Investigation towards bivalent chemically defined glycoconjugate immunogens prepared from acid-detoxified lipopolysaccharide of Vibrio cholerae O1, serotype Inaba.
A free amino group present on the acid-detoxified lipopolysaccharide (pmLPS) of V. cholerae O1 serotype Inaba was investigated for site-specific conjugation. Chemoselective pmLPS biotinylation afforded the corresponding mono-functionalized derivative, which retained antigenicity. Thus, pmLPS was bound to carrier proteins using thioether conjugation chemistry. Induction of an anti-LPS antibody (Ab) response in BALB/c mice was observed for all conjugates. Interestingly, the sera had vibriocidal activity against both Ogawa and Inaba strains opening the way to a possible bivalent vaccine. However, the level of this Ab response was strongly affected by both the nature of the linker and of the carrier. Furthermore, no switch from IgM to IgG, i.e. from a T cell-independent to a T cell-dependent immune response was detected, a result tentatively explained by the possible presence of free polysaccharide in the formulation. Taken together, these results encourage further investigation towards the development of potent pmLPS-based neoglycoconjugate immunogens, fully aware of the challenge faced in the development of a cholera vaccine that will provide efficient serogroup coverage.


Robot-assisted intersphincteric resection for low rectal cancer: technique and short-term outcome for 29 consecutive patients.
Intersphincteric resection (ISR) for low rectal cancer has been described as the ultimate sphincter-saving procedure. Laparoscopic ISR has been proved safe with early postoperative benefits. Recently, some colorectal surgeons have begun to perform robot-assisted ISR to harness the advantages of the da Vinci robotic system. The authors present their short-term results for a robotic technique of ISR. Data from 29 consecutive patients at a single institution with very low rectal cancer (<4 cm) from the anal verge who underwent robot-assisted ISR were prospectively collected between December 2007 and March 2010. The study enrolled 23 men and 6 women with a median age of 61.5 years (range, 36-82 years). Their median body mass index (BMI) was 23.3 kg/m(2) (range, 17.9-32.5 kg/m(2)). The median distance of the tumor from the anal verge was 3 cm (range, 1-4 cm). The median operative time was 325 min (range, 235-435 min), with a console time of 130 min (range, 110-210 min). There were no conversions to open surgery. A protecting ileostomy was performed for all the patients. The median blood loss was less than 50 ml (range, < 50-1,000 ml). The median size of the tumor was 3 cm (range, 0-6.9 cm), and the median number of lymph nodes harvested was 16 (range, 1-44). The median distal margin was 0.8 cm (range, 0-4 cm), and one margin was positive. The circumferential margin was negative (>2 mm) for 27 patients. Therefore, complete resection (R0) was achieved for 26 (90%) of the 29 patients. The median hospital stay was 9 days (range, 5-15 days). Nine patients experienced complications, including three anastomotic leaks (10%). All the leaks were managed conservatively. No surgical mortalities occurred. Robot-assisted intersphincteric resection for very low rectal cancer is feasible, and its short-term outcome is acceptable.


De-escalation and discontinuation strategies in high-risk neutropenic patients: an interrupted time series analyses of antimicrobial consumption and impact on outcome.
Febrile neutropenia (FN) is the main reason for antibiotic prescription in hematology wards where, on the other hand, antibiotic stewardship (AS) is poorly explored. The objectives of the present study were to evaluate (1) the impact of an AS intervention on antibiotic consumption and (2) the applicability and acceptance rate of the intervention and its clinical impact. A persuasive AS intervention based on European Conference on Infection in Leukaemia (ECIL) guidelines for FN was implemented in a high-risk hematology ward in a tertiary referral public university hospital. This included the creation and diffusion of flow charts on de-escalation and discontinuation of antibiotics for FN, and the introduction in the team of a doctor dedicated to the implementation of flow charts and to antibiotic prescription revision. All consecutive patients receiving antibiotics during hospitalization were included. A segmented linear regression model was performed for the evaluation of antibiotic consumption, taking into account 1-year pre-intervention period and 6-month intervention period. Overall, 137 consecutive antibiotic prescriptions were re-evaluated, 100 prescriptions were for FN. A significant reduction of the level of carbapenem consumption was observed during the intervention period (level change (estimate coefficient ± standard error) = - 135.28 ± 59.49; p = 0.04). Applicability and acceptability of flow charts were high. No differences in terms of intensive care unit transfers, bacteremia incidence, and mortality were found. A persuasive AS intervention in hematology significantly reduced carbapenem consumption without affecting outcome and was well accepted. This should encourage further applications of ECIL guidelines for FN.


Menu-labeling usage and its association with diet and exercise: 2011 BRFSS Sugar Sweetened Beverage and Menu Labeling module.
The primary objective of our study was to investigate the association between menu-labeling usage and healthy behaviors pertaining to diet (consumption of fruits, vegetables, sodas, and sugar-sweetened beverages) and exercise. Data from the 2011 Behavioral Risk Factor Surveillance System, Sugar Sweetened Beverage and Menu-Labeling module, were used. Logistic regression was used to determine the association between menu-labeling usage and explanatory variables that included fruit, vegetable, soda, and sugar-sweetened beverage consumption as well as exercise. Nearly half (52%) of the sample indicated that they used menu labeling. People who used menu labeling were more likely to be female (odds ratio [OR], 2.29; 95% confidence interval [CI], 2.04-2.58), overweight (OR, 1.13; 95% CI, 1.00-1.29) or obese (OR, 1.29; 95% CI, 1.12-1.50), obtain adequate weekly aerobic exercise (OR, 1.18; 95% CI, 1.06-1.32), eat fruits (OR, 1.20; 95% CI, 1.12-1.29) and vegetables (OR, 1.12; 95% CI, 1.05-1.20), and drink less soda (OR, 0.76; 95% CI, 0.69-0.83). Although obese and overweight people were more likely to use menu labeling, they were also adequately exercising, eating more fruits and vegetables, and drinking less soda. Menu labeling is intended to combat the obesity epidemic; however the results indicate an association between menu-labeling usage and certain healthy behaviors. Thus, efforts may be necessary to increase menu-labeling usage among people who are not partaking in such behaviors.


Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design.
To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.


Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning.
Here we report PPB2 as a target prediction tool assigning targets to a query molecule based on ChEMBL data. PPB2 computes ligand similarities using molecular fingerprints encoding composition (MQN), molecular shape and pharmacophores (Xfp), and substructures (ECfp4) and features an unprecedented combination of nearest neighbor (NN) searches and Naı̈ve Bayes (NB) machine learning, together with simple NN searches, NB and Deep Neural Network (DNN) machine learning models as further options. Although NN(ECfp4) gives the best results in terms of recall in a 10-fold cross-validation study, combining NN searches with NB machine learning provides superior precision statistics, as well as better results in a case study predicting off-targets of a recently reported TRPV6 calcium channel inhibitor, illustrating the value of this combined approach. PPB2 is available to assess possible off-targets of small molecule drug-like compounds by public access at http://gdb.unibe.ch .


Innovative strategic Canadian research training from TomorrOw's Research Cardiovascular Health Care Professionals (TORCH).
Cardiovascular research training is experiential, and "skills" are traditionally acquired through a master-apprentice paradigm. The complexity of contemporary clinical research requires a new model for research training. Facilitated through a Strategic Training Program Initiative, the Canadian Institutes of Health Research (CIHR), with its partners the Alberta Heritage Foundation for Medical Research and the Heart and Stroke Foundation, supported the Universities of Alberta and Calgary to create a new and innovative training model. Tomorrow's Research Cardiovascular Health Professionals (TORCH) is an integrated 2-year program for health care professionals from diverse disciplines to be mentored toward careers as leaders in translational cardiovascular research, applying discovery to human health. This report describes the vision, mission, core values, objectives, design and curriculum of the program. Our vision is the development of a new generation of cardiovascular research clinician-scientists, with particular emphasis on thought, leadership and collaboration. The program incorporates 4 core values: innovation and discovery, a translational and transdisciplinary focus, an emphasis on collaboration and integration of research concepts, and the teaching of a core body of research knowledge coupled with real-world "survival" skills. The core curriculum, organized according to a cluster concept, traverses the 4 pillars of the CIHR. Through the medium of 1-hour weekly videoconferences, the curriculum cycles through case studies, seminars and a journal club in focused areas of cardiovascular research. Mentors in the TORCH program have diverse backgrounds that epitomize the transdisciplinary translational aspects of the program and are chosen for their proven record of research accomplishment and prior history of successful mentoring. The program has recruited 19 trainees from a broad cross-section of disciplines, integrating 2 University of Alberta campuses. The preliminary experience has been both favourable and gratifying.


Sarcoid-like reaction to malignancy on whole-body integrated (18)F-FDG PET/CT: prevalence and disease pattern.
To evaluate the prevalence of sarcoid-like reaction to malignancy detected using integrated 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography and computed tomography (PET/CT) in patients undergoing staging or restaging of solid-organ malignancy. A systematic search was performed using the institutional radiology information system of 2048 consecutive PET/CT examinations performed in cancer patients at a tertiary-referral centre. Cases that were considered suspicious for sarcoid-like reaction were identified from the initial radiological report and were retrospectively reviewed by three experienced PET/CT reporters. Sarcoid-like reaction was initially suspected in 23 of the 2048 (1.1%) FDG PET/CT examinations, with the diagnosis confirmed histologically or by clinico-radiological follow-up in 13 of the 23 cases (57%). Sarcoid-like reaction was more commonly seen in patients undergoing FDG PET/CT for restaging of suspected recurrence rather than for primary tumour staging (77% versus 23%; p=0.05). The mean maximum standardized uptake value (SUV(max)) of confirmed hilar and mediastinal sarcoid-like reaction was 7.3 (range 3.1-13.6). Symmetric hilar uptake was demonstrated in 11 of the 13 (85%) and all 13 had additional mediastinal nodal uptake. Pulmonary uptake was seen in seven of the 13 cases (54%). Extra-thoracic involvement was present in eight of the 13 (61.5%), including nodal, splenic, and hepatic lesions. Sarcoid-like reaction was suspected in 1.1% of cancer patients at FDG PET/CT examination, with confirmation of the diagnosis in 0.6%. With the increasing use of FDG PET/CT in cancer patients, it is important to be aware of the prevalence of this uncommon, but important, disease entity and to consider this diagnosis in appropriate cases in order to avoid a false-positive interpretation of metastatic disease.


