Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma.
Currently, five biologic treatment options are available for use in patients with uncontrolled persistent asthma: three interleukin (IL)-5 antagonists, which either bind to the anti-IL-5 ligand (mepolizumab, reslizumab) or to the IL-5 receptor (benralizumab); one anti-immunoglobulin E (anti-IgE) therapy (omalizumab); and one anti-IL-4/IL-13 therapy (dupilumab). To date, no comparative data from head-to-head clinical trials are available for these biologics. An indirect treatment comparison (ITC) of dupilumab versus each of the anti-IL-5 and anti-IgE therapies using the endpoints of annualized severe asthma exacerbation rates and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1). Embase®, MEDLINE®, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published between January 1, 1980 and March 25, 2019. Eligible articles included randomized controlled trials (RCTs) in patients aged ≥ 12 years with persistent/uncontrolled asthma using at least medium-to-high dose inhaled corticosteroid plus long-acting β2-agonist with add-on biologic therapy. Bucher ITCs were performed to compare subgroups of dupilumab patients with the anti-IL-5s and anti-IgE trial populations. Fourteen RCTs were included in the analyses. The matched dupilumab subgroups were associated with greater reductions in annualized severe exacerbation rates compared with benralizumab, mepolizumab, reslizumab, and omalizumab (54%, 28%, 38%, and 26% greater reduction, respectively). A greater improvement in FEV1 was also observed for dupilumab at week 12 and/or week 24/52 than for the other biologics (0.06-0.14 L). In this ITC, dupilumab was associated with lower severe asthma exacerbation rates and greater improvements in lung function than anti-IL-5s and omalizumab.


Health technology assessment and public health: a commentary.
This article reviews the developments in HTA in four countries, France, The Netherlands, Sweden, and United Kingdom, in relation to public health. It emphasizes that the majority of assessments made are concerned with individual clinical care rather than with the optimization of health. Possible reasons for the neglect of public health issues are that these are inherently more complex than the assessment of individual procedures or drugs. They are usually multisectoral, politically charged, and often considered mundane and "common sense" and, thus, not requiring evaluation (although when evaluations are done they are often counterintuitive). Unless more emphasis is given to the development and evaluation of public health measures, it is unlikely that there will be any major advances in health status. Possible areas for future assessment should include such issues as smoking, drug and other substance misuse, nutrition, and health inequalities. However, it is unlikely that these major areas of concern will be included in the future unless the methods of choice for priorities of development and assessment are changed to include measures that improve health status rather than only clinical services.


Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model.
Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.


Thoracoscopic surgical approaches for treating various thoracic spinal region diseases.
Minimally invasive surgery is currently a goal for surgical intervention in the spine. The effectiveness of endoscopic thoracic spine surgery and technological improvements are two factors that are always under consideration in the practice of spinal surgery. We present twenty-five patients whose thoracoscopic spinal surgeries were performed between 2002 and 2008 for the treatment of various spinal diseases. Eleven patients with thoracic disc herniation, five patients with traumatic thoracic spinal compressive fracture, six patients with metastatic thoracic spinal tumors and three patients with tubercular spondylitis underwent thoracoscopic spine surgery. Clinical evaluations were performed at 3, 6,12 and 24 months post-surgery. The Oswestry disability questionnaire and linear visual analog scale (VAS) were used for the evaluation of pain. Postoperatively, two patients had lung contusions, one patient had pneumonia and one patient had instability. There were significant initial improvements in both the Oswestry score and the VAS pain score up to 6 months (p<0.05). The average relative difference in pain scores in all groups was not significant at 12 and 24 months (p>0.05). The favorable results of thoracoscopic spinal surgery encourage its application to situations in which a conventional thoracic approach is indicated. Thoracoscopic spine surgery is applicable to all patients with various spinal diseases.


Assembly-line synthesis of organic molecules with tailored shapes.
Molecular 'assembly lines', in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes-helical or linear-depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.


Amelanotic melanoma presenting with cervical lymphadenopathy.
We present a rare case of an amelanotic melanoma of unknown primary presenting with cervical lymphadenopathy. A 20-year-old man presented with large left sided neck lump, associated dysphagia and weight loss. Examination revealed a hard mass in the left posterior triangle of neck and sacral sensory loss. Fine needle aspiration cytology of the mass suggested a poorly differentiated carcinoma. Computed tomography showed a left sided, 8×13 cm cervical mass with liver, lung and bony metastases. Histological examination of the lymph nodal mass confirmed the diagnosis of a metastatic amelanotic melanoma. The patient was treated with glucocorticoids, radiation therapy for the sacral bony deposit, and chemotherapy. Despite an initial reduction of his target lesions, his condition subsequently deteriorated and he died 4 months after diagnosis.


Developmental changes of erythropoiesis in cultured chick blastoderms.
The erythropoietic area of very early chick embryos was cultured as a tissue for up to nine days to study the changes in red cell type and hemoglobin type, the cell cycle time, the cell population kinetics, and the DNA synthetase activity of these cells. It was found that the area vasculosa without the participation of the embryo proper contained the information and the timing mechanism required to produce not only the early primitive erythroid cell population, but also in due course, the later definitive cell type, each with its appropriate hemoglobin types. Also the precursors of the definitive cell type are active in DNA synthesis and therefore are probably in cycle very early in the culture period.


Anionic phospholipid interactions of the prion protein N terminus are minimally perturbing and not driven solely by the octapeptide repeat domain.
Although the N terminus of the prion protein (PrP(C)) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP(C) and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.


Cloning and expression of a human kinesin heavy chain gene: interaction of the COOH-terminal domain with cytoplasmic microtubules in transfected CV-1 cells.
To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances.


Development and performance evaluation of the second model 256-detector row CT.
Since our initial development of the 256-detector row CT scanner (256-row CT) for four-dimensional (4D) imaging of moving organs in 2003, the results of physical performance and those in animal and human studies have suggested that this scanner may be useful in the examination of moving organs such as the heart and lungs. We have now developed a second model of the 256-row CT with improved specifications, with a scan time of 0.5 s/rotation at the highest speed and real-time reconstruction and display of dynamic 3D images (4D images). Here, we investigated the image characteristics of the new model, including spatial resolution, noise, and low-contrast detectability, as well as the dose profile and its integral in stationary phantoms. One volunteer and one patient with lung cancer were scanned, and their images were evaluated. The results show that all characteristics have been improved compared with those of the first model, with a remarkable improvement in the low-contrast detectability and slice sensitivity profile. In a contrast study, coronary arteries were clearly visualized in the normal heart without electrocardiographic gating. Movement and deformation of the tumor in the patient with lung cancer was captured in a study of a single breath cycle. The second model 256-row CT with improved characteristics may be beneficial in imaging of moving organs such as the heart and lungs, and may enable cerebral perfusion studies of the whole brain.


Change in Serum Level of Interleukin 6 and Delirium After Coronary Artery Bypass Graft.
Serum level of interleukin 6 (IL-6) is known to be associated with postoperative delirium. However, no consensus has emerged on the postoperative time point at which IL-6 level may predict postoperative delirium after coronary artery bypass graft surgery. To compare trends in IL-6 levels in patients with and without postoperative delirium and to examine the relationship between IL-6 levels at different times and postoperative delirium after coronary artery bypass graft. A prospective cohort study of patients who underwent their first elective isolated coronary artery bypass graft between November 2013 and August 2015 at a cardiac intensive care unit in Beijing, China. Concentrations of IL-6 were measured before the operation and at the 6th, 12th, and 18th postoperative hours. Participants were assessed for postoperative delirium twice daily for 5 days. Univariate and multivariate logistic regression analyses were done to determine associations between IL-6 levels at different time points, postoperative changes in IL-6 levels, and the occurrence of postoperative delirium. Postoperative delirium was diagnosed in 85 of 266 patients (32%). Levels of IL-6 were significantly higher in patients with postoperative delirium than in patients without it at the 6th, 12th, and 18th postoperative hours (P = .03, .004, and .001, respectively). Change in IL-6 level (odds ratio, 2.97; 95% CI, 1.20-7.31; P = .02) and IL-6 level of 583 pg/mL or higher at the 18th postoperative hour (odds ratio, 5.20; 95% CI, 1.84-14.70; P = .002) were associated with higher incidence of postoperative delirium. Interleukin 6 level (≥ 583 pg/mL) at the 18th postoperative hour may serve as a potent predictor of postoperative delirium in coronary artery bypass graft patients.


