Perspectives on the Genetic Associations of Ankylosing Spondylitis.
Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.


Hemispheric asymmetries in the resolution of lexical ambiguity.
The linguistic phenomenon of lexical ambiguity has been intensively investigated as a means of gaining insight into general mechanisms of lexical access. It is now evident that both context and meaning frequency are significant factors in the determination of lexical outcomes. This suggests that hemispheric processes may be relevant to the resolution of lexical ambiguity, because both factors have been shown to have differential implications for the processing of language in the hemispheres. This study set out to examine the effects of context and meaning frequency on the resolution of ambiguous word meanings within the hemispheres. Sentences presented at the beginning of each trial embodied contexts which expressed either the dominant or subordinate meaning of a terminating homographic prime. Laterally presented target words reflected senses of the prime which were either consistent with, or inconsistent with, the context created by the preceding sentence. The most interesting results were observed at short prime-target intervals where it was found that although dominant meanings of the target did not give rise to visual field differences, subordinate meanings evoked facilitated responses only in the left visual field. This result suggests that the right hemisphere immediately and exhaustively activates the various meanings associated with a word, while in the left hemisphere initial access is selectively restricted to the dominant meaning. It is proposed that this reflects a model of language comprehension in which the right hemisphere plays a supportive role by making available a set of alternative and less probable word meanings, thus freeing the left hemisphere to focus cognitive resources upon the most probable meaning of a word in a given context.


Changing composition of the global stratosphere.
The current understanding of stratospheric chemistry is reviewed with particular attention to the influence of human activity. Models are in good agreement with measurements for a variety of species in the mid-latitude stratosphere, with the possible exception of ozone (O(3)) at high altitude. Rates calculated for loss of O(3) exceed rates for production by about 40 percent at 40 kilometers, indicating a possible but as yet unidentified source of high-altitude O(3). The rapid loss of O(3) beginning in the mid-1970s at low altitudes over Antarctica in the spring is due primarily to catalytic cycles involving halogen radicals. Reactions on surfaces of polar stratospheric clouds play an important role in regulating the abundance of these radicals. Similar effects could occur in northern polar regions and in cold regions of the tropics. It is argued that the Antarctic phenomenon is likely to persist: prompt drastic reduction in the emission of industrial halocarbons is required if the damage to stratospheric O(3) is to be reversed.


Comparison of the brain tissue response in rats to injury by argon and carbon dioxide lasers.
This study compares the acute and chronic response of brain tissue to injury by equal power density, focused argon (Ar) and carbon dioxide (CO2) laser beams. A cortical incision from 0.2-second laser pulses of 12.5 X 10(3) W/cm2 power density was made in the exposed cortex of 32 rats using either the CO2 or the Ar laser. The brains were examined at intervals from 1/2 hour to 1 month after injury. Histologically, all brain incisions were sharply demarcated hemispheroidal defects with a vaporized center bordered by a zone of coagulation necrosis surrounded by edema. The laser incisions were found to be of equal depth (less than 1 mm). The average cortical surface diameter of the CO2 laser incision was 0.86 mm for a focused beam spot size 0.45 mm in diameter, compared with 0.65 mm with the Ar laser, which had a focused beam spot size 0.15 mm in diameter. In both incisions, some delayed depth effect was observed. A progression of the tissue necrosis by approximately 17% was observed during the first 24 hours after injury. During the first 4 hours after injury, the Evans blue blood-brain barrier defect (EBBD) surrounding the cortical incisions averaged 5.80 mm2 for the CO2 incision and 0.888 mm2 for the Ar incision. In both types of brain incision, the EBBD appeared to resolve by 24 hours after injury. At 1 month after injury, a core of coagulation necrosis surrounded by mild fibrillary gliosis was observed. At the power density and focused beam spot sizes used, there was no significant difference in the overall brain tissue response to Ar and CO2 laser lesions.


Frequency dependent alterations in regional homogeneity of baseline brain activity in schizophrenia.
Low frequency oscillations are essential in cognitive function impairment in schizophrenia. While functional connectivity can reveal the synchronization between distant brain regions, the regional abnormalities in task-independent baseline brain activity are less clear, especially in specific frequency bands. Here, we used a regional homogeneity (ReHo) method combined with resting-state functional magnetic resonance imaging to investigate low frequency spontaneous neural activity in the three different frequency bands (slow-5:0.01-0.027 Hz; slow-4:0.027-0.08 Hz; and typical band: 0.01-0.08 Hz) in 69 patients with schizophrenia and 62 healthy controls. Compared with controls, schizophrenia patients exhibited decreased ReHo in the precentral gyrus, middle occipital gyrus, and posterior insula, whereas increased ReHo in the medial prefrontal cortex and anterior insula. Significant differences in ReHo between the two bands were found in fusiform gyrus and superior frontal gyrus (slow-4> slow-5), and in basal ganglia, parahippocampus, and dorsal middle prefrontal gyrus (slow-5> slow-4). Importantly, we identified significant interaction between frequency bands and groups in the inferior occipital gyrus and caudate body. This study demonstrates that ReHo changes in schizophrenia are widespread and frequency dependent.


Healthcare encounters and return to work: a qualitative study on sick-listed patients' experiences.
Sickness absence is a complex phenomenon affected by aspects other than disease. One important factor that can affect sick leave is the individual's experience of healthcare encounters. It is therefore essential to consider the quality of the encounter with health professionals and its impact on the patient's rehabilitation and return to work. The aim was to explore how sick-listed patients in Sweden perceive their contact with healthcare professionals in primary healthcare and to analyse what they view as crucial components for returning to work. A qualitative approach was used. Data were collected by semi-structured telephonic interviews with patients who were or had been on sick leave. The transcribed interview text was analysed according to qualitative content analysis. The analysis revealed two themes that highlight important areas for persons on sick leave in their healthcare encounters. The theme 'Trust in the relationship' contains categories describing the patients' feelings of participation, and of being believed, confirmed, and listened to, and also dedication on the part of healthcare providers. Healthcare encounters that were characterised by professionalism, knowledge, continuity, and a holistic approach seemed to create trust. The theme 'Structure and balance' contains the participants' views on important factors that could support the return-to-work process. All participants stated the importance of follow-up and a plan for rehabilitation. Sick leave itself can make a person passive, and participants in this study asked for support to balance activity, exercise, and work demands, which could facilitate their return to work. Healthcare professionals can facilitate sick-listed persons' rehabilitation back to work by providing a clear structure in the process and support in occupational balance. The healthcare encounters must build on a mutual trust.


Recognizing and overcoming inadequate health literacy, a barrier to care.
Health literacy-the ability to understand and act on health information-is essential for high-quality care. Many people, especially the elderly, who bear the greatest burden of disease, have inadequate health literacy. This adversely affects their quality of care, and places increased cost burdens on society. Learning to recognize when a patient may have low literacy skills and understanding the common ways in which these people misinterpret medical information can help physicians develop strategies to improve patients' health literacy.


Quality of care in nursing homes: an analysis of relationships among profit, quality, and ownership.
Recent work has highlighted a negative correlation between proprietary status and nursing home quality of care. This relationship might be explained by the context in which proprietary homes operate. However, another possible explanation is that some proprietary homes take excessive profit to the detriment of care quality. To examine the relationship between profit levels and quality in proprietary and nonproprietary nursing homes (NHs), accounting for resident and market characteristics. Data on 1098 free-standing NHs were taken from the California Office of Statewide Health Planning and Development, the On-line Survey Certification and Reporting System, and California licensing and statistical reports for 1998 and 1999. Tobit multivariate techniques were used to examine the relationship between deficiency citations and a range of explanatory variables, including profit. Proprietary homes in California had significantly lower quality of care than nonproprietary homes. A stratified analysis revealed that, controlling for resident, facility, and market characteristics, profits located within the highest 14% of the proprietary sector's profit distribution were associated with significantly more total deficiencies and serious deficiencies. This relationship was not found in nonproprietary facilities. Other factors related to deficiencies included the ethnic mix of residents and facility size. Within the context in which proprietary homes operate, profit above a given threshold is associated with a higher number of deficiencies. Given this and the role of the proprietary sector in NH care, careful monitoring of profit levels in this sector appears warranted.


Genetic association, seasonal infections and autoimmune basis of narcolepsy.
In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.