Endosomal signaling and oncogenesis.
The endosomal system provides a route whereby nutrients, viruses, and receptors are internalized. During the course of endocytosis, activated receptors can accumulate within endosomal structures and certain signal-transducing molecules can be recruited to endosomal membranes. In the context of signaling and cancer, they provide platforms within the cell from which signals can be potentiated or attenuated. Regulation of the duration of receptor signaling is a pivotal means of refining growth responses in cells. In cancers, this is often considered in terms of mutations that affect receptor tyrosine kinases and maintain them in hyperactivated states of dimerization and/or phosphorylation. However, disruption to the regulatory control exerted by the assembly of protein complexes within the endosomal network can also contribute to disease among which oncogenesis is characterized in part by dysregulated growth, enhanced cell survival, and changes in the expression of markers of differentiation. In this chapter, we will discuss the role of proteins that regulate in endocytosis as tumor suppressors or oncogenes and how changing the fate of internalized receptors and concomitant endosomal signaling can contribute to cancer.


Research priorities for coordinating management of food safety and water quality.
Efforts to exclude disease organisms from farms growing irrigated lettuce and leafy vegetables on California's central coast are conflicting with traditionally accepted strategies to protect surface water quality. To begin resolving this dilemma, over 100 officials, researchers, and industry representatives gathered in April 2007 to set research priorities that could lead to effective co-management of both food safety and water quality. Following the meeting, research priorities were refined and ordered by way of a Delphi process completed by 35 meeting participants. Although water quality and food safety experts conceptualized the issues differently, there were no deep disagreements with respect to research needs. Top priority was given to investigating the fate of pathogens potentially present on farms. Intermediate priorities included characterizing the influence of specific farm management practices on food safety and improving our understanding of vector processes. A scientific subdiscipline focusing on competing risks is needed to characterize and resolve conflicts between human and environmental health.


Interplay between electric and magnetic effect in adiabatic polaritonic systems.
We report on the possibility of realizing adiabatic compression of polaritonic wave on a metallic conical nano-structure through an oscillating electric potential (quasi dynamic regime). By comparing this result with an electromagnetic wave excitation, we were able to relate the classical lighting-rod effect to adiabatic compression. Furthermore, we show that while the magnetic contribution plays a marginal role in the formation of adiabatic compression, it provides a blue shift in the spectral region. In particular, magnetic permeability can be used as a free parameter for tuning the polaritonic resonances. The peculiar form of adiabatic compression is instead dictated by both the source and the metal permittivity. The analysis is performed by starting from a simple electrostatic system to end with the complete electromagnetic one through intermediate situations such as the quasi-electrostatic and quasi-dynamic regimes. Each configuration is defined by a particular set of equations which allows to clearly determine the individual role played by the electric and magnetic contribution in the generation of adiabatic compression. We notice that these findings can be applied for the realization of a THz nano-metric generator.


2021 AAHA Working, Assistance, and Therapy Dog Guidelines.
The guidelines are the first comprehensive consensus report on veterinary healthcare recommendations for working, assistance, and therapy dogs. This category of canine patients includes a broad assortment of animals, some with well-defined functions and others that provide a more generalized support role. The guidelines discuss recommendations for dogs trained for protection, odor/scent detection, service functions for people with diagnosed disabilities or physical limitations, emotional support, and therapeutic intervention. Although the term is often used to describe dogs providing animal-assisted activities, true therapy dogs provide goal-directed therapy, often under the supervision of a healthcare professional such as an occupational therapist or psychologist. Many working dogs undergo extensive training and have rigorous physical demands placed upon them. These factors make working, assistance, and therapy dogs inherently valuable and impose a need for a high level of primary veterinary care as described in the guidelines. Because working dogs have a particularly close relationship with their handlers, a trust relationship between the practice team and the working-dog client is imperative.


Long-term persistence of monotypic dengue transmission in small size isolated populations, French Polynesia, 1978-2014.
Understanding the transition of epidemic to endemic dengue transmission remains a challenge in regions where serotypes co-circulate and there is extensive human mobility. French Polynesia, an isolated group of 117 islands of which 72 are inhabited, distributed among five geographically separated subdivisions, has recorded mono-serotype epidemics since 1944, with long inter-epidemic periods of circulation. Laboratory confirmed cases have been recorded since 1978, enabling exploration of dengue epidemiology under monotypic conditions in an isolated, spatially structured geographical location. A database was constructed of confirmed dengue cases, geolocated to island for a 35-year period. Statistical analyses of viral establishment, persistence and fade-out as well as synchrony among subdivisions were performed. Seven monotypic and one heterotypic dengue epidemic occurred, followed by low-level viral circulation with a recrudescent epidemic occurring on one occasion. Incidence was asynchronous among the subdivisions. Complete viral die-out occurred on several occasions with invasion of a new serotype. Competitive serotype replacement has been observed previously and seems to be characteristic of the South Pacific. Island population size had a strong impact on the establishment, persistence and fade-out of dengue cases and endemicity was estimated achievable only at a population size in excess of 175 000. Despite island remoteness and low population size, dengue cases were observed somewhere in French Polynesia almost constantly, in part due to the spatial structuration generating asynchrony among subdivisions. Long-term persistence of dengue virus in this group of island populations may be enabled by island hopping, although could equally be explained by a reservoir of sub-clinical infections on the most populated island, Tahiti.


Extending neutron autoradiography technique for boron concentration measurements in hard tissues.
The neutron autoradiography technique using polycarbonate nuclear track detectors (NTD) has been extended to quantify the boron concentration in hard tissues, an application of special interest in Boron Neutron Capture Therapy (BNCT). Chemical and mechanical processing methods to prepare thin tissue sections as required by this technique have been explored. Four different decalcification methods governed by slow and fast kinetics were tested in boron-loaded bones. Due to the significant loss of the boron content, this technique was discarded. On the contrary, mechanical manipulation to obtain bone powder and tissue sections of tens of microns thick proved reproducible and suitable, ensuring a proper conservation of the boron content in the samples. A calibration curve that relates the 10B concentration of a bone sample and the track density in a Lexan NTD is presented. Bone powder embedded in boric acid solution with known boron concentrations between 0 and 100 ppm was used as a standard material. The samples, contained in slim Lexan cases, were exposed to a neutron fluence of 1012 cm-2 at the thermal column central facility of the RA-3 reactor (Argentina). The revealed tracks in the NTD were counted with an image processing software. The effect of track overlapping was studied and corresponding corrections were implemented in the presented calibration curve. Stochastic simulations of the track densities produced by the products of the 10B thermal neutron capture reaction for different boron concentrations in bone were performed and compared with the experimental results. The remarkable agreement between the two curves suggested the suitability of the obtained experimental calibration curve. This neutron autoradiography technique was finally applied to determine the boron concentration in pulverized and compact bone samples coming from a sheep experimental model. The obtained results for both type of samples agreed with boron measurements carried out by ICP-OES within experimental uncertainties. The fact that the histological structure of bone sections remains preserved allows for future boron microdistribution analysis.


Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates.
To determine the frequency and distribution of mitochondrial DNA mutations in breast cancer, 18 primary breast tumors were analyzed by direct sequencing. Twelve somatic mutations not present in matched lymphocytes and normal breast tissues were detected in 11 of the tumors screened (61%). Of these mutations, five (42%) were deletions or insertions in a homopolymeric C-stretch between nucleotides 303-315 (D310) within the D-loop. The remaining seven mutations (58%) were single-base substitutions in the coding (ND1, ND4, ND5, and cytochrome b genes) or noncoding regions (D-loop) of the mitochondrial genome. In three cases (25%), the mutations detected in coding regions led to amino acid substitutions in the protein sequence. We then screened an additional 46 primary breast tumors with a rapid PCR-based assay to identify poly-C alterations in D310, and we found seven more cancers with alterations. Using D310 mutations as clonal marker, we detected identical changes in five of five matched fine-needle aspirates and in four of four metastases-positive lymph nodes. The high frequency of D310 alterations in primary breast cancer combined with the high sensitivity of the PCR-based assays provides a new molecular tool for cancer detection.


Exposure-response relationships for select cancer and non-cancer health outcomes in a cohort of U.S. firefighters from San Francisco, Chicago and Philadelphia (1950-2009).
To examine exposure-response relationships between surrogates of firefighting exposure and select outcomes among previously studied US career firefighters. Eight cancer and four non-cancer outcomes were examined using conditional logistic regression. Incidence density sampling was used to match each case to 200 controls on attained age. Days accrued in firefighting assignments (exposed-days), run totals (fire-runs) and run times (fire-hours) were used as exposure surrogates. HRs comparing 75th and 25th centiles of lagged cumulative exposures were calculated using loglinear, linear, log-quadratic, power and restricted cubic spline general relative risk models. Piecewise constant models were used to examine risk differences by time since exposure, age at exposure and calendar period. Among 19,309 male firefighters eligible for the study, there were 1333 cancer deaths and 2609 cancer incidence cases. Significant positive associations between fire-hours and lung cancer mortality and incidence were evident. A similar relation between leukaemia mortality and fire-runs was also found. The lung cancer associations were nearly linear in cumulative exposure, while the association with leukaemia mortality was attenuated at higher exposure levels and greater for recent exposures. Significant negative associations were evident for the exposure surrogates and colorectal and prostate cancers, suggesting a healthy worker survivor effect possibly enhanced by medical screening. Lung cancer and leukaemia mortality risks were modestly increasing with firefighter exposures. These findings add to evidence of a causal association between firefighting and cancer. Nevertheless, small effects merit cautious interpretation. We plan to continue to follow the occurrence of disease and injury in this cohort.


