Predicting inpatient violence using an extended version of the Brøset-Violence-Checklist: instrument development and clinical application.
Patient aggression is a common problem in acute psychiatric wards and calls for preventive measures. The timely use of preventive measures presupposes a preceded risk assessment. The Norwegian Brøset-Violence-Checklist (BVC) is one of the few instruments suited for short-time prediction of violence of psychiatric inpatients in routine care. Aims of our study were to improve the accuracy of the short-term prediction of violence in acute inpatient settings by combining the Brøset-Violence-Checklist (BVC) with an overall subjective clinical risk-assessment and to test the application of the combined measure in daily practice. We conducted a prospective cohort study with two samples of newly admitted psychiatric patients for instrument development (219 patients) and clinical application (300 patients). Risk of physical attacks was assessed by combining the 6-item BVC and a 6-point score derived from a Visual Analog Scale. Incidents were registered with the Staff Observation of Aggression Scale-Revised SOAS-R. Test accuracy was described as the area under the receiver operating characteristic curve (AUCROC). The AUCROC of the new VAS-complemented BVC-version (BVC-VAS) was 0.95 in and 0.89 in the derivation and validation study respectively. The BVC-VAS is an easy to use and accurate instrument for systematic short-term prediction of violent attacks in acute psychiatric wards. The inclusion of the VAS-derived data did not change the accuracy of the original BVC.


Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer.
Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.


Increasing trauma deaths in the United States.
To determine the impact of the increasing aging population on trauma mortality relative to mortality from cancer and heart disease in the United States. The population in the United States continues to increase as medical advancements allow people to live longer. The resulting changes in the leading causes of death have not yet been recognized. Data were obtained (2000-2010) from the Web-based Injury Statistics Query and Reporting System database of the Centers for Disease Control and Prevention. We defined trauma deaths as unintentional injuries, suicides, and homicides. From 2000 to 2010, the US population increased by 9.7% and the number of trauma deaths increased by 22.8%. Trauma deaths and death rates deceased in individuals younger than 25 years but increased for those 25 years and older. During this period, death rates for cancer and heart disease decreased. The largest increases in trauma deaths were in individuals in their fifth and sixth decades of life. Since 2000, the largest proportional increase (118%) in crude trauma deaths occurred in 54-year-olds. Overall, in 2010, trauma was the leading cause of death in individuals 46 years and younger. Trauma remains the leading cause of years of life lost. Trauma is now the leading cause of death for individuals 46 years and younger. The largest increase in the number of trauma deaths and the highest crude number of trauma deaths occurred in baby boomers. Policy makers allocating resources should be made aware of the larger impact of trauma on our aging and burgeoning US population.


Mitotic phosphorylation stimulates DNA relaxation activity of human topoisomerase I.
Human DNA topoisomerase I (topo I) is an essential mammalian enzyme that regulates DNA supercoiling during transcription and replication. In addition, topo I is specifically targeted by the anticancer compound camptothecin and its derivatives. Previous studies have indicated that topo I is a phosphoprotein and that phosphorylation stimulates its DNA relaxation activity. The locations of most topo I phosphorylation sites have not been identified, preventing a more detailed examination of this modification. To address this issue, mass spectrometry was used to identify four topo I residues that are phosphorylated in intact cells: Ser(10), Ser(21), Ser(112), and Ser(394). Immunoblotting using anti-phosphoepitope antibodies demonstrated that these sites are phosphorylated during mitosis. In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1. When wild type topo I was pulled down from mitotic cells and dephosphorylated with alkaline phosphatase, topo I activity decreased 2-fold. Likewise, topo I polypeptide with all four phosphorylation sites mutated to alanine exhibited 2-fold lower DNA relaxation activity than wild type topo I after isolation from mitotic cells. Further mutational analysis demonstrated that Ser(21) phosphorylation was responsible for this change. Consistent with these results, wild type topo I (but not S21A topo I) exhibited increased sensitivity to camptothecin-induced trapping on DNA during mitosis. Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.


Evaluation of the efficacy of hydroxyl radical (OH˙) release for disinfection of the air and surfaces in the dental clinic: an in vitro study.
Concerning about the quality of room air has increased exponentially. Specially in dental clinics where diary practice is characterized by the important generation of aerosols. An in vitro model was used in which samples were collected from the surfaces and room air of a dental clinic before and after the use of an OH˙ radical generator. A total of 1260 samples were collected for bacteriological analysis and 14 samples for the detection of SARS-CoV-2. Following OH˙ treatment, the tested surface samples showed a decrease in the number of colony forming units (CFUs) of 76.9% in TSA culture medium. The circulating room air samples in turn showed a decrease in CFUs of 66.7% in Sabouraud medium and 71.4% in Mannitol agar medium. No presence of SARS-CoV-2 was observed on the surface of the face shield. The disinfectant technology based on the use of hydroxyl radicals (OH˙) is effective in reducing the presence of moulds and yeasts and Staphylococcus in the air, and in reducing total aerobic bacteria on the tested surfaces.


Childhood tuberculosis: an emerging and previously neglected problem.
Although awareness is growing, childhood tuberculosis (TB) remains a neglected disease in many resource-limited settings. In part this reflects operational difficulties, lack of visibility in official reports, as well as perceptions that children tend to develop mild disease, contribute little to disease transmission, and do not affect epidemic control. At an international level there is greater appreciation that children contribute significantly to the global TB disease burden and suffer severe TB-related morbidity and mortality, particularly in TB-endemic areas, where the disease often remains undiagnosed. However, this is not always the case at the national or local level and there remains an urgent need for feasible and implementable policies to guide clinical practice. Pediatric TB can be regarded as an emerging epidemic in areas where the adult epidemic remains out of control and Mycobacterium tuberculosis transmission is ongoing. This article reviews important concepts, challenges, and management principles related to childhood TB; it also summarizes the main priorities for future research.


Repetition effects elicited by objects and their contexts: an fMRI study.
Event-related fMRI responses were recorded during a recognition memory test for previously studied visual objects. Some studied objects were superimposed on the same context (landscape scenes) as at study, some were superimposed on a different studied context, and some were paired with new contexts. Unstudied objects were paired with either a studied or a new context. Relative to all other stimulus classes, test stimuli where both components were unstudied elicited enhanced responses in lateral and ventral extrastriate visual cortex. This effect, which is analogous to a previously described electrophysiological result obtained with the same experimental procedure, had the same magnitude regardless of whether a test item was composed of one or two studied components, or whether a single studied component was task relevant or task irrelevant. The findings point to the existence of repetition-sensitive neural mechanisms that operate in a non-linear manner.


A bioeconomic approach to marriage and the sexual division of labor.
Children may be viewed as public goods whereby both parents receive equal genetic benefits yet one parent often invests more heavily than the other. We introduce a microeconomic framework for understanding household investment decisions to address questions concerning conflicts of interest over types and amount of work effort among married men and women. Although gains and costs of marriage may not be spread equally among marriage partners, marriage is still a favorable, efficient outcome under a wide range of conditions. This bioeconomic framework subsumes both cooperative and conflictive views on the sexual division of labor. We test hypotheses concerning marriage markets, assortative mating, and men's labor motivations among Tsimane forager-horticulturalists of Bolivia and find that: (1) men and women both value work effort in marital partners, (2) marital labor contributions are complementary, (3) work effort is correlated between spouses, (4) total production is correlated with total reproduction, and (5) better hunters have higher fitness gains within marital unions.


A case of extramammary inguinal Paget disease in a male patient: surgical treatment with an abdominal advancement cutaneous flap.
Extramammary Paget disease (EMPD) is a rare neoplasm. The clinical case of a 55-year-old man with a two-year history of a pruritic, painless erythematous skin rash on the inguinal region and scrotum is described. After a delay due to improper diagnosis and improper treatments, the patient came to the attention of the Division of plastic surgery. He underwent a punch biopsy and the pathology report came back as EMPD. Surgical excision was carried out, and an abdominal advancement cutaneous flap was performed for the defect repair. This is the first description of a reconstruction after surgical removal of inguinal EMPD with a flap of this type and we think that this type of treatment can be useful and reliable for disease localization in the groin area, especially for patients that present an excess of abdominal skin.