Risk factors associated with secondary enucleation after fractionated stereotactic radiotherapy in uveal melanoma.
To evaluate risk factors for secondary enucleation after fractionated stereotactic radiotherapy (fSRT) in uveal melanoma. In this retrospective study, clinical data of 118 consecutive patients who had initially been treated with fSRT between 1999 and 2009 were collected and analysed. The patients who had undergone secondary enucleation were identified and examined for clinical, histopathological and cytogenetical (fluorescence in situ hybridization determined) data. Also, the reasons for secondary enucleation, such as treatment failure (progressive tumour growth or tumour recurrence) or complications following fSRT (painful blind eye), were recorded and examined. The secondary enucleation rate was 16% after a median follow-up of 4.7 years, with 5% due to treatment failure and 11% due to complications. In the univariate analysis, large tumour diameter (p = 0.019) and large tumour height (p = 0.001) were associated with secondary enucleation, tumour involvement of the optic disc showed borderline significance (p = 0.068). Cox regression multivariate analysis displayed large tumour height as independent prognostic factor (HR 1.42, 95% CI 1.12-1.81, p = 0.004). Following secondary enucleation, mitotic figures were present in five of 18 tumours, and gain of chromosome 8q was also present in five tumours. Within the subgroup of patients who required secondary enucleation due to failed tumour control by fSRT (N = 6), mitotic figures were present in four of six tumours while gain of 8q was present in three of six tumours. Secondary enucleation after previous fSRT was associated with large tumour height. High mitotic counts and gain of chromosome 8q were frequently found in secondary enucleations and possibly indicate a more aggressive or radiation-resistant tumour.


Utility of the Standardized Assessment of Concussion (SAC) to Detect Insufficient Effort in Independent Medical Examinations and Civil Litigation Cases.
The Standardized Assessment of Concussion (SAC) is a standardized mental status screening instrument initially developed for assessment and tracking of concussion symptoms in athletes. The purpose of the current study was to validate the utility of the SAC as an embedded screening measure for insufficient effort in independent medical examinations (IME) and personal injury cases. A known-groups design was used to examine the SAC's utility for the detection of insufficient effort in 75 de-identified private IME and civil litigation evaluations. Initial classifications of insufficient effort were made independently of SAC scores, on the basis of having two or more scores falling below established cut-offs on previously validated neuropsychological measures. Results suggest that the total score on the SAC significantly distinguishes effortful respondents from those exhibiting insufficient effort. Empirically derived cut-off scores yielded adequate sensitivity (.62-.95) and negative predictive power (.93-.97). While optimal cut-off scores depend upon intended use, our data suggest that the SAC is useful as a potential screener for insufficient effort, after which one can employ additional measures to rule out false-positives. Further research is required before cut-off scores can be recommended for clinical use.


Delivering a pathology curriculum in an integrated medical course.
Modern integrated medical curricula usually do not include a separate pathology course. Consequently, there is a risk that important pathological principles may be omitted. We aimed to ensure that pathology is properly represented by developing a core pathology curriculum created in consultation with local pathologists. Appropriate information technology to track the delivery of this material within the integrated curriculum structure was developed using a learning content management system in which a metadata schema was constructed. This allows a sophisticated view of where and how pathology appears in the course and can also increase the visibility of the subject by demonstrating the central place of pathology in medicine. In conclusion, a core curriculum in pathology that can be tracked by information technology with sufficient power and flexibility is a solution to the potential loss of pathology from integrated medical courses. We believe the result is superior to a stand-alone pathology course.


Two hemispheres for better memory in old age: role of executive functioning.
This experiment explored the functional significance of age-related hemispheric asymmetry reduction associated with episodic memory and the cognitive mechanisms that mediate this brain pattern. ERPs were recorded while young and older adults performed a word-stem cued-recall task. Results confirmed that the parietal old/new effect was of larger latency and reduced magnitude and less lateralized in the older group than the young group. Correlational and regression analyses indicated that the degree of laterality of brain activity determines the accuracy of memory performance and mediates age-related differences in memory performance among older participants. They also confirmed a cascade model in which the individual level of executive functioning of older adults mediates age-related differences in the degree of lateralization of brain activity, which in turn mediates age-related differences in memory performance.


Variations in the relation between education and cause-specific mortality in 19 European populations: a test of the "fundamental causes" theory of social inequalities in health.
Link and Phelan have proposed to explain the persistence of health inequalities from the fact that socioeconomic status is a "fundamental cause" which embodies an array of resources that can be used to avoid disease risks no matter what mechanisms are relevant at any given time. To test this theory we compared the magnitude of inequalities in mortality between more and less preventable causes of death in 19 European populations, and assessed whether inequalities in mortality from preventable causes are larger in countries with larger resource inequalities. We collected and harmonized mortality data by educational level on 19 national and regional populations from 16 European countries in the first decade of the 21st century. We calculated age-adjusted Relative Risks of mortality among men and women aged 30-79 for 24 causes of death, which were classified into four groups: amenable to behavior change, amenable to medical intervention, amenable to injury prevention, and non-preventable. Although an overwhelming majority of Relative Risks indicate higher mortality risks among the lower educated, the strength of the education-mortality relation is highly variable between causes of death and populations. Inequalities in mortality are generally larger for causes amenable to behavior change, medical intervention and injury prevention than for non-preventable causes. The contrast between preventable and non-preventable causes is large for causes amenable to behavior change, but absent for causes amenable to injury prevention among women. The contrast between preventable and non-preventable causes is larger in Central & Eastern Europe, where resource inequalities are substantial, than in the Nordic countries and continental Europe, where resource inequalities are relatively small, but they are absent or small in Southern Europe, where resource inequalities are also large. In conclusion, our results provide some further support for the theory of "fundamental causes". However, the absence of larger inequalities for preventable causes in Southern Europe and for injury mortality among women indicate that further empirical and theoretical analysis is necessary to understand when and why the additional resources that a higher socioeconomic status provides, do and do not protect against prevailing health risks.


Advanced driver assistance systems for teen drivers: Teen and parent impressions, perceived need, and intervention preferences.
From the advent of airbags to electronic stability control, technological advances introduced into automobile design have significantly reduced injury and death from motor vehicle crashes. These advances are especially pertinent among teen drivers, a population whose leading cause of death is motor vehicle crashes. Recently developed advanced driver assistance systems (ADAS) have the potential to compensate for skill deficits and reduce overall crash risk. Yet, ADAS is only effective if drivers are willing to use it. Limited research has been conducted on the suitability of ADAS for teen drivers. The goal of this study is to identify teen drivers' perceived need for ADAS, receptiveness to in-vehicle technology, and intervention preferences. The long-term goal is to understand public perceptions and barriers to ADAS use and to help determine how these systems must evolve to meet the needs of the riskiest driving populations. Three focus groups (N = 24) were conducted with licensed teen drivers aged 16-19 years and 2 focus groups with parents of teen drivers (N = 12). Discussion topics included views on how ADAS might influence driving skills and behaviors; trust in technology; and data privacy. Discussions were transcribed; the team used conventional content analysis and open coding methods to identify 12 coding domains and code transcripts with NVivo 10. Interrater reliability testing showed moderate to high kappa scores. Overall, participants recognized potential benefits of ADAS, including improved safety and crash reduction. Teens suggested that ADAS is still developing and therefore has potential to malfunction. Many teens reported a greater trust in their own driving ability over vehicle technology. They expressed that novice drivers should learn to drive on non-ADAS-equipped cars and that ADAS should be considered a supplemental aid. Many teens felt that overreliance on ADAS may increase distracted driving or risky behaviors among teens. Parents also expressed skepticism for the technology but felt that it would likely be a useful support for teen drivers after the initial learning phase. This study elicited important end-user viewpoints by exploring the intersection between advanced automobile safety technology and human perception for the particular use case of teen drivers. For example, despite evidence that teens are the highest risk driving population, teens trust their own driving skills and competence more than in-vehicle technology. This understanding will ultimately advance the safety of teen drivers by identifying barriers to effective ADAS use.


Leveraging crosslinking mass spectrometry in structural and cell biology.
Crosslinking mass spectrometry (crosslinking-MS) is a versatile tool providing structural insights into protein conformation and protein-protein interactions. Its medium-resolution residue-residue distance restraints have been used to validate protein structures proposed by other methods and have helped derive models of protein complexes by integrative structural biology approaches. The use of crosslinking-MS in integrative approaches is underpinned by progress in estimating error rates in crosslinking-MS data and in combining these data with other information. The flexible and high-throughput nature of crosslinking-MS has allowed it to complement the ongoing resolution revolution in electron microscopy by providing system-wide residue-residue distance restraints, especially for flexible regions or systems. Here, we review how crosslinking-MS information has been leveraged in structural model validation and integrative modeling. Crosslinking-MS has also been a key technology for cell biology studies and structural systems biology where, in conjunction with cryoelectron tomography, it can provide structural and mechanistic insights directly in situ.