A prospective study of the effects of sustained vector surveillance following community-wide insecticide application on Trypanosoma cruzi infection of dogs and cats in rural Northwestern Argentina.
Domestic dogs were used as natural sentinels to assess prospectively the long-term impact of selective, community-based spraying with pyrethroid insecticides after community-wide spraying on transmission of Trypanosoma cruzi in rural villages under surveillance between 1992 and 2002. In 2000 and 2002 light infestations by Triatoma infestans were recorded, and 523 dogs and cats were examined serologically or by xenodiagnosis. The prevalence of T. cruzi infection in dogs decreased from 65% at baseline to 8.9% and 4.7% at 7.5 and 10 years after sustained vector surveillance, respectively. The average annual force of infection dropped 260-fold from 72.7 per 100 dog-years at baseline to <0.3% in 2002, as determined prospectively and retrospectively from the age-prevalence curve of native dogs born during surveillance. Multiple logistic regression analysis showed that prevalent cases in dogs in 2000 and 2002 were associated positively and significantly with the peak number of T. infestans caught in domestic areas at the dog's compound during its lifetime. The sustained decline in T. cruzi infections in dogs and cats is the result of selective, community-based insecticide spraying that kept the abundance of infected T. infestans at marginal levels, fast host population turnover, and low immigration rates from areas with active transmission.


Mood configurations and their relationship to immune system responses: Exploring the relationship between moods, immune system responses, thyroid hormones, and social support.
Analyzing data on 2,057 healthy subjects in the Dutch Lifelines database we explore the relationship between immune system responses, thyroid hormone functioning and people's mood that is expected to be moderated by social support. We focus (1) on the innate immune system cell count: monocytes, eosinophil granulocytes, basophilic granulocytes, neutrophil granulocytes; and thrombocytes; and (2) on the adaptive immune system cell count: lymphocytes (T, B and NK cells). Moods were measured on the positive (PA) and negative (NA) dimensions of the PANAS scale, divided in four groups based on their PA and NA median scores: hedonic, positive mood, negative mood and anhedonic. We focus further on (3) thyroid cells: T3 and T4; and (4) on social support. We found significant differences between mood groups and mean cell counts for basophilic granulocytes and thrombocytes but not for monocytes, eosinophil granulocytes and neutrophil granulocytes in the innate immune system. However, in the adaptive immune system we found mean lymphocyte cell counts to be different in all four mood groups. We also found that T3 and T4 levels differ significantly across all mood groups and work in very close association with lymphocytes to activate the adaptive immune system. These differences were most significant in the hedonic and anhedonic groups. The findings allow us to better understand mood groups, especially the hedonic and anhedonic groups, and open up new avenues for intervention.


Dynamic perfluorinated gas MRI reveals abnormal ventilation despite normal FEV1 in cystic fibrosis.
We hypothesized that dynamic perfluorinated gas MRI would sensitively detect mild cystic fibrosis (CF) lung disease. This cross-sectional study enrolled 20 healthy volunteers and 24 stable subjects with CF, including a subgroup of subjects with normal forced expiratory volume in the first second (FEV1; >80% predicted, n = 9). Dynamic fluorine-19-enhanced MRI (19F MRI) were acquired during sequential breath holds while breathing perfluoropropane (PFP) and during gas wash-out. Outcomes included the fraction of lung without significant ventilation (ventilation defect percent, VDP) and time constants that described PFP wash-in and wash-out kinetics. VDP values (mean ± SD) of healthy controls (3.87% ± 2.7%) were statistically different from moderate CF subjects (19.5% ± 15.5%, P = 0.001) but not from mild CF subjects (10.4% ± 9.9%, P = 0.24). In contrast, the fractional lung volume with slow gas wash-out was elevated both in subjects with mild (9.61% ± 4.87%; P = 0.0066) and moderate CF (16.01% ± 5.01%; P = 0.0002) when compared with healthy controls (3.84% ± 2.16%) and distinguished mild from moderate CF (P = 0.006). 19F MRI detected significant ventilation abnormalities in subjects with CF. The ability of gas wash-out kinetics to distinguish between healthy and mild CF lung disease subjects makes 19F MRI a potentially valuable method for the characterization of early lung disease in CF. This study has been registered at ClinicalTrials.gov (NCT03489590).


Cigarette brand-switching: effects on smoke exposure and smoking behavior.
This study examined the effects of cigarette yield (Federal Trade Commission-determined deliveries of nicotine, tar and CO) on both biological exposure to smoke constituents and smoking behaviors. Smokers (N = 10) of high-yield cigarettes were switched in random order among five different commercially available cigarette brands with nicotine yields of 0.1, 0.4, 0.7, 1.1 (altered brand) and 1.0 (usual brand) mg and smoked each cigarette type for 5 days while a wide variety of assessments were performed. Steady-state cotinine and CO levels were substantially lower after 5 days of smoking ultra-low yield cigarettes (cotinine, 152 ng/ml; CO, 25 ppm) than when smoking usual-brand high-yield cigarettes (cotinine, 252 ng/ml; CO, 38 ppm). Both CO and nicotine boost (acute exposure) were related to yield. However, relative between-yield differences in all nicotine and CO exposure measures were smaller than predicted from Federal Trade Commission yield ratings. Substantial yield-related alterations were observed in smoking behavior. Subjects smoked more cigarettes and took larger and more closely spaced puffs when smoking low- as compared with high-yield cigarettes. The amount of tobacco burned per day was similar across all yield conditions. However, filter vent-blocking of ultra-low yield cigarettes did not appear to occur on a consistent basis. Subjective reports indicated poor acceptability of lower-yield cigarettes. We conclude that switching to lower-yield cigarettes brings about substantial alterations in smoking behavior which are at least partially responsible for the observed biological compensation associated with these cigarettes.


Role of the PD-1 pathway in the immune response.
Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.


Molecular Combing of Single DNA Molecules on the 10 Megabase Scale.
DNA combing allows the investigation of DNA replication on genomic single DNA molecules, but the lengths that can be analysed have been restricted to molecules of 200-500 kb. We have improved the DNA combing procedure so that DNA molecules can be analysed up to the length of entire chromosomes in fission yeast and up to 12 Mb fragments in human cells. Combing multi-Mb-scale DNA molecules revealed previously undetected origin clusters in fission yeast and shows that in human cells replication origins fire stochastically forming clusters of fired origins with an average size of 370 kb. We estimate that a single human cell forms around 3200 clusters at mid S-phase and fires approximately 100,000 origins to complete genome duplication. The procedure presented here will be adaptable to other organisms and experimental conditions.


Narrow-linewidth light source for a coherent Raman transfer of ultracold molecules.
We describe a tunable two-color CW light source sufficient for realizing a coherent Raman transfer between two molecular states that are more than 0.5 eV (120 THz) apart. The simultaneous frequency stabilization of 901 nm and 655 nm light was achieved by locking diode lasers to a single ultralow expansion cavity with dual wavelengths coating. By utilizing offset-locking and optical phase-locked loop (OPLL), we ensured a large mode-hop free tuning range (> 2 GHz). The obtained short term linewidth (<10 Hz) and the linear drift of frequency (65 mHz/s) were both sufficient to eliminate the influence of laser linewidths on the efficiency of coherent Raman transition.


Child Sexual Abuse Prevention Opportunities: Parenting, Programs, and the Reduction of Risk.
To date, child sexual abuse (CSA) prevention has relied largely on child-focused education, teaching children how to identify, avoid, and disclose sexual abuse. The purpose of this article is to explore how prevention opportunities can include parents in new and innovative ways. We propose that parents can play a significant role as protectors of their children via two pathways: (i) directly, through the strong external barriers afforded by parent supervision, monitoring, and involvement; and (ii) indirectly, by promoting their children's self-efficacy, competence, well-being, and self-esteem, which the balance of evidence suggests will help them become less likely targets for abuse and more able to respond appropriately and disclose abuse if it occurs. In this article, we first describe why teaching young children about CSA protective behaviors might not be sufficient for prevention. We then narratively review the existing research on parents and prevention and the parenting and family circumstances that may increase a child's risk of experiencing sexual abuse. Finally, we make a number of recommendations for future approaches to prevention that may better inform and involve parents and other adult protectors in preventing CSA.


Activity in the visual cortex is modulated by top-down attention locked to reaction time.
We studied the correlation between perception and hemodynamic activity in the visual cortex in a change detection task. Whenever the observer perceived the location of a change, rightly or wrongly, the blood oxygenation level-dependent signal increased in the primary visual cortex and the nearby extrastriate areas above the baseline activity caused by the visual stimulation. This non-sensory-evoked activity was localized and corresponded to the perceived location of the change. When a change was missed, or when observers attended to a different task, the change failed to evoke such a response. The latency of the nonsensory component increased linearly with subjects' reaction time, with a slope of one, and its amplitude was independent of contrast. Control experiments are compatible with the hypothesis that the nonsensory hemodynamic signal is mediated by top-down spatial attention, linked to (but separate from) awareness of the change.