Compartmental neck fat accumulation and its relation to cardiovascular risk and metabolic syndrome.
Neck circumference is a predictor of cardiovascular disease (CVD) risk. However, detailed assessment of neck fat has not been explored, and the contribution from individual neck fat compartments to CVD risk is unknown. The objective was to measure neck adipose tissue (NAT) compartments and examine relations with CVD risk markers, with the hypothesis that neck adipose tissue (NAT) accumulation preferentially involves specific compartments that contribute differently to metabolic risk. We retrospectively studied 303 subjects with successfully treated malignancies or benign etiologies [151 women, 152 men; mean (± SD) age: 55 ± 17 y; mean body mass index (BMI; in kg/m(2)): 28 ± 6] who underwent whole-body positron emission tomography/computed tomography. NAT was measured at the level of the C5 vertebral body, subdivided into posterior (NATpost), subcutaneous (NATsc), and perivertebral (NATperivert) compartments. Data on CVD risk factors (BMI, abdominal circumference, visceral and abdominal subcutaneous adipose tissue, blood pressure, serum lipids, and fasting plasma glucose) were collected. We compared NAT compartments across lean, overweight, and obese groups and performed multivariate regression models correlating NAT with CVD risk factors. Receiver operating characteristic curve and prevalence ratio analyses were performed to examine the association of NAT compartments with metabolic syndrome. NATpost and NATsc were more consistently associated with cardiometabolic risk, especially in women, correlating with visceral adipose tissue (P < 0.0001) and triglycerides (P < 0.001) and a nearly 1.5-fold increase in the prevalence ratio for metabolic syndrome after adjustment for age and BMI (P < 0.05). NATsc was most abundant in women, whereas intermuscular compartments (NATpost and NATperivert) were higher in men. In both sexes, NATpost and NATperivert showed the largest increment between lean and obese subjects. Neck fat compartments expand differently with increasing adiposity, correlate with CVD risk factors, and are associated with metabolic syndrome, most notably NATpost and NATsc in women. Although neck circumference remains an important method to assess metabolic risk, cross-sectional NAT assessment provides further insight into fat accumulation in the neck. This trial was registered at clinicaltrials.gov as NCT02205021.


The role of cannabis in treating anxiety: an update.
Cannabis use for medical purposes has become increasingly common, including as treatment for mental health disorders such as anxiety. Unfortunately, the evidence examining its use in mental health has been slow to evolve, but is emerging. Given the widespread use of cannabis, it is important for both clinicians and those who suffer with anxiety to understand the effects of cannabis on symptoms of anxiety. In this review, we present recent, available evidence from animal models, clinical trials, and survey studies and evaluate the contribution of these studies to the current understanding of the role of cannabis in treating anxiety. In reviewing recent evidence, we observed significant inconsistencies across findings from preclinical studies. Large-scale surveys suggest that cannabis may be effective in reducing anxiety, however, these results stand in contrast to equivocal findings from clinical trials. The literature evaluating the efficacy of cannabis in anxiety disorders is in its infancy. The survey data is generally positive. Although, while some animal studies posit cannabis constituents to have anxiolytic effects, others suggest the opposite or null results. Few new clinical trials have been conducted recently, and the extant trials have significant flaws in methodology. Although anecdotal evidence from survey studies, and a small signal found in animal studies and single-dose clinical trials provide early support that cannabis may be effective for alleviating anxiety, ultimately, the current evidence is equivocal. More high-quality clinical trials must be published before sound conclusions regarding the efficacy of cannabis for treating anxiety can be drawn.


Pediatric condition falsification (Munchausen syndrome by Proxy) as a continuum of maternal factitious disorder (Munchausen syndrome).
Pediatric condition falsification (PCF), also known as Munchausen syndrome by Proxy or Medical Child Abuse, is a somewhat rare form of child abuse and neglect. Its association with a history of adult factitious disorder (AFD) or Munchausen syndrome in the perpetrator is also well known. Exogenous insulin injection to cause hypoglycemia both in the context of PCF and AFD has been reported in the literature. However, the coexistence of both conditions via insulin injection in the same family has not been reported in the literature. This paper presents a family, in which the mother was diagnosed with AFD and her three children with PCF perpetrated by their mother via exogenous insulin injection.


The Genome Sequence of the Halobacterium salinarum Type Strain Is Closely Related to That of Laboratory Strains NRC-1 and R1.
High-coverage long-read sequencing of the Halobacterium salinarum type strain (91-R6) revealed a 2.17-Mb chromosome and two large plasmids (148 and 102 kb). Population heterogeneity and long repeats were observed. Strain 91-R6 and laboratory strain R1 showed 99.63% sequence identity in common chromosomal regions and only 38 strain-specific segments. This information resolves the previously uncertain relationship between type and laboratory strains.


Photoacoustic and ultrasound imaging using dual contrast perfluorocarbon nanodroplets triggered by laser pulses at 1064 nm.
Recently, a dual photoacoustic and ultrasound contrast agent-named photoacoustic nanodroplet-has been introduced. Photoacoustic nanodroplets consist of a perfluorocarbon core, surfactant shell, and encapsulated photoabsorber. Upon pulsed laser irradiation the perfluorocarbon converts to gas, inducing a photoacoustic signal from vaporization and subsequent ultrasound contrast from the resulting gas microbubbles. In this work we synthesize nanodroplets which encapsulate gold nanorods with a peak absorption near 1064 nm. Such nanodroplets are optimal for extended photoacoustic imaging depth and contrast, safety and system cost. We characterized the nanodroplets for optical absorption, image contrast and vaporization threshold. We then imaged the particles in an ex vivo porcine tissue sample, reporting contrast enhancement in a biological environment. These 1064 nm triggerable photoacoustic nanodroplets are a robust biomedical tool to enhance image contrast at clinically relevant depths.


Bronsted acid-promoted olefin aziridination and formal anti-aminohydroxylation.
A straightforward synthesis of aziridines is reported from an electron-rich azide (alkyl or aryl azide), electron-deficient olefin, and triflic acid in cold acetonitrile. The only coproduct of the reaction is dinitrogen (N2). Active ester substrates bearing a nucleophilic carbonyl engage the putative protonated aziridine intermediate to produce the product of olefin aminohydroxylation in which the nitrogen is benzyl protected and the oxygen is acylated. The possibility that a triazoline need not be an intermediate in aziridine production is advanced.


XACT-Seq Comprehensively Defines the Promoter-Position and Promoter-Sequence Determinants for Initial-Transcription Pausing.
Pausing by RNA polymerase (RNAP) during transcription elongation, in which a translocating RNAP uses a "stepping" mechanism, has been studied extensively, but pausing by RNAP during initial transcription, in which a promoter-anchored RNAP uses a "scrunching" mechanism, has not. We report a method that directly defines the RNAP-active-center position relative to DNA with single-nucleotide resolution (XACT-seq; "crosslink-between-active-center-and-template sequencing"). We apply this method to detect and quantify pausing in initial transcription at 411 (∼4,000,000) promoter sequences in vivo in Escherichia coli. The results show initial-transcription pausing can occur in each nucleotide addition during initial transcription, particularly the first 4 to 5 nucleotide additions. The results further show initial-transcription pausing occurs at sequences that resemble the consensus sequence element for transcription-elongation pausing. Our findings define the positional and sequence determinants for initial-transcription pausing and establish initial-transcription pausing is hard coded by sequence elements similar to those for transcription-elongation pausing.


The frequency modulated auditory evoked response (FMAER), a technical advance for study of childhood language disorders: cortical source localization and selected case studies.
Language comprehension requires decoding of complex, rapidly changing speech streams. Detecting changes of frequency modulation (FM) within speech is hypothesized as essential for accurate phoneme detection, and thus, for spoken word comprehension. Despite past demonstration of FM auditory evoked response (FMAER) utility in language disorder investigations, it is seldom utilized clinically. This report's purpose is to facilitate clinical use by explaining analytic pitfalls, demonstrating sites of cortical origin, and illustrating potential utility. FMAERs collected from children with language disorders, including Developmental Dysphasia, Landau-Kleffner syndrome (LKS), and autism spectrum disorder (ASD) and also normal controls - utilizing multi-channel reference-free recordings assisted by discrete source analysis - provided demonstratrions of cortical origin and examples of clinical utility. Recordings from inpatient epileptics with indwelling cortical electrodes provided direct assessment of FMAER origin. The FMAER is shown to normally arise from bilateral posterior superior temporal gyri and immediate temporal lobe surround. Childhood language disorders associated with prominent receptive deficits demonstrate absent left or bilateral FMAER temporal lobe responses. When receptive language is spared, the FMAER may remain present bilaterally. Analyses based upon mastoid or ear reference electrodes are shown to result in erroneous conclusions. Serial FMAER studies may dynamically track status of underlying language processing in LKS. FMAERs in ASD with language impairment may be normal or abnormal. Cortical FMAERs can locate language cortex when conventional cortical stimulation does not. The FMAER measures the processing by the superior temporal gyri and adjacent cortex of rapid frequency modulation within an auditory stream. Clinical disorders associated with receptive deficits are shown to demonstrate absent left or bilateral responses. Serial FMAERs may be useful for tracking language change in LKS. Cortical FMAERs may augment invasive cortical language testing in epilepsy surgical patients. The FMAER may be normal in ASD and other language disorders when pathology spares the superior temporal gyrus and surround but presumably involves other brain regions. Ear/mastoid reference electrodes should be avoided and multichannel, reference free recordings utilized. Source analysis may assist in better understanding of complex FMAER findings.


