Sleep duration and breast cancer incidence: results from the Million Women Study and meta-analysis of published prospective studies.
To investigate the association between sleep duration and breast cancer incidence, we examined the association in a large UK prospective study and conducted a meta-analysis of prospective studies. In the Million Women Study, usual sleep duration over a 24-h period was collected in 2001 for 713,150 participants without prior cancer, heart problems, stroke, or diabetes (mean age = 60 years). Follow-up for breast cancer was by record linkage to national cancer registry data for 14.3 years on average from the 3-year resurvey. Cox regression models yielded multivariable-adjusted breast cancer relative risks (RR) and 95% confidence intervals (CIs) for sleep duration categories. Published prospective studies of sleep duration and breast cancer risk were included in a meta-analysis, which estimated the inverse-variance weighted average of study-specific log RRs for short and for long versus average duration sleep. After excluding the first 5 years to minimize reverse causation bias in the Million Women Study, 24,476 women developed breast cancer. Compared with 7-8 h of sleep, the RRs for <6, 6, 9, and >9 h of sleep were 1.01 (95% CI, 0.95-1.07), 0.99 (0.96-1.03), 1.01 (0.96-1.06), and 1.03 (0.95-1.12), respectively. In a meta-analysis of 14 prospective studies plus the Million Women Study, including 65,410 breast cancer cases, neither short (RR < 7 h = 0.99 [0.98-1.01]) nor long (RR > 8 h = 1.01 [0.98-1.04]) versus average duration sleep was associated with breast cancer risk. The totality of the prospective evidence does not support an association between sleep duration and breast cancer risk.


Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review.
Disodium cromoglycate (DSCG) is included in the BTS guidelines on the treatment of asthma for use in children, but is now used only infrequently. We have identified and interpreted the findings of all published randomised, placebo controlled trials of DSCG in the prophylactic treatment of children with asthma. Several databases were searched to identify trials. Studies were included if they investigated subjects with asthma aged 0-18 years old, addressed maintenance treatment with inhaled DSCG, and were published in English. The methodological quality of the studies was assessed independently by three reviewers. The 95% confidence intervals (CI) of differences in the treatment effect for cough and wheeze between placebo and treatment with DSCG were computed. The estimates were pooled and tested for homogeneity and, to assess possible publication bias, a funnel plot was made and tested for symmetry. Of the 24 randomised, placebo controlled trials identified, the methodological scores varied widely. The null hypothesis of homogeneity was rejected. Under the assumption of heterogeneity the overall CI for wheeze was 0.11 to 0.26 and for cough was 0.13 to 0.27. The overall tolerance intervals (-0.11 to 0. 48 and -0.04 to 0.43 for wheeze and cough, respectively) both included zero, so it cannot be concluded that future studies will show an effect of DSCG compared with placebo. Older studies were more often in favour of DSCG. The funnel plots suggest publication bias; small studies with negative or equal outcomes are lacking. Given the apparent publication bias, the small overall treatment effect, and the tolerance interval including zero, there is insufficient evidence that DSCG has a beneficial effect as maintenance treatment in children with asthma.


Very preterm birth is reduced in women receiving an integrated behavioral intervention: a randomized controlled trial.
This study examines whether an integrated behavioral intervention with proven efficacy in reducing psycho-behavioral risks (smoking, environmental tobacco smoke exposure (ETSE), depression, and intimate partner violence (IPV)) in African-Americans is associated with improved pregnancy outcomes. A randomized controlled trial targeting risks during pregnancy was conducted in the District of Columbia. African-American women were recruited if reporting at least one of the risks mentioned above. Randomization to intervention or usual care was site and risk specific. Sociodemographic, health risk and pregnancy outcome data were collected. Data on 819 women, and their singleton live born infants were analyzed using an intent-to-treat approach. Bivariate analyses preceded a reduced logistical model approach to elucidate the effect of the intervention on the reduction of prematurity and low birth weight. The incidence of low birthweight (LBW) was 12% and very low birthweight (VLBW) was 1.6%. Multivariate logistic regression results showed that depression was associated with LBW (OR = 1.71, 95% CI = 1.12-2.62). IPV was associated with preterm birth (PTB) and very preterm birth (VPTB) (OR 1.64, 95% CI = 1.07-2.51, OR = 2.94, 95% CI = 1.40-6.16, respectively). The occurrence of VPTB was significantly reduced in the intervention compared to the usual care group (OR = 0.42, 95% CI = 0.19-0.93). Our study confirms the significant associations between multiple psycho-behavioral risks and poor pregnancy outcomes, including LBW and PTB. Our behavioral intervention with demonstrated efficacy in addressing multiple risk factors simultaneously reduced VPTB within an urban minority population.


Psychosocial Impact of Dysarthria: The Patient-Reported Outcome as Part of the Clinical Management.
Dysarthria in neurological disorders can have psychosocial consequences. The dysarthric speaker's perspective towards the disorder's psychosocial impact is essential in its global assessment and management. For such purposes, assessment tools such as the Dysarthria Impact Profile (DIP) are indispensable. We aimed to confirm the relevance of using the DIP to quantify the psychosocial consequences of dysarthria in neurological diseases. We studied 120 participants, 15 healthy controls and 105 patients with different kinds of dysarthria induced by several neurological disorders (Parkinson's disease [PD], Huntington's disease, dystonia, cerebellar ataxia, progressive supranuclear palsy [PSP], multiple system atrophy, lateral amyotrophic sclerosis). All participants underwent a cognitive evaluation and a speech intelligibility assessment and completed three self-reported questionnaires: the 36-Item Short Form Health Survey, the Voice Handicap Index (VHI), and the DIP. The psychometric properties of the DIP were confirmed, including internal consistency (α = 0.93), concurrent validity (correlation with the VHI: r = -0.77), and discriminant validity (accuracy = 0.93). Psychosocial impact of dysarthria was revealed by the DIP for all patients. Intelligibility loss was found strongly correlated with the psychosocial impact of dysarthria: for a similar level of intelligibility impairment, the DIP total score was similar regardless of the pathological group. However, our findings suggest that the psychosocial impact measured by the DIP could be partially independent from the severity of dysarthria (indirectly addressed here via speech intelligibility): the DIP was able to detect patients without any intelligibility impairment, but with a psychosocial impact. All patients reported a communication complaint, attested by the DIP scores, despite the fact that not all patients, notably PD, ataxic, and PSP patients, had an intelligibility deficit. The DIP should be used in clinical practice to contribute to a holistic evaluation and management of functional communication in patients with dysarthria.


Informed dispersal, heterogeneity in animal dispersal syndromes and the dynamics of spatially structured populations.
There is accumulating evidence that individuals leave their natal area and select a breeding habitat non-randomly by relying upon information about their natal and future breeding environments. This variation in dispersal is not only based on external information (condition dependence) but also depends upon the internal state of individuals (phenotype dependence). As a consequence, not all dispersers are of the same quality or search for the same habitats. In addition, the individual's state is characterized by morphological, physiological or behavioural attributes that might themselves serve as a cue altering the habitat choice of conspecifics. These combined effects of internal and external information have the potential to generate complex movement patterns and could influence population dynamics and colonization processes. Here, we highlight three particular processes that link condition-dependent dispersal, phenotype-dependent dispersal and habitat choice strategies: (1) the relationship between the cause of departure and the dispersers' phenotype; (2) the relationship between the cause of departure and the settlement behaviour and (3) the concept of informed dispersal, where individuals gather and transfer information before and during their movements through the landscape. We review the empirical evidence for these processes with a special emphasis on vertebrate and arthropod model systems, and present case studies that have quantified the impacts of these processes on spatially structured population dynamics. We also discuss recent literature providing strong evidence that individual variation in dispersal has an important impact on both reinforcement and colonization success and therefore must be taken into account when predicting ecological responses to global warming and habitat fragmentation.


How resilient is reading to letter rotations? A parafoveal preview investigation.
Skilled readers have developed a certain amount of tolerance to variations in the visual form of words (e.g., CAPTCHAs, handwritten text, etc.). To examine how visual distortion affects the mapping from the visual input onto abstract word representations during normal reading, we focused on a single type of distortion: letter rotation. Importantly, two leading neurally inspired models of word recognition (SERIOL model, Whitney, 2001; LCD model, Dehaene et al., 2005) make distinct predictions: Whereas the SERIOL model postulates that the cost of letter rotation increases gradually, the LCD model assumes an all-or-none boundary at around 40° to 45° rotation angle. To examine these predictions in a normal reading scenario, we conducted a parafoveal preview experiment using the gaze-contingent boundary change paradigm. The parafoveal previews were identical or unrelated to the target word. Critically, each preview's individual letters were rotated 15°, 30°, 45°, or 60°. Apart from the parafoveal previews, all text, including target words, was presented with letters in their canonical upright orientation. Results showed that the advantage of the identity preview condition in eye fixation times on the target word decreased progressively by rotation angle. This pattern of results favors the view that the cost of letter rotation during normal reading increases gradually as a function of the angle of rotation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Reduced size and abnormal asymmetry of parietal cortex in women with borderline personality disorder.
Evidence is accumulating that suggests borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) are related to small hippocampal size. Psychotic symptoms are frequent in both disorders. Psychotic spectrum disorders are known to be related to abnormalities of temporoparietal cortices. Using structural magnetic resonance imaging (3D-MRI), parietal cortex and hippocampal volumes were assessed in 30 young women with BPD who had been exposed to severe childhood sexual and physical abuse and in 25 healthy control subjects. Compared with control subjects, BPD subjects had significantly smaller right parietal cortex (-11%) and hippocampal (-17%) volumes. The parietal cortex of borderline subjects showed a significantly stronger leftward asymmetry when compared with control subjects. Stronger psychotic symptoms and schizoid personality traits in borderline subjects were significantly related to reduced leftward asymmetry. Stronger trauma-related clinical symptoms and neuropsychologic deficits were significantly related to smaller hippocampal size. Our results are consistent with previous findings of small hippocampal size in BPD and PTSD. Reduced right parietal cortex size in individuals with BPD may reflect a neurodevelopmental deficit of the right hemisphere.


