Time-based prospective memory in children and adolescents with traumatic brain injury: Impact of working memory demands.
Difficulties with prospective memory are frequently reported following pediatric traumatic brain injury (TBI), but rarely researched. We aimed to (i) investigate time-based prospective memory post-pediatric TBI; (ii) examine whether time-based prospective memory is differentially impacted by the demand placed on working memory; and (iii) explore which components of working memory (viz., central executive, phonological loop, and visuospatial sketchpad) are involved in time-based prospective memory under low and high cognitive load following pediatric TBI. Thirty-nine children and adolescents (20 survivors of moderate-severe TBI and 19 healthy controls) completed (i) a newly developed time-based prospective memory task (TBPMT), embedded in an ongoing lexical-decision task, with two conditions: low and high working memory load; and (ii) tests of working memory components from the Automated Working Memory Assessment. Compared to controls, participants with TBI had significantly lower prospective memory accuracy on the TBPMT across working memory loads (low, high). In contrast, the groups did not differ in time monitoring or accuracy on the ongoing task. In the TBI group, higher scores on tests of the central executive (but not phonological loop or visuospatial sketchpad) were associated with higher prospective memory accuracy and time monitoring (controlling for age). Time-based prospective memory is impaired following moderate-severe pediatric TBI, irrespective of the level of working memory demand. Our findings suggest that children and adolescents with TBI may be at risk of failing to perform future intentions at the right time in daily life, especially for individuals identified as having deficits in central executive functioning. (PsycINFO Database Record


Development and Initial Validation of the PROMIS®-Plus-HF Profile Measure.
Background Bringing together generic and heart failure (HF)-specific items in a publicly available, patient-reported outcome measure may facilitate routine health status assessment for improving clinical care and shared decision-making, assessing quality of care, evaluating new interventions, and comparing groups with different conditions. Methods and Results We performed a mixed-methods study to develop and validate the PROMIS®-Plus-HF (Patient-Reported Outcomes Measurement Information System®-Plus-Heart Failure) profile measure-a HF-specific instrument based on the generic PROMIS. We conducted 8 focus groups with 61 patients with HF and phone interviews with 10 HF clinicians. The measure was developed via an iterative process of reviewing existing PROMIS items and developing and testing new HF items. In a 600-patient sample, we estimated reliability (internal consistency; test-retest, with n=100 participants). We conducted validity analyses using Pearson r and Spearman ρ correlations with Kansas City Cardiomyopathy Questionnaire subscores. In a longitudinal sample, we performed responsiveness testing (paired t tests) with 75 patients with HF receiving interventions with expected health status improvement. The PROMIS-Plus-HF measure comprises 86 items (64 existing; 22 new) across 18 domains. Internal consistency reliability (Cronbach α) coefficients ranged from 0.52 to 0.96, with α≥0.70 in 12 of 17 domains. Test-retest intraclass correlation coefficients were ≥0.90. Correlations with Kansas City Cardiomyopathy Questionnaire subscores supported expected convergent ( r/ρ>0.60) and divergent validity ( r/ρ<0.30). In the longitudinal sample, 10 of 18 domains had improved ( P<0.05) scores from baseline to follow-up. Conclusions The PROMIS-Plus-HF profile measure-a complete assessment of physical, mental, and social health-exhibited good psychometric characteristics and may facilitate patient-centered care and research. Subsets of domains and items can be used depending on the clinical or research purpose.


The impact of postpartum hemorrhage on hospital length of stay and inpatient mortality: a National Inpatient Sample-based analysis.
Postpartum hemorrhage is a major cause of maternal morbidity and mortality, but the association between postpartum hemorrhage and hospital length of stay has not been rigorously investigated. We explored the impact of postpartum hemorrhage on hospital length of stay and inpatient mortality, as these outcomes have both clinical and economic significance. We performed a retrospective analysis using data from the National Inpatient Sample database during the 2012 through 2013 time period. Deliveries were classified as postpartum hemorrhage due to uterine atony, nonatonic postpartum hemorrhage, or not complicated by postpartum hemorrhage (nonpostpartum hemorrhage). Average length of stay and inpatient mortality rates were compared between groups. Over the study interval, postpartum hemorrhage occurred in 3% of deliveries. Among deliveries complicated by postpartum hemorrhage, 76.6% were attributed to uterine atony and 23.4% were nonatonic. Women with nonatonic postpartum hemorrhage had the highest average length of stay (3.67 days) followed by atonic postpartum hemorrhage (2.98 days) and nonpostpartum hemorrhage (2.63 days); P < .001, all comparisons. Inpatient mortality rate of nonatonic postpartum hemorrhage over the entire study period was 104 per 100,000 compared to 019 per 100,000 for atonic postpartum hemorrhage and 3 per 100,000 for nonpostpartum hemorrhage deliveries (P < .001). From 2012 through 2013, women with postpartum hemorrhage experienced significantly longer length of stay and higher inpatient mortality rates than women without postpartum hemorrhage, largely attributable to nonatonic causes of postpartum hemorrhage. As hospital length of stay and inpatient mortality are important outcomes from both clinical and societal perspectives, interventions to reduce morbidity and mortality related to postpartum hemorrhage may simultaneously facilitate delivery of more cost-effective care and improve both maternal and population health.


First Report of Puccinia veronicae-longifoliae on Veronica spicata 'Royal Candles' in Minnesota.
In September 2008, Veronica spicata 'Royal Candles' plants showing foliar symptoms typical of a rust infection were brought to the Plant Disease Clinic at the University of Minnesota. Plants were grown in a local nursery in Dakota County, Minnesota. A dark brown discoloration was apparent on the upper surface of the leaf with lighter brown pustules on the underside. Teliospores collected from the pustules were 2-celled with smooth walls and 36.35 to 48.87 μm long, 11.96 to 18.28 μm wide, and had a wall thickness of 1.33 to 2.61 μm, which is in accordance with type specimen of Puccinia veronicae-longifoliae (4). Pathogen identity was confirmed by comparison of the DNA sequence of nuclear ribosomal RNA region containing the internal transcribed spacer regions 1 and 2, 5.8S and the 5' end of the 28S subunits between herbarium samples from the U.S. National Fungus Collection (BPI 841971/GenBank Accession JQ627617 and BPI 871789/GenBank Accession JQ627618) and the collected specimen (BPI 882886/GenBank Accession JQ627616). P. veronicae-longifoliae was first reported in the United States in 2004 from a commercial nursery in Michigan (2). Veronica rust has also been found in Michigan in 2005 and more recently in 2011 (1). The only other known report of Veronica rust in the United States occurred in Connecticut in 2007 (3). P. veronicae-longifoliae is not considered a quarantine pest by The Animal and Plant Health Inspection Service due to the limited host range, the host not being on the threatened or endangered list and the host being of little economic or environmental importance (2). References: (1) T. A. Dudek et al. MSU Extension News. Retrieved from http://msue.anr.msu.edu/news/veronica_rust_observed_this_season/ , 2011. (2) North American Plant Protection Organization's Phytosanitary Alert System. Retrieved from http://www.pestalert.org/oprDetail.cfm?oprID=129 , 2004. (3) Pundt, L. Floriculture Greenhouse Update. Retrieved from http://www.negreenhouseupdate.info/index.php/july/194-rust-on-veronica , 2007. (4) D. B. O. Savile. Can. J. Bot. 46:631, 1968.


New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.
Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC. We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status. SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04). SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.


Neuroanatomical substrates of foresight in schizophrenia.
The ability to think of the long-term consequences of one's behavior and use this information to guide present and future actions, commonly referred to as foresight, is a key higher-order cognitive ability that may be deficient among persons with schizophrenia and substantially limit the degree to which such individuals experience a functional recovery from the disease. This research investigated the neuroanatomical basis of foresight in schizophrenia, in order to identify potential brain regions that may underlie impaired foresight among this population. Participants in the early course of schizophrenia or schizoaffective disorder (N=50) were assessed using structural magnetic resonance imaging and clinician-rated measures of foresight and psychopathology. Voxel-based morphometry was used to examine the relationship between foresight and regional gray matter volume in the ventromedial prefrontal, orbitofrontal and cingulate cortices. Significant positive associations were observed between foresight and gray matter volume density in the right orbitofrontal, ventromedial prefrontal, and posterior cingulate cortices, as well as the left ventromedial prefrontal and anterior cingulate cortices, after correcting for multiple comparisons. These relationships persisted after adjusting for age, gender, illness duration, and psychopathology. Better foresight was most strongly associated with increased gray matter in the right orbitofrontal/ventromedial prefrontal cortex, suggesting that reductions in gray matter volume in this region may be associated with impaired foresight in schizophrenia. Implications and directions for future research are discussed.


