Comparison of device-based physical activity and sedentary behaviour following percutaneous coronary intervention in a cohort from Sweden and Australia: a harmonised, exploratory study.
Few studies have measured device-based physical activity and sedentary behaviour following a percutaneous coronary intervention (PCI), with no studies comparing these behaviours between countries using the same methods. The aim of the study was to compare device-based physical activity and sedentary behaviour, using a harmonised approach, following a PCI on-entry into centre-based cardiac rehabilitation in two countries. A cross-sectional study was conducted at two outpatient cardiac rehabilitation centres in Australia and Sweden. Participants were adults following a PCI and commencing cardiac rehabilitation (Australia n = 50, Sweden n = 133). Prior to discharge from hospital, Australian participants received brief physical activity advice (< 5 mins), while Swedish participants received physical activity counselling for 30 min. A triaxial accelerometer (Actigraph GT3X/ActiSleep) was used to objectively assess physical activity (light (LPA), moderate-to-vigorous (MVPA)) and sedentary behaviour. Outcomes included daily minutes of physical activity and sedentary behaviour, and the proportion and distribution of time spent in each behaviour. There was no difference in age, gender or relationship status between countries. Swedish (S) participants commenced cardiac rehabilitation later than Australian (A) participants (days post-PCI A 16 vs S 22, p < 0.001). Proportionally, Swedish participants were significantly more physically active and less sedentary than Australian participants (LPA A 27% vs S 30%, p < 0.05; MVPA A 5% vs S 7%, p < 0.01; sedentary behaviour A 68% vs S 63%, p < 0.001). When adjusting for wear-time, Australian participants were doing less MVPA minutes (A 42 vs S 64, p < 0.001) and more sedentary behaviour minutes (A 573 vs S 571, p < 0.001) per day. Both Swedish and Australian participants spent a large part of the day sedentary, accumulating 9.5 h per day in sedentary behaviour. Swedish PCI participants when commencing cardiac rehabilitation are more physically active than Australian participants. Potential explanatory factors are differences in post-PCI in-hospital physical activity education between countries and pre-existing physical activity levels. Despite this, sedentary behaviour is high in both countries. Internationally, interventions to address sedentary behaviour are indicated post-PCI, in both the acute setting and cardiac rehabilitation, in addition to traditional physical activity and cardiac rehabilitation recommendations. Australia: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12615000995572. Registered 22 September 2015, Sweden: World Health Organization Trial Registration Data Set: NCT02895451.


Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.
We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs. A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.


Laparoscopic versus open sigmoid colectomy for diverticulitis.
This study compared laparoscopic with open sigmoid colectomy for patients with a diagnosis of diverticulitis. Increased use of less invasive techniques makes it vitally important to evaluate outcomes of these techniques as compared with standard open procedures. Patients undergoing sigmoid colectomy for diverticulitis without hemorrhage (code 56211) between January 1997 and December 2001 were reviewed. Two groups were identified: those undergoing open sigmoid colectomy and those undergoing laparoscopic sigmoid colectomy; American Society of Anesthesiologists (ASA) scores, operative time, intensive care unit (ICU) and hospital length of stay, morbidity/mortality, and hospital charges were compared. During the study period 271 sigmoid colectomies were performed for diverticulitis without hemorrhage: 56 laparoscopically and 215 with the standard open technique. Four patients required conversion from laparoscopic to open colectomy. Mean ASA scores were: open group 2.4; laparoscopic group, 1.9 (P < 0.001). Mean operative times were: laparoscopic group, 170 +/- 45 minutes; open group, 140 +/- 49 minutes (P < 0.001). In the open group 39 patients required transfer to the ICU; one patient in the laparoscopic group required transfer to the ICU. Average hospital lengths of stay for the open and laparoscopic groups were 9.06 and 4.12 days, respectively (P < 0.001). Complications were recorded in 57 (27%) of 215 patients who underwent an open procedure versus 5 (9%) of 56 patients who underwent laparoscopic sigmoid colectomy (P < 0.01). There were three deaths in the open group and none in laparoscopic group. Average total hospital charges were 25,700 dollars for open sigmoid colectomy and 17,414 dollars for laparoscopic colectomy. Laparoscopic sigmoid colectomy compares favorably with open sigmoid colectomy for patients with a diagnosis of diverticulitis.


Identifying the Needs for a Web-Based Postpartum Platform Among Parents of Newborns and Health Care Professionals: Qualitative Focus Group Study.
During the turbulent postpartum period, there is an urgent need by parents for support and information regarding the care for their infant. In the Netherlands, professional support is provided during the first 8 days postpartum and for a maximum of 8 hours a day. This care is delivered by maternity care assistants (MCAs). Despite the availability of this extensive care, a majority of women prefer to make use of a lesser amount of postpartum care. After this period, access to care is less obvious. Where parents are automatically offered care in the first 8 days after birth, they must request care in the period thereafter. To compensate for a possible gap in information transfer, electronic health (eHealth) can be a valuable, easily accessible addition to regular care. We explored the needs and preferred content by new parents and health care professionals of a web-based platform dedicated to the postpartum period and identified barriers and facilitators for using such a platform. We conducted 3 semistructured focus groups among (1) parents of newborns, (2) MCAs, and (3) clinicians and administrators in maternity care. A topic list based on a framework designed for innovation processes was used. Thematic content analysis was applied. In the focus group for parents, 5 mothers and 1 male partner participated. A total of 6 MCAs participated in the second focus group. A total of 5 clinicians and 2 administrators-a member of a stakeholder party and a manager of a maternity care organization-participated in the third focus group. All user groups underlined that a platform focusing on the postpartum period was missing in current care, especially by parents experiencing a gap following the intensive care ending after the first week of childbirth. Parents indicated that they would perceive a postpartum platform as a proper source of reliable information on topics regarding breastfeeding, growth, and developmental milestones, but also as a tool to support them in seeking care with appropriate professionals. They also emphasized the need to receive personalized information and the opportunity to ask questions via the platform. MCAs acknowledged added value of providing additional information on topics that they address during the early postpartum period. MCAs as well as clinicians and administrators would guide parents to such a platform for additional support. All user groups experienced disadvantages of using an authentication procedure and filling out extra questionnaires to receive tailored information. Our research shows that parents of newborns, MCAs, and clinicians and administrators foresee the additional value of a web-based postpartum platform for at least the whole postpartum period. The platform should be easily accessible and personalized. Content on the platform should contain information regarding breastfeeding, growth, and developmental milestones. A chat function with professionals could be considered as an option.


Associations of regular glucosamine use with all-cause and cause-specific mortality: a large prospective cohort study.
To evaluate the associations of regular glucosamine use with all-cause and cause-specific mortality in a large prospective cohort. This population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study. Participants were recruited from 2006 to 2010 and were followed up through 2018. We evaluated all-cause mortality and mortality due to cardiovascular disease (CVD), cancer, respiratory and digestive disease. HRs and 95% CIs for all-cause and cause-specific mortality were calculated using Cox proportional hazards models with adjustment for potential confounding variables. At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years (IQR 8.3-9.7 years), 19 882 all-cause deaths were recorded, including 3802 CVD deaths, 8090 cancer deaths, 3380 respiratory disease deaths and 1061 digestive disease deaths. In multivariable adjusted analyses, the HRs associated with glucosamine use were 0.85 (95% CI 0.82 to 0.89) for all-cause mortality, 0.82 (95% CI 0.74 to 0.90) for CVD mortality, 0.94 (95% CI 0.88 to 0.99) for cancer mortality, 0.73 (95% CI 0.66 to 0.81) for respiratory mortality and 0.74 (95% CI 0.62 to 0.90) for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers (p for interaction=0.00080). Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases.


Quantification of excess water loss in plant canopies warmed with infrared heating.
Here we investigate the extent to which infrared heating used to warm plant canopies in climate manipulation experiments increases transpiration. Concerns regarding the impact of the infrared heater technique on the water balance have been raised before, but a quantification is lacking. We calculate transpiration rates under infrared heaters and compare these with air warming at constant relative humidity. As infrared heating primarily warms the leaves and not the air, this method increases both the gradient and the conductance for water vapour. Stomatal conductance is determined both independently of vapour pressure differences and as a function thereof, while boundary layer conductance is calculated using several approaches. We argue that none of these approaches is fully accurate, and opt to present results as an interval in which the actual water loss is likely to be found. For typical conditions in a temperate climate, our results suggest a 12-15% increase in transpiration under infrared heaters for a 1 °C warming. This effect decreases when stomatal conductance is allowed to vary with the vapour pressure difference. Importantly, the artefact is less of a concern when simulating heat waves. The higher atmospheric water demand underneath the heaters reflects naturally occurring increases of potential evapotranspiration during heat waves resulting from atmospheric feedback. While air warming encompasses no increases in transpiration, this fully depends on the ability to keep humidity constant, which in the case of greenhouses requires the presence of an air humidification system. As various artefacts have been associated with chamber experiments, we argue that manipulating climate in the field should be prioritized, while striving to limit confounding factors. The excess water loss underneath infrared heaters reported upon here could be compensated by increasing irrigation or applying newly developed techniques for increasing air humidity in the field.


Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma.
High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.


Molecular cloning and functional expression of the cardiac sarcolemmal Na(+)-Ca2+ exchanger.
The Na(+)-Ca2+ exchanger of the cardiac sarcolemma can rapidly transport Ca2+ during excitation-contraction coupling. To begin molecular studies of this transporter, polyclonal antibodies were used to identify a complementary DNA (cDNA) clone encoding the Na(+)-Ca2+ exchanger protein. The cDNA hybridizes with a 7-kilobase RNA on a Northern blot and has an open reading frame of 970 amino acids. Hydropathy analysis suggests that the protein has multiple transmembrane helices, and a small region of the sequence is similar to that of the Na(+)- and K(+)-dependent adenosine triphosphatase. Polyclonal antibodies to a synthetic peptide from the deduced amino acid sequence react with sarcolemmal proteins of 70, 120, and 160 kilodaltons on immunoblots. RNA, synthesized from the cDNA clone, induces expression of Na(+)-Ca2+ exchange activity when injected into Xenopus oocytes.


Myeloid-Derived Suppressor Cells Contribute to Susceptibility to Trypanosoma congolense Infection by Suppressing CD4+ T Cell Proliferation and IFN-γ Production.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow-derived myeloid cells that have immune-suppressive activities. These cells have been reported to suppress T cell immunity against tumors as well as in some parasitic and bacterial infections. However, their role during Trypanosoma congolense infection has not been studied. Given that immunosuppression is a hallmark of African trypanosomiasis, we investigated the role of MDSCs in immunity to T. congolense infection. We found increased numbers of MDSCs in the spleen and liver of infected mice, which correlated with increased parasitemia. Depletion of MDSCs significantly increased the percentage of proliferating and IFN-γ-producing CD4+ T cells from the spleen of T. congolense-infected mice. Furthermore, MDSCs from T. congolense-infected mice directly suppressed CD4+ T cell proliferation in a coculture setting. This suppressive effect was abolished by the arginase-1 inhibitor, Nω-hydroxy-nor-l-arginine (nor-NOHA), indicating that MDSCs suppress CD4+ T cell proliferation and function in an arginase-1-dependent manner. Indeed, depletion of MDSCs during infection led to control of the first wave of parasitemia and prolonged survival of infected mice. This was also associated with increased CD4+ T cell proliferation and IFN-γ production. Taken together, our findings identify an important role of MDSCs in the pathogenesis of experimental T. congolense infection via suppression of T cell proliferative and effector cytokine responses in an arginase-1-dependent manner.


Duration of viral shedding in hospitalized patients infected with pandemic H1N1.
The first influenza pandemic of the 21th century was ignited by a new strain of influenza A virus (A/H1N1pdm). Specific patient groups, including those with comorbidities, pregnant women, young children, older and immunocompromised patients, are at increased risk for serious influenza-related disease. This study was aimed at investigating the influence of clinical presentation, antiviral treatment and possible drug resistance-associated mutations, on the extent and duration of viral shedding in patients infected with A/H1N1pdm. An observational study was performed, based on retrospective review of clinical and laboratory records of patients who were hospitalized for A/H1N1pdm infection at the National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy, between April 24 and December 31, 2009. Among 119 hospitalized patients, 39 were selected for a post hoc analysis, based on the availability of serial nasopharyngeal swabs samples and related information. Eleven out of the 39 study patients (28.2%) presented with pneumonia; 29 (74.4%) received antiviral treatment. Patients with pneumonia were significantly older than patients without pneumonia. The mean values of viral RNA concentration were not significantly increased in patients with pneumonia, but a significant increase in the duration of viral shedding was observed as compared to patients without pneumonia. In patients receiving antivirals, the viral RNA concentration was significantly reduced in comparison to untreated patients at days 4-5 after symptom onset, while the overall duration of viral shedding was only marginally affected. A significant correlation between duration of viral shedding and time elapsed between symptom onset and therapy start was observed, with a significant reduction of days of viral shedding when therapy was initiated within 2 days of symptoms appearance. No known drug resistance mutations were detected in patients with prolonged viral shedding. Our results show that severe respiratory illness is associated with delayed virus clearance in patients with A/H1N1pdm infection. Antivirals caused an early reduction of viral load, but only marginally affected the overall duration of shedding. Prolonged shedding was not associated with the emergence of strains carrying known drug-resistance mutations.


Variation in freshwater fish assemblages along a regional elevation gradient in the northern Andes, Colombia.
Studies on elevation diversity gradients have covered a large number of taxa and regions throughout the world; however, studies of freshwater fish are scarce and restricted to examining their changes along a specific gradient. These studies have reported a monotonic decrease in species richness with increasing elevation, but ignore the high taxonomic differentiation of each headwater assemblage that may generate high β-diversity among them. Here, we analyzed how fish assemblages vary with elevation among regional elevation bands, and how these changes are related to four environmental clines and to changes in the distribution, habitat use, and the morphology of fish species. Using a standardized field sampling technique, we assessed three different diversity and two structural assemblage measures across six regional elevation bands located in the northern Andes (Colombia). Each species was assigned to a functional group based on its body shape, habitat use, morphological, and/or behavioral adaptations. Additionally, at each sampling site, we measured four environmental variables. Our analyses showed: (1) After a monotonic decrease in species richness, we detected an increase in richness in the upper part of the gradient; (2) diversity patterns vary depending on the diversity measure used; (3) diversity patterns can be attributed to changes in species distribution and in the richness and proportions of functional groups along the regional elevation gradient; and (4) diversity patterns and changes in functional groups are highly correlated with variations in environmental variables, which also vary with elevation. These results suggest a novel pattern of variation in species richness with elevation: Species richness increases at the headwaters of the northern Andes owing to the cumulative number of endemic species there. This highlights the need for large-scale studies and has important implications for the aquatic conservation of the region.


From cooperation to conflict? Swedish rehabilitation professionals' experiences of interorganizational cooperation.
This article analyses Swedish rehabilitation professionals' experiences of interorganizational cooperation in return-to-work and labour market reintegration. Two groups (n = 15) from different organizations met on a regular basis to discuss their practice from a cooperation perspective. The participants had experience of cooperation in the organizational setting of Coordination Associations. The groups worked with a tutor according to a problem-based methodology, to discuss how their practice is influenced by new structures for cooperation. The material was analysed inductively using qualitative content analysis. Interorganizational cooperation in rehabilitation is generally perceived as promoting coherence and communication. Nevertheless, there are several contradictory factors in the implementation of such work forms, primarily inflexible sickness insurance regulations and inability of managers to implement cooperation in regular practice. While interorganizational cooperation promotes professional discretion and tailored solutions, the insurance system contradicts such ambitions through increased governance. Ultimately, the contradictory tendencies of cooperative initiatives and the stricter governance of sickness insurance regulations are political matters. If political attempts to promote interorganizational cooperation are to succeed, the increasing sectorization that results from strict governance of sickness insurance regulations needs to be targeted on a system level.


Noneruptive fever revealing murine typhus in a traveler returning from Tunisia.
Rickettsia species are increasingly being recognized as a cause of infection among returning travelers. Murine typhus (MT) was mistakenly thought to have disappeared in the 1970s in Tunisia, yet recent serological data show that Rickettsia typhi, the causative agent of MT, still circulates in the Tunisian population. We report here a case of MT in a woman returning from Tunisia and hospitalized in France. Her presentation was nonspecific, with acute noneruptive fever. Diagnosis was confirmed by cross-adsorption and immunoblotting. Clinicians taking care of returning travelers with fever should be aware of MT, and know how to diagnose and treat it.


Levels of environmental contaminants in human follicular fluid, serum, and seminal plasma of couples undergoing in vitro fertilization.
Environmental chemicals are thought to adversely affect human reproductive function, however there are no studies that have explored the association between failed fertilization and exposure of both partners to environmental contaminants. Therefore, we collected blood and follicular fluid from the female partner and seminal plasma from the male partner of 21 couples attending an in vitro fertilization (IVF) program, in order to determine the extent of the existence of environmental chemicals in these fluids. Any relationship to the outcome of IVF was also considered. Sera and fluids were analysed for a variety of contaminants, including polychlorinated biphenyls, pesticides, cotinine, and the steroids progesterone and estradiol. Of the couples examined, 18 had fertilizations, three of whom became pregnant. There were no fertilizations in three other couples. The contaminants most frequently found in follicular fluid, more than 50% of the samples tested, were p,p'-DDE, mirex, hexachloroethane, 1,2,4-trichlorobenzene, PCB 49, PCB 153, and PCB 180. Cadmium was detected in eight of 21 (38.1%) samples of follicular fluid whereas cotinine was detected in 18 (85.7%). Residue levels of p,p'-DDE, endosulfan I, PCB 99, PCB 138, PCB 153, PCB 180 were quantified in more than 50% of the sera samples examined. Seminal plasma was relatively free of pollutants with mirex being the most frequently detected contaminant found in seven of 21 (33.3%) samples. Mirex could not be detected in the seminal plasma of the husbands whose partner's oocytes failed to fertilize whereas significant levels of mirex were found in the seminal plasma of all couples who had a pregnancy. Cadmium was also found in the follicular fluid of these pregnant subjects. No relationship was found between follicular fluid cotinine in pregnant and non-pregnant subjects. Where identical contaminants were found in both sera and follicular fluids, the levels were about twofold higher in serum and were positively correlated in both fluids. Fertilization was negatively correlated with serum and follicular fluid p,p'-DDE whereas pregnancy was positively correlated with follicular fluid PCB 49. These data reveal that more than 50% of the population of women attending a fertility program have had exposure to environmental chemicals sufficient to produce detectable concentrations in their serum and ovarian follicular fluid. Of the chemical contaminants detected in the serum and follicular fluid of these women, p,p'-DDE was the most frequently detected, had the highest residue levels, and was associated with failed fertilization.