Outcomes of visceral leishmaniasis in pregnancy: A retrospective cohort study from South Sudan.
Visceral leishmaniasis (VL) is endemic in South Sudan, where outbreaks occur frequently. Because of changes in the immune system during pregnancy, pregnant women are considered particularly vulnerable for developing complications of VL disease, including opportunistic infections. There is limited evidence available about clinical aspects and treatment outcomes of VL in pregnancy. We describe characteristics, maternal and pregnancy outcomes from a cohort of pregnant women with VL. We conducted a retrospective analysis using routine programme data from a MSF health facility in Lankien, Jonglei State, South Sudan, between Oct 2014 and April 2018. Records were extracted of women diagnosed with VL while pregnant, and those symptomatic during pregnancy but diagnosed during the first two weeks postpartum. Records were matched with a random sample of non-pregnant women of reproductive age (15-45 years) with VL from the same period. We included 113 women with VL in pregnancy, and 223 non-pregnant women with VL. Women with VL in pregnancy presented with more severe anaemia, were more likely to need blood transfusion (OR 9.3; 95%CI 2.5-34.2) and were more often prescribed antibiotics (OR 6.0; 95%CI 3.4-10.6), as compared to non-pregnant women with VL. Adverse pregnancy outcomes, including miscarriage and premature delivery, were reported in 20% (16/81) where VL was diagnosed in pregnancy, and 50% 13/26) where VL was diagnosed postpartum. Postpartum haemorrhage was common. Pregnant women were more likely to require extension of treatment to achieve cure (OR 10.0; 95%CI 4.8-20.9), as compared to non-pregnant women with VL. Nevertheless, overall initial cure rates were high (96.5%) and mortality was low (1.8%) in this cohort of pregnant women with VL. This is the largest cohort in the literature of VL in pregnancy. Our data suggest that good maternal survival rates are possible in resource-limited settings, despite the high incidence of complications.


Efficient counting of k-mers in DNA sequences using a bloom filter.
Counting k-mers (substrings of length k in DNA sequence data) is an essential component of many methods in bioinformatics, including for genome and transcriptome assembly, for metagenomic sequencing, and for error correction of sequence reads. Although simple in principle, counting k-mers in large modern sequence data sets can easily overwhelm the memory capacity of standard computers. In current data sets, a large fraction-often more than 50%-of the storage capacity may be spent on storing k-mers that contain sequencing errors and which are typically observed only a single time in the data. These singleton k-mers are uninformative for many algorithms without some kind of error correction. We present a new method that identifies all the k-mers that occur more than once in a DNA sequence data set. Our method does this using a Bloom filter, a probabilistic data structure that stores all the observed k-mers implicitly in memory with greatly reduced memory requirements. We then make a second sweep through the data to provide exact counts of all nonunique k-mers. For example data sets, we report up to 50% savings in memory usage compared to current software, with modest costs in computational speed. This approach may reduce memory requirements for any algorithm that starts by counting k-mers in sequence data with errors. A reference implementation for this methodology, BFCounter, is written in C++ and is GPL licensed. It is available for free download at http://pritch.bsd.uchicago.edu/bfcounter.html.


Tailored edge-ray designs for illumination with tubular sources.
The rubric tailored edge-ray designs (TED's) refers to the procedure for tailoring lighting reflectors to produce a prescribed flux distribution for an extended Lambertian source while ensuring maximum radiative efficiency (no radiation being returned to the source). Most TED studies to date have been restricted to the case in which the two edges of the image of the source in the reflectors are bound by a source edge ray and a reflector edge. The extension to the more general, and challenging, solution in which both edges of the image can be bound by rays from opposite edges of the source was recently begun by Ries and Winston [J. Opt. Soc. Am. A 11, 1260-1264 (1994)] but was described in detail only for one particular design. We show that there are four topologically distinct classes of such reflectors; we derive the governing differential equations and obtain the solution in analytical form. Our results are illustrated for the case of uniform far-field illuminance production with symmetric configurations in two dimensions. Relative to earlier TED's, these new devices can offer increased uniform core regions and superior glare control, although they are somewhat less compact. We offer a comprehensive analysis of the geometric properties, flux-map characteristics, and limitations of these new TED's.


A laboratory test setup for in situ measurements of the dielectric properties of catalyst powder samples under reaction conditions by microwave cavity perturbation: set up and initial tests.
The catalytic behavior of zeolite catalysts for the ammonia-based selective catalytic reduction (SCR) of nitrogen oxides (NOX) depends strongly on the type of zeolite material. An essential precondition for SCR is a previous ammonia gas adsorption that occurs on acidic sites of the zeolite. In order to understand and develop SCR active materials, it is crucial to know the amount of sorbed ammonia under reaction conditions. To support classical temperature-programmed desorption (TPD) experiments, a correlation of the dielectric properties with the catalytic properties and the ammonia sorption under reaction conditions appears promising. In this work, a laboratory test setup, which enables direct measurements of the dielectric properties of catalytic powder samples under a defined gas atmosphere and temperature by microwave cavity perturbation, has been developed. Based on previous investigations and computational simulations, a resonator cavity and a heating system were designed, installed and characterized. The resonator cavity is designed to operate in its TM010 mode at 1.2 GHz. The first measurement of the ammonia loading of an H-ZSM-5 zeolite confirmed the operating performance of the test setup at constant temperatures of up to 300 °C. It showed how both real and imaginary parts of the relative complex permittivity are strongly correlated with the mass of stored ammonia.


Changes of non-invasive markers and FibroScan values during HCV treatment.
The recent advent of non-invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non-invasive methods, in a large cohort of HCV-infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV-infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow-up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non-invasive methods with liver biopsy. These non-invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.


A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut.
The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives.


Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.
Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.


Prevalence of intestinal complications in inflammatory bowel disease: a comparison between paediatric-onset and adult-onset patients.
Intestinal complications in inflammatory bowel disease indicate active inflammation and typically result in the intensification of therapy. To analyse whether the rates of intestinal complications were associated with age at disease onset. Data from 1506 individuals with Crohn's disease (CD) and 1201 individuals with ulcerative colitis (UC) were obtained from the Swiss inflammatory bowel disease cohort study database, classified into groups on the basis of age at diagnosis (<10, <17, <40 and >40 years of age), and retrospectively analysed. In CD patients, the rates of stricturing (29.1-36.2%), abdominal penetrating disease (11.9-18.2%), resectional surgery (17.9-29.8%) and perianal disease (14.7-34.0%) were correlated with disease duration, but not age at diagnosis. However, paediatric-onset CD was associated with higher rates of multiple, rectal and anal strictures and earlier colon surgery. In addition, perianal disease occurred earlier, required earlier surgical intervention, and was more often combined with stricturing and penetrating disease. Finally, anal fissures were more prevalent among younger patients. In UC patients, the rates of progression or extension of disease (0-25.8%) and colectomy (3.0-8.7%) were dependent on disease duration, but not age at disease onset. Paediatric-onset disease was associated with a higher rate of extensive colitis at diagnosis and earlier progression or extension of disease, and nonsurgically treated patients with the youngest ages at onset more frequently required antitumour necrosis factor-α treatments. The higher rates of intestinal complications, including those of the small and large bowel and in the anal region, in paediatric-onset CD patients point towards a level of inflammation that is more difficult to control. Similar findings were also evident in UC patients.