Altering User Movement Behaviour in Virtual Environments.
In immersive Virtual Reality systems, users tend to move in a Virtual Environment as they would in an analogous physical environment. In this work, we investigated how user behaviour is affected when the Virtual Environment differs from the physical space. We created two sets of four environments each, plus a virtual replica of the physical environment as a baseline. The first focused on aesthetic discrepancies, such as a water surface in place of solid ground. The second focused on mixing immaterial objects together with those paired to tangible objects. For example, barring an area with walls or obstacles. We designed a study where participants had to reach three waypoints laid out in such a way to prompt a decision on which path to follow based on the conflict between the mismatching visual stimuli and their awareness of the real layout of the room. We analysed their performances to determine whether their trajectories were altered significantly from the shortest route. Our results indicate that participants altered their trajectories in presence of surfaces representing higher walking difficulty (for example, water instead of grass). However, when the graphical appearance was found to be ambiguous, there was no significant trajectory alteration. The environments mixing immaterial with physical objects had the most impact on trajectories with a mean deviation from the shortest route of 60 cm against the 37 cm of environments with aesthetic alterations. The co-existance of paired and unpaired virtual objects was reported to support the idea that all objects participants saw were backed by physical props. From these results and our observations, we derive guidelines on how to alter user movement behaviour in Virtual Environments.


Differential Targeting of Stem Cells and Differentiated Glioblastomas by NK Cells.
We have recently shown that Natural Killer (NK) cells control survival and differentiation of Cancer Stem-like Cells (CSCs) through two distinct phenotypes of cytotoxic and anergic NK cells, respectively. In this report, brain CSCs and their serum and NK cell differentiated counterparts were studied. Serum-differentiated brain CSCs were significantly less susceptible to NK cells and CTL direct cytotoxicity as well as NK cell mediated Antibody Dependent Cellular Cytotoxicity (ADCC), whereas their CSCs were highly susceptible. The levels of CD44 and EGFR were higher in brain tumor CSCs when compared to the serum-differentiated tumors. No differences could be observed for the expression of MHC class I between brain tumor stem cells and their serum-differentiated counterparts. Moreover, supernatants from the combination of IL-2 and anti-CD16mAb treated NK cells (anergized NK cells) induced resistance of brain tumor CSCs to NK cell mediated cytotoxicity. Unlike serum-differentiated CSCs, NK supernatant induced differentiation and resistance to cytotoxicity in brain CSCs correlated with the increased expression of CD54 and MHC class I. The addition of anti-MHC class I antibody moderately inhibited NK mediated cytotoxicity against untreated or serum-differentiated CSCs, whereas it increased cytotoxicity against NK supernatant differentiated tumors. Therefore, two distinct mechanisms govern serum and NK supernatant mediated differentiation of brain tumors.


Hypoxia-related parameters during septic shock resuscitation: Pathophysiological determinants and potential clinical implications.
Assessment of tissue hypoxia at the bedside has yet to be translated into daily clinical practice in septic shock patients. Perfusion markers are surrogates of deeper physiological phenomena. Lactate-to-pyruvate ratio (LPR) and the ratio between veno-arterial PCO2 difference and Ca-vO2 (ΔPCO2/Ca-vO2) have been proposed as markers of tissue hypoxia, but they have not been compared in the clinical scenario. We studied acute septic shock patients under resuscitation. We wanted to evaluate the relationship of these hypoxia markers with clinical and biochemical markers of hypoperfusion during septic shock resuscitation. Secondary analysis of a randomized controlled trial. Septic shock patients were randomized to fluid resuscitation directed to normalization of capillary refill time (CRT) versus normalization or significant lowering of lactate. Multimodal assessment of perfusion was performed at 0, 2, 6 and 24 hours, and included macrohemodynamic and metabolic perfusion variables, CRT, regional flow and hypoxia markers. Patients who attained their pre-specified endpoint at 2-hours were compared to those who did not. Forty-two patients were recruited, median APACHE-II score was 23 [15-31] and 28-day mortality 23%. LPR and ΔPCO2/Ca-vO2 ratio did not correlate during early resuscitation (0-2 h) and the whole study period (24-hours). ΔPCO2/Ca-vO2 ratio derangements were more prevalent than LPR ones, either in the whole cohort (52% vs. 23%), and in association with other perfusion abnormalities. In patients who reached their resuscitation endpoints, the proportion of patients with altered ΔPCO2/Ca-vO2 ratio decreased significantly (66% to 33%, P=0.045), while LPR did not (14% vs. 25%, P=0.34). Hypoxia markers did not exhibit correlation during resuscitation in septic shock patients. They probably interrogate different pathophysiological processes and mechanisms of dysoxia during early septic shock. Future studies should better elucidate the interaction and clinical role of hypoxia markers during septic shock resuscitation.


Right frontal brain activity, cortisol, and withdrawal behavior in 6-month-old infants.
Although several studies have examined anterior asymmetric brain electrical activity and cortisol in infants, children, and adults, the direct association between asymmetry and cortisol has not systematically been reported. In nonhuman primates, greater relative right anterior activation has been associated with higher cortisol levels. The current study examines the relation between frontal electroencephalographic (EEG) asymmetry and cortisol (basal and reactive) and withdrawal-related behaviors (fear and sadness) in 6-month-old infants. As predicted, the authors found that higher basal and reactive cortisol levels were associated with extreme right EEG asymmetry. EEG during the withdrawal-negative affect task was associated with fear and sadness behaviors. Results are interpreted in the context of the previous primate work, and some putative mechanisms are discussed.


A centuries-old manmade reef in the Caribbean does not substitute natural reefs in terms of species assemblages and interspecific competition.
With increasing maritime activities in the proximity of coral reefs, a growing number of manmade structures are becoming available for coral colonisation. Yet, little is known about the sessile community composition of such artificial reefs in comparison with that of natural coral reefs. Here, we compared the diversity of corals and their competitors for substrate space between a centuries-old manmade structure and the nearest natural reef at St. Eustatius, eastern Caribbean. The artificial reef had a significantly lower species richness and fewer competitive interactions than the natural reef. The artificial reef was dominated by a cover of crustose coralline algae and zoantharians, instead of turf algae and fire corals on the natural reef. Significant differences in species composition were also found between exposed and sheltered sites on both reefs. Our study indicates that even a centuries-old manmade reef cannot serve as a surrogate for natural reefs.


Comparative efficacy and safety of baricitinib 2 mg and 4 mg in patients with active rheumatoid arthritis : A Bayesian network meta-analysis of randomized controlled trials.
This study aimed to assess the relative efficacy and safety of once-daily baricitinib 2 mg and 4 mg administration in patients with active rheumatoid arthritis (RA). In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and safety of baricitinib in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. Seven RCTs involving 3461 patients met the inclusion criteria. There were ten pairwise comparisons, including seven direct comparisons and five interventions. The ACR20 response rate was significantly higher in the baricitinib 4 mg in combination with disease-modifying antirheumatic drugs (DMARD) group than in the placebo+DMARD group (odds ratio, OR 3.13; 95% credible interval, CrI 2.32-4.33). Compared with the placebo+DMARD group, the baricitinib 4 mg, baricitinib 2 mg + DMARD, and adalimumab 40 mg + methotrexate (MTX) groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + DMARD was likely to elicit the best ACR20 response rate (SUCRA = 0.7930), followed by baricitinib 4 mg (SUCRA = 0.7034), baricitinib 2 mg + DMARD (SUCRA = 0.6304), adalimumab 40 mg + MTX (SUCRA = 0.3687), and placebo+DMARD (SUCRA = 0.0045). By contrast, the safety based on the number of treatment-emergent adverse events (TEAEs) did not differ significantly among the five interventions. Baricitinib 2 mg and 4 mg administered once daily, in combination with DMARD, were efficacious interventions for active RA that had no significant risk of TEAE development.