A new method of wet scanning electron microscopy for the analysis of myelination in EAE mouse model of multiple sclerosis.
Development of effective therapies for multiple sclerosis (MS) is dependent on the advancement of improved tools for evaluation of progression of this disease in animal models. We present a novel technique utilizing scanning electron microscopy (SEM) for imaging wet biological specimens thus enabling rapid and high-resolution imaging of myelin in mouse spinal cord (SC). We demonstrate the advantages of using the wet SEM technique to image myelin in a murine model of MS, experimental autoimmune encephalomyelitis (EAE) induced in the Biozzi (antibody-high) mouse, by sensitization with spinal cord homogenate (SCH) in adjuvant. Our studies show that the methodology allows easy identification of normal and pathological components with great clarity, which is then correlated with light microscopy (LM) and validated thereby. Furthermore, we demonstrate gold immunolabeling of specific epitopes. We conclude that the new technique provides a quick, accurate, and detailed structural evaluation of the SC that can be applied to advance the research of MS.


Validation of the Thai version of the family reported outcome measure (FROM-16)© to assess the impact of disease on the partner or family members of patients with cancer.
Cancer not only impairs a patient's physical and psychosocial functional behaviour, but also contributes to negative impact on family members' health related quality of life. Currently, there is an absence of a relevant tool in Thai with which to measure such impact. The aim of this study was to translate and validate the Family Reported Outcome Measure (FROM-16) in Thai cancer patients' family members. Thai version of FROM-16 was generated by interactive forward-backward translation process following standard guidelines. This was tested for psychometric properties including reliability and validity, namely content validity, concurrent validity, known group validity, internal consistency, exploratory and confirmatory factor analysis. Construct validity was examined by comparing the Thai FROM-16 version with the WHOQOL-BREF-THAI. The internal consistency reliability was strong (Cronbach's alpha = 0.86). A Negative moderate correlation between the Thai FROM-16 and WHOQOL-BREF-THAI was observed (r = - 0.4545, p < 0.00), and known group validity was proved by a statistically significant higher score in family members with high burden of care and insufficient income. The factor analysis supported both 3-factor and 2-factor loading model with slight difference when compared with the original version. The Thai FROM-16 showed good reliability and validity in Thai family members of patients with cancer. A slight difference in factor analysis results compared to the original version could be due to cross-culture application.


Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions.
Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.


The mouse polyubiquitin gene Ubb is essential for meiotic progression.
Ubiquitin is encoded in mice by two polyubiquitin genes, Ubb and Ubc, that are considered to be stress inducible and two constitutively expressed monoubiquitin (Uba) genes. Here we report that targeted disruption of Ubb results in male and female infertility due to failure of germ cells to progress through meiosis I and hypogonadism. In the absence of Ubb, spermatocytes and oocytes arrest during meiotic prophase, before metaphase of the first meiotic division. Although cellular ubiquitin levels are believed to be maintained by a combination of functional redundancy among the four ubiquitin genes, stress inducibility of the two polyubiquitin genes, and ubiquitin recycling by proteasome-associated isopeptidases, our results indicate that ubiquitin is required for and consumed during meiotic progression. The striking similarity of the meiotic phenotype in Ubb(-/-) germ cells to the sporulation defect in fission yeast (Schizosaccharomyces pombe) lacking a polyubiquitin gene suggests that a meiotic role of the polyubiquitin gene has been conserved throughout eukaryotic evolution.


Use of sevoflurane for anesthetic management of horses during thoracotomy.
To evaluate sevoflurane as an inhalation anesthetic for thoracotomy in horses. 18 horses between 2 and 15 years old. 4 horses were used to develop surgical techniques and were euthanatized at the end of the procedure. The remaining 14 horses were selected, because they had an episode of bleeding from their lungs during strenuous exercise. General anesthesia was induced with xylazine (1.0 mg/kg of body weight, IV) followed by ketamine (2.0 mg/kg, IV). Anesthesia was maintained with sevoflurane in oxygen delivered via a circle anesthetic breathing circuit. Ventilation was controlled to maintain PaCO2 at approximately 45 mm Hg. Neuromuscular blocking drugs (succinylcholine or atracurium) were administered to eliminate spontaneous breathing efforts and to facilitate surgery. Cardiovascular performance was monitored and supported as indicated. 2 of the 14 horses not euthanatized died as a result of ventricular fibrillation. Mean (+/- SD) duration of anesthesia was 304.9 +/- 64.1 minutes for horses that survived and 216.7 +/- 85.5 minutes for horses that were euthanatized or died. Our subjective opinion was that sevoflurane afforded good control of anesthetic depth during induction, maintenance, and recovery. Administration of sevoflurane together with neuromuscular blocking drugs provides stable and easily controllable anesthetic management of horses for elective thoracotomy and cardiac manipulation.


Tunable resolution terahertz dual frequency comb spectrometer.
Terahertz dual frequency comb spectroscopy (THz-DFCS) yields high spectral resolution without compromising bandwidth. Nonetheless, the resolution of THz-DFCS is usually limited by the laser repetition rate, which is typically between 80 MHz and 1 GHz. In this paper, we demonstrate a new method to achieve sub-repetition rate resolution in THz-DFCS by adaptively modifying the effective laser repetition rate using integrated Mach-Zehnder electro-optic modulators (MZ-EOMs). Our results demonstrate that it is possible to improve the 100 MHz resolution of a terahertz frequency comb by at least 20x (down to 5 MHz) across the terahertz spectrum without compromising the average output power, and to a large extent, its bandwidth. Our approach can augment a wide range of existing THz-DFCS systems to provide a significant and easily adaptable resolution improvement.


Evaluation and treatment of infertility.
Infertility is defined as the inability to achieve pregnancy after one year of regular, unprotected intercourse. Evaluation may be initiated sooner in patients who have risk factors for infertility or if the female partner is older than 35 years. Causes of infertility include male factors, ovulatory dysfunction, uterine abnormalities, tubal obstruction, peritoneal factors, or cervical factors. A history and physical examination can help direct the evaluation. Men should undergo evaluation with a semen analysis. Abnormalities of sperm may be treated with gonadotropin therapy, intrauterine insemination, or in vitro fertilization. Ovulation should be documented by serum progesterone level measurement at cycle day 21. Evaluation of the uterus and fallopian tubes can be performed by hysterosalpingography in women with no risk of obstruction. For patients with a history of endometriosis, pelvic infections, or ectopic pregnancy, evaluation with hysteroscopy or laparoscopy is recommended. Women with anovulation may be treated in the primary care setting with clomiphene to induce ovulation. Treatment of tubal obstruction generally requires referral for subspecialty care. Unexplained infertility in women or men may be managed with another year of unprotected intercourse, or may proceed to assisted reproductive technologies, such as intrauterine insemination or in vitro fertilization.


External quality assessment of the molecular diagnostics and genotyping of meticillin-resistant Staphylococcus aureus.
Two multicentre external quality assessments (EQA) for the molecular detection and genotyping of meticillin-resistant Staphylococcus aureus (MRSA) were arranged. Firstly, 11 samples containing various amounts of inactivated MRSA strains, meticillin-susceptible S. aureus (MSSA), meticillin-resistant coagulase-negative staphylococci (MRCoNS) or Escherichia coli were distributed to 82 laboratories. Samples containing 102 or 103 MRSA cells were correctly scored in only 16 and 46% of the datasets returned, respectively. Two of the used MSSA strains contained an SCCmec cassette lacking the mecA gene. There was a marked difference in the percentage of correct results for these two MSSA strains (37 and 39%) compared to the MSSA strain lacking the SCCmec cassette (88%). Secondly, a panel for MRSA genotyping, consisting of ten samples (two identical, three genetically related and five unique strains) was distributed to 19 laboratories. Seventy-three percent of the datasets recorded all samples correctly. Most pulsed-field gel electrophoresis (PFGE) protocols proved to be suboptimal, resulting in inferior resolution in the higher or lower fragment regions. The performance of molecular diagnostics for MRSA shows no significant changes since our first EQA in 2006. The first molecular typing results are encouraging. Both assessments indicate that programme expansion is required and that major performance discrepancies continue to exist.