Molecularly Imprinted Microrods via Mesophase Polymerization.
The aim of the present research work was the synthesis of molecularly imprinted polymers (MIPs) with a rod-like geometry via "mesophase polymerization". The ternary lyotropic system consisting of sodium dodecyl sulfate (SDS), water, and decanol was chosen to prepare a hexagonal mesophase to direct the morphology of the synthesized imprinted polymers using theophylline, methacrylic acid, and ethylene glycol dimethacrylate as a drug model template, a functional monomer, and a crosslinker, respectively. The obtained molecularly imprinted microrods (MIMs) were assessed by performing binding experiments and in vitro release studies, and the obtained results highlighted good selective recognition abilities and sustained release properties. In conclusion, the adopted synthetic strategy involving a lyotropic mesophase system allows for the preparation of effective MIPs characterized by a rod-like morphology.


Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.


Metallothionein gene and protein expression as a biomarker for metal pollution in natural gudgeon populations.
Gudgeons (Gobio gobio) from historically Cd and Zn contaminated sites in Flanders (Belgium) were found to be resistant to elevated Cd levels. In previous work, this increased resistance was largely explained by increased metallothionein (MT) expression. Recently, environmental cleanup efforts resulted in a significant decrease in Cd concentrations in the surface water. In this study, we evaluated the use of hepatic metal and metallothionein (MT) concentrations as biomarkers of metal exposure before and after the cleanup. Hepatic MT mRNA levels were determined after the environmental metal levels decreased in order to assess the applicability of MT gene expression as an environmental biomarker in natural fish populations. Our data show that both metallothionein protein and gene expression have the potential to be sensitive biomarkers for metal exposure. Significant correlations were found (a) among accumulated metal concentrations and both MT protein and mRNA levels, and (b) between MT protein and mRNA levels. However, our data illustrated that while MT protein and gene expression give a quantitative picture of metal load at a single time point, quantitative information in natural populations cannot always be obtained when different time points (including different years) are compared, since MT gene and protein expression are affected by many other factors in addition to the metal load. Furthermore, the result of the environmental cleanup was reflected in a decrease of hepatic Cd concentrations. Zn remained the most important factor determining MT concentrations. Finally, two differently sized MT mRNAs were amplified to test the hypothesis that 3'-UTR length can offer a protective advantage in conditions of environmental stress. Our data provided no evidence to support this hypothesis. In contrast, the ratio of the long mRNA variant relative to total MT mRNA was surprisingly constant, and independent of exposure history.


Temporal limitations in object processing across the human ventral visual pathway.
Behavioral studies have shown that object recognition becomes severely impaired at fast presentation rates, indicating a limitation in temporal processing capacity. Here, we studied whether this behavioral limit in object recognition reflects limitations in the temporal processing capacity of early visual areas tuned to basic features or high-level areas tuned to complex objects. We used functional MRI (fMRI) to measure the temporal processing capacity of multiple areas along the ventral visual pathway progressing from the primary visual cortex (V1) to high-level object-selective regions, specifically the fusiform face area (FFA) and parahippocampal place area (PPA). Subjects viewed successive images of faces or houses at presentation rates varying from 2.3 to 37.5 items/s while performing an object discrimination task. Measures of the temporal frequency response profile of each visual area revealed a systematic decline in peak tuning across the visual hierarchy. Areas V1-V3 showed peak activity at rapid presentation rates of 18-25 items/s, area V4v peaked at intermediate rates (9 items/s), and the FFA and PPA peaked at the slowest temporal rates (4-5 items/s). Our results reveal a progressive loss in the temporal processing capacity of the human visual system as information is transferred from early visual areas to higher areas. These data suggest that temporal limitations in object recognition likely result from the limited processing capacity of high-level object-selective areas rather than that of earlier stages of visual processing.


Real-time nanoscale organization of amyloid precursor protein.
Despite an intuitive understanding of the role of APP in health and disease, there exist few attempts to dissect its molecular localization at excitatory synapses. Though the biochemistry involved in the enzymatic processing of APP is well understood, there is a void in understanding the nonuniformity of the product formation in vivo. Here, we employed multiple paradigms of single molecules and ensemble based nanoscopic imaging to reveal that APP molecules are organized into regulatory nanodomains that are differentially compartmentalized in the functional zones of an excitatory synapse. Furthermore, with the aid of high density single particle tracking, we show that the lateral diffusion of APP in live cells dictates an equilibrium between these nanodomains and their nano-environment, which is affected in a detrimental variant of APP. Additionally, we incorporate this spatio-temporal detail 'in silico' to generate a realistic nanoscale topography of APP in dendrites and synapses. This approach uncovers a nanoscale heterogeneity in the molecular organization of APP, depicting a locus for differential APP processing. This holistic paradigm, to decipher the real-time heterogeneity of the substrate molecules on the nanoscale, could enable us to better evaluate the molecular constraints overcoming the ensemble approaches used traditionally to understand the kinetics of product formation.


First Report of Cylindrocladium Black Rot of Peanut Caused by Cylindrocladium parasiticum (Teleomorph Calonectria ilicicola) in Jiangxi Province, China.
In July 2010, a serious disease of peanut (Arachis hypogaea) resembling Cylindrocladium black rot (CBR) was found in Longnan County, Jiangxi Province, China. Symptoms included chlorotic, yellowish and blighted leaves, and wilting of the plants. Taproots and hypocotyls were blackened and rotted. Clusters of reddish orange spherical fruiting bodies appeared in the lesions present on basal stems, pegs, pods, and roots of peanut. Disease incidence reached as much as 50% in some patches of the field. Plants with symptoms were sampled from fields. Microscopic examination revealed that the reddish orange, spherical fruiting bodies were the perithecia and measured 461.6 (337.5 to 609.4) × 395.5 (309.4 to 496.9) μm. With gentle pressure, asci and ascospores were exuded from perithecia. The asci were hyaline, thin walled, and long stalked. Ascospores were hyaline, falcate with one septum, and measured 43.5 (27.3 to 54.5) × 5.6 (4.1 to 6.8) μm with a length/width (L/W) ratio of 7.8 ± 1.3. A fungus with white-to-pale buff border mycelia and yellowish brown pigment was consistently isolated from the edge of basal stem lesions on potato dextrose agar at 25°C. Mycelia grew at temperatures ranging from 8 to 32°C and the optimum was 25 to 26°C. To determine the species, single-conidial isolates of the fungus were cultured on carnation leaf agar for 7 days at 25°C and 12 h of light/dark conditions. Conidia were hyaline, cylindrical with one to three septa (mostly three septa), and measured 49.3 (27.3 to 70.9) × 5.9 (4.1 to 6.8) μm with L/W ratio of 8.4 ± 1.6. Vesicles were globose and measured 5.5 to 10.9 μm in diameter. The fungus was identified as Cylindrocladium parasiticum (teleomorph Calonectria ilicicola) (1,2). A PCR assay was conducted on one representative isolate (JXLN32) by analyzing multilocus sequences of the TUB2 (coding β-tubulin protein), ACT (coding actin), and CaM gene (coding calmodulin protein) and were amplified and sequenced using the primers reported by Crous et al. (3). Sequences of the studied DNA regions were submitted to GenBank (Accession Nos. TUB2: JF429649; ACT: JQ070809; and CaM: JQ070808). BLAST searches with the existing sequences in GenBank showed that there was 99 to 100% identity with the existing sequences of C. ilicicola (GenBank Accession Nos. TUB2: AY725643; ACT: GQ280446; and CaM: GQ267402). To complete Koch's postulates, inoculum was prepared by mixing the microsclerotia (MS) suspension of the isolate (JXLN32) with soil at a proportion of 10 MS per g of soil. Ten replicate plastic pots containing five peanut seeds (cv. Yueyou 7) each were planted and placed in a glasshouse at 25 ± 2°C. The same number of peanut seeds was used as an uninoculated control. Typical basal stem and roots rot symptoms of CBR were observed in 2 months and C. parasiticum was reisolated from these inoculated diseased plants. No symptoms were detected on the control plants. To our knowledge, this is the first finding of Cylindrocladium black rot in Jiangxi Province, which is the main peanut-producing area in China. The disease has been previously reported in Guangdong Province in southern China but is not known elsewhere (4). Because of its ability to spread through seed and soil and its destructive potential, this pathogen may pose a serious threat to peanut production in China. References: (1) D. K. Bell and E. K. Sobers. Phytopathology 56:1361, 1966. (2) P. W. Crous et al. Mycol. Res. 97:889, 1993. (3) P. W. Crous et al. Stud. Mycol. 50:415, 2004. (4) R. Pan et al. Plant Pathol. 58:1176, 2009.