Optimizing the electrical stimulation of retinal ganglion cells.
Epiretinal prostheses aim to restore visual perception in the blind through electrical stimulation of surviving retinal ganglion cells (RGCs). While the effects of several waveform parameters (e.g., phase duration) on stimulation efficacy have been described, their relative influence remains unclear. Further, morphological differences between RGC classes represent a key source of variability that has not been accounted for in previous studies. Here we investigate the effect of electrical stimulus waveform parameters on activation of an anatomically homogenous RGC population and describe a technique for identifying optimal stimulus parameters to minimize the required stimulus charge. Responses of rat A2-type RGCs to a broad array of biphasic stimulation parameters, delivered via an epiretinal stimulating electrode (200 × 200 μ m) were recorded using whole-cell current clamp techniques. The data demonstrate that for rectangular charge-balanced stimuli, phase duration and polarity have the largest effect on threshold current amplitude-cells were most responsive to cathodic-first pulses of short phase duration. Waveform asymmetry and increases in interphase interval further reduced thresholds. Using optimal waveform parameters, we observed a drop in stimulus efficacy with increasing stimulation frequency. This was more pronounced for large cells. Our results demonstrate that careful choice of electrical waveform parameters can significantly improve the efficacy of electrical stimulation and the efficacy of implantable neurostimulators for the retina.


The multidrug resistance P-glycoprotein modulates cell regulatory volume decrease.
Cell volume is frequently down-regulated by the activation of anion channels. The role of cell swelling-activated chloride channels in cell volume regulation has been studied using the patch-clamp technique and a non-invasive microspectrofluorimetric assay for changes in cell volume. The rate of activation of these chloride channels was shown to limit the rate of regulatory volume decrease (RVD) in response to hyposmotic solutions. Expression of the human MDR1 or mouse mdr1a genes, but not the mouse mdr1b gene, encoding the multidrug resistance P-glycoprotein (P-gp), increased the rate of channel activation and the rate of RVD. In addition, P-gp decreased the magnitude of hyposmotic shock required to activate the channels and to elicit RVD. Tamoxifen selectively inhibited both chloride channel activity and RVD. No effect on potassium channel activity was elicited by expression of P-gp. The data show that, in these cell types, swelling-activated chloride channels have a central role in RVD. Moreover, they clarify the role of P-gp in channel activation and provide direct evidence that P-gp, through its effect on chloride channel activation, enhances the ability of cells to down-regulate their volume.


Outcome trends and safety measures after 30 years of laparoscopic cholecystectomy: a systematic review and pooled data analysis.
Laparoscopic cholecystectomy (LC), one of the most commonly performed surgical procedures, remains associated with significant major morbidity including bile leak and bile duct injury (BDI). The effect of changes in practice over time, and of interventions to improve patient safety, on morbidity rates is not well understood. The aim of this review was to describe current incidence rates and trends for BDI and other complications during and after LC, and to identify risk factors and preventative measures associated with morbidity and BDI. PubMed, MEDLINE, and Web of Science database searches and data extraction were conducted for studies which reported individual complications and complication rates following laparoscopic cholecystectomy in a representative population. Outcomes data were pooled. Meta-regression analysis was performed to assess factors associated with conversion, morbidity, and BDI rates. One hundred and fifty-one studies reporting outcomes for 505,292 patients were included in the final quantitative synthesis. Overall morbidity, BDI, and mortality rates were 1.6-5.3%, 0.32-0.52%, and 0.08-0.14%, respectively. Reported BDI rates reduced over time (1994-1999: 0.69(0.52-0.84)% versus 2010-2015 0.22(0.02-0.40)%, p = 0.011). Meta-regression analysis suggested higher conversion rates in developed versus developing countries (4.7 vs. 3.4%), though a greater degree of reporting bias was present in these studies, with no other significant associations identified. Overall, trends suggest a reduction in BDI over time with unchanged morbidity and mortality rates. However, data and reporting are heterogenous. Establishment of international outcomes registries should be considered.


RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.
In Caenorhabditis elegans the Toll-interleukin receptor domain adaptor protein TIR-1 via a conserved mitogen-activated protein kinase (MAPK) signaling cascade induces innate immunity and upregulates serotonin (5-HT) biosynthesis gene tph-1 in a pair of ADF chemosensory neurons in response to infection. Here, we identify transcription factors downstream of the TIR-1 signaling pathway. We show that common transcription factors control the innate immunity and 5-HT biosynthesis. We demonstrate that a cysteine to tyrosine substitution in an ARM motif of the HEAT/Arm repeat region of the TIR-1 protein confers TIR-1 hyperactivation, leading to constitutive tph-1 upregulation in the ADF neurons, increased expression of intestinal antimicrobial genes, and enhanced resistance to killing by the human opportunistic pathogen Pseudomonas aeruginosa PA14. A forward genetic screen for suppressors of the hyperactive TIR-1 led to the identification of DAF-19, an ortholog of regulatory factor X (RFX) transcription factors that are required for human adaptive immunity. We show that DAF-19 concerts with ATF-7, a member of the activating transcription factor (ATF)/cAMP response element-binding B (CREB) family of transcription factors, to regulate tph-1 and antimicrobial genes, reminiscent of RFX-CREB interaction in human immune cells. daf-19 mutants display heightened susceptibility to killing by PA14. Remarkably, whereas the TIR-1-MAPK-DAF-19/ATF-7 pathway in the intestinal immunity is regulated by DKF-2/protein kinase D, we found that the regulation of tph-1 expression is independent of DKF-2 but requires UNC-43/Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Our results suggest that pathogenic cues trigger a common core-signaling pathway via tissue-specific mechanisms and demonstrate a novel role for RFX factors in neuronal and innate immune responses to infection.


A snake toxin inhibitor of inward rectifier potassium channel ROMK1.
Mamba snake dendrotoxins have been used extensively in biochemical and physiological studies of K+ channels of the brain. Their known targets of inhibition have been limited to the family of voltage-gated K+ channels. We report the isolation of a dendrotoxin inhibitor of ROMK1, a channel belonging to the inward rectifier family of K+ channels. The inhibitory activity, fractionated to purity with FPLC and HPLC, is identical to a previously identified delta-dendrotoxin. To verify that delta-dendrotoxin blocks ROMK1 channels, a cDNA encoding the toxin was synthesized and recombinant toxin expressed in Escherichia coli. Electrophysiological recordings reveal that recombinant delta-dendrotoxin has a half-maximal inhibition constant (Kd) of 150 nM when applied to ROMK1 channels expressed in Xenopus laevis oocytes. That the delta-dendrotoxin binding site exists on separate K+ channel classes is shown by its high affinity for two of the voltage-gated family of channels, Kv1.1 (Kd < 0.1 nM) and Kv1.6 (Kd = 23 nM). Single amino acid substitutions in ROMK1 indicate that delta-dendrotoxin binds to the pore region of ROMK1 even though it does not completely block conduction through the pore. These results suggest that dendrotoxins inhibit K+ channels by recognizing the structurally conserved pore region of these channels.


Modelling of human transplacental transport as performed in Copenhagen, Denmark.
Placenta perfusion models are very effective when studying the placental mechanisms in order to extrapolate to real-life situations. The models are most often used to investigate the transport of substances between mother and foetus, including the potential metabolism of these. We have studied the relationships between maternal and foetal exposures to various compounds including pollutants such as polychlorinated biphenyls, polybrominated flame retardants, nanoparticles as well as recombinant human antibodies. The compounds have been studied in the human placenta perfusion model and to some extent in vitro with an established human monolayer trophoblast cell culture model. Results from our studies distinguish placental transport of substances by physicochemical properties, adsorption to placental tissue, binding to transport and receptor proteins and metabolism. We have collected data from different classes of chemicals and nanoparticles for comparisons across chemical structures as well as different test systems. Our test systems are based on human material to bypass the extrapolation from animal data. By combining data from our two test systems, we are able to rank and compare the transport of different classes of substances according to their transport ability. Ultimately, human data including measurements in cord blood contribute to the study of placental transport.


Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea?
Nutrients and properties of lipases affect survival of lipolytic activity during aboral gastrointestinal transit. Whether different doses and formulations of bacterial lipase and diets affect steatorrhea was tested in pancreatic-insufficient dogs. A dose of 0-600,000 IU of powdered and 135,000 and 300,000 IU of liquid bacterial lipase was given with a standard meal to 5 dogs with ligated pancreatic ducts. In 4 dogs, 0 or 300,000 IU (normal 6-hour postprandial amount) of powder bacterial lipase was also given with five meals containing 850 kcal with different nutrient caloric densities (mixture design). Coefficients of fat absorption during 72-hour fecal balance studies were used to assess treatments. With the standard meal, powder bacterial lipase reduced steatorrhea in a dose-dependent manner (P = 0.03), and 135,000 and 300,000 IU of the liquid form decreased steatorrhea more than powder bacterial lipase (P = 0.017 and 0.057, respectively). Coefficients of fat absorption with 300,000 IU of powder bacterial lipase correlated (r2 = 0.79; P < 0.001) with increasing proportions of fat calories in diets. Liquid bacterial lipase decreases steatorrhea more than powder, and 300,000 IU of powder bacterial lipase ingested with high-fat meals corrects canine pancreatic steatorrhea. The combination of adequate mixing of small amounts (milligrams) of bacterial lipase and high-fat meals abolishes canine steatorrhea and may abolish human pancreatic steatorrhea.


Heat-transfer-method-based cell culture quality assay through cell detection by surface imprinted polymers.
Previous work has indicated that surface imprinted polymers (SIPs) allow for highly specific cell detection through macromolecular cell imprints. The combination of SIPs with a heat-transfer-based read-out technique has led to the development of a selective, label-free, low-cost, and user-friendly cell detection assay. In this study, the breast cancer cell line ZR-75-1 is used to assess the potential of the platform for monitoring the quality of a cell culture in time. For this purpose, we show that the proposed methodology is able to discriminate between the original cell line (adherent growth, ZR-75-1a) and a descendant cell line (suspension growth, ZR-75-1s). Moreover, ZR-75-1a cells were cultured for a prolonged period of time and analyzed using the heat-transfer method (HTM) at regular time intervals. The results of these experiments demonstrate that the thermal resistance (Rth) signal decays after a certain number of cell culture passages. This can likely be attributed to a compromised quality of the cell culture due to cross-contamination with the ZR-75-1s cell line, a finding that was confirmed by classical STR DNA profiling. The cells do not express the same functional groups on their membrane, resulting in a weaker bond between cell and imprint, enabling cell removal by mechanical friction, provided by flushing the measuring chamber with buffer solution. These findings were further confirmed by HTM and illustrate that the biomimetic sensor platform can be used as an assay for monitoring the quality of cell cultures in time.


First anatomical network analysis of fore- and hindlimb musculoskeletal modularity in bonobos, common chimpanzees, and humans.
Studies of morphological integration and modularity, and of anatomical complexity in human evolution typically focus on skeletal tissues. Here we provide the first network analysis of the musculoskeletal anatomy of both the fore- and hindlimbs of the two species of chimpanzee and humans. Contra long-accepted ideas, network analysis reveals that the hindlimb displays a pattern opposite to that of the forelimb: Pan big toe is typically seen as more independently mobile, but humans are actually the ones that have a separate module exclusively related to its movements. Different fore- vs hindlimb patterns are also seen for anatomical network complexity (i.e., complexity in the arrangement of bones and muscles). For instance, the human hindlimb is as complex as that of chimpanzees but the human forelimb is less complex than in Pan. Importantly, in contrast to the analysis of morphological integration using morphometric approaches, network analyses do not support the prediction that forelimb and hindlimb are more dissimilar in species with functionally divergent limbs such as bipedal humans.


The method of variation of constants and multiple time scales in orbital mechanics.
The method of variation of constants is an important tool used to solve systems of ordinary differential equations, and was invented by Euler and Lagrange to solve a problem in orbital mechanics. This methodology assumes that certain "constants" associated with a homogeneous problem will vary in time in response to an external force. It also introduces one or more constraint equations. We show that these constraints can be generalized in analogy to gauge theories in physics, and that different constraints can offer conceptual advances and methodological benefits to the solution of the underlying problem. Examples are given from linear ordinary differential equation theory and from orbital mechanics. However, a slow driving force in the presence of multiple time scales contained in the underlying (homogeneous) problem nevertheless requires special care, and this has strong implications to the analytic and numerical solutions of problems ranging from celestial mechanics to molecular dynamics. (c) 2003 American Institute of Physics.


Killing Range: Explaining Lethality Variance within a Terrorist Organization.
This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level.


Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C. elegans neurons.
Cilia have diverse roles in motility and sensory reception and their dysfunction contributes to cilia-related diseases. Assembly and maintenance of cilia depends on the intraflagellar transport (IFT) of axoneme, membrane, matrix and signalling proteins to appropriate destinations within the organelle. In the current model, these diverse cargo proteins bind to multiple sites on macromolecular IFT particles, which are moved by a single anterograde IFT motor, kinesin-II, from the ciliary base to its distal tip, where cargo-unloading occurs. Here, we describe the observation of fluorescent IFT motors and IFT particles moving along distinct domains within sensory cilia of wild-type and IFT-motor-mutant Caenorhabditis elegans. We show that two anterograde IFT motor holoenzymes, kinesin-II and Osm-3-kinesin, cooperate in a surprising way to control two pathways of IFT that build distinct parts of cilia. Instead of each motor independently moving its own specific cargo to a distinct destination, the two motors function redundantly to transport IFT particles along doublet microtubules adjacent to the transition zone to form the axoneme middle segment. Next, Osm-3-kinesin alone transports IFT particles along the distal singlet microtubules to stabilize the distal segment. Thus, the subtle coordinate activity of these IFT motors creates two sequential transport pathways.


Objective neuropsychological test performance of professional divers reporting a subjective complaint of "forgetfulness or loss of concentration".
This study attempted to determine whether the higher prevalence of reported "forgetfulness or loss of concentration" among professional divers can be confirmed using objective neuropsychological tests. Secondary aims were to qualify the functional nature of the complaints and to ascertain whether reduced performance was linked to diving history. In a case-control study, the neuropsychological test performance of divers complaining of moderate or severe "forgetfulness or loss of concentration" was compared with two age-matched control groups reporting no or slight "forgetfulness or loss of concentration" ("nonforgetful" divers and "nonforgetful" nondivers). The group differences were analyzed using a multivariate analysis of co-variance, followed by canonical discriminant function analysis. Altogether 102 divers with a complaint, 100 nonforgetful divers, and 100 nonforgetful nondivers completed the study. The overall neuropsychological performance differed significantly between the groups [Pillai's trace: F(24,484)=2.04, P=0.003]. Verbal memory (Logical Memory and the California Verbal Learning Test), current intelligence (Wechsler Abbreviated Scale of Intelligence), and sustained attention (rapid visual processing) were poorer among the divers with a complaint than among the nonforgetful divers or the nonforgetful nondivers. The tests of memory, but not those of executive function, differentiated the divers with complaints from the two control groups. Mixed gas bounce diving and surface oxygen decompression diving, but not other techniques, were negatively associated with memory performance. A cognitive complaint of divers was confirmed using objective tests of neuropsychological performance. Memory, rather than executive function, was affected at the group level, but only to a mild degree. The relationships between diving experience and neuropsychological test performance were small and only seen with diving techniques used in the offshore oil and gas industry.


Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene.
Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts. Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively. Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD. ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.


Regional gray matter correlates of perceived emotional intelligence.
Coping with stressful life events requires a degree of skill in the ability to attend to, comprehend, label, communicate and regulate emotions. Individuals vary in the extent to which these skills are developed, with the term 'alexithymia' often applied in the clinical and personality literature to those individuals most compromised in these skills. Although a frontal lobe model of alexithymia is emerging, it is unclear whether such a model satisfactorily reflects brain-related patterns associated with perceived emotional intelligence at the facet level. To determine whether these trait meta-mood facets (ability to attend to, have clarity of and repair emotions) have unique gray matter volume correlates, a voxel-based morphometry study was conducted in 30 healthy adults using the Trait Meta Mood Scale while co-varying for potentially confounding sociodemographic variables. Poorer Attention to Emotion was associated with lower gray matter volume in clusters distributed primarily throughout the frontal lobe, with peak correlation in the left medial frontal gyrus. Poorer Mood Repair was related to lower gray matter volume in three clusters in frontal and inferior parietal areas, with peak correlation in the left anterior cingulate. No significant volumetric correlations emerged for the Clarity of Emotion facet. We discuss the localization of these areas in the context of cortical circuits known to be involved in processes of self-reflection and cognitive control.