Brain metastasis and intracranial leptomeningeal metastasis from malignant peripheral nerve sheath tumors: illustrative cases.
Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue tumors. Intracranial metastasis from MPNSTs is quite rare. The authors report on a 73-year-old male whose MPNST metastasized to the brain and a 32-year-old male with leptomeningeal metastasis from MPNST and review 41 cases of MPNST that developed intracranial metastasis, as reported in the literature. Brain metastasis and leptomeningeal metastasis of MPNSTs show different clinical courses and require pathology-specific treatment.


Cytotechnologist performance for detecting nuclear atypia in indeterminate thyroid fine needle aspirates.
The thyroid gland is arguably the fastest growing anatomic site for fine needle aspiration (FNA). With the increase of thyroid cases, a reevaluation of cytotechnologist screening quality metrics in terms of thyroid FNA is called for. We present our institutional cytotechnologist performance at screening for nuclear atypia by applying established quality metrics. Information on 8,814 consecutive thyroid cytopathology cases over a 10-year period was retrieved from computerized records. A subsample of cases categorized either as atypia of uncertain significance with nuclear atypia or suspicious for malignancy with features suspicious for papillary thyroid carcinoma. The cytotechnologist and cytopathologist diagnoses were compared using step discrepancies and Δ-ratios. Overall discrepancy between the cytotechnologist and cytopathologist diagnoses existed in <10% of all thyroid cases. One-category discrepancies were the most common (7.8%), while two-category discrepancies were rare (0.5%). The one-category discrepancy rate correlated with cytotechnologist experience. One-category under calls were twice as common as over calls (5.3 vs. 2.5%, p < 0.0001). We identified a high level of quality in the screening for nuclear atypia in thyroid FNA. The one-category discrepancy rate is suited to tracking individual cytotechnologist performance, identifies outliers and appears to correlate with cytotechnologist experience.


Reliability and concurrent validity of postural asymmetry measurement in adolescent idiopathic scoliosis.
To investigate the reliability and concurrent validity of the Baseline® Body Level/Scoliosis meter for adolescent idiopathic scoliosis postural assessment in three anatomical planes. This is an observational reliability and concurrent validity study of adolescent referrals to the Orthopaedic department for scoliosis screening at Karolinska University Hospital, Stockholm, Sweden between March-May 2012. A total of 31 adolescents with idiopathic scoliosis (13.6 ± 0.6 years old) of mild-moderate curvatures (25° ± 12°) were consecutively recruited. Measurement of cervical, thoracic and lumbar curvatures, pelvic and shoulder tilt, and axial thoracic rotation (ATR) were performed by two trained physiotherapists in one day. The intraclass correlation coefficient (ICC) was used to determine the inter-examiner reliability (ICC2,1) and the intra-rater reliability (ICC3,3) of the Baseline® Body Level/Scoliosis meter. Spearman's correlation analyses were used to estimate concurrent validity between the Baseline® Body Level/Scoliosis meter and Gold Standard Cobb angles from radiographs and the Orthopaedic Systems Inc. Scoliometer. There was excellent reliability between examiners for thoracic kyphosis (ICC2,1 = 0.94), ATR (ICC2,1 = 0.92) and lumbar lordosis (ICC2,1 = 0.79). There was adequate reliability between examiners for cervical lordosis (ICC2,1 = 0.51), however poor reliability for pelvic and shoulder tilt. Both devices were reproducible in the measurement of ATR when repeated by one examiner (ICC3,3 0.98-1.00). The device had a good correlation with the Scoliometer (rho = 0.78). When compared with Cobb angle from radiographs, there was a moderate correlation for ATR (rho = 0.627). The Baseline® Body Level/Scoliosis meter provides reliable transverse and sagittal cervical, thoracic and lumbar measurements and valid transverse plan measurements of mild-moderate scoliosis deformity.


Romidepsin: a histone deacetylase inhibitor for refractory cutaneous T-cell lymphoma.
To evaluate the efficacy and safety of romidepsin in refractory cutaneous T-cell lymphoma (CTCL). An English-language literature search of PubMed and MEDLINE (Nov 2011-April 2012) was performed using the terms romidepsin, CTCL, and depsipeptide (FK228). The National Comprehensive Cancer Network guidelines, American Society of Clinical Oncology abstracts, American Society of Hematology abstracts, clinical trial registry, and prescribing information from the manufacturer were reviewed for additional information. Phase 1 and 2 trials evaluating the efficacy and safety of romidepsin were reviewed with a specific focus on its use in cutaneous T-cell lymphoma. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. In advanced stage CTCL, single or combination chemotherapy regimen responses are variable and lack durability. Romidepsin is a histone deacetylase inhibitor approved for refractory cutaneous T-cell lymphoma. Romidepsin has shown an improvement in duration of response and pruritus over traditional therapy. In 2 independent Phase 2 trials, romidepsin showed an overall response rate of 34% and durable response of 13-15 months in patients with refractory CTCL. The most frequent toxicities of romidepsin include nausea, vomiting, fatigue, or myelosuppression. Clinically insignificant QT interval changes have been observed but did not correlate with a decrease in left ventricular ejection fraction, or elevated laboratory markers of myocardial damage. Romidepsin is an effective, durable, and well-tolerated single-agent therapy in patients with refractory CTCL and should be considered for formulary addition in this population.


Intentional updating in episodic memory: Low testosterone associates with enhanced memory updating.
Although there is consensus that sex hormones modulate memory, we have an incomplete understanding of their role in remembering and forgetting. Humans continuously update memory, forgetting old, out-of-date information and encoding new, more relevant information. Updating processes can be studied with the list method of directed forgetting. In the list method of directed forgetting task, subjects study two lists of items and, after study of list 1, are asked to either forget or remember the list for an upcoming memory test. Free testosterone level was quantified from saliva samples. Directed forgetting and saliva testosterone were evaluated in young men (aged between 18 and 28 years). Following a forget cue, recall of list-1 items was reduced and recall of list-2 items was enhanced. However, only recall of list-2 items was associated with free testosterone level. Following a forget cue, participants with low testosterone levels showed higher recall of list-2 items than participants with high testosterone levels. The selective association between testosterone level and list-2 recall is consistent with two-mechanism accounts of memory updating, where the forgetting effect is due to impaired retrieval and the enhancement effect to improved encoding. On the basis of this view, the present results indicate that low testosterone levels are associated with improved binding of the newly encoded memories to their context cue.


Understanding Preferences for Treatment After Hypothetical First-Time Anterior Shoulder Dislocation: Surveying an Online Panel Utilizing a Novel Shared Decision-Making Tool.
Although surgical management of a first-time anterior shoulder dislocation (FTASD) can reduce the risk of recurrent dislocation, other treatment characteristics, costs, and outcomes are important to patients considering treatment options. While patient preferences, such as those elicited by conjoint analysis, have been shown to be important in medical decision-making, the magnitudes or effects of patient preferences in treating an FTASD are unknown. To test a novel shared decision-making tool after sustained FTASD. Specifically measured were the following: (1) importance of aspects of operative versus nonoperative treatment, (2) respondents' agreement with results generated by the tool, (3) willingness to share these results with physicians, and (4) association of results with choice of treatment after FTASD. Cross-sectional study; Level of evidence, 3. A tool was designed and tested using members of Amazon Mechanical Turk, an online panel. The tool included an adaptive conjoint analysis exercise, a method to understand individuals' perceived importance of the following attributes of treatment: (1) chance of recurrent dislocation, (2) cost, (3) short-term limits on shoulder motion, (4) limits on participation in high-risk activities, and (5) duration of physical therapy. Respondents then chose between operative and nonoperative treatment for hypothetical shoulder dislocation. Overall, 374 of 501 (75%) respondents met the inclusion criteria, of which most were young, active males; one-third reported prior dislocation. From the conjoint analysis, the importance of recurrent dislocation and cost of treatment were the most important attributes. A substantial majority agreed with the tool's ability to generate representative preferences and indicated that they would share these preferences with their physician. Importance of recurrence proved significantly predictive of respondents' treatment choices, independent of sex or age; however, activity level was important to previous dislocators. A total of 125 (55%) males and 33 (23%) females chose surgery after FTASD, as did 37% of previous dislocators compared with 45% of nondislocators. When given thorough information about the risks and benefits, respondents had strong preferences for operative treatment after an FTASD. Respondents agreed with the survey results and wanted to share the information with providers. Recurrence was the most important attribute and played a role in decisions about treatment.


Observational constraint on cloud susceptibility weakened by aerosol retrieval limitations.
Aerosol-cloud interactions remain a major uncertainty in climate research. Studies have indicated that model estimates of cloud susceptibility to aerosols frequently exceed satellite estimates, motivating model reformulations to increase agreement. Here we show that conventional ways of using satellite information to estimate susceptibility can serve as only a weak constraint on models because the estimation is sensitive to errors in the retrieval procedures. Using instrument simulators to investigate differences between model and satellite estimates of susceptibilities, we find that low aerosol loading conditions are not well characterized by satellites, but model clouds are sensitive to aerosol perturbations in these conditions. We quantify the observational requirements needed to constrain models, and find that the nighttime lidar measurements of aerosols provide a better characterization of tenuous aerosols. We conclude that observational uncertainties and limitations need to be accounted for when assessing the role of aerosols in the climate system.


Antimalarial drug discovery: old and new approaches.
New drugs against malaria are greatly needed. Many approaches to antimalarial drug discovery are available. These approaches must take into account specific concerns, in particular the requirement for very inexpensive and simple to use new therapies and the need to limit the cost of drug discovery. Among important efforts that are currently ongoing are the optimization of therapy with available drugs, including the use of combination therapy, the development of analogs of existing agents, the discovery of natural products, the use of compounds that were originally developed against other diseases, the evaluation of drug resistance reversers, and the consideration of new chemotherapeutic targets. The last category benefits from recent advances in malaria research technologies and genomics and is most likely to identify new classes of drugs. A number of new antimalarial therapies will likely be needed over the coming years, so it is important to pursue multiple strategies for drug discovery.