Nerve growth factor increases sodium channel expression in pancreatic beta cells: implications for insulin secretion.
The importance of nerve growth factor (NGF) modulation of pancreatic beta cells is demonstrated by the fact that these cells secrete and respond to this trophic factor. Among NGF effects on beta cells is an increase in Na+ and Ca2+ current densities. This study investigates the mechanisms involved in the NGF-induced increase in Na+ current and the implications of this effect for insulin secretion. The following results were obtained in single beta cells cultured with NGF for 5-7 days: 1) A steady-state level of mRNA coding for type III sodium channel alpha subunit increased twofold compared with that for control cells. 2) The increase in Na+ current density was blocked either by cycloheximide or by actinomycin D, indicating that it is mediated by protein synthesis and mRNA transcription. 3) NGF treatment strengthened, by nearly fourfold, the beta-cell electrical activity; this effect is partially related to the increased Na+ current, because tetrodotoxin (TTX) decreased the duration of the depolarized plateau level. 4) Single beta cells secreted nearly two times more insulin in response to 5.6 or 15.6 mM glucose. This effect was inhibited by TTX, indicating that the enhanced Na+ current plays an important role. These data suggest that NGF could preserve an adequate expression of sodium channels and that impairment of NGF modulation could lead to deficient insulin secretion and diabetes mellitus.


United Kingdom Frozen Shoulder Trial (UK FROST), multi-centre, randomised, 12 month, parallel group, superiority study to compare the clinical and cost-effectiveness of Early Structured Physiotherapy versus manipulation under anaesthesia versus arthroscopic capsular release for patients referred to secondary care with a primary frozen shoulder: study protocol for a randomised controlled trial.
Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy. We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods. The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults. International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014.


Population differences in von Willebrand factor levels affect the diagnosis of von Willebrand disease in African-American women.
Diagnosis of von Willebrand disease (vWD) is based on a panel of laboratory tests that measure the amount and function of von Willebrand factor (vWF). In population studies, vWF is higher in African Americans than Caucasians. Bleeding time, factor VIII activity (FVIII), vWF antigen (vWF:Ag), "vWF activity" ELISA (vWF:Act), ristocetin cofactor (vWF:RCof), and ristocetin-induced platelet aggregation (RIPA) were measured on 123 women with menorrhagia and 123 randomly selected control women; 70 cases and 76 controls were African American. Among controls, African Americans had significantly higher levels of vWF:Ag (mean 120 vs. 102 U/dl, P = 0.017). Among all subjects, African Americans had higher levels of vWF:Ag (mean 123 vs. 103, P = 0.001), vWF:Act (mean 101 vs. 89, P = 0.006), and FVIII (mean 118 vs. 104, P = 0.008). VWF:RCof did not differ between races (93 vs. 94 U/dl). RIPA was reduced in African Americans (P < 0.0001). In both races, women with type O blood differed significantly from those with other ABO types in vWF:Ag, vWF:Act, FVIII, and vWF:RCof. Based on criteria of two or more tests below race- and ABO-specific reference ranges, 6.5% of menorrhagia cases and 0.8% of controls were classified as having vWD, or its phenocopy. Among Caucasians, no controls and 7 cases (15.6%) were classified as affected, and in African Americans, 1 control (1.3%) and 1 case (1.4%) were so classified. Racial differences in vWF further complicate the issues surrounding diagnosis of vWD. The finding of increased vWF:Ag not accompanied by increased vWF:RCof has implications for understanding the structure-function relationships of vWF. Published 2001 Wiley-Liss, Inc.


Molecular detection and diversity of novel diterpenoid dioxygenase DitA1 genes from proteobacterial strains and soil samples.
Resin acids are tricyclic diterpenoids naturally synthesized by trees that are released from wood during pulping processes. Using a newly designed primer set, genes similar to that encoding the DitA1 catalytic alpha-subunit of the diterpenoid dioxygenase, a key enzyme in abietane resin acid degradation by Pseudomonas abietaniphila BKME-9, could be amplified from different Pseudomonas strains, whereas ditA1 gene sequence types representing distinct branches in the evolutionary tree were amplified from Burkholderia and Cupriavidus isolates. All isolates harbouring a ditA1-homologue were capable of growth on dehydroabietic acid as the sole source of carbon and energy and reverse transcription polymerase chain reaction analysis in three strains confirmed that ditA1 was expressed constitutively or in response to DhA, demonstrating its involvement in DhA-degradation. Evolutionary analyses indicate that gyrB (as a phylogenetic marker) and ditA1 genes have coevolved under purifying selection from their ancestral variants present in the most recent common ancestor of the genera Pseudomonas, Cupriavidus and Burkholderia. A polymerase chain reaction-single-strand conformation poylmorphism fingerprinting method was established to monitor the diversity of ditA1 genes in environmental samples. The molecular fingerprints indicated the presence ofa broad, previously unrecognized diversity of diterpenoid dioxygenase genes in soils, and suggest that other bacterial phyla may also harbour the genetic potential for DhA-degradation.


Ameliorative Effect of Aspalathin and Nothofagin from Rooibos (Aspalathus linearis) on HMGB1-Induced Septic Responses In Vitro and In Vivo.
The ubiquitous nuclear protein, high mobility group box 1 (HMGB1), is released by activated macrophages and human umbilical vein endothelial cells (HUVECs) and functions as a late mediator of experimental sepsis. Aspalathin (Asp) and nothofagin (Not), which have been reported to have anti-oxidant activity, are the two major active dihydrochalcones found in green rooibos. In this study, we investigated the antiseptic effects and underlying mechanisms of Asp and Not against HMGB1-mediated septic responses in HUVECs and mice. The anti-inflammatory activities of Asp and Not were determined by measuring permeability, monocyte adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, Asp and Not effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, Asp and Not suppressed the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by HMGB1. Collectively, these results indicate that Asp and Not could be potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.


The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy.
Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.


Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone.
This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected (125)I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting (125)I-labeled PSA30. Tissue uptake of (125)I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, (18)F-fluoro-deoxy-glucose ((18)F-FDG) or (18)F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high (125)I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either (18)F-FDG or (18)F-choline. Biodistribution of (125)I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24-48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.


Changes in resting-state connectivity in pediatric temporal lobe epilepsy.
OBJECTIVE Functional connectivity magnetic resonance imaging (fcMRI) is a form of fMRI that allows for analysis of blood oxygen level-dependent signal changes within a task-free, resting paradigm. This technique has been shown to have efficacy in evaluating network connectivity changes with epilepsy. Presurgical data from patients with unilateral temporal lobe epilepsy were evaluated using the fcMRI technique to define connectivity changes within and between the diseased and healthy temporal lobes using a within-subjects design. METHODS Using presurgical fcMRI data from pediatric patients with unilateral temporal lobe epilepsy, the authors performed seed-based analyses within the diseased and healthy temporal lobes. Connectivity within and between temporal lobe seeds was measured and compared. RESULTS In the cohort studied, local ipsilateral temporal lobe connectivity was significantly increased on the diseased side compared to the healthy temporal lobe. Connectivity of the diseased side to the healthy side, on the other hand, was significantly reduced when compared to connectivity of the healthy side to the diseased temporal lobe. A statistically significant regression was observed when comparing the changes in local ipsilateral temporal lobe connectivity to the changes in inter-temporal lobe connectivity. A statistically significant difference was also noted in ipsilateral connectivity changes between patients with and those without mesial temporal sclerosis. CONCLUSIONS Using fcMRI, significant changes in ipsilateral temporal lobe and inter-temporal lobe connectivity can be appreciated in unilateral temporal lobe epilepsy. Furthermore, fcMRI may have a role in the presurgical evaluation of patients with intractable temporal lobe epilepsy.