Resident simulation training in endoscopic endonasal surgery utilizing haptic feedback technology.
Simulated practice may improve resident performance in endoscopic endonasal surgery. Using the NeuroTouch haptic simulation platform, we evaluated resident performance and assessed the effect of simulation training on performance in the operating room. First- (N=3) and second- (N=3) year residents were assessed using six measures of proficiency. Using a visual analog scale, the senior author scored subjects. After the first session, subjects with lower scores were provided with simulation training. A second simulation served as a task-learning control. Residents were evaluated in the operating room over six months by the senior author-who was blinded to the trained/untrained identities-using the same parameters. A nonparametric bootstrap testing method was used for the analysis (Matlab v. 2014a). Simulation training was associated with an increase in performance scores in the operating room averaged over all measures (p=0.0045). This is the first study to evaluate the training utility of an endoscopic endonasal surgical task using a virtual reality haptic simulator. The data suggest that haptic simulation training in endoscopic neurosurgery may contribute to improvements in operative performance. Limitations include a small number of subjects and adjudication bias-although the trained/untrained identity of subjects was blinded. Further study using the proposed methods may better describe the relationship between simulated training and operative performance in endoscopic Neurosurgery.


Depression symptoms and quality of life among individuals with aspirin-exacerbated respiratory disease.
Patients with aspirin-exacerbated respiratory disease (AERD) have high disease burden due to the severity of asthma and sinonasal symptoms. There is limited research on the psychological well-being and subjective experiences of patients with AERD. This study examined levels of depression symptoms, asthma-related quality of life and asthma control among AERD patients. Thirty-two adults with AERD and 39 patients without AERD (asthma-only) were recruited from outpatient asthma/allergy clinics. The sample was largely comprised of ethnic minority, inner-city patients who ranged in age from 19 to 84 years old. Participants completed the Beck Depression Inventory (BDI), the Mini Asthma Quality of Life Questionnaire (Mini AQLQ), a self-report rating of asthma severity and spirometry testing. Asthma control and severity were determined following national guidelines. AERD patients reported lower levels of depression symptoms (p = 0.049), better overall asthma-related quality of life (p < 0.001), and perceived their asthma to be less severe (p = 0.01) compared to asthma-only patients. However, clinician ratings of asthma severity were more severe for AERD than asthma-only patients (p = 0.006). No significant differences were found between the groups on asthma controller medications or oral corticosteroid bursts for asthma. AERD patients may be resilient given their low levels of depression symptoms and positive views of asthma-related impairment despite higher clinician-rated asthma severity. The adult onset nature of asthma in AERD might be a protective factor on mental health. Future studies should explore mechanisms linking AERD and positive psychological health outcomes and subjective perception of asthma.


A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1.
Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). We generated a mouse expressing SUR1-E1506K in place of SUR1. KATP channel inhibition by MgATP was enhanced in both homozygous (homE1506K) and heterozygous (hetE1506K) mutant mice, due to impaired channel activation by MgADP. As a consequence, mutant β-cells showed less on-cell KATP channel activity and fired action potentials in glucose-free solution. HomE1506K mice exhibited enhanced insulin secretion and lower fasting blood glucose within 8 weeks of birth, but reduced insulin secretion and impaired glucose tolerance at 6 months of age. These changes correlated with a lower insulin content; unlike wild-type or hetE1506K mice, insulin content did not increase with age in homE1506K mice. There was no difference in the number and size of islets or β-cells in the three types of mice, or evidence of β-cell proliferation. We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age.


Specific destruction of kinetochore protein CENP-C and disruption of cell division by herpes simplex virus immediate-early protein Vmw110.
Examination of cells at the early stages of herpes simplex virus type 1 infection revealed that the viral immediate-early protein Vmw110 (also known as ICP0) formed discrete punctate accumulations associated with centromeres in both mitotic and interphase cells. The RING finger domain of Vmw110 (but not the C-terminal region) was essential for its localization at centromeres, thus distinguishing the Vmw110 sequences required for centromere association from those required for its localization at other discrete nuclear structures known as ND10, promyelocytic leukaemia (PML) bodies or PODs. We have shown recently that Vmw110 can induce the proteasome-dependent loss of several cellular proteins, including a number of probable SUMO-1-conjugated isoforms of PML, and this results in the disruption of ND10. In this study, we found some striking similarities between the interactions of Vmw110 with ND10 and centromeres. Specifically, centromeric protein CENP-C was lost from centromeres during virus infection in a Vmw110- and proteasome-dependent manner, causing substantial ultrastructural changes in the kinetochore. In consequence, dividing cells either became stalled in mitosis or underwent an unusual cytokinesis resulting in daughter cells with many micronuclei. These results emphasize the importance of CENP-C for mitotic progression and suggest that Vmw110 may be interfering with biochemical mechanisms which are relevant to both centromeres and ND10.


Activated biochar derived from cactus fibres--preparation, characterization and application on Cu(II) removal from aqueous solutions.
The adsorption efficiency of activated biochar prepared from cactus fibres regarding the removal of Cu(II) from aqueous solutions has been investigated as a function of various physicochemical parameters (e.g. pH, initial metal concentration, ionic strength, temperature and contact time). Activation of the biochar took place using nitric acid oxidation and characterisation was performed by SEM analysis, FTIR spectroscopy, N2 adsorption and acid-base titrations. The results show that laminar structures constitute the material and carboxylic moieties are the predominant binding sites. The experimental data were analyzed by the Langmuir, Freundlich and Dubinin-Radushkevich adsorption models and the monolayer adsorption capacity was found to be 3.5 mol kg(-1). The effect of ionic strength and temperature on the adsorption efficiency indicates that at low pH outer-sphere and at near neutral pH inner-sphere complexes are the predominant surface species and the kinetic data obtained were fitted very well by the Lagergren rate expression.


A Q Method Approach to Evaluating Farmers' Perceptions of Foot-and-Mouth Disease Vaccination in Vietnam.
This study aims to explore the farmers' perceptions of foot-and-mouth disease (FMD) vaccination using a reflexive research method called Q methodology. A structured sample was composed of 46 farmers selected according to gender, farming experience, level of education, and production type. Statements relevant to the farmers' perceptions of and attitudes toward FMD vaccination, related to confidence, logistics, costs, and impacts of vaccination were developed. Results were analyzed by principal component analysis and factor analysis. The influence of demographics and characterized variables on the respondent's contribution to each factor was also tested. Regarding the different beliefs and behavior toward FMD vaccination, the common perceptions held by Vietnamese cattle and pig farmers were divided into three discourses named Confidence (24 subjects), Belief (12 subjects), and Challenge (6 subjects). The identified discourses represented 57.3% of the variances. Consensus points were found, such as the feeling of being more secure after FMD vaccination campaigns; the fact that farmers take vaccination decisions themselves without being influenced by other stakeholders; the opinion that FMD vaccination is cheaper than the costs of treating a sick animal; and that vaccines provided by governmental authorities are of high quality. Part of the studied population did not consider vaccination to be the first choice strategy in prevention. This raises the question of how to improve the active participation of farmers in the FMD vaccine strategy. Taking into consideration farmers' perceptions can help to implement feasible vaccination strategies at the local level.


