Wavelet-based regularity analysis reveals recurrent spatiotemporal behavior in resting-state fMRI.
One of the major findings from multimodal neuroimaging studies in the past decade is that the human brain is anatomically and functionally organized into large-scale networks. In resting state fMRI (rs-fMRI), spatial patterns emerge when temporal correlations between various brain regions are tallied, evidencing networks of ongoing intercortical cooperation. However, the dynamic structure governing the brain's spontaneous activity is far less understood due to the short and noisy nature of the rs-fMRI signal. Here, we develop a wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform to measure recurrent temporal pattern stability within the rs-fMRI signal across multiple temporal scales. The method consists of performing a stationary wavelet transform to preserve signal structure, followed by construction of "lagged" subsequences to adjust for correlated features, and finally the calculation of sample entropy across wavelet scales based on an "objective" estimate of noise level at each scale. We found that the brain's default mode network (DMN) areas manifest a higher level of irregularity in rs-fMRI time series than rest of the brain. In 25 aged subjects with mild cognitive impairment and 25 matched healthy controls, wavelet-based regularity analysis showed improved sensitivity in detecting changes in the regularity of rs-fMRI signals between the two groups within the DMN and executive control networks, compared with standard multiscale entropy analysis. Wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform is a promising technique to characterize the dynamic structure of rs-fMRI as well as other biological signals.


Image modeling using inverse filtering criteria with application to textures.
Statistical approaches to image modeling have largely relied upon random models that characterize the 2-D process in terms of its first- and second-order statistics, and therefore cannot completely capture phase properties of random fields that are non-Gaussian. This constrains the parameters of noncausal image models to be symmetric and, therefore, the underlying random field to be spatially reversible. Research indicates that this assumption may not be always valid for texture images. In this paper, higher- than second-order statistics are used to derive and implement two classes of inverse filtering criteria for parameter estimation of asymmetric noncausal autoregressive moving-average (ARMA) image models with known orders. Contrary to existing approaches, FIR inverse filters are employed and image models with zeros on the unit bicircle can be handled. One of the criteria defines the smallest set of cumulant lags necessary for identifiability of these models to date, Consistency of these estimators is established, and their performance is evaluated with Monte Carlo simulations as well as texture classification and synthesis experiments.


Effect of sink region cooling on translocation of photosynthate.
The effect of metabolic inhibition of the sink tissues on translocation of (14)C-labeled photosynthate was studied by cooling part or all of the sink region in a translocating sugar beet plant (Beta vulgaris L. var Klein Wanzleben).When the sink region was cooled, 4 phases were observed: a temporary decline, a period of translocation at the pre-treatment rate, a period of decline, and a new steady rate at 35 to 45% of the original rate. The new rate persisted throughout 26 hours of cooling.Cooling half the blade of a developing leaf caused a decline in translocation to the uncooled half. When a portion of the beet was cooled, translocation to a developing leaf located above the supply leaf node increased 30%.Translocation into the treated region recovered rapidly and completely when cooling ceased indicating that cooling had not caused serious damage to tissues. Enhancement of the proportion of (14)C as sucrose in the cooled portion of the sink leaf as compared with the corresponding warm side indicated that sucrose is the chief species of translocate molecule arriving in the sink.The data suggest that the translocation process includes active uptake into storage and growing areas.


Combining demographic and genetic factors to assess population vulnerability in stream species.
Accelerating climate change and other cumulative stressors create an urgent need to understand the influence of environmental variation and landscape features on the connectivity and vulnerability of freshwater species. Here, we introduce a novel modeling framework for aquatic systems that integrates spatially explicit, individual-based, demographic and genetic (demogenetic) assessments with environmental variables. To show its potential utility, we simulated a hypothetical network of 19 migratory riverine populations (e.g., salmonids) using a riverscape connectivity and demogenetic model (CDFISH). We assessed how stream resistance to movement (a function of water temperature, fluvial distance, and physical barriers) might influence demogenetic connectivity, and hence, population vulnerability. We present demographic metrics (abundance, immigration, and change in abundance) and genetic metrics (diversity, differentiation, and change in differentiation), and combine them into a single vulnerability index for identifying populations at risk of extirpation. We considered four realistic scenarios that illustrate the relative sensitivity of these metrics for early detection of reduced connectivity: (1) maximum resistance due to high water temperatures throughout the network, (2) minimum resistance due to low water temperatures throughout the network, (3) increased resistance at a tributary junction caused by a partial barrier, and (4) complete isolation of a tributary, leaving resident individuals only. We then applied this demogenetic framework using empirical data for a bull trout (Salvelinus confluentus) metapopulation in the upper Flathead River system, Canada and USA, to assess how current and predicted future stream warming may influence population vulnerability. Results suggest that warmer water temperatures and associated barriers to movement (e.g., low flows, dewatering) are predicted to fragment suitable habitat for migratory salmonids, resulting in the loss of genetic diversity and reduced numbers in certain vulnerable populations. This demogenetic simulation framework, which is illustrated in a web-based interactive mapping prototype, should be useful for evaluating population vulnerability in a wide variety of dendritic and fragmented riverscapes, helping to guide conservation and management efforts for freshwater species.


Is Branched-Chain Amino Acids Supplementation an Efficient Nutritional Strategy to Alleviate Skeletal Muscle Damage? A Systematic Review.
Amino acids and more precisely, branched-chain amino acids (BCAAs), are usually consumed as nutritional supplements by many athletes and people involved in regular and moderate physical activities regardless of their practice level. BCAAs have been initially shown to increase muscle mass and have also been implicated in the limitation of structural and metabolic alterations associated with exercise damage. This systematic review provides a comprehensive analysis of the literature regarding the beneficial effects of BCAAs supplementation within the context of exercise-induced muscle damage or muscle injury. The potential benefit of a BCAAs supplementation was also analyzed according to the supplementation strategy-amount of BCAAs, frequency and duration of the supplementation-and the extent of muscle damage. The review protocol was registered prospectively with Prospective Register for Systematic Reviews (registration number CRD42017073006) and followed Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Literature search was performed from the date of commencement until August 2017 using four online databases (Medline, Cochrane library, Web of science and ScienceDirect). Original research articles: (i) written in English; (ii) describing experiments performed in Humans who received at least one oral BCAAs supplementation composed of leucine, isoleucine and valine mixture only as a nutritional strategy and (iii) reporting a follow-up of at least one day after exercise-induced muscle damage, were included in the systematic review analysis. Quality assessment was undertaken independently using the Quality Criteria Checklist for Primary Research. Changes in indirect markers of muscle damage were considered as primary outcome measures. Secondary outcome measures were the extent of change in indirect markers of muscle damage. In total, 11 studies were included in the analysis. A high heterogeneity was found regarding the different outcomes of these studies. The risk of bias was moderate considering the quality ratings were positive for six and neutral for three. Although a small number of studies were included, BCAAs supplementation can be efficacious on outcomes of exercise-induced muscle damage, as long as the extent of muscle damage was low-to-moderate, the supplementation strategy combined a high daily BCAAs intake (>200 mg kg-1 day-1) for a long period of time (>10 days); it was especially effective if taken prior to the damaging exercise.


A Protein-Engineered, Enhanced Yeast Display Platform for Rapid Evolution of Challenging Targets.
Here, we enhanced the popular yeast display method by multiple rounds of DNA and protein engineering. We introduced surface exposure-tailored reporters, eUnaG2 and DnbALFA, creating a new platform of C and N terminal fusion vectors. The optimization of eUnaG2 resulted in five times brighter fluorescence and 10 °C increased thermostability than UnaG. The optimized DnbALFA has 10-fold the level of expression of the starting protein. Following this, different plasmids were developed to create a complex platform allowing a broad range of protein expression organizations and labeling strategies. Our platform showed up to five times better separation between nonexpressing and expressing cells compared with traditional pCTcon2 and c-myc labeling, allowing for fewer rounds of selection and achieving higher binding affinities. Testing 16 different proteins, the enhanced system showed consistently stronger expression signals over c-myc labeling. In addition to gains in simplicity, speed, and cost-effectiveness, new applications were introduced to monitor protein surface exposure and protein retention in the secretion pathway that enabled successful protein engineering of hard-to-express proteins. As an example, we show how we optimized the WD40 domain of the ATG16L1 protein for yeast surface and soluble bacterial expression, starting from a nonexpressing protein. As a second example, we show how using the here-presented enhanced yeast display method we rapidly selected high-affinity binders toward two protein targets, demonstrating the simplicity of generating new protein-protein interactions. While the methodological changes are incremental, it results in a qualitative enhancement in the applicability of yeast display for many applications.