Mapping kinematic functional abilities of the hand to three dimensional shapes for inclusive design.
Loss of hand function can have adverse effects on an individual's ability to maintain independence. The ability to perform daily activities, such as food preparation and medication delivery, is dependent on the hand's ability to grasp and manipulate objects. Therefore, the goal of this research was to demonstrate that three dimensional (3D) modeling of hand function can be used to improve the accessibility of handheld objects for individuals with reduced functionality through informed design. Individual models of hand functionality were created for 43 participants and group models were developed for groups of individuals without (Healthy) and with reduced functionality due to arthritis (RFA) of the hand. Cylindrical models representative of auto-injectors of varying diameters were analyzed in 3D space relative to hand function. The individual model mappings showed the cylinder diameter with the highest mapped functional values varied depending on the type of functional weighting chosen: kinematic redundancy of fingertip pad positional placement, fingertip pad orientation, or finger force directionality. The group mappings showed that for a cylinder to be grasped in a power grasp by at least 75% of the Healthy or RFA groups, a diameter of 40mm was required. This research utilizes a new hand model to objectively compare design parameters across three different kinematic factors of hand function and across groups with different functional abilities. The ability to conduct these comparisons enables the creation of designs that are universal to all - including accommodation of individuals with limits in their functional abilities.


Predictors of readmission and health related quality of life in patients with chronic heart failure: a comparison of different psychosocial aspects.
Psychological distress is common in patients with chronic heart failure. The impact of different psychological variables on prognosis has been shown but the comparative effects of these variables remain unclear. This study examines the impact of depression, anxiety, vital exhaustion, Type D personality, and social support on prognosis in chronic heart failure patients. One hundred eleven patients (mean age 57 ± 14 years) having participated in an exercise based ambulatory cardiac rehabilitation program were enrolled in a prospective cohort study. Psychological baseline data were assessed at program entry. Mortality, readmission, and health-related quality of life were assessed at follow up (mean 2.8 ± 1.1 years). After controlling for disease severity none of the psychological variables were associated with mortality, though severe anxiety predicted readmission [HR = 3.21 (95% CI, 1.04-9.93; P = .042)]. Health-related quality of life was independently explained by vital exhaustion, anxiety and either body mass index (physical dimension) or sex (emotional dimension). As psychological variables have a strong impact on health-related quality of life they should be routinely assessed in chronic heart failure patients` treatment.


Quantitative, architectural analysis of immune cell subsets in tumor-draining lymph nodes from breast cancer patients and healthy lymph nodes.
To date, pathological examination of specimens remains largely qualitative. Quantitative measures of tissue spatial features are generally not captured. To gain additional mechanistic and prognostic insights, a need for quantitative architectural analysis arises in studying immune cell-cancer interactions within the tumor microenvironment and tumor-draining lymph nodes (TDLNs). We present a novel, quantitative image analysis approach incorporating 1) multi-color tissue staining, 2) high-resolution, automated whole-section imaging, 3) custom image analysis software that identifies cell types and locations, and 4) spatial statistical analysis. As a proof of concept, we applied this approach to study the architectural patterns of T and B cells within tumor-draining lymph nodes from breast cancer patients versus healthy lymph nodes. We found that the spatial grouping patterns of T and B cells differed between healthy and breast cancer lymph nodes, and this could be attributed to the lack of B cell localization in the extrafollicular region of the TDLNs. Our integrative approach has made quantitative analysis of complex visual data possible. Our results highlight spatial alterations of immune cells within lymph nodes from breast cancer patients as an independent variable from numerical changes. This opens up new areas of investigations in research and medicine. Future application of this approach will lead to a better understanding of immune changes in the tumor microenvironment and TDLNs, and how they affect clinical outcomes.


Data envelopment analysis model for the appraisal and relative performance evaluation of nurses at an intensive care unit.
The appraisal and relative performance evaluation of nurses are very important and beneficial for both nurses and employers in an era of clinical governance, increased accountability and high standards of health care services. They enhance and consolidate the knowledge and practical skills of nurses by identification of training and career development plans as well as improvement in health care quality services, increase in job satisfaction and use of cost-effective resources. In this paper, a data envelopment analysis (DEA) model is proposed for the appraisal and relative performance evaluation of nurses. The model is validated on thirty-two nurses working at an Intensive Care Unit (ICU) at one of the most recognized hospitals in Lebanon. The DEA was able to classify nurses into efficient and inefficient ones. The set of efficient nurses was used to establish an internal best practice benchmark to project career development plans for improving the performance of other inefficient nurses. The DEA result confirmed the ranking of some nurses and highlighted injustice in other cases that were produced by the currently practiced appraisal system. Further, the DEA model is shown to be an effective talent management and motivational tool as it can provide clear managerial plans related to promoting, training and development activities from the perspective of nurses, hence increasing their satisfaction, motivation and acceptance of appraisal results. Due to such features, the model is currently being considered for implementation at ICU. Finally, the ratio of the number DEA units to the number of input/output measures is revisited with new suggested values on its upper and lower limits depending on the type of DEA models and the desired number of efficient units from a managerial perspective.


Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin.
Characteristic features of alcoholic liver injury include fibrosis and striking membrane alterations, with associated phospholipid changes. To offset some of these abnormalities, a 10-yr study was conducted in baboons: 12 animals (eight females, four males) were fed a liquid diet supplemented with polyunsaturated lecithin (4.1 mg/kcal) for up to 8 yr, with either ethanol (50% of total energy) or isocaloric carbohydrate. They were compared with another group of 18 baboons fed an equivalent amount of the same diet (with or without ethanol), but devoid of lecithin. In the two groups, comparable increases in lipids developed in the ethanol-fed animals, but striking differences in the degree of fibrosis were seen. Whereas at least septal fibrosis (with cirrhosis in two) and transformation of their lipocytes into transitional cells developed in seven of the nine baboons fed the regular diet with ethanol, septal fibrosis did not develop in any animals fed lecithin (p less than 0.005). They did not progress beyond the stage of perivenular fibrosis (sometimes associated with pericellular and perisinusoidal fibrosis) and had a significantly lesser activation of lipocytes to transitional cells. Furthermore, when three of these animals were taken off lecithin, but continued on the same amount of the ethanol-containing diet, they rapidly (within 18 to 21 mo) progressed to cirrhosis, accompanied by an increased transformation of their lipocytes to transitional cells. These results indicate that some component of lecithin exerts a protective action against the fibrogenic effects of ethanol. Because we had previously found that choline, in amounts present in lecithin, has no comparable action, the polyunsaturated phospholipids themselves might be responsible for the protective effect.


Physiologic and pathologic events mediated by intramembranous and juxtamembranous proteolysis.
Intramembranous proteolysis (IP) is a recently recognized mechanism for transmembrane signal transduction that involves proteolysis of transmembrane proteins within their membrane-spanning domains. Juxtamembranous proteolysis (JP) is similar, but proteolytic cleavage of a transmembrane protein occurs at a site close to, but not within, the transmembrane domain of the target protein. In both IP and JP, a soluble domain of a transmembrane protein is released from its membrane tether. This domain can then transmit a signal either locally or at some distance from the site of cleavage. In certain signaling pathways, JP and IP are linked. JP on one side of the membrane results in secondary IP, which then releases a signaling domain from the membrane. Whereas well-characterized proteases such as caspases, the proteasome, and metalloprotease disintegrins, have been implicated in JP, three families of multipass membrane proteases (MpMPs) have now been shown to carry out IP. Recent studies of events mediated by IP and JP indicate that they regulate key cellular signaling events including pathways involved in sterol regulation, cell fate selection, and growth regulation. Moreover, IP and JP have important roles in certain diseases such as Alzheimer's disease. Because some of the proteases mediating IP and JP can be selectivity inhibited, inhibitors targeting these proteases are likely to alter both physiologic and pathologic events triggered by IP and JP.


Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts.
Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm(3) and continued until tumors reached approximately 1.5-2.0 cm(3). Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.