Biocompute Objects-A Step towards Evaluation and Validation of Biomedical Scientific Computations.
The unpredictability of actual physical, chemical, and biological experiments due to the multitude of environmental and procedural factors is well documented. What is systematically overlooked, however, is that computational biology algorithms are also affected by multiplicity of parameters and have no lesser volatility. The complexities of computation protocols and interpretation of outcomes is only a part of the challenge: There are also virtually no standardized and industry-accepted metadata schemas for reporting the computational objects that record the parameters used for computations together with the results of computations. Thus, it is often impossible to reproduce the results of a previously performed computation due to missing information on parameters, versions, arguments, conditions, and procedures of application launch. In this article we describe the concept of biocompute objects developed specifically to satisfy regulatory research needs for evaluation, validation, and verification of bioinformatics pipelines. We envision generalized versions of biocompute objects called biocompute templates that support a single class of analyses but can be adapted to meet unique needs. To make these templates widely usable, we outline a simple but powerful cross-platform implementation. We also discuss the reasoning and potential usability for such concept within the larger scientific community through the creation of a biocompute object database initially consisting of records relevant to the U.S. Food and Drug Administration. A biocompute object database record will be similar to a GenBank record in form; the difference being that instead of describing a sequence, the biocompute record will include information related to parameters, dependencies, usage, and other information related to specific computational instance. This mechanism will extend similar efforts and also serve as a collaborative ground to ensure interoperability between different platforms, industries, scientists, regulators, and other stakeholders interested in biocomputing.


A high-speed, high-performance, microfabricated comprehensive two-dimensional gas chromatograph.
A small, consumable-free, low-power, ultra-high-speed comprehensive GC×GC system consisting of microfabricated columns, nanoelectromechanical system (NEMS) cantilever resonators for detection, and a valve-based stop-flow modulator is demonstrated. The separation of a highly polar 29-component mixture covering a boiling point range of 46 to 253 °C on a pair of microfabricated columns using a Staiger valve manifold in less than 7 seconds, and just over 4 seconds after the ensemble holdup time is demonstrated with a downstream FID. The analysis time of the second dimension was 160 ms, and peak widths in the second dimension range from 10-60 ms. A peak capacity of just over 300 was calculated for a separation of just over 6 s. Data from a continuous operation testing over 40 days and 20 000 runs of the GC×GC columns with the NEMS resonators using a 4-component test set is presented. The GC×GC-NEMS resonator system generated second-dimension peak widths as narrow as 8 ms with no discernable peak distortion due to under-sampling from the detector.


Twenty-four hour survival in a canine model of cardiac arrest comparing three methods of manual cardiopulmonary resuscitation.
Two new modifications of manual cardiopulmonary resuscitation, high impulse compression at a rate of 120/min and interposed abdominal compression at a rate of 60/min, have been reported to produce better hemodynamic responses than standard cardiopulmonary resuscitation at 60/min. However, the effect of these two new methods on initial resuscitation success and 24 hour survival is unknown. In this study, 30 mongrel dogs were divided into three equal groups, each treated with one of three types of manual cardiopulmonary resuscitation. Ventricular fibrillation was induced electrically in morphinized, endotracheally intubated dogs emerging from halothane anesthesia. After 3 minutes of circulatory arrest without intervention, one of the three techniques of manual cardiopulmonary resuscitation was begun, and continued for 17 minutes. Defibrillation was performed at 20 minutes. Successful resuscitation was defined as a mean arterial blood pressure of at least 60 mm Hg, without chest compressions, 10 minutes after the initial defibrillation attempt. Intensive care was provided for 2 hours, including hemodynamic and respiratory monitoring, and drug intervention when required. Twenty-four hour survival and neurologic deficit were used as critical measures of outcome. Ten of 30 animals survived 24 hours with a mean neurologic deficit score of 5% (normal = 0, brain dead = 100). There was no difference in initial resuscitation success, 24 hour survival or neurologic deficit of the survivors among the three manual cardiopulmonary resuscitation methods. Aortic diastolic and calculated coronary perfusion pressures were similar for all three methods. Well performed standard manual cardiopulmonary resuscitation is as effective as these modified versions (high impulse compression and interposed abdominal compression) when compared in the same animal model.


Attitudes of clinicians following large-scale pharmacogenomics implementation.
Clinician attitudes toward multiplexed genomic testing may be vital to the success of translational programs. We surveyed clinicians at an academic medical center about their views on a large pharmacogenomics implementation, the PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) program. Participants were asked about test ordering, major factors influencing use of results, expectations of efficacy and responsibility for applying results to patient care. Virtually all respondents (99%) agreed that pharmacogenomics variants influence patients' response to drug therapy. The majority (92%) favored immediate, active notification when a clinically significant drug-genome interaction was present. However, clinicians were divided on which providers were responsible for acting on a result when a prescription change was indicated and whether patients should be directly notified of a significant result. We concluded genotype results were valued for tailoring prescriptions, but clinicians do not agree on how to appropriately assign clinical responsibility for actionable results from a multiplexed panel.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.57.


Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor.
Purified growth inhibitor from BSC-1 cells and type beta transforming growth factor from human platelets are shown to have nearly identical biological activity and to compete for binding to the same cell membrane receptor. These findings suggest that the growth inhibitor and the type beta transforming growth factor are similar molecules. The data also show that the same purified polypeptide can either stimulate or inhibit cell proliferation depending on the experimental conditions.


Cardio-protective role of Terminalia arjuna bark extract is possibly mediated through alterations in thyroid hormones.
Terminalia arjuna bark extract is believed to exhibit cardio-protective effects. In the present study we investigated the possible involvement of thyroid hormones in the amelioration of cardiac and hepatic lipid peroxidation (LPO) by a bark extract of the plant in albino rats. While L-thyroxine (L-T4) treatment increased the level of thyroid hormones, heart/body weight ratio as well as cardiac and hepatic lipid peroxidation, simultaneous administration of 21.42 and 42.84 mg/kg of the plant extract decreased the level of thyroid hormones and also the cardiac LPO, suggesting the possible mediation of the drug action through an inhibition in thyroid function. These effects were comparable to a standard antithyroid drug, propyl thiouracil (PTU). When the drug was administered to euthyroid animals, serum concentrations of thyroid hormones were decreased, whereas the hepatic LPO increased indicating a drug induced toxicity in euthyroid subjects. Although a suboptimal dose of the drug was found to be non-toxic to the liver, it appeared to be of no use, as it could neither affect the thyroid functions nor the cardiac lipid peroxidation. Since in euthyroid animals, thyroid hormones were decreased and hepatic LPO was increased, it is suggested that high amounts of this plant extract should not be consumed, as hepatotoxicity as well as hypothyroidism may be caused.


Influence of leisure activity on the incidence of Alzheimer's disease.
To determine whether leisure activities modify the risk for incident dementia. Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated. A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects' leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities. Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered. The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.


Evaluation of the pattern of human albumin utilization at a university affiliated hospital.
Albumin is a protein colloidal solution that possesses great value in the clinic, particularly for the resuscitation of critically ill patients. It has accounted for a high percentage of the cost in our center. This study evaluates the appropriateness of albumin usage at Masih Daneshvari Hospital, Tehran, Iran. This study evaluated 69 patient charts. Data included patient demographics, ward of admission, primary reasons for prescribing albumin, and details of albumin use. Possible correlations between the appropriateness of albumin usage, the number of albumin vials, and mortality rate were analyzed. Albumin was prescribed appropriately in 63.8% of patients. Cardiac surgery accounted for 37.3% of all indications. The most prevalent inappropriate indication of albumin was for mild hypoalbuminemia and nutritional support. There was a significant correlation between the number of used albumin vials and mortality rate. In conclusion, the albumin use in Masih Daneshvari Hospital was not completely in accordance with the accredited references. Albumin is an expensive medication prescribed unnecessarily for many patients. Using the clinical pharmacist's prepared guideline could minimize the situations where its administration is not needed.