Delayed replantation of an avulsed maxillary premolar with open apex: a 24 months follow-up case report.
Avulsion of permanent teeth is most serious of all dental injuries and accounts for 1-16% of all traumatic injuries, of which maxillary incisors are most commonly involved. However, in this report a rare case of isolated avulsed immature premolar has been described. The patient had reported more than 3 hours after the trauma with a tooth stored in dry condition and soil contamination. The prognosis depends on measures taken at the place of accident or the time immediately after avulsion. Replantation is the treatment of choice, but cannot always be performed immediately. An appropriate emergency management and treatment plan is important for good prognosis. In this report stepwise management of an avulsed immature maxillary premolar with extended period of dry storage has been described followed up for a period of 2 yrs.


Can We Achieve Intuitive Prosthetic Elbow Control Based on Healthy Upper Limb Motor Strategies?
Most transhumeral amputees report that their prosthetic device lacks functionality, citing the control strategy as a major limitation. Indeed, they are required to control several degrees of freedom with muscle groups primarily used for elbow actuation. As a result, most of them choose to have a one-degree-of-freedom myoelectric hand for grasping objects, a myoelectric wrist for pronation/supination, and a body-powered elbow. Unlike healthy upper limb movements, the prosthetic elbow joint angle, adjusted prior to the motion, is not involved in the overall upper limb movements, causing the rest of the body to compensate for the lack of mobility of the prosthesis. A promising solution to improve upper limb prosthesis control exploits the residual limb mobility: like in healthy movements, shoulder and prosthetic elbow motions are coupled using inter-joint coordination models. The present study aims to test this approach. A transhumeral amputated individual used a prosthesis with a residual limb motion-driven elbow to point at targets. The prosthetic elbow motion was derived from IMU-based shoulder measurements and a generic model of inter-joint coordinations built from healthy individuals data. For comparison, the participant also performed the task while the prosthetic elbow was implemented with his own myoelectric control strategy. The results show that although the transhumeral amputated participant achieved the pointing task with a better precision when the elbow was myoelectrically-controlled, he had to develop large compensatory trunk movements. Automatic elbow control reduced trunk displacements, and enabled a more natural body behavior with synchronous shoulder and elbow motions. However, due to socket impairments, the residual limb amplitudes were not as large as those of healthy shoulder movements. Therefore, this work also investigates if a control strategy whereby prosthetic joints are automatized according to healthy individuals' coordination models can lead to an intuitive and natural prosthetic control.


Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer.
Cornichon homolog 4 (CNIH4) belongs to the CNIH family. It functions as an oncogene in many tumors. However, CNIH4's significance in the immune landscape and its predictive potential in cervical cancer (CESC) is unexplored. CNIH4 levels and its effect on the survival of patients with CESC were evaluated using data retrieved from The Cancer Genome Atlas (TCGA). The oncogenic effect of CNIH4 in CESC was determined using small interfering RNA-mediated transfected cell lines and tumorigenesis experiments in animal models. Higher expression of CNIH4 was found in advanced tumor and pathological stages, as well as lymph node metastasis. CNIH4 expression correlated positively with the infiltration of macrophages M2 and resting dendritic cells into the affected tissue. Additionally, functional enrichment of RNA-sequencing of CNIH4-knocked down CESC cell lines showed the association of CNIH4 to the PI3K-Akt signaling pathway. Single-sample gene set enrichment analysis highlighted several immune pathways that were elevated in the CESC samples with enhanced levels of CNIH4, including Type-I and Type-II IFN-response pathways. The impact of CNIH4 on drug sensitivity was further assessed using the GDSC database. As CNIH4 is linked to the immune landscape in CESC, this study determined a four-gene risk prediction signature utilizing CNIH4-related immunomodulators. The risk score quantified from the prediction signature was an independent predictive indicator in CESC. Receiver operating characteristic curve analysis verified the good predictive ability of the four-gene signature in TCGA-CESC cohort. Thus, the CNIH4-related model showed potential as an auxiliary TNM staging system tool. CNIH4 may be an effective predictive biomarker for patients with cervical cancer, thus providing new ideas and research directions for CESC.


Latent toxoplasmosis and psychiatric symptoms - A role of tryptophan metabolism?
Toxoplasma gondii (TOX) is a common parasite which infects approximately one third of the human population. In recent years, it has been suggested that latent toxoplasmosis may be a risk factor for the development of mental disorders, particularly schizophrenia and anxiety. With regards to depression the results have been varied. The main objective of this study was to examine subpopulations from the Danish PRISME and GENDEP populations for TOX IgG antibodies. These consisted of: a group with symptoms of anxiety, a group suffering from burnout syndrome, as well as two different subpopulations with depression of differing severity. The secondary objective of this study was to examine whether tryptophan metabolism was altered in TOX-positive subjects within each subpopulation. Our results show that the anxiety and burnout populations were more likely to be TOX IgG seropositive. Furthermore, we find that the moderate-severe but not mild-moderate depressive subpopulation were associated with TOX seropositivety, suggesting a possible role of symptom severity. Additionally, we found that TOX positive subjects in the anxiety and burnout subpopulations had altered tryptophan metabolism. This relationship did not exist in the mild-moderate depressive subpopulation. These results suggest that TOX seropositivity may be related to anxiety, burnout and potentially to severity of depression. We furthermore show that the psychiatric symptoms could be associated with an altered tryptophan metabolism.


Effect of thoracic blood volume changes on steady state cardiac output.
We have investigated the extent to which shifts of blood volume out of or into the thoracic region influence the steady state cardiac output. The systemic circulation of anesthetized dogs was replaced with an artificial circuit which stimulated the pertinent mechanical characteristics of an intact circulation. As in the normal animal, the steady state venous return was proportional to the pressure gradient for venous return (i.e, mean systemic minus right atrial pressure). Cardiac function was altered either by administration of epinephrine or by changes in left ventricular afterload. At a constant mean aortic pressure of 100 mm Hg, epinephrine administration increased the steady state cardiac output by 55%. Half of this increase resulted from the lowered mean right atrial pressure (caused by improved cardiac function); the remainder resulted from an increased mean systemic pressure (caused by the volume shift to the systemic circulation). Increases in afterload transferred sufficient volume to the heart-lung compartment to reduce significantly the mean systemic pressure and, hence, the steady state venous return. Our results indicate that the heart-lung compartment contains a significant volume which is under cardiac control. In addition to being able to alter the right atrial pressure, the heart can modulate the steady state cardiac output by adjusting the mean systemic pressure. To this degree the heart can adjust its own venous return.


Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network.
Antioxidant supplementation is thought to improve immunity and thereby reduce infectious morbidity. However, few large trials in elderly people have been conducted that include end points for clinical variables. To determine the effects of long-term daily supplementation with trace elements (zinc sulfate and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) on immunity and the incidence of infections in institutionalized elderly people. This randomized, double-blind, placebo-controlled intervention study included 725 institutionalized elderly patients (>65 years) from 25 geriatric centers in France. Patients received an oral daily supplement of nutritional doses of trace elements (zinc and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) or a placebo within a 2 x 2 factorial design for 2 years. Delayed-type hypersensitivity skin response, humoral response to influenza vaccine, and infectious morbidity and mortality. Correction of specific nutrient deficiencies was observed after 6 months of supplementation and was maintained for the first year, during which there was no effect of any treatment on delayed-type hypersensitivity skin response. Antibody titers after influenza vaccine were higher in groups that received trace elements alone or associated with vitamins, whereas the vitamin group had significantly lower antibody titers (P<.05). The number of patients without respiratory tract infections during the study was higher in groups that received trace elements (P = .06). Supplementation with neither trace elements nor vitamins significantly reduced the incidence of urogenital infections. Survival analysis for the 2 years did not show any differences between the 4 groups. Low-dose supplementation of zinc and selenium provides significant improvement in elderly patients by increasing the humoral response after vaccination and could have considerable public health importance by reducing morbidity from respiratory tract infections.


