Adaptive Multi-Channel Event Segmentation and Feature Extraction for Monitoring Health Outcomes.
To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution. We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring a priori information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to an H1N1 influenza pathogen. Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data, the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time. The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring. Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.


Some medicinal plants with antiasthmatic potential: a current status.
Asthma is a common disease that is rising in prevalence worldwide with the highest prevalence in industrialized countries. Asthma affects about 300 million people worldwide and it has been estimated that a further 100 million will be affected by 2025. Since the ancient times, plants have been exemplary sources of medicine. Current asthma therapy lack satisfactory success due to adverse effect, hence patients are seeking complementary and alternative medicine to treat their asthma. Ayurveda and other Indian literature mention the use of plants in various human ailments. India has about 45,000 plant species and among them several thousand are claimed to possess medicinal properties. Researches conducted in the last few decades on the plants mentioned in ancient literature or used traditionally for asthma have shown antiasthmatic, antihistaminic and antiallergic activity. This review reveals that some plants and their extract have antiasthmatic, antihistaminic, anticholinergic and antiallergic activity.


Predictors of quality of life and psychological health in infertile couples: the moderating role of duration of infertility.
To investigate the influence of individual characteristics (age, gender, educational level, coping strategies), perceived couple's Dyadic Adjustment, type of diagnosis and duration of infertility on self-reported quality of life (QoL) and psychological health in infertile couples, examining the potential moderating role of duration of infertility. A questionnaire composed by socio-demographics, Coping Orientations to Problem Experienced, Dyadic Adjustment Scale, FertiQoL, State-Trait Anxiety Inventory and Edinburgh Depression Scale was submitted to 206 couples undergoing infertility treatments. Female patients perceived significantly lower levels of QoL and higher levels of Anxiety and Depression. High Educational level and Social Support Coping strategy were associated with higher QoL and psychological health only in female patients. Problem Solving Coping strategy was associated with higher QoL and psychological health only in male patients. Positive Attitude and Avoidance/Distancing Coping strategies and perceived couple's Dyadic Adjustment were associated with higher QoL and psychological health in both male and female patients. Duration of infertility > 3 years was associated with a reduction of protective effects of all coping strategies but did not affect protective effects of Educational level and couple's Dyadic Adjustment. Both positive/active and avoiding/distancing coping strategies are effective to promote QoL and psychological health in infertile couples, but they are all compromised by a long duration of infertility. Conversely, positive effects of educational level and couple's Dyadic Adjustment persist and should be emphasised in the definition of interventions to promote well-being in couples undergoing long-term treatments.


The SUPERFAMILY database in structural genomics.
The SUPERFAMILY hidden Markov model library representing all proteins of known structure predicts the domain architecture of protein sequences and classifies them at the SCOP superfamily level. This analysis has been carried out on all completely sequenced genomes. The ways in which the database can be useful to crystallographers is discussed, in particular with a view to high-throughput structure determination. The application of the SUPERFAMILY database to different target-selection strategies is suggested: novel folds, novel domain combinations and targeted attacks on genomes. Use of the database for more general inquiry in the context of structural studies is also explained. The database provides evolutionary relationships between target proteins and other proteins of known structure through the SCOP database, genome assignments and multiple sequence alignments.


Probiotics and oral health.
Probiotics are living microorganisms (e.g., bacteria) that are either the same as or similar to organisms found naturally in the human body and may be beneficial to health. Current researches have shown that the balance between beneficial and pathogenic bacteria is essential in order to maintain the oral health. Therefore, oral cavity has recently been suggested as a relevant target for probiotic applications. Dental caries can be seen as a microbial imbalance where the oral microbiota shift towards community dominance which produces acidogenic and acid-tolerant gram positive bacteria. Similarly, the accumulation of bacteria within the biofilm, facilitated by poor oral hygiene, predisposes to allogenic shifts in the microbial community, leading to the onset of periodontal inflammation. Probiotic bacteria belonging to the genus of Lactobacillus, Bifidobacterium and Streptococcus have been proven effective for preventing caries by reducing the number of cariogenic bacteria in saliva after a short period of consuming the probiotic. In contrast, the effect of probiotics on improving gingivitis and periodontitis has been less investigated. The currently available studies on the effect of probiotics on periodontal pathogens and clinical periodontal parameters showed differing results depending on the strains used and the endpoints analyzed. Many of the clinical studies are pilot in nature and with low quality, therefore, properly conducted clinical trials, using probiotic strains with in vitro proven periodontal probiotic effects, are needed. The putative beneficial effects of probiotics on oral malodour have also been evaluated, but further evidence is needed to fully explore the potential of probiotics for preventing malodour.


A prospective investigation of oral contraceptive use and breast cancer mortality: findings from the Swedish women's lifestyle and health cohort.
The association between oral contraceptive (OC) use and long-term mortality remains uncertain and previous studies have reported conflicting findings. We aim to assess the long-term impact of OC use on all-cause and cancer-specific mortality. Out of 49,259 participants, we analysed data on 2120 (4.3%) women diagnosed with first primary breast cancer between 1993 and 2012, in the Swedish Women's Lifestyle and Health Study. Kaplan-Meier plots were used to graph the hazard of mortality in association with oral contraceptives use, stage of disease and hormone receptors status at diagnosis. Cox proportional hazard model were used to estimate hazard ratios (HR) between OC use and all-cause mortality. The same association was studied for breast cancer-specific mortality by modelling the log cumulative mortality risk, adjusting for clinical stage at diagnosis, hormone receptor status, body mass index and smoking. Among 2120 women with breast cancer, 1268 (84%) reported ever use of OC and 254 died within 10 years of diagnosis. The risk of death for OC ever-users relative to never-users was: HR = 1.13 (95% CI: 0.66-1.94) for all-cause mortality and HR = 1.29 (95% CI: 0.53-3.18) for breast cancer-specific mortality. A high percentage of women (42.9%) were diagnosed at early stage disease (stage I). Among women with primary breast cancer, OC ever-users compared to never- users did not have a higher all-cause or breast cancer specific-mortality, after the adjustment of risk factors.


Role of stearoyl-CoA desaturase-1 in skin integrity and whole body energy balance.
The skin is the single largest organ in humans, serving as a major barrier to infection, water loss, and abrasion. The functional diversity of skin requires the synthesis of large amounts of lipids, such as triglycerides, wax esters, squalene, ceramides, free cholesterol, free fatty acids, and cholesterol and retinyl esters. Some of these lipids are used as cell membrane components, signaling molecules, and a source of energy. An important class of lipid metabolism enzymes expressed in skin is the Δ(9)-desaturases, which catalyze the synthesis in Δ(9)-monounsaturated lipids, primarily oleoyl-CoA (18:1n-9) and palmitoyl-CoA (16:1n-7), the major monounsaturated fatty acids in cutaneous lipids. Mice with a deletion of the Δ(9)-desaturase-1 isoform (SCD1) either globally (Scd1(-/-)) or specifically in the skin (skin-specific Scd1-knockout; SKO) present with marked changes in cutaneous lipids and skin integrity. Interestingly, these mice also exhibit increased whole body energy expenditure, protection against diet-induced adiposity, hepatic steatosis, and glucose intolerance. The increased energy expenditure in skin-specific Scd1-knockout (SKO) mice is a surprising phenotype, as it links cutaneous lipid homeostasis with whole body energy balance. This minireview summarizes the role of skin SCD1 in regulating skin integrity and whole body energy homeostasis and offers a discussion of potential pathways that may connect these seemingly disparate phenotypes.


A comprehensive strategy to overhaul FDA authority for misleading food labels.
The modern food environment is considered a primary driver of obesity and other nutrition-related chronic diseases. A significant contribution to this environment is the proliferation of claims on food packaging that provides a misleading picture of a product's healthfulness. The Food and Drug Administration (FDA) is the agency responsible for food labels but it lacks the regulatory authority and adequate resources to address the majority of questionable labeling practices. The FDA's current system of enforcement is thus essentially based on voluntary compliance and consumer- and manufacturer-initiated litigation has not successfully filled the regulatory gap. This manuscript reviews the current state of food labeling claims and the FDA's inadequate authority over misbranded food products. It analyzes competing views on regulatory compliance strategies and argues that a regulatory overhaul consistent with the best science and the First Amendment is necessary. With increased resources and authority, the FDA can meet current public health challenges and adequately ensure that labels are clear and consumers are properly informed and protected.


Addressing dyslipidemic risk beyond LDL-cholesterol.
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.