The association between social participation and lower extremity muscle strength, balance, and gait speed in US adults.
Social participation is associated with healthy aging, and although associations have been reported between social participation and demographics, no published studies have examined a relationship between social participation and measures amenable to intervention. The purpose was to explore the association between self-reported social participation and lower extremity strength, balance, and gait speed. A cross-sectional analysis of US adults (n = 2291; n = 1,031 males; mean ± standard deviation age 63.5 ± 0.3 years) from the 2001-2 National Health and Nutrition Examination Survey was conducted. Two questions about self-reported difficulty with social participation were categorized into limited (yes/no). The independent variables included knee extension strength (n = 1537; classified as tertiles of weak, normal, and strong), balance (n = 1813; 3 tests scored as pass/fail), and gait speed (n = 2025; dichotomized as slow [less than 1.0 m/s] and fast [greater than or equal to 1.0 m/s]). Logistic regression, accounting for the complex survey design and adjusting for age, sex, physical activity, and medical conditions, was used to estimate the odds of limitation in social participation with each independent variable. Alpha was decreased to 0.01 due to multiple tests. Slower gait speed was significantly associated with social participation limitation (odds ratio = 3.1; 99% confidence interval: 1.5-6.2). No significant association was found with social participation and lower extremity strength or balance. The odds of having limitation in social participation were 3 times greater in those with slow gait speed. Prospective studies should examine the effect of improved gait speed on levels of social participation.


Feasibility for mapping cartilage t1 relaxation times in the distal metacarpus3/metatarsus3 of thoroughbred racehorses using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC): normal cadaver study.
Osteoarthritis of the metacarpo/metatarsophalangeal joints is one of the major causes of poor performance in horses. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) may be a useful technique for noninvasively quantifying articular cartilage damage in horses. The purpose of this study was to describe dGEMRIC characteristics of the distal metacarpus3/metatarsus3 (Mc3/Mt3) articular cartilage in 20 cadaver specimens collected from normal Thoroughbred horses. For each specimen, T1 relaxation time was measured from scans acquired precontrast and at 30, 60, 120, and 180 min post intraarticular injection of Gd-DTPA(2-) (dGEMRIC series). For each scan, T1 relaxation times were calculated using five regions of interest (sites 1-5) in the cartilage. For all sites, a significant decrease in T1 relaxation times occurred between precontrast scans and 30, 60, 120, and 180 min scans of the dGEMRIC series (P < 0.0001). A significant increase in T1 relaxation times occurred between 60 and 180 min and between 120 and 180 min post Gd injection for all sites. For sites 1-4, a significant increase in T1 relaxation time occurred between 30 and 180 min postinjection (P < 0.05). Sites 1-5 differed significantly among one another for all times (P < 0.0001). Findings from this cadaver study indicated that dGEMRIC using intraarticular Gd-DTPA(2-) is a feasible technique for measuring and mapping changes in T1 relaxation times in equine metacarpo/metatarsophalangeal joint cartilage. Optimal times for postcontrast scans were 60-120 min. Future studies are needed to determine whether these findings are reproducible in live horses.


Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy.
The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).


Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea.
Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over 4 hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil-treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy.


The rural older adult memory (ROAM) study: a practice-based intervention to improve dementia screening and diagnosis.
The aim of the Rural Older Adult Memory (ROAM) pilot study was to evaluate the feasibility of screening and diagnosing dementia in patients aged 75 years or older in 6 rural primary care practices in a practice-based research network. Clinicians and medical assistants were trained in dementia screening using the ROAM protocol via distance learning methods. Medical assistants screened patients aged 75 years of age and older. For patients who screened positive, the clinician was alerted to the need for a dementia work-up. Outcomes included change in the proportion of patients who were screened and diagnosed with dementia or mild cognitive impairment, clinician confidence in diagnosing and managing dementia, and response to the intervention. Results included a substantial increase in screening for dementia, a modest increase in the proportion of patients who were diagnosed with dementia or mild cognitive impairment, and improved clinician confidence in diagnosing dementia. Although clinicians and medical assistants found the ROAM protocol easy to implement, there was substantial variability in adherence to the protocol among the 6 practices. This study demonstrated the complex issues that must be addressed in implementing a dementia screening process in rural primary care. Further study is needed to develop effective strategies for overcoming the factors that impeded the full uptake of the protocol, including the logistic challenges in implementing practice change and clinicians' attitudes toward dementia screening and diagnosis.


Management and treatment of femoral neck stress fractures in recreational runners: a report of four cases and review of the literature.
Femoral neck stress fractures (FNSFs) in healthy young subjects are uncommon and most prevalent among long-distance runners and military recruits. Women seem to be at higher risk of developing stress fractures because of possible eating disorders followed by amenorrhea and osteoporosis. This case report describes four young and middle-aged, active female recreational runners who developed stress fractures of the femoral neck. In three of them, with a clinical history of persistent pain in the groin region, which worsened during training, early diagnosis by MRI was considered essential in detecting the fractures. The patients were clinically, metabolically and radiographically evaluated; they were then treated and followed-up at our institution. Only one case was treated conservatively, while the others underwent surgical internal fixation using a screw-plate (DHS®). All of them returned to sport physical activity after a recovery period. Regarding the challenging management of FNSFs, our report highlights the importance of groin pain, especially in athletic females, an early diagnosis by MRI, and a proper classification of these injuries for a correct choice of treatment in order to prevent further dislocation and avoid avascular necrosis of the femoral head.


The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities.
An autosomal recessive mutation, termed fatty liver dystrophy (fld), can be identified in neonatal mice by their enlarged and fatty liver (Sweet, H. O., Birkenmeier, E. H., and Davisson, M. T. (1988) Mouse News Letter 81, 69). We have examined the underlying metabolic abnormalities in fld/fld mice from postnatal days 3-40. Serum and hepatic triglyceride levels were elevated 5-fold in suckling fld/fld mice compared to their +/? littermates but abruptly resolved at the suckling/weaning transition. Blot hybridization analysis of liver and intestinal RNAs revealed a liver-specific increase in apolipoprotein (apo) A-IV and C-II mRNA concentrations (100- and 6-fold, respectively) that was limited to the suckling and early weaning stages in fld/fld mice. Resolution of these differences during the weaning period could not be delayed by prolonging suckling to the 20th postnatal day nor could the mutant phenotype be elicited in young adult animals with a high fat diet. Lipoprotein lipase (LPL) activity was reduced 16-fold in the white adipose tissue of fld/fld mice until the onset of weaning. Heart activity was decreased less than 2-fold, but there were no deficits in brown adipose tissue or liver. Hepatic lipase (HL) mRNA levels and activity were significantly reduced in fld/fld livers and sera, respectively, during the suckling period. Mapping studies show the fld locus to be distinct from loci encoding LPL, HL, and apoA-IV, and those responsible for the combined lipase deficiencies in cld/cld and W/Wv mice. These data suggest that the fld mutation is associated with developmentally programmed tissue-specific defects in the neonatal expression of LPL and HL activities and provide evidence for a new regulatory locus which affects these lipase activities. This mutation could serve as a useful model for (i) analyzing the homeostatic mechanisms controlling lipid metabolism in newborn mice and (ii) understanding and treating certain inborn errors in human triglyceride metabolism.


Rhizoremediation of diesel-contaminated soil with two rapeseed varieties and petroleum degraders reveals different responses of the plant defense mechanisms.
Plant-assisted bioremediation (rhizoremediation) stands out as a potential tool to inactivate or completely remove xenobiotics from the polluted environment. Therefore, it is of key importance to find an adequate combination of plant species and microorganisms that together enhance the clean-up process. To understand the response of plants upon bioaugmentation, the antioxidative and detoxification system was analyzed in high and low erucic acid rapeseed varieties (HEAR and LEAR, respectively), after 8 weeks of their treatment with petroleum degraders and 6000 mg diesel oil/kg dry soil. The oxidative stress was enhanced in LEAR being exposed to sole diesel oil, in comparison with HEAR. However, when LEAR plants were additionally inoculated with bacteria, suppression of total catalase (CAT) and ascorbate peroxidase (APX) activity were observed. Interestingly, glutathione transferase (GST) activity was found in these plants at a much higher level than in HEAR, which correlated with a more efficient diesel removal performed by LEAR in the polluted soil and upon bioaugmentation. A distinct profile of polycyclic aromatic hydrocarbons (PAH) was detected in leaves of these plants. Neither LEAR nor HEAR experienced any changes in the photosynthetic capacity upon diesel pollution and presence of petroleum degraders, which supports the usefulness of rhizoremediation with rapeseed.


Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy.
In patients with hypertrophic cardiomyopathy (HCM), the role of small vessel disease and myocardial perfusion remains incompletely understood and data on absolute myocardial blood flow (MBF, mL/g/min) are scarce. We measured MBF using cardiovascular magnetic resonance fully quantitative perfusion mapping to determine the relationship between perfusion, hypertrophy and late gadolinium enhancement (LGE) in HCM. 101 patients with HCM with unobstructed epicardial coronary arteries and 30 controls (with matched cardiovascular risk factors) underwent pixel-wise perfusion mapping during adenosine stress and rest. Stress, rest MBF and the myocardial perfusion reserve (MPR, ratio of stress to rest) were calculated globally and segmentally and then associated with segmental wall thickness and LGE. In HCM, 79% had a perfusion defect on clinical read. Stress MBF and MPR were reduced compared with controls (mean±SD 1.63±0.60 vs 2.30±0.64 mL/g/min, p<0.0001 and 2.21±0.87 vs 2.90±0.90, p=0.0003, respectively). Globally, stress MBF fell with increasing indexed left ventricle mass (R2 for the model 0.186, p=0.036) and segmentally with increasing wall thickness and LGE (both p<0.0001). In 21% of patients with HCM, MBF was lower during stress than rest (MPR <1) in at least one myocardial segment, a phenomenon which was predominantly subendocardial. Apparently normal HCM segments (normal wall thickness, no LGE) had reduced stress MBF and MPR compared with controls (mean±SD 1.88±0.81 mL/g/min vs 2.32±0.78 mL/g/min, p<0.0001). Microvascular dysfunction is common in HCM and associated with hypertrophy and LGE. Perfusion can fall during vasodilator stress and is abnormal even in apparently normal myocardium suggesting it may be an early disease marker.


Feedback and Direction Sources Influence Navigation Decision Making on Experienced Routes.
When navigating in a new environment, it is typical for people to resort to external guidance such as Global Positioning System (GPS), or people. However, in the real world, even though navigators have learned the route, they may still prefer to travel with external guidance. We explored how the availability of feedback and the source of external guidance affect navigation decision-making on experienced routes in the presence of external guidance. In three experiments, participants navigated a simulated route three times and then verbally confirmed that they had learned it. They then traveled the same route again, accompanied with no, correct, or incorrect direction guidance, which latter two were provided by a GPS (Experiment 1), a stranger (Experiment 2), or a friend (Experiment 3). Half of the participants received immediate feedback on their navigation decisions, while the other half without feedback did not know if they had selected the correct directions. Generally, without feedback, participants relied on external guidance, regardless of the direction sources. Results also showed that participants trusted the GPS the most, but performed best with their friends as a direction source. With feedback, participants did not show differences in performance between the correct and incorrect guidance conditions, indicating that feedback plays a critical role in evaluating the reliability of external guidance. Our findings suggest that incorrect guidance without any feedback might disturb navigation decision-making, which was further moderated by the perceived credibility of direction sources. We discuss these results within the context of navigation decision-making theory and consider implications for wayfinding behaviors as a social activity.


[Factors associated with the presence of tuberculosis in patients with acquired immunodeficiency syndrome in Cuba].
To determine the factors associated with the development of tuberculosis in patients with acquired immunodeficiency syndrome (AIDS) and to identify the most frequent symptoms and signs of tuberculosis in this group of patients. This retrospective observational case-control study was carried out with 143 patients diagnosed with AIDS who were discharged from the Pedro Kourí Institute of Tropical Medicine, which is in the city of Havana, Cuba, between January 1997 and March 2001. The cases were 72 patients with AIDS and some clinical form of tuberculosis, while the control group was made up of the first 71 AIDS patients without tuberculosis who were discharged. The following variables were evaluated: AIDS stage before the study, serious opportunistic infections suffered before the diagnosis of tuberculosis (pulmonary pneumocystosis, cerebral toxoplasmosis, systemic candidiasis, isosporiasis, and recurrent pneumonia), concentration of CD4+ T lymphocytes, and clinical symptoms and signs of tuberculosis. The primary data were taken from the clinical files of the patients. We calculated the frequency of the nominal qualitative variables and the crude odd ratios (ORs) and their 95% confidence intervals (CIs). The statistical association among the variables was determined with the chi-square test with Yates correction. The individual effect of each variable was assessed through multivariate logistic regression analysis. The level of statistical significance was 0.05. Tuberculosis in this group of patients showed a statistically significant association with: being ill with AIDS before the study (OR = 3.57; 95% CI: 1.78 to 7.17); a history of pulmonary pneumocystosis (OR = 4.73; 95% CI: 1.51 to 15.76), cerebral toxoplasmosis (OR = 6.22; 95% CI: 1.21 to 42.99), or systemic candidiasis (OR = 11.29; 95% CI: 1.40 to 246.5); and having CD4+ T lymphocyte concentrations lower than 200 cells/mm(3). However, the logistic regression showed a significant association only with the history of systemic candidiasis (OR = 10.47; 95% CI: 1.06 to 103.5; P = 0.0446). The symptoms associated with the clinical diagnosis of tuberculosis were hemoptysis (OR = 7.54; 95% CI: 1.88 to 170.34), fever of unknown origin (OR = 13.38; 95% CI: 5.55 to 32.96), night sweats (OR = 21.95; 95% CI: 4.66 to 142.43), and weight loss (OR = 3.52; 95% CI: 1.65 to 7.55). The associated signs were regional lymphadenopathies (OR = 10.00; 95% CI: 1.22 to 220.3), hepatomegaly (OR = 5.44; 95% CI: 1.76 to 17.95), and splenomegaly (OR = 5.08; 95% CI: 1.63 to 16.83). The symptoms and signs seen most frequently in the patients with AIDS and tuberculosis are the characteristics of tuberculosis in patients without AIDS. In patients with AIDS, tuberculosis can be associated with other diseases whose symptoms are similar to those of tuberculosis. Nevertheless, these results indicate that the traditional symptoms of tuberculosis can help diagnose tuberculosis in this group of patients.


Association between tobacco plain packaging and Quitline calls: a population-based, interrupted time-series analysis.
To investigate whether the introduction of tobacco plain packaging in Australia from 1 October 2012 was associated with a change in the number of calls to the smoking cessation helpline, Quitline, and to compare this with the impact of the introduction of graphic health warnings from 1 March 2006. Whole-of-population interrupted time-series analysis in New South Wales and the Australian Capital Territory between 1 March 2005 and October 2006 for the comparator, graphic health warnings, and October 2011 and April 2013 for the intervention of interest, tobacco plain packaging. Weekly number of calls to the Quitline, after adjusting for seasonal trends, anti-tobacco advertising, cigarette costliness and the number of smokers in the community. There was a 78% increase in the number of calls to the Quitline associated with the introduction of plain packaging (baseline, 363/week; peak, 651/week [95% CI, 523-780/week; P < 0.001]). This peak occurred 4 weeks after the initial appearance of plain packaging and has been prolonged. The 2006 introduction of graphic health warnings had the same relative increase in calls (84%; baseline, 910/week; peak, 1673/week [95% CI, 1383-1963/week; P < 0.001]) but the impact of plain packaging has continued for longer. There has been a sustained increase in calls to the Quitline after the introduction of tobacco plain packaging. This increase is not attributable to anti-tobacco advertising activity, cigarette price increases nor other identifiable causes. This is an important incremental step in comprehensive tobacco control.


Attenuation correction synthesis for hybrid PET-MR scanners: application to brain studies.
Attenuation correction is an essential requirement for quantification of positron emission tomography (PET) data. In PET/CT acquisition systems, attenuation maps are derived from computed tomography (CT) images. However, in hybrid PET/MR scanners, magnetic resonance imaging (MRI) images do not directly provide a patient-specific attenuation map. The aim of the proposed work is to improve attenuation correction for PET/MR scanners by generating synthetic CTs and attenuation maps. The synthetic images are generated through a multi-atlas information propagation scheme, locally matching the MRI-derived patient's morphology to a database of MRI/CT pairs, using a local image similarity measure. Results show significant improvements in CT synthesis and PET reconstruction accuracy when compared to a segmentation method using an ultrashort-echo-time MRI sequence and to a simplified atlas-based method.