Optometrists Association Australia Universal (entry-level) and Therapeutic Competency Standards for Optometry 2008.
Competency standards for entry-level to the profession of optometry in Australia were first developed in 1993, revised in 1997 and expanded in 2000 to include therapeutic competency standards. The entry-level standards cover the competencies required by a person entering the profession without therapeutic endorsement of their registration. The therapeutic competency standards address the additional competencies required for therapeutic endorsement of registration. This paper presents a revised version of the universal (entry-level) and therapeutic competency standards for the profession of optometry in Australia in 2008. Expert members of the profession and representatives from schools of optometry, registration boards in Australia, state divisions of Optometrists Association Australia and the New Zealand Association of Optometrists were consulted in the process of updating the standards. Three new elements of competency have been added to the standards. Twenty-three new performance criteria with associated indicators have been added. Some performance criteria from the earlier document have been combined. Substantial alterations were made to the presentation of indicators throughout the document. The updated entry-level (universal) and therapeutic competency standards were adopted on behalf of the profession by the National Council of Optometrists Association Australia in November 2008. Competency standards are used by Australian and New Zealand registration authorities for the purposes of registration and therapeutic endorsement of registration via the Optometry Council of Australia and New Zealand accreditation and assessment processes. They have also been used as the basis of the World Council of Optometry Global Competency-Based Model.


Gene therapy in liver diseases: state-of-the-art and future perspectives.
Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.


Area-level socioeconomic characteristics, prevalence and trajectories of cardiometabolic risk.
This study examines the relationships between area-level socioeconomic position (SEP) and the prevalence and trajectories of metabolic syndrome (MetS) and the count of its constituents (i.e., disturbed glucose and insulin metabolism, abdominal obesity, dyslipidemia, and hypertension). A cohort of 4,056 men and women aged 18+ living in Adelaide, Australia was established in 2000-2003. MetS was ascertained at baseline, four and eight years via clinical examinations. Baseline area-level median household income, percentage of residents with a high school education, and unemployment rate were derived from the 2001 population Census. Three-level random-intercepts logistic and Poisson regression models were performed to estimate the standardized odds ratio (SOR), prevalence risk ratio (SRR), ratio of SORs/SRRs, and (95% confidence interval (CI)). Interaction between area- and individual-level SEP variables was also tested. The odds of having MetS and the count of its constituents increased over time. This increase did not vary according to baseline area-level SEP (ratios of SORs/SRRs ≈ 1; p ≥ 0.42). However, at baseline, after adjustment for individual SEP and health behaviours, median household income (inversely) and unemployment rate (positively) were significantly associated with MetS prevalence (SOR (95%CI) = 0.76 (0.63-0.90), and 1.48 (1.26-1.74), respectively), and the count of its constituents (SRR (95%CI) = 0.96 (0.93-0.99), and 1.06 (1.04-1.09), respectively). The inverse association with area-level education was statistically significant only in participants with less than post high school education (SOR (95%CI) = 0.58 (0.45-0.73), and SRR (95%CI) = 0.91 (0.88-0.94)). Area-level SEP does not predict an elevated trajectory to developing MetS or an elevated count of its constituents. However, at baseline, area-level SEP was inversely associated with prevalence of MetS and the count of its constituents, with the association of area-level education being modified by individual-level education. Population-level interventions for communities defined by area-level socioeconomic disadvantage are needed to reduce cardiometabolic risks.


Breeding French bulldogs so that they breathe well-A long way to go.
Brachycephalic syndrome (BS) is a pathophysiological disorder caused by excessive soft tissue within the upper airways of short-nosed dog breeds, causing obstruction of the nasal, pharyngeal and laryngeal lumen, resulting in severe respiratory distress. As the prevalence of BS appears to be high among some of the affected breeds, there is an urgent need for breeding efforts to improve the health status of those dogs. In the present study, we evaluated correlations between morphometric and other phenotypic characteristics and BS in a population of 69 French bulldogs from Denmark to identify parameters that could serve as a basis for breeding against BS. Furthermore, the genetic variation was monitored to determine whether it would be possible to breed based on these characteristics without simultaneously causing a critical reduction in genetic variation. Six phenotypic characteristics were correlated with the Brachycephalic Syndrome Functional (BSF) score. Among the morphometric risk factors, nostril stenosis (NS) and neck girth (NG) had the highest impact on the BSF score, accounting for 32% and 4% of the variation, respectively. The genetic variation in the population was comparable to other pure breeds, i.e. estimated and observed heterozygosity was 0.60 and the average inbreeding coefficient was 0.01. If only dogs with Grades 1 and 2 NS (no or only mild NS) were selected for breeding the mean BSF score would be reduced significantly. However, it would result in the exclusion of 81% of the population for breeding and this is not prudent. Excluding only dogs with severe stenosis (Grade 4) would exclude 50% of the population without any adverse impact on genetic variation within the population. Although exclusion of dogs with Grade 4 would result in an apparent reduction in the mean BSF score, this reduction is not significant. As NS accounts for 32% of the variation in BSF score, a possible long term strategy to reduce the prevalence of the BS in French bulldogs would seem to be a selection scheme that first excluded dogs with the most severe NS from breeding, gradually moving towards selecting dogs with lower NS grades. According to our findings there is no viable short term solution for reducing the prevalence of BS in the French bulldog population.


Observation of Subradiant Atomic Momentum States with Bose-Einstein Condensates in a Recoil Resolving Optical Ring Resonator.
We experimentally investigate the formation of subradiant atomic momentum states in Bose-Einstein condensates inside a recoil resolving optical ring resonator according to the theoretical proposal of Cola, Bigerni, and Piovella. The atoms are pumped from the side with laser light that contains two frequency components. They resonantly drive cavity assisted Raman transitions between three discreet atomic momentum states. Within a few hundred microseconds, the system evolves into a stationary subradiant state. In this state, the condensate develops two density gratings suitable to diffract the two frequency components of the pump field into the resonator. Both components destructively interfere such that scattering is efficiently suppressed. A series of subradiant states for various amplitude ratios of the two pump components between 0 and 2.1 have been observed. The results are well explained with a three state quantum model in mean field approximation.


Microbial phylogenetic profiling with the Pacific Biosciences sequencing platform.
High-throughput sequencing of 16S rRNA gene amplicons has revolutionized the capacity and depth of microbial community profiling. Several sequencing platforms are available, but most phylogenetic studies are performed on the 454-pyrosequencing platform because its longer reads can give finer phylogenetic resolution. The Pacific Biosciences (PacBio) sequencing platform is significantly less expensive per run, does not rely on amplification for library generation, and generates reads that are, on average, four times longer than those from 454 (C2 chemistry), but the resulting high error rates appear to preclude its use in phylogenetic profiling. Recently, however, the PacBio platform was used to characterize four electrosynthetic microbiomes to the genus-level for less than USD 1,000 through the use of PacBio's circular consensus sequence technology. Here, we describe in greater detail: 1) the output from successful 16S rRNA gene amplicon profiling with PacBio, 2) how the analysis was contingent upon several alterations to standard bioinformatic quality control workflows, and 3) the advantages and disadvantages of using the PacBio platform for community profiling.


Objective outcomes 14 years after laparoscopic anterior 180-degree partial versus nissen fundoplication: results from a randomized trial.
To investigate late objective outcomes 14 years after laparoscopic anterior 180-degree partial versus Nissen fundoplication. Clinical outcomes from randomized clinical trials suggest good outcomes for anterior 180-degree partial fundoplication, with similar control of reflux symptoms and less side effects, compared with Nissen fundoplication. However, objective outcomes at late follow-up have not been reported. A subset of participants from a randomized trial of anterior 180-degree versus Nissen fundoplication underwent stationary esophageal high-resolution manometry and ambulatory 24-hour impedance-pH monitoring at 14 years' follow-up. The subset and other patients in the trial also completed a standardized clinical questionnaire to ensure that they were representative of the overall trial. Eighteen patients (8 anterior, 10 Nissen) underwent objective testing and had a symptom profile similar to those who did not (n = 59) have testing. Total esophageal acid exposure time and the total number of acid and weakly acidic reflux episodes per 24 hours were higher after anterior fundoplication than after Nissen fundoplication. Proximal, midesophageal and distal reflux were proportionately increased after anterior 180-degree fundoplication. The number of liquid and mixed reflux episodes was also higher after anterior fundoplication, which was accompanied by higher clinical heartburn scores. There were no differences in gas reflux, gastric belches, and supragastric belches, which is in line with the observation that gas-related symptoms were similar for both groups. Mean LES resting and relaxation nadir pressure were lower after anterior fundoplication, which was reflected by lower dysphagia scores. Patient satisfaction was similar after both procedures. At 14 years after randomization, this study demonstrated that acid, weakly acidic, liquid and mixed reflux episodes are more common after anterior 180-degree fundoplication than after Nissen fundoplication. On the contrary, gas reflux and gastric belching and patient satisfaction are similar for both procedures. Mean LES resting and relaxation nadir pressure are lower after anterior fundoplication. Overall, these findings suggest less effective reflux control after anterior 180-degree partial fundoplication, offset by less dysphagia, leading to a clinical outcome that is equivalent to Nissen fundoplication at late follow-up.