A Simple Microbiome in the European Common Cuttlefish, Sepia officinalis.
The European common cuttlefish, Sepia officinalis, is used extensively in biological and biomedical research, yet its microbiome remains poorly characterized. We analyzed the microbiota of the digestive tract, gills, and skin in mariculture-raised S. officinalis using a combination of 16S rRNA amplicon sequencing, quantitative PCR (qPCR), and fluorescence spectral imaging. Sequencing revealed a highly simplified microbiota consisting largely of two single bacterial amplicon sequence variants (ASVs) of Vibrionaceae and Piscirickettsiaceae. The esophagus was dominated by a single ASV of the genus Vibrio. Imaging revealed bacteria in the family Vibrionaceae distributed in a discrete layer that lines the esophagus. This Vibrio was also the primary ASV found in the microbiota of the stomach, cecum, and intestine, but occurred at lower abundance, as determined by qPCR, and was found only scattered in the lumen rather than in a discrete layer via imaging analysis. Treatment of animals with the commonly used antibiotic enrofloxacin led to a nearly 80% reduction of the dominant Vibrio ASV in the esophagus but did not significantly alter the relative abundance of bacteria overall between treated versus control animals. Data from the gills were dominated by a single ASV in the family Piscirickettsiaceae, which imaging visualized as small clusters of cells. We conclude that bacteria belonging to the Gammaproteobacteria are the major symbionts of the cuttlefish Sepia officinalis cultured from eggs in captivity and that the esophagus and gills are major colonization sites. IMPORTANCE Microbes can play critical roles in the physiology of their animal hosts, as evidenced in cephalopods by the role of Vibrio (Aliivibrio) fischeri in the light organ of the bobtail squid and the role of Alpha- and Gammaproteobacteria in the reproductive system and egg defense in a variety of cephalopods. We sampled the cuttlefish microbiome throughout the digestive tract, gills, and skin and found dense colonization of an unexpected site, the esophagus, by a microbe of the genus Vibrio, as well as colonization of gills by Piscirickettsiaceae. This finding expands the range of organisms and body sites known to be associated with Vibrio and is of potential significance for understanding host-symbiont associations, as well as for understanding and maintaining the health of cephalopods in mariculture.


Structural basis of regulation of von Willebrand factor binding to glycoprotein Ib.
Activation by elongational flow of von Willebrand factor (VWF) is critical for primary hemostasis. Mutations causing type 2B von Willebrand disease (VWD), platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF A1 domain and platelet glycoprotein Ibα (GPIbα) for one another; however, the structural basis for these observations remains elusive. Directed evolution was used to discover a further gain-of-function mutation in A1 that shifts the long range disulfide bond by one residue. We solved multiple crystal structures of this mutant A1 and A1 containing two VWD mutations complexed with GPIbα containing two PT-VWD mutations. We observed a gained interaction between A1 and the central leucine-rich repeats (LRRs) of GPIbα, previously shown to be important at high shear stress, and verified its importance mutationally. These findings suggest that structural changes, including central GPIbα LRR-A1 contact, contribute to VWF affinity regulation. Among the mutant complexes, variation in contacts and poor complementarity between the GPIbα β-finger and the region of A1 harboring VWD mutations lead us to hypothesize that the structures are on a pathway to, but have not yet reached, a force-induced super high affinity state.


Reflections from a systematic review of dietary energy density and weight gain: is the inclusion of drinks valid?
The association between dietary energy density, increased energy intake and weight gain is supported by experimental evidence, but confirmation of an effect in free-living humans is limited. Experimental evidence supports a role of energy density in obesity through changes in food composition, not drinks consumption. The inclusion of drinks in the calculation creates a variable of questionable validity and has a substantive impact on the estimated energy density of the diet. We posit, based on the experimental evidence, that calculating the energy density of diets by excluding drinks and including calories from drinks as a covariate in the analysis is the most valid and reliable method of testing the relationship between energy density and weight gain in free-living humans. We demonstrate, by systematically reviewing existing observational studies of dietary energy density and weight gain in free-living humans, how current variation in the method for calculating energy density hampers the interpretation of these data. Reaching an a priori decision on the appropriate methodology will reduce the error caused by multiple comparisons and facilitate meaningful interpretation of epidemiological evidence to inform the development of effective obesity prevention strategies.


Quantitative and functional characterization of muscarinic receptor subtypes in insulin-secreting cell lines and rat pancreatic islets.
Expression of muscarinic receptors in rat islets, RINm5F cells, and INS-1 cells was established by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantified by RNase protection. Both methods indicated that m3 and m1 receptors were expressed approximately equally in the various cellular preparations and to a much greater extent than the m5 subtype. However, the cell lines, especially RINm5F cells, expressed less of a given receptor subtype than did islets. Immunohistochemistry indicated that m3 receptors were expressed throughout the islet core. Binding studies using the radiolabeled muscarinic receptor antagonist QNB demonstrated a maximal binding capacity of INS-1 cells of 23.0+/-2.9 fmol/mg protein. Functional analyses were undertaken using INS-1 cells stably transfected with either m1 or m3 receptor cDNAs. Overexpression of either receptor did not affect basal responses but markedly enhanced maximal responses to the muscarinic receptor agonist carbachol. Although maximal hydrolysis of phosphatidylinositol 4,5-bisphosphate (Ptd InsP2) was twofold greater in m1-transfectants as compared with m3-transfectants, cell lines overexpressing either receptor gave essentially equivalent secretory responses to a full range of carbachol doses. The results demonstrate that both m1 and m3 muscarinic receptors are well expressed in pancreatic beta-cells, functionally linked to signaling pathways, and capable of initiating insulin secretion with equal potencies.


Release of enzymes from adult rat heart myocytes.
The release of lactic dehydrogenase, creatine phosphokinase, and aspartate aminotransferase from initially viable, metabolically competent adult rat heart myocytes has been examined. Freshly isolated cells contain levels of total lactic dehydrogenase, creatine phosphokinase, and aspartate aminotransferase, as well as lactic dehydrogenase and creatine phosphokinase isoenzyme profiles that are quite comparable to those of intact heart tissue. When the cells are lysed with digitonin, 89% of total lactic dehydrogenase, but only 58% of creatine phosphokinase and 27% of aspartate aminotransferase are released. The retention of creatine phosphokinase by the digitonin-lysed cells is accounted for by complete retention of mitochondrial creatine phosphokinase and 20% of MM-creatine phosphokinase. When intact myocytes are incubated under anoxic, substrate-deprived conditions, there is a gradual loss of the three enzymes to the suspending medium and a parallel increase in the fraction of the cells permeable to trypan blue. The fraction of freely soluble cytoplasmic enzymes lost was equivalent to the fraction of the cells permeable to the dye over a wide range of viability (17-95% viable by dye exclusion criteria), but permeable cells retained mitochondrial creatine phosphokinase and particulate aspartate aminotransferase. These results suggest that simultaneous and complete release of soluble cytoplasmic enzymes occurs as each individual cell sustains sarcolemmal damage.


Gastric juice levels of lactoferrin and Helicobacter pylori infection.
Recently, in vitro studies suggested that lactoferrin (Lf) might play an important role in the physiopathology of Helicobacter pylori-associated gastritis. However, whether Lf is present in the gastric juice and its relationship with H. pylori infection have not as yet been reported. In the present investigation the presence of Lf in gastric juice and its correlation with H. pylori infection were assessed. This study comprised 30 H. pylori-positive and 14-negative patients with chronic gastritis. Gastric juice levels of Lf were measured with enzyme-linked immunoassays. Gastric juice concentration of Lf was also investigated in accordance with the histologic findings of biopsy specimens in the gastric body and antrum. Lf concentration in gastric juice was significantly higher in H. pylori-positive than in -negative patients (P = 0.033). The pH values are known to influence the levels of Lf. However, intragastric Lf levels were also significantly increased in H. pylori-positive patients as compared with H. pylori-negative patients after correcting the Lf levels for pH values (P = 0.029) or after adjusting the pH values of the gastric juice with NaHCO3 solution in both groups of patients (P = 0.0007). In addition, the gastric juice levels of Lf correlated significantly with the gastric mucosal concentrations of Lf in the gastric body (P < 0.005, r = 0.568) and the antrum (P < 0.05, r = 0.401). This study showed for the first time that Lf is present in gastric juice and that it correlates with H. pylori infection. Lf may constitute a good marker for H. pylori-associated gastritis. Although correlation does not prove causation, this study suggests that Lf might play an important role in the physiopathology of H. pylori-associated gastritis.


Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial.
This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring. A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.


Effects of the alkylamine functionalization of graphene oxide on the properties of polystyrene nanocomposites.
Alkylamine-functionalized graphene oxides (FGOs) have superior dispersibility in low-polar solvents and, as a result, they interact with low-polar polymers such as polystyrene. In this work, the functionalization of graphene oxide using three types of alkylamines, octylamine (OA), dodecylamine (DDA), and hexadecylamine (HDA), was performed, and nanocomposites of polystyrene (PS) and FGOs were prepared via solution blending. Different dispersions of FGOs over PS were obtained for the three alkylamines, and the properties of the PS composites were influenced by the length of the alkylamine. A better thermal stability was observed with a longer chain length of the alkylamine. On the other hand, functionalization with the shortest chain length alkylamine resulted in the highest increase in the storage modulus (3,640 MPa, 140%) at a 10 wt.% loading of FGO.


Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma.
To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma. The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured. Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo. ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.