Protein ingestion to stimulate myofibrillar protein synthesis requires greater relative protein intakes in healthy older versus younger men.
Adequate protein ingestion-mediated stimulation of myofibrillar protein synthesis (MPS) is required to maintain skeletal muscle mass. It is currently unknown what per meal protein intake is required to maximally stimulate the response in older men and whether it differs from that of younger men. We retrospectively analyzed data from our laboratories that measured MPS in healthy older (~71 years) and younger (~22 years) men by primed constant infusion of l-ring-[(13)C6]phenylalanine after ingestion of varying amounts (0-40 g) of high-quality dietary protein as a single bolus and normalized to body mass and, where available, lean body mass (LBM). There was no difference (p = .53) in basal MPS rates between older (0.027±0.04%/h; means ± 95% CI) and young (0.028 ± 0.03%/h) men. Biphase linear regression and breakpoint analysis revealed the slope of first line segment was lower (p < .05) in older men and that MPS reached a plateau after ingestion of 0.40 ± 0.19 and 0.24 ± 0.06 g/kg body mass (p = .055) and 0.60 ± 0.29 and 0.25 ± 0.13 g/kg lean body mass (p < .01) in older and younger men, respectively. This is the first report of the relative (to body weight) protein ingested dose response of MPS in younger and older men. Our data suggest that healthy older men are less sensitive to low protein intakes and require a greater relative protein intake, in a single meal, than young men to maximally stimulate postprandial rates of MPS. These results should be considered when developing nutritional solutions to maximize MPS for the maintenance or enhancement of muscle mass with advancing age.


Full scale evaluation of diffuser ageing with clean water oxygen transfer tests.
Aeration is a crucial part of the biological wastewater treatment in activated sludge systems and the main energy user of WWTPs. Approximately 50 to 60% of the total energy consumption of a WWTP can be attributed to the aeration system. The performance of the aeration system, and in the case of fine bubble diffused aeration the diffuser performance, has a significant impact on the overall plant efficiency. This paper seeks to isolate the changes of the diffuser performance over time by eliminating all other influencing parameters like sludge retention time, surfactants and reactor layout. To achieve this, different diffusers have been installed and tested in parallel treatment trains in two WWTPs. The diffusers have been performance tested in clean water tests under new conditions and after one year of operation. A set of material property tests describing the diffuser membrane quality was also performed. The results showed a significant drop in the performance of the EPDM diffuser in the first year which resulted in similar oxygen transfer efficiency around 16 g/m3/m for all tested systems. Even though the tested silicone diffusers did not show a drop in performance they had a low efficiency in the initial tests. The material properties indicate that the EPDM performance loss is partly due to the washout of additives.


The construction of Arabidopsis expressed sequence tag assemblies. A new resource to facilitate gene identification.
The generation of large numbers of partial cDNA sequences, or expressed sequence tags (ESTs), has provided a method with which to sample a large number of genes from an organism. More than 25,000 Arabidopsis thaliana ESTs have been deposited in public databases, producing the largest collection of ESTs for any plant species. We describe here the application of a method of reducing redundancy and increasing information content in this collection by grouping overlapping ESTs representing the same gene into a "contig" or assembly. The increased information content of these assemblies allows more putative identifications to be assigned based on the results of similarity searches with nucleotide and protein databases. The results of this analysis indicate that sequence information is available for approximately 12,600 nonoverlapping ESTs from Arabidopsis. Comparison of the assemblies with 953 Arabidopsis coding sequences indicates that up to 57% of all Arabidopsis genes are represented by an EST. Clustering analysis of these sequences suggests that between 300 and 700 gene families are represented by between 700 and 2000 sequences in the EST database. A database of the assembled sequences, their putative identifications, and cellular roles is available through the World Wide Web.


Clinical usefulness of the 2010 clinical and laboratory standards institute revised breakpoints for cephalosporin use in the treatment of bacteremia caused by Escherichia coli or Klebsiella spp.
We investigated the clinical usefulness of the revised 2010 Clinical and Laboratory Standards Institute (CLSI) breakpoints for Escherichia coli and Klebsiella spp. Of 2,623 patients with bacteremia caused by E. coli or Klebsiella spp., 573 who had been treated appropriately with cephalosporin based on the CLSI 2009 guidelines were enrolled. There were no differences in the rates of treatment failure or mortality between the appropriately and inappropriately treated groups according to the CLSI 2010 guidelines. Additionally, in the matched case-control analysis, the treatment failure rate was higher in bacteremic patients with extended-spectrum β-lactamase- (ESBL-) producing but cephalosporin-susceptible organisms than in those with ESBL-nonproducing isolates when patients with urinary tract infections were excluded (44% and 0%, resp., P = 0.026). In patients with bacteremia caused by E. coli or Klebsiella spp., the revised CLSI 2010 guidelines did not lead to poorer outcomes. However, ESBL production appeared to be associated with poor clinical outcomes in patients with bacteremia from sources other than the urinary tract.


Evaluation of the role of N-methyl-D-aspartate (NMDA) receptors in insulin secreting beta-cells.
The possibility that antagonism of N-methyl-D-aspartate (NMDA) receptors represent a novel drug target for diabetes prompted the current studies probing NMDA receptor function in the detrimental actions of homocysteine on pancreatic beta-cell function. Cellular insulin content and release, changes in membrane potential and intracellular Ca(2+) and gene expression were assessed following acute (20min) and long-term (18h) exposure of pancreatic clonal BRIN-BD11 beta-cells to known NMDA receptor modulators in the absence and presence of cytotoxic concentrations of homocysteine. As expected, acute or long-term exposure to homocysteine significantly suppressed basal and secretagogue-induced insulin release. In addition, NMDA reduced glucose-stimulated insulin secretion (GSIS). Interestingly, the selective NMDA receptor antagonist, MK-801, had no negative effects on GSIS. The effects of the NMDA receptor modulators were largely independent of effects on membrane depolarisation and increases of intracellular Ca(2+). However, combined culture of the NMDA antagonist, MK-801, with homocysteine did enhance intracellular Ca(2+) levels. Actions of NMDA agonists/antagonists and homocysteine on signal transduction pathways were independent of changes in cellular insulin content, cell viability, DNA damage or expression of key beta-cell genes. Taken together, the data support a role for NMDA receptors in controlling pancreatic beta-cell function. However, modulation of NMDA receptor function was unable to prevent the detrimental beta-cell effects of homocysteine.


The influence of belief that a car crashed on witnesses' estimates of civilian and police car speed.
The authors performed 2 experiments investigating the influence of the belief that a vehicle crashed on witnesses' estimates of the vehicle's speed. In Experiment 1, participants saw a video of a civilian car being driven, after which they were assigned to 1 of 2 conditions. The 1st group was told that the vehicle subsequently crashed; the 2nd group was not told that the vehicle crashed. The results indicted no differences between the 2 groups on a number of factors, including estimates of the vehicle's speed. Experiment 2 was identical except that the video showed a police car using flashing lights and sirens. Participants who had been told that the car had crashed overestimated speed, the likelihood of a crash, and the likelihood of someone being killed. Participants who were not told that the vehicle crashed estimated the speed of the vehicle accurately. Confidence in their estimates of speed was not significantly different between the 2 groups. Results are discussed with regard to police investigations of road accidents.


Conducting rigorous research with subgroups of at-risk youth: lessons learned from a teen pregnancy prevention project in Alaska.
In 2010, Alaska Department of Health and Social Services (DHSS) received federal funding to test an evidence-based teen pregnancy prevention program. The grant required a major modification to an existing program and a randomized control trial (RCT) to test its effectiveness. As the major modifications, Alaska used peer educators instead of adults to deliver the program to youth aged 14-19 instead of the original curriculum intended age range of 12-14. Cultural and approach adaptations were included as well. After 4 years of implementation and data collection, the sample was too small to provide statistically significant results. The lack of findings gave no information about the modification, nor any explanation of how the curriculum was received, or reasons for the small sample. This paper reports on a case study follow-up to the RCT to better understand outcome and implementation results. For this study, researchers reviewed project documents and interviewed peer educators, state and local staff, and evaluators. Three themes emerged from the data: (a) the professional growth of peer educators and development of peer education, (b) difficulties resulting from curriculum content, especially for subpopulations of sexually active youth, youth identified as lesbian, gay, bisexual, transgender, queer, intersex and/or asexual, pregnant, and parenting youth and (c) the appropriateness of an RCT with subpopulations of at-risk youth. Three recommendations emerged from the case study. First, including as many stakeholders as possible in the program and evaluation design phases is essential, and must be supported by appropriate funding streams and training. Second, there must be recognition of the multiple small subpopulations found in Alaska when adapting programs designed for a larger and more homogeneous population. Third, RCTs may not be appropriate for all population subgroups.