Three day versus five day treatment with amoxicillin for non-severe pneumonia in young children: a multicentre randomised controlled trial.
To assess the efficacy of three days versus five days of treatment with oral amoxicillin for curing non-severe pneumonia in children. Randomised, double blind, placebo controlled multicentre trial. Outpatient departments of seven referral hospitals in India. 2188 children aged 2-59 months, 1095 given three days of treatment and 1093 given five days. Oral amoxicillin 31-54 mg/kg/day in three divided doses. Treatment failure: defined as development of chest indrawing, convulsions, drowsiness, or inability to drink at any time; respiratory rate above age specific cut points on day 3 or later; or oxygen saturation by pulse oximetry < 90% on day 3. The clinical cure rates with three days and five days of treatment were 89.5% and 89.9%, respectively (absolute difference 0.4 (95% confidence interval--2.1 to 3.0)). Adherence to treatment regimen was 94% and 85% for three day and five day treatments, respectively. Loss to follow up was 5.4% by day 5. There were no deaths, 41 hospitalisations, and 36 minor adverse reactions. There were 225 (10.3%) clinical failures and 106 (5.3%) relapses, and rates were similar in both treatments. At enrollment, 513 (23.4%) children tested positive for respiratory syncytial virus, and Streptococcus pneumoniae and Haemophilus influenzae were isolated from the nasopharynx in 878 (40.4%) and 496 (22.8%) children, respectively. Clinical failure was associated with isolation of respiratory syncytial virus (adjusted odds ratio 1.95 (95% confidence interval 1.0 to 3.8)), excess respiratory rate of > 10 breaths/minute (2.89 (1.83 to 4.55)), and non-adherence with treatment at day 5 (11.57 (7.4 to 18.0)). Treatment with oral amoxicillin for three days was as effective as for five days in children with non-severe pneumonia.


Predicting post-translational lysine acetylation using support vector machines.
Lysine acetylation is a post-translational protein modification and a primary regulatory mechanism that controls many cell signaling processes. Lysine acetylation sites are recognized by acetyltransferases and deacetylases through sequence patterns (motifs). Recently, we used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 human proteins covering most of the previously annotated sites and providing the most comprehensive acetylome so far. This dataset should provide an excellent source to train support vector machines (SVMs) allowing the high accuracy in silico prediction of acetylated lysine residues. We developed a SVM to predict acetylated residues. The precision of our acetylation site predictor is 78% at 78% recall on input data containing equal numbers of modified and non-modified residues. The online predictor is available at http://www.phosida.com email@example.com


Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis.
Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.


Chlorogenic acid-enriched green coffee bean extract affects arterial stiffness assessed by the cardio-ankle vascular index in healthy men: a pilot study.
The effect of chlorogenic acid-enriched green coffee bean extract (cGCE) intake on arterial stiffness was investigated using the cardio-ankle vascular index (CAVI) as a novel surrogate marker for predicting arteriosclerosis. A placebo-controlled double-blind pilot study was conducted with 16 healthy Japanese men. Subjects were divided into two groups and consumed beverages containing either cGCE or placebo daily for 2 weeks. The CAVI, the primary endpoint of the study, was evaluated at the beginning of the study and 2 weeks later. Endothelium-dependent flow-mediated dilation (FMD) and sympathetic nervous activity (SNA), which are thought to be related to the CAVI, were also measured. The CAVI change was significantly greater in the cGCE group than in the placebo group. In addition, FMD increased and SNA decreased in the cGCE group. These findings suggest that 2-week ingestion of cGCE may improve arterial stiffness as assessed by the CAVI.


Kelvin Probe Force Microscopy and Calculation of Charge Transport in a Graphene/Silicon Dioxide System at Different Relative Humidity.
The article shows how the dynamic mapping of surface potential (SP) measured by Kelvin probe force microscopy (KPFM) in combination with calculation by a diffusion-like equation and the theory based on the Brunauer-Emmett-Teller (BET) model of water condensation and electron hopping can provide the information concerning the resistivity of low conductive surfaces and their water coverage. This is enabled by a study of charge transport between isolated and grounded graphene sheets on a silicon dioxide surface at different relative humidity (RH) with regard to the use of graphene in ambient electronic circuits and especially in sensors. In the experimental part, the chemical vapor-deposited graphene is precisely patterned by the mechanical atomic force microscopy (AFM) lithography and the charge transport is studied through a surface potential evolution measured by KPFM. In the computational part, a quantitative model based on solving the diffusion-like equation for the charge transport is used to fit the experimental data and thus to find the SiO2 surface resistivity ranging from 107 to 1010 Ω and exponentially decreasing with the RH increase. Such a behavior is explained using the formation of water layers predicted by the BET adsorption theory and electron-hopping theory that for the SiO2 surface patterned by AFM predicts a high water coverage even at low RHs.


The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis.
Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tumorigenesis, and observe marked differences in CNA prevalence between mouse mammary tumours initiated with distinct drivers. Some aberrations are recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumorigenesis. Synteny-based comparison of mouse and human tumours narrows critical regions in CNAs, thereby identifying candidate driver genes. We experimentally validate that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis to inform the pathogenesis of human cancer.


Health service access and utilization among Syrian refugees in Jordan.
The influx of Syrian refugees into Jordan presents an immense burden to the Jordanian health system. Changing lifestyles and aging populations are shifting the global disease burden towards increased non-infectious diseases including chronic conditions, co-morbidities, and injuries which are more complicated and costly to manage. The strain placed on health systems threatens the ability to ensure the health needs of both refugees and host country populations are adequately addressed. In light of the increasing challenges facing host governments and humanitarian actors to meet health needs of Syrian refugees and affected host communities, this study was undertaken to assess utilization of health services among Syrian refugees in non-camp settings. A survey of Syrian refugees in Jordan was undertaken in June 2014 to characterize health seeking behaviors and issues related to accessing care. A cluster design with probability proportional to size sampling was used to attain a nationally representative sample of 1550 non-camp Syrian refugee households. Differences in household characteristics by geographic region, facility type, and sector utilized were examined using chi-square and t-test methods. Care-seeking was high with 86.1 % of households reporting an adult sought medical care the last time it was needed. Approximately half (51.5 %) of services were sought from public sector facilities, 38.7 % in private facilities, and 9.8 % in charity/NGO facilities. Among adult care seekers, 87.4 % were prescribed medication during the most recent visit, 89.8 % of which obtained the medication. Overall, 51.8 % of households reported out-of-pocket expenditures for the consultation or medications at the most recent visit (mean US$39.9, median US$4.2). Despite high levels of care-seeking, cost was an important barrier to health service access for Syrian refugees in Jordan. The cessation of free access to health care since the time of the survey is likely to have worsened health equity for refugees. Dependence of refugees on the public facilities for primary and specialist care has placed a great burden on the Jordanian health system. To improve accessibility and affordability of health services in an equitable manner for both refugees and Jordanian host communities, strategies that should be considered going forward include shifting resources for non-communicable diseases and other traditional hospital services to the primary level and creating strong health promotion programs emphasizing prevention and self-care are strategies.


Polyglutamate forms of folate in resting and proliferating mammalian tissues.
1. Tritiated folic acid (pteroylglutamic acid) was injected into rats whose livers were undergoing regeneration after partial hepatectomy, and into normal control rats. 2. The major form of labelled liver folate was found to be pteroylpentaglutamate in both hepatectomized and normal rats and there was no difference in the proportion of pteroylpentaglutamate to other forms of folate in the regenerating or resting liver. 3. Folate concentrations were also measured in leucocytes from normal and leukaemic patients. 4. Pteroylpolyglutamates constituted the main form of folate in both sets of cells. There was again no difference in proportion of pteroylpolyglutamate to pteroylmonoglutamate forms of folate between normal mature cells and primitive blast cells. 5. It is therefore suggested that pteroylpolyglutamates, which constitute nearly all the folates in cells actively synthesizing DNA and protein as well as in resting cells, probably act as the coenzymes in vivo for the folate-dependent reactions in DNA, RNA and protein synthesis in mammalian systems.


Affect modulated startle in schizophrenia: subjective experience matters.
Data suggests that emotion reactivity as measured by the affect-modulated startle paradigm in those with schizophrenia (SZ) may be similar to healthy controls (HC). However, normative classification of the stimuli may not accurately reflect emotional experience, especially for those with SZ. To examine this possibility, the present study measured the affect-modulated startle response with images classified according to both normative and subjective ratings. Seventeen HC and 17 SZ completed an image viewing task during which startle probes were presented, followed by subjective valence and arousal ratings. Both groups exhibited inhibited startle responses to positive images, intermediate startle amplitudes to neutral images, and potentiated startle amplitudes to negative images. SZ rated the positive images as less positive than HC. When images were reclassified based on subjective valence ratings, both groups' startle magnitudes increased in response to subjectively rated positive images and decreased to subjectively rated neutral images. The number of trials classified into each valence condition suggested a tendency for SZ to classify neutral images as negative more often than HC. Overall, these findings suggest that affective stimuli modulate the startle response in HC and SZ in similar ways, but subjective emotional experience may differ in those with schizophrenia.