A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency.
Bone metabolism has a close relationship with iron homeostasis. To examine the effects of iron excess and iron deficiency on the biological activities of osteoblast in vitro, human osteoblast cells (hFOB1.19) were incubated in a medium supplemented with 0-200 μmol/L ferric ammonium citrate and 0-20 μmol/L deferoxamine. The intracellular iron was measured by a confocal laser scanning microscope. Proliferation of osteoblasts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptotic cells were detected using annexin intervention V/PI staining with a flow cytometry. Alkaline phosphatase (ALP) activity was measured using an ALP assay kit. The number of calcified nodules and mineral area was evaluated by von Kossa staining assay. The expressions of type I collagen and osteocalcin of cultured osteoblasts were detected by reverse transcriptase polymerase chain reaction and Western blot. Intracellular reactive oxygen species (ROS) was measured using the oxidation-sensitive dye 2,7-dichlorofluorescin diacetate by flow cytometry. The results indicated that excessive iron inhibited osteoblast activity in a concentration-dependent manner. Low iron concentrations, in contrast, produced a biphasic manner on osteoblasts: mild low iron promoted osteoblast activity, but serious low iron inhibited osteoblast activity. Osteogenesis was optimal in certain iron concentrations. The mechanism underlying biological activity invoked by excessive iron may be attributed to increased intracellular ROS levels.


Sham-Controlled Study of Optokinetic Stimuli as Treatment for Mal de Debarquement Syndrome.
Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a perception of self-motion in the absence of a stimulus, with two onset types: Motion-Triggered and Spontaneous. Currently, the pathophysiology is unknown and consequently, the therapeutic options are limited. One proposed treatment protocol, developed by Dai and colleagues is based on optokinetic stimulation, which aims to re-adapt the vestibular ocular reflex. This study aimed to reproduce the treatment protocol developed by Dai and colleagues and to assess if a placebo effect is present in the treatment protocol and lastly, aimed to further investigate the treatment on MdDS patient outcomes. Method: Twenty-five MdDS patients (13 Motion-Triggered and 12 Spontaneous) were exposed to 5 consecutive days of optokinetic treatment (consisting of exposure to optokinetic stimuli with head movements). Eleven of these 25 patients were also exposed to 2 days of a sham treatment prior to the OKN treatment. Posturography measurements and reported symptoms [e.g., using the visual analog scale (VAS)] of patients were assessed throughout the treatment. Posturography data of the patients was compared with the data of 20 healthy controls. Results: No placebo effect was recorded with any changes in postural data and VAS scale. After the optokinetic treatment, a significant improvement in postural control was observed in 48% of patients, of whom 70% were of the Motion-Triggered subtype (p-values: Area under the Curve-Anterior Posterior < 0.001; Area under the Curve-Medio Lateral p < 0.001, Confidence Ellipse Area (CEA) < 0.001, Velocity < 0.001). Conclusion: The protocol was effective in approximately half of the MdDS patients that took part in the study, with no placebo effect recorded. The Motion-Triggered group responded better to treatment than the Spontaneous group. In addition to this, this study indicates that the greatest postural changes occur within the first 3 days of treatment, suggesting that a shorter protocol is possible. Overall, these findings support what was previously observed in Dai's studies, that optokinetic stimulation can reduce and ease self-motion perception in those with MdDS. Thus, validating the reproducibility of this protocol, suggesting that a consistent and uncomplicated implementation across treatment centers is possible.


Electron optics with p-n junctions in ballistic graphene.
Electrons transmitted across a ballistic semiconductor junction are expected to undergo refraction, analogous to light rays across an optical boundary. In graphene, the linear dispersion and zero-gap band structure admit highly transparent p-n junctions by simple electrostatic gating. Here, we employ transverse magnetic focusing to probe the propagation of carriers across an electrostatically defined graphene junction. We find agreement with the predicted Snell's law for electrons, including the observation of both positive and negative refraction. Resonant transmission across the p-n junction provides a direct measurement of the angle-dependent transmission coefficient. Comparing experimental data with simulations reveals the crucial role played by the effective junction width, providing guidance for future device design. Our results pave the way for realizing electron optics based on graphene p-n junctions.


Surfing the urge: brief mindfulness-based intervention for college student smokers.
The current study investigates effects of a brief mindfulness-based instruction set, based on Marlatt's "urge surfing" technique (Marlatt & Gordon, 1985), on smoking-related urges and behavior. Undergraduate smokers (N = 123) who were interested in changing their smoking, but not currently involved in a cessation program, participated in a cue exposure paradigm designed to elicit urges to smoke. They were randomly assigned either to a group receiving brief mindfulness-based instructions or to a no-instruction control group. Results suggest that groups did not differ significantly on measures of urges. However, those in the mindfulness group smoked significantly fewer cigarettes over a 7-day follow-up period as compared to those in the control group. These findings suggest that the mindfulness techniques may not initially reduce urges to smoke but may change the response to urges. The study provides preliminary data for future studies examining both mechanisms and effectiveness of mindfulness-based interventions for cigarette smoking.


Assessment of rectal feces storage condition by a point-of-care pocket-size ultrasound device for healthy adult subjects: A preliminary study.
The aim of this study was to assess rectal feces storage condition by a pocket-size ultrasonography (PUS) in healthy adults so as to define normal rectal defecation desire. Participants were first assessed rectum by PUS imaging immediately after defecation desire (pre-defecation). Nurses checked the amount and quality of the participants' feces using King's Stool Chart and Bristol stool scale. Finally, PUS was performed for defecation with no defecation desire (post-defecation). Pre-defecation PUS detected high echo area in all patients. All of the post-defecation PUS did not detect high echo area (perfectly no recognizable high echo area in 54.5%, high echo line in 36.4%, and low echo of entire circumference in 9.1% of the patients). Average diameter of rectal crescent was 4.22 ± 0.8 cm. Bristol Stool Scale 1 or 2 (indicating hard stool) of pre-defecation PUS indicated high echo area and acoustic shadow in 100% of the patients. This study showed that healthy adult with defecation desire had high average rectal echo area of 4.0 cm in diameter. PUS may be able to define the rectum diameter for defecation desire of elderly people. PUS is capable of assessing fecal retention of the rectum for point-of-care examinations in home care.


Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas.
Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.


The FERM protein Epb4.1l5 is required for organization of the neural plate and for the epithelial-mesenchymal transition at the primitive streak of the mouse embryo.
During early mouse development, a single-layered epithelium is transformed into the three germ layers that are the basis of the embryonic body plan. Here we describe an ENU-induced mutation, limulus (lulu), which disrupts gastrulation and the organization of all three embryonic germ layers. Positional cloning and analysis of additional alleles show that lulu is a null allele of the FERM-domain gene erythrocyte protein band 4.1-like 5 (Epb4.1l5). During gastrulation, some cells in lulu mutants are trapped in the primitive streak at an intermediate stage of the epithelial-mesenchymal transition; as a result, the embryos have very little paraxial mesoderm. Epithelial layers of the later lulu embryo are also disrupted: definitive endoderm is specified but does not form a gut tube, and the neural plate is broad and forms ectopic folds rather than closing to make the neural tube. In contrast to zebrafish and Drosophila, in which orthologs of Epb4.1l5 control the apical localization and activity of Crumbs proteins, mouse Crumbs proteins are localized normally to the apical surface of the lulu mutant epiblast and neural plate. However, the defects in both the lulu primitive streak and neural plate are associated with disruption of the normal organization of the actin cytoskeleton. We propose that mouse Lulu (Epb4.1l5) helps anchor the actin-myosin contractile machinery to the membrane to allow the dynamic rearrangements of epithelia that mediate embryonic morphogenesis.


Mechanism of ATP-dependent promoter melting by transcription factor IIH.
We show that transcription factor IIH ERCC3 subunit, the DNA helicase responsible for adenosine triphosphate (ATP)-dependent promoter melting during transcription initiation, does not interact with the promoter region that undergoes melting but instead interacts with DNA downstream of this region. We show further that promoter melting does not change protein-DNA interactions upstream of the region that undergoes melting but does change interactions within and downstream of this region. Our results rule out the proposal that IIH functions in promoter melting through a conventional DNA-helicase mechanism. We propose that IIH functions as a molecular wrench: rotating downstream DNA relative to fixed upstream protein-DNA interactions, thereby generating torque on, and melting, the intervening DNA.


Multifunctional tin dioxide materials: advances in preparation strategies, microstructure, and performance.
Tin oxide materials are a class of unique semiconductor materials with widespread technological applications because of their valuable semiconducting, gas sensing, electrical and optical properties in the fields of macro/mesoscopic materials and micro/nanodevices. In this review, we describe the efforts toward understanding the synthetic strategies and formation mechanisms of the micro/nanostructures of various tin dioxide thin films prepared by pulsed laser ablation, highlighting contributions from our laboratory. First, we present the preparation and formation processes of tetragonal-phase tin dioxide thin films with interesting fractal clusters. In addition, the quantum-dot formation and dynamic scaling behavior in tetragonal-phase tin dioxide thin films induced by pulsed delivery will be discussed experimentally and theoretically. Finally, we emphasize the fabrication, properties and formation mechanism of orthorhombic-phase tin dioxide thin films by using pulsed laser deposition. This research may provide a novel approach to modulate their competent performance and promote rational design of micro/nanodevices. Once mastered, tin dioxide thin films with a variety of fascinating micro/nanostructures will offer vast and unforeseen opportunities in the semiconductor industry as well as in other fields of science and technology.