Protein phosphatase 1 (PP1) is a post-translational regulator of the mammalian circadian clock.
Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.


In situ accessibility of Saccharomyces cerevisiae 26S rRNA to Cy3-labeled oligonucleotide probes comprising the D1 and D2 domains.
Fluorescence in situ hybridization (FISH) has proven to be most useful for the identification of microorganisms. However, species-specific oligonucleotide probes often fail to give satisfactory results. Among the causes leading to low hybridization signals is the reduced accessibility of the targeted rRNA site to the oligonucleotide, mainly for structural reasons. In this study we used flow cytometry to determine whole-cell fluorescence intensities with a set of 32 Cy3-labeled oligonucleotide probes covering the full length of the D1 and D2 domains in the 26S rRNA of Saccharomyces cerevisiae PYCC 4455(T). The brightest signal was obtained with a probe complementary to positions 223 to 240. Almost half of the probes conferred a fluorescence intensity above 60% of the maximum, whereas only one probe could hardly detect the cells. The accessibility map based on the results obtained can be extrapolated to other yeasts, as shown experimentally with 27 additional species (14 ascomycetes and 13 basidiomycetes). This work contributes to a more rational design of species-specific probes for yeast identification and monitoring.


Cost-utility analysis of a decade of liver screening for metastases using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO).
This paper outlines a method for cost-utility analysis of liver screening for metastases in patients with posterior uveal melanoma (UM). A semiparametric model of the cumulative incidence of onset of liver metastases was fitted to a retrospective data set of 615 subjects with clinical follow-up with respect to liver surveillance imaging and outcome. The model was internally validated via bootstrap resampling in terms of its discrimination and calibration performance. Receiver operating characteristics (ROC) were derived at different time points. The discrimination performances are consistent across time. The area under the ROC curve at 5 years post treatment was 0.85 [95% CI: 0.81-0.88]. A goodness-of-fit test gives χ2(10)=5.3,p=0.9 demonstrating no evidence against the null hypothesis of zero difference between observed and expected onset of metastatic events. Results showed that at 80% sensitivity, 87% of UM patients will avoid unnecessary radiological scans. This provides potential cost savings of between £46,000 and £97,000 per year to the National Health Service assuming 600 new cases per year.


Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity.
Rationale: Abnormal expression of programmed death-1 (PD-1) ligand-1(PD-L1) in cancer cells plays a crucial role in cancer immune evasion and progression. The immune checkpoint molecules PD-1 and PD-L1 have been targeted for cancer treatment with significant benefits for cancer patients. However, the response rate is relatively low in certain types of cancer and the underlying mechanism remains poorly understood. Better understanding of the molecular mechanism of PD-L1 expression regulation in cancer cells is urgently needed to improve the treatment response rate and overall survival of patients. Fructose-1, 6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is implicated in human cancer due to its frequent loss in various cancer types. Methods: Expression of FBP1 and PD-L1 was analyzed in various cancer cell lines. Western blot and RT-qPCR were performed to determine whether FBP1 regulates PD-L1 expression. Co-immunoprecipitation and glutathione S-transferase (GST) pulldown assay were employed to define the underlying regulatory mechanisms. Immunohistochemistry was conducted to determine the correlation between FBP1 and PD-L1 expression in a cohort of patients. A cancer syngeneic mouse model was utilized to examine how FBP1 affects tumor immunity. Results: We demonstrated that in a manner independent of its enzymatic activity FBP1 downregulates the expression of PD-L1 in various cell lines of different cancer types including pancreatic and prostate cancer. We further showed that this regulation occurs at the transcriptional level and is mediated by FBP1 inhibition of signal transducer and activator of transcription-3 (STAT3)-dependent PD-L1 transcription. Moreover, FBP1 and PD-L1 protein expression were negatively correlated in pancreatic ductal adenocarcinoma (PDAC) specimens from a cohort of patients. Most importantly, we demonstrated that decreased FBP1 expression promotes tumor growth and resistance to immune checkpoint blockade therapy in mice. Conclusions: Our findings reveal a new tumor suppressor function of FBP1 in inhibiting PD-L1 expression and enhancing cancer immunity. They also suggest that FBP1-deficient human cancers could be therapeutically targeted by PD-1/PD-L1-based immune checkpoint blockade therapy.


A review of eHealth interventions for physical activity and dietary behavior change.
To review eHealth intervention studies for adults and children that targeted behavior change for physical activity, healthy eating, or both behaviors. Systematic literature searches were performed using five databases: MEDLINE, PsychInfo, CINAHL, ERIC, and the Cochrane Library to retrieve articles. Articles published in scientific journals were included if they evaluated an intervention for physical activity and/or dietary behaviors, or focused on weight loss, used randomized or quasi-experimental designs, measured outcomes at baseline and a follow-up period, and included an intervention where participants interacted with some type of electronic technology either as the main intervention or an adjunct component. All studies were published between 2000 and 2005. Eighty-six publications were initially identified, of which 49 met the inclusion criteria (13 physical activity publications, 16 dietary behaviors publications, and 20 weight loss or both physical activity and diet publications), and represented 47 different studies. Studies were described on multiple dimensions, including sample characteristics, design, intervention, measures, and results. eHealth interventions were superior to comparison groups for 21 of 41 (51%) studies (3 physical activity, 7 diet, 11 weight loss/physical activity and diet). Twenty-four studies had indeterminate results, and in four studies the comparison conditions outperformed eHealth interventions. Published studies of eHealth interventions for physical activity and dietary behavior change are in their infancy. Results indicated mixed findings related to the effectiveness of eHealth interventions. Interventions that feature interactive technologies need to be refined and more rigorously evaluated to fully determine their potential as tools to facilitate health behavior change.


Confirmation of novel type 1 diabetes risk loci in families.
Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.


Effects of MDMA Injections on the Behavior of Socially-Housed Long-Tailed Macaques (Macaca fascicularis).
3,4-methylenedioxy-N-methyl amphetamine (MDMA) is one of the few known molecules to increase human and rodent prosocial behaviors. However, this effect has never been assessed on the social behavior of non-human primates. In our study, we subcutaneously injected three different doses of MDMA (1.0, 1.5 or 2.0mg/kg) to a group of three, socially housed, young male long-tailed macaques. More than 200 hours of behavioral data were recorded, during 68 behavioral sessions, by an automatic color-based video device that tracked the 3D positions of each animal and of a toy. This data was then categorized into 5 exclusive behaviors (resting, locomotion, foraging, social contact and object play). In addition, received and given social grooming was manually scored. Results show several significant dose-dependent behavioral effects. At 1.5mg/kg only, MDMA induces a significant increase in social grooming behavior, thus confirming the prosocial effect of MDMA in macaques. Additionally, at 1.5 and 2.0 mg/kg MDMA injection substantially decreases foraging behavior, which is consistent with the known anorexigenic effect of this compound. Furthermore, at 2.0 mg/kg MDMA injection induces an increase in locomotor behavior, which is also in accordance with its known stimulant property. Interestingly, MDMA injected at 1.0mg/kg increases the rate of object play, which might be interpreted as a decrease of the inhibition to manipulate a unique object in presence of others, or, as an increase of the intrinsic motivation to manipulate this object. Together, our results support the effectiveness of MDMA to study the complex neurobiology of primates' social behaviors.


Ginsenoside Re Ameliorates Brain Insulin Resistance and Cognitive Dysfunction in High Fat Diet-Induced C57BL/6 Mice.
The ameliorating effects of ginsenoside Re (G Re) on high fat diet (HFD)-induced insulin resistance in C57BL/6 mice were investigated to assess its physiological function. In the results of behavioral tests, G Re improved cognitive dysfunction in diabetic mice using Y-maze, passive avoidance, and Morris water maze tests. G Re also significantly recovered hyperglycemia and fasting blood glucose level. In the results of serum analysis, G Re decreased triglyceride (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDLC), glutamic-oxaloacetic transaminase (GOT), and glutamic-pyruvic transaminase (GPT) and increased the ratio of high-density lipoprotein cholesterol (HDLC). G Re regulated acetylcholine (ACh), acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), and oxidized glutathione (GSH)/total GSH by regulating the c-Jun N-terminal protein kinase (JNK) pathway. These findings suggest that G Re could be used to improve HFD-induced insulin resistance condition by ameliorating hyperglycemia via protecting the cholinergic and antioxidant systems in the mouse brains.