X inactivation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse.
Previously reported data on the X inactivation status of the ubiquitin activating enzyme E1 (UBE1) gene have been contradictory, and the issue has remained unsettled. Here we present three lines of evidence that UBE1 is expressed from the inactive X chromosome and therefore escapes X inactivation. First, by RNA in situ hybridization, UBE1 RNA is detected from both the active and inactive X chromosomes in human female fibroblasts. Second, UBE1 is expressed in a large panel of somatic cell hybrids retaining inactive human X chromosomes, including two independent hybrids that did not require UBE1 expression for survival. And third, sites at the 5' end of UBE1 are unmethylated on both active and inactive X chromosomes, consistent with the gene escaping inactivation. In order to address whether other genes that escape inactivation map to the same region of the X chromosome, we have also examined the expression of genes mapping adjacent to UBE1. The gene for PCTAIRE-1 (PCTK1) maps within 5 kb of UBE1 and similarly escapes X inactivation by the somatic cell hybrid assay, whereas six other genes that are within 1 Mb of UBE1 in Xp11.23 are silenced on the inactive X chromosome. Comparative mapping studies of the homologous loci in mouse establish that Ube1-x and Pctk1 are also within close physical proximity on the murine X chromosome, and expression studies of the Pctk1 gene determine that, similar to Ube1-x, it is subject to X inactivation in mouse. Methylation of CpG residues at restriction sites at the 5' end of both genes on the murine inactive X chromosome is consistent with both genes being subject to X inactivation in mouse, in contrast to their expression status in humans.


Complications and Effects of Dorsal Root Ganglion Stimulation in the Treatment of Chronic Neuropathic Pain: A Nationwide Cohort Study in Denmark.
Dorsal root ganglion (DRG) stimulation is a novel treatment of chronic neuropathic pain and has been shown to be efficacious across several case reports and randomized trials. However, long-term follow-up is limited, as are reports of complication rates. This study presents efficacy and complications for patients treated with DRG stimulation. We performed an observational, multicenter cohort study of all patients in Denmark implanted with FDA-approved DRG stimulation systems to treat chronic, neuropathic pain between 2014 and 2018. Follow-up period was one to three years. Forty-three patients underwent trial DRG stimulation; 33 were subsequently fully implanted. Pain location: 58% lower extremity; 21% upper extremity; 21% thoracic/abdominal. At the end of the observation period, 58% of fully implanted patients were still implanted; 42% had fully functional systems. In these patients, average Numerical Rating Scale (NRS)-score of pain was reduced from 6.8 to 3.5 (p = 0.00049) and worst NRS-score was reduced from 8.6 to 6.0 (p = 0.0039) at 12 months follow-up. Pain Catastrophizing Score was reduced from 32 to 15 (p = 0.0039). Thirteen patients experienced complications related to defect leads (39% of implanted systems). In four patients (12%), lead removal left fragments in the root canal due to lead fracture, and three patients suffered permanent nerve damage during attempts to replace broken leads. This study suggests a significant, clinically relevant effect of DRG stimulation on neuropathic pain, but also demonstrates substantial problems with maintenance and revision of currently available systems. Consequently, treatment with equipment marketed specifically for DRG stimulation is currently paused in Denmark.


Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports.
To explore the structure and content of a non-random sample of clinical study reports (CSRs) to guide clinicians and systematic reviewers. We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators. CSRs reporting sufficient information for extraction ('adequate'). Presence and length of essential elements of trial design and reporting and compression factor (ratio of page length for CSRs compared to its published counterpart in a scientific journal). Data were extracted on standard forms and crosschecked for accuracy. We assembled a population of 78 CSRs (covering 90 randomised controlled trials; 144 610 pages total) dated 1991-2011 of 14 pharmaceuticals. Report synopses had a median length of 5 pages, efficacy evaluation 13.5 pages, safety evaluation 17 pages, attached tables 337 pages, trial protocol 62 pages, statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages, respectively. While 16 (21%) of CSRs contained completed case report forms, these were accessible to us in only one case (765 pages representing 16 individuals). Compression factors ranged between 1 and 8805. Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial. They should be consulted by independent parties interested in a detailed record of a clinical trial, and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias. We cannot say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs.


Functional evidence implicating S100P in prostate cancer progression.
S100P protein regulates calcium signal transduction and mediates cytoskeletal interaction, protein phosphorylation and transcriptional control. We have previously shown how elevated S100P levels in prostate cancer strongly correlate with progression to metastatic disease. In our study, we evaluated the functional significance of S100P expression on prostate tumor growth in vitro and in vivo. S100P levels were modulated by overexpressing S100P in PC3 prostate cancer cells and by silencing S100P levels in 22Rv1 prostate cancer cells. Overexpression of S100P in PC3 cells promoted cell growth, increased the percentage of S-phase cells, decreased basal apoptosis rate and promoted anchorage independent growth in soft agar. Furthermore, prostate cancer cells overexpressing S100P were protected against camptothecin-induced apoptosis. Conversely, silencing of S100P in 22Rv1 cells using siRNA resulted in a prominent cytostatic effect. The influence of S100P on tumor growth and metastases were assessed in vivo. S100P-overexpressing PC3 cells had a dramatically increased tumor formation compared to controls. Microarray analysis showed the involvement of growth pathways including increased androgen receptor expression in S100P-overexpressing cells. These results provide the first functional proof that S100P overexpression can upregulate androgen receptor expression and thereby promote prostate cancer progression by increasing cell growth. Moreover, the results confirm the oncogenic nature of S100P in prostate cancer and suggest that the protein may directly confer resistance to chemotherapy. Hence, S100P could be considered a potential drug target or a chemosensitization target, and could also serve as a biomarker for aggressive, hormone-refractory and metastatic prostate cancer.


Effect of Resting-State fNIRS Scanning Duration on Functional Brain Connectivity and Graph Theory Metrics of Brain Network.
As an emerging brain imaging technique, functional near infrared spectroscopy (fNIRS) has attracted widespread attention for advancing resting-state functional connectivity (FC) and graph theoretical analyses of brain networks. However, it remains largely unknown how the duration of the fNIRS signal scanning is related to stable and reproducible functional brain network features. To answer this question, we collected resting-state fNIRS signals (10-min duration, two runs) from 18 participants and then truncated the hemodynamic time series into 30-s time bins that ranged from 1 to 10 min. Measures of nodal efficiency, nodal betweenness, network local efficiency, global efficiency, and clustering coefficient were computed for each subject at each fNIRS signal acquisition duration. Analyses of the stability and between-run reproducibility were performed to identify optimal time length for each measure. We found that the FC, nodal efficiency and nodal betweenness stabilized and were reproducible after 1 min of fNIRS signal acquisition, whereas network clustering coefficient, local and global efficiencies stabilized after 1 min and were reproducible after 5 min of fNIRS signal acquisition for only local and global efficiencies. These quantitative results provide direct evidence regarding the choice of the resting-state fNIRS scanning duration for functional brain connectivity and topological metric stability of brain network connectivity.


Forgetting in dementia with and without subcortical lacunes.
Alzheimer's disease (AD) and subcortical ischemic vascular disease (SIVD) are common causes of dementia, often co-occur, and can present quite similarly, making differential diagnosis clinically challenging. This study tested the hypothesis that patients with SIVD retain information better than AD patients. Participants were 35 dementia patients with subcortical lacunes (SIVD group), 27 dementia patients without lacunar infarction (AD group), and 56 normal controls. Results indicated that despite comparable levels of initial acquisition, AD patients showed more rapid forgetting. Further analysis indicated that memory patterns within the SIVD group were heterogeneous, with some participants exhibiting rapid forgetting and some exhibiting good retention. SIVD participants with good retention showed a trend for greater executive impairments relative to SIVD participants with rapid forgetting and AD participants. Results suggest that rapid forgetting in SIVD may imply concomitant AD, whereas the dementia in patients with good retention may be purely vascular in origin. Three SIVD patients with rapid forgetting followed to autopsy all had AD pathology, further supporting the link between memory patterns and AD.


Genome-wide association study of breast cancer in the Japanese population.
Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0 × 10(-5)) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31 × 10(-12), OR = 1.23; 95% CI = 1.16-.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79 × 10(-11), OR = 1.21; 95% CI = 1.15-.28) and rs12922061 (combined P-value of 3.97 × 10(-10), OR = 1.23; 95% CI = 1.15-.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.