Calmodulin activation limits the rate of KCNQ2 K+ channel exit from the endoplasmic reticulum.
The potential regulation of protein trafficking by calmodulin (CaM) is a novel concept that remains to be substantiated. We proposed that KCNQ2 K+ channel trafficking is regulated by CaM binding to the C-terminal A and B helices. Here we show that the L339R mutation in helix A, which is linked to human benign neonatal convulsions, perturbs CaM binding to KCNQ2 channels and prevents their correct trafficking to the plasma membrane. We used glutathione S-transferase fused to helices A and B to examine the impact of this and other mutations in helix A (I340A, I340E, A343D, and R353G) on the interaction with CaM. The process appears to require at least two steps; the first involves the transient association of CaM with KCNQ2, and in the second, the complex adopts an "active" conformation that is more stable and is that which confers the capacity to exit the endoplasmic reticulum. Significantly, the mutations that we have analyzed mainly affect the stability of the active configuration of the complex, whereas Ca2+ alone appears to affect the initial binding step. The spectrum of responses from this collection of mutants revealed a strong correlation between adopting the active conformation and channel trafficking in mammalian cells. These data are entirely consistent with the concept that CaM bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane and fully explaining the requirement of CaM binding for KCNQ2 function.


Antibody 9D5 recognizes oligomeric pyroglutamate amyloid-β in a fraction of amyloid-β deposits in Alzheimer's disease without cross-reactivity with other protein aggregates.
Recent evidence suggests that soluble oligomeric amyloid-β (Aβ) assemblies are critically involved in the pathogenesis of Alzheimer's disease (AD). We have generated a conformation-dependent monoclonal antibody (9D5) that selectively recognizes low-molecular weight AβpE3 oligomers, and demonstrated its diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a spectrum of neurodegeneration-related protein deposits for cross-reactivity, and by comparing the staining pattern of 9D5 with a generic Aβ antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent Aβ antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5 antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43 inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the specificity of 9D5 for Aβ deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total Aβ plaque load in the entorhinal cortex, the CA1 region, and the temporal neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of an epitope found only in oligomeric assemblies of AβpE3 of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of Aβ deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits.


On the shoulders of Hubrecht: From embryos to stem cells.
One hundred years of the Hubrecht Institute were celebrated in May 2016 with the organization of a one-day symposium "From embryos to stem cells" on the Uithof Campus, Utrecht, the Netherlands. Nine distinguished speakers were invited. They all represent a research branch originating from the passion of Institute founder, Ambrosius Hubrecht, for embryology:, regulation of gene expression, genome structure and function, embryonic and adult stem cells, nuclear reprogramming, and understanding cancer and other diseases using model organisms. The centennial symposium not only retraced the history of the Institute and of modern developmental biology, but was also a tribute to basic research. From there, avenues to therapeutics are being developed and implemented. The symposium was organized, introduced and chaired by Jeroen den Hertog and Alexander van Oudenaarden, the present Directors of the Institute, who also stand on Hubrecht's shoulders.


Identification of a bilirubin receptor that may mediate a component of cholestatic itch.
Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.


Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women's Health Initiative Observational Study.
Elective bilateral salpingo-oophorectomy (BSO) is routinely performed with hysterectomy for benign conditions despite conflicting data on long-term outcomes. This is a prospective cohort of 25 448 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative Observational Study who had a history of hysterectomy and BSO (n = 14 254 [56.0%]) or hysterectomy with ovarian conservation (n = 11 194 [44.0%]) and no family history of ovarian cancer. Multivariable Cox proportional hazards regression models were used to examine the effect of BSO on incident cardiovascular disease, hip fracture, cancer, and death. Current or past use of estrogen and/or progestin was common irrespective of BSO status (78.6% of cohort). In multivariable analyses, BSO was not associated with an increased risk of fatal and nonfatal coronary heart disease (hazard ratio, 1.00 [95% confidence interval, 0.85-1.18]), coronary artery bypass graft/percutaneous transluminal coronary angioplasty (0.95 [0.82-1.10]), stroke (1.04 [0.87-1.24]), total cardiovascular disease (0.99 [0.91-1.09]), hip fracture (0.83 [0.63-1.10]), or death (0.98 [0.87-1.10]). Bilateral salpingo-oophorectomy decreased incident ovarian cancer (0.02% in the BSO group; 0.33% in the ovarian conservation group; number needed to treat, 323) during a mean (SD) follow-up of 7.6 (1.6) years, but there were no significant associations for breast, colorectal, or lung cancer. In this large prospective cohort study, BSO decreased the risk of ovarian cancer compared with hysterectomy and ovarian conservation, but incident ovarian cancer was rare in both groups. Our findings suggest that BSO may not have an adverse effect on cardiovascular health, hip fracture, cancer, or total mortality compared with hysterectomy and ovarian conservation.


Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage. National Institute of Child Health and Human Development Neonatal Research Network.
To identify prenatal and perinatal risk and protective factors for grade III and IV intracranial hemorrhage (ICH) in 4795 singleton infants (weight, < or = 1500 g). Prenatal and perinatal risk and protective factors for ICH were examined initially by univariate analysis and adjusted for year of birth, followed by multivariate logistic regression analysis that adjusted simultaneously for the effects of year of birth and prenatal and perinatal characteristics. Seven tertiary care neonatal-perinatal centers. By univariate analysis, African-American race, prenatal care, older maternal age, hypertension or preeclampsia, antenatal steroid administration, cesarean section delivery, increasing birth weight, increasing gestational age, and female gender of the infant were protective prenatal or perinatal factors. Antepartum hemorrhage, the presence of labor, and breech presentation were perinatal factors that were associated with an increased risk of ICH. By using staged logistic regression, a model of combined prenatal and perinatal characteristics that influenced grade III and IV ICH was developed. Significant protective factors against ICH included a complete course of antenatal steroid therapy, African-American maternal race, female gender of the infant, hypertension or preeclampsia with no antepartum hemorrhage, increasing gestational age, and increasing birth weight. Antenatal steroid administration is a therapeutic intervention that is associated with a decreased risk for neonatal grade III and IV ICH.


Abstinence-Related Motivational Engagement Scale: Validity and Reliability in Turkish People.
This research aimed to conduct a validity and reliability study of the Turkish version of the abstinence-related motivational engagement (ARME) scale. This study included 122 people and was administered in a smoking cessation clinic. The sociodemographic-smoking status characteristics questionnaire and the ARME scale were used for data collection. A psycholinguistic language adaptation was performed. In the validity, analyses, content, construct, and criterion-related validities were used. For content validity, expert evaluation was performed. For construct validity, principal component analyses (exploratory factor analyses) were performed. Orthogonal (Varimax) rotation was used to explore multiple factors. The Kaiser-Meyer-Olkin test was used to assess the adequacy of the sample size. For criterion-related validity, we compared the ARME scale points of people who were abstinent and had relapse for smoking at the end of the sixth month. In the reliability analysis, standard deviation (SD) and item analysis, internal consistency, and test-retest methods were used. The four factors explain 58% of the total variance. Items have factor loading between 0.409 and 0.805. When the factor structure of the scale was assessed, the items in each factor group have a factor load of at least "0.40." Due to one-dimensional use of the original scale, it has been decided to maintain this scale in its original form. The ARME scale points of people who quit smoking were statistically higher than the points of people who had relapse at the end of the sixth month. Cronbach's alpha coefficients were between 0.846 and 0.763. Significant and positive correlation was found between the test-retest scale scores. The Turkish adaptation of the ARME scale, which was developed for adults who quitted smoking, is an adequately valid and reliable measurement instrument. It is considered that the scale might be used reliably in different cultures as well.


Alterations in regional myocardial metabolism, perfusion, and wall motion in Duchenne muscular dystrophy studied by radionuclide imaging.
Studies at necropsy have shown that the cardiomyopathy of Duchenne muscular dystrophy selects the posterobasal and contiguous lateral left ventricular (LV) walls as initial and primary sites of myocardial dystrophy in the absence of small-vessel coronary artery disease in these areas. The present investigation was designed chiefly to determine whether a myocardial metabolic abnormality could be identified in these same areas during a patient's life. Positron emission computed tomography was used to study regional LV metabolism with 18F 2-fluorodeoxyglucose, and metabolism and/or perfusion was studied with 13NH3. In addition, all subjects had the following performed: thallium-201 scans, technetium-99m multiple-gated equilibrium blood pool imaging, electrocardiograms, vectorcardiograms, and M mode and two-dimensional echocardiograms. 18F 2-fluorodeoxyglucose activity was selectively increased in the posterobasal and posterolateral walls of the left ventricle in 11 of 12 patients with technically adequate images, indicating accelerated regional exogenous glucose utilization. 13NH3 activity was selectively decreased in the same areas in 13 of 15 patients, indicating either a regional metabolic alteration in uptake and trapping, a reduction in regional blood flow, or both. These data identify a myocardial metabolic abnormality concentrated in specific segments of the LV free wall in living patients with Duchenne dystrophy.