Fifty shades of brown: Macroevolution of plumage brightness in the Furnariida, a large clade of drab Neotropical passerines.
Both natural and sexual selection are thought to affect the evolution of bird color. Most studies of the topic have focused on sexually dichromatic taxa and showy plumages, which are expected to be more influenced by social selection and usually result in increased conspicuousness. However, many bird clades display dull brown or gray plumages that vary greatly in brightness (lightness), but little in hue (shade). Here, we examine the macroevolution of brightness in one such clade, the Furnariida. We make comparisons across light environments, body parts, monochromatic lineages, and each sex of dichromatic lineages. We found that support for models including light environments is greater for the dorsum than for the venter, and that brightness evolution is more constrained in the former than in the latter. Plumages in this clade have evolved to be darker in darker habitats, consistent with natural selection for increased crypsis. Finally, the features of brightness macroevolution are broadly similar across the sexes of the dichromatic clade, challenging the view that sexual dichromatism is driven by different evolutionary processes acting in each sex. We conclude that, in the Furnariida, light environments and dorsal-ventral variation are more important than sex as axes of color evolution.


Dual protection in sexually active women.
To determine the prevalence and co-factors associated with the practice of dual protection against sexually transmitted infections (STIs) and unwanted pregnancy in a cross-sectional sample of South African women. Secondary analysis of cross-sectional household survey data. Statistical analysis of responses by sexually active women to the question, 'Was a condom used on the last occasion you had sex?' were obtained from the women's questionnaire of the South African Demographic and Health Survey in relation to a number of other variables. (i) 10.5% of all sexually active women aged 15-49 years used a condom at last sex and 6.3% used a condom as well as another contraceptive method; (ii) condom use is more likely among younger, more educated, more affluent, and urban women, and among women who change partners more frequently; (iii) reasons for not using condoms are more likely to be associated with the personal attitudes of women or their partners than with poor knowledge of or lack of access to condoms; (iv) women who have no need or desire to prevent pregnancy are less likely to use condoms; and (v) there is a minority of sexually active women, characterised by social disadvantage, who have difficulty obtaining condoms. There is an urgent need for targeted programmes that increase dual protection with condoms.


The FvMK1 mitogen-activated protein kinase gene regulates conidiation, pathogenesis, and fumonisin production in Fusarium verticillioides.
Fusarium verticillioides is one of the most important fungal pathogens to cause destructive diseases of maize worldwide. Fumonisins produced by the fungus are harmful to human and animal health. To date, our understanding of the molecular mechanisms associated with pathogenicity and fumonisin biosynthesis in F. verticillioides is limited. Because MAP kinase pathways have been implicated in regulating diverse processes important for plant infection in phytopathogenic fungi, in this study we identified and functionally characterized the FvMK1 gene in F. verticillioides. FvMK1 is orthologous to FMK1 in F. oxysporum and GPMK1 in F. graminearum. The Fvmk1 deletion mutant was reduced in vegetative growth and production of microconidia. However, it was normal in sexual reproduction and increased in the production of macroconidia. In infection assays with developing corn kernels, the Fvmk1 mutant was non-pathogenic and failed to colonize through wounding sites. It also failed to cause stalk rot symptoms beyond the inoculation sites on corn stalks, indicating that FvMK1 is essential for plant infection. Furthermore, the Fvmk1 mutant was significantly reduced in fumonisin production and expression levels of FUM1 and FUM8, two genes involved in fumonisin biosynthesis. The defects of the Fvmk1 mutant were fully complemented by re-introducing the wild type FvMK1 allele. These results demonstrate that FvMK1 plays critical roles in the regulation of vegetative growth, asexual reproduction, fumonisin biosynthesis, and pathogenicity.


Pentoxifylline enhances the radioprotective properties of γ-tocotrienol: differential effects on the hematopoietic, gastrointestinal and vascular systems.
The vitamin E analog γ-tocotrienol (GT3) is a potent radioprotector and mitigator. This study was performed to (a) determine whether the efficacy of GT3 can be enhanced by the addition of the phosphodiesterase inhibitor pentoxifylline (PTX) and (b) to obtain information about the mechanism of action. Mice were injected subcutaneously with vehicle, GT3 [400 mg/kg 24 h before total-body irradiation (TBI)], PTX (200 mg/kg 30 min before TBI), or GT3+PTX before being exposed to 8.5-13 Gy TBI. Overall lethality, survival time and intestinal, hematopoietic and vascular injury were assessed. Cytokine levels in the bone marrow microenvironment were measured, and the requirement for endothelial nitric oxide synthase (eNOS) was studied in eNOS-deficient mice. GT3+PTX significantly improved survival compared to GT3 alone and provided full protection against lethality even after exposure to 12.5 Gy. GT3+PTX improved bone marrow CFUs, spleen colony counts and platelet recovery compared to GT3 alone. GT3 and GT3+PTX increased bone marrow plasma G-CSF levels as well as the availability of IL-1α, IL-6 and IL-9 in the early postirradiation phase. GT3 and GT3+PTX were equally effective in ameliorating intestinal injury and vascular peroxynitrite production. Survival studies in eNOS-deficient mice and appropriate controls revealed that eNOS was not required for protection against lethality after TBI. Combined treatment with GT3 and PTX increased postirradiation survival over that with GT3 alone by a mechanism that may depend on induction of hematopoietic stimuli. GT3+PTX did not reduce GI toxicity or vascular oxidative stress compared to GT3 alone. The radioprotective effect of either drug alone or both drugs in combination does not require the presence of eNOS.


Rates of domestic violence against adult women by men partners.
This study examines the rate of domestic violence against adult women by men partners. Two hundred eighteen women at two primary care clinics responded anonymously to a questionnaire. Forty-eight percent reported verbal abuse, 44 percent minor physical abuse, and 28 percent severe physical abuse. Abuse was common (16 percent) before marriage. Respondents whose partners were reported to be chemically dependent or sexually abusive were at greater risk for verbal and physical abuse. Respondents with lower socioeconomic status were at increased risk for verbal and physical abuse, as were women whose partners had less formal education. Ages of respondents and partners were not significant factors in abuse. Boyfriends not cohabitating were the least abusive, while couples together for 4 to 6 years had more domestic violence than other couples. Because spouse abuse is common and the consequences are devastating, it is important that family physicians become astute in making this diagnosis and initiate early treatment.


An Investigation into the Relationship between Owner Knowledge, Diet, and Dental Disease in Guinea Pigs (Cavia porcellus).
Recent studies have highlighted a high prevalence of dental disease in domestic guinea pigs, yet the aetiology of this multi-factorial disease is still unclear. Factors that have been associated with dental disease include feeding a diet that is high in energy but low in fibre, feeding an insufficiently abrasive diet, a lack of dietary calcium, and genetics. As many of these factors relate to the husbandry requirements of guinea pigs, owner awareness of dietary requirements is of the utmost importance. An online questionnaire was created based on previous research into the husbandry and feeding of rabbits. Guinea pig owners were asked to answer questions on the clinical history of their animals and their diet and management. In total, 150 surveys were completed for 344 guinea pigs, where owners of multiple animals could complete the survey for individuals. According to the owners, 6.7% of guinea pigs had been clinically diagnosed with dental disease, but 16.6% had signs consistent with dental disease. The specific clinical signs of having difficulty eating (Exp(B) = 33.927, Nagelkerke R ² = 0.301, p < 0.05) and producing fewer or smaller faecal droppings (Exp(B) = 13.733, Nagelkerke R ² = 0.149, p < 0.05) were predictive for the presence of dental disease. Having access to an outside environment, including the use of runs on both concrete and grass, was significantly related to not displaying clinical signs of dental disease (Exp(B) = 1.894, Nagelkerke R ² = 0.021, p < 0.05). There was no significant relationship between owner knowledge, guinea pig diet, and dental disease in the study population. This study highlights the importance of access to the outdoors for the health and welfare of guinea pigs in addition to the need for owners to be alert to key clinical signs. A relationship between diet and dental disease was not identified in this study; however, the underlying aetiological causes of this condition require further investigation.


Endoscopic ultrasound-through-the-needle biopsy in pancreatic cystic lesions: A multicenter study.
Tissue acquisition in pancreatic cystic lesions (PCL) is the ideal method for diagnosis and risk stratification for malignancy of these lesions. Direct sampling from the walls of PCL with different devices has shown better results than cytology from cystic fluid. We carried out a retrospective, multicenter study to evaluate the feasibility, safety, and diagnostic yield of a micro-forceps, specifically designed to be used through a 19-gauge needle after endoscopic ultrasonography (EUS)-guided puncture of PCL. We retrospectively collected data from patients who underwent EUS-through-the-needle biopsy (EUS-TTNB) in PCL at six referral centers. The sampling procedure was carried out in 56 patients (mean age 57.5 ± 13.1 years, M:F 17:39), and was technically successful in all of them (100%; 95% confidence interval [CI], 94-100%). Adverse events occurred in 9/56 (16.1%; 95% CI, 8-28%) patients, with self-limited intracystic hemorrhage the most common (7/56, 12.5%; 95% CI, 5-24%). All adverse events were mild, and resolved without any specific intervention. Specimens were considered adequate for histological diagnosis in 47/56 (83.9%; 95% CI, 72-92%). In two of these patients, despite the histological adequacy, a diagnosis could not be reached. In two other cases, a specimen sufficient for a cytological diagnosis was obtained. Overall diagnostic yield by combining cytological and histological samples was 47/56 (83.9%; 95% CI, 72-92%). EUS-TTNB with micro-forceps in PCL is feasible, safe, and has a high diagnostic yield. Future prospective studies are needed to better assess the clinical impact of EUS-TTNB on the management of PCL.