Post-hoc power estimation for topological inference in fMRI.
When analyzing functional MRI data, several thresholding procedures are available to account for the huge number of volume units or features that are tested simultaneously. The main focus of these methods is to prevent an inflation of false positives. However, this comes with a serious decrease in power and leads to a problematic imbalance between type I and type II errors. In this paper, we show how estimating the number of activated peaks or clusters enables one to estimate post-hoc how powerful the selection procedure performs. This procedure can be used in real studies as a diagnostics tool, and raises awareness on how much activation is potentially missed. The method is evaluated and illustrated using simulations and a real data example. Our real data example illustrates the lack of power in current fMRI research.


Nuclear structure relevant to neutrinoless double beta decay: 76Ge and 76Se.
The possibility of observing neutrinoless double beta decay offers the opportunity of determining the effective neutrino mass if the nuclear matrix element were known. Theoretical calculations are uncertain, and measurements of the occupations of valence orbits by nucleons active in the decay can be important. The occupation of valence neutron orbits in the ground states of 76Ge (a candidate for such decay) and 76Se (the daughter nucleus) were determined by precisely measuring cross sections for both neutron-adding and removing transfer reactions. Our results indicate that the Fermi surface is much more diffuse than in theoretical calculations. We find that the populations of at least three orbits change significantly between these two ground states while in the calculations, the changes are confined primarily to one orbit.


Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin.
Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection.


A theory of self-nonself discrimination.
1) Induction of humoral antibody formation involves the obligatory recognition of two determinants on an antigen, one by the receptor antibody of the antigen-sensitive cell and the other by carrier antibody (associative interaction). 2) Paralysis of antibody formation involves the obligatory recognition of only one determinant by the receptor antibody of the antigen-sensitive cell; that is, a nonimmunogenic molecule (a hapten) can paralyze antigen-sensitive cells. 3) There is competition between paralysis and induction at the level of the antigen-sensitive cell. 4) The mechanisms of low- and high-zone paralysis, and maintenance of the unresponsive state, are identical. 5) High-zone paralysis occurs when both the carrier antibody and the receptor antibody are saturated, so that associated interactions cannot take place. 6) The mechanisms of paralysis and induction for the carrier-antigen-sensitive cell are identical to those for the humoral-antigen-sensitive cell. 7) The formation of carrier-antigen-sensitive cells is thymus-dependent, whereas humoral-antigen-sensitive cells are derived from bone marrow. Since carrier antibody is required for induction, all antigens are thymus-dependent. 8) The interaction of antigen with the receptor antibody on an antigen-sensitive cell results in a conformational change in an invariant region of the receptor and consequently paralyzes the cell. As the receptor is probably identical to the induced antibody, all antibody molecules are expected to be able to undergo a conformational change on binding a hapten. The obligatory associated recognition by way of carrier antibody (inductive signal) involves a conformational change in the carrier antibody, leading to a second signal to the antigen-sensitive cell. 9) The foregoing requirements provide an explanation for self-nonself discrimination. Tolerance to self-antigens involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.


Clinical outcomes of pars plicata anterior vitrectomy: 2-year results.
To demonstrate the safety and outcome of a surgical approach that uses pars plicata site for anterior vitrectomy during phacoemulsification procedure complicated by posterior capsule rupture and residual cortical matter. Single center, retrospective, interventional, noncomparative study. Medical records of a consecutive series of 35 eyes of 35 patients who underwent pars plicata anterior vitrectomy (PPAV) were reviewed. The main outcome measures were corrected and uncorrected distance visual acuity (CDVA, UDVA), early and late postoperative complications and intraocular pressure (IOP). Ultrasound biomicroscopic (UBM) evaluation of sclerotomy site and spectral domain optical coherence tomography analysis for central macular thickness (CMT) was performed. The final visual outcome at 2 years was evaluated. At 2 years follow-up, the mean postoperative UDVA (logarithm of the minimum angle of resolution [logMAR]) and CDVA (logMAR) was 0.49 ± 0.26 and 0.19 ± 0.14, respectively. There was no significant change in the IOP (P = 0.061) and the mean CMT at 2 years was 192.5 ± 5.54 mm. The postoperative UBM image of the sclerotomy site at 8 weeks demonstrated a clear wound without any vitreous adhesion or incarceration. Intraoperative hyphema was seen in 1 (2.8%) case and postoperative uveitis was seen in 2 (5.7%) cases, which resolved with medications. No case of an iatrogenic retinal break or retinal detachment was reported. PPAV enables a closed chamber approach, allows thorough cleanup of vitreous in the pupillary plane and anterior chamber and affords better access to the subincisional and retropupillary cortical remnant with a significant visual outcome and an acceptable complication rate.


Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.


Ten modifiable health risk factors are linked to more than one-fifth of employer-employee health care spending.
An underlying premise of the Affordable Care Act provisions that encourage employers to adopt health promotion programs is an association between workers' modifiable health risks and increased health care costs. Employers, consultants, and vendors have cited risk-cost estimates developed in the 1990s and wondered whether they still hold true. Examining ten of these common health risk factors in a working population, we found that similar relationships between such risks and total medical costs documented in a widely cited study published in 1998 still hold. Based on our sample of 92,486 employees at seven organizations over an average of three years, $82,072,456, or 22.4 percent, of the $366,373,301 spent annually by the seven employers and their employees in the study was attributed to the ten risk factors studied. This amount was similar to almost a quarter of spending linked to risk factors (24.9 percent) in the 1998 study. High risk for depression remained most strongly associated with increased per capita annual medical spending (48 percent, or $2,184, higher). High blood glucose, high blood pressure, and obesity were strongly related to increased health care costs (31.8 percent, 31.6 percent, and 27.4 percent higher, respectively), as were tobacco use, physical inactivity, and high stress. These findings indicate ongoing opportunities for well-designed and properly targeted employer-sponsored health promotion programs to produce substantial savings.


Vertical and Horizontal Jump Tests Are Strongly Associated With Competitive Performance in 100-m Dash Events.
Fourteen male elite sprinters performed short-distance sprints and jump tests until 18 days before 100-m dash competitions in track and field to determine if these tests are associated with 100-m sprint times. Testing comprised of squat jumps (SJ), countermovement jumps (CMJ), horizontal jumps (HJ), maximum mean propulsive power relative to body mass in loaded jump squats, and a flying start 50-m sprint. Moderate associations were found between speed tests and competitive 100-m times (r = 0.54, r = 0.61, and r = 0.66 for 10-, 30-, and 50-m, respectively, p ≤ 0.05). In addition, the maximum mean propulsive power relative to body mass was very largely correlated with 100-m sprinting performance (r = 0.75, p < 0.01). The correlations of SJ, CMJ, and HJ with actual 100-m sprinting times amounted to -0.82, -0.85, and -0.81, respectively. Because of their practicality, safeness, and relationship with the actual times obtained by top-level athletes in 100-m dash events, it is highly recommended that SJ, CMJ, and HJ be regularly incorporated into elite sprint-testing routines.


Improved Ribosome-Footprint and mRNA Measurements Provide Insights into Dynamics and Regulation of Yeast Translation.
Ribosome-footprint profiling provides genome-wide snapshots of translation, but technical challenges can confound its analysis. Here, we use improved methods to obtain ribosome-footprint profiles and mRNA abundances that more faithfully reflect gene expression in Saccharomyces cerevisiae. Our results support proposals that both the beginning of coding regions and codons matching rare tRNAs are more slowly translated. They also indicate that emergent polypeptides with as few as three basic residues within a ten-residue window tend to slow translation. With the improved mRNA measurements, the variation attributable to translational control in exponentially growing yeast was less than previously reported, and most of this variation could be predicted with a simple model that considered mRNA abundance, upstream open reading frames, cap-proximal structure and nucleotide composition, and lengths of the coding and 5' UTRs. Collectively, our results provide a framework for executing and interpreting ribosome-profiling studies and reveal key features of translational control in yeast.