[Insulin-resistance and metabolic syndrome in patients with coronary heart disease defined by angiography].
The frequency of insulin-resistance (IR) and metabolic syndrome (MS) were examined in coronary patients using different criteria of definition. It was also analyzed which of them indicated a strong association with the presence and severity of the disease. This was a case-control study on 100 patients between 40 and 70 years old, assisted in a hospital center and there examined by angiography. IR was defined by insulin >15 mU/l, Homeostatic Model Assessment for insulin-resistance (HOMA-IR) >3.1 and the combination body mass index (BMI) >27.5 kg/m2 with HOMA-IR >3.6. MS was defined according to International Diabetes Federation and American Heart Association/National Heart, Lung and Blood Institute. Insulin >15 mU/l and HOMA-IR >3.1 had similar sensibility, 60.3%, and were significantly associated with the extension of coronary heart disease, p = 0.001 and p = 0.009 respectively. Whereas, BMI>27.5 kg/m2 with HOMA-IR>3.6 showed a lower sensibility, 43.1% and less association with severity, p = 0.028. The odds ratio (OR) for coronary heart disease were respectively: 3.16 (CI 95 1.28-7.79), p = 0.012; 2.93 (CI 95% 1.20-7.19) p = 0.019; 2.86 (CI 95% 1.10-7.41), p = 0.031. The frequency of SM defined according to American Heart Association/National Heart, Lung and Blood Institute was higher in coronary patients vs. controls (62.1% vs. 33.3%, p = 0.003). It was associated with disease in one or more vases (p = 0.011) and was its predictor, OR = 4.22 (CI 95% 1.65-10.83) p = 0.003. However, SM defined according to International Diabetes Federation was not associated with the presence or severity of coronary heart disease.


Tuning biaxiality of nematic phases of board-like colloids by an external magnetic field.
We study the influence of a magnetic field on the biaxial nematic phase of board-like goethite colloids both experimentally and theoretically. Using synchrotron small angle X-ray scattering techniques we find that applying a magnetic field along the main director of the biaxial nematic phase leads to a clear decrease in biaxiality with increasing magnetic field strength. Above a certain magnetic field strength the biaxiality is completely suppressed and the biaxial nematic phase transforms into an ordinary prolate uniaxial nematic phase. In order to interpret the physical mechanism behind this phenomenon, we develop a mean-field theory for the liquid crystal phase behaviour of the suspension. Within this theory the magnetic properties of the particles are modelled by taking into account the effect of both the permanent and the induced magnetic dipoles. The resulting phase diagrams support our experimental findings of the field-induced biaxial nematic to prolate uniaxial nematic transition. They additionally predict that for more plate-like particles, which initially would only display oblate nematic ordering of the shortest axis, the rare biaxial phase can be induced by applying a magnetic field with a carefully chosen field strength, a parameter which can be easily tuned.


Superfluid helium quantum interference devices: physics and applications.
We present an overview of recent developments related to superfluid helium quantum interference devices (SHeQUIDs). We discuss the physics of two reservoirs of superfluid helium coupled together and describe the quantum oscillations that result from varying the coupling strength. We explain the principles behind SHeQUIDs that can be built based on these oscillations and review some techniques and applications.


Transdifferentiation of pancreas to liver.
Transdifferentiation is the name used to describe the direct conversion of one differentiated cell type into another. Cells which have the potential to interconvert by transdifferentiation generally arise from adjacent regions in the developing embryo. For example, the liver and pancreas arise from the same region of the endoderm. The transdifferentiation of pancreas to liver (and vice versa) has been observed in animal experiments and in certain human pathologies. Understanding transdifferentiation is important to developmental biologists because it will help elucidate the cellular and molecular differences that distinguish neighbouring regions of the embryo. While the in vivo models for the transdifferentiation of liver to pancreas have been valuable, it is more difficult to extrapolate from these studies to individual changes at the cellular or molecular levels. The recent development of two in vitro systems (AR42J cells and embryonic pancreatic cultures) for the transdifferentiation of pancreas to liver has shown that an environmental change in the form of an exogenous glucocorticoid can cause the conversion of pancreatic exocrine cells into hepatocytes. The AR42J cell system has been used to elucidate the cell lineage and the molecular basis of transdifferentiation of pancreas to liver.


Characterization of uterine epidermal growth factor during early pregnancy in pigs.
Genomic research has identified a quantitative trait locus for uterine capacity, a component trait contributing to litter size, on porcine chromosome 8. The epidermal growth factor (EGF) gene, on porcine chromosome 8, may influence uterine capacity because of its growth-promoting activities. Using reverse transcription-polymerase chain reaction (PCR) and iterative screening of a porcine reproductive tissue cDNA library, 4932 bp cDNA sequence coding for porcine EGF precursor was obtained. The predicted protein sequence of the EGF precursor contained 1214 amino acids, similar to human EGF precursor (1207 amino acids, 81% identity). Curiously, the sequence of the mature peptide was less homologous between species than other regions of EGF precursor. The presence of conserved regions outside the mature peptide may suggest that these regions are functionally important. Expression of EGF mRNA in the endometrium of White crossbred gilts (n = 3 to 5 each) was determined by Northern blotting using 20 microg of total RNA from endometrium of D 10, 13, and 15 cyclic, and D 10, 13, 15, 20, 30, and 40 of pregnant gilts. A 3342 bp probe from EGF precursor was used. The bands corresponding to EGF mRNA were quantified by densitometry and results were analyzed by ANOVA. EGF mRNA expression decreased significantly from D 13 to 15 of the cycle and pregnancy (P = 0.04), and from D 30 to 40 of pregnancy (P = 0.01). These findings show that EGF mRNA expression is temporally regulated during the cycle and early pregnancy, and this pattern of gene expression may be important during early conceptus development.


Partitioning of persistent organic pollutants between blubber and blood of wild bottlenose dolphins: implications for biomonitoring and health.
Biomonitoring surveys of wild cetaceans commonly utilize blubber as a means to assess exposure to persistent organic pollutants (POPs), but the relationship between concentrations in blubber and those in blood, a better indicator of target organ exposure, is poorly understood. To define this relationship, matched blubber and plasma samples (n = 56) were collected from free-ranging bottlenose dolphins (Tursiops truncatus) and analyzed for 61 polychlorinated biphenyl (PCB) congeners, 5 polybrominated diphenyl ether (PBDE) congeners, and 13 organochlorine pesticides (OCPs). With the exception of PCB 209, lipid-normalized concentrations of the major POPs in blubber and plasma were positively and significantly correlated (R(2) = 0.828 to 0.976). Plasma concentrations, however, significantly increased with declining blubber lipid content, suggesting that as lipid is utilized, POPs are mobilized into blood. Compound- and homologue- specific blubber/blood partition coefficients also differed according to lipid content, suggesting POPs are selectively mobilized from blubber. Overall, these results suggest that with the regression parameters derived here, blubber may be used to estimate blood concentrations and vice versa. Additionally, the mobilization of lipid from blubber and concomitant increase in contaminants in blood suggests cetaceans with reduced blubber lipid may be at greater risk for contaminant-associated health effects.


Biofeedback and other therapies for the treatment of urinary incontinence in the elderly.
Alternative therapies hold potential promise for the treatment of urinary incontinence in the elderly. Assessment and comparisons of the efficacies of such therapies have been hindered by a lack of standardized definitions of urinary incontinence in the study populations, lack of standardization of treatment protocols, inadequate sample sizes, and lack of blinding and appropriate controls. Biofeedback has been the most extensively studied therapy and may provide appropriate adjunctive or primary therapy for select individuals. Other potential therapies, such as acupuncture, hypnosis, and herbal therapies, have not been sufficiently examined to make definitive recommendations.


MafB restricts M-CSF-dependent myeloid commitment divisions of hematopoietic stem cells.
While hematopoietic stem cell (HSC) self-renewal is well studied, it remains unknown whether distinct control mechanisms enable HSC divisions that generate progeny cells with specific lineage bias. Here, we report that the monocytic transcription factor MafB specifically restricts the ability of M-CSF to instruct myeloid commitment divisions in HSCs. MafB deficiency specifically enhanced sensitivity to M-CSF and caused activation of the myeloid master-regulator PU.1 in HSCs in vivo. Single-cell analysis revealed that reduced MafB levels enabled M-CSF to instruct divisions producing asymmetric daughter pairs with one PU.1(+) cell. As a consequence, MafB(-/-) HSCs showed a PU.1 and M-CSF receptor-dependent competitive repopulation advantage specifically in the myelomonocytic, but not T lymphoid or erythroid, compartment. Lineage-biased repopulation advantage was progressive, maintained long term, and serially transplantable. Together, this indicates that an integrated transcription factor/cytokine circuit can control the rate of specific HSC commitment divisions without compromising other lineages or self-renewal.


Perforator mapping reduces the operative time of DIEP flap breast reconstruction: A systematic review and meta-analysis of preoperative ultrasound, computed tomography and magnetic resonance angiography.
Prior to DIEP flap breast reconstruction, mapping the perforators of the lower abdominal wall using ultrasound, computed tomography angiography (CTA) or magnetic resonance angiography (MRA) reduces the risk of flap failure. This review aimed to investigate the additional potential benefit of a reduction in operating time. We systematically searched the literature for studies concerning adult women undergoing DIEP flap breast reconstruction, which directly compared the operating times and adverse outcomes for those with and without preoperative perforator mapping by ultrasound, CTA or MRA. Outcomes were extracted, data meta-analysed and the quality of the evidence appraised. Fourteen articles were included. Preoperative perforator mapping by CTA or MRA significantly reduced operating time (mean reduction of 54 minutes [95% CI 3, 105], p = 0.04), when directly compared to DIEP flap breast reconstruction with no perforator mapping. Further, perforator mapping by CTA was superior to ultrasound, as CTA saved more time in theatre (mean reduction of 58 minutes [95% CI 25, 91], p < 0.001) and was associated with a lower risk of partial flap failure (RR 0.15 [95% CI 0.04, 0.6], p = 0.007). All studies were at risk of methodological bias and the quality of the evidence was very low. The quality of research regarding perforator mapping prior to DIEP flap breast reconstruction is poor and although preoperative angiography appears to save operative time, reduce morbidity and confer cost savings, higher quality research is needed. PROSPERO ID CRD42017065012.


Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin.
Non-steroidal anti-inflammatory drugs (NSAIDs) can cause significant small bowel injuries. The role of gut microbiota in this NSAID-induced enteropathy is poorly understood. We studied the dynamic changes in gut microbiota following indomethacin administration in mice, and investigated the effects of these adaptive changes on subsequent NSAID-induced enteropathy. The changes in gut microbiota were studied using 16S rRNA sequencing, and the effects of such changes were investigated using antibiotics and a faecal transplantation model. After indomethacin treatment, significant adaptive changes in gut microbiota were observed, including increased abundance of Firmicutes and decreased abundance in that of Bacteroidetes. Depletion of gut microbiota with antibiotics led to a higher mortality (P = 0.0021) in mice compared to controls. Mice pre-transplanted with adaptively changed microbiota showed less small bowel injury and lower levels of pro-inflammatory cytokines when exposed to indomethacin. In summary, this study identifies adaptive changes in the gut microbiota upon indomethacin administration, which can in turn ameliorate further NSAID-induced injury. The heightened mortality with antibiotic depletion of the adaptively changed microbiota suggests its important role in protecting against such injury. This study provides insight for future efforts to target the microbiota as a therapeutic strategy.


Temporal changes in the gene expression heterogeneity during brain development and aging.
Cells in largely non-mitotic tissues such as the brain are prone to stochastic (epi-)genetic alterations that may cause increased variability between cells and individuals over time. Although increased inter-individual heterogeneity in gene expression was previously reported, whether this process starts during development or if it is restricted to the aging period has not yet been studied. The regulatory dynamics and functional significance of putative aging-related heterogeneity are also unknown. Here we address these by a meta-analysis of 19 transcriptome datasets from three independent studies, covering diverse human brain regions. We observed a significant increase in inter-individual heterogeneity during aging (20 + years) compared to postnatal development (0 to 20 years). Increased heterogeneity during aging was consistent among different brain regions at the gene level and associated with lifespan regulation and neuronal functions. Overall, our results show that increased expression heterogeneity is a characteristic of aging human brain, and may influence aging-related changes in brain functions.


Citrate as a siderophore in Bradyrhizobium japonicum.
Under iron-limiting conditions, many bacteria secrete ferric iron-specific ligands, generically termed siderophores, to aid in the sequestering and transport of iron. One strain of the nitrogen-fixing soybean symbiont Bradyrhizobium japonicum, 61A152, was shown to produce a siderophore when 20 B. japonicum strains were screened with all six chemical assays commonly used to detect such production. Production by strain 61A152 was detected via the chrome azurol S assay, a general test for siderophores which is independent of siderophore structure. The iron-chelating compound was neither a catechol nor a hydroxamate and was ninhydrin negative. It was determined to be citric acid via a combination of thin-layer chromatography and high-voltage paper electrophoresis; this identification was verified by a specific enzymatic assay for citric acid. The inverse correlation which was observed between citric acid release and the iron content of the medium suggested that ferric citrate could serve as an iron source. This was confirmed via growth and transport assays. Exogenously added ferric citrate could be used to overcome iron starvation, and iron-deficient cells actively transported radiolabeled ferric citrate. These results, taken together, indicate a role for ferric citrate in the iron nutrition of this strain, which has been shown to be an efficient nitrogen-fixing strain on a variety of soybean cultivars.


[Behavior therapy and neurotic behavior].
The first part of the lecture presents three classical aspects of behavior therapy: therapeutic efficiency, utilisation of well defined methods, rapidity of treatment. Emphasis is brought to the importance of behavior analysis and to the dangers arisen from insufficient knowledge or ignorance of learning theories and fundamental principles of behavior analysis. One insists on experimental analysis which is the basis for methods of action having as consequence for the therapeut: controlling strategy of treatment and direct responsibility concerning success and failure. Then, actual limitations of behaviour therapy are described. The second part deals with one of the most important working hypothesis on human neurosis originating from laboratory and clinical research. Behavior therapy refuses to elaborate hypothetical deductive constructions, unless working hypotheses to be verified. Then the four essential clues to behavioural psychotherapy are formulated. The main methods of action presently utilized are presented: aversive methods, operational and systematic desensitization technics through reciprocal inhibition. Finally, some of the main criticism usually made on behaviour therapy are being discussed.


Dimalononitrile-containing probe based on aggregation-enhanced emission features for the multi-mode fluorescence detection of volatile amines.
A novel multi-mode probe consisting of a hexaphenyl-1,3-butadiene derivative, 2,2'-((((1Z,3Z)-1,2,3,4-tetraphenylbuta-1,3-diene-1,4-diyl)bis(4,1-phenylene))bis(methanylylidene))dimalononitrile (ZZ-HPB-CN), with typical aggregation-enhanced emission (AEE) features was easily prepared for the highly sensitive and rapid detection of amine vapors. The ZZ-HPB-CN sensor, which was prepared by simply depositing ZZ-HPB-CN on filter paper, could detect low concentration vapors of volatile amines using fluorescence, ultraviolet and naked-eye detection. The limit of detection of the sensor was as low as 1 ppb for the fluorescence detection. The color change of the sensor caused by 1-10 ppm amine vapors could be observed under UV light or with the naked eye. The high sensitivity, quick response and easy operation of the probe give it great potential for real-life applications.


The national system of scientific measurement.
Mandated measurement methods are required by regulatory agencies and other government groups. These methods exist for measuring almost all physical, chemical, and biological phenomena. The methods have been culled from the literature, from the organizations that write voluntary standards, and some have been developed by the agencies. Few provide adequate estimates of precision, and fewer still provide any evaluation of interlaboratory bias. The societal costs of these poor measurements are large. Much needs to be done to meet the physical and statistical requirements for establishing and maintaining dependable measurements. Excepting those directly supported by the National Bureau of Standards, most of the nation's measurement systems are uncontrolled.


Next-generation sequencing data interpretation: enhancing reproducibility and accessibility.
Areas of life sciences research that were previously distant from each other in ideology, analysis practices and toolkits, such as microbial ecology and personalized medicine, have all embraced techniques that rely on next-generation sequencing instruments. Yet the capacity to generate the data greatly outpaces our ability to analyse it. Existing sequencing technologies are more mature and accessible than the methodologies that are available for individual researchers to move, store, analyse and present data in a fashion that is transparent and reproducible. Here we discuss currently pressing issues with analysis, interpretation, reproducibility and accessibility of these data, and we present promising solutions and venture into potential future developments.


Grinder: a versatile amplicon and shotgun sequence simulator.
We introduce Grinder (http://sourceforge.net/projects/biogrinder/), an open-source bioinformatic tool to simulate amplicon and shotgun (genomic, metagenomic, transcriptomic and metatranscriptomic) datasets from reference sequences. This is the first tool to simulate amplicon datasets (e.g. 16S rRNA) widely used by microbial ecologists. Grinder can create sequence libraries with a specific community structure, α and β diversities and experimental biases (e.g. chimeras, gene copy number variation) for commonly used sequencing platforms. This versatility allows the creation of simple to complex read datasets necessary for hypothesis testing when developing bioinformatic software, benchmarking existing tools or designing sequence-based experiments. Grinder is particularly useful for simulating clinical or environmental microbial communities and complements the use of in vitro mock communities.


Performance of the DSM-5-based criteria for Internet addiction: A factor analytical examination of three samples.
The diagnosis "Internet Gaming Disorder" (IGD) has been included in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders. However, the nine criteria have not been sufficiently reviewed for their diagnostic value. This study focuses on a broader approach of Internet addiction (IA) including other Internet activities. It is not yet clear what the construct of IA is in terms of dimensionality and homogeneity and how the individual criteria contribute to explained variance. Three separate exploratory factor analyses and multinomial logistic regression analyses were carried out based on information collected from a general population-based sample (n = 196), a sample of people recruited at job centers (n = 138), and a student sample (n = 188). Both of the adult samples show a distinct single-factor solution. The analysis of the student sample suggests a two-factor solution. Only one item (criterion 8: escape from a negative mood) can be assigned to the second factor. Altogether, high endorsement rates of the eighth criterion in all three samples indicate low discriminatory power. Overall, the analysis shows that the construct of IA is represented one dimensionally by the diagnostic criteria of the IGD. However, the student sample indicates evidence of age-specific performance of the criteria. The criterion "Escape from a negative mood" might be insufficient in discriminating between problematic and non-problematic Internet use. The findings deserve further examination, in particular with respect to the performance of the criteria in different age groups as well as in non-preselected samples.