Genetic variation in yellow fever virus: duplication in the 3' noncoding region of strains from Africa.
The nucleotide sequences of three regions of the genomes of 13 yellow fever (YF) virus isolates were determined to define genetic variation and evolution of the virus. Phylogenetic trees generated from sequences of either the 5' terminal 1320 nucleotides of the genome, 754 nucleotides from the NS4A and NS4B genes, or the 3' terminal 511 nucleotides were very similar and contained minor differences. Overall, these results suggested that there were at least four major genotypes of YF virus, including one in Central/East Africa, one in West Africa, and two in South America. Examination of the 3' noncoding region (3'NCR) showed that only West African strains had a 3'NCR of 511 nucleotides while strains from Central/East Africa and South America had shorter 3'NCRs (443-469 nucleotides) due to the absence of YF specific repeat sequences (RYFs). Central/East African strains have two RYFs and West African strains have three RYFs while South American strains only have one copy of the RYF. It is speculated that duplication of the RYF took place in West Africa subsequent to the presumed introduction of YF virus into South America. Thus, both tick-borne (Mandl et al., J. Virol. 65, 4070-4077, 1991 and Wallner et al., Virology 213, 169-178, 1995) and mosquito-borne flaviviruses have variable 3'NCRs.


Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells.
Adult mammalian auditory hair cells (HCs) and their associated supporting cells (SCs) do not proliferate, and HC death leads to irreversible neurosensory hearing loss and balance impairment. In nonmammalian vertebrates, loss of HCs induces mitotic proliferation of adjacent nonsensory SCs and/or direct SC transdifferentiation to generate replacement cells. This results in the structural and functional recovery of the nonmammalian sensory systems. Potential replacement of mammalian auditory HCs, either by transplanting cells or by transforming existing cells through molecular therapy, has long been proposed. However, HC replacement strategies with clear therapeutic potential remain elusive. The retinoblastoma (pRB) family of cell cycle regulators, Rb1, Rbl1 (p107), and Rbl2 (p130), regulate the G(1)- to S-phase transition in proliferating cells. In the inner ear, the biochemical and molecular pathways involving pRBs, particularly p107 and p130, are relatively unexplored and their therapeutic suitability is yet to be determined. In this study, we analyzed the cochleae of adult p130 knock-out (p130(-/-)) mice and showed that lack of the p130 gene results in extra rows of HCs and SCs in the more apical regions of the cochlea. No evidence of transdifferentiation of these supernumerary SCs into HCs was observed in the p130(-/-) mouse. Nevertheless, unscheduled proliferation of SCs in the adult p130(-/-) cochlea coupled to downregulation of bona fide cell cycle inhibitors provides a mechanistic basis for the role of p130 as a regulator of SC and HC mitotic quiescence in the more apical regions of the cochlea. Interestingly, p130(-/-) mice exhibited nearly normal peripheral auditory sensitivity.


Reptile-associated Borrelia spp. In Amblyomma ticks, Thailand.
A total of 127 Amblyomma ticks (A. helvolum, A. varanense and A. geoemydae) were collected from reptiles: water monitors (Varanus salvator), Bengal monitors (Varanus bengalensis), Burmese pythons (Python bivittatus), yellow-spotted keelbacks (Xenochrophis flavipunctatus), keeled rat snakes (Ptyas carinata) and elongated tortoises (Indotestudo elongata) from nine provinces in Thailand. The presence of Borrelia spp. of the 16S rRNA, flaB, glpQ, groEL and gyrB genes was examined by conventional, semi-nested and nested PCR. Phylogenetic analyses using maximum likelihood method of housekeeping genes showed that most sequences of Borrelia spp. in these Amblyomma ticks belonged to the clade of reptile-associated (REP) borreliae. Interestingly, one Borrelia sp. in an A. geoemydae tick collected from an elongated tortoise clustered in the same clade as a Borrelia sp. detected from an A. geoemydae-infested turtle in Japan (it may belong to the same species given the identical sequences of their 16S rRNA, flaB and glpQ genes) and formed the same group with tick-borne relapsing fever (RF) borreliae of B. miyamotoi and B. theileri. Our findings are the first report on the presence of Borrelia spp. in A. helvolum and A. geoemydae ticks from reptiles in Thailand adding to the geographic distribution of Borrelia spp. in Asia.


Long-term Physical and Psychological Outcomes of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is known to cause multiple end-organ complications in its acute phase, but less is known about the long-term association with patients' mental health and quality of life. To examine the chronic physical and psychological sequelae affecting patients with SJS/TEN. A survey study conducted at 11 academic health centers in the US evaluated 121 adults diagnosed with SJS/TEN by inpatient consultive dermatologists between January 1, 2009, and September 30, 2019. Patients completed a survey that included the following validated questionnaires: Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Primary Care Post-Traumatic Stress Disorder Screen (PC-PTSD), and the 12-item Short Form Health Survey (SF-12). The survey also included questions created by the study team regarding fear, patient education, and long-term sequelae relevant to SJS/TEN. Primary outcome measures were the percentage of patients reporting long-term physical sequelae; the percentage of patients with positive results on PHQ-9, GAD-7, and PC-PTSD screening; and the numeric score on the SF-12 (score of 50 defined as average physical and mental well-being). A total of 121 individuals (73 women [60.3%]; mean [SD] age, 52.5 [17.1] years) completed the survey (response rate, 29.2%). The most common long-term physical sequelae reported were cutaneous problems (102 of 121 [84.3%]), ocular problems (72 of 121 [59.5%]), and oral mucosal problems (61 of 120 [50.8%]). A total of 53.3% (64 of 120) of the respondents had results indicating depression on the PHQ-9, 43.3% (52 of 120) showed signs of anxiety on the GAD-7, and 19.5% had results indicating PTSD on the PC-PTSD. The mean (SD) SF-12 Physical Component Summary score was 42.4 (22.8), and the mean Mental Component Summary score was 46.1 (20.9). A total of 28.2% (33 of 117) of the respondents were unable to work, 68.1% (81 of 119) were fearful of taking new medications, and 30.0% (36 of 120) avoided taking prescribed medications for a diagnosed medical condition. This survey study found that long-term physical sequelae, depression, and anxiety appear to be common in patients with SJS/TEN, with implications for health and well-being. Improved awareness of these complications may assist health professionals in offering medical care, counseling, and support to patients with SJS/TEN.


Treg-recruiting microspheres prevent inflammation in a murine model of dry eye disease.
Dry eye disease (DED) is a common ocular disorder affecting millions of individuals worldwide. The pathology of DED involves the infiltration of CD4+ lymphocytes, leading to tear film instability and destructive inflammation. In the healthy steady state, a population of immunosuppressive T-cells called regulatory T-cells (Treg) regulates proliferation of immune cells that would otherwise lead to a disruption of immunological homeostasis. For this reason, it has been suggested that Tregs could restore the immunological imbalance in DED. To this end, one possible approach would be to recruit the body's own, endogenous Tregs in order to enrich them at the site of inflammation and tissue destruction. Previously, we have demonstrated a reduction of inflammation and disease symptoms in models of periodontitis corresponding to recruitment of endogenous Tregs, which was accomplished by local placement of controlled release systems that sustain a gradient of the chemokine CCL22, referred to here as Treg-recruiting microspheres. Given that DED is characterized by a pro-inflammatory environment resulting in local tissue destruction, we hypothesized that the controlled release of CCL22 could also recruit Tregs to the ocular surface potentially mediating inflammation and symptoms of DED. Indeed, data suggest that Treg-recruiting microspheres are capable of overcoming the immunological imbalance of Tregs and CD4+ IFN-γ+ cells in the lacrimal gland. Administration of Treg-recruiting microspheres effectively mitigated the symptoms of DED as measured through a number of outcomes such as tear clearance, goblet cells density and corneal epithelial integrity, suggesting that recruitment of endogenous Treg can mitigate inflammation associated with DED.


Comparison of honey and dextrose solution on post-operative peritoneal adhesion in rat model.
Peritoneal adhesion between abdominal organs is a complication of surgery. It causes major complications like pain, bowel obstruction, infertility and increases risk of death. Honey is known to have anti-inflammatory and antioxidant properties potentially relevant for adhesive protection. Thirty rats were divided into five groups: negative control without any surgical procedure (normal group), control group treated with normal saline, experimental group I treated with 1ml of 10% honey, experimental group II treated with honey at half concentration of group I (honey0.5), and positive control group receiving 1ml of dextrose 5%. Inflammatory, growth and angiogenesis factors (TNF-α, Il-6, IL-1β, TGF-β1 and VEGF) of the adhesion tissue were assessed using ELISA. Antioxidant factors (NO, GSH and MDA) were also assessed using biochemical procedures. The difference between peritoneal adhesion scores, TNF-α, IL-1β, IL-6, TGF-β1, VEGF, NO, GSH and MDA value of all groups was strongly significant (p<0.001). We showed that honey can decrease peritoneal adhesion (p<0.001), TNF-α (p<0.001), IL-1β (p<0.001), IL-6 (p<0.001), TGF-β1 (p<0.001), VEGF (p<0.001), NO (p<0.001), MDA (p<0.001) and increase GSH (p<0.001) compared with control group. Honey 0.5 also significantly decreased peritoneal adhesion (p<0.001), TNF-α (p<0.001), IL-1β (p<0.01), IL-6 (p<0.001), VEGF (p<0.001), NO (p<0.001), MDA (p<0.01) and increase GSH (p<0.001) compared with control group. We find that honey can decrease inflammatory, growth and angiogenesis factors which can advance peritoneal adhesion and increase antioxidant factors. Honey could serve as a protective agent for peritoneal adhesion.