Histone hyperacetylation can induce unfolding of the nucleosome core particle.
A direct correlation exists between the level of histone H4 hyperacetylation induced by sodium butyrate and the extent to which nucleosomes lose their compact shape and become elongated (62.0% of the particles have a length/width ratio over 1.6; overall mean in the length/width ratio = 1.83 +/- 0.48) when bound to electron microscope specimen grids at low ionic strength (1mM EDTA, 10mM Tris, pH 8.0). A marked proportion of elongated core particles is also observed in the naturally occurring hyperacetylated chicken testis chromatin undergoing spermatogenesis when analyzed at low ionic strength (36.8% of the particles have a length/width ratio over 1.6). Core particles of elongated shape (length/width ratio over 1.6) generated under low ionic strength conditions are absent in the hypoacetylated chicken erythrocyte chromatin and represent only 2.3% of the untreated Hela S3 cell core particles containing a low proportion of hyperacetylated histones. The marked differences between control and hyperacetylated core particles are absent if the particles are bound to the carbon support film in the presence of 0.2 M NaCl, 6mM MgCl2 and 10mM Tris pH 8.0, conditions known to stabilize nucleosomes. A survey of the published work on histone hyperacetylation together with the present results indicate that histone hyperacetylation does not produce any marked disruption of the core particle 'per se', but that it decreases intranucleosomal stabilizing forces as judged by the lowered stability of the hyperacetylated core particle under conditions of shearing stress such as cationic competition by the carbon support film of the EM grid for DNA binding.


Breast cancer - one term, many entities?
Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups. Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables. A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.


Measles and atopy in Guinea-Bissau.
Epidemiological studies have led to speculation that infections in early childhood may prevent allergic sensitisation but evidence to support this hypothesis is lacking. We investigated whether measles infection protects against the development of atopy in children of Guinea-Bissau, West Africa. We conducted a historical cohort study in Bandim, a semi-rural district of Bissau, the capital of Guinea-Bissau. 395 young adults, first surveyed in 1978-80 aged 0-6 years, were followed up in 1994. Our analyses were restricted to 262 individuals still living in Bandim for whom a measles history, documented in childhood, was judged to be reliable. We defined atopy as skin-prick test positivity (> or = 3 mm weal) to one or more of seven allergens. 17 (12.8 percent) of 133 participants who had had measles infection were atopic compared with 33 (25.6 percent) of 129 of those who had been vaccinated and not had measles (odds ratio, adjusted for potential confounding variables 0.36 [95 percent CI 0.17-0.78], p=O.O1). Participants who had been breastfed for more than a year were less likely to have a positive skin test to housedust mite. After adjustment for breastfeeding and other variables, measles infection was associated with a large reduction in the risk of skin-prick test positivity to housedust mite (odds ratio for Dermatophagoides pteronyssinus 0.20 [0.05-0.81], p=0.02; D farinae 0.20 [0.06-0.71], p=0.01). Measles infection may prevent the development of atopy in African children.


Optimization of multicore fiber for high-temperature sensing.
We demonstrate a novel high-temperature sensor using multicore fiber (MCF) spliced between two single-mode fibers. Launching light into such fiber chains creates a supermode interference pattern in the MCF that translates into a periodic modulation in the transmission spectrum. The spectrum shifts with changes in temperature and can be easily monitored in real time. This device is simple to fabricate and has been experimentally shown to operate at temperatures up to 1000°C in a very stable manner. Through simulation, we have optimized the multicore fiber design for sharp spectral features and high overall transmission in the optical communications window. Comparison between the experiment and the simulation has also allowed determination of the thermo-optic coefficient of the MCF as a function of temperature.


A high-density scan of the Z chromosome in Ficedula flycatchers reveals candidate loci for diversifying selection.
Theoretical and empirical data suggest that genes located on sex chromosomes may play an important role both for sexually selected traits and for traits involved in the build-up of hybrid incompatibilities. We investigated patterns of genetic variation in 73 genes located on the Z chromosomes of two species of the flycatcher genus Ficedula, the pied flycatcher and the collared flycatcher. Sequence data were evaluated for signs of selection potentially related to genomic differentiation in these young sister species, which hybridize despite reduced fitness of hybrids. Seven loci were significantly more divergent between the two species than expected under neutrality and they also displayed reduced nucleotide diversity, consistent with having been influenced by directional selection. Two of the detected candidate regions contain genes that are associated with plumage coloration in birds. Plumage characteristics play an important role in species recognition in these flycatchers suggesting that the detected genes may have been involved in the evolution of sexual isolation between the species.


Atmospheric conditions and composition that influence PM2.5 oxidative potential in Beijing, China.
Epidemiological studies have consistently linked exposure to PM2.5 with adverse health effects. The oxidative potential (OP) of aerosol particles has been widely suggested as a measure of their potential toxicity. Several acellular chemical assays are now readily employed to measure OP; however, uncertainty remains regarding the atmospheric conditions and specific chemical components of PM2.5 that drive OP. A limited number of studies have simultaneously utilised multiple OP assays with a wide range of concurrent measurements and investigated the seasonality of PM2.5 OP. In this work, filter samples were collected in winter 2016 and summer 2017 during the atmospheric pollution and human health in a Chinese megacity campaign (APHH-Beijing), and PM2.5 OP was analysed using four acellular methods: ascorbic acid (AA), dithiothreitol (DTT), 2,7-dichlorofluorescin/hydrogen peroxidase (DCFH) and electron paramagnetic resonance spectroscopy (EPR). Each assay reflects different oxidising properties of PM2.5, including particle-bound reactive oxygen species (DCFH), superoxide radical production (EPR) and catalytic redox chemistry (DTT/AA), and a combination of these four assays provided a detailed overall picture of the oxidising properties of PM2.5 at a central site in Beijing. Positive correlations of OP (normalised per volume of air) of all four assays with overall PM2.5 mass were observed, with stronger correlations in winter compared to summer. In contrast, when OP assay values were normalised for particle mass, days with higher PM2.5 mass concentrations (μgm-3) were found to have lower mass-normalised OP values as measured by AA and DTT. This finding supports that total PM2.5 mass concentrations alone may not always be the best indicator for particle toxicity. Univariate analysis of OP values and an extensive range of additional measurements, 107 in total, including PM2.5 composition, gas-phase composition and meteorological data, provided detailed insight into the chemical components and atmospheric processes that determine PM2.5 OP variability. Multivariate statistical analyses highlighted associations of OP assay responses with varying chemical components in PM2.5 for both mass- and volume-normalised data. AA and DTT assays were well predicted by a small set of measurements in multiple linear regression (MLR) models and indicated fossil fuel combustion, vehicle emissions and biogenic secondary organic aerosol (SOA) as influential particle sources in the assay response. Mass MLR models of OP associated with compositional source profiles predicted OP almost as well as volume MLR models, illustrating the influence of mass composition on both particle-level OP and total volume OP. Univariate and multivariate analysis showed that different assays cover different chemical spaces, and through comparison of mass- and volume-normalised data we demonstrate that mass-normalised OP provides a more nuanced picture of compositional drivers and sources of OP compared to volume-normalised analysis. This study constitutes one of the most extensive and comprehensive composition datasets currently available and provides a unique opportunity to explore chemical variations in PM2.5 and how they affect both PM2.5 OP and the concentrations of particle-bound reactive oxygen species.


The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial.
Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. NTR2657.


Manufacture of elastic biodegradable PLCL scaffolds for mechano-active vascular tissue engineering.
A soft and very elastic poly(lactide-co-epsilon-caprolactone) (PLCL)(50:50, Mn 185 x 10(3)) was synthesized. Tubular scaffolds were prepared by an extrusion-particulate leaching method for mechano-active vascular tissue engineering. The copolymer was very flexible but completely rubber-like elastic. Even the high porous PLCL scaffolds (90% salt wt) exhibited 200% elongation, but recovery over 85% in a tensile test. Moreover, the PLCL scaffolds maintained their high elasticity also in culture media under cyclic mechanical strain conditions. The highly porous scaffold (90% salt wt) withstood for an initial 1 week without any deformation and sustained for 2 weeks in culture media under cyclic stress of 10% amplitude and at 1 Hz frequency which are similar to the natural vascular conditions. Vascular smooth muscle cells (VSMCs) were seeded on to the PLCL scaffolds. The cell adhesion and proliferation on the scaffolds of various pore-size were increased with increasing pore size. For the pore sizes of 50-100 microm, 100-150 microm, 150-200 microm and 200-250 microm, the ratios of cell numbers were about 1:1.2:1.9:2.2, respectively, at both 12 h and 5 days. Similarly, the higher porous scaffolds exhibited more cell adhesion and proliferation compared to lower porous one, where the effect was more pronounced in the longer proliferation period. SMC-seeded scaffolds were implanted subcutaneously in athymic nude mice to confirm the biocompatibility. Such a high elastic property and proper biocompatibility to SMCs of PLCL scaffolds prepared in this study will be very useful to engineer SM-containing tissues such as blood vessels under mechanically dynamic environments (mechano-active tissue engineering).


Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness.
Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory-motor cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-striatal-cerebellar regions relative to controls, possibly reflective of sensory gating and top-down control disturbances. Clustering revealed that this dysconnectivity was prominent for thalamic nuclei densely connected with the prefrontal cortex. Classification and cross-diagnostic results suggest that thalamic dysconnectivity may be a neural marker for disturbances across diagnoses. Present findings, using one of the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness.


Methods of identifying mood disorders in stroke patients: experience in the Oxfordshire Community Stroke Project.
Four simple methods for assessing mood disorders were examined in a cohort of stroke patients: the Beck Depression Inventory; a visual analogue mood scale; a nurses' depression rating; and a carers' depression rating. None of the measures was entirely satisfactory, either because of inaccuracy when compared to a standardized psychiatric interview, or because of low response rates. A review of their case records showed that the patients' general practitioners were aware of nearly all those with severe persistent mood disorders. The implications of these findings for clinical practice are discussed.


Petasin potently inhibits mitochondrial complex I-based metabolism that supports tumor growth and metastasis.
Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells.


Model-based prediction of human hair color using DNA variants.
Predicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic purposes, is human eye color, for which it has been recently demonstrated that highly accurate prediction is feasible from a small number of DNA variants. Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies. We analyzed in Polish Europeans with single-observer hair color grading 45 single nucleotide polymorphisms (SNPs) from 12 genes previously associated with human hair color variation. We found that a model based on a subset of 13 single or compound genetic markers from 11 genes predicted red hair color with over 0.9, black hair color with almost 0.9, as well as blond, and brown hair color with over 0.8 prevalence-adjusted accuracy expressed by the area under the receiver characteristic operating curves (AUC). The identified genetic predictors also differentiate reasonably well between similar hair colors, such as between red and blond-red, as well as between blond and dark-blond, highlighting the value of the identified DNA variants for accurate hair color prediction.


Gender disparities in retreatment patients of tuberculosis: A north Indian study.
'Retreatment' for tuberculosis (TB) has long been a neglected area in global TB control India. However India disproportionately accounts for nearly half of retreatment TB cases notified globally. Sex differences vary in different age groups and in different parts of the world. The present study focuses on whether gender-based differences are present in notification rates, clinical presentation, and treatment outcomes of different subcategories of patients registered under category II of Revised National TB Control Programme (RNTCP) Chandigarh. A longitudinal study was designed and the patients registered under RNTCP category II from June 2010 to December 2011. Out of total 607 patients registered during this period under category II of RNTCP in Chandigarh, 545 consented to participate in the study. These were followed-up to September 2012 till the completion of treatment. All 545 recruited cases were stratified into males and females and the results analyzed. The Z test for proportion (for comparing differences in proportions) and Student's t-test (for comparing mean) were performed for statistical analysis. From the cohort of 545 patients, 348 (63.9%) were males and 197 (36.1%) were female patients with overall male to female ratio 1.8:1. The proportion of male patients notified was significantly higher than females (Z = 5.93, P < 0.001). The proportion of extrapulmonary cases was higher in the females (28.4%) as compared with males (17%) (P < 0.001). Males outnumbered females in all the unfavorable outcomes death, default, and failure. The default in males was significant as compared to the females (Z = 5.21, P < 0.001). The findings of this study suggest a sex difference in the notification rate of retreatment cases of TB. Reasons for a better outcome and low notification rate for TB in females are more due to epidemiological factors than a differential access of the health care. Integrated research is required to outline the relative roles played by epidemiology.


Neurofeedback Training Effects on Inhibitory Brain Activation in ADHD: A Matter of Learning?
Neurofeedback training (NF) is a promising non-pharmacological treatment for ADHD that has been associated with improvement of attention-deficit/hyperactivity disorder (ADHD)-related symptoms as well as changes in electrophysiological measures. However, the functional localization of neural changes following NF compared to an active control condition, and of successful learning during training (considered to be the critical mechanism for improvement), remains largely unstudied. Children with ADHD (N=16, mean age: 11.81, SD: 1.47) were randomly assigned to either slow cortical potential (SCP, n=8) based NF or biofeedback control training (electromyogram feedback, n=8) and performed a combined Flanker/NoGo task pre- and post-training. Effects of NF, compared to the active control, and of learning in transfer trials (approximating successful transfer to everyday life) were examined with respect to clinical outcome and functional magnetic resonance imaging (fMRI) changes during inhibitory control. After 20 sessions of training, children in the NF group presented reduced ADHD symptoms and increased activation in areas associated with inhibitory control compared to baseline. Subjects who were successful learners (n=9) also showed increased activation in an extensive inhibitory network irrespective of the type of training. Activation increased in an extensive inhibitory network following NF training, and following successful learning through NF and control biofeedback. Although this study was only powered to detect large effects and clearly requires replication in larger samples, the results suggest a crucial role for learning effects in biofeedback trainings.


Increase in facility-based deliveries associated with a maternal health voucher programme in informal settlements in Nairobi, Kenya.
To measure whether there was an association between the introduction of an output-based voucher programme and the odds of a facility-based delivery in two Nairobi informal settlements. Nairobi Urban Health and Demographic Surveillance System (NUHDSS) and two cross-sectional household surveys in Korogocho and Viwandani informal settlements in 2004-05 and 2006-08. Odds of facility-based delivery were estimated before and after introduction of an output-based voucher. Supporting NUHDSS data were used to determine whether any trend in maternal health care was coincident with immunizations, a non-voucher outpatient service. As part of NUHDSS, households in Korogocho and Viwandani reported place of delivery and the presence of a skilled birth attendant (2003-10) and vaccination coverage (2003-09). A detailed maternal and child health (MCH) tool was added to NUHDSS (September 2006-10). Prospective enrolment in NUHDSS-MCH was conditional on having a newborn after September 2006. In addition to recording mother's place of delivery, NUHDSS-MCH recorded the use of the voucher. There were significantly greater odds of a facility-based delivery among respondents during the voucher programme compared with similar respondents prior to voucher launch. Testing whether unrelated outpatient care also increased, a falsification exercise found no significant increase in immunizations for children 12-23 months of age in the same period. Although the proportion completing any antenatal care (ANC) visit remained above 95% of all reported pregnancies and there was a significant increase in facility-based deliveries, the proportion of women completing 4+ ANC visits was significantly lower during the voucher programme. A positive association was observed between vouchers and facility-based deliveries in Nairobi. Although there is a need for higher quality evidence and validation in future studies, this statistically significant and policy relevant finding suggests that increases in facility-based deliveries can be achieved through output-based finance models that target subsidies to underserved populations.


MARCH ubiquitin ligases alter the itinerary of clathrin-independent cargo from recycling to degradation.
Following endocytosis, internalized plasma membrane proteins can be recycled back to the cell surface or trafficked to late endosomes/lysosomes for degradation. Here we report on the trafficking of multiple proteins that enter cells by clathrin-independent endocytosis (CIE) and determine that a set of proteins (CD44, CD98, and CD147) found primarily in recycling tubules largely failed to reach late endosomes in HeLa cells, whereas other CIE cargo proteins, including major histocompatibility complex class I protein (MHCI), trafficked to both early endosome antigen 1 (EEA1) and late endosomal compartments in addition to recycling tubules. Expression of the membrane-associated RING-CH 8 (MARCH8) E3 ubiquitin ligase completely shifted the trafficking of CD44 and CD98 proteins away from recycling tubules to EEA1 compartments and late endosomes, resulting in reduced surface levels. Cargo affected by MARCH expression, including CD44, CD98, and MHCI, still entered cells by CIE, suggesting that the routing of ubiquitinated cargo occurs after endocytosis. MARCH8 expression led to direct ubiquitination of CD98 and routing of CD98 to late endosomes/lysosomes.