Spermatophoric reaction reappraised: novel insights into the functioning of the loliginid spermatophore based on Doryteuthis plei (Mollusca: Cephalopoda).
During copulation, spermatophores produced by male coleoid cephalopods undergo the spermatophoric reaction, a complex process of evagination that culminates in the attachment of the spermatangium (everted spermatophore containing the sperm mass) on the female's body. To better understand this complicated phenomenon, the present study investigated the functional morphology of the spermatophore of the squid Doryteuthis plei applying in vitro analysis of the reaction, as well as light and electron microscopy investigation of spermatangia obtained either in vitro, or naturally attached on females. Hitherto unnoticed functional features of the loliginid spermatophore require a reappraisal of some important processes involved in the spermatophoric reaction. The most striking findings concern the attachment mechanism, which is not carried out solely by cement adhesive material, as previously believed, but rather by an autonomous, complex process performed by multiple structures during the spermatophoric reaction. During evagination, the ejaculatory apparatus provides anchorage on the targeted tissue, presumably due to the minute stellate particles present in the exposed spiral filament. Consequently, the ejaculatory apparatus maintains the attachment of the tip of the evaginating spermatophore until the cement body is extruded. Subsequently, the cement body passes through a complex structural rearrangement, which leads to the injection of both its viscid contents and pointed oral region onto the targeted tissue. The inner membrane at the oral region of the cement body contains numerous stellate particles attached at its inner side; eversion of this membrane exposes these sharp structures, which presumably adhere to the tissue and augment attachment. Several naturally attached spermatangia were found with their bases implanted at the deposition sites, and the possible mechanisms of perforation are discussed based on present evidence. The function of the complex squid spermatophore and its spermatophoric reaction is revisited in light of these findings. J. Morphol. 2012. © 2011 Wiley Periodicals, Inc.


Viewing humorous film improves nighttime wakening in children with atopic dermatitis.
Patients with atopic dermatitis suffered from night-time wakening, but the exact mechanism of it was not known. Ghrelin was involved in growth hormone secretion, regulation of appetite, anxiety,night-time wakening and stress. Thus salivary ghreli levels during the night were measured in 40 healthy children or 40 patients with atopic dermatitis with night-time wakening. Salivary ghrelin levels at 02:00 h were markedly elevated in patients with atopic dermatitis compared to those in healthy children. Neither viewing control non-humorous film nor viewing humorous film had any effect on healthy children. In contrast, viewing humorous film improved night-time wakening and reduced elevation of salivary ghrelin levels in patients with atopic dermatitis, while viewing control film failed to do so. Viewing humorous film may be useful in the treatment of night-time wakening in patients with atopic dermatitis.


Pyridoxine enhances chemo-responsiveness of breast cancer stem cells via redox reconditioning.
A plethora of molecular strategies are employed by breast cancer stem cells (bCSCs) to evade chemotherapy-induced death signals, redox modulation being a crucial factor among those. Here, we observed that bCSCs are resistant to DNA damage and generate low ROS upon doxorubicin (Dox) treatment. Further exploration revealed inherently high NEIL2, a base excision repair (BER) enzyme that plays a key regulatory role in repairing DNA damage, in bCSCs. However, its role in modulating the redox status of bCSCs remains unexplored. In addition, Dox not only upregulates NEIL2 in bCSCs at both transcriptional and translational levels but also declines p300-induced acetylation thus activating NEIL2 and providing a protective effect against the stress inflicted by the genotoxic drug. However, when the redox status of bCSCs is altered by inducing high ROS, apoptosis of the resistant population is accomplished. Subsequently, when NEIL2 is suppressed in bCSCs, chemo-sensitization of the resistant population is enabled by redox reconditioning via impaired DNA repair. This signifies a possibility of therapeutically disrupting the redox balance in bCSCs to enhance their chemo-responsiveness. Our search for an inhibitor of NEIL2 revealed that vitamin B6, i.e., pyridoxine (PN), hinders NEIL2-mediated transcription-coupled repair process by not only decreasing NEIL2 expression but also inhibiting its association with RNA Pol II, thus stimulating DNA damage and triggering ROS. As a consequence of altered redox regulation, bCSCs become susceptible towards Dox, which then induces apoptosis via caspase cascade. These findings signify that PN enhances chemo-responsiveness of bCSCs via redox reconditioning.


Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR.
The development of atherosclerosis is often associated with altered concentrations of systemic lipoproteins, which are determined by the concentration and/or activity of three groups of different proteins, i.e. apolipoproteins (apo), enzymes, and receptors. The effects of diet or therapeutic interventions on lipid metabolism are mediated by changes in activity or concentrations of these three components. Fibrates have been shown to activate nuclear receptors belonging to the steroid hormone receptor super-family, termed peroxisome proliferator activated receptor (PPAR). These activated PPARs are potent transcription factors which influence the expression of several target genes implicated in lipoprotein homeostasis, e.g. LPL, apo C-III and apo A-1. Fibrates decrease apo C-III transcription and increase LPL production via these PPARs resulting in a profound hypotriglyceridaemic effect. Apolipoproteins and enzymes are important in governing lipid metabolism, thus therapeutically altering the expression of these genes constitutes an efficient therapeutic option.


Sensori-motor adaptation to novel limb dynamics influences the representation of peripersonal space.
Peripersonal space can be considered as the interface between the body and the environment, where objects can be reached and which may serve as a reference for the central nervous system with regard to possible actions. Peripersonal space can be studied by assessing the perception of the reachable space, which depends on the body's physical characteristics (i.e., arm length) since their modifications have been shown to be associated with a change in peripersonal space representation. However, it remains unclear whether the representation of limb dynamics also influences the representation of peripersonal space. The present study investigated this issue by perturbing the force-field environment. A novel force field was created by rotating an experimental platform where participants were seated while they reached towards visual targets. Manual reaching performance was assessed before, during and after platform rotation. Crucially, perception of peripersonal space was also assessed, with reachability judgments, before and after platform rotation. As expected, sensori-motor adaptation to the perturbed force field was observed. Our principal finding is that peripersonal space was systematically perceived as closer to the body after force-field adaptation. Two control experiments showed no significant difference in reachability judgments when no reaching movements were performed during platform rotation or when reaching movements were performed without platform rotation, suggesting that the change in perceived peripersonal space resulted from exposure to new limb dynamics. Overall, our findings show that sensori-motor adaptation of reaching movements to a new force field, which does not directly influence arm length but results in the updating of the arm's internal model of limb dynamics, interacts with the perceptual categorisation of space, supporting a motor contribution to the representation of peripersonal space.


Impact craters on venus: initial analysis from magellan.
Magellan radar images of 15 percent of the planet show 135 craters of probable impact origin. Craters more than 15 km across tend to contain central peaks, multiple central peaks, and peak rings. Many craters smaller than 15 km exhibit multiple floors or appear in clusters; these phenomena are attributed to atmospheric breakup of incoming meteoroids. Additionally, the atmosphere appears to have prevented the formation of primary impact craters smaller than about 3 km and produced a deficiency in the number of craters smaller than about 25 km across. Ejecta is found at greater distances than that predicted by simple ballistic emplacement, and the distal ends of some ejecta deposits are lobate. These characteristics may represent surface flows of material initially entrained in the atmosphere. Many craters are surrounded by zones of low radar albedo whose origin may have been deformation of the surface by the shock or pressure wave associated with the incoming meteoroid. Craters are absent from several large areas such as a 5 million square kilometer region around Sappho Patera, where the most likely explanation for the dearth of craters is volcanic resurfacing. There is apparently a spectrum of surface ages on Venus ranging approximately from 0 to 800 million years, and therefore Venus must be a geologically active planet.


Phospho.ELM: a database of phosphorylation sites--update 2008.
Phospho.ELM is a manually curated database of eukaryotic phosphorylation sites. The resource includes data collected from published literature as well as high-throughput data sets. The current release of Phospho.ELM (version 7.0, July 2007) contains 4078 phospho-protein sequences covering 12 025 phospho-serine, 2362 phospho-threonine and 2083 phospho-tyrosine sites. The entries provide information about the phosphorylated proteins and the exact position of known phosphorylated instances, the kinases responsible for the modification (where known) and links to bibliographic references. The database entries have hyperlinks to easily access further information from UniProt, PubMed, SMART, ELM, MSD as well as links to the protein interaction databases MINT and STRING. A new BLAST search tool, complementary to retrieval by keyword and UniProt accession number, allows users to submit a protein query (by sequence or UniProt accession) to search against the curated data set of phosphorylated peptides. Phospho.ELM is available on line at: http://phospho.elm.eu.org.


SU-E-J-204: The Dosimetric Impact of Daily Setup Error and Inter-Fraction Prostate Motion on the Calculated Treatment Plan for Patients Receiving IMRT Based Radiation Therapy.
Evaluate the dosimetric impact of daily setup error and inter-fraction organ motion on the radiation treatment plan. Twelve patients undergoing definitive IMRT treatments for prostate cancer were evaluated. All patients underwent fiducial marker placement prior to treatment planning CT scan, and were treated to a dose of 8100cGy given in 45 fractions. We retrospectively created a plan for each treatment day that had a shift available. To calculate the dose the patient would have received with no setup correction, we mathematically 'negated' the shift by moving the isocenter in the opposite direction of the shift. The individualized daily plans were combined to generate an overall plan sum. The dose distribution from these uncorrected plans was compared to the actual treatment plans. A total of 390 shifts were negated and their corresponding plans evaluated. The mean isocenter shift based on the location of the fiducial markers was 3.3±6.5mm to the right, 1.6±5.1mm posteriorly, and 1.0±5.0mm along the caudal direction. The mean D95 dose when setup error was corrected and uncorrected for the PTV8100 volume was 8089cGy and 7303cGy (p < 0.001) and for prostate volume was 8228cGy and 7844cGy (p < 0.002). The mean V95 values when setup error was corrected and uncorrected for the PTV8100 volume was 99.9% vs. 87.3% (p < 0.0001). At an individual level, the difference in D95 value approached 1200cGy for the prostate volume and 2000cGy for the PTV8100 volume. There was no statistically significant difference in the D35 parameter for the surrounding normal tissue except for the dose received by the right hip and the penile bulb. This work indicates that significant underdosing, approaching 2000cGy for the PTV8100 volume, can occur as a Result of inaccurate patient setup, and emphasizes the importance of accurate patient setup and target localization.