Ancient genome-wide admixture extends beyond the current hybrid zone between Macaca fascicularis and M. mulatta.
Macaca fascicularis and Macaca mulatta are two of the most commonly used laboratory macaques, yet their genetic differences at a genome-wide level remain unclear. We analysed the multilocus DNA sequence data of 54 autosomal loci obtained from M. fascicularis samples from three different geographic origins and M. mulatta samples of Burmese origin. M. fascicularis shows high nucleotide diversity, four to five times higher than humans, and a strong geographic population structure between Indonesian-Malaysian and Philippine macaques. The pattern of divergence and polymorphism between M. fascicularis and M. mulatta shows a footprint of genetic exchange not only within their current hybrid zone but also across a wider range for more than 1 million years. However, genetic admixture may not be a random event in the genome. Whereas randomly selected genic and intergenic regions have the same evolutionary dynamics between the species, some cytochrome oxidase P450 (CYP) genes (major chemical metabolizing genes and potential target genes for local adaptation) have a significantly larger species divergence than other genes. By surveying CYP3A5 gene sequences of more than a hundred macaques, we identified three nonsynonymous single nucleotide polymorphisms that were highly differentiated between the macaques. The mosaic pattern of species divergence in the genomes may be a consequence of genetic differentiation under ecological adaptation and may be a salient feature in the genomes of nascent species under parapatry.


SNAPSHOT USA 2019: a coordinated national camera trap survey of the United States.
With the accelerating pace of global change, it is imperative that we obtain rapid inventories of the status and distribution of wildlife for ecological inferences and conservation planning. To address this challenge, we launched the SNAPSHOT USA project, a collaborative survey of terrestrial wildlife populations using camera traps across the United States. For our first annual survey, we compiled data across all 50 states during a 14-week period (17 August-24 November of 2019). We sampled wildlife at 1,509 camera trap sites from 110 camera trap arrays covering 12 different ecoregions across four development zones. This effort resulted in 166,036 unique detections of 83 species of mammals and 17 species of birds. All images were processed through the Smithsonian's eMammal camera trap data repository and included an expert review phase to ensure taxonomic accuracy of data, resulting in each picture being reviewed at least twice. The results represent a timely and standardized camera trap survey of the United States. All of the 2019 survey data are made available herein. We are currently repeating surveys in fall 2020, opening up the opportunity to other institutions and cooperators to expand coverage of all the urban-wild gradients and ecophysiographic regions of the country. Future data will be available as the database is updated at eMammal.si.edu/snapshot-usa, as will future data paper submissions. These data will be useful for local and macroecological research including the examination of community assembly, effects of environmental and anthropogenic landscape variables, effects of fragmentation and extinction debt dynamics, as well as species-specific population dynamics and conservation action plans. There are no copyright restrictions; please cite this paper when using the data for publication.


Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future.
To review the available evidence evaluating the toxicological profiles of electronic cigarettes (e-cigarettes) in order to understand the potential impact of e-cigarettes on individual users and the public health. Systematic literature searches were conducted between October 2012 and October 2013 using five electronic databases. Search terms such as 'e-cigarettes' and 'electronic delivery devices' were used to identify the toxicology information for e-cigarettes. As of October 2013, the scientific literature contains very limited information regarding the toxicity of e-cigarettes commercially available in the USA. While some preliminary toxicology data suggests that e-cigarette users are exposed to lower levels of toxicants relative to cigarette smokers, the data available is extremely limited at this time. At present, there is insufficient toxicological data available to perform thorough risk assessment analyses for e-cigarettes; few toxicology studies evaluating e-cigarettes have been conducted to date, and standard toxicological testing paradigms have not been developed for comparing disparate types of tobacco products such as e-cigarettes and traditional cigarettes. Overall, the limited toxicology data on e-cigarettes in the public domain is insufficient to allow a thorough toxicological evaluation of this new type of tobacco product. In the future, the acquisition of scientific datasets that are derived from scientifically robust standard testing paradigms, include comprehensive chemical characterisation of the aerosol, provide information on users' toxicant exposure levels, and from studies replicated by independent researchers will improve the scientific community's ability to perform robust toxicological evaluations of e-cigarettes.


Prevalence of hyperdense paraspinal vein sign in patients with spontaneous intracranial hypotension without dural CSF leak on standard CT myelography.
A recently identified and treatable cause of spontaneous intracranial hypotension (SIH) is cerebrospinal fluid (CSF)-venous fistula, and a recently described computed tomography myelogram (CTM) finding highly compatible with but not diagnostic of this entity is the hyperdense paraspinal vein sign. We aimed to retrospectively measure the prevalence of the hyperdense paraspinal vein sign on CTMs in SIH patients without dural CSF leak, in comparison with control groups. Three CTM groups were identified: 1) SIH study group, which included dural CSF leak-negative standard CTMs performed for SIH, with early and delayed imaging; 2) Early control CTMs, which were performed for indications other than SIH, with imaging shortly after intrathecal contrast administration; 3) Delayed control CTMs, which included delayed imaging. CTMs were retrospectively reviewed for the hyperdense paraspinal vein sign by experienced neuroradiologists, blinded to the group assignment. All CTMs deemed by a single reader to be positive for the hyperdense paraspinal vein sign were independently reviewed by two additional neuroradiologists; findings were considered positive only if consensus was present among all three readers. For positive cases, noncontrast CTs and prior CTMs, if available, were reviewed for the presence of the sign. Seven of 101 (7%) SIH patients had contrast in a spinal/paraspinal vein consistent with the hyperdense paraspinal vein sign; no patient in either control group (total n=54) demonstrated the hyperdense paraspinal vein sign (P = 0.0463). The finding occurred only at thoracic levels. Each patient had a single level of involvement. Six (86%) occurred on the right. Four occurred in female patients (57%). The sign was seen on early images in 3 of 7 cases (43%) and on both early and delayed images in 4 of 7 cases (57%). In 2 of 7 patients (29%), a noncontrast CT covering the relevant location was available and negative for the sign. A prior CTM was available in 2 of 7 patients (29%), and in both cases the hyperdense paraspinal vein sign was also evident. The prevalence of the hyperdense paraspinal vein sign in SIH patients with dural CSF leak-negative standard CTM was 7%. As the sign was not seen in control groups, this sign is highly compatible with the presence of CSF-venous fistula. Since the CTMs were not specifically dedicated to identifying hyperdense paraspinal veins (i.e., they were not dynamic and were not preceded by digital subtraction myelography), the true prevalence of the sign may be higher. Radiologists should scrutinize conventional CTMs for this sign, especially in patients in whom a traditional dural CSF leak is not identified.


Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.
The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8(+)-T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <10(7) copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8(+) T cells are consistently detected. Furthermore, CD8(+) T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8(+) T cells are associated with viral control, while CD8(+) T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>10(7) copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.


Detecting slant-in-depth of real trapezoidal and rectangular surfaces: moving-monocular viewing equivalent to stationary-binocular viewing.
Cues from binocularity and observer motion are often believed to be more important in perceiving depth than pictorial cues such as relative visual size and linear perspective. Both binocularity and motion are effective in simulated displays. However, for real stimuli evincing nonveridical pictorial cues, binocularity has been more effective than motion; sometimes motion has had an insignificant effect. This may reflect inadequate extent of motion, an assertion investigated in the present study. Two groups of observers determined whether rectangular and trapezoidal surfaces were slanted-in-depth under stationary-monocular (SM), stationary-binocular (SB), and moving-monocular conditions with 15-cm (15MM) and 25-cm (25MM) lateral head-motion extents according to group. The trapezoidal surfaces appeared as rectangular during SM viewing to mislead regarding slant. The effect of pictorial cues was substantially diminished during SB viewing whereas 15MM viewing was weak, 25MM was as effective as SB viewing. Comparison of the overall numbers of correct responses for the two groups indicated no contextual biasing.


The right compound in the right assay at the right time: an integrated discovery DMPK strategy.
The high rate of attrition during drug development and its associated high research and development (R&D) cost have put pressure on pharmaceutical companies to ensure that candidate drugs going to clinical testing have the appropriate quality such that the biological hypothesis could be evaluated. To help achieve this ambition, drug metabolism and pharmacokinetic (DMPK) science and increasing investment have been deployed earlier in the R&D process. To gain maximum return on investment, it is essential that DMPK concepts are both appropriately integrated into the compound design process and that compound selection is focused on accurate prediction of likely outcomes in patients. This article describes key principles that underpin the contribution of DMPK science for small-molecule research based on 15 years of discovery support in a major pharmaceutical company. It does not aim to describe the breadth and depth of DMPK science, but more the practical application for decision making in real-world situations.