Core outcome set for behavioural weight management interventions for adults with overweight and obesity: Standardised reporting of lifestyle weight management interventions to aid evaluation (STAR-LITE).
Behavioural weight management interventions in research studies and clinical practice differ in length, advice, frequency of meetings, staff, and cost. Few real-world programmes have published patient outcomes and those that have used different ways of reporting information, making it impossible to compare interventions and develop the evidence base. To address this issue, we have developed a core outcome set for behavioural weight management intervention programmes for adults with overweight and obesity. Outcomes were identified via systematic review of the literature. A representative expert group was formed comprising people with experience of adult weight management services. An online Delphi process was employed to reach consensus as to which outcomes should be measured and reported and which definitions/instruments should be utilised. The expert group identified eight core outcomes and 12 core processes for reporting by weight management services. Eleven outcomes and five processes were identified as optional. The most appropriate definitions/instruments for measuring each outcome/process were also agreed. Our core outcome set will ensure consistency of reporting. This will allow behavioural weight management interventions to be compared, revealing which interventions work best for which members of the population and helping inform development of adult behavioural weight management interventions.


Jobs, food, taxis and journals: complexities of implementing Stepping Stones and Creating Futures in urban informal settlements in South Africa.
This paper seeks to refocus debates on structural interventions away from 'assessing' their effectiveness towards understanding processes around how such interventions are implemented. Implementation Science is focused on understanding potential challenges of translating interventions from highly controlled conditions into 'real life' settings. Using the case study of Stepping Stones and Creating Futures a structural and behavioural intervention to reduce intimate partner violence and HIV risk behaviours amongst young women and men in urban informal settlements, we explore the challenges of implementing such an approach. We move beyond simply describing challenges of implementing, to understand how these challenges had an impact on the safe social space the intervention seeks to create as its underlying theory of change. We identify four major challenges of implementation: taxi fares, food provided during the intervention, young people's ongoing need to work and journals provided during the intervention. We suggest that, in different ways, these factors all impinged on the emergence of a safe social space. Understanding the challenges of implementing the intervention is critical for reflecting on scaling up interventions. Central to this is the need to work with participants to help them negotiate the challenges of participating in interventions.


The allocation of organs donated by altruistic strangers.
In many transplant centers, organ retrieval from altruistic strangers is accepted practice; patients use Internet Web sites and other public media to locate strangers willing to give them an organ. It is argued that altruistic strangers should be permitted to select the recipients of their organs because 1) personal relationships are morally important; 2) it increases the number of available organs; and 3) no one is hurt by the process. Nonetheless, using public media to obtain organs may undermine equity in organ allocation. Organs donated by altruistic strangers do not go necessarily to patients who have the best immunologic match or the most urgent need or who have waited the longest. A publicly chartered organization should be established to coordinate live organ donation, including donation by altruistic strangers. Altruistic strangers should be educated to allocate their donated organs according to a prudent balance of equity and utility rather than their emotional response to a particular patient's plight, identity, or circumstances.


Hypoxic vasoconstriction in pulmonary arterioles and venules.
Pulmonary microvessels (<70 microm) lack a complete muscular media. We tested the hypothesis that these thin-walled vessels do not participate in the hypoxic pressor response. Isolated canine lobes were pump perfused at precisely known microvascular pressures. A videomicroscope, coupled to a computerized image-enhancement system, permitted accurate diameter measurements of subpleural arterioles and venules, with each vessel serving as its own control. While vascular pressure was maintained constant throughout the protocol, hypoxia caused an average reduction of 25% of microvessel diameters. The constriction was reversed when nitric oxide was added to the hypoxic gas mixture. The nitric oxide reversal, combined with a lack of lobar blood flow redistribution as measured by fluorescent microspheres, shows that the constriction was active. This response suggests the unexpected potential for active intra-acinar ventilation-perfusion matching.


Experimental endoscopic submucosal dissection training in a porcine model: learning experience of skilled Western endoscopists.
Endoscopic submucosal dissection (ESD) demands a new level of endoscopic skill in Europe. A 2-day workshop was set up for trainees to carry out five ESD each in order to obtain the skill level required to perform ESD in the stomach or rectum. This study describes: (i) the workshop setup; (ii) the participant's performance; and (iii) the training effect on post-workshop clinical ESD performance. Eighteen very experienced European endoscopists participated in four half-day (4.5 h) training sessions, with everybody rotating daily through six separate training stations (two each with dual, hook, or hybrid knives) with expert tutors. One anesthetized piglet was used per station and session. After 1 year, the clinical ESD performance was surveyed to estimate the training effect of the workshop. Overall, 74 ESD were performed, that is, 4.1 ESD per participant. On average ESD lasted 57 min for 6 cm(2) specimens. We detected a 22% rate of perforation (16 of 74 ESD with perforations), mostly attributable to participants with less experience in ESD. Those who started clinical ESD within 1 year after the workshop performed 144 clinical ESD (median 8 [0-20] per trainee) mostly in the stomach (40%) and large bowel (46%) with an acceptable rate of perforation (9.7%) and surgical repair (3.5%) without mortality or persistent morbidity. Intense skill training for ESD is needed to reduce the risk of perforation, as demonstrated by the results of this workshop. We show that experimental ESD training, however, enables skilled European endoscopists to perform ESD in standard locations with moderate risk of perforation during the clinical learning curve.


A comparison of the surgical caseloads of selected companion animal hospitals and a veterinary academic hospital in South Africa.
Educational institutions should be aware of the frequency of surgical procedures in private practice, to assist both the student and the lecturer in evaluating the relative importance of procedures and to structure training programmes accordingly. The surgical caseload for 1 year at a veterinary academic hospital and 13 private companion animal hospitals registered with the South African Veterinary Council were compared. Surgical records were entered into a spreadsheet and sorted according to 96 selected surgical procedures to facilitate comparisons. Surgical procedures were in turn grouped according to date, species, degree of difficulty and frequency of occurrence. Feline procedures were more commonly performed in private hospitals. The academic hospital's caseload was dominated by major and advanced procedures while the private hospitals carried out more minor procedures. At the private hospitals more general surgery, and ear, nose and throat surgery as well as dental procedures were performed, while at the academic hospital more ophthalmic, orthopaedic, thoracic and neurosurgical procedures were carried out. The most commonly performed procedures at the academic hospital differed from those at the private hospitals. No seasonal trends were evident.


Zoonotic impact and epidemiological changes of leishmaniasis in Ethiopia.
Leishmaniasis is one of the growing public health challenges in Ethiopia and estimated over 7,000 and 50,000 new cases of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) per year, respectively. The aim of the review is to address zoonotic impact and epidemiological changes of leishmaniasis in Ethiopia. VL is caused by L. donovani and it is endemic in many parts of the country with one third of the country's landmass is highly suitable for VL. CL is principally caused by L. aethiopica. CL is endemic and widespread in the highland of Ethiopia. Northern lowland foci are Humera and Metema plains in the Tigray and Amhara regional states constitute the main VL endemic areas in the country, contributing over 60% of the total burden. The southern foci are the south-western savannah, and the south-eastern semi-arid lowlands which account for approximately 20 % of the total VL burden in Ethiopia. Leishmaniasis is a serious zoonotic disease in Ethiopia with more reservoir hosts maintaining the disease. Dogs and hyraxes are the main reservoir hosts for visceral and cutaneous leishmaniasis in the country, respectively. Epidemiological changes of leishmaniasis may relate to environmental changes and expansion of mega projects such as irrigations and sugar cane factories, knowledge and socio-economic factors, development of new settlements, migration of peoples and HIV/AIDS co-infection. Expansions of mega projects such as sugar factories and irrigations are suitable for reproduction of stray dogs, rodents, wild canids and vectors. VL is one of the major challenges to prevent and control in the endemic areas of the country. Therefore, new research should be imperative, especially in the mega projects to design strategic control and prevention methods.