Purification and functional analysis of a novel leucine-zipper/nucleotide-fold protein, BZAP45, stimulating cell cycle regulated histone H4 gene transcription.
Regulation of histone gene transcription at the G1/S phase transition via the Site II cell cycle control element is distinct from E2F-dependent mechanisms operative at the growth factor-related restriction point. E2F-independent activation of histone H4 gene expression combines contributions of several promoter factors, including HiNF-M/IRF2 and the HiNF-D/CDP-cut complex which contains pRB, CDK1, and cyclin A as non-DNA binding subunits. Mutational analyses suggest additional rate-limiting factors for Site II function. Using sequence-specific Site II DNA affinity chromatography, we identified a 45 kDa protein (KIAA0005 or BZAP45) that is embryonically expressed and phylogenetically conserved. Based on amino acid sequence analysis, BZAP45 contains a unique decapeptide that is part of a putative leucine-zipper protein with a nucleotide (ATP or GTP) binding fold. Bacterial expression of a full-length cDNA produces a 45 kDa protein. Binding studies reveal that highly purified BZAP45 does not interact with Site II, suggesting that BZAP45 function may require partner proteins. Forced expression of BZAP45 strongly stimulates H4 promoter (nt -215 to -1)/CAT reporter gene activity. Deletion analyses and point mutations indicate that BZAP45 enhances H4 gene transcription through Site II. Thus, BZAP45 is a novel regulatory factor that contributes to transcriptional control at the G1/S phase transition.


Nonmutational compensation of the fitness cost of antibiotic resistance in mycobacteria by overexpression of tlyA rRNA methylase.
Several studies over the last few decades have shown that antibiotic resistance mechanisms frequently confer a fitness cost and that these costs can be genetically ameliorated by intra- or extragenic second-site mutations, often without loss of resistance. Another, much less studied potential mechanism by which the fitness cost of antibiotic resistance could be reduced is via a regulatory response where the deleterious effect of the resistance mechanism is lowered by a physiological alteration that buffers the mutational effect. In mycobacteria, resistance to the clinically used tuberactinomycin antibiotic capreomycin involves loss-of-function mutations in rRNA methylase TlyA or point mutations in 16S rRNA (in particular the A1408G mutation). Both of these alterations result in resistance by reducing drug binding to the ribosome. Here we show that alterations of tlyA gene expression affect both antibiotic drug susceptibility and fitness cost of drug resistance. In particular, we demonstrate that the common resistance mutation A1408G is accompanied by a physiological change that involves increased expression of the tlyA gene. This gene encodes an enzyme that methylates neighboring 16S rRNA position C1409, and as a result of increased TlyA expression the fitness cost of the A1408G mutation is significantly reduced. Our findings suggest that in mycobacteria, a nonmutational mechanism (i.e., gene regulatory) can restore fitness to genetically resistant bacteria. Our results also point to a new and clinically relevant treatment strategy to combat evolution of resistance in multidrug-resistant tuberculosis. Thus, by utilizing antagonistic antibiotic interactions, resistance evolution could be reduced.


Sequence based analysis of U-2973, a cell line established from a double-hit B-cell lymphoma with concurrent MYC and BCL2 rearrangements.
Double-hit lymphoma is a complex and highly aggressive sub-type of B-cell lymphoma, which has recently been classified and is an area of active research interest due to the poor prognosis for patients with this disease. It is characterized by the presence of both an activating MYC chromosomal translocation and a simultaneous additional oncogenic translocation, often of the BCL2 gene. Recently, a cell line was established from a patient with this complex lymphoma and analyzed using conventional tools revealing it contains both MYC and BCL2 translocation events. In this work, we reanalyzed the genome of the cell line using next generation whole genome sequencing technology in order to catalogue translocations, insertions and deletions which may contribute to the pathology of this lymphoma type. We describe the cell line in much greater detail, and pinpoint the exact locations of the chromosomal breakpoints. We also find several rearrangements within cancer-associated genes, which were not found using conventional tools, suggesting that high throughput sequencing may reveal novel targets for therapy, which could be used concurrently with existing treatments.


Environmental tobacco smoke revisited: the reliability of the data used for risk assessment.
Several epidemiological studies have found a weak, but consistent association between lung cancer in nonsmokers and exposure to environmental tobacco smoke (ETS). In addition, a purported link between such exposure and coronary heart disease (CHD) has been of major concern. Although it is biologically plausible that ETS has a contributory role in the induction of lung cancer in nonsmoking individuals, dose-response extrapolation-supported by the more solid database for active smokers-gives an additional risk for lung cancer risk that is more than one order of magnitude lower than that indicated by major positive epidemiological studies. The discrepancy between available epidemiological data and dosimetric estimates seems, to a major part, to reflect certain systematic biases in the former that are difficult to control by statistical analysis when dealing with risks of such low magnitudes. These include, most importantly, misclassification of smoking status, followed by inappropriate selection of controls, as well as certain confounding factors mainly related to lifestyle, and possibly also hereditary disposition. A significant part of an association between lung cancer and exposure to ETS would disappear, if, on the average, 1 patient out of 20 nonsmoking cases had failed to tell the interviewer that he had, in fact, recently stopped smoking. In the large International Agency for Research on Cancer (IARC) multicenter study even lower misclassification rates would abolish the weak, statistically nonsignificant associations that were found. In the former study an apparent significant protective effect from exposure to ETS in childhood with respect to lung cancer later in life was reported, a most surprising finding. The fact that the mutation spectrum of the p53 tumor suppressor gene in lung tumors of ETS-exposed nonsmokers generally differs from that found in tumors of active smokers lends additional support to the notion that the majority of tumors found in ETS-exposed nonsmokers have nothing to do with tobacco smoke. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors. Due to the high prevalence of cardiovascular disease in the population, even a modest causal association with ETS would, if valid, constitute a serious public health problem. By pooling data from 20 published studies on ETS and heart disease, some of which reported higher risks than is known to be caused by active smoking, a statistically significant association with spousal smoking is obtained. However, in most of these studies, many of the most common confounding risk factors were ignored and there appears to be insufficient evidence to support an association between exposure to ETS and CHD. Further, it seems highly improbable that exposure to a concentration of tobacco smoke at a level that is generally much less than 1% of that inhaled by a smoker could result in an excess risk for CHD that-as has been claimed-is some 30% to 50% of that found in active smokers. There are certainly valid reasons to limit exposure to ETS as well as to other air pollutants in places such as offices and homes in order to improve indoor air quality. This goal can be achieved, however, without the introduction of an extremist legislation based on a negligible risk of lung cancer as well as an unsupported and highly hypothetical risk for CHD.


Detection and characterization of human pathogenic viruses circulating in community wastewater using multi target microarrays and polymerase chain reaction.
Sewage pollution remains the most significant source of human waterborne pathogens. This study describes the detection and characterization of human enteric viruses in community wastewaters using cell culture coupled with multiple target microarrays (with a total of 780 unique probes targeting 27 different groups of both DNA and RNA viruses) and polymerase chain reaction (PCR) assays. Over a 13-month sampling period, RNA viruses (astroviruses and enteroviruses) were more frequently detected compared to DNA viruses (adenoviruses, particularly type 41 and BK polyomavirus). Overall, many more viruses were shed during the winter months (December-February) compared to the summer months. Exploration of the multiple types of enteric viruses particularly in winter months identified much more significant prevalence of key viral pathogens associated with sewage pollution of the water environment than previously realized and seasonal disinfection used in some parts of the world may lead to a seeding of ambient waters. Molecular characterization of pathogenic viruses in community wastewater will improve the understanding of the potential risk of waterborne disease transmission of viral pathogens.