Seniors Online: Attitudes Toward the Internet and Coping With Everyday Life.
Many older people do not use the Internet. We investigated the attitudes of older people who do (onliners) or do not (offliners) use the Internet, to assess their views of the Internet and whether they see the Internet as a resource for coping with everyday life situations. Participants aged ≥65 years ( N = 1,037), living in Switzerland, were interviewed in a telephone survey. Descriptive and multivariate analyses were conducted. The data show (a) many of the respondents viewed the Internet as useful, in general, and for coping with everyday life situations; (b) onliners saw more positive aspects of the Internet than did offliners; and


Oral health status and treatment need among preschool children attending Anganwadi centres - a comparative study.
To assess and compare the oral health status and treatment need among the preschool children attending Anganwadi Centres associated with a special learning programme (SLP) and the control group. The study was designed to include 3- to 5-year-old preschool children attending Anganwadis. An Anganwadi (meaning courtyard) Centre is the focal point for the delivery of services to children and mothers. The Anganwadis associated with the special learning programme and the control group Anganwadis consisted of 255 and 275 children, respectively. The special learning programme comprised general health education and growth monitoring services that were continuously reinforced to expectant and nursing mothers of children below 6 years of age by a team of members of a nearby medical college. Information on demographic and socioeconomic parameters (maternal literacy and occupation, paternal literacy and occupation, family income), oral hygiene practices, dietary habits and dental visits was obtained, and oral examination was done in the two groups. The mean plaque index and mean gingival index score among the SLP Anganwadi group were 0.18 ± 0.22 and 0.15 ± 0.28, respectively, and among the control group these indices were 1.06 ± 0.50 and 0.50 ± 0.00, respectively. The mean dmft score among the SLP group was 3.40 ± 4.84 vs 4.32 ± 4.69 in the control group (p < 0.05). The distribution of children without any treatment need was 50.2% in the SLP group and 33.5% in the control group. The SLP Anganwadi group had a better oral health status and less treatment need than the control Anganwadi group. This demonstrates that there is a beneficial effect of general health education on oral health.


Prospecting Biotechnologically-Relevant Monooxygenases from Cold Sediment Metagenomes: An In Silico Approach.
The goal of this work was to identify sequences encoding monooxygenase biocatalysts with novel features by in silico mining an assembled metagenomic dataset of polar and subpolar marine sediments. The targeted enzyme sequences were Baeyer-Villiger and bacterial cytochrome P450 monooxygenases (CYP153). These enzymes have wide-ranging applications, from the synthesis of steroids, antibiotics, mycotoxins and pheromones to the synthesis of monomers for polymerization and anticancer precursors, due to their extraordinary enantio-, regio-, and chemo- selectivity that are valuable features for organic synthesis. Phylogenetic analyses were used to select the most divergent sequences affiliated to these enzyme families among the 264 putative monooxygenases recovered from the ~14 million protein-coding sequences in the assembled metagenome dataset. Three-dimensional structure modeling and docking analysis suggested features useful in biotechnological applications in five metagenomic sequences, such as wide substrate range, novel substrate specificity or regioselectivity. Further analysis revealed structural features associated with psychrophilic enzymes, such as broader substrate accessibility, larger catalytic pockets or low domain interactions, suggesting that they could be applied in biooxidations at room or low temperatures, saving costs inherent to energy consumption. This work allowed the identification of putative enzyme candidates with promising features from metagenomes, providing a suitable starting point for further developments.


Please understand when I cry out in pain: women's accounts of maternity services during labour and delivery in Ghana.
This study was undertaken to investigate women's accounts of interactions with health care providers during labour and delivery and to assess the implications for acceptability and utilisation of maternity services in Ghana. Twenty-one individual in-depth interviews and two focus group discussions were conducted with women of reproductive age who had delivered in the past five years in the Greater Accra Region. The study investigated women's perceptions and experiences of care in terms of factors that influenced place of delivery, satisfaction with services, expectations of care and whether they would recommend services. One component of care which appeared to be of great importance to women was staff attitudes. This factor had considerable influence on acceptability and utilisation of services. Otherwise, a successful labour outcome and non-medical factors such as cost, perceived quality of care and proximity of services were important. Our findings indicate that women expect humane, professional and courteous treatment from health professionals and a reasonable standard of physical environment. Women will consciously change their place of delivery and recommendations to others if they experience degrading and unacceptable behaviour. The findings suggest that inter-personal aspects of care are key to women's expectations, which in turn govern satisfaction. Service improvements which address this aspect of care are likely to have an impact on health seeking behaviour and utilisation. Our findings suggest that user-views are important and warrant further investigation. The views of providers should also be investigated to identify channels by which service improvements, taking into account women's views, could be operationalised. We also recommend that interventions to improve delivery care should not only be directed to the health professional, but also to general health system improvements.


Ebola Holding Units at government hospitals in Sierra Leone: evidence for a flexible and effective model for safe isolation, early treatment initiation, hospital safety and health system functioning.
The 2014-2015 West African outbreak of Ebola Virus Disease (EVD) claimed the lives of more than 11,000 people and infected over 27,000 across seven countries. Traditional approaches to containing EVD proved inadequate and new approaches for controlling the outbreak were required. The Ministry of Health & Sanitation and King's Sierra Leone Partnership developed a model for Ebola Holding Units (EHUs) at Government Hospitals in the capital city Freetown. The EHUs isolated screened or referred suspect patients, provided initial clinical care, undertook laboratory testing to confirm EVD status, referred onward positive cases to an Ebola Treatment Centre or negative cases to the general wards, and safely stored corpses pending collection by burial teams. Between 29th May 2014 and 19th January 2015, our five units had isolated approximately 37% (1159) of the 3097 confirmed cases within Western Urban and Rural district. Nosocomial transmission of EVD within the units appears lower than previously documented at other facilities and staff infection rates were also low. We found that EHUs are a flexible and effective model of rapid diagnosis, safe isolation and early initial treatment. We also demonstrated that it is possible for international partners and government facilities to collaborate closely during a humanitarian crisis.


Physical and transcriptional map of the critical region for keratolytic winter erythema (KWE) on chromosome 8p22-p23 between D8S550 and D8S1759.
Keratolytic winter erythema is an autosomal dominant skin disorder characterised by erythema, hyperkeratosis, and peeling of the skin of the palms and soles, especially during winter. The keratolytic winter erythema locus has been mapped to human chromosome 8p22-p23. This chromosomal region has also been associated with frequent loss of heterozygosity in different types of cancer. To identify positional candidate genes for keratolytic winter erythema, a BAC contig located between the markers at D8S550 and D8S1695 was constructed and sequenced. It could be extended to D8S1759 by a partially sequenced BAC clone identified by database searches. In the 634 404 bp contig 13 new polymorphic microsatellite loci and 46 single nucleotide and insertion/deletion polymorphisms were identified. Twelve transcripts were identified between D8S550 and D8S1759 by exon trapping, cDNA selection, and sequence analyses. They were localised on the genomic sequence, their exon/intron structure was determined, and their expression analysed by RT-PCR. Only one of the transcripts corresponds to a known gene, encoding B-lymphocyte specific tyrosine kinase, BLK. A putative novel myotubularin-related protein gene (MTMR8), a potential human homologue of the mouse acyl-malonyl condensing enzyme gene (Amac1), and two transcripts showing similarities to the mouse L-threonine 3-dehydrogenase gene and the human SEC oncogene, respectively, were identified. The remaining seven transcripts did not show similarities to known genes. There were no potentially pathogenic mutations identified in any of these transcripts in keratolytic winter erythema patients.


Decreased expression of gene cluster at chromosome 1q21 defines molecular subgroups of chemoradiotherapy response in esophageal cancers.
Resistance to preoperative chemoradiotherapy (CTXRT) in 75% of patients with esophageal adenocarcinoma (EAC) underscores the need for identification of biomarkers of CTXRT response. We previously noted an association between decreased expression of epidermal differentiation complex (EDC) genes S100A2 and SPRR3 at chromosome 1q21 and CTXRT resistance. In the current study, we did an in-depth investigation of the expression of 1q21-1q25 region genes to uncover the role of the EDC and its flanking genes in CTXRT response. We compared 19 pretreatment EAC specimens with normal squamous mucosa for the expression of 517 genes at chromosome 1q21-1q25 and selected target genes based on their differential expression. Using the pathologic complete-response (pathCR) status of the resected specimens as a representation of CTXRT sensitivity, we assessed the association between the expression of target genes and CTXRT response and clinical outcomes. On the basis of the expression levels of IVL, CRNN, NICE-1, S100A2, and SPPR3, genes within and in close proximity to the EDC, cancers were segregated into high (subgroup I) or low (subgroup II) expressers. Four of the five pathCRs were high expressers. Thus, low expressers, with one exception, were all nonresponders. Patients in subgroup I also had longer survival than those in subgroup II, although this result was not statistically significant owing to the small study number. The expression levels of genes mapping within and close to the EDC define CTXRT response subgroups in EACs.


Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus.
beta-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophila. Previous studies suggest that increased cytoplasmic levels of beta-catenin correlate with signaling, raising questions about the need for in- teraction with cadherins in this process. We have tested the role of the beta-catenin-cadherin interaction in axis formation. Using beta-catenin deletion mutants, we demonstrate that significant binding to cadherins can be eliminated without affecting the signaling activity. Also, depletion of the soluble, cytosolic pool of beta-catenin by binding to overexpressed C-cadherin completely inhibited beta-catenin-inducing activity. We conclude that binding to cadherins is not required for beta-catenin signaling, and therefore the signaling function of beta-catenin is independent of its role in cell adhesion. Moreover, because beta-catenin signaling is antagonized by binding to cadherins, we suggest that cadherins can act as regulators of the intracellular beta-catenin signaling pathway.


The diurnal secretory characteristics of individual meibomian glands.
To investigate the diurnal secretory characteristics of individual meibomian glands (MGs). Ten subjects (4 females and 6 males) with healthy eyelid appearance and without dry eye symptoms were recruited (mean age = 23.8 +/- 1.8 years). Both right and left lower eyelids were marked in 3 places to locate 5 consecutive MGs in each third (temporal, central, and nasal) of the lower eyelid. A total of 15 MGs per eye were diagnostically expressed for 10 seconds on both right and left lower eyelids every 3 hours for 4 consecutive measurements over a 9-hour period. Thirty-four percent of all tested MGs yielded liquid secretion at all measurements. Sixty-nine percent of the tested nasal MGs yielded liquid secretion at all measurements in contrast to 31% of the central MGs and only 22% of the temporal MGs. The mean numbers of MGs secreting liquid oil were significantly higher in the nasal section relative to the central and temporal sections at all measurements (p < 0.001, all measurements). (1) A single MG is capable of secreting oil on demand over the course of a working day ( approximately 9 hours); (2) nasal MGs were the most likely to secrete upon demand over the course of day compared with the temporal and to a lesser degree the central MGs; and (3) secretory characteristics of individual MGs examined as a function of their location in the lower eyelid does not change diurnally.


[Effects of puerarin on ADRP gene expression in fatty tissue of type 2 diabetes mellitus rats].
To observe the effects of puerarin on ADRP gene mRNA expression in fatty tissue of type 2 diabetes mellitus rats (T2DM). Wiastar rats of T2DM model were made by feeding with high glucose and fat diet and injecting with small dose of streptozocin (25 mg x kg(-1)). 40 model rats were randomly divided into model control group and three puerarin groups (40, 80, 160 mg x kg(-1)), another 10 rats were selected as normal control group. FBG and FINS were measured to calculate IR after rats were injected consecutively for 6 weeks. The level of ADRP gene mRNA in fatty tissue was determined by RT-PCR after rats were injected eight weeks. Compared with model control group, high and middle dosage of puerarin can decreased ADRP gene mRNA expression in fatty tissue obviously, FBG, IR level in each puerarin group and FINS in high and middle dosage puerarin groups decreased obviously. Puerarin can decrease the blood glucose level of T2DM by downregulating ADRP mRNA expression and depressing the insulin resistance.


Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement.
Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.


Angiotensin-converting enzyme gene polymorphism and stroke in type 2 diabetic patients in Taiwan.
The effect of traditional risk factors on the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and stroke was rarely studied previously. We investigated such effect in Taiwanese type 2 diabetic patients. A total of 872 (422 men and 450 women) patients aged 63.5 (SD: 11.6) years were recruited. Among them, 92 cases (48 men and 44 women) had stroke. Polymerase chain reaction was used to classify the genotypes as II, ID and DD. Analyses were performed in separate sexes. The adjusted odds ratios for stroke for ID vs. II and DD vs. II were 0.837 (0.413-1.697) and 1.778 (0.596-5.300), respectively, for men; but were 1.700 (0.824-3.505) and 3.706 (1.375-9.985), respectively, for women. In models assuming recessive (DD vs. II + ID), dominant (DD + ID vs. II) and additive (II = 0, ID = 1 and DD = 2) transmission, none of the odds ratios was significant for men; but were all significant for women: 2.784 (1.137-6.818), 1.996 (1.006-3.962) and 1.877 (1.155-3.050), respectively. In models using patients without risk factors (hypertension, obesity, smoking or dyslipidaemia ) as a referent group and comparing them to patients with the risk factor and with ID/II, and with DD genotypes, all models (except for smoking) favoured an increasing trend of risk with patients having the risk factor and DD genotype at the highest risk in women. Similar trends for hypertension and dyslipidaemia were also observed in men. Traditional risk factors play an important role in the association between the ACE genotypes and stroke. Patients with DD genotype and having traditional risk factors are at the highest risk.


Dense packings of the Platonic and Archimedean solids.
Dense particle packings have served as useful models of the structures of liquid, glassy and crystalline states of matter, granular media, heterogeneous materials and biological systems. Probing the symmetries and other mathematical properties of the densest packings is a problem of interest in discrete geometry and number theory. Previous work has focused mainly on spherical particles-very little is known about dense polyhedral packings. Here we formulate the generation of dense packings of polyhedra as an optimization problem, using an adaptive fundamental cell subject to periodic boundary conditions (we term this the 'adaptive shrinking cell' scheme). Using a variety of multi-particle initial configurations, we find the densest known packings of the four non-tiling Platonic solids (the tetrahedron, octahedron, dodecahedron and icosahedron) in three-dimensional Euclidean space. The densities are 0.782..., 0.947..., 0.904... and 0.836..., respectively. Unlike the densest tetrahedral packing, which must not be a Bravais lattice packing, the densest packings of the other non-tiling Platonic solids that we obtain are their previously known optimal (Bravais) lattice packings. Combining our simulation results with derived rigorous upper bounds and theoretical arguments leads us to the conjecture that the densest packings of the Platonic and Archimedean solids with central symmetry are given by their corresponding densest lattice packings. This is the analogue of Kepler's sphere conjecture for these solids.


A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology.
Bronchopulmonary dysplasia (BPD) is a leading complication of premature birth and occurs primarily in infants delivered during the saccular stage of lung development. Histopathology shows decreased alveolarization and a pattern of fibroblast proliferation and differentiation to the myofibroblast phenotype. Little is known about the molecular pathways and cellular mechanisms that define BPD pathophysiology and progression. We have developed a novel three-dimensional human model of the fibroblast activation associated with BPD, and using this model we have identified the Notch pathway as a key driver of fibroblast activation and proliferation in response to changes in oxygen. Fetal lung fibroblasts were cultured on sodium alginate beads to generate lung organoids. After exposure to alternating hypoxia and hyperoxia, the organoids developed a phenotypic response characterized by increased α-smooth muscle actin (α-SMA) expression and other genes known to be upregulated in BPD and also demonstrated increased expression of downstream effectors of the Notch pathway. Inhibition of Notch with a γ-secretase inhibitor prevented the development of the pattern of cellular proliferation and α-SMA expression in our model. Analysis of human autopsy tissue from the lungs of infants who expired with BPD demonstrated evidence of Notch activation within fibrotic areas of the alveolar septae, suggesting that Notch may be a key driver of BPD pathophysiology.


A new perspective for advanced positron emission tomography-based molecular imaging in neurodegenerative proteinopathies.
Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications.


Landscape genetics of California mule deer (Odocoileus hemionus): the roles of ecological and historical factors in generating differentiation.
Landscape genetics is an emerging discipline that utilizes environmental and historical data to understand geographic patterns of genetic diversity. Niche modelling has added a new dimension to such efforts by allowing species-environmental associations to be projected into the past so that hypotheses about historical vicariance can be generated and tested independently with genetic data. However, previous approaches have primarily utilized DNA sequence data to test inferences about historical isolation and may have missed very recent episodes of environmentally mediated divergence. We type 15 microsatellite loci in California mule deer and identify five genetic groupings through a Structure analysis that are also well predicted by environmental data. We project the niches of these five deer ecotypes to the last glacial maximum (LGM) and show they overlap to a much greater extent than today, suggesting that vicariance associated with the LGM cannot explain the present-day genetic patterns. Further, we analyse mitochondrial DNA (mtDNA) sequence trees to search for evidence of historical vicariance and find only two well-supported clades. A coalescence-based analysis of mtDNA data shows that the genetic divergence of the mule deer genetic clusters in California is recent and appears to be mediated by ecological factors. The importance of environmental factors in explaining the genetic diversity of California mule deer is unexpected given that they are highly mobile species and have a broad habitat distribution. Geographic differences in the timing of reproduction and peak vegetation as well as habitat choice reflecting natal origin may explain the persistence of genetic subdivision.