Prevalence of Smokeless Tobacco among Low Socioeconomic Populations: A Cross-Sectional Analysis.
Cost, social acceptability and non-stringent regulations pertaining to smokeless tobacco (SLT) product sales have made people choose and continue using SLT. If disaggregated data on smokeless forms and smoked practices of tobacco are reviewed, the incidence of SLT remains static. There is a strong positive correlation of SLT intake with the occurrence of adverse cardiovascular disease, particularly in the low socioeconomic populations. To investigate the prevalence of smokeless tobacco, its initiation influence and risk factors associated with the practice among lower socioeconomic populations of Bangladesh. In this study, we explore the utilization of SLT among lower socioeconomic populations in industrialized zone of Bangladesh. A cross-sectional analysis using both quantitative and categorical approaches was employed. Using systematic random sampling method, four focus group discussions (FGDs) were conducted and 459 participants were interviewed. Multiple logistic regression model was applied to distinguish the significant factors among the SLT users. Almost fifty percent of the respondents initiated SLT usage at the age of 15-24 years and another 22 percent respondents were smoking and using SLT concurrently. The bulk of the women respondents used SLT during their pregnancy. Nearly twenty five percent of the respondents tried to quit the practice of SLT and one-quarter had a plan to quit SLT in the future. More than twenty percent respondents were suffering from dental decay. A noteworthy correlation was found by gender (p<0.01), sufferings from SLT related disease (p<0.05). The multiple logistic regression analysis suggested that, males were 2.7 times more knowledgeable than that of females (p<0.01) about the adversative health condition of SLT usage. The respondents suffering from SLT related diseases were 3.7 times as more knowledgeable about the effect of the practice of SLT than the respondents without diseases (p<0.01). Regarding the knowledge about the health consequences of the practice of SLT, one participant in the FGD session commented that "although the mouth is the gateway to health, we infected our mouth by using Zarda and Gul". Again, informants opined that peer, family, curiosity and hospitality, culture are influencing factors for SLT initiation. counselling on tobacco, including SLT, health hazards have to be emphasized through mass media and it is essential for development of relevant policies and communication messages to make people aware of serious health consequences of SLT usages.


Risk and rate advancement periods of total hip replacement due to primary osteoarthritis in relation to cumulative physical workload.
This study aims to (i) evaluate relative risks, excess fraction of cases, and rate advancement periods for total hip replacement (THR) due to primary osteoarthritis in relation to lifelong cumulative physical workload and (2) describe temporal trends in the proportion employed in the most highly exposed industries from 1986-2006. In a cohort study of the Danish working population, we assessed cumulative physical workload by combining year-by-year register information on employment industry with an industry exposure matrix that provided point scores (0-2) of physical workload. Cumulative physical workload was expressed as point-years corresponding to the pack-year concept of smoking. We retrieved register information on first-time THR during 1996-2006 and used a logistic regression technique to fit discrete time hazards models adjusting for age and other factors. We calculated excess fraction of cases and rate advancement periods. Total numbers of point-years ranged from 0-86. For men, an exposure-response relation was observed reaching an odds ratio of 1.33 [95% confidence interval (95% CI) 1.17-1.53] for the highest exposure category (35-86 point-years) compared to 0 point-years. The excess fraction of cases was 18%, and THR took place up to 3.4 years earlier with increasing exposure. For women, no exposure-response relation was found. At the population level, cumulative physical workload increased the risk of THR among men, with surgery being performed slightly earlier in life. The proportion employed in the most highly exposed industries remained constant.


Intermediary metabolism in protists: a sequence-based view of facultative anaerobic metabolism in evolutionarily diverse eukaryotes.
Protists account for the bulk of eukaryotic diversity. Through studies of gene and especially genome sequences the molecular basis for this diversity can be determined. Evident from genome sequencing are examples of versatile metabolism that go far beyond the canonical pathways described for eukaryotes in textbooks. In the last 2-3 years, genome sequencing and transcript profiling has unveiled several examples of heterotrophic and phototrophic protists that are unexpectedly well-equipped for ATP production using a facultative anaerobic metabolism, including some protists that can (Chlamydomonas reinhardtii) or are predicted (Naegleria gruberi, Acanthamoeba castellanii, Amoebidium parasiticum) to produce H(2) in their metabolism. It is possible that some enzymes of anaerobic metabolism were acquired and distributed among eukaryotes by lateral transfer, but it is also likely that the common ancestor of eukaryotes already had far more metabolic versatility than was widely thought a few years ago. The discussion of core energy metabolism in unicellular eukaryotes is the subject of this review. Since genomic sequencing has so far only touched the surface of protist diversity, it is anticipated that sequences of additional protists may reveal an even wider range of metabolic capabilities, while simultaneously enriching our understanding of the early evolution of eukaryotes.


Taxonomic revision of Stigmatomma Roger (Hymenoptera: Formicidae) in the Malagasy region.
In this study we present the first taxonomic revision of the ant genus Stigmatomma in the Malagasy biogeographic region, re-describe the previously known S. besucheti Baroni-Urbani, and describe seven new species to science (S. bolabola sp. n., S. irayhady sp. n., S. janovitsika sp. n., S. liebe sp. n., S. roahady sp. n., S. sakalava sp. n., and S. tsyhady sp. n.). The revision is based on the worker caste, but we provide brief descriptions of gynes and males for some species. Species descriptions, diagnosis, character discussion, identification key, and glossary are illustrated with 360 high-quality montage and SEM images. The distribution of Stigmatomma species in Madagascar are mapped and discussed within the context of the island's biomes and ecoregions. We also discuss how some morphometric variables describe the differences among the species in the bioregion. Open science is supported by providing access to R scripts, raw measurement data, and all specimen data used. All specimens used in this study were given unique identifies, and holotypes were imaged. Specimens and images are made accessible on AntWeb.org.


Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+ /taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin-receptor agonists might prevent NASH.


Physical Activity Throughout Adolescence and Hba1c in Early Adulthood: Birth Cohort Study.
Physical inactivity is responsible for 7% of diabetes deaths worldwide, but little is known whether low levels of physical activity (PA) during adolescence increase the risk of diabetes in early adulthood. We evaluated the cross-sectional and longitudinal associations between PA throughout adolescence and HbA1c concentration in early adulthood. HbA1c was measured by high performance liquid chromatography. PA was assessed by self-report at the ages of 11, 15, and 18 years and by accelerometry at the ages of 13 (subsample) and 18 years. The loss percentages of follow up were 12.5% at 11 years, 14.4% at 15 years, and 18.7% at 18 years. At 18 years, boys showed higher HbA1c than girls. At age 18 years, accelerometrybased PA at 18 years was inversely related to HbA1c levels in boys. Self-reported leisure-time PA at ages 11, 15, and 18 were unrelated to HbA1c in both genders. PA at 13 years of age was unrelated to HbA1c among both genders. In trajectory analysis, PA and accelerometer PA trajectories were not associated with later HbA1c. Objectively measured PA at 18 years was cross-sectionally inversely associated with HbA1c in boys only. No prospective associations were identified.


The Pittsburgh Fistula Classification System: a standardized scheme for the description of palatal fistulas.
Vague terminology is a problem in cleft palate research. No classification scheme for palatal fistulas has been proposed to date. Although a well-healed velum is a significant outcome of palatoplasty, it is nearly impossible to compare fistula-related palatoplasty results in the literature or in medical records without a standardized vocabulary. We endeavor to devise a palatal fistula classification system that may have clinical and research applicability. PubMed was searched for definitions and classifications of palatal fistula as well as incidence and recurrence rates of this outcome. Next, a 25-year retrospective review of our Cleft Center's records was performed, and fistulas were identified (n=641 charts reviewed). The fistula descriptions yielded by this chart review were evaluated in the context of anatomical descriptions in the literature, and a clinician-friendly classification scheme was designed. A literature review failed to reveal a standardized fistula classification system. An anatomically based numerical fistula classification system was devised: type I, bifid uvula; type II, soft palate; type III, junction of the soft and hard palate; type IV, hard palate; type V, junction of the primary and secondary palates (for Veau IV clefts); type VI, lingual alveolar; and type VII, labial alveolar. We propose a standardized numerical classification system for palatal fistulas. Its clinical adoption may prospectively clarify ambiguities in the literature and facilitate future cleft palate research and clinical practice.


Italian cardiological guidelines for sports eligibility in athletes with heart disease: part 2.
In Italy the existence of a law on health protection of competitive sports since 1982 has favored the creation and the revision of these cardiological guidelines (called COCIS), which have reached their fourth edition (1989-2009). The present article is the second English version, which has summarized the larger version in Italian. The experience of the experts consulted in the course of these past 20 years has facilitated the application and the compatibility of issues related to clinical cardiology to the sports medicine field. Such prolonged experience has allowed the clinical cardiologist to acquire knowledge of the applied physiology of exercise and, on the other hand, has improved the ability of sports physicians in cardiological diagnostics. All this work has produced these guidelines related to the judgment of eligibility for competitive sports in the individual clinical situations and in the different cardiovascular abnormalities and/or heart disease. Numerous arguments are debated, such as interpretation of the athlete's ECG, the utility of a preparticipation screening, arrhythmias, congenital heart disease, cardiomyopathies, arterial hypertension, ischemic heart disease and other particular issues.