Why are Dutch rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis?
The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial has proved that combination therapy with prednisolone, methotrexate and sulphasalazine is superior to sulphasalazine monotherapy in suppressing disease activity and radiological progression of early rheumatoid arthritis (RA). In addition, 5 years of follow-up proved that COBRA therapy results in sustained reduction of the rate of radiological progression. Despite this evidence, Dutch rheumatologists seem reluctant to prescribe COBRA therapy. To explore the reasons for the reluctance in Dutch rheumatologists to prescribe COBRA therapy. A short structured questionnaire based on social-psychological theories of behaviour was sent to all Dutch rheumatologists (n = 230). The response rate was 50%. COBRA therapy was perceived as both effective and safe, but complex to administer. Furthermore, rheumatologists expressed their concern about the large number of pills that had to be taken, the side effects of high-dose prednisolone and the low dose of methotrexate. Although the average attitude towards the COBRA therapy was slightly positive (above the neutral point), the majority of responding rheumatologists had a negative intention (below the neutral point) to prescribe COBRA therapy in the near future. The reluctance of Dutch rheumatologists to prescribe effective COBRA therapy may be due to perceptions of complexity of the treatment schedule and negative patient-related consequences of the therapy.


Concerted molecular displacements in a thermally-induced solid-state transformation in crystals of DL-norleucine.
Martensitic transformations are of considerable technological importance, a particularly promising application being the possibility of using martensitic materials, possibly proteins, as tiny machines. For organic crystals, however, a molecular level understanding of such transformations is lacking. We have studied a martensitic-type transformation in crystals of the amino acid DL-norleucine using molecular dynamics simulation. The crystal structures of DL-norleucine comprise stacks of bilayers (formed as a result of strong hydrogen bonding) that translate relative to each other on transformation. The simulations reveal that the transformation occurs by concerted molecular displacements involving entire bilayers rather than on a molecule-by-molecule basis. These observations can be rationalized on the basis that at sufficiently high excess temperatures, the free energy barriers to concerted molecular displacements can be overcome by the available thermal energy. Furthermore, in displacive transformations, the molecular displacements can occur by the propagation of a displacement wave (akin to a kink in a carpet), which requires the molecules to overcome only a local barrier. Concerted molecular displacements are therefore considered to be a significant feature of all displacive transformations. This finding is expected to be of value toward developing strategies for controlling or modulating martensitic-type transformations.


Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis.
Low carbohydrate diets, which restrict carbohydrate in favour of increased protein or fat intake, or both, are a popular weight-loss strategy. However, the long-term effect of carbohydrate restriction on mortality is controversial and could depend on whether dietary carbohydrate is replaced by plant-based or animal-based fat and protein. We aimed to investigate the association between carbohydrate intake and mortality. We studied 15 428 adults aged 45-64 years, in four US communities, who completed a dietary questionnaire at enrolment in the Atherosclerosis Risk in Communities (ARIC) study (between 1987 and 1989), and who did not report extreme caloric intake (<600 kcal or >4200 kcal per day for men and <500 kcal or >3600 kcal per day for women). The primary outcome was all-cause mortality. We investigated the association between the percentage of energy from carbohydrate intake and all-cause mortality, accounting for possible non-linear relationships in this cohort. We further examined this association, combining ARIC data with data for carbohydrate intake reported from seven multinational prospective studies in a meta-analysis. Finally, we assessed whether the substitution of animal or plant sources of fat and protein for carbohydrate affected mortality. During a median follow-up of 25 years there were 6283 deaths in the ARIC cohort, and there were 40 181 deaths across all cohort studies. In the ARIC cohort, after multivariable adjustment, there was a U-shaped association between the percentage of energy consumed from carbohydrate (mean 48·9%, SD 9·4) and mortality: a percentage of 50-55% energy from carbohydrate was associated with the lowest risk of mortality. In the meta-analysis of all cohorts (432 179 participants), both low carbohydrate consumption (<40%) and high carbohydrate consumption (>70%) conferred greater mortality risk than did moderate intake, which was consistent with a U-shaped association (pooled hazard ratio 1·20, 95% CI 1·09-1·32 for low carbohydrate consumption; 1·23, 1·11-1·36 for high carbohydrate consumption). However, results varied by the source of macronutrients: mortality increased when carbohydrates were exchanged for animal-derived fat or protein (1·18, 1·08-1·29) and mortality decreased when the substitutions were plant-based (0·82, 0·78-0·87). Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50-55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality. National Institutes of Health.


Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes.
In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA.


Expression of myosin heavy chain mRNA in rat laryngeal muscles.
The composition of myosin heavy chain mRNA was analysed quantitatively in 5 intrinsic laryngeal muscles of rats, using a competitive polymerase chain reaction. Intrinsic laryngeal muscles with the fastest contraction times, e.g. ventricular thyroarytenoid muscle. lateral cricoarytenoid muscle. and vocalis muscle, contained 2 fast isoforms, comprising mainly type 2B myosin heavy chains (52.1, 44.6 and 8.2%, respectively) and type 2X myosin heavy chains (21.9, 37.6 and 80.8%, respectively). Conversely, muscles with slower contraction times, such as posterior cricoarytenoid muscle and cricothyroid muscle, contained more than 85% of 2 fast isoforms; mainly type 2X myosin heavy chains (52.4-72.1%, respectively) and type 2A myosin heavy chains (34.6-25.2%, respectively). The results show a strong correlation between the composition of fast myosin heavy chain isoforms and muscle contraction times. Type 2L myosin heavy chain transcripts specific for laryngeal muscles and extra-ocular muscles were expressed in the order of ventricular thyroarytenoid (9.5%) > lateral cricoarytenoid (4.8%) > vocalis (2.5%) > posterior cricoarytenoid muscle (0.9%), but were not expressed in cricothyroid muscle. Neonatal myosin heavy chain was also expressed in all laryngeal muscles, ranging from 0.04 to 3%, but embryonic myosin heavy chain was expressed in ventricular thyroarytenoid, posterior cricoarytenoid and cricothyroid muscle at very low levels. These results suggest that intrinsic laryngeal muscles have different expression patterns for myosin heavy chain isoforms and may have different regulatory roles related to their functional requirement.


Anemia and Iron Deficiency in Heart Failure: Current Concepts and Emerging Therapies.
Anemia and iron deficiency are important and common comorbidities that often coexist in patients with heart failure. Both conditions, together or independently, are associated with poor clinical status and worse outcomes. Whether anemia and iron deficiency are just markers of heart failure severity or whether they mediate heart failure progression and outcomes and therefore should be treated is not entirely clear. Treatment of anemia in patients with heart failure with erythropoiesis-stimulating agents has been evaluated intensively during the past several years. Unfortunately, these agents did not improve outcomes but were associated with a higher risk of adverse events. Iron deficiency in patients with heart failure can be absolute, when total body iron is decreased, or functional, when total body iron is normal or increased but is inadequate to meet the needs of target tissues because of sequestration in the storage pool. Whereas iron replacement is appropriate in patients with anemia resulting from absolute iron deficiency, it has been unclear whether and how absolute or functional iron deficiency should be treated in nonanemic patients with heart failure. Recently, small studies found that administration of intravenous iron in patients with heart failure and absolute or functional iron deficiency with or without anemia improves symptoms and exercise capacity, but long-term outcomes and safety data are not yet available. In this review, we discuss the causes and pathogenesis of and treatment options for anemia and iron deficiency in patients with heart failure.


Acid rain recovery may help to mitigate the impacts of climate change on thermally sensitive fish in lakes across eastern North America.
From the 1970s to 1990s, more stringent air quality regulations were implemented across North America and Europe to reduce chemical emissions that contribute to acid rain. Surface water pH slowly increased during the following decades, but biological recovery lagged behind chemical recovery. Fortunately, this situation is changing. In the past few years, northeastern US fish populations have begun to recover in lakes that were historically incapable of sustaining wild fish due to acidic conditions. As lake ecosystems across the eastern United States recover from acid deposition, the stress to the most susceptible populations of native coldwater fish appears to be shifting from acidification effects to thermal impacts associated with changing climate. Extreme summer temperature events - which are expected to occur with increasing frequency in the coming century - can stress and ultimately kill native coldwater fish in lakes where thermal stratification is absent or highly limited. Based on data from northeastern North America, we argue that recovery from acid deposition has the potential to improve the resilience of coldwater fish populations in some lakes to impacts of climate change. This will occur as the amount of dissolved organic carbon (DOC) in the water increases with increasing lake pH. Increased DOC will reduce water clarity and lead to shallower and more persistent lake thermoclines that can provide larger areas of coldwater thermal refuge habitat. Recovery from acidification will not eliminate the threat of climate change to coldwater fish, but secondary effects of acid recovery may improve the resistance of coldwater fish populations in lakes to the effects of elevated summer temperatures in historically acidified ecosystems. This analysis highlights the importance of considering the legacy of past ecosystem impacts and how recovery or persistence of those effects may interact with climate change impacts on biota in the coming decades.