Flexible Nonvolatile Transistor Memory with Solution-Processed Transition Metal Dichalcogenides.
Nonvolatile field-effect transistor (FET) memories containing transition metal dichalcogenide (TMD) nanosheets have been recently developed with great interest by utilizing some of the intriguing photoelectronic properties of TMDs. The TMD nanosheets are, however, employed as semiconducting channels in most of the memories, and only a few works address their function as floating gates. Here, a floating-gate organic-FET memory with an all-in-one floating-gate/tunneling layer of the solution-processed TMD nanosheets is demonstrated. Molybdenum disulfide (MoS2 ) is efficiently liquid-exfoliated by amine-terminated polystyrene with a controlled amount of MoS2 nanosheets in an all-in-one floating-gate/tunneling layer, allowing for systematic investigation of concentration-dependent charge-trapping and detrapping properties of MoS2 nanosheets. At an optimized condition, the nonvolatile memory exhibits memory performances with an ON/OFF ratio greater than 104 , a program/erase endurance cycle over 400 times, and data retention longer than 7 × 103 s. All-in-one floating-gate/tunneling layers containing molybdenum diselenide and tungsten disulfide are also developed. Furthermore, a mechanically-flexible TMD memory on a plastic substrate shows a performance comparable with that on a hard substrate, and the memory properties are rarely altered after outer-bending events over 500 times at the bending radius of 4.0 mm.


Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to β-lactam Antibiotics.
Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β-lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β-lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β-lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, 'paradoxical hypersusceptibility' to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.


Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1.
Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.


Impact of patient's health-related quality of life on physicians' therapy and perceived benefit in acute coronary syndromes: protocol for a systemic review of quantitative and qualitative studies.
Percutaneous coronary interventions (PCIs) and coronary angiography are two of the treatments administered to acute coronary syndrome (ACS) patients. However, whether and how patients' health-related quality of life (HRQoL) influences treatment decisions and subsequent risk benefit analyses is unclear. In this study, we will review the available evidence on the impact of patients' HRQoL on physicians' prescribing or treatment decisions and on the estimation of mortality and bleeding risk in ACS patients. We will undertake a systematic review of all quantitative and qualitative studies. The search will include studies that describe the impact of HRQoL on prescribing PCIs or angiography, and impact of HRQoL on perceived risks in terms of mortality and bleeding events. We will conduct an initial search on Google scholar and MEDLINE to build the searching terms followed by a full search strategy using all identified keywords and index terms across the five databases, namely MEDLINE, PubMed, CINAHL, SCOPUS and Web of Sciences. We will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for protocol guidelines to present the protocol. Only English language articles will be included for the review. We will use a standardised Joanna Briggs Institute data extraction tool to synthesise the information extracted from the selected studies into themes with summary findings presented in a table. We will not require a formal ethical approval as we will not be collecting primary data. Review findings will be disseminated through a peer-reviewed publication, workshops, conference presentations and a media release. CRD42018108438.


An experimental and simulation study on the self-assembly of colloidal cubes in external electric fields.
When a suspension of colloidal particles is placed in an oscillating electric field, the contrast in dielectric constant between the particles and the solvent induces a dipole moment in each of the colloidal particles. The resulting dipole-dipole interactions can strongly influence the phase behavior of the system. We investigate the phase behavior of cube-shaped colloidal particles in electric fields, using both experiments and Monte Carlo simulations. In addition to a string fluid phase and a body centered tetragonal (BCT) crystal phase, we observe a columnar phase consisting of hexagonally ordered strings of rotationally disordered cubes. By simulating the system for a range of pressures and electric field strengths, we map out the phase diagram, and compare the results to the experimentally observed phases. Additionally, we estimate the accuracy of a point-dipole approximation on the alignment of cubes in string-like clusters.


Dynamic viscoelastic coagulometry of blood obtained from healthy chickens.
To assess feasibility of the use of a dynamic viscoelastic coagulometer on chicken blood and compare coagulation variables for fresh whole blood and sodium citrate-preserved whole blood as well as effects of 3 coagulation activators on blood from chickens. Blood samples from 30 hens. Chickens were allowed to rest undisturbed for 1 hour. A blood sample was collected from an ulnar vein; 1.4 mL was analyzed immediately, and 1.8 mL was mixed with sodium citrate and subsequently recalcified and analyzed. A separate coagulation activator (glass beads, kaolin clay, or tissue factor) was in each of the 2 channels of the analyzer. Chickens were allowed a 1-hour rest period, and another blood sample was collected from the contralateral ulnar vein; it was processed in the same manner as for the first sample, except both channels of the analyzer contained the same coagulation activator. Compared with fresh samples, citrated samples had higher values for activated clotting time and platelet function and lower clotting rates. Intra-assay coefficients of variation of coagulation profiles for citrated samples were markedly greater than the limit of 10%, whereas values for fresh samples were close to or < 10%. Results suggested that use of a dynamic viscoelastic coagulometer on chicken blood was feasible and that analysis of fresh whole blood from healthy chickens provided results with less variability than did analysis of citrated blood. Samples preserved with sodium citrate were associated with significant relative hypocoagulability, compared with results for fresh blood.


First Report of Sugar Beet Seedling Damping-Off Caused by Binucleate Rhizoctonia AG-A in China.
Sugar beet (Beta vulgaris L.) is grown worldwide and produces one-third of the world's sugar supply. Sugar beet seedling Rhizoctonia damping-off is an important disease mainly caused by Rhizoctonia solani AG-2, AG-4, and AG-5 (2). In 2010, diseased sugar beet seedlings with about 20% incidence affected by damping-off, which showed dark brown lesions on the stems just below the soil surface and portions of the roots, were collected from nurseries in three locations in Heilongjiang province, northeast China. Root fragments taken from the margins of healthy tissues and lesions on roots were surface disinfected with 0.5% sodium hypochlorite for 2 min, rinsed with sterile water, then placed on potato dextrose agar (PDA) and incubated at 25°C in the dark. Three (designed HLJ-RAA1, HLJ-RAB1, HLJ-RAB2) of nine Rhizoctonia isolates were obtained from diseased tissues and preliminarily identified as binucleate Rhizoctonia (BNR) anamorph (teleomorph Ceratobasidium Rogers) species-like. Fungal colonies were white with large amounts of floccose, aerial hyphae. Hyphal cells were determined to be binucleate when stained with 4'-6-diamidino-2-phenylindole (DAPI) (1). No sclerotia were produced after 14 days on PDA. Average hyphal diameter of the three isolates were 4.2, 4.3, and 4.8 μm, respectively. Further, the internal transcribed spacer (ITS) region of rDNA was amplified from the genomic DNA extracted from hyphae by bead beating in 2% CTAB solution using stainless steel beads with primers ITS1 and ITS4. The ITS sequences (GenBank Accession Nos. JX073668, JX073669, and JX073670) were over 99% identical to those of more than 50 Ceratobasidium sp. AG-A isolates (e.g., GenBank Accession No. JQ688054.1; strain HY-15). Therefore, based on morphological and molecular characteristics, these isolates were identified to be BNR AG-A. To determine the pathogenicity of the isolates, sugar beet (cv. HI0305) seedlings were inoculated with wheat seeds colonized with each of the isolated Rhizoctonia strains (one seed per seedling), and grew in pots under greenhouse conditions (3). After 3 weeks, some inoculated plants showed damping-off as observed in the nurseries, whereas noninoculated control plants (sterile wheat seeds only) remained healthy. Disease incidence from the trials averaged 53.3%, 70%, and 53.3% for the isolates HLJ-RAA1, HLJ-RAB1, and HLJ-RAB2, respectively. The three BNR cultures of the pathogens were consistently reisolated from symptomatic roots, and their identities confirmed by morphological and molecular characteristics as described above, fulfilling Koch's postulates. BNR AG-A was previously reported to be pathogenic to soybean, pea, snap bean, and pak choy in China (4). However, to our knowledge, this is the first report of BNR AG-A causing sugar beet seedling damping-off in China. Sugar beet is often grown in crop rotation with soya bean and such a rotation could increase the risk of soilborne infection to either crop by BNR AG-A. References: (1) W. C. Kronland and M. E. Stanghellini. Phytopathology 78:820, 1988. (2) E. O'Sullivan and J. A. Kavanagh. Plant Pathol. 40:128, 1991. (3) C. E. Windels and D. J. Nabben. Phytopathology 79:83, 1989. (4) G. H. Yang et al. J. Phytopathol. 153:333, 2005.


Perspectives for sensitivity enhancement in proton-detected solid-state NMR of highly deuterated proteins by preserving water magnetization.
In this work, we show how the water flip-back approach that is widely employed in solution-state NMR can be adapted to proton-detected MAS solid-state NMR of highly deuterated proteins. The scheme allows to enhance the sensitivity of the experiment by decreasing the recovery time of the proton longitudinal magnetization. The method relies on polarization transfer from non-saturated water to the protein during the inter-scan delay.