Midazolam premedication in attenuating ketamine psychic sequelae.
The objective of the study was to evaluate the effectiveness of midazolam premedication in attenuating the psychic sequelae of ketamine dissociative anaesthesia. Sixty patients undergoing various short surgical and urological procedures were taken in the study. All patients were premedicated with midazolam (0.05mg/kg i.v) five minutes before ketamine induction (1mg/kg i.v). The excitatory phenomenon, emergence delirium, occurrence of unpleasant dreams and patient acceptability of ketamine anaesthesia were recorded. Out of 60 patients studied, 15% had excitatory effects, 8% had mild delirium and 3% patients had unpleasant dreams in post operative period. Patient acceptability of ketamine anaesthesia was 100%. Hence from the study it was concluded that, midazolam premedication is effective in attenuating ketamine psychic sequelae.


Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases.
A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression.


Degradation of nuclease-stabilized RNA oligonucleotides in Mycoplasma-contaminated cell culture media.
Artificial RNA reagents such as small interfering RNAs (siRNAs) and aptamers often must be chemically modified for optimal effectiveness in environments that include ribonucleases. Mycoplasmas are common bacterial contaminants of mammalian cell cultures that are known to produce ribonucleases. Here we describe the rapid degradation of nuclease-stabilized RNA oligonucleotides in a human embryonic kidney 293 (HEK) cell culture contaminated with Mycoplasma fermentans, a common species of mycoplasma. RNA with 2'-fluoro- or 2'-O-methyl- modified pyrimidines was readily degraded in conditioned media from this culture, but was stable in conditioned media from uncontaminated HEK cells. RNA completely modified with 2'-O-methyls was not degraded in the mycoplasma-contaminated media. RNA zymogram analysis of conditioned culture media and material centrifuged from the media revealed several distinct protein bands (ranging from 30 to 68 kDa) capable of degrading RNA with 2'-fluoro- or 2'-O-methyl-modified pyrimidines. Finally, the mycoplasma-associated nuclease was detected in material centrifuged from the contaminated culture supernatants in as little as 15 minutes with an RNA oligo-containing 2'-O-methyl-modified pyrimidines and labeled with a 5'-fluorescein amidite (FAM) and 3'-quencher. These results suggest that mycoplasma contamination may be a critical confounding variable for cell culture experiments involving RNA-based reagents, with particular relevance for applications involving naked RNA (e.g., aptamer-siRNA chimeras).


Methylphenidate effects on functional outcomes in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).
The purpose of this study was to examine the effects of methylphenidate (MPH) on functional outcomes, including children's social skills, classroom behavior, emotional status, and parenting stress, during the 4-week, double-blind placebo controlled phase of the Preschoolers with Attention Deficit/Hyperactivity Disorder (ADHD) Treatment Study (PATS). A total of 114 preschoolers who had improved with acute MPH treatment, were randomized to their best MPH dose (M = 14.22 mg/day; n = 63) or placebo (PL; n = 51). Assessments included the Clinical Global Impression-Severity (CGI-S), parent and teacher versions of the Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale (SCS), Social Skills Rating System (SSRS), and Early Childhood Inventory (ECI), and Parenting Stress Index (PSI). Medication effects varied by informant and outcome measure. Parent measures and teacher SWAN scores did not differentially improve with MPH. Parent-rated depression (p < 0.02) and dysthymia (p < 0.001) on the ECI worsened with MPH, but scores were not in the clinical range. Significant medication effects were found on clinician CGI-S (p < 0.0001) and teacher social competence ratings (SCS, p < 0.03). Preschoolers with ADHD treated with MPH for 4 weeks improve in some aspects of functioning. Additional improvements might require longer treatment, higher doses, and/or intensive behavioral treatment in combination with medication.


Promoting the Value of Mental Health Nursing: The Contribution of a Consumer Academic.
Mental illness is known to occur frequently in the general population and is more common within the general health care system. High-quality health care requires nurses to have the skills, knowledge and attitudes to provide care for people experiencing mental illness or mental distress. Research suggests health professionals, including nurses, tend to share similar negative attitudes to mental illness as the general population, and consequently, mental health nursing is not a popular career path. These two factors signify a need to influence more positive attitudes toward mental illness and mental health nursing among nursing students. A qualitative exploratory research study was undertaken to examine the experiences, opinions and attitudes of an academic and research team to the introduction of a consumer academic within an undergraduate mental health nursing subject. In-depth interviews were conducted with teaching and research team members. The importance of mental health skills emerged as a major theme and included sub-themes: mental health across the health care system; contribution of consumer academic to nursing skills; addressing fear and stigma, and inspiring passion in mental health nursing. Findings suggest academic input from people with lived experience of recovery from mental illness can influence the development of mental health nursing skills and enhance the popularity of mental health nursing as a career.


Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes.
To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 (111In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous 111In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed (p less than .01). In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures.


The demographic, system, and psychosocial origins of mammographic screening disparities: prediction of initiation versus maintenance screening among immigrant and non-immigrant women.
Disparities in breast screening are well documented. Less clear are differences within groups of immigrant and non-immigrant minority women or differences in adherence to mammography guidelines over time. A sample of 1,364 immigrant and non-immigrant women (African American, English Caribbean, Haitian, Dominican, Eastern European, and European American) were recruited using a stratified cluster-sampling plan. In addition to measuring established predictors of screening, women reported mammography frequency in the last 10 years and were (per ACS guidelines at the time) categorized as never, sub-optimal (<1 screen/year), or adherent (1+ screens/year) screeners. Multinomial logistic regression showed that while ethnicity infrequently predicted the never versus sub-optimal comparison, English Caribbean, Haitian, and Eastern European women were less likely to screen systematically over time. Demographics did not predict the never versus sub-optimal distinction; only regular physician, annual exam, physician recommendation, and cancer worry showed effects. However, the adherent categorization was predicted by demographics, was less likely among women without insurance, a regular physician, or an annual exam, and more likely among women reporting certain patterns of emotion (low embarrassment and greater worry). Because regular screening is crucial to breast health, there is a clear need to consider patterns of screening among immigrant and non-immigrant women as well as whether the variables predicting the initiation of screening are distinct from those predicting systematic screening over time.


A smartphone intervention for adolescent obesity: study protocol for a randomised controlled non-inferiority trial.
There are few evidence-based mobile health solutions for treating adolescent obesity. The primary aim of this parallel non-inferiority trial is to assess the effectiveness of an experimental smartphone application in reducing obesity at 12 months, compared to the Temple Street W82GO Healthy Lifestyles intervention. The primary outcome measure is change in body mass index standardised deviation score at 12 months. The secondary aim is to compare the effect of treatment on secondary outcomes, including waist circumference, insulin sensitivity, quality of life, physical activity and psychosocial health. Adolescents with a body mass index at or above the 98th percentile (12 to 17 years) will be recruited from the Obesity clinic at Temple Street Children's University Hospital in Dublin, Ireland. W82GO is a family-based lifestyle change intervention delivered in two phases over 12 months. In the current study, participants will be randomised for phase two of treatment to either usual care or care delivered via smartphone application. One hundred and thirty-four participants will be randomised between the two study arms. An intention-to-treat analysis will be used to compare treatment differences between the groups at 12 months. The results of this study will be disseminated via open access publication and will provide important information for clinicians, patients and policy makers regarding the use of mobile health interventions in the management of adolescent obesity. Clinicaltrials.gov NCT01804855.


Multi-dimensional indices to stage idiopathic pulmonary fibrosis: a systematic review.
Idiopathic pulmonary fibrosis (IPF) has the highest mortality rate among all interstitial lung diseases, with a mean survival time of 2 to 3 years from the time of diagnosis. Prognosis is difficult to determine, due to the recognized heterogeneous progression of the disease, as well as lack of a well recognized staging system. This in turn raises challenges when considering therapeutic options for IPF patients, such as lung transplantation, versus a more conservative approach. Multiple independent factors have been identified as prognostic indicators in IPF, and a number of studies have proposed multi-dimensional indices that combine several parameters in order to achieve a more accurate delineation of disease progression. In this systematic review, the Pubmed database was used to identify studies in the area of multi-dimensional staging of IPF. We analysed and critically appraised previously proposed prognostic scoring systems. Our aim is to encourage research developments in this area to help identify an optimal multi-dimensional staging system for IPF.


CT and MR imaging of gastrointestinal stromal tumor of stomach: a pictorial review.
This pictorial review illustrates CT and MR imaging appearance of gastrointestinal stromal tumor (GIST) of the stomach and other lesions with similar imaging appearance. GIST of the stomach appears as well-defined enhanced masses with characteristics of subeppthial neoplasms. Majority are exophytic growth, but can also be of intra-luminal growth. GIST can growth into a large mass without gastrointestinal tract obstruction. Necrosis is often seen in GIST and results in heterogeneous enhancement and communication with gastrointestinal tract. CT and MRI features of several other neoplasms mimicking GISTs in the stomach are also described in this review.