The effects of melatonin on human hepatoma (Hep G2) cell line.
Melatonin has been suggested to have antiproliferative effects on cancer cells. These effects can be attributed to immunomodulation, growth factor inhibition, induction of apoptosis and prooxidant properties. Melatonin is considered as a safe drug with minimal adverse effects. We planned to investigate the effects of melatonin in hepatoma (Hep G2) cell line. In this study, different concentrations of melatonin were studied to assess its effects on human hepatoma (Hep G2) cell line in vitro. In this study, different doses (5 x 10(-5) M, 5 x 10(-4) M, 10(-3) M) of melatonin were administered into hepatocellular carcinoma cell line in vitro. After an incubation period of 72 hours, the studied and control groups were evaluated for cell cycle, morphology, proliferating index and apoptosis percentage. A significant decrease in percentage of phase G0/G1 cells was found in high-dose melatonin group (10(-3) M) compared to control group. Melatonin increased the cell counts in S phase of cell cycle at high doses as well. However, phase G2/M cell percentage did not change with the administration of melatonin. Cell proliferation was increased in all melatonin groups, but the only statistically significant difference was found between the high-dose and control groups. There was a significant increase in proliferative index between the control group and high-dose melatonin group. High dose of melatonin increases the cell count in S phase and shows an antiproliferative effect on hepatoma cells. This indicates that melatonin can be considered a promising drug when used along with other antineoplastic agents for the treatment of hepatoma.However, it has no effect on apoptosis and colony counts (Tab. 1, Fig. 2, Ref. 19). Full Text (Free, PDF) www.bmj.sk.


Spontaneous breathing during veno-venous extracorporeal membrane oxygenation.
Veno-venous extracorporeal membrane oxygenation (VV ECMO) has started to be applied in awake spontaneously breathing patients as an alternative to invasive mechanical ventilation. As the physiologic cardiorespiratory variability is increased in this condition, the dynamic interaction between patient respiratory activity and extracorporeal system function affects the clinical management. The effect of extracorporeal CO2 removal on patient respiratory drive is variable and not always predictable, with some patients responding to CO2 removal with a decrease in respiratory rate and effort and other patients demonstrating a persistently high work of breathing independent on CO2 unload. While the pathophysiological mechanisms of this different interactions are still to be clarified, improved monitoring ability is needed both to titrate the support in responders and to avoid the risk of ventilation injury in non-responders. Acute changes in patient respiratory patterns may also occur during spontaneous breathing, making it difficult to maintain constant levels of extracorporeal respiratory support, also because changes in the distribution of venous blood volume due to lung-heart interactions affect extracorporeal blood flow. Assessment of native lung function and of its evolution over time is challenging while respiratory gas exchanges are provided by the extracorporeal system, since both oxygenation and decarboxylation capabilities can be fully evaluated only when alveolar ventilation is restored reducing extracorporeal CO2 removal. The rationale for using "awake ECMO" varies across different types of acute respiratory failure: the pathophysiological mechanisms of the underlying disease affect the patient-ECMO interaction and the goal of support. In this review we discuss the pathophysiology, technical challenges and monitoring issues of the use of ECMO in awake spontaneously breathing patients with acute respiratory failure of different etiologies.


Nuclear import of hnRNP A1 is mediated by a novel cellular cofactor related to karyopherin-beta.
Heterogeneous nuclear ribonucleoprotein A1 contains a sequence, termed M9, that functions as a potent nuclear localization signal (NLS) yet bears no similarity to the well-defined basic class of NLSs. Here, we report the identification of a novel human protein, termed MIP, that binds M9 specifically both in vivo and in vitro yet fails to interact with non-functional M9 point mutants. Of note, the 101 kDa MIP protein bears significant homology to human karyopherin/importin-beta, a protein known to mediate the function of basic NLSs. The in vitro nuclear import of a protein substrate containing the M9 NLS was found to be dependent on provision of the MIP protein in trans. Cytoplasmic microinjection of a truncated form of MIP that retains the M9 binding site blocked the in vivo nuclear import of a substrate containing the M9 NLS yet failed to affect the import of a similar substrate bearing a basic NLS. These data indicate that nuclear import of hnRNP A1 is mediated by a novel cellular import pathway that is distinct from, yet evolutionarily related to, the pathway utilized by basic NLS sequences.


Aging escalates baroreceptor reflex suppression by the posterior hypothalamus in rats.
To examine whether baroreceptor reflex regulation by the posterior hypothalamus becomes modified with age, we compared baroreceptor reflex sensitivity and hypothalamic responsiveness in 2- and 10-month-old rats anesthetized with urethane-chloralose. Hypothalamic regulation of baroreceptor reflex sensitivity was assessed by recording responses to intravenously infused phenylephrine and afferent aortic nerve stimulation after sham operation or electrolytic destruction of the posterior hypothalamus. Regardless of age, reflex bradycardia and sympathoinhibition elicited during pressor responses to phenylephrine, as well as all cardiovascular and sympathetic nerve responses to afferent aortic nerve stimulation, were stronger in rats with bilateral hypothalamic lesions than in age-matched, sham-operated controls. Distinctively, because baroreceptor reflex sensitivity differed with age only in sham-operated controls but not in lesioned rats, we concluded that age-related differences in baroreceptor reflex sensitivity had been abolished by posterior hypothalamic lesions. Other experiments were then performed to compare responses to graded electrical stimulation of the posterior hypothalamus in baroreceptor-intact rats. Pressor and sympathoexcitatory responses to hypothalamic stimulation were larger, and stimulus thresholds were lower at 10 than at 2 months of age thereby suggesting that hypothalamic responsiveness had increased with age. Our results are in accord with the interpretation that aging exacerbates the baroreceptor reflex suppression normally exerted by the posterior hypothalamus.


Environmental Free-Living Amoebae Isolated from Soil in Khon Kaen, Thailand, Antagonize Burkholderia pseudomallei.
Presence of Burkholderia pseudomallei in soil and water is correlated with endemicity of melioidosis in Southeast Asia and northern Australia. Several biological and physico-chemical factors have been shown to influence persistence of B. pseudomallei in the environment of endemic areas. This study was the first to evaluate the interaction of B. pseudomallei with soil amoebae isolated from B. pseudomallei-positive soil site in Khon Kaen, Thailand. Four species of amoebae, Paravahlkampfia ustiana, Acanthamoeba sp., Naegleria pagei, and isolate A-ST39-E1, were isolated, cultured and identified based on morphology, movement and 18S rRNA gene sequence. Co-cultivation combined with a kanamycin-protection assay of B. pseudomallei with these amoebae at MOI 20 at 30°C were evaluated during 0-6 h using the plate count technique on Ashdown's agar. The fate of intracellular B. pseudomallei in these amoebae was also monitored by confocal laser scanning microscopy (CLSM) observation of the CellTracker™ Orange-B. pseudomallei stained cells. The results demonstrated the ability of P. ustiana, Acanthamoeba sp. and isolate A-ST39-E1 to graze B. pseudomallei. However, the number of internalized B. pseudomallei substantially decreased and the bacterial cells disappeared during the observation period, suggesting they had been digested. We found that B. pseudomallei promoted the growth of Acanthamoeba sp. and isolate A-ST39-E1 in co-cultures at MOI 100 at 30°C, 24 h. These findings indicated that P. ustiana, Acanthamoeba sp. and isolate A-ST39-E1 may prey upon B. pseudomallei rather than representing potential environmental reservoirs in which the bacteria can persist.


A high-throughput drop microfluidic system for virus culture and analysis.
High mutation rates and short replication times lead to rapid evolution in RNA viruses. New tools for high-throughput culture and analysis of viral phenotypes will enable more effective studies of viral evolutionary processes. A water-in-oil drop microfluidic system to study virus-cell interactions at the single event level on a massively parallel scale is described here. Murine norovirus (MNV-1) particles were co-encapsulated with individual RAW 264.7 cells in 65 pL aqueous drops formed by flow focusing in 50 μm microchannels. At low multiplicity of infection (MOI), viral titers increased greatly, reaching a maximum 18 h post-encapsulation. This system was employed to evaluate MNV-1 escape from a neutralizing monoclonal antibody (clone A6.2). Further, the system was validated as a means for testing escape from antibody neutralization using a series of viral point mutants. Finally, the replicative capacity of single viral particles in drops under antibody stress was tested. Under standard conditions, many RNA virus stocks harbor minority populations of genotypic and phenotypic variants, resulting in quasispecies. These data show that when single cells are encapsulated with single viral particles under antibody stress without competition from other virions, the number of resulting infectious particles is nearly equivalent to the number of viral genomes present. These findings suggest that lower fitness virions can infect cells successfully and replicate, indicating that the microfluidics system may serve as an effective tool for isolating mutants that escape evolutionary stressors.