A Molecular Portrait of High-Grade Ductal Carcinoma In Situ.
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.


Effects of omega-3 and -6 fatty acids on Mycobacterium tuberculosis in macrophages and in mice.
We recently showed that treatment of macrophages prior to Mycobacterium tuberculosis infection with the pro-inflammatory omega-6 lipid, arachidonic acid (AA) enhanced bacterial killing whereas the anti-inflammatory, omega-3 lipid eicosapentaenoic acid (EPA) stimulated bacterial growth. Here we tested if these effects were depending on when lipids were added to macrophages: before or during Mycobacterium smegmatis or M. tuberculosis infection. Collectively, our data suggested that a high omega-6 diet might be beneficial against mycobacteriosis, while a high omega-3 diet might be detrimental. AA also stimulated TNF-alpha secretion in M. tuberculosis-infected macrophages whereas EPA inhibited this process. AA strongly activated the MAP kinase p38 in uninfected cells but M. tuberculosis infected cells blocked the ability of AA to activate p38; AA-dependent killing is therefore independent of p38. We therefore tested diets enriched in omega-3 and omega-6 lipids on a mouse model of tuberculosis. In contrast to the in vitro results, the omega-6 tended to increase survival of M. tuberculosis in mice, while omega-3- tended to increase pathogen killing. Overall our results together with those previously reported in the literature suggest that it is almost impossible to predict, at the whole organism level, if a diet enriched in omega-3 or -6 will be beneficial or detrimental to intracellular pathogens.


Avian influenza vaccination: the experience in China.
Highly pathogenic H5N1 avian influenza virus was first detected in the People's Republic of China (China) in 1996 and has caused over 100 outbreaks of disease in poultry since 2004. The Chinese Government has pursued a vaccination strategy to control avian influenza infection in poultry. A series of vaccines including whole-virus inactivated vaccine, recombinant fowlpox vaccine and recombinant Newcastle disease virus vaccine have been developed and billions of doses of the vaccines are produced every year. The Government has also developed strategies to fund vaccine production and to offer financial compensation for the slaughter of infected poultry. The vaccination strategy has been effective and has played an important role in reducing the incidence of H5N1 infection in poultry and in markedly reducing the number of cases of human infection. Despite the successes obtained with the vaccination strategy, China still faces challenges in its efforts to eliminate H5N1 virus circulation in poultry.


Predicting basal metabolic rates in Malaysian adult elite athletes.
This study aimed to measure the basal metabolic rate (BMR) of elite athletes and develop a gender specific predictive equation to estimate their energy requirements. 92 men and 33 women (aged 18-31 years) from 15 sports, who had been training six hours daily for at least one year, were included in the study. Body composition was measured using the bioimpedance technique, and BMR by indirect calorimetry. The differences between measured and estimated BMR using various predictive equations were calculated. The novel equation derived from stepwise multiple regression was evaluated using Bland and Altman analysis. The predictive equations of Cunningham and the Food and Agriculture Organization/World Health Organization/United Nations University either over- or underestimated the measured BMR by up to ± 6%, while the equations of Ismail et al, developed from the local non-athletic population, underestimated the measured BMR by 14%. The novel predictive equation for the BMR of athletes was BMR (kcal/day) = 669 + 13 (weight in kg) + 192 (gender: 1 for men and 0 for women) (R2 0.548; standard error of estimates 163 kcal). Predicted BMRs of elite athletes by this equation were within 1.2% ± 9.5% of the measured BMR values. The novel predictive equation presented in this study can be used to calculate BMR for adult Malaysian elite athletes. Further studies may be required to validate its predictive capabilities for other sports, nationalities and age groups.


Effect of mixing two environmental stressors, pH and metal contaminants, on offspring of rats exposed during gestation and lactation.
In large urban centers, the toxicity of metal mixtures may be enhanced by physicochemical factors and environmental variables, including pH. Rio Grande, a municipality located in the extreme south of Brazil, has soils with high levels of contamination due to urban and industrial activities and a high prevalence of acid rain events. Previous studies have shown that contact with elutriate of these soils can cause physiological and reproductive changes. Thus, the objective of the present study was to evaluate, through animal experimentation, the effects of a metal-contaminated soil, acidified by hydrofluoric acid at two different pH values (5.2 and 3.6), on the health of offspring of rats exposed during gestation and lactation. Female Wistar rats were gavaged daily for 42 days (gestation and breastfeeding) with soil elutriate contaminated with metals, using solvent with different pH values (6.0, 5.2, and 3.6). The following parameters were evaluated in their offspring: body and organ weight, length, appearance of developmental characteristics, and swimming. Experimental groups in which the progenitors were exposed to the solution at pH 3.6 exhibited a delayed increase in weight as well as motor deficit, with a decreased weight (onset) and length (beginning and end), while exposure in association with soil was an aggravating factor for the damages to the body. Exposure to the solution at pH 5.2 decreased the initial weight of the animals, impaired some parameters of weight development, and caused motor deficit on the 14th day. These novel findings reveal that the exposure of progenitors to environmental stressors can compromise the health of the offspring. Special attention should be given to populations living in areas with high prevalence of acid rain.


Twist renormalization in molecular crystals driven by geometric frustration.
Symmetry considerations preclude the possibility of twist or continuous helical symmetry in bulk crystalline structures. However, as has been shown nearly a century ago, twisted molecular crystals are ubiquitous and can be formed by about 1/4 of organic substances. Despite its ubiquity, this phenomenon has so far not been satisfactorily explained. In this work we study twisted molecular crystals as geometrically frustrated assemblies. We model the molecular constituents as uniaxially twisted cubes and examine their crystalline assembly. We exploit a renormalization group (RG) approach to follow the growth of the rod-like twisted crystals these constituents produce, inquiring in every step into the evolution of their morphology, response functions and residual energy. The gradual untwisting of the rod-like frustrated crystals predicted by the RG approach is verified experimentally using silicone rubber models of similar geometry. Our theory provides a mechanism for the conveyance of twist across length-scales observed experimentally and reconciles the apparent paradox of a twisted single crystal as a finite size effect.


Development of zinc alkyl/air systems as radical initiators for organic reactions.
This paper reports a series of comparative experiments on the activity of carbon- and oxygen-centred radical species in a model reaction of the radical addition of THF to imines mediated by a series of zinc alkyl/air reaction systems. The study strongly contradicts the notion that generally R˙ radicals are the initiating species in organic reactions mediated by R n M/air systems, and simultaneously demonstrates that oxygen-centred radical species are the key intermediates responsible for the initiation process. In addition, a new efficient RZn(L)/air initiating system for radical organic reactions exampled by a model reaction of radical addition of THF to imines is developed. Moreover, the isolation and structural characterization of the first zinc alkylperoxide supported by a carboxylate ligand, [Zn4(μ3-OOtBu)3(μ4-O)(O2CEt)3]2, as well as the novel octanuclear zinc oxo(alkoxide) aggregate with entrapped O-THF species, [Zn4(μ4-O)(μ3-2-O-THF)(O2CEt)5]2, provide clear mechanistic signatures for the mode of function of the RZn(O2CR')/air system.


High-throughput genome scanning in constant tension fluidic funnels.
Genome Sequence Scanning (GSS) is a bacterial identification technology that detects sparse sequence-specific fluorescent tags on long DNA molecules linearized in a continuous-flow microfunnel. The efficiency and sensitivity of GSS depends on the detection throughput of well-stretched molecules. Previous studies have investigated the fundamental roles of elongational and shear flow on DNA stretching in continuous flow devices. Here, we present a novel compound funnel design that significantly improves effective molecule throughput over previously described devices. First, exploring the relationship between fluid strain rate and molecule tension allows for design of funnel geometries that accommodate high fluid velocities without compromising molecules due to overstretching under high tension. Second, a constant-strain detection channel is utilized to significantly reduce the number of molecules lost to further analysis due to shear-induced molecular tumbling and relaxation. Finally, application of the constant-strain detection channel allows for a priori prediction of spatial resolution bias due to accelerating flow. In all, the refined funnel geometries presented here yield over thirty-fold increase in effective molecule throughput due to increased fluid flow and improved retention of stretched molecules, compared to previously described devices.