Risk prediction in patients presenting with suspected cardiac pain: the GRACE and TIMI risk scores versus clinical evaluation.
Identifying which patients presenting with undifferentiated chest pain are at risk of major cardiac events is a major clinical challenge. Clinical evaluation may lack sufficient precision, leading to unnecessary admission or inappropriate discharge. It is uncertain whether risk scores derived from ACS populations apply to unselected patients with chest pain. To determine the predictive accuracies of the GRACE risk score, the TIMI risk score and clinical evaluation in unselected patients with suspected cardiac pain. Prospective observational study. We recruited 347 sequential patients with suspected cardiac pain presenting to a large teaching hospital. The main outcome measures were death, non-fatal myocardial infarction and emergency revascularization, in hospital and at 3 months. Receiver operating characteristic (ROC) curves were plotted for TIMI and GRACE risk scores and clinical evaluation. Overall 54 patients (15.6%) experienced a major cardiac event (16 deaths, seven myocardial infarctions (MIs), one emergency revascularization) or emergency re-admission (n=30) within 3 months. Both GRACE (p<0.001) and TIMI scores (p<0.001) predicted death/MI/revascularization (and the composite including re-admission), but the GRACE score was superior to the TIMI score for predicting major cardiac events (z=2.05), and both scores were superior to clinical evaluation (ROC areas 0.82, 0.74 and 0.55 respectively). The GRACE score predicted an ACS discharge diagnosis (p<0.001) and duration of hospital stay (p<0.001). In unselected patients presenting with suspected cardiac pain, the GRACE risk score is superior to the TIMI risk score in predicting major cardiac events, and both risk scores are superior to using ECG and troponin findings at presentation.


Computational modeling of depth ordering in occlusion through accretion or deletion of texture.
Understanding the depth ordering of surfaces in the natural world is one of the most fundamental operations of the primate visual system. Surfaces that undergo accretion or deletion (AD) of texture are always perceived to behind an adjacent surface. An updated ForMotionOcclusion model (Barnes & Mingolla, 2013) includes two streams for computing motion signals and boundary signals. The two streams generate depth percepts such that AD signals together with boundary signals generate a farther depth on the occluded side of the boundary. The model fits the classical data (Kaplan, 1969) as well as the observation that moving surfaces tend to appear closer in depth (Royden, Baker, & Allman, 1988), for both binary and grayscale stimuli. The recent "Moonwalk illusion" described by Kromrey, Bart, and Hegdé (2011) upends the classical view that the surface undergoing AD always becomes the background. Here the surface that undergoes AD appears to be in front of the surrounding surface-a result of the random flickering noise in the surround. As an additional challenge, we developed an AD display with dynamic depth ordering. A new texture version of the Michotte rabbit hole phenomenon (Michotte, Thinès, & Crabbé, 1964/1991) generates depth that changes in part of the display area. Because the ForMotionOcclusion model separates the computation of boundaries from the computation of AD signals, it is able to explain the counterintuitive Moonwalk stimulus. We show simulations that explain the workings of the model and how the model explains the Moonwalk and textured Michotte phenomena.


Allez Hop, a nationwide programme for the promotion of physical activity in Switzerland: what is the evidence for a population impact after one decade of implementation?
To present evidence for a population impact of a national physical activity promotion programme after a decade of implementation. The programme Allez Hop offered local physical activity courses (mainly walking and Nordic walking) once a week over 12 weeks. Data from a pretest posttest survey in 2005 course participants (N=2157 at baseline (of 4130, 52.2%), 1587 at first follow-up (73.6%); smaller subsample with second follow-up) and from repeated cross-sectional national surveys have been analysed regarding changes in physical activity behaviour. The total number of Allez Hop courses was 18 684 between 1997 and 2008. 89.2% of participants were women, the mean age was 48.5 years. The proportion meeting the physical activity recommendations was 31.7% at baseline, in participants with first follow-up data it increased from 33.1% to 42.3% (p<0.001). On the population level in the main user group of Allez Hop (middle-aged women) the proportion not engaging in any sport decreased from 50.1% (1997) to 47.2% (2002) and to 43.1% (2007) (p<0.01). Walking/hiking was the second most frequently performed sport (33.7%) in 2007, with the most remarkable increase since 2000 (+11.1%). Allez Hop was successfully implemented for more than a decade, reached middle-aged women and a high proportion of insufficiently active individuals. Changes in participants' physical activity behaviour must be interpreted cautiously because of low response rates and short follow-up. However, indications for behavioural changes were observed at the population level, even though these data do not allow a causal link to Allez Hop.


Fast patient-specific Monte Carlo brachytherapy dose calculations via the correlated sampling variance reduction technique.
To demonstrate potential of correlated sampling Monte Carlo (CMC) simulation to improve the calculation efficiency for permanent seed brachytherapy (PSB) implants without loss of accuracy. CMC was implemented within an in-house MC code family (PTRAN) and used to compute 3D dose distributions for two patient cases: a clinical PSB postimplant prostate CT imaging study and a simulated post lumpectomy breast PSB implant planned on a screening dedicated breast cone-beam CT patient exam. CMC tallies the dose difference, ΔD, between highly correlated histories in homogeneous and heterogeneous geometries. The heterogeneous geometry histories were derived from photon collisions sampled in a geometrically identical but purely homogeneous medium geometry, by altering their particle weights to correct for bias. The prostate case consisted of 78 Model-6711 (125)I seeds. The breast case consisted of 87 Model-200 (103)Pd seeds embedded around a simulated lumpectomy cavity. Systematic and random errors in CMC were unfolded using low-uncertainty uncorrelated MC (UMC) as the benchmark. CMC efficiency gains, relative to UMC, were computed for all voxels, and the mean was classified in regions that received minimum doses greater than 20%, 50%, and 90% of D(90), as well as for various anatomical regions. Systematic errors in CMC relative to UMC were less than 0.6% for 99% of the voxels and 0.04% for 100% of the voxels for the prostate and breast cases, respectively. For a 1 × 1 × 1 mm(3) dose grid, efficiency gains were realized in all structures with 38.1- and 59.8-fold average gains within the prostate and breast clinical target volumes (CTVs), respectively. Greater than 99% of the voxels within the prostate and breast CTVs experienced an efficiency gain. Additionally, it was shown that efficiency losses were confined to low dose regions while the largest gains were located where little difference exists between the homogeneous and heterogeneous doses. On an AMD 1090T processor, computing times of 38 and 21 sec were required to achieve an average statistical uncertainty of 2% within the prostate (1 × 1 × 1 mm(3)) and breast (0.67 × 0.67 × 0.8 mm(3)) CTVs, respectively. CMC supports an additional average 38-60 fold improvement in average efficiency relative to conventional uncorrelated MC techniques, although some voxels experience no gain or even efficiency losses. However, for the two investigated case studies, the maximum variance within clinically significant structures was always reduced (on average by a factor of 6) in the therapeutic dose range generally. CMC takes only seconds to produce an accurate, high-resolution, low-uncertainly dose distribution for the low-energy PSB implants investigated in this study.


Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.
Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82). Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation. The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.


First in situ evidence of wakes in the far field behind offshore wind farms.
More than 12 GW of offshore wind turbines are currently in operation in European waters. To optimise the use of the marine areas, wind farms are typically clustered in units of several hundred turbines. Understanding wakes of wind farms, which is the region of momentum and energy deficit downwind, is important for optimising the wind farm layouts and operation to minimize costs. While in most weather situations (unstable atmospheric stratification), the wakes of wind turbines are only a local effect within the wind farm, satellite imagery reveals wind-farm wakes to be several tens of kilometres in length under certain conditions (stable atmospheric stratification), which is also predicted by numerical models. The first direct in situ measurements of the existence and shape of large wind farm wakes by a specially equipped research aircraft in 2016 and 2017 confirm wake lengths of more than tens of kilometres under stable atmospheric conditions, with maximum wind speed deficits of 40%, and enhanced turbulence. These measurements were the first step in a large research project to describe and understand the physics of large offshore wakes using direct measurements, together with the assessment of satellite imagery and models.