Prevalence and Risk Factors for Bariatric Surgery Readmissions: Findings From 130,007 Admissions in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program.
To evaluate readmissions following laparoscopic adjustable gastric banding (LAGB), laparoscopic sleeve gastrectomy (LSG), and laparoscopic Roux-en-Y gastric bypass (LRYGB). Few studies have evaluated national readmission rates for primary bariatric surgery with national, bariatric-specific data. Patients undergoing primary LAGB, LSG, or LRYGB from January 1, 2014 to December 31, 2014, at 698 centers were identified based upon Current Procedural Terminology codes. The primary outcome was 30-day readmission from date of initial operation. A total of 130,007 patients who underwent primary bariatric surgery were identified: 7378 LAGB (5.7%), 80,646 LSG (62.0%), and 41,983 LRYGB (32.3%). A total of 5663 (4.4%) patients were readmitted within 30 days for all causes. Patients undergoing LAGB had the lowest related readmission rate of 1.4%, followed by LSG (2.8%), and LRYGB (4.9%). Of patients who had a complication, 17.9% (n = 785) were readmitted, whereas those without readmission had a complication 1.9% of the time (P < 0.001). The most common cause of a related readmission was nausea, vomiting, fluid, electrolyte, and nutritional depletion (35.4%), followed by abdominal pain (13.5%), anastomotic leak (6.4%), and bleeding (5.8%), accounting for more than 61% of readmissions. When compared with LAGB, LSG, and LRYGB had significantly higher rates of readmission (LSG: odds ratio 1.89; 95% confidence interval 1.52-2.33; LRYGB: odds ratio 3.06; 95% confidence interval 2.46-3.81). National bariatric readmissions after primary procedures were closely associated with complications, varied based on the type of procedure, and were most commonly due to nausea, vomiting, electrolyte, and nutritional depletion.


Generalized structural motif model for studying the thermodynamic stability of fullerenes: from C60 to graphene passing through giant fullerenes.
We present an extension of the structural motif model [Cioslowski et al., J. Am. Chem. Soc., 2000, 122, 8265], originally proposed to predict the relative stability of medium-sized neutral fullerenes (C60-C102), to account for the correct graphene limit, thus widening its range of applicability to giant and supergiant icosahedral fullerenes. The new model has been parameterized using the density functional theory (DFT) energies of 426 distinct fullerenes ranging from C60 to C180, most of which correspond to the lowest-energy isomers of each cage size. While the original model is inapplicable for fullerenes larger than C150, the new model performs very well for these systems, with typical deviations of 3.4 kcal mol-1 from the DFT energies. Based on the optimized parameters, we have obtained the actual energy contributions for all motifs, which we show are closely related to the number and separation of pentagonal rings, in contrast to the original version of the model. We also point out that, in general, motif models result in large deviations for largely aspherical fullerenes and propose a way to correct the errors.


A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.
Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.


Pancreatic mucinous ductal ectasia and intraductal papillary neoplasms. A single malignant clinicopathologic entity.
The purpose of the study is to review a single institutional experience with mucinous ductal ectasia (MDE) and intraductal papillary neoplasms (IPNs) and to compare the clinicopathologic features of the two groups of tumors. Mucinous ductal ectasia and IPNs represent newly recognized categories of pancreatic exocrine tumors, previously confused with pancreatic cystic neoplasms. The natural history of MDE and IPN is not well understood, and it is unclear whether MDE and IPN represent two distinct tumors or the same clinicopathologic entity. The authors reviewed the clinical presentation, treatment, histopathology, and outcomes of 23 patients diagnosed with MDE or IPN at their institution over the past 6 years. The mean age at presentation for the cohort of patients with MDE and IPN was 62.5 years. The prevalence of abdominal pain was 75%, jaundice 25%, weight loss 42%, steatorrhea 37.5%, diabetes 37.5%, and history of pencreatitis 29%. Serum CA 19-9 levels ranged from 0 to 5350 units/mL with high levels reflecting advanced disease. There were no significant differences between MDE and IPN with respect to these parameters. Both MDE and IPN comprised papillary villous epithelial neoplasms involving the main and large pancreatic ducts. The tumors ranged from a few millimeters in size to panductal and were distinguished easily from cystic neoplasms in all cases. Invasive carcinoma was present in 11 (46%) of 24 patients, carcinoma in situ in an additional 10 (42%) of 24 patients, and low grade dysplasia in the remaining 3 (12%) of 24 patients. Mucinous ductal ectasia and IPN differed histopathologically only in degree of mucin secretion and tumor location. Mucinous ductal ectasia, but not IPN, was characteristically mucin-hypersecreting and more frequently involved the head of the gland than did IPN (11/16 vs. 1/8 p < 0.04). All patients were explored surgically and 20 (83%) of 24 of the tumors were resectable with frozen section control of the duct margins (9 pancreatoduodenectomies, 4 distal pencreatectomies, 7 total pancreatectomies). Despite the 88% prevalence of cancer, the overall survival at a mean follow-up of 21 months was 13 (87%) of 15 for MDE and 5 (71%) of 7 for IPN. Intraductal papillary neoplasms with or without MDE represent a spectrum of main duct papillary tumors ranging from adenoma to carcinoma with differing amounts of extracellular mucin production. Malignant IPNs with or without MDE typically exhibit extensive intraductal growth but are slow to invade the periductal tissues and slow to metastasize. The majority of patients with these tumors have resectable disease and a favorable prognosis; endoscopic therapy is inappropriate. The encompessing term intraductal papillary-mucinous tumors is appropriate.


Use of a single-strand specific nuclease for analysis of bacterial and plasmid deoxyribonucleic acid homo- and heteroduplexes.
Bacterial and plasmid homo- and heteroduplexes have been analyzed with a single-strand specific endonuclease, S1, of Aspergillus oryzae. Under appropriate assay conditions, there was a high degree of correlation between the degree of deoxyribonucleic acid (DNA)-DNA homoduplex formation assessed by the S1 endonuclease and by hydroxyapatite (HA). Heteroduplexes which contain extensive regions of polynucleotide sequences in common are similarly recognized by the S1 endonuclease and HA. In instances where there is little or imperfect complementarity between heterologous DNA strands, the S1 endonuclease and the HA method give slightly different estimates. From DNA duplex thermal stability experiments assayed with the S1 endonuclease, there is preliminary evidence that well-matched sequences identified by the enzyme are not similarly recognized by HA. The assay of homo- and heteroduplexes with the S1 endonuclease permits an accurate, reproducible and rapid determination of polynucleotide sequence relationships and may be seriously considered as a method of choice for survey work and for investigations which require a large number of DNA-DNA hybridization assays.


Acute interventions and referral of patients with bipolar disorder by the psychiatric consultation liaison service in a general hospital in Germany: a retrospective analysis.
To investigate the population of bipolar patients in a general hospital in Germany who required treatment by a consultant psychiatrist. A retrospective analysis was conducted of the clinical records of 47 patients diagnosed with bipolar disorder (DSM-IV-TR criteria) who were treated by a consultant psychiatrist between 2009 and 2012 in one of the general hospitals of Charité Berlin, Campus Benjamin Franklin, Berlin, Germany. We investigated the sections of the hospital that requested psychiatric consultations for bipolar patients, the status of these patients, and their primary cause of treatment, as well as the intervention (including pharmacotherapy) recommended by the consultant psychiatrist. For more than half of the patients, their psychiatric illness was either directly or indirectly the reason they presented to the hospital. The remaining bipolar patients were treated for various somatic illnesses unrelated to their bipolar disorder throughout the hospital, with a relative overrepresentation of patients in the neurology department. More than half of the patients were referred to a psychiatric hospital by the consultant psychiatrist. Benzodiazepines were the most commonly administered drugs for acute pharmacologic intervention. Psychiatric consultations are not frequently requested for bipolar patients compared to those with other psychiatric disorders. However, more than half of the bipolar patients needed further psychiatric treatment in a psychiatric hospital. This finding emphasizes the importance of psychiatric consultations in a general hospital for bipolar patients. The administration of benzodiazepines as an acute treatment seems to be the standard pharmacologic procedure, not a specific pharmacotherapy like mood stabilizers.


Vital signs: HIV infection, testing, and risk behaviors among youths - United States.
In 2009, 6.7% of the estimated 1.1 million persons living with human immunodeficiency virus (HIV) infection in the United States were youths (defined in this report as persons aged 13-24 years); more than half of youths with HIV (59.5%) were unaware of their infection. CDC used National HIV Surveillance System data to estimate, among youths, prevalence rates of diagnosed HIV infection in 2009 and the number of new infections (incidence) in 2010. To assess the prevalence of risk factors and HIV testing among youths, CDC used the 2009 and 2011 Youth Risk Behavior Surveillance System for 9th-12th grade students and the 2010 National Health Interview Survey (NHIS) for persons 18-24 years. Prevalence of diagnosed HIV was 69.5 per 100,000 youths at the end of 2009. Youths accounted for 12,200 (25.7%) new HIV infections in 2010. Of these, 7,000 (57.4%) were among blacks/African Americans, 2,390 (19.6%) among Hispanics/Latinos, and 2,380 (19.5%) among whites; 8,800 (72.1%) were attributed to male-to-male sexual contact. The percentage of youths tested for HIV overall was 12.9% among high school students and 34.5% among those aged 18-24 years; it was lower among males than females, and lower among whites and Hispanics/Latinos than blacks/African Americans. A disproportionate number of new HIV infections occurs among youths, especially blacks/African Americans, Hispanics/Latinos, and men who have sex with men (MSM). The percentage of youths tested for HIV, however, was low, particularly among males. Implications for Public Health: More effort is needed to provide effective school- and community-based interventions to ensure all youths, particularly MSM, have the knowledge, skills, resources, and support necessary to avoid HIV infection. Health-care providers and public health agencies should ensure that youths are tested for HIV and have access to sexual health services, and that HIV-positive youths receive ongoing health-care and prevention services.


Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2.
Biosynthesis of the prostaglandin endoperoxide by the cyclooxygenase (COX) enzymes is accompanied by formation of a small amount of 11R-hydroxyeicosatetraenoic acid (HETE), 15R-HETE, and 15S-HETE as by-products. Acetylation of COX-2 by aspirin abrogates prostaglandin synthesis and triggers formation of 15R-HETE as the sole product of oxygenation of arachidonic acid. Here, we investigated the formation of by-products of the transformation of 5S-HETE by native COX-2 and by aspirin-acetylated COX-2 using HPLC-ultraviolet, GC-MS, and LC-MS analysis. 5S,15S- dihydroxy (di)HETE, 5S,15R-diHETE, and 5S,11R-diHETE were identified as by-products of native COX-2, in addition to the previously described di-endoperoxide (5S,15S-dihydroxy-9S,11R,8S,12S-diperoxy-6E,13E-eicosadienoic acid) as the major oxygenation product. 5S,15R-diHETE was the only product formed by aspirin-acetylated COX-2. Both 5,15-diHETE and 5,11-diHETE were detected in CT26 mouse colon carcinoma cells as well as in lipopolysaccharide-activated RAW264.7 cells incubated with 5S-HETE, and their formation was attenuated in the presence of the COX-2 specific inhibitor, NS-398. Aspirin-treated CT26 cells gave 5,15-diHETE as the most prominent product formed from 5S-HETE. 5S,15S-diHETE has been described as a product of the cross-over of 5-lipoxygenase (5-LOX) and 15-LOX activities in elicited rat mononuclear cells and human leukocytes, and our studies implicate cross-over of the 5-LOX and COX-2 pathways as an additional biosynthetic route.


Attending to emotional cues for drug abuse: bridging the gap between clinic and home behaviors.
Classical conditioning models of addiction provide keys to understanding the vexing discrepancy between substance abuse patients' desire to abstain when they are in therapy sessions and their tendency to relapse. Experiments using these models demonstrate the power of environmental relapse cues and support clinical approaches, including active exposure, aimed at helping patients recognize and withstand them. Internal cues, including emotions and somatic states such as withdrawal, can trigger urges as powerfully as external cues such as people, places, and things associated with prior abuse. The authors describe a cognitive-behavioral therapy approach that focuses on identifying and actively inducing each patient's high-risk emotions, then helping him or her develop and practice healthy responses. Clinical trials support the approach for patients with panic disorder who have trouble discontinuing benzodiazepines, and early trials suggest it may be useful for patients addicted to other drugs as well.


Learning relational concepts from within- versus between-category comparisons.
This article examines relational category learning in light of 2 influential theories of concept acquisition: the structure-mapping theory of analogy and theories of feature-based category learning. According to current theories of analogy, comparing 2 instances of a relational concept enables alignment of their elements and reveals their shared relational structure. Therefore, learning relationally defined categories should be faster when comparing items of the same category than when comparing items of different categories. By contrast, feature-based theories predict a benefit of between-category comparisons, because such comparisons direct attention to the features that discriminate the categories. The present experiments tested these predictions using a 2-category classification-learning task in which 2 items are presented on every trial: either in the same category (match condition) or in different categories (contrast condition). Subjects in the contrast condition outperformed those in the match condition for feature-based categories (Experiment 1) and across 4 different types of relational categories (Experiments 1-4). Although theorists have posited that structure-mapping theory is directly applicable to relational category learning, the present findings pose a distinct challenge to this assertion. We propose that many relational categories are learnable based solely on which relations are present in the stimulus rather than requiring explicitly compositional representations based on role-filler binding. This process would be akin to feature processing and would not require structural alignment. This theoretical proposal, together with the empirical results, may lead to a better understanding of when people do and do not engage in the cognitively demanding process of structural alignment. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Striatal iron content predicts its shrinkage and changes in verbal working memory after two years in healthy adults.
The accumulation of non-heme iron in the brain has been proposed as a harbinger of neural and cognitive decline in aging and neurodegenerative disease, but support for this proposal has been drawn from cross-sectional studies, which do not provide valid estimates of change. Here, we present longitudinal evidence of subcortical iron accumulation in healthy human adults (age 19-77 at baseline). We used R2* relaxometry to estimate regional iron content twice within a 2 year period, measured volumes of the striatum and the hippocampus by manual segmentation, and assessed cognitive performance by working memory tasks. Two-year change and individual differences in the change of regional volumes, regional iron content, and working memory were examined by latent change score models while taking into account the age at baseline and metabolic risk indicators. Over the examined period, volume reduction occurred in the caudate nucleus and hippocampus, but iron content increased only in the striatum, where it explained shrinkage. Higher iron content in the caudate nucleus at baseline predicted lesser improvement in working memory after repeat testing. Although advanced age and elevated metabolic syndrome risk were associated with greater iron content in the putamen at baseline, neither age nor metabolic risk influenced change in any variable. Thus, longitudinal evidence supports the notion that accumulation of subcortical iron is a risk factor for neural and cognitive decline in normal aging.


Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm.
The cellular interactions that control the differentiation of dorsal cell types from neural progenitors have been examined in neural plate explants. Certain genes that are expressed in the dorsal neural tube are initially expressed uniformly within the neural plate and appear to achieve their dorsal restriction through a Sonic hedgehog (SHH)-mediated repressive signal from the notochord. The acquisition of definitive dorsal cell fates, however, requires a contact-dependent signal from the epidermal ectoderm. BMP4 and BMP7 are expressed in the epidermal ectoderm, and both proteins mimic its inductive activity. BMP4 and a related gene, DSL1, are subsequently expressed by cells in the dorsal neural tube. The differentiation of dorsal cell types, therefore, appears to be initiated at the neural plate stage and to involve the opponent activities of a BMP-mediated dorsalizing signal from the epidermal ectoderm and a SHH-mediated ventralizing signal from the notochord.


EDTA addition enhances bacterial respiration activities and hydrocarbon degradation in bioaugmented and non-bioaugmented oil-contaminated desert soils.
The low number and activity of hydrocarbon-degrading bacteria and the low solubility and availability of hydrocarbons hamper bioremediation of oil-contaminated soils in arid deserts, thus bioremediation treatments that circumvent these limitations are required. We tested the effect of Ethylenediaminetetraacetic acid (EDTA) addition, at different concentrations (i.e. 0.1, 1 and 10 mM), on bacterial respiration and biodegradation of Arabian light oil in bioaugmented (i.e. with the addition of exogenous alkane-degrading consortium) and non-bioaugmented oil-contaminated desert soils. Post-treatment shifts in the soils' bacterial community structure were monitored using MiSeq sequencing. Bacterial respiration, indicated by the amount of evolved CO2, was highest at 10 mM EDTA in bioaugmented and non-bioaugmented soils, reaching an amount of 2.2 ± 0.08 and 1.6 ± 0.02 mg-CO2 g(-1) after 14 days of incubation, respectively. GC-MS revealed that 91.5% of the C14-C30 alkanes were degraded after 42 days when 10 mM EDTA and the bacterial consortium were added together. MiSeq sequencing showed that 78-91% of retrieved sequences in the original soil belonged to Deinococci, Alphaproteobacteria, Gammaproteobacteia and Bacilli. The same bacterial classes were detected in the 10 mM EDTA-treated soils, however with slight differences in their relative abundances. In the bioaugmented soils, only Alcanivorax sp. MH3 and Parvibaculum sp. MH21 from the exogenous bacterial consortium could survive until the end of the experiment. We conclude that the addition of EDTA at appropriate concentrations could facilitate biodegradation processes by increasing hydrocarbon availability to microbes. The addition of exogenous oil-degrading bacteria along with EDTA could serve as an ideal solution for the decontamination of oil-contaminated desert soils.


Patterns and predictors of referrals to allied health services for individuals with Parkinson's disease: A Parkinson's foundation (PF) QII study.
Rehabilitation therapies are critical for optimizing quality-of-life and daily functions for individuals living with Parkinson's disease (PD). Thus, understanding the patterns of and under what conditions physicians make rehabilitation referrals is important for optimizing care. We analyzed data from 5020 participants (4 countries) collected from 1/3/2016 to 4/20/2018 as part of the Parkinson's Foundation Quality Improvement Initiative (PF QII). Data were analyzed for single discipline and multidiscipline referrals to speech language pathology (SLP), physical therapy (PT), and occupational therapy (OT). Group comparisons (referred vs. not-referred) and regression procedures were implemented to determine demographic and clinical variables that were associated with an increased likelihood of rehabilitation referral. 35.3% of participants were referred to rehabilitation services. Of these, 25.1% received a multidiscipline referral. There was a statistically significant effect of disease stage on both single discipline (χ2(2) = 45.1, p < 0.0001) and multidiscipline (χ2(2) = 74.2, p < 0.0001) referrals, with higher rates in later stages. Referred vs. not-referred participants differed significantly on a number of variables; however, only falls in the 6-months prior, advanced- and moderate-stage disease, older age, hospital admissions, and higher caregiver burden were associated with an increased likelihood of rehabilitation referral (adjusted odds ratios ≥ 1, Range = 1.08 to 1.62). Despite evidence supporting multidiscipline and proactive rehabilitation in PD, the majority of referrals were made to a single service and may be reactions to falls or advancing disease. Data suggest there may be missed opportunities for optimizing care through proactive rehabilitation interventions.