Microsurgical Gross Total Resection of a Large Residual/Recurrent Vestibular Schwannoma via Translabyrinthine Approach.
Although, gross total resection in large vestibular schwannomas is an ideal goal, subtotal resection is frequently performed due to lack of expertise, concerns for facial palsy, or overuse of stereotactic radiation. In this video, we present a 31-year-old man with a 7-year history of tinnitus, dizziness, and hearing loss. The patient had a subtotal resection of a 2.5 cm right-sided vestibular schwannoma via retrosigmoid craniotomy at an outside hospital. He was referred for further surgical resection due to the increased size of the tumor on surveillance magnetic resonance imagings (MRIs) and worsening symptoms. MRI showed a residual/recurrent large schwannoma with extension to the full length of the internal acoustic canal and brain stem compression. He underwent microsurgical gross total resection via a translabyrinthine approach. The facial nerve was preserved and stimulated with 0.15 mA at the brainstem entry zone. He awoke with House-Brackmann grade III facial function, with an otherwise uneventful postoperative course. In this video, microsurgical techniques and important resection steps for this residual/recurrent vestibular schwannoma are demonstrated, and nuances for microsurgical technique are discussed. The link to the video can be found at: https://youtu.be/a0ZxE41Tqzw .


Exploratory laparotomy for potential abdominal sepsis in patients with multiple-organ failure.
We studied 29 patients with multiple-organ failure (MOF) who underwent exploratory laparotomy because of suspected intra-abdominal sepsis. The purpose was to identify predictors of continuing abdominal sepsis and to assess outcome of operation in these severely ill patients. The strongest predictor of continuing intra-abdominal sepsis was development of unexplained single-organ failure, which occurred in 17 patients. Physical findings were not a totally reliable indicator of abdominal sepsis since only 15 of 29 patients had acute abdominal findings. The main clue to sepsis in patients without acute abdominal findings was worsening organ failure. Fifteen of 29 patients died of continuing MOF. Only one patient older than 50 years survived. We suggest that earlier operation is indicated in certain patients with organ failure. Particularly aggressive operative therapy seems justified in young patients with unexplained single-organ failure or worsening MOF.


The deeper self: an expanded view of consciousness.
As science continues to explore the mysteries of the unconscious, two critical questions remain. First, can unconscious impulses, desires, and feelings be willfully raised to the level of the conscious self?, and, if so, would the unveiling of unconscious mechanisms lead to genuine self-knowledge or empowerment? Second, can we methodically tap into the unconscious to gear ourselves along more creative lines? If the unconscious is a source of intuitive and creative inspiration, how might a more expansive understanding of consciousness help us to flourish? How can we harness the intuitive parts of ourselves to think "outside the box," transcending the limitations of preconceived categories? And along those same lines, how would an expanded view of the unconscious frame our spiritual experiences or offer spiritual nourishment? Writer Siri Hustvedt, historian of psychology Sonu Shamdasani, and neuropsychologist Mark Solms will tackle everything from noetic experiences and the role of intuition to the phenomenon of peak experience and Jung's "collective unconscious."


What's the Score? Do Pleural Effusion Clinical Scoring Systems Help in Management of Disease?
Pleural effusion is a common condition, affecting over 3,000 people per million population every year. More than 50 causes of pleural effusions are known, including pleural infection and malignant pleural disease. These conditions place a large burden on healthcare systems with one-fourth of patients with pleural infection having a length of hospital stay of more than 1 month. Malignant pleural effusion represents advanced malignant disease with a correspondingly high mortality. Prognostic models using clinical information in combination with blood or pleural fluid biomarkers predicting survival and other outcome measures are therefore a priority in improving clinical care, and potentially outcomes. Identifying patients with poor prognosis may help avoid discomfort and unnecessary interventions at the end of their lives, while, on the other hand, individuals with scores predicting a particularly good prognosis might be selected for more aggressive early treatment. Such scores must be based on data representing routine practice in a general hospital and variables chosen based on their clinical availability at clinical decision points (i.e., before treatment is instituted), making the findings widely applicable.


Control of paratuberculosis (Johne's disease) in goats by vaccination.
After several years of unsuccessful efforts to eradicate paratuberculosis in goats in Norway by conventional methods such as general hygienic precautions and the isolation and slaughtering of clinically affected and serologically positive animals, a vaccination programme was initiated in 1967. The vaccine used consists of two live attenuated strains of Mycobacterium paratuberculosis suspended in a mixture of liquid paraffin, olive oil and pumice powder. The vaccine may be stored at 4 degrees C for two weeks, the dose is 1 ml and the goat kids are vaccinated at the age of two to four weeks. The efficacy of the vaccine has been judged mainly by post mortem examination of vaccinated and unvaccinated goats in the period 1967-82. During this period about 131,000 goats were vaccinated and, based on the post mortem examination of 15,219 goats, the infection rate was reduced from 53 to 1 per cent. Moreover, infection occurred almost exclusively in goats which for some reason or other had not been vaccinated or which had been too old when vaccinated. The results of these examinations showed that the adjuvanted vaccine with live M paratuberculosis bacteria offers a high degree of protection against paratuberculosis in goats.


Maternal Mortality in the United States: Recent Trends, Current Status, and Future Considerations.
Rigorous studies carried out by the National Center for Health Statistics show that previously reported increases in maternal mortality rates in the United States were an artifact of changes in surveillance. The pregnancy checkbox, introduced in the revised 2003 death certificate and implemented by the states in a staggered manner, resulted in increased identification of maternal deaths and in reported maternal mortality rates. This Commentary summarizes the findings of the National Center for Health Statistics reports, describes temporal trends and the current status of maternal mortality in the United States, and discusses future concerns. Although the National Center for Health Statistics studies, based on recoding of death certificate information (after excluding information from the pregnancy checkbox), showed that crude maternal mortality rates did not change significantly between 2002 and 2018, age-adjusted analyses show a temporal reduction in the maternal mortality rate (21% decline, 95% CI 13-28). Specific causes of maternal death, which were not affected by the pregnancy checkbox, such as preeclampsia, showed substantial temporal declines. However, large racial disparities continue to exist: Non-Hispanic Black women had a 2.5-fold higher maternal mortality rate compared with non-Hispanic White women in 2018. This overview of maternal mortality underscores the need for better surveillance and more accurate identification of maternal deaths, improved clinical care, and expanded public health initiatives to address social determinants of health. Challenges with ascertaining maternal deaths notwithstanding, several causes of maternal death (unaffected by surveillance artifacts) show significant temporal declines, even though there remains substantial scope for preventing avoidable maternal death and reducing disparities.


Differential Gene Expression Following Noise Trauma in Birds and Mammals.
Acoustic overstimulation has very different outcomes in birds and mammals. When noise exposure kills hair cells in birds, these cells can regenerate and hearing will recover. In mammals, however, the hair cell loss, and resulting hearing loss, is permanent. Changes in gene expression form the basis for important biological processes, including repair, regeneration, and plasticity. We are therefore using a battery of molecular approaches to identify and compare changes in gene expression following noise trauma in birds and mammals. Both differential display and subtractive hybridisation were used to identify genes whose expression increased in the chick basilar papilla immediately following exposure to an octave band noise (118 dB, centre frequency 1.5 kHz) for 4-6 hr. Among those upregulated genes were two involved in actin signalling: the CDC42 gene encoding a Rho GTPase, and WDR1, which encodes a protein involved in actin dynamics. A third gene, UBE3B, encodes an E3 ubiquitin ligase involved in protein turnover. A fourth gene encodes a cystein-rich secreted protein that may interact with calcium channels. To examine the mammalian response, gene microarrays on nylon membranes (Clontech Atlas Gene Arrays) were used to examine global changes in gene expression 30 minutes after TTS (110 dB broadband noise 50% duty cycle) or PTS (125 dB, 100% duty cycle) noise overstimulation (each for 90 minutes) in the rat cochlea. Several genes, including classic immediate early response genes such as c-fos, EGR1/NGFI-A, and NGFI-B, were upregulated at this early time point following the PTS exposure, but were not upregulated following the TTS exposure.


Generation and amplification of ultrashort shaped pulses in the visible by a two-stage noncollinear optical parametric process.
We report the generation and amplification of ultrashort shaped pulses in the visible by a two-stage noncollinear optical parametric amplification process. Phase and amplitude profiles of the shaped pulses are conserved in our amplification scheme. The energy losses normally associated with the production of complex shaped pulses are eliminated.


Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance.
Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways.


Collection of genomic DNA from adults in epidemiological studies by buccal cytobrush and mouthwash.
Blood samples are an excellent source of large amounts of genomic DNA. However, alternative sources are often needed in epidemiological studies because of difficulties in obtaining blood samples. This report evaluates the buccal cytobrush and alcohol-containing mouthwash protocols for collecting DNA by mail. Several DNA extraction techniques are also evaluated. The study was conducted in two phases. In phase 1, we compared cytobrush and mouthwash samples collected by mail in two different epidemiological studies: (a) cytobrush samples (n = 120) from a United States case-control study of breast cancer; and (b) mouthwash samples (n = 40) from a prospective cohort of male United States farmers. Findings from phase 1 were confirmed in phase 2, where we randomized cytobrush (n = 28) and mouthwash (n = 25) samples among participants in the breast cancer study to directly compare both collection methods. The median human DNA yield determined by hybridization with a human DNA probe from phenol-chloroform extracts was 1.0 and 1.6 microg/2 brushes for phases 1 and 2, respectively, and 27.5 and 16.6 microg/mouthwash sample for phases 1 and 2, respectively. Most (94-100%) mouthwash extracts contained high molecular weight DNA (>23 kb), in contrast to 55-61% of the brush extracts. PCR success rates for amplification of beta-globin gene fragments (268, 536, and 989 bp) were similar for cytobrush and mouthwash phenol-chloroform extracts (range, 94.4-100%). Also, we obtained high success rates in determining the number of CAG repeats in the androgen receptor gene, characterizing tetranucleotide microsatellites in six gene loci, and screening for mutations in the BRCA1/2 genes in a subset of phenol-chloroform DNA extracts. Relative to DNA extracted by phenol-chloroform from cytobrush samples, DNA extracted by NaOH had lower molecular weight, decreased PCR success rates for most assays performed, and unreliably high spectrophotometer readings for DNA yields. In conclusion, although DNA isolated from either mouthwash or cytobrush samples collected by mail from adults is adequate for a wide range of PCR-based assays, a single mouthwash sample provides substantially larger amounts and higher molecular weight DNA than two cytobrush samples.


A phylogenetic revision of Penicillium sect. Exilicaulis, including nine new species from fynbos in South Africa.
A survey of the fynbos biome in South Africa resulted in the isolation of 61 Penicillium species from Protea repens infructescences, air, and soil samples. Fourteen of these belong to Penicillium sect. Exilicaulis and therefore we considered it an opportunity to re-evaluate the taxonomy of the section. Phylogenetic comparisons of the ITS, β-tubulin, calmodulin and RPB2 gene regions of the 76 section Exilicaulis species, revealed 52 distinct species, including nine new species from fynbos. Morphological comparisons confirmed the novelty for most of these, however, new species closely related to P. rubefaciens did not show significant or consistent morphological differences and we thus placed a bias on phylogenetic data applying the Genealogical Concordance Phylogenetic Species Recognition (GCPSR) concept. In this paper we describe the nine new species and update the accepted species list and resolve synonyms in the section. Importantly, we reveal that P. citreosulfuratum is the correct name for the clade previously considered to represent P. toxicarium fide Serra et al. (2008). The nine new species are: Penicillium atrolazulinum, P. consobrinum, P. cravenianum, P. hemitrachum, P. pagulum, P. repensicola, P. momoii, P. subturcoseum, and P. xanthomelinii spp. nov.


National mortality burden due to communicable, non-communicable, and other diseases in Ethiopia, 1990-2015: findings from the Global Burden of Disease Study 2015.
Ethiopia lacks a complete vital registration system that would assist in measuring disease burden and risk factors. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) estimates to describe the mortality burden from communicable, non-communicable, and other diseases in Ethiopia over the last 25 years. GBD 2015 mainly used cause of death ensemble modeling to measure causes of death by age, sex, and year for 195 countries. We report numbers of deaths and rates of years of life lost (YLL) for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non-communicable diseases (NCDs), and injuries with 95% uncertainty intervals (UI) for Ethiopia from 1990 to 2015. CMNN causes of death have declined by 65% in the last two-and-a-half decades. Injury-related causes of death have also decreased by 70%. Deaths due to NCDs declined by 37% during the same period. Ethiopia showed a faster decline in the burden of four out of the five leading causes of age-standardized premature mortality rates when compared to the overall sub-Saharan African region and the Eastern sub-Saharan African region: lower respiratory infections, tuberculosis, HIV/AIDS, and diarrheal diseases; however, the same could not be said for ischemic heart disease and other NCDs. Non-communicable diseases, together, were the leading causes of age-standardized mortality rates, whereas CMNN diseases were leading causes of premature mortality in 2015. Although lower respiratory infections, tuberculosis, and diarrheal disease were the leading causes of age-standardized death rates, they showed major declines from 1990 to 2015. Neonatal encephalopathy, iron-deficiency anemia, protein-energy malnutrition, and preterm birth complications also showed more than a 50% reduction in burden. HIV/AIDS-related deaths have also decreased by 70% since 2005. Ischemic heart disease, hemorrhagic stroke, and ischemic stroke were among the top causes of premature mortality and age-standardized death rates in Ethiopia in 2015. Ethiopia has been successful in reducing deaths related to communicable, maternal, neonatal, and nutritional deficiency diseases and injuries by 65%, despite unacceptably high maternal and neonatal mortality rates. However, the country's performance regarding non-communicable diseases, including cardiovascular disease, diabetes, cancer, and chronic respiratory disease, was minimal, causing these diseases to join the leading causes of premature mortality and death rates in 2015. While the country is progressing toward universal health coverage, prevention and control strategies in Ethiopia should consider the double burden of common infectious diseases and non-communicable diseases: lower respiratory infections, diarrhea, tuberculosis, HIV/AIDS, cardiovascular disease, cancer, and diabetes. Prevention and control strategies should also pay special attention to the leading causes of premature mortality and death rates caused by non-communicable diseases: cardiovascular disease, cancer, and diabetes. Measuring further progress requires a data revolution in generating, managing, analyzing, and using data for decision-making and the creation of a full vital registration system in the country.


Breastfeeding effects on intelligence quotient in 4- and 11-year-old children.
A study of preterm children found an IQ advantage among those who were breastfed as infants after controlling for maternal social class and educational status. However, this advantage needs to be examined in light of other maternal characteristics, such as maternal IQ and parenting skills, which were not measured in that study and which have been found to be related to breastfeeding. IQ was assessed in 323 children at 4 years of age on the McCarthy Scales of Children's Abilities and the Peabody Picture Vocabulary Test-Revised and in 280 children on the Wechsler Intelligence Test for Children-Revised at 11 years of age. Children who were breastfed in infancy had significantly higher scores on IQ tests at both ages, even after adjusting for social class and education, confirming the earlier findings and extending them to a predominantly full-term sample. However, the effect of breastfeeding was no longer significant after adjusting for maternal IQ assessed on the Peabody Picture Vocabulary Test-Revised and for parenting skills assessed on the Home Observation for Measurement of the Environment. Significant relations between breastfeeding and Woodcock Reading Achievement scores at 11 years were also reduced to nonsignificant levels after the inclusion of maternal IQ and the Home Observation for Measurement of the Environment. These findings suggest that the observed advantage of breastfeeding on IQ is related to genetic and socioenvironmental factors rather than to the nutritional benefits of breastfeeding on neurodevelopment. They should not be interpreted as detracting from the medical benefits associated with breastfeeding.


Interleukin 3 is a growth factor for human follicular B cell lymphoma.
More than one-half of adults with non-Hodgkin's B cell lymphomas present with low-grade follicular lymphomas. These tumor cells are found in close association with follicular T lymphocytes and dendritic cells, suggesting that the surrounding cells may play a role in the support of follicular tumors. Supernatants from activated human peripheral blood lymphocytes were found to promote the in vitro proliferation of follicular tumor cells. This effect was entirely due to interleukin 3 (IL-3), a factor generally thought to cause the growth and differentiation of immature hematopoietic cells. IL-3 receptors were detected on fresh isolates of all primary follicular cell tumors examined. These findings suggest that follicular cell tumors may be dependent in vivo on IL-3 and that therapies directed against IL-3, its receptor, or the T cells that produce it may be effective treatment for follicular lymphoma.


Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial.
Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. Lundbeck.


Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration.
The lipid kinase PIK3C3 (also known as VPS34) regulates multiple aspects of endo-membrane trafficking processes. PIK3C3 is widely expressed by neurons in the CNS, and its catalytic product PI3P is enriched in dendritic spines. Here we generated a line of conditional mutant mouse in which Pik3c3 is specifically deleted in hippocampal and in small subsets of cortical pyramidal neurons using the CaMKII-Cre transgene. We found that Pik3c3-deficiency initially causes loss of dendritic spines accompanied with reactive gliosis, which is followed by progressive neuronal degeneration over a period of several months. Layers III and IV cortical neurons are more susceptible to Pik3c3-deletion than hippocampal neurons. Furthermore, in aged conditional Pik3c3 mutant animals, there are extensive gliosis and severe secondary loss of wild type neurons. Our analyses show that Pik3c3 is essential for CNS neuronal homeostasis and Pik3c3flox/flox; CaMKII-Cre mouse is a useful model for studying pathological changes in progressive forebrain neurodegeneration.


High density lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy.
In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.


Perturbation of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Induces Trans-regional Metaplasticity at the Medial Prefrontal Cortex.
GABAergic synapses in the basolateral amygdala (BLA) play an important role in fear memory generation. We have previously reported that reduction in GABAergic synapses innervating specifically at the axon initial segment (AIS) of principal neurons of BLA, by neurofascin (NF) knockdown, impairs fear extinction. BLA is bidirectionally connected with the medial prefrontal cortex (mPFC), which is a key region involved in extinction of acquired fear memory. Here, we showed that reducing AIS GABAergic synapses within the BLA leads to impairment of synaptic plasticity in the BLA-mPFC pathway, as well as in the ventral subiculum (vSub)-mPFC pathway, which is independent of BLA involvement. The results suggest that the alteration within the BLA subsequently resulted in a form of trans-regional metaplasticity in the mPFC. In support of that notion, we observed that NF knockdown induced a severe deficit in behavioral flexibility as measured by reversal learning. Interestingly, reversal learning similar to extinction learning is an mPFC-dependent behavior. In agreement with that, measurement of the immediate-early gene, c-Fos immunoreactivity after reversal learning was reduced in the mPFC and BLA, supporting further the notion that the BLA GABAergic manipulation resulted in trans-regional metaplastic alterations within the mPFC.


The log-linear relationship between sexual isolation and sequence divergence in Bacillus transformation is robust.
The relationship between sexual isolation and sequence divergence in Bacillus transformation was previously shown to be log linear. In the present study, we have shown that this relationship is robust with respect to naturally occurring genetic variation among recipient strains of Bacillus subtilis and B. mojavensis. Naturally occurring restriction endonuclease activity was shown not to affect this relationship. Also, seven out of eight recombination mutants tested for their sensitivity to sequence divergence have shown the same relationship between sequence divergence and sexual isolation; a mutant for recH was more sensitive to sequence divergence, suggesting that the product of this gene may be involved in resolution of mismatches in heterogamic transformation. We have also shown that the relationship between sexual isolation and sequence divergence is robust with respect to variation in the conditions of transformation, including variation in the length of donor DNA, the concentration of donor DNA, and intracellular competition between donor-derived and recipient-derived DNA. The robustness of the relationship between sexual isolation and sequence divergence among naturally occurring strains and across transformation conditions allows us to predict the eventual outcome of sequence divergence among B. subtilis and its closest relatives.


Transcription and expression of the exotoxin A gene of Pseudomonas aeruginosa.
The exotoxin A genes from Pseudomonas aeruginosa strains PA103 and PAO1 have been independently cloned in a pUC9-derived plasmid. In a non-toxigenic mutant of PAO1 as host, the cloned genes directed the synthesis of intact exotoxin A that expressed ADP-ribosyltransferase activity upon treatment with urea and dithiothreitol. Western-blot analysis of culture supernatants identified a polypeptide of 67 kDa, the molecular mass of intact exotoxin A. There was an approximately 15-fold increase in the toxin yield from P. aeruginosa cells carrying a cloned PA103 gene compared to PA103, and a 40-fold increase in the yield of toxin gene yielded about four times more toxin than those carrying the cloned PAO1 gene. Toxin expression was correlated with the presence of a transcript that was initiated 88 bp upstream from the translational start site. Little or no messenger RNA from either cloned gene could be detected in an Escherichia coli host, or in a P. aeruginosa host grown in the presence of 0.1 mM-Fe2+, a condition that inhibits toxin expression. The nucleotide sequences of two regions, each of approximately 500 bp, near the 5' and 3' termini of the structural gene were established. In these regions, three exotoxin A gene from PAO1 has ten base-pair differences compared to the PA103 gene, three in the non-coding region, and seven in the structural gene, four of which should lead to amino-acid differences. No apparent sequence similarities were found between the inferred promoter region of the exotoxin A gene and that of other Pseudomonas genes, nor with the consensus sequence of E. coli promoters.


Value of cancer care: ethical considerations for the practicing oncologist.
The value of cancer care has emerged at the center of a national discourse on fiscal responsibility and resource allocation. The cost of cancer care is rising at a higher pace than any other area of health care. As we struggle to address this unsustainable rise in cancer expenditures, oncology providers are forced to examine our practice patterns and our contributions to the overall health care cost burden. This article provides an oncologist-centered examination of our duties to individual patients and how they may seem at odds with our duties to society. It also discusses how oncology providers can do their part to contain health care costs while honoring their professional obligation to do their best for each patient.


Localizing pre-attentive auditory memory-based comparison: magnetic mismatch negativity to pitch change.
Changes in the pitch of repetitive sounds elicit the mismatch negativity (MMN) of the event-related brain potential (ERP). There exist two alternative accounts for this index of automatic change detection: (1) A sensorial, non-comparator account according to which ERPs in oddball sequences are affected by differential refractory states of frequency-specific afferent cortical neurons. (2) A cognitive, comparator account stating that MMN reflects the outcome of a memory comparison between a neuronal model of the frequently presented standard sound with the sensory memory representation of the changed sound. Using a condition controlling for refractoriness effects, the two contributions to MMN can be disentangled. The present study used whole-head MEG to further elucidate the sensorial and cognitive contributions to frequency MMN. Results replicated ERP findings that MMN to pitch change is a compound of the activity of a sensorial, non-comparator mechanism and a cognitive, comparator mechanism which could be separated in time. The sensorial part of frequency MMN consisting of spatially dipolar patterns was maximal in the late N1 range (105-125 ms), while the cognitive part peaked in the late MMN-range (170-200 ms). Spatial principal component analyses revealed that the early part of the traditionally measured MMN (deviant minus standard) is mainly due to the sensorial mechanism while the later mainly due to the cognitive mechanism. Inverse modeling revealed sources for both MMN contributions in the gyrus temporales transversus, bilaterally. These MEG results suggest temporally distinct but spatially overlapping activities of non-comparator-based and comparator-based mechanisms of automatic frequency change detection in auditory cortex.


Mitigating Sulfidogenesis With Simultaneous Perchlorate and Nitrate Treatments.
Sulfide biogenesis (souring) in oil reservoirs is an extensive and costly problem. Nitrate is currently used as a souring inhibitor but often requires high concentrations and yields inconsistent results. Recently, perchlorate has displayed promise as a more potent inhibitor in lab scale studies. However, combining the two treatments to determine synergy and effectiveness in a dynamic system has never been tested. Nitrate inhibits perchlorate consumption by perchlorate reducing bacteria, suggesting that the combined treatment may allow deeper penetration of the perchlorate into the reservoir matrix. Furthermore, the metabolic intermediates of perchlorate and nitrate reduction (nitrite and chlorite, respectively) are synergistic with the primary electron acceptors for inhibition of sulfate reduction. To assess the possible synergies between nitrate and perchlorate treatments, triplicate glass columns packed with pre-soured marine sediment were flushed with media containing sulfate and an inhibitor treatment [(i) perchlorate; (ii) nitrate; (iii) perchlorate and nitrate; or (iv) none]. Internal geochemistry and microbial community changes were monitored along the length of the columns during six phases of increasing treatment concentrations. In a final phase all treatments were removed. Sulfide production decreased in all treated columns in conjunction with increased inhibitor concentrations relative to the untreated control. Interestingly, the potency of the "mixed" treatment was additive relative to the individual treatments suggesting no interaction. Microbial community analyses indicated community shifts and clustering by treatment. The mixed treatment column community's trajectory closely resembled that of the community found in the perchlorate only treatment, suggesting that perchlorate was the dominant control on the "mixed" community structure. In contrast, the nitrate and untreated column communities had unique trajectories. This study indicates that concurrent nitrate and perchlorate treatment is not more effective than perchlorate treatment alone but is more effective than nitrate treatment. As such, treatment decisions may be based on economic factors.