Visible Human 2.0--the next generation.
The National Library of Medicine has initiated the development of new anatomical methods and techniques for the acquisition of higher resolution data sets, aiming to address the anatomical artifacts encountered in the development of the Visible Human Male and Female and to insure enhanced detection of structures, providing data in greater depth and breadth. Given this framework, we acquired a complete data set of the head and neck. CT and MR scans were also obtained with registration hardware inserted prior to imaging. The arterial and venous systems were injected with colorized araldite-F. After freezing, axial cryosectioning and digital photography at 147 microns/voxel resolution was performed. Two slabs of the specimen were acquired with a special tissue harvesting technique. The resulting tissue slices of the whole specimen were stained for different tissue types. The resulting histological material was then scanned at a 60x magnification using the Virtual Slice technology at 2 microns/pixel resolution (each slide approximately 75,000 x 100,000 pixels). In this data set, for the first time anatomy is presented as a continuum from a radiologic granularity of 1 mm/voxel, to a macroscopic resolution of .147 mm/voxel, to microscopic resolution of 2 microns/pixel. The hiatus between gross anatomy and histology has been assumed insurmountable, and until the present time this gap was bridged by extrapolating findings on minute samples. The availability of anatomical data with the fidelity presented will render it possible to perform a seamless study of whole organs at a cellular level and provide a testbed for the validation of histological estimation techniques. A future complete Visible Human created from data acquired at a cellular resolution, aside from its daunting size, will open new possibilities in multiple directions in medical research and simulation.


Reoperation rates and impact on outcome in a large, prospective, multicenter, adult spinal deformity database: clinical article.
Complications and reoperation for surgery to correct adult spinal deformity are not infrequent, and many studies have analyzed the rates and factors that influence the likelihood of reoperation. However, there is a need for more comprehensive analyses of reoperation in adult spinal deformity surgery from a global standpoint, particularly focusing on the 1st year following operation and considering radiographic parameters and the effects of reoperation on health-related quality of life (HRQOL). This study attempts to determine the prevalence of reoperation following surgery for adult spinal deformity, assess the indications for these reoperations, evaluate for a relation between specific radiographic parameters and the need for reoperation, and determine the potential impact of reoperation on HRQOL measures. A retrospective review was conducted of a prospective, multicenter, adult spinal deformity database collected through the International Spine Study Group. Data collected included age, body mass index, sex, date of surgery, information regarding complications, reoperation dates, length of stay, and operation time. The radiographic parameters assessed were total number of levels instrumented, total number of interbody fusions, C-7 sagittal vertical axis, uppermost instrumented vertebra (UIV) location, and presence of 3-column osteotomies. The HRQOL assessment included Oswestry Disability Index (ODI), 36-Item Short Form Health Survey physical component and mental component summary, and SRS-22 scores. Smoking history, Charlson Comorbidity Index scores, and American Society of Anesthesiologists Physical Status classification grades were also collected and assessed for correlation with risk of early reoperation. Various statistical tests were performed for evaluation of specific factors listed above, and the level of significance was set at p < 0.05. Fifty-nine (17%) of a total of 352 patients required reoperation. Forty-four (12.5%) of the reoperations occurred within 1 year after the initial surgery, including 17 reoperations (5%) within 30 days. Two hundred sixty-eight patients had a minimum of 1 year of follow-up. Fifty-three (20%) of these patients had a 3-column osteotomy, and 10 (19%) of these 53 required reoperation within 1 year of the initial procedure. However, 3-column osteotomy was not predictive of reoperation within 1 year, p = 0.5476). There were no significant differences between groups with regard to the distribution of UIV, and UIV did not have a significant effect on reoperation rates. Patients needing reoperation within 1 year had worse ODI and SRS-22 scores measured at 1-year follow-up than patients not requiring operation. Analysis of data from a large multicenter adult spinal deformity database shows an overall 17% reoperation rate, with a 19% reoperation rate for patients treated with 3-column osteotomy and a 16% reoperation rate for patients not treated with 3-column osteotomy. The most common indications for reoperation included instrumentation complications and radiographic failure. Reoperation significantly affected HRQOL outcomes at 1-year follow-up. The need for reoperation may be minimized by carefully considering spinal alignment, termination of fixation, and type of surgical procedure (presence of osteotomy). Precautions should be taken to avoid malposition or instrumentation (rod) failure.


Exercise-Based Interventions to Enhance Long-Term Sustainability of Physical Activity in Older Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Exercise is a form of physical activity (PA). PA is an important marker of health and quality of life in older adults. The purpose of this study was to conduct a systematic review of the literature to assess the effect of exercise-based interventions on an at least six-month follow up PA measure, and to describe the specific strategies implemented during the intervention to strengthen the sustainability of PA in community-dwelling 65+ year-old adults. We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42017070892) of randomized clinical trials (RCT). We searched three electronic databases during January 2018 to identify RCT assessing any type of exercise-based intervention. Studies had to report a pre-, post-, and at least 6-month post-intervention follow-up. To be included, at least one PA outcome had to be assessed. The effect of exercise-based interventions was assessed compared to active (e.g., a low-intensity type of exercise, such as stretching or toning activities) and non-active (e.g., usual care) control interventions at several time points. Secondary analyses were conducted, restricted to studies that reported specific strategies to enhance the sustainability of PA. The intervention effect was measured on self-reported and objective measures of time spent in PA, by means of standardized mean differences. Standardized mean differences of PA level were pooled. Pooled estimates of effect were computed with the DerSimonian-Laird method, applying a random effects model. The risk of bias was also assessed. We included 12 studies, comparing 18 exercise intervention groups to four active and nine non-active control groups. Nine studies reported specific strategies to enhance the long-term sustainability of PA. The strategies were mostly related to the self-efficacy, self-control, and behavior capability principles based on the social cognitive theory. Exercise interventions compared to active control showed inconclusive and heterogeneous results. When compared to non-active control, exercise interventions improved PA time at the six-months follow up (standardized mean difference (SMD) 0.30; 95%CI 0.15 to 0.44; four studies; 724 participants; I2 0%), but not at the one- or two-years follow-ups. No data were available on the mid- and long-term effect of adding strategies to enhance the sustainability of PA. Exercise interventions have small clinical benefits on PA levels in community-dwelling older adults, with a decline in the observed improvement after six months of the intervention cessation.


Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.
Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.


A socio-interpersonal perspective on PTSD: the case for environments and interpersonal processes.
Post-traumatic stress disorder (PTSD) is a common reaction to traumatic experiences. We propose a socio-interpersonal model of PTSD that complements existing models of post-traumatic memory processes or neurobiological changes. The model adds an interpersonal perspective to explain responses to traumatic stress. The framework draws from lifespan psychology, cultural psychology and research into close relationships and groups. Additionally, clinical knowledge about PTSD is incorporated. This involves knowledge about shame, guilt, estrangement feelings and protective factors, such as social support and forgiveness. Three levels are proposed at which relevant interpersonal processes can be situated and should be adequately researched. First, the individual level comprises social affective states, such as shame, guilt, anger and feelings of revenge. Second, at the close relationship level, social support, negative exchange (ostracism and blaming the victim), disclosure and empathy are proposed as dyadic processes relevant to PTSD research and treatment. Third, the distant social level represents culture and society, in which the collectivistic nature of trauma, perceived injustice, and social acknowledgement are concepts that predict the response trajectories to traumatic stress. Research by the current authors and others is cited in an effort to promote future investigation based on the current model. Methodological implications, such as multi-level data analyses, and clinical implications, such as the need for couple, community or larger-level societal interventions, are both outlined. The socio-interpersonal model proposes an interpersonal view of the processes that occur in the aftermath of a traumatic experience. At the individual level, the model integrates the social affective phenomena that clinical research identifies in PTSD patients, including shame, guilt, anger, revenge and the urges or reluctance to disclose. At the level of close relationships, there is an emphasis on the role of the individuals' partner, family or social support in the development or maintenance of PTSD and its recovery. At the distant social level, societal and cultural factors, e.g., individualistic versus collectivistic or other human value orientations, are acknowledged as contributing to the severity and course of PTSD. Increasing attention should be given to new approaches of PTSD treatment that refer to an interpersonal view of PTSD, e.g., communication training, PTSD-specific couples' therapy or community programs.


Proximity-induced subgaps in andreev billiards.
We examine the density of states of an Andreev billiard and show that any billiard with a finite upper cutoff in the path length distribution P(s) will possess an energy gap on the scale of the Thouless energy. An exact quantum mechanical calculation for different Andreev billiards gives good agreement with the semiclassical predictions when the energy dependent phase shift for Andreev reflections is properly taken into account. Based on this new semiclassical Bohr-Sommerfeld approximation of the density of states, we derive a simple formula for the energy gap. We show that the energy gap, in units of Thouless energy, may exceed the value predicted earlier from random matrix theory for chaotic billiards.