Planning and self-efficacy can increase fruit and vegetable consumption: a randomized controlled trial.
Fruit and vegetable consumption represents a nutritional goal to prevent obesity and chronic illness. To change dietary behaviors, people must be motivated to do so, and they must translate their motivation into actual behavior. The present experiment aims at the psychological mechanisms that support such changes, with a particular focus on dietary self-efficacy and planning skills. A randomized controlled trial compared a theory-based psychological intervention with a health education session in 114 participants. Dependent variables were fruit and vegetable consumption, intention to consume more fruit and vegetables, planning to consume more, and dietary self-efficacy, assessed before the intervention, 1 week afterwards, and at 6-week follow up. Significant group by time interactions for all four dependent variables documented superior treatment effects for the psychological intervention group, with substantially higher scores at posttest and follow-up for the experimental group, although all students benefited from participation. To identify the contribution of the main intervention ingredients (self-efficacy and planning), regression analyses yielded mediator effects for these two factors. A social-cognitive intervention to improve fruit and vegetable consumption was superior to a knowledge-based education session. Self-efficacy and planning seem to play a major role in the mechanisms that facilitate dietary changes.


Alkaline phosphatase as a treatment of sepsis-associated acute kidney injury.
Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI). Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions. Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP). In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function. The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage. The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation. Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism. Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP. In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI.


Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.
AMPK plays a crucial role in the regulation of the energy metabolism of the heart. During ischaemia, AMPK activation is a known adaptative prosurvival mechanism that helps to maintain the energy levels of the myocardium. However, it still remains unclear if activation of AMPK during reperfusion is beneficial for the heart. Two known AMPK activators (metformin and AICAR) were used to verify the hypothesis that a transitory activation of AMPK at reperfusion may exert cardioprotection, as reflected in a reduction in myocardial infarct size. Perfused rat hearts were subjected to 35 min ischaemia and 120 min reperfusion. Metformin (50 microM) or AICAR (0.5 mM) were added for 15 min at the onset of reperfusion alone or with Compound C (CC, 10 microM), an AMPK inhibitor. Infarct size and alpha-AMPK phosphorylation were measured. Metformin significantly reduced infarct size from 47.8 +/- 1.7% in control to 31.4 +/- 2.9%, an effect abolished by CC when the drugs were given concomitantly. Similarly, AICAR also induced a significant reduction in infarct size to 32.3 +/- 4.8%, an effect also abrogated by CC. However, metformin's protection was not abolished if CC was administered later in reperfusion. In addition, alpha-AMPK phosphorylation was significantly increased in the metformin treated group during the initial 30 min of reperfusion. Our data demonstrated that, in our ex vivo model of myocardial ischaemia-reperfusion injury, AMPK activation in early reperfusion is associated with a reduction in infarct size.


Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa.
There are few published data from South Africa (SA) on the outcomes of black HIV-positive patients receiving chronic haemodialysis. This retrospective study compared the incidences of vascular and infectious morbidity and mortality in black HIV-positive patients with those in a group of HIV-negative patients matched for ethnicity, age and gender. All the patients were receiving chronic haemodialysis in the medically insured healthcare sector of SA. The incidence of tuberculosis and hospital admission rates for vascular access-related infections were significantly higher in the HIV-positive group than the HIV-negative group. The HIV-positive group had significantly lower albumin (p<0.05) and haemoglobin levels (p<0.01), but this did not impact on mortality. Survival in both groups was excellent. In the HIV-positive group, viral suppression rates were suboptimal with <50% of patients on antiretroviral therapy completely virally suppressed. This study has shown that black HIV-positive patients receiving chronic haemodialysis in a healthcare-funded environment in SA have excellent overall survival in spite of higher hospital admission rates and higher infectious morbidity compared with HIV-negative patients.


Evaluation of usefulness in surfactant protein D as a predictor of mortality in myositis-associated interstitial lung disease.
Surfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data. We enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively. Seventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived. Serum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.


Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.
Diabetes severely impairs male reproduction. The present study assessed the effects and mechanisms of action of advanced glycation end products (AGEs), which play an important role in the development of diabetes complications, on testosterone secretion by rat Leydig cells. Primary rat Leydig cells were cultured and treated with AGEs (25, 50, 100 and 200 µg/ml). Testosterone production induced by human chorionic gonadotropin (hCG) was determined by ELISA. The mRNA and protein expression levels of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), which are involved in testosterone biosynthesis, were measured by reverse transcription-quantitative PCR and western blot analyssi, respectively. Reactive oxygen species (ROS) production in Leydig cells was measured using the dichlorofluorescein diacetate (DCFH-DA) probe. The expression levels of endoplasmic reticulum stress-related proteins [C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78)] in the Leydig cells were measured by western blot analysis. We found that the AGEs markedly suppressed testosterone production by rat Leydig cells which was induced by hCG in a concentration-dependent manner compared with the control (P<0.01). The mRNA and protein expression levels of StAR, 3β-HSD and P450scc were downregulated by the AGEs in a dose-dependent manner compared with the control (P<0.01). The antioxidant agent, N-acetyl‑L‑cysteine (NAC), and the endoplasmic reticulum stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the inhibitory effects of AGEs. In addition, the content of ROS in Leydig cells treated with AGEs increased significantly. The expression levels of CHOP and GRP78 were markedly upregulated by the AGEs in the Leydig cells. From these findings, it can be concluded that AGEs inhibit testosterone production by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.


microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia.
A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22-23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL.


Accelerated atherosclerosis in premenopausal women with rheumatoid arthritis - 15-year follow-up.
Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased mortality and morbidity due to the higher cardiovascular risk in these patients. Traditional risk factors are not the only answer for the accelerated atherosclerosis. In a long-term prospective study, we investigated the relationship between asymptomatic atherosclerosis and traditional risk factors and inflammatory markers in patients with RA and matched healthy controls. We studied the laboratory test results, the concentrations of inflammatory mediators, matrix metalloproteases (MMP), and inflammation markers in a total of 70 (60 at follow-up) premenopausal healthy women with RA and 40 (34 at follow-up) matched controls. We used the B-mode ultrasound imaging of carotid arteries for the detection of asymptomatic atherosclerosis. Correlation with different factors was evaluated. Statistically significant higher values of inflammatory markers such as selective adhesion molecules ICAM and VCAM, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and MMP-3 in the patients group were found in the follow-up study. More plaques were found in the patients group (42.4% vs. 12.9%; p=0.005), as compared with the controls group. The patients had also higher values of cIMT (p=0.001). Using bivariate regression analysis only VCAM was found as a prognostic factor for plaque occurrence (r= 0. 341, p=0.016), but not for cIMT (r= -0.130, p=0.327) in premenopausal female patients with RA after the follow-up. Therefore, asymptomatic atherosclerosis is accelerated in premenopausal women with RA. The results of our follow-up study showed the association between inflammation and accelerated atherosclerosis. Furthermore, VCAM was found to have a statistically significant correlation with plaque occurrence in these patients.


Gentamicin in vitro activity and tentative gentamicin interpretation criteria for the CLSI and calibrated dichotomous sensitivity disc diffusion methods for Neisseria gonorrhoeae.
XDR Neisseria gonorrhoeae imposes the threat of untreatable gonorrhoea. Gentamicin is considered for future treatment; however, no interpretation criteria for the CLSI and calibrated dichotomous sensitivity (CDS) disc diffusion (DD) techniques are available for N. gonorrhoeae. We investigated the in vitro gentamicin activity by MIC and DD methods, proposed DD breakpoints and determined DD ranges for 10 international quality control (QC) strains. Gentamicin susceptibility of 333 N. gonorrhoeae isolates, including 323 clinical isolates and 10 QC strains, was determined. MIC determination (Etest) and DD methods (CLSI and CDS) were performed. The relationship between MIC, inhibition zone diameter and annular radius was determined by linear regression analysis and the correlation coefficient (r) was calculated. Gentamicin MICs for the QC strains were within published ranges. Of the 323 clinical isolates, according to published breakpoints 75.9%, 23.5% and 0.6% were susceptible, intermediately susceptible and resistant, respectively. Based on error minimization with MICs of ≤4, 8-16 and ≥32 mg/L, breakpoints proposed are susceptible ≥16 mm, intermediately susceptible 13-15 mm and resistant ≤12 mm for the CLSI method and susceptible ≥6 mm, less susceptible 3-5 mm and resistant ≤2 mm for the CDS technique. Low resistance to gentamicin was identified and gentamicin might be a future treatment option for gonorrhoea. Tentative gentamicin zone breakpoints were defined for two DD methods and QC ranges for 10 international reference strains were established. Our findings suggest that in resource-poor settings where MIC testing is not a feasible option, the DD methods can be used to indicate gentamicin resistance.