Complete Genome Sequence of Serratia marcescens SmUNAM836, a Nonpigmented Multidrug-Resistant Strain Isolated from a Mexican Patient with Obstructive Pulmonary Disease.
Serratia marcescens SmUNAM836 is a multidrug-resistant clinical strain isolated in Mexico City from a patient with chronic obstructive pulmonary disease. Its complete genome sequence was determined using PacBio RS II SMRT technology, consisting of a 5.2-Mb chromosome and a 26.3-kb plasmid, encoding multiple resistance determinants and virulence factors.


Charge-state dependent compaction and dissociation of protein complexes: insights from ion mobility and molecular dynamics.
Collapse to compact states in the gas phase, with smaller collision cross sections than calculated for their native-like structure, has been reported previously for some protein complexes although not rationalized. Here we combine experimental and theoretical studies to investigate the gas-phase structures of four multimeric protein complexes during collisional activation. Importantly, using ion mobility-mass spectrometry (IM-MS), we find that all four macromolecular complexes retain their native-like topologies at low energy. Upon increasing the collision energy, two of the four complexes adopt a more compact state. This collapse was most noticeable for pentameric serum amyloid P (SAP) which contains a large central cavity. The extent of collapse was found to be highly correlated with charge state, with the surprising observation that the lowest charge states were those which experience the greatest degree of compaction. We compared these experimental results with in vacuo molecular dynamics (MD) simulations of SAP, during which the temperature was increased. Simulations showed that low charge states of SAP exhibited compact states, corresponding to collapse of the ring, while intermediate and high charge states unfolded to more extended structures, maintaining their ring-like topology, as observed experimentally. To simulate the collision-induced dissociation (CID) of different charge states of SAP, we used MS to measure the charge state of the ejected monomer and assigned this charge to one subunit, distributing the residual charges evenly among the remaining four subunits. Under these conditions, MD simulations captured the unfolding and ejection of a single subunit for intermediate charge states of SAP. The highest charge states recapitulated the ejection of compact monomers and dimers, which we observed in CID experiments of high charge states of SAP, accessed by supercharging. This strong correlation between theory and experiment has implications for further studies as well as for understanding the process of CID and for applications to gas-phase structural biology more generally.


Pregnancy intentions and teenage pregnancy among Latinas: a mediation analysis.
The extent to which pregnancy intentions mediate the relationship between individual, familial and cultural characteristics and adolescent pregnancy is not well understood. The role of intentions may be particularly important among Latina teenagers, whose attitudes toward pregnancy are more favorable than those of other groups and whose pregnancy rates are high. Prospective, time-varying data from 2001-2004 were used to investigate whether two measures of pregnancy intentions, wantedness and happiness, mediated associations between risk factors and pregnancy among 213 Latina adolescents in San Francisco. Participants were tested for pregnancy and interviewed about pregnancy intentions, partnerships, family characteristics and activities every six months for two years. Associations and mediation were examined using logistic regression. Neither pregnancy intention variable mediated relationships between participant characteristics and pregnancy. After adjustment for other measures, wantedness was strongly associated with pregnancy (odds ratio, 2.6), while happiness was not. Having a strong family orientation was associated with happiness (3.7) but unrelated to pregnancy. Low power in a sexual relationship with a main partner was associated with an elevated risk of pregnancy (3.3). If the pregnancy intentions of all participants were changed to definitely not wanting pregnancy, the estimated decline in pregnancy risk would be 16%. Pregnancy intentions were important not as mediators but rather as independent risk factors for pregnancy. Differences in pregnancy rates between groups of Latinas may be less a function of intentional choice than of situational factors. Interventions and research should focus on identifying and targeting factors that hinder effective contraceptive use among teenagers who want to avoid pregnancy.


Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study.
The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. To estimate the occurrence of AD as a function of age and number of APOE epsilon4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. A total of 3308 elderly residents of Cache County, Utah. Cumulative incidence of AD; in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, especially, 2 APOE, epsilon4 alleles but observed no meaningful difference in 100-year lifetime incidence related to number of epsilon4 alleles. The APOE epsilon4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE. Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.


The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.


Durability of radiofrequency ablation in Barrett's esophagus with dysplasia.
Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.


Adherence to Physical Activity Among Older Adults Using a Geographic Information System: Korean National Health and Nutrition Examinations Survey IV.
The purpose of this study was to examine the adherence to physical activity (PA) among older adults in Korea using data from the Fourth Korean National Health and Nutrition Examination Survey (KNHANESIV), and to illustrate geographic variations in PA using Geographic Information Systems (GIS). A secondary analysis of the KNHANES IV data from 2007 to 2008 was used for this study. Participants of the study included 2,241 older adults over the age of 65. Estimates on adherence to PA were obtained for vigorous, moderate, walking, strengthening, and stretching activities. All estimates were weighted to represent Korean population. The association between participants' characteristics and PA was analyzed using Wald chi-square test. Maps depicting regional variations in PA were created using GIS software. Adherence to PA among Korean older adults who met national recommendations during the period of year 2007-2008 was about 9% in vigorous activity, 10% in moderate activity, and 48% in walking. The most common type of PA was walking. A higher level of PA was associated with male gender, younger age, high level of income and education, and living with family. The majority of older adults did not meet the national PA recommendations, suggesting that consistent surveillance and intervention for PA in the geriatric population are needed in the future. Maps generated using GIS visually showed regional differences in PA among the study participants.


The natural history and prognosis of epilepsy.
Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Generally, prognosis refers to the probability of attaining seizure freedom on treatment and little is known about the natural history of the untreated condition. Here, we summarize aspects of the prognosis and prognostic predictors of treated and untreated epilepsy and of its different syndromes. Usually, epilepsy is a fairly benign condition. Most epilepsies have a good prognosis for full seizure control and eventual discontinuation of AEDs, but epilepsy syndromes have differing outcomes and responses to treatment. Prognostic factors include aetiology, EEG abnormalities, type of seizures and the number of seizures experienced before treatment onset, and poor early effects of drugs. Early response to treatment is an important positive predictor of long-term prognosis, while the history of a high number of seizures at the time of diagnosis, intellectual disability, and symptomatic aetiology are negative predictors. Different prognostic patterns can be identified, suggesting that the epileptogenic process is not static. Epilepsy carries a greater than expected risk of premature death. Aetiology is the single most important risk factor for premature death.


The concept of disease.
The connotations of the term "a disease" were investigated by studying the ways in which both medical and non-medical people used the word. A list of common diagnostic terms was read slowly to groups of non-medical academic staff of a university, secondary-school students, medical academics, and family practitioners, who then indicated whether they thought each word referred to disease.All groups rated illnesses due to infections as diseases, but the doctors, and particularly the general practitioners, were more generous in accepting as diseases the terms for non-infectious conditions. Apart from the nature of the cause, the most influential factor in determining whether or not an illness was considered to be a disease was the importance of the doctor in diagnosis and treatment.These findings provide further evidence that there is ambiguity about the meaning of the term disease. To the layman a disease seems to be a living agency that causes illness. Doctors have obviously accepted more heterogeneous defining characteristics but remain reluctant to adopt unequivocally nominalist ways of thought. The position is not unlike that in the physical sciences, in which there is a good precedent for distinguishing between the formal scientific and the everyday uses of terms such as "force" and "power."


Type 2 diabetes self-management education programs in high and low mortality developing countries: a systematic review.
Although self-management education is a key factor in the care for diabetes patients, its implementation in developing countries is not well documented. This systematic review considers the published literature on diabetes self-management education in high and low mortality developing countries. The aim is to provide a state of the art of current practices and assess program outcomes, cultural sensitivity, and accessibility to low literate patients. The Cochrane Library, PubMed, MEDLINE, PsycInfo, and PsycArticles databases were searched for peer-reviewed articles on type 2 diabetes published in English between 2009 and 2013. The World Bank and WHO burden of disease criteria were applied to distinguish between developing countries with high and low mortality. Information was extracted using a validated checklist. Three reviews and 23 primary studies were identified, 18 of which were from low mortality developing countries. Studies from high mortality countries were mostly quasi-experimental, those from low mortality countries experimental. Interventions were generally effective on behavior change and patients' glycemic control in the short term (≤9 months). While 57% of the studies mentioned cultural tailoring of interventions, only 17% reported on training of providers, and 39% were designed to be accessible for people with low literacy. The limited studies available suggest that diabetes self-management education programs in developing countries are effective in the short term but must be tailored to conform to the cultural aspects of the target population.


Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection.
The pathogenesis of Cryptococcus neoformans infection has been studied extensively with respect to inflammatory and pathological changes, but very little information is available regarding the morphology of yeast cells during the course of infection. Electron microscopy of Cryptococcus neoformans in murine pulmonary infection revealed increased cell wall thickness with time, but this difference was only partially accounted for by increases in cell diameter. Cell walls of melanized cells were thicker than those of nonmelanized cells 2 h after infection, and the cell wall of yeast became blacker with time, suggesting that melanization contributes to the increased cell wall thickness. Heterogeneous cell populations emerged, with the appearance of giant forms. While for C. neoformans ATCC strain 24067 (serotype D) the full spectrum of cell sizes were observed, for strains H99 (serotype A) and 3501 (serotype D) cells were divisible into two populations, giant and micro forms. In contrast to cellular heterogeneity, the epitope recognized by a protective mAb on the capsular glucuronoxylomannan (GXM) was found at all times of infection. Immunoelectron microscopy using mAbs to GXM demonstrated reactivity with intracellular structures, suggesting that synthesis of capsular polysaccharide occurs, at least in part, in the cytoplasm. In summary, the results indicate that: (i) the infection is dynamic with respect to yeast cell morphology; (ii) giant cell forms arise in tissue during the course of infection; (iii) cell walls blacken and thicken during the course of infection, consistent with melanin synthesis during infection; and (iv) GXM epitopes are found in the capsule, cell wall and cytoplasm, consistent with intracellular polysaccharide synthesis. The results indicate that the population of C. neoformans cells in tissue is in a highly dynamic state, implying that the immune system must confront cells with varying characteristics during the course of infection.


Motor unit number estimates and neuromuscular transmission in the tibialis anterior of master athletes: evidence that athletic older people are not spared from age-related motor unit remodeling.
Muscle motor unit numbers decrease markedly in old age, while remaining motor units are enlarged and can have reduced neuromuscular junction transmission stability. However, it is possible that regular intense physical activity throughout life can attenuate this remodeling. The aim of this study was to compare the number, size, and neuromuscular junction transmission stability of tibialis anterior (TA) motor units in healthy young and older men with those of exceptionally active master runners. The distribution of motor unit potential (MUP) size was determined from intramuscular electromyographic signals recorded in healthy male Young (mean ± SD, 26 ± 5 years), Old (71 ± 4 years) and Master Athletes (69 ± 3 years). Relative differences between groups in numbers of motor units was assessed using two methods, one comparing MUP size and muscle cross-sectional area (CSA) determined with MRI, the other comparing surface recorded MUPs with maximal compound muscle action potentials and commonly known as a "motor unit number estimate (MUNE)". Near fiber (NF) jiggle was measured to assess neuromuscular junction transmission stability. TA CSA did not differ between groups. MUNE values for the Old and Master Athletes were 45% and 40%, respectively, of the Young. Intramuscular MUPs of Old and Master Athletes were 43% and 56% larger than Young. NF jiggle was slightly higher in the Master Athletes, with no difference between Young and Old. These results show substantial and similar motor unit loss and remodeling in Master Athletes and Old individuals compared with Young, which suggests that lifelong training does not attenuate the age-related loss of motor units.


Preventive behaviors adults report using to avoid catching or spreading influenza, United States, 2015-16 influenza season.
Influenza vaccination can prevent influenza and potentially serious influenza-related complications. Although the single best way to prevent influenza is annual vaccination, everyday preventive actions, including good hygiene, health, dietary, and social habits, might help, too. Several preventive measures are recommended, including: avoiding close contact with people who are sick; staying home when sick; covering your mouth and nose when coughing or sneezing; washing your hands often; avoiding touching your eyes, nose, and mouth; and practicing other good health habits like cleaning and disinfecting frequently touched surfaces, getting plenty of sleep, and drinking plenty of fluids. Understanding public acceptance and current usage of these preventive behaviors can be useful for planning both seasonal and pandemic influenza prevention campaigns. This study estimated the percentage of adults in the United States who reported practicing preventive behaviors to avoid catching or spreading influenza, and explored associations of reported behaviors with sociodemographic factors. We analyzed data from 2015 National Internet Flu Survey, a nationally representative probability-based Internet panel survey of the non-institutionalized U.S. population ≥18 years. The self-reported behaviors used to avoid catching or spreading influenza were grouped into four and three non-mutually exclusive subgroups, respectively. Weighted proportions were calculated. Multivariable logistic regression models were used to calculate adjusted prevalence differences and to determine independent associations between sociodemographic characteristics and preventive behavior subgroups. Common preventive behaviors reported were: 83.2% wash hands often, 80.0% cover coughs and sneezes, 78.2% stay home if sick with a respiratory illness, 64.4% avoid people sick with a respiratory illness, 51.7% use hand sanitizers, 50.2% get treatment as soon as possible, and 49.8% report getting the influenza vaccination. Race/ethnicity, gender, age, education, income, region, receipt of influenza vaccination, and household size were associated with use of preventive behaviors after controlling for other factors. Many adults in the United States reported using preventive behaviors to avoid catching or spreading influenza. Though vaccination is the most important tool available to prevent influenza, the addition of preventive behaviors might play an effective role in reducing or slowing transmission of influenza and complement prevention efforts.


Latent tuberculous infection in the United States and Canada: who completes treatment and why?
To assess latent tuberculous infection (LTBI) treatment completion rates in a large prospective US/Canada multisite cohort and identify associated risk factors. This prospective cohort study assessed factors associated with LTBI treatment completion through interviews with persons who initiated treatment at 12 sites. Interviews were conducted at treatment initiation and completion/cessation. Participants received usual care according to each clinic's procedure. Multivariable models were constructed based on stepwise assessment of potential predictors and interactions. Of 1515 participants initiating LTBI treatment, 1323 had information available on treatment completion; 617 (46.6%) completed treatment. Baseline predictors of completion included male sex, foreign birth, not thinking it would be a problem to take anti-tuberculosis medication, and having health insurance. Participants in stable housing who received monthly appointment reminders were more likely to complete treatment than those without stable housing or without monthly reminders. End-of-treatment predictors of non-completion included severe symptoms and the inconvenience of clinic/pharmacy schedules, barriers to care and changes of residence. Common reasons for treatment non-completion were patient concerns about tolerability/toxicity, appointment conflicts, low prioritization of TB, and forgetfulness. Less than half of treatment initiators completed treatment in our multisite study. Addressing tangible issues such as not having health insurance, toxicity concerns, and clinic accessibility could help to improve treatment completion rates.


A transcript map of the chromosome 19q-arm glioma tumor suppressor region.
Allelic loss of the chromosome 19q arm is a frequent event in human diffuse gliomas, suggesting that it contains a tumor suppressor gene. Recent deletion mapping studies have broadly implicated a 1.6-Mb interval between D19S241E and D19S596, with a limited subset of tumors, suggesting that the region may be as narrow as 150 kb. Focusing on this smaller interval, we have used cDNA selection, exon amplification, and genomic sequencing to identify three novel transcripts (EHD2, GLTSCR1, and GLTSCR2) and to map two known genes (SEPW1 and CRX). A partial transcript map of 19 transcripts and two EST markers has been constructed for the 1.6-Mb interval D19S241E-D19S596. Ten of these transcripts, including the 5 mapped to the 150-kb deletion interval, have been examined for alterations in a panel of gliomas with allelic loss of 19q. Tumor-specific alterations have not been identified in the transcripts examined thus far. Collectively, these data should facilitate subsequent efforts to identify and characterize the remaining transcripts in the 1.6-Mb interval.


Estrogen and retinoic acid antagonistically regulate several microRNA genes to control aerobic glycolysis in breast cancer cells.
In addition to estrogen receptor modulators, retinoic acid and other retinoids are promising agents to prevent breast cancer. Retinoic acid and estrogen exert antagonistic regulations on the transcription of coding genes and we evaluated here whether these two compounds have similar effects on microRNAs. Using an integrative approach based on several bioinformatics resources together with experimental validations, we indeed found that retinoic acid positively regulates miR-210 and miR-23a/24-2 expressions and is counteracted by estrogen. Conversely, estrogen increased miR-17/92 and miR-424/450b expressions and is inhibited by retinoic acid. In silico functional enrichment further revealed that this combination of transcriptional/post-transcriptional regulations fully impacts on the molecular effects of estrogen and retinoic acid. Besides, we unveiled a novel effect of retinoic acid on aerobic glycolysis. We specifically showed that it increases extracellular lactate production, an effect counteracted by the miR-210 and the miR-23a/24-2, which simultaneously target lactate dehydrogenase A and B mRNAs. Together our results provide a new framework to better understand the estrogen/retinoic acid antagonism in breast cancer cells.


Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival.
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273⁻317) and end-tail (aa 318⁻333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death.