Iodine-123 alpha-methyl tyrosine single-photon emission tomography of cerebral gliomas: standardised evaluation of tumour uptake and extent.
Single-photon emission tomography (SPET) with the amino acid analogue l-3-[123I]iodo-alpha-methyl tyrosine (IMT) is helpful in the diagnosis and monitoring of cerebral gliomas. Radiolabelled amino acids seem to reflect tumour infiltration more specifically than conventional methods like magnetic resonance imaging and computed tomography. Automatic tumour delineation based on maximal tumour uptake may cause an overestimation of mean tumour uptake and an underestimation of tumour extension in tumours with circumscribed peaks. The aim of this study was to develop a program for tumour delineation and calculation of mean tumour uptake which takes into account the mean background activity and is thus optimised to the problem of tumour definition in IMT SPET. Using the frequency distribution of pixel intensities of the tomograms a program was developed which automatically detects a reference brain region and draws an isocontour region around the tumour taking into account mean brain radioactivity. Tumour area and tumour/brain ratios were calculated. A three-compartment phantom was simulated to test the program. The program was applied to IMT SPET studies of 20 patients with cerebral gliomas and was compared to the results of manual analysis by three different investigators. Activity ratios and chamber extension of the phantom were correctly calculated by the automatic analysis. A method based on image maxima alone failed to determine chamber extension correctly. Manual region of interest analysis in patient studies resulted in a mean inter-observer standard deviation of 8.7% +/ -6.1% (range 2.7% -25.0%). The mean value of the results of the manual analysis showed a significant correlation to the results of the automatic analysis (r = 0.91, P<0. 0001 for the uptake ratio; r = 0.87, P<0.0001 for the tumour area). We conclude that the algorithm proposed simplifies the calculation of uptake ratios and may be used for observer-independent evaluation of IMT SPET studies. Three-dimensional tumour recognition and transfer to co-registered morphological images based on this program may be useful for the planning of surgical and radiation treatment.


Differential sub-nuclear distribution of hypoxia-inducible factors (HIF)-1 and -2 alpha impacts on their stability and mobility.
Cellular adaptation to hypoxia occurs via a complex programme of gene expression mediated by the hypoxia-inducible factor (HIF). The oxygen labile alpha subunits, HIF-1α/-2α, form a heterodimeric transcription factor with HIF-1β and modulate gene expression. HIF-1α and HIF-2α possess similar domain structure and bind to the same consensus sequence. However, they have different oxygen-dependent stability and activate distinct genes. To better understand these differences, we used fluorescent microscopy to determine precise localization and dynamics. We observed a homogeneous distribution of HIF-1α in the nucleus, while HIF-2α localized into speckles. We demonstrated that the number, size and mobility of HIF-2α speckles were independent of cellular oxygenation and that HIF-2α molecules were capable of exchanging between the speckles and nucleoplasm in an oxygen-independent manner. The concentration of HIF-2α into speckles may explain its increased stability compared with HIF-1α and its slower mobility may offer a mechanism for gene specificity.


Seasonal migration patterns and the maintenance of evolutionary diversity in a cryptic bird radiation.
Morphological differentiation associated with evolutionary diversification is often explained with adaptive benefits but the processes and mechanisms maintaining cryptic diversity are still poorly understood. Using genome-wide data, we show here that the pale sand martin Riparia diluta in Central and East Asia consists of three genetically deeply differentiated lineages which vary only gradually in morphology but broadly reflect traditional taxonomy. We detected no signs of gene flow along the eastern edge of the Qinghai-Tibetan plateau between lowland south-eastern Chinese R. d. fohkienensis and high-altitude R. d. tibetana. Largely different breeding and migration timing between these low and high altitude populations as indicated by phenology data suggests that allochrony might act as prezygotic isolation mechanism in the area where their ranges abut. Mongolian populations of R. d. tibetana, however, displayed signs of limited mixed ancestries with Central Asian R. d. diluta. Their ranges meet in the area of a well-known avian migratory divide, where western lineages take a western migration route around the Qinghai-Tibetan plateau to winter quarters in South Asia, and eastern lineages take an eastern route to Southeast Asia. This might also be the case between western R. d. diluta and eastern R. d. tibetana as indicated by differing wintering grounds. We hypothesize that hybrids might have nonoptimal intermediate migration routes and selection against them might restrict gene flow. Although further potential isolation mechanisms might exist in the pale sand martin, our study points towards contrasting migration behaviour as an important factor in maintaining evolutionary diversity under morphological stasis.


Conditions for young infants' failure to perceive trajectory continuity.
When viewing an event in which an object moves behind an occluder on part of its trajectory, 4-month-old infants perceive the trajectory as continuous only when time or distance out of sight is short. Little is known, however, about the conditions under which young infants perceive trajectories to be discontinuous. In the present studies we focus first on infants' perception of trajectories that change during a period of occlusion. Four-month-olds perceive discontinuity in trajectories that change in height or orientation while behind an occluder, and this is true even when a change in direction could be due to an invisible bouncing collision with a surface. Further experiments reveal that infants do not perceive diagonal linear trajectories as continuous across an occlusion unless the occluding and revealing edges are orthogonal to the path of movement. Implications for theories of perceptual and cognitive development are discussed.


Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics.
Lungs are one of the most common target organs of sepsis [1]. Hydrogen gas (H2), which has selective anti-oxidative effects, can be effectively used to treat septic mice. Mitochondrial dysfunction and dynamics play important roles in sepsis-induced organ damage. By using cecal ligation and puncture (CLP), a classic septic model, we explored the role of 2% H2 treatment in sepsis-induced acute lung injury (ALI) linked to mitochondrial function and dynamics. We randomized male Institute for Cancer Research (ICR) mice into 4 groups: sham, sham + H2, CLP and CLP + H2. At 24 h after CLP or sham operations, we used histological examination and transmission electron microscopy (TEM) to observe lung slices. We analyzed oxygenation index (PaO2/FiO2), mitochondrial-membrane potential (MMP), adenosine triphosphate (ATP) levels, respiration control ratio (RCR) and mitochondrial-respiration complex activities (I and II) using commercial kits, and dynamin-related protein 1 (Drp1) and mitofusin-2 (MFN2) using Western blot. Therapy with 2% H2 increased PaO2/FiO2 ratios, MMP and ATP levels, RCR, complex I activity and MFN2 expression but decreased histological score and Drp1 levels in the presence of sepsis. These data indicated that inhalation of 2% H2 to regulate mitochondrial function and dynamics may be a promising therapeutic strategy for lung injuries induced by severe sepsis.


An analysis of the complete sequence of a sugarcane bacilliform virus genome infectious to banana and rice.
The genome of sugarcane bacilliform virus (ScBV), a badnavirus, consists of a circular dsDNA. The complete sequence of a cloned infective ScBV genome is reported here. The genome is 7568 bp in size and possesses a number of features suggesting that ScBV is a pararetrovirus. A tRNA(Met)-binding site that may serve as a primer for minus-strand synthesis is present. The plus-strand of the ScBV genome contains three open reading frames (ORFs) which are capable of encoding proteins with calculated M(r) values of 22K, 13K and 215K. The 215K protein has regions with similarity to the RNA-binding domains, aspartic proteases and replicases of retro-elements. In addition, the 215K protein also has a region with restricted similarity to the intercellular transport proteins of plant viruses. Comparisons with the other sequenced badnaviruses, Commelina yellow mottle (CoYMV) and rice tungro bacilliform (RTBV) viruses, indicate that the arrangement of the ORFs in these viruses is conserved. Located next to the putative RNA-binding domain is a cysteine-rich region that is unique to the badnaviruses. When the molecular relationships of a portion of the reverse transcriptases of plant pararetroviruses were determined, two badnaviruses, CoYMV and ScBV, form one distinct cluster, whereas three caulimoviruses, cauliflower mosaic virus, carnation etched ring virus and figwort mosaic virus, form a second cluster. The badnavirus RTBV and the caulimovirus soybean chlorotic mottle virus occupy intermediate positions between the clusters. When introduced by Agrobacterium-mediated inoculation, a construct containing 1.1 copies of the cloned ScBV genome is infectious to both rice and banana.