Enroller Experience and Parental Familiarity of Disease Influence Participation in a Pediatric Trial.
Acquiring parental consent is critical to pediatric clinical research, especially in interventional trials. In this study we investigated demographic, clinical, and environmental factors associated with likelihood of parental permission for enrollment in a study of therapies for diabetic ketoacidosis (DKA) in children. We analyzed data from patients and parents who were approached for enrollment in the Pediatric Emergency Care Applied Research Network (PECARN) Fluid Therapies Under Investigation in DKA (FLUID) trial at one major participating center. We determined the influence of various factors on patient enrollment, including gender, age, distance from home to hospital, insurance status, known vs new onset of diabetes, glycemic control (hemoglobin A1c), DKA severity, gender of the enroller, experience of the enroller, and time of enrollment. Patients whose parents consented to participate were compared to those who declined participation using bivariable and multivariable analyses controlling for the enroller. A total of 250 patient/parent dyads were approached; 177 (71%) agreed to participate, and 73 (29%) declined. Parents of patients with previous episodes of DKA agreed to enroll more frequently than those with a first DKA episode (94.3% for patients with 1-2 previous DKA episodes, 92.3% for > 2 previous episodes, vs 64.9% for new onset diabetes and 63.2% previously diagnosed but no previous DKA). Participation was also more likely with more experienced enrollers (odds ratio [95% confidence interval] of participation for an enroller with more than two years' experience vs less than two years: 2.46 [1.53, 3.97]). After adjusting for demographic and clinical factors, significant associations between participation and both DKA history and enroller experience remained. Patient age, gender, distance of home from hospital, glycemic control, insurance status, and measures of DKA severity were not associated with likelihood of participation. Familiarity with the disease process (previously diagnosed diabetes and previous experience with DKA) and experience of the enroller favorably influenced the likelihood of parental permission for enrollment in a study of DKA in children.


Autoantibody profiling to follow evolution of lupus syndromes.
Identification of patients who are in early stages of lupus is currently done through clinical evaluation and is not greatly facilitated by available diagnostic tests. Profiling for patient characteristics and antibody specificities that predict disease would enhance the ability of physicians to identify and treat early cases prior to onset of organ damaging illness. A group of 22 patients with 4 or fewer diagnostic criteria for lupus were studied for changes in clinical and autoantibody profiles after a mean follow up period of 2.4 years. An array with more than 80 autoantigens was used to profile immunoglobulin G (IgG) and immunoglobulin M (IgM) autoantibodies. Correlations with clinical disease progression were examined. 3 of the 22 patients (14%) added sufficient criteria during follow up to satisfy a diagnosis of systemic lupus erythematosus (SLE) or to acquire a diagnosis of SLE renal disease. Patients who progressed were all females and were younger than those who did not progress (P=0.00054). IgG but not IgM autoreactivity showed greater increases in the progressor group than in the non-progressor group (P=0.047). IgG specificities that were higher at baseline in progressors included proliferating cell nuclear antigen (PCNA), beta 2 microglobulin, C1q and hemocyanin (P<0.019). Progressors had significant increases in La/SSB and liver cytosol type 1 (LC1) IgG autoantibodies over the period of evaluation (P≤0.0072). A quantitative risk profile generated from baseline demographic and autoantibody variables yielded highly different scores for the progressor and non-progressor groups (P=1.38 × 10⁻⁷) In addition to demographic features, autoantibody profiles using an expanded array of specificities were correlated with the risk of progressive disease in patients with lupus. These findings suggest the feasibility of developing a simple diagnostic that could be applied by nonspecialists to screen for lupus and permit effective triage for specialty care.


Association between physical activity and body fat percentage, with adjustment for BMI: a large cross-sectional analysis of UK Biobank.
The objective of this study was to examine if, in the general population, physically active adults have less body fat after taking body mass index (BMI) into account. A cross-sectional analysis of participants recruited into UK Biobank in 2006-2010. UK Biobank assessment centres throughout the UK. 119 230 men and 140 578 women aged 40-69 years, with complete physical activity information, and without a self-reported long-term illness, disability or infirmity. Physical activity measured as excess metabolic equivalent (MET)-hours per week, estimated from a combination of walking, and moderate and vigorous physical activity. BMI from measured height and weight. Body fat percentage estimated from bioimpedance. BMI and body fat percentage were highly correlated (r=0.85 in women; r=0.79 in men), and both were inversely associated with physical activity. Compared with <5 excess MET-hours/week at baseline, ≥100 excess MET-hours/week were associated with a 1.1 kg/m2 lower BMI (27.1 vs 28.2 kg/m2) and 2.8 percentage points lower body fat (23.4% vs 26.3%) in men, and 2.2 kg/m2 lower BMI (25.6 vs 27.7 kg/m2) and 4.0 percentage points lower body fat (33.9% vs 37.9%) in women. For a given BMI, greater physical activity was associated with lower average body fat percentage (for a BMI of 22.5-24.99 kg/m2: 2.0 (95% CI 1.8 to 2.2), percentage points lower body fat in men and 1.8 (95% CI 1.6 to 2.0) percentage points lower body fat in women, comparing ≥100 excess MET-hours per week with <5 excess MET-hours/week). In this sample of middle-aged adults, drawn from the general population, physical activity was inversely associated with BMI and body fat percentage. For people with the same BMI, those who were more active had a lower body fat percentage.


Neural representation of reward in recovered depressed patients.
Anhedonia, a loss of interest and pleasure in normally rewarding stimuli, is a key diagnostic criterion for major depression. It has been suggested that deficits in the processing of reward-relevant stimuli could represent an endophenotype for depression. We hypothesized that people at risk of depression by virtue of a personal history of the illness would show impaired neural responses to a primary rewarding stimulus. Using functional magnetic resonance imaging, we measured the neural response to the sight and flavor of chocolate, and their combination, in 13 unmedicated recovered patients with a history of major depression and 14 healthy controls matched for age and gender. We also examined a control aversive condition consisting of the sight of moldy strawberries and a corresponding unpleasant taste. Participants simultaneously recorded subjective ratings of "pleasantness," "intensity," and "wanting." Despite no differences between the groups in stimulus ratings, patients showed decreased neural responses to the pleasant stimulus in the ventral striatum and increases in the caudate nucleus to the aversive stimulus. Furthermore, patients had a diminished neural supralinearity response (the potentiation produced by simultaneous presentation of the sight and flavor of the stimuli) in the prefrontal cortex for both aversive and pleasant conditions. Patients recovered from depression appear to have deficits in the neural basis of reward and may also have impairments in the cross-modal integration of sensory stimuli. These findings support the view that abnormal neural responses to reward may be an endophenotype for depression and a potential target for intervention and prevention strategies.


Morphological changes in the neuritic growth cone and target neuron during synaptic junction development in culture.
Our object was to characterize the morphological changes occurring in pre- and postsynaptic elements during their initial contact and subsequent maturation into typical synaptic profiles. Neurons from superior cervical ganglia (SCG) of perinatal rats were freed of their supporting cells and established as isolated cells in culture. To these were added explants of embryonic rat thoracic spinal cord to allow interaction between outgrowing cord neurites and the isolated autonomic neurons. Time of initial contact was assessed by light microscopy; at timed intervals thereafter, cultures were fixed for electron microscopy. Upon contact, growth cone filopodia became extensively applied to the SCG neuronal plasmalemma and manifested numerous punctate regions in which the apposing plasma membranes were separated by only 7-10 nm. The Golgi apparatus of the target neuron hypertrophied, and its production of coated vesicles increased. Similar vesicles were seen in continuity with the SCG plasmalemma near the close contact site; their apparent contribution of a region of postsynaptic membrane with undercoating was considered to be the first definitive sign of synapse formation. Tracer work with peroxidase and ferritin confirmed that the traffic of coated vesicles within the neuronal soma is largely from Golgi region to somal surface. Subsequent to the appearance of postsynaptic density, the form and content of the growth cone was altered by the loss of filopodia and the appearance of synaptic vesicles which gradually became clustered opposite the postsynaptic density. As the synapse matured, synaptic vesicles increased in number, cleft width and content increased, presynaptic density appeared, branched membranous reticulum became greatly diminished, and most lysosomal structures disappeared. Coated vesicles continued to be associated with the postsynaptic membrane at all stages of maturation. The incorporation of Golgi-derived vesicles into discrete regions of the cell membrane could provide the mechanism for confining specific characteristics of the neuronal membrane to the synaptic region.