Role of diagnostic labeling in antibiotic prescription.
To evaluate the association between diagnostic labeling of respiratory tract infections (RTIs) and antibiotic prescription rates in family practice. Descriptive analysis of outpatient chart review supplemented by interviews with physicians. Charts of patients attending 73 general practitioners were reviewed between October 1997 and February 1998. Two days of practice were evaluated per physician. Urban family practices in greater St John's, Nfld. Of 96 family physicians contacted, 73 (76%) agreed to participate. Rates of diagnoses and antibiotic prescriptions for acute infections. Physicians were divided into "low prescribers" and "high prescribers" based on overall rates of prescription to patients with infections. Low prescribers were compared with high prescribers with respect to physician characteristics, patient characteristics, and diagnoses assigned. Of all patients seen, 22% were seen for acute infections; RTIs accounted for 76% of diagnoses. Low prescribers and high prescribers were of similar ages and saw similar numbers of patients of similar ages with very similar presenting complaints. Both groups diagnosed urinary tract and skin and soft-tissue infections at similar rates, but differed markedly in their rates of diagnoses of RTIs. High prescribers diagnosed bacterial RTIs in 65.4% (147/225) of their patients; low prescribers diagnosed bacterial RTIs in 31.0% (66/213 (P < .001). Family doctors frequently prescribe antibiotics. The difference in rates of prescription between high prescribers and low prescribers is largely explained by assignment of diagnoses of RTIs.


The impact of ovarian stimulation on the expression of candidate reprogramming genes in mouse preimplantation embryos.
Ovarian stimulation with gonadotrophins is an integral part of assisted reproductive technologies in human subfertility/infertility treatment. Recent findings have associated ovarian stimulation with the increased incidence of imprinting disorders in humans as well as defects in genome-wide methylation reprogramming and, in particular, imprinting in mice. Here, we present the first study that determined the impact of ovarian stimulation on the expression of developmentally important reprogramming genes (Apex1, Lig1, Lig3, Mbd2, Mbd3, Mbd4, and Polb) in single early mouse morula embryos (16-cell stage). Using absolute quantification of mRNA by quantitative real-time PCR, we observed an association of ovarian stimulation with a downregulation of mRNAs encoding the base excision repair proteins APEX1 and POLB as well as the 5-methyl-CpG-binding domain protein MBD3 in individual morula embryos. Whole mount immunofluorescence staining of early and late morula embryos with an antibody against APEX1 revealed individual embryos with lower protein expression levels after ovarian stimulation and a correlation of mRNA expression with protein abundance. Our data argue for a negative impact of ovarian stimulation during female gametogenesis and/or early embryo development affecting the expression of candidate reprogramming factors.


Building a research consortium of large health systems: the Cancer Research Network.
Critical questions about cancer prevention, care, and outcomes increasingly require research involving large patient populations and their care delivery organizations. The Cancer Research Network (CRN) includes 11 integrated health systems funded by the National Cancer Institute (NCI) to conduct collaborative cancer research. This article describes the challenges of constructing a productive consortium of large health systems, and explores the CRN's responses. The CRN was initially funded through an NCI cooperative agreement in 1999 and has since received a second 4-year grant. Leadership and policy development are provided through a steering committee, subcommittees, and an external advisory committee. The CRN includes integral and affiliated research projects supported by a Scientific and Data Resources Core. Three characteristics of the CRN intensified the general challenges of consortium research: 1) its members are large health systems with legitimate concerns about confidentiality of data about enrollees, providers, and the organization; 2) CRN research projects often generate highly sensitive data about quality of care; and therefore 3) each participating organization wants a strong voice in CRN direction. CRN experience to date confirms that a consortium of health systems with internal research capacity can address a range of important cancer research questions that would be difficult to study in other venues. The advantages and challenges of consortium research are explored, with suggestions for the development, execution, and management of multisystem population laboratories.


Sex-Reassignment Rules in Shiite Jurisprudence.
The "Sex-Reassignment Surgery" is a solution that besides behavioral therapy has been suggested to people suffering from gender identity disorders in recent years. In Iran, this trend has become more popular over the past years due to the inclination to reach to the goal rapidly with less effort and also the surgery has attracted many patients with the problem. Religious clerics have tried to determine the religious doctrines for this practice and as a result a group of them favor an absolute permission while others choose prohibition and some of them favor a middle path. The aim of this study was to determine the religious doctrines for Sex-Reassignment and legitimate treatment for GID. The research method was a library research based on which an investigation was done by analyzing the relevant books, articles and dissertations. Primary documents of Islamic sources (Quran and tradition) along with scientific, medical and psychological materials were used in this research. In this study, the survey shows that none of the reasons have the power to deliver a definitive and religious ruling on this issue because the validity of its reasons is related to the reality of "Sex-Reassignment". The results demonstrate that Sex-Reassignment is prohibited and it is not authorized. In case of urgency for doing the surgery, the gender of the person should not be changed.


Hypertrophy dependent doubling of L-cells in Roux-en-Y gastric bypass operated rats.
Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal. The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells. RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell. Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.


Electro-optic tuning of split ring resonators embedded in a liquid crystal.
Two-dimensional arrays of split ring resonators for near-infrared frequencies are embedded in a liquid crystal (LC) and the influences of LC alignment, temperature, and electric fields on the resonance frequencies are studied. The results show that tunability can not only be achieved by influencing the state of polarization of the incident radiation, but also by direct interaction of the evanescent field of the resonant modes with the LC. Depending on the LC alignment, the field-induced shift of the resonance frequency is found to vary for different excited modes. Some guidelines for the design of tunable frequency selective metasurfaces can be deduced from these experimental results.


Local Resection and Brachytherapy for Primary Orbital Rhabdomyosarcoma: Outcome and Failure Pattern Analysis.
Survival in patients with orbital rhabdomyosarcoma (RMS) is excellent. Therefore, new local treatment modalities, such as brachytherapy, have been developed to minimize adverse events. Since 1990, patients with orbital RMS and a residual tumor after induction chemotherapy were eligible for resection and brachytherapy. Otherwise patients received external beam radiotherapy. In this study, the authors describe the outcome for 20 patients with primary orbital RMS. The aim was to assess risk factors for treatment failure in this single center cohort. In this retrospective cohort study, the authors reviewed imaging studies, surgery reports, histology reports, and radiotherapy plans in a multidisciplinary setting. The authors included 20 consecutive patients with orbital RMS, treated between 1990 and 2007, (median age: 7.4 years, range: 0.7-16.1; median follow up: 11.5 years). After induction chemotherapy, 12 patients were treated with surgery and brachytherapy, 2 with external beam radiotherapy, and in 5 patients who achieved complete remission, local treatment was withheld. In 1 patient, brachytherapy was incorrectly withheld after delayed surgery. Seven patients relapsed (no local treatment, N = 2; surgery and brachytherapy, N = 2; external beam radiotherapy, N = 2; surgery only, N = 1). The authors found no patient, tumor, or treatment characteristics that predisposed for treatment failure. Ten-year-overall survival and event-free survival were 89% and 65%, respectively. Overall survival in this cohort of orbital RMS patients was good, including surgery and brachytherapy as treatment modality for orbital RMS resulted in an effective local treatment approach with fewer adverse events than external beam radiotherapy. The authors could not identify factors predisposing for treatment failure.


The 3'-terminal hexamer sequence of classical swine fever virus RNA plays a role in negatively regulating the IRES-mediated translation.
The 3' untranslated region (UTR) is usually involved in the switch of the translation and replication for a positive-sense RNA virus. To understand the 3' UTR involved in an internal ribosome entry site (IRES)-mediated translation in Classical swine fever virus (CSFV), we first confirmed the predicted secondary structure (designated as SLI, SLII, SLIII, and SLIV) by enzymatic probing. Using a reporter assay in which the luciferase expression is under the control of CSFV 5' and 3' UTRs, we found that the 3' UTR harbors the positive and negative regulatory elements for translational control. Unlike other stem loops, SLI acts as a repressor for expression of the reporter gene. The negative cis-acting element in SLI is further mapped to the very 3'-end hexamer CGGCCC sequence. Further, the CSFV IRES-mediated translation can be enhanced by the heterologous 3'-ends such as the poly(A) or the 3' UTR of Hepatitis C virus (HCV). Interestingly, such an enhancement was repressed by flanking this hexamer to the end of poly(A) or HCV 3' UTR. After sequence comparison and alignment, we have found that this hexamer sequence could hypothetically base pair with the sequence in the IRES IIId1, the 40 S ribosomal subunit binding site for the translational initiation, located at the 5' UTR. In conclusion, we have found that the 3'-end terminal sequence can play a role in regulating the translation of CSFV.