Machine learning and word sense disambiguation in the biomedical domain: design and evaluation issues.
Word sense disambiguation (WSD) is critical in the biomedical domain for improving the precision of natural language processing (NLP), text mining, and information retrieval systems because ambiguous words negatively impact accurate access to literature containing biomolecular entities, such as genes, proteins, cells, diseases, and other important entities. Automated techniques have been developed that address the WSD problem for a number of text processing situations, but the problem is still a challenging one. Supervised WSD machine learning (ML) methods have been applied in the biomedical domain and have shown promising results, but the results typically incorporate a number of confounding factors, and it is problematic to truly understand the effectiveness and generalizability of the methods because these factors interact with each other and affect the final results. Thus, there is a need to explicitly address the factors and to systematically quantify their effects on performance. Experiments were designed to measure the effect of "sample size" (i.e. size of the datasets), "sense distribution" (i.e. the distribution of the different meanings of the ambiguous word) and "degree of difficulty" (i.e. the measure of the distances between the meanings of the senses of an ambiguous word) on the performance of WSD classifiers. Support Vector Machine (SVM) classifiers were applied to an automatically generated data set containing four ambiguous biomedical abbreviations: BPD, BSA, PCA, and RSV, which were chosen because of varying degrees of differences in their respective senses. Results showed that: 1) increasing the sample size generally reduced the error rate, but this was limited mainly to well-separated senses (i.e. cases where the distances between the senses were large); in difficult cases an unusually large increase in sample size was needed to increase performance slightly, which was impractical, 2) the sense distribution did not have an effect on performance when the senses were separable, 3) when there was a majority sense of over 90%, the WSD classifier was not better than use of the simple majority sense, 4) error rates were proportional to the similarity of senses, and 5) there was no statistical difference between results when using a 5-fold or 10-fold cross-validation method. Other issues that impact performance are also enumerated. Several different independent aspects affect performance when using ML techniques for WSD. We found that combining them into one single result obscures understanding of the underlying methods. Although we studied only four abbreviations, we utilized a well-established statistical method that guarantees the results are likely to be generalizable for abbreviations with similar characteristics. The results of our experiments show that in order to understand the performance of these ML methods it is critical that papers report on the baseline performance, the distribution and sample size of the senses in the datasets, and the standard deviation or confidence intervals. In addition, papers should also characterize the difficulty of the WSD task, the WSD situations addressed and not addressed, as well as the ML methods and features used. This should lead to an improved understanding of the generalizablility and the limitations of the methodology.


Effect of Molecular Weight and Functionality on Acrylated Poly(caprolactone) for Stereolithography and Biomedical Applications.
Degradable polymers are integral components in many biomedical polymer applications. The ability of these materials to decompose in situ has become a critical component for tissue engineering, allowing scaffolds to guide cell and tissue growth while facilitating gradual regeneration of native tissue. The objective of this work is to understand the role of prepolymer molecular weight and functionality of photocurable poly(caprolactone) (PCL) in determining reaction kinetics, mechanical properties, polymer degradation, biocompatibility, and suitability for stereolithography. PCL, a degradable polymer used in a number of biomedical applications, was functionalized with acrylate groups to enable photopolymerization and three-dimensional printing via stereolithography. PCL prepolymers with different molecular weights and functionalities were studied to understand the role of molecular structure in reaction kinetics, mechanical properties, and degradation rates. The mechanical properties of photocured PCL were dependent on cross-link density and directly related to the molecular weight and functionality of the prepolymers. High-molecular weight, low-functionality PCLDA prepolymers exhibited a lower modulus and a higher strain at break, while low-molecular weight, high-functionality PCLTA prepolymers exhibited a lower strain at break and a higher modulus. Additionally, degradation profiles of cross-linked PCL followed a similar trend, with low cross-link density leading to degradation times up to 2.5 times shorter than those of more highly cross-linked polymers. Furthermore, photopolymerized PCL showed biocompatibility both in vitro and in vivo, causing no observed detrimental effects on seeded murine-induced pluripotent stem cells or when implanted into pig retinas. Finally, the ability to create three-dimensional PCL structures is shown by fabrication of simple structures using digital light projection stereolithography. Low-molecular weight, high-functionality PCLTA prepolymers printed objects with feature sizes near the hardware resolution limit of 50 μm. This work lays the foundation for future work in fabricating microscale PCL structures for a wide range of tissue regeneration applications.