Does this patient have Barrett's esophagus? The utility of predicting Barrett's esophagus at the index endoscopy.
Few studies have evaluated the ability of the endoscopist to predict the presence of Barrett's esophagus (BE) at index endoscopy. The goals of this study were to determine the operating characteristics of endoscopy in diagnosing BE, and to determine the clinical and endoscopic predictors of BE in suspected BE patients at the index endoscopy. From September 1993 to October 1997, endoscopic reports were examined to identify patients with suspected BE. All esophageal pathology reports during the same period were evaluated for the presence of specialized intestinal metaplasia. During the study period, 4053 endoscopies were performed on 2393 patients. Eight percent of all procedures were performed for suspected or confirmed BE. Fifty-three patients were known to have BE and thus their reports were excluded from this analysis. Five hundred seventy of the remaining patients had esophageal biopsies performed, and were included in this analysis. Among these 570 patients, 146 were suspected to have BE on endoscopy, while 424 were not suspected to have BE at the time of endoscopy. There were no differences among the two groups in terms of gender, race, and dyspepsia as an indication for the endoscopy. However, suspected BE patients were slightly younger and were more likely to have heartburn, but were less likely to have dysphagia as an indication for the endoscopy. The sensitivity and specificity of the endoscopists' assessments were 82% (95% confidence interval [CI], 72-92) and 81% (95% CI, 78-84), respectively. The positive predictive value and the negative predictive value were 34% and 97%, respectively. The positive likelihood ratio was 4.32 (95% CI, 3.49-5.31) and the negative likelihood ratio was 0.22 (95% CI, 0.13-0.38). Univariate analysis showed that endoscopists diagnosed BE in those with long-segment BE (LSBE) more accurately than in those with short-segment BE (SSBE) (55% vs 25% p = 0.001; odds ratio [OR] = 3.63, 95% CI, 1.71-7.70). Barrett's esophagus was correctly diagnosed in 38.5% of white patients but in only 14.7% of black patients (p = 0.01; OR = 3.63, 95% CI, 1.31-10.13). Multivariable logistic regression identified only the length of the columnar-appearing segment (p = 0.002; OR = 3.33, 95% CI, 1.54-7.17) and race (p = 0.08; OR = 2.31, 95% CI, 0.88-6.03) to be associated with the presence of BE on biopsy. Barrett's esophagus is frequently suspected at endoscopy; SSBE was more frequently suspected than LSBE, but was correctly diagnosed only 25% of the time, versus 55% for LSBE. Endoscopists diagnosed BE with a sensitivity of 82% and a specificity of 81%. However, the positive predictive value was only 34%, whereas the negative predictive value was 97%. The length of the columnar-appearing segment is the strongest predictor of BE at endoscopy. Alternative methods are needed to better identify BE patients endoscopically, especially those with SSBE.


Constitutively active aryl hydrocarbon receptor expressed in T cells increases immunization-induced IFN-gamma production in mice but does not suppress T(h)2-cytokine production or antibody production.
The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) has been implicated in various immune functions. Our previous studies have shown that AhR activation by exposure of ovalbumin (OVA)-immunized mice to the potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases immunization-induced IFN-gamma production in the spleen and suppresses the production of T(h)2 cytokines and OVA-specific antibodies. In the present study, we used transgenic (Tg) mice that express a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) specifically in T-lineage cells to clarify the role of AhR activation in T cells in these reactions. The results of this study clearly demonstrated that AhR activation only in the T cells augments IFN-gamma production upon OVA immunization. By contrast, production of T(h)2 cytokines and antibodies were not significantly suppressed by CA-AhR in the T cells. These results suggest that suppression of T(h)2 cytokines and antibodies production require AhR activation not only in T cells but also in other cell types as caused by TCDD exposure. Alternatively, these results may indicate that IFN-gamma augmentation and T(h)2 cytokines and antibodies suppression depend on different ways of functions of AhR in the T cells and that CA-AhR does not replicate the suppressive effect of TCDD-activated AhR on T(h)2 cytokines and antibodies. Expression of CA-AhR in the T cells was also shown to increase the percentage of CD25(+) cells among CD4(+) cells in the thymus and spleen. Thus, studies using T-cell-specific CA-AhR Tg mice provide a way to dissect the role of AhR in individual cell types and how the AhR functions.


Antigen-induced immunomodulation in the pathogenesis of atherosclerosis.
Atherosclerosis is a chronic inflammatory disorder characterised by the accumulation of monocytes/macrophages, smooth muscle cells, and lymphocytes within the arterial wall in response to the release of proinflammatory molecules. Such accumulation results in the formation of the atherosclerotic plaque, which would eventually evolve to complications such as total artery occlusion, rupture, calcification, or aneurysm. Although the molecular mechanism responsible for the development of atherosclerosis is not completely understood, it is clear that the immune system plays a key role in the development of the atherosclerotic plaque and in its complications. There are multiple antigenic stimuli that have been associated with the pathogenesis of atherosclerosis. Most of these stimuli come from modified self-molecules such as oxidised low-density lipoproteins (oxLDLs), beta2glycoprotein1 (beta2GP1), lipoprotein a (LP(a)), heat shock proteins (HSPs), and protein components of the extracellular matrix such as collagen and fibrinogen in the form of advanced glycation-end (AGE) products. In addition, several foreign antigens including bacteria such as Porphyromonas gingivalis and Chlamydia pneumoniae and viruses such as enterovirus and cytomegalovirus have been associated with atherosclerosis as potentially causative or bystander participants, adding another level of complexity to the analysis of the pathophysiology of atherosclerosis. The present review summarises the most important scientific findings published within the last two decades on the importance of antigens, antigen stimulation, and adaptive immune responses in the development of atherosclerotic plaques.


The sociocultural health behavioral model and disparities in colorectal cancer screening among Chinese Americans.
The purpose of this study was to validate a Sociocultural Health Behavior Model using a structural equation analysis to determine the direction and magnitude of the interdependence of model components in relation to health behavior associated with colorectal cancer (CRC) screening among Chinese Americans. A cross-sectional design included a sample of 311 Chinese American men and women age 50 and older. The initial step involved use of confirmatory factor analysis which included the following variables: access/satisfaction with health care, enabling, predisposing, cultural, and health belief factors. Structural equation modeling analyses were conducted on factors for CRC screening. Education and health insurance status were significantly related to CRC screening. Those with less than a high school education and without health insurance were more likely to be "never screened" for CRC than those having more education and health insurance. The path analysis findings also lend support for components of the Sociocultural Health Belief Model and indicated that there was a positive and significant relationship between CRC screening and the enabling factors, between cultural factors and predisposing, enabling, and access/satisfaction with health care factors and between enabling factors and access/satisfaction with health care. The model highlights the significance that sociocultural factors play in relation to CRC screening and reinforced the need to assist Chinese with poor English proficiency in translation and awareness of the importance of CRC screening. The use of community organizations may play a role in assisting Chinese to enhance colorectal cancer screening rates.


Geobacter hydrogenophilus, Geobacter chapellei and Geobacter grbiciae, three new, strictly anaerobic, dissimilatory Fe(III)-reducers.
Recent studies on the diversity and ubiquity of Fe(III)-reducing organisms in different environments led to the isolation and identification of four new dissimilatory Fe(III)-reducers (strains H-2T, 172T, TACP-2T and TACP-5). All four isolates are non-motile, Gram-negative, freshwater, mesophilic, strict anaerobes with morphology identical to that of Geobacter metallireducens strain GS-15T. Analysis of the 16S rRNA sequences indicated that the new isolates belong to the genus Geobacter, in the delta-Proteobacteria. Significant differences in phenotypic characteristics, DNA-DNA homology and G+C content indicated that the four isolates represent three new species of the genus. The names Geobacter hydrogenophilus sp. nov. (strain H-2T), Geobacter chapellei sp. nov. (strain 172T) and Geobacter grbiciae sp. nov. (strains TACP-2T and TACP-5) are proposed. Geobacter hydrogenophilus and Geobacter chapellei were isolated from a petroleum-contaminated aquifer and a pristine, deep, subsurface aquifer, respectively. Geobacter grbiciae was isolated from aquatic sediments. All of the isolates can obtain energy for growth by coupling the oxidation of acetate to the reduction of Fe(III). The four isolates also coupled Fe(III) reduction to the oxidation of other simple, volatile fatty acids. In addition, Geobacter hydrogenophilus and Geobacter grbiciae were able to oxidize aromatic compounds such as benzoate, whilst Geobacter grbiciae was also able to use the monoaromatic hydrocarbon toluene.


ICTV Virus Taxonomy Profile: Iflaviridae.
Iflaviridae is a family of small non-enveloped viruses with monopartite, positive-stranded RNA genomes of approximately 9-11 kilobases. Viruses of all classified species infect arthropod hosts, with the majority infecting insects. Both beneficial and pest insects serve as hosts, and infections can be symptomless (Nilaparvatalugens honeydew virus 1) or cause developmental abnormalities (deformed wing virus), behavioural changes (sacbrood virus) and premature mortality (infectious flacherie virus). The host range has not been examined for most members. The most common route of infection for iflaviruses is the ingestion of virus-contaminated food sources. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Iflaviridae, which is available at www.ictv.global/report/iflaviridae.