization, such as cumulus expansion, hyperactivation of sperm motility, and oocyte pick-up by the oviduct are all impaired by smoke exposure in animal models. Steps crucial to fertilization such as the acrosome reaction and sperm binding to the zona pellucida are likewise inhibited by cigarette smoke. Preimplantation embryos and stem cells that model embryos show a number of adverse responses to smoke exposure, including poor adhesion to extracellular matrices, diminished survival and proliferation, and increased apoptosis. The current literature demonstrates that the earliest stages of prenatal development are sensitive to smoke exposure and indicates that pregnant women should be advised not to smoke during this time.


Why have small multidrug resistance proteins not evolved into fused, internally duplicated structures?
The increasing number of solved membrane protein structures has led to the recognition of a common feature in a large fraction of the small-molecule transporters: inverted repeat structures, formed by two fused homologous membrane domains with opposite orientation in the membrane. An evolutionary pathway in which the ancestral state is a single gene encoding a dual-topology membrane protein capable of forming antiparallel homodimers has been posited. A gene duplication event enables the evolution of two oppositely orientated proteins that form antiparallel heterodimers. Finally, fusion of the two genes generates an internally duplicated transporter with two oppositely orientated membrane domains. Strikingly, however, in the small multidrug resistance (SMR) family of transporters, no fused, internally duplicated proteins have been found to date. Here, we have analyzed fused versions of the dual-topology transporter EmrE, a member of the SMR family, by blue-native PAGE and in vivo activity measurements. We find that fused constructs give rise to both intramolecular inverted repeat structures and competing intermolecular dimers of varying activity. The formation of several intramolecularly and intermolecularly paired species indicates that a gene fusion event may lower the overall amount of active protein, possibly explaining the apparent absence of fused SMR proteins in nature.