Risk assessment in winter backcountry travel.
Risk assessment is an important part of safe backcountry travel in avalanche terrain. The purpose of this study was to determine and compare the ability of backcountry travelers to accurately estimate the avalanche danger for their destination and time of travel. We surveyed 353 winter backcountry users, asking them to rate the avalanche danger for their destination that day. We then compared this estimation to the Utah Avalanche Center daily advisory for that specific location, aspect, and elevation. Tendency to underestimate the avalanche danger was then compared across 6 different sports (backcountry skiing, backcountry snowboarding, snowshoeing, snowmobiling, out-of-bounds skiing, and out-of-bounds snowboarding) as well as across age, gender, and subject participation in an avalanche safety course. A comparison across different sports, adjusted for age and gender, showed that snowshoers were 7.11 times more likely than skiers to underestimate the avalanche danger (95% CI, 2.95, 17.11). This difference was maintained after adjusting for past education in an avalanche safety course (odds ratio, 5.74; 95% CI, 2.28, 14.46). Snowmobilers were also significantly more likely to underestimate the avalanche danger when compared to skiers (odds ratio, 3.11; 95% CI, 1.12, 8.24), but these differences ceased to be significant when the data were adjusted for avalanche safety course (odds ratio, 2.39; 95% CI, 0.84, 6.74). While there was a trend for women and older age groups to underestimate the avalanche danger when compared to men, these trends were not significant. Snowshoers and snowmobilers are groups that tend to underestimate avalanche danger when traveling in the backcountry. These groups may be unknowingly assuming a higher risk and should be targeted for avalanche education and awareness.


Fibrin fragment D-dimer and fibrinogen B beta peptides in plasma as markers of clot lysis during thrombolytic therapy in acute myocardial infarction.
The validity of markers in plasma of in vitro thrombolysis was investigated in 12 patients with extensive fibrinogen breakdown (greater than 80%, group 1) and in 12 patients with minimal breakdown (less than 20%, group 2). The patients were treated with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) in the "Thrombolysis in Myocardial Infarction II" (TIMI II) trial. Cross-linked fibrin degradation product levels were measured with two variant enzyme-linked immunosorbent assays (ELISAs), both using a fibrin fragment D-dimer specific capture antibody. In one instance, a tag antibody was used that cross-reacts with fibrinogen (pan-specific tag ELISA); in the other, the tag antibody was specific for fibrin fragment D (fibrin-specific tag ELISA). Apparent concentrations of cross-linked fibrin degradation products at baseline were within normal limits with both assays in most patients. At 8 hours after rt-PA infusion, the measured cross-linked fibrin degradation products were increased about twofold to fourfold in group 2 with both assays. However, in group 1, levels were significantly higher with the pan-specific tag ELISA (5.8 +/- 4.2 micrograms/mL) compared with the fibrin-specific tag ELISA (1.5 +/- 1.3 micrograms/mL). This observation was most likely a result of detection of fibrinogen degradation products in the pan-specific ELISA. Apparent levels of fibrinopeptide B beta 1-42, a marker of fragment X formation, increased during thrombolysis from 4.2 +/- 2.8 pmol/mL to 2,000 +/- 230 pmol/mL in group 1 and from 4.1 +/- 2.1 pmol/mL to 300 +/- 43 pmol/mL in group 2, and were correlated significantly with the extent of fibrinogen breakdown (r = -0.8). Fibrinopeptide beta 15-42 levels increased from 4.3 +/- 3 pmol/mL to 70 +/- 19 pmol/mL in group 1, but did not increase in group 2. The apparent increase in group 1 could be explained by cross-reactivity of fibrinopeptide B beta 1-42 in the fibrinopeptide beta 15-42 assay. We conclude that cross-linked fibrin degradation product levels as measured with a pan-specific tag ELISA and fibrinopeptide beta 15-42 levels as measured with certain monoclonal antibody-based ELISA are influenced by the extent of fibrinogen degradation. Fibrinopeptide B beta 1-42 is a marker specific for fibrinogen breakdown. Cross-linked fibrin degradation product levels, measured with a fibrin-specific tag ELISA, appear to be markers specific for thrombolysis. Consequently, assays similar to the fibrin-specific tag ELISA may provide more accurate information when correlated with clinical endpoints.


A cost effectiveness analysis of maintenance cognitive stimulation therapy (MCST) for people with dementia: examining the influence of cognitive ability and living arrangements.
Identify if cost-effectiveness of Maintenance Cognitive Simulation Therapy (MCST) differs by type of living arrangement and cognitive ability of the person with dementia. Next, a value of information analysis is performed to inform decisions about future research. Incremental cost-effectiveness analysis applying seemingly unrelated regressions using data from a multicentre RCT of MCST versus treatment as usual in a population which had already received 7 weeks of CST for dementia (ISRCTN: 26286067). The findings from the cost-effectiveness analysis are used to inform a value of information analysis. The results are dependent upon how quality adjusted life years (QALYs) are measured. MCST might be cost-effective compared to standard treatment for those who live alone and those with higher levels of cognitive functioning. If a further RCT was to be conducted for this sub-group of the population, value of information analysis suggests a total sample of 48 complete cases for both sub-groups would be required for a two-arm trial. The expected net gain of conducting this future research is £920 million. Preliminary results suggest that MCST may be most cost-efficient for people with dementia who live alone and/or who have higher cognition. Future research in this area is needed.


A new heteropolysaccharide from the seed husks of Plantago asiatica L. with its thermal and antioxidant properties.
A new heteropolysaccharide (PMH) with a molecular weight of 1.4 × 103 kDa was isolated from the seed husks of Plantago asiatica L. The monosaccharide composition of PMH was determined as glucose, xylose, arabinose, rhamnose, galactose and galacturonic acid with a molar ratio of 1.0 : 1.8 : 2.4 : 3.8 : 4.9 : 8.5. The backbone of PMH consisted of 1,4-β-d-GalpA with the side chains mainly composed of 1,3-α-d-Galp and 1,2-α-d-Galp which were attached to the O-3 of GlapA. The thermal analysis using the Flynn-Wall-Ozawa (FWO) method revealed that PMH had an apparent activation energy (Ea) of 173.1 kJ mol-1. PMH experienced a major decomposition during the heating process at a temperature of 91.1 °C with a dry weight loss of 31.1%. Moreover, PMH exhibited stronger antioxidant ability than commercial psyllium, partially due to its higher content of uronic acid. The results suggested that PMH could be used in functional foods due to its structural, thermal and antioxidant characteristics.


Effect of working hours on cardiovascular-autonomic nervous functions in engineers in an electronics manufacturing company.
A field survey of 147 engineers (23-49 years) in an electronics manufacturing company was conducted to investigate the effect of working hours on cardiovascular-autonomic nervous functions (urinary catecholamines, heart rate variability and blood pressure). The subjects were divided into 3 groups by age: 23-29 (n = 49), 30-39 (n = 74) and 40-49 (n = 24) year groups. Subjects in each age group were further divided into shorter (SWH) and longer (LWH) working hour subgroups according to the median of weekly working hours. In the 30-39 year group, urinary noradrenaline in the afternoon for LWH was significantly lower than that for SWH and a similar tendency was found in the LF/HF ratio of heart rate variability at rest. Because these two autonomic nervous indices are related to sympathetic nervous activity, the findings suggested that sympathetic nervous activity for LWH was lower than that for SWH in the 30-39 year group. Furthermore, there were significant relationships both between long working hours and short sleeping hours, and between short sleeping hours and high complaint rates of "drowsiness and dullness" in the morning in this age group. Summarizing these results, it appeared that long working hours might lower sympathetic nervous activity due to chronic sleep deprivation.


Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.
Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.


Risk and prognosis of inguinal hernia in relation to occupational mechanical exposures--a systematic review of the epidemiologic evidence.
The aim of this review was to evaluate the epidemiologic evidence for (i) a causal effect of occupational mechanical exposures on incidence of inguinal hernia, and (ii) a prognostic effect of such exposures on hernia recurrence and persistent pain after inguinal hernia repair. We performed a literature search in Medline, Embase, and Web of Science up to 3 November 2011. Central information was extracted from included studies, and strengths and limitations were discussed. All 23 included studies focused on effects of (work) activities that hardly reflected specific occupational risk factors. Eight studies provided information on risk by occupation or occupational activities. Increased risk was reported in six studies, but inflationary bias was likely. The negative findings in two studies might well be explained by bias towards the null due to crude exposure and/or outcome assessment. Three studies on single strenuous events primarily reflected patients` beliefs regarding risk factors. Information on prognosis with respect to recurrence was found in seven studies. The studies used crude exposure assessment, and two were also underpowered. Four suggested an increased risk. Six studies on prognosis with respect to persistent pain (one of which also concerned recurrence) were practically non-informative for the purpose of this review. There is insufficient epidemiologic evidence to draw meaningful conclusions about (i) the existence of causal associations between specific occupational mechanical exposures and the development of inguinal hernia, and (ii) the influence of these exposures on prognosis after inguinal hernia repair with respect to hernia recurrence and persistent pain.