Combinatorial library based engineering of Candida antarctica lipase A for enantioselective transacylation of sec-alcohols in organic solvent.
A method for determining lipase enantioselectivity in the transacylation of sec-alcohols in organic solvent was developed. The method was applied to a model library of Candida antarctica lipase A (CalA) variants for improved enantioselectivity (E values) in the kinetic resolution of 1-phenylethanol in isooctane. A focused combinatorial gene library simultaneously targeting seven positions in the enzyme active site was designed. Enzyme variants were immobilized on nickel-coated 96-well microtiter plates through a histidine tag (His6-tag), screened for transacylation of 1-phenylethanol in isooctane, and analyzed by GC. The highest enantioselectivity was shown by the double mutant Y93L/L367I. This enzyme variant gave an E value of 100 (R), which is a dramatic improvement on the wild-type CalA (E=3). This variant also showed high to excellent enantioselectivity for other secondary alcohols tested.


Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells.
Interleukin 7 is essential for the survival of naive T lymphocytes. Despite its importance, its cellular source in the periphery remains poorly defined. Here we report a critical function for lymph node access in T cell homeostasis and identify T zone fibroblastic reticular cells in these organs as the main source of interleukin 7. In vitro, T zone fibroblastic reticular cells were able to prevent the death of naive T lymphocytes but not of B lymphocytes by secreting interleukin 7 and the CCR7 ligand CCL19. Using gene-targeted mice, we demonstrate a nonredundant function for CCL19 in T cell homeostasis. Our data suggest that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4(+) and CD8(+) T cell homeostasis by providing a limited reservoir of survival factors.


Adult stem cell activity in naked mole rats for long-term tissue maintenance.
The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5+) in their native in vivo state, we find an expanded pool of Lgr5+ cells in NMRs, and these cells specifically at the crypt base (Lgr5+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5+CBC cells. Instead of entering quiescence (G0), NMR Lgr5+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.


Levels of tritium in soils and vegetation near Canadian nuclear facilities releasing tritium to the atmosphere: implications for environmental models.
Concentrations of organically bound tritium (OBT) and tritiated water (HTO) were measured over two growing seasons in vegetation and soil samples obtained in the vicinity of four nuclear facilities and two background locations in Canada. At the background locations, with few exceptions, OBT concentrations were higher than HTO concentrations: OBT/HTO ratios in vegetation varied between 0.3 and 20 and values in soil varied between 2.7 and 15. In the vicinity of the four nuclear facilities OBT/HTO ratios in vegetation and soils deviated from the expected mean value of 0.7, which is used as a default value in environmental transfer models. Ratios of the OBT activity concentration in plants ([OBT]plant) to the OBT activity concentration in soils ([OBT]soil) appear to be a good indicator of the long-term behaviour of tritium in soil and vegetation. In general, OBT activity concentrations in soils were nearly equal to OBT activity concentrations in plants in the vicinity of the two nuclear power plants. [OBT]plant/[OBT]soil ratios considerably below unity observed at one nuclear processing facility represents historically higher levels of tritium in the environment. The results of our study reflect the dynamic nature of HTO retention and OBT formation in vegetation and soil during the growing season. Our data support the mounting evidence suggesting that some parameters used in environmental transfer models approved for regulatory assessments should be revisited to better account for the behavior of HTO and OBT in the environment and to ensure that modelled estimates (e.g., plant OBT) are appropriately conservative.


Novel induction therapies for pleural mesothelioma.
Malignant mesothelioma is becoming increasingly common, and rates of diagnosis are expected to continue to increase in the coming years because of the extensive use of asbestos in industrialized countries and the long time interval between exposure and onset of disease. Although much research has been done on the optimal treatment for this disease, the overall prognosis remains grim. The main components of therapy are surgery, chemotherapy, and radiation therapy, but there is controversy in the literature about the optimal inclusion and sequencing of these treatments, as each has unique risk profiles. We have developed a new Surgery for Mesothelioma After Radiation Therapy protocol consisting of induction-accelerated hemithoracic radiation followed by extrapleural pneumonectomy. The rationale behind this protocol is to maximize both the tumoricidal and immunogenic potential of the radiotherapy while minimizing the radiation toxicity to the ipsilateral lung. Our initial trial demonstrated the feasibility of this approach and has shown encouraging results in patients with epithelial histology. In this article, we reviewed the current literature on induction chemotherapy for mesothelioma as well as described the Surgery for Mesothelioma After Radiation Therapy protocol and upcoming studies of novel induction therapies for mesothelioma.


Can balance in children with cerebral palsy improve through use of an activity promoting computer game?
This study aimed to evaluate if use of an activity promoting computer game, used in the home (Nintendo Wii Fit; Nintendo Co Ltd, Japan), could influence balance related outcome measures in children with cerebral palsy. Eighteen children with hemiplegic or diplegic cerebral palsy were recruited for the study. A randomised cross-over design was used with children tested at baseline, after five weeks of playing Wii Fit games and after five weeks without any intervention. Outcome measures of interest included: performance on the modified sensory organisation test, reactive balance test and rhythmic weight shift test. No significant difference was observed between testing occasions for any of the balance measures investigated (p > 0.05). Our results suggest that use of a Nintendo Wii balance board and Wii Fit software for a minimum of thirty minutes per day in the patient's own home, over a five week period, is not effective as a balance training tool in children with cerebral palsy.


Risk factors for open-angle glaucoma. The Barbados Eye Study.
To evaluate risk factors for open-angle glaucoma among black participants in the Barbados Eye Study. Population-based study of demographic, medical, ocular, familial, and other factors possibly related to open-angle glaucoma. The Barbados Eye Study included 4709 Barbados residents identified by a simple random sample of Barbadian-born citizens, 40 to 84 years of age; participation was 84%. This report is based on the 4314 black participants examined at the study site; 302 (7%) met the Barbados Eye Study criteria for open-angle glaucoma. A standardized protocol included applanation tonometry, Humphrey perimetry, fundus photography, blood pressure, anthropometry, and an interview. An ophthalmologic examination was performed for participants who met specific criteria. Open-angle glaucoma was defined by the presence of both characteristic visual field defects and optic disc damage. Association of open-angle glaucoma with specific factors was evaluated in logistic regression analyses. Age, male gender, high intraocular pressure, and family history of open-angle glaucoma were major risk factors; the latter association was stronger in men than women. Lean body mass and cataract history were the only other factors related to open-angle glaucoma. Although hypertension and diabetes were common in Barbados Eye Study participants, they were unrelated to the prevalence of open-angle glaucoma. However, associations were found with low diastolic blood pressure-intraocular pressure differences and low systolic and diastolic blood pressure/intraocular pressure ratios. In the Barbados Eye Study black population, persons most likely to have open-angle glaucoma were older men and had a family history of open-angle glaucoma, high intraocular pressure, lean body mass, and cataract history. These results suggest the importance of possible genetic or familial factors in open-angle glaucoma. The role of vascular risk factors is consistent with our finding of low blood pressure to intraocular pressure relationships, but the results could be explained by the high intraocular pressure in open-angle glaucoma.


Reciprocal Associations between Depressive Symptoms and Mastery among Older Adults; Black-White Differences.
Purpose: Although higher levels of depressive symptoms and lower levels of sense of mastery tend to be comorbid, limited information exists on racial differences in the longitudinal associations between the two over time. The current study compared Black and White American older adults for the longitudinal links between depressive symptoms and mastery in the United States. Methods: Using data from the Religion, Aging, and Health Survey, 2001-2004, this longitudinal cohort study followed 1493 Black (n = 734) and White (n = 759) elderly individuals (age 66 or more) for 3 years. Depressive symptoms [Center for Epidemiological Studies-Depression scale (CES-D), 8 items] and mastery (Pearlin Mastery Scale, 7 items) were measured in 2001 and 2004. Demographics, socio-economics, and physical health were covariates and race was the focal moderator. Multi-group structural equation modeling was used for data analysis, where groups were defined based on race. Results: Among White but not Black older adults, higher levels of depressive symptoms at baseline predicted a greater decline in sense of mastery over 3 years of follow-up. Similarly among Whites but not Blacks, individuals with lower mastery at baseline developed more depressive symptoms over time. Conclusion: Findings are indicative of Black-White differences in reciprocal associations between depressive symptoms and mastery over time. Race alters how depression is linked to changes in evaluation of self (e.g., mastery) over time.