A role for cryptochromes in sleep regulation.
The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-) lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes. Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and albumin d-binding protein (dbp), which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1epsilon did not change with sleep deprivation. These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep.


Case series of selenium toxicity from a nutritional supplement.
Selenium is an essential trace element, but can be toxic in excess. In May 2008, US FDA reported 201 individuals with adverse reactions to liquid nutritional supplements containing excess selenium and chromium resulting in the largest epidemic of selenosis in the history of the United States. To describe the clinical features, biomonitoring data of selenium levels, and the estimated total dose of selenium ingestions of nine patients with selenium toxicity who presented after use of a liquid dietary supplement with a formulation error. A retrospective observational case series was performed on nine patients presenting to our medical toxicology clinic between March 2008 and May 2008 with symptoms of selenosis after consuming a nutritional supplement. Institutional IRB approval was obtained for this case series. Supplement testing revealed almost 200 times the reported amount of selenium. There were 5 males and 4 females and their ages ranged from 15 to 57 years (median 46 years, mean 44.2 years). The mean estimated cumulative dose of selenium ingested in our patients was 1.3 gram over a mean period of 37.5 days (10-60 days). In each case, the symptoms of selenium toxicity manifested within 1 week from the start of ingestion. Initial symptoms included alopecia, dystrophic fingernail changes, GI symptoms, and memory difficulties. The initial whole blood selenium concentrations ranged from 150 to 732 mcg/L (reference mean range 123-193 mcg/L) at an average of 27 days post cessation of the formula. The urinary selenium concentrations ranged from 41 to 220 mcg/g Creat (reference < 25 mcg/g Creatinine). None of the patients required more than supportive care for symptoms and none required hospitalization. Selenium is an essential element, which can result in significant toxicity if ingested in large amounts.


Plugging of a model rock system by using starved bacteria.
The effects of starvation on bacterial penetration through artificial rock cores were examined. Klebsiella pneumoniae was starved in a simple salts solution for a duration of up to 4 weeks. These cell suspensions were injected into sintered glass bead cores, and the resulting reductions in core permeabilities were recorded. Vegetative cell cultures of K. pneumoniae grown in a sodium citrate medium were injected into other, similar cores, and the reductions in core permeabilities were recorded. The starved cell suspensions did not completely block the core pores, whereas the vegetative cultures reduced core permeability to less than 1%. Scanning electron microscopy of core sections infiltrated with either vegetative or starved cells showed that the former produced shallow "skin" plugs and copious amounts of glycocalyx at the inlet face, whereas the latter produced very little glycocalyx and the cells were distributed evenly throughout the length of the core. The use of a DNA assay to produce a cell distribution profile showed that, compared with the vegetative cells, starved bacteria were able to penetrate deeper into the cores. This was due to the smaller size of the cells and the reduction in biofilm production. This ability of starved bacteria to penetrate further into cores than the normal-size vegetative cells can be usefully applied to selective plugging for enhanced oil recovery. To further test the suitability of starved cells for use in selective plugging, the activities of starved cells present within cores were monitored before and after nutrient stimulation. Our data indicate that with nutrient stimulation, the starved cells lose their metabolic dormancy and produce reductions in core permeability due to cell growth and polymer production.


Geometrical analysis for assessing torsional alignment of humerus.
Compared to other types of surgeries, minimally invasive surgeries (MISs) of humeral shaft fractures are associated with less radial nerve injury, less soft tissue injury and higher union rate. However, malrotation often occurs in MISs when closed reduction methods are used. This study aims to define specific palpable landmarks to help surgeons determine the correct torsional angle and reduce the incidence of malrotation. Twenty-eight normal humeral computed tomography scans were retrieved from our image database. One line was drawn through the vertices of the intertubercular sulcus of the humeral head in the coronal view, and another line was drawn through the longest axis between the medial and lateral condyles in the coronal view. The angle between these two lines was measured at least 3 times for each scan. The profile of the intertubercular sulcus tangent line of the humeral head and the axis of the distal humerus was identified as the most accurate method for assessing the precision of torsion during MIS for humeral shaft fractures. The transepicondylar axis line is more internally rotated than the intertubercular sulcus tangent line. The mean angle was measured to be 41.1 degrees. The axis of the distal humeral condyles is internally rotated by approximately 41.1 degrees compared with the intertubercular sulcus tangent line of the humeral head. Minimally invasive surgeries can be performed by using these palpable landmarks. The torsional deformities can be reduced with the proper angle adjustment without the need for fluoroscopy. It can also be used to treat unstable comminuted humeral fractures. Retrospective Study, Diagnostic study, Level III.


Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice.
The loss of nigrostriatal dopamine neurons in Parkinson's disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson's disease.


Flaviviral protease inhibitors identified by fragment-based library docking into a structure generated by molecular dynamics.
Fragment-based docking was used to select a conformation for virtual screening from a molecular dynamics trajectory of the West Nile virus nonstructural 3 protease. This conformation was chosen from an ensemble of 100 molecular dynamics snapshots because it optimally accommodates benzene, the most common ring in known drugs, and two positively charged fragments (methylguanidinium and 2-phenylimidazoline). The latter fragments were used as probes because of the large number of hydrogen bond acceptors in the substrate binding site of the protease. Upon high-throughput docking of a diversity set of 18,694 molecules and pose filtering, only five compounds were chosen for experimental validation, and two of them are active in the low micromolar range in an enzymatic assay and a tryptophan fluorescence quenching assay. Evidence for specific binding to the protease active site is provided by nuclear magnetic resonance spectroscopy. The two inhibitors have different scaffolds (diphenylurea and diphenyl ester) and are promising lead candidates because they have a molecular weight of about 300 Da.


Aptamer-based impedimetric sensor for bacterial typing.
The development of an aptamer-based impedimetric sensor for typing of bacteria (AIST-B) is presented. Highly specific DNA aptamers to Salmonella enteritidis were selected via Cell-SELEX technique. Twelve rounds of selection were performed; each comprises a positive selection step against S. enteritidis and a negative selection step against a mixture of related pathogens, including Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Citrobacter freundii, to ensure the species-specificity of the selected aptamers. After sequencing of the pool showing the highest binding affinity to S. enteritidis, a DNA sequence of high affinity to the bacteria was integrated into an impedimetric sensor via self-assembly onto a gold nanoparticles-modified screen-printed carbon electrode (GNPs-SPCE). Remarkably, this aptasensor is highly selective and can successfully detect S. enteritidis down to 600 CFU mL(-1) (equivalent to 18 CFU in 30 μL assay volume) in 10 min and distinguish it from other Salmonella species, including S. typhimurium and S. choleraesuis. This report is envisaged to open a new venue for the aptamer-based typing of a variety of microorganisms using a rapid, economic, and label-free electrochemical platform.


Using mRNAs lengths to accurately predict the alternatively spliced gene products in Caenorhabditis elegans.
Computational gene prediction methods are an important component of whole genome analyses. While ab initio gene finders have demonstrated major improvements in accuracy, the most reliable methods are evidence-based gene predictors. These algorithms can rely on several different sources of evidence including predictions from multiple ab initio gene finders, matches to known proteins, sequence conservation and partial cDNAs to predict the final product. Despite the success of these algorithms, prediction of complete gene structures, especially for alternatively spliced products, remains a difficult task. LOCUS (Length Optimized Characterization of Unknown Spliceforms) is a new evidence-based gene finding algorithm which integrates a length-constraint into a dynamic programming-based framework for prediction of gene products. On a Caenorhabditis elegans test set of alternatively spliced internal exons, its performance exceeds that of current ab initio gene finders and in most cases can accurately predict the correct form of all the alternative products. As the length information used by the algorithm can be obtained in a high-throughput fashion, we propose that integration of such information into a gene-prediction pipeline is feasible and doing so may improve our ability to fully characterize the complete set of mRNAs for a genome. LOCUS is available from http://ural.wustl.edu/software.html