Ocular adnexal lymphoma and Helicobacter pylori gastric infection.
There is a causal association between Helicobacter pylori (Hp) gastric infection and the development of gastric MALT lymphoma. In contrast, the link between Hp gastric infection and the development of extragastric lymphoma has not been thoroughly investigated. We, therefore, studied the prevalence of gastric Hp infection at initial diagnosis of ophthalmologic and nonophthalmologic extragastric lymphoma patients. Three cohorts of patients were studied: a first one of 83 patients with OAL, a second one of 101 patients with extraophthalmologic extragastric lymphoma, and a third one of 156 control individuals (control) without malignant lymphoma. Gastric Hp infection was investigated by histopathological analysis and Hp-specific PCR assay on gastric biopsy tissue samples. We found gastric Hp infection in 37 OAL patients (45%), in 25 extraophthalmologic extragastric lymphoma cases (25%), and in 18 controls individuals (12%) (P < 0.0001 OAL/C and P < 0.01 OAL/extra-OAL cases). Gastritis was found in 51% and 9% of Hp-positive and Hp-negative lymphoma patients, respectively (P < 10(-4)). Gastric Hp infection only correlated with MALT/LPL lymphoma (P = 0.03). There is a significant association between gastric Hp infection and MALT/LPL OAL. This suggests a novel mechanism of indirect infection-associated lymphomagenesis whereby chronic local antigen stimulation would lead to the emergence of ectopic B-cell lymphoma.


Public health policy in a time of change and disaster in South Africa: 1910-1920.
With the establishment of the Union of South Africa in 1910, the central focus of the newly appointed government was to alter and consolidate the policies of the pre-Union colonies that differed materially in many respects and to substitute them with uniform policies that had to be implemented as a consolidated whole for the Union. This central focus was applied to a number of policies, notably those for the black people, immigration, education, labour, national defence and the development and implementation of railway, mining and agricultural policies. However, an omission occurred with regard to the consideration of a comprehensive public health policy by the political parties and the Union Parliament, consisting of white people only. This article examines this omission during the first 10 years of the Union of South Africa (1910-1920), during the three 5-yearly general elections (on 15 September 1910, 20 October 1915 and 10 March 1920), and argues that this lack of consideration of a comprehensive public health policy can be found in the theory of party political responsible government during unification, which was further developed by Kavanagh, that party political manifestos act as the guiding force behind the policy matters that are discussed and decided upon in Parliament. The article confirms that the reason for not establishing a comprehensive public health policy prior to the outbreak of the influenza epidemic in 1918 was the incidental and piecemeal fashion in which expressions on public health appeared in the published party political manifestos, which in turn influenced the proceedings of Parliament. This political negligence was, however, quickly overturned by Parliament immediately after the epidemic, showing the influence of this demographic disaster on political thinking and action.


Psychiatric morbidity in a sample of accidents.
The coroner's records of 110 accidental deaths resulting from poisoning, drowning and falling were examined for evidence of mental illness. Sixty per cent were classified as mentally ill before they died, depression, drug dependence and alcoholism accounting for over three-quarters of the diagnoses. Deaths given accident verdicts should be included in the study of the mortality of the mentally ill.


The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity.
Hexarelin is a synthetic six-amino-acid compound capable of releasing GH in animals and in man. Its mechanism of action is not understood and little is known about the GH response after repeated administration. The aim of this study was to determine the GH response to the administration of two intravenous boluses of hexarelin, growth hormone releasing hormone (GHRH) or hexarelin with GHRH. Single boluses of hexarelin (1 microgram/kg), GHRH-(1-29)-NH2 (1 microgram/kg) or hexarelin with GHRH-(1-29)-NH2 were administered intravenously. Each study was performed on two further occasions, with a second bolus being administered 60 or 120 minutes after the first. A control study was performed giving saline intravenously. Studies were performed in a random order. Six healthy adult males (25.4-34.1 years) were studied. Serum GH was measured by radioimmunoassay. GH secretion rates were derived from the measured serum GH concentrations using the technique of deconvolution analysis. The peak GH secretion rate following the first intravenous bolus of hexarelin was greater than that following the first bolus of GHRH-(1-29)-NH2 (P < 0.001), and was greatest following the administration of hexarelin with GHRH-(1-29)-NH2 (P < 0.001). The coadministration of the two secretagogues resulted in peak GH secretion rates significantly greater than the arithmetic sum of those following their isolated administration (P = 0.001), demonstrating synergism. Compared to saline, the administration of a second bolus of hexarelin, GHRH-(1-29)-NH2 or both resulted in significant further GH secretion (P = 0.02, P = 0.002, P = 0.03, respectively). The administration of a second bolus of hexarelin or hexarelin with GHRH-(1-29)-NH2 120 minutes after the first bolus resulted in lower peak GH secretion rates (P = 0.03). The reductions in peak GH secretion rates following the 60-minute boluses were not statistically significant. The peak GH secretion rates following the first GHRH-(1-29)-NH2 boluses were similar to those following the 60 and 120-minute GHRH-(1-29)-NH2 boluses (P = NS). Irrespective of the interval between the boluses of hexarelin with GHRH-(1-29)-NH2, the peak GH secretion rates following the second boluses were not significantly different from the arithmetic sum of those following the administration of the second boluses of hexarelin or GHRH-(1-29)-NH2, indicating loss of synergism on repeated administration. This study shows that hexarelin is a potent GH secretagogue active after two successive doses; the magnitude of the GH response to the second dose was influenced by the dosing interval. Hexarelin and GHRH-(1-29)-NH2 are synergistic, a property which is lost after repeated administration. These findings may help our understanding of GHRPs and may have implications for the potential use of hexarelin and other GHRPs as therapeutic agents.


Characterization of body louse midgut proteins recognized by resistant hosts.
The human body louse, Pediculus humanus, showed eighteen midgut proteins ranging between 12 and 117 kDa, when analysed by SDS-PAGE electrophoresis. Seven of them (12 kDa, 17 kDa, 29 kDa, 35 kDa, 40 kDa, 55 kDa and 97 kDa) were major bands based on their intensity of staining. The immunization of rabbits with a midgut extract elicited the production of protective polyclonal antibodies. These antibodies reacted strongly with all major midgut proteins as well as with 63 kDa and 117 kDa proteins when tested by the Western blot technique. The analysis of the proteins revealed that the 12 kDa, 25 kDa, 29 kDa, 35 kDa, 45 kDa, 87 kDa and 97 kDa proteins are glycosylated and none of them contained a lipid moiety. By electroelution, the proteins of 35 kDa and 63 kDa were purified. On trypsinization, the proteins of 35 kDa and 63 kDa produced four major fragments (F1, F2, F3, and F4) when resolved on a 18% SDS-PAGE. The F1 fragment of the 35 kDa protein reacted with the polyclonal antibodies by the immunoblot technique.


Consensus guidelines for the safe prescription and administration of oral bowel-cleansing agents.
Oral bowel-cleansing preparations are used before colonic surgery and endoscopic and radiological assessment of the intestine to minimise faecal contamination. In February 2009, the UK National Patient Safety Agency issued a Rapid Response Report highlighting the potential risk of harm associated with the use of these preparations and instructing local NHS Trusts to implement safeguards to reduce this risk. This guidance has been prepared to help NHS Trusts to respond to these concerns, as the risk of complications is influenced by both individual patient risk factors and the choice of bowel preparation, for which definitive guidance was not previously available. This document provides an outline of the different available oral bowel-cleansing agents and the complications that may arise. This is followed by recommendations for their use in different patient groups and circumstances. The recommendations are based on consensus between the authors, each of whom circulated drafts to members of their specialist society. The evidence for these recommendations has been assessed using the modified GRADE system. The recommendations cover the choice, administration and complications (relative and absolute) of the different oral bowel-cleansing agents, with specific guidance provided for different patient groups.


Family adversity in DSM-IV ADHD combined and inattentive subtypes and associated disruptive behavior problems.
This study evaluated the relationship between a family adversity index and DSM-IV attention-deficit/hyperactivity disorder (ADHD) subtypes and associated behavior problems. The relationship of family adversity to symptoms and subtypes of ADHD was examined. Parents and 206 children aged 7-13 completed diagnostic interviews and rating scales about socioeconomic status, parental lifetime psychiatric disorders, marital conflict, and stressful life events. Children with ADHD combined type experienced more risk factors than community controls (p = .002) or children with ADHD predominantly inattentive type (p = .02). The families of children with ADHD combined type described more risk factors associated with family adversity than the families of children with ADHD inattentive type and the control group. Parent-rated symptoms of child inattention/disorganization were related uniquely to the adversity index score independently of conduct disorder symptoms. Children's perceptions of marital conflict were independently related to inattention and hyperactivity behaviors as rated by parents and teachers after control of all other risk factors. Oppositional defiant symptoms were independently related to marital conflict and maternal psychopathology, whereas conduct disorder symptoms were uniquely related to low socioeconomic status and maternal psychopathology. Family adversity is related to ADHD combined type in children and may be related specifically to ADHD symptoms in addition to conduct disorder symptoms.


Three-Dimensional Culture of Cells and Matrix Biomolecules for Engineered Tissue Development and Biokinetics Model Validation.
There has been considerable progress in cellular and molecular engineering due to recent advances in multiscale technology. Such technologies allow controlled manipulation of physiochemical interactions among cells in tissue culture. In particular, a novel chemomechanical bioreactor has recently been designed for the study of bone and cartilage tissue development, with particular focus on extracellular matrix formation. The bioreactor is equally significant as a tool for validation of mathematical models that explore biokinetic regulatory thresholds (Saha, A. K., and Kohles, S. S., 2010, "A Distinct Catabolic to Anabolic Threshold Due to Single-Cell Nanomechanical Stimulation in a Cartilage Biokinetics Model," J. Nanotechnol. Eng. Med., 1(3), p. 031005; 2010, "Periodic Nanomechanical Stimulation in a Biokinetics Model Identifying Anabolic and Catabolic Pathways Associated With Cartilage Matrix Homeostasis," J. Nanotechnol. Eng. Med., 1(4), p. 041001). In the current study, three-dimensional culture protocols are described for maintaining the cellular and biomolecular constituents within defined parameters. Preliminary validation of the bioreactor's form and function, expected bioassays of the resulting matrix components, and application to biokinetic models are described. This approach provides a framework for future detailed explorations combining multiscale experimental and mathematical analyses, at nanoscale sensitivity, to describe cell and biomolecule dynamics in different environmental regimes.


Estimating the normal background rate of species extinction.
A key measure of humanity's global impact is by how much it has increased species extinction rates. Familiar statements are that these are 100-1000 times pre-human or background extinction levels. Estimating recent rates is straightforward, but establishing a background rate for comparison is not. Previous researchers chose an approximate benchmark of 1 extinction per million species per year (E/MSY). We explored disparate lines of evidence that suggest a substantially lower estimate. Fossil data yield direct estimates of extinction rates, but they are temporally coarse, mostly limited to marine hard-bodied taxa, and generally involve genera not species. Based on these data, typical background loss is 0.01 genera per million genera per year. Molecular phylogenies are available for more taxa and ecosystems, but it is debated whether they can be used to estimate separately speciation and extinction rates. We selected data to address known concerns and used them to determine median extinction estimates from statistical distributions of probable values for terrestrial plants and animals. We then created simulations to explore effects of violating model assumptions. Finally, we compiled estimates of diversification-the difference between speciation and extinction rates for different taxa. Median estimates of extinction rates ranged from 0.023 to 0.135 E/MSY. Simulation results suggested over- and under-estimation of extinction from individual phylogenies partially canceled each other out when large sets of phylogenies were analyzed. There was no evidence for recent and widespread pre-human overall declines in diversity. This implies that average extinction rates are less than average diversification rates. Median diversification rates were 0.05-0.2 new species per million species per year. On the basis of these results, we concluded that typical rates of background extinction may be closer to 0.1 E/MSY. Thus, current extinction rates are 1,000 times higher than natural background rates of extinction and future rates are likely to be 10,000 times higher.


Microscopic mechanism of thermomolecular orientation and polarization.
Recent molecular dynamics simulations show that thermal gradients can induce electric fields in water that are comparable in magnitude to electric fields seen in ionic thin films and biomembranes. This surprising non-equilibrium phenomenon of thermomolecular orientation is also observed more generally in simulations of polar and non-polar size-asymmetric dumbbell fluids. However, a microscopic theory linking thermomolecular orientation and polarization to molecular properties is yet unknown. Here, we formulate an analytically solvable microscopic model of size-asymmetric dumbbell molecules in a temperature gradient using a mean-field, local equilibrium approach. Our theory reveals the relationship between the extent of thermomolecular orientation and polarization, and molecular volume, size anisotropy and dipole moment. Predictions of the theory agree quantitatively with molecular dynamics simulations. Crucially, our framework shows how thermomolecular orientation can be controlled and maximized by tuning microscopic molecular properties.


Health Care Access Among Asian American Subgroups: The Role of Residential Segregation.
Few studies have examined differences in health care access across Asian American ethnicities and none have considered the effects of residential segregation. The segregation of Asians by neighborhood has been steadily increasing over the past few decades due in part to the settlement patterns of immigrants. Data from the 2009 National Longitudinal Study of Adolescent Health (n = 746) were used. We examined differences in yearly medical checkups between Asian subgroups as well as among foreign-born and US-born Asians. Results showed that immigrant Filipinos and Vietnamese were less likely to get a checkup compared with foreign-born Chinese. The effect of Asian subgroup was modified by the percentage of Asians in a census tract (p < 0.01). Koreans and other Asians had a higher probability of getting a checkup when living in a predominately Asian neighborhood. For Chinese and Vietnamese residential concentration of Asians had a stronger inverse association with having a yearly checkup.


Molecular cloning, chromosomal mapping, and developmental expression of a novel protein tyrosine phosphatase-like gene.
Protein tyrosine phosphatases (PTPs) mediate the dephosphorylation of phosphotyrosine. PTPs are known to be involved in many signal transduction pathways leading to cell growth, differentiation, and oncogenic transformation. We have cloned a new family of novel protein tyrosine phosphatase-like genes, the Ptpl (protein tyrosine phosphatase-like; proline instead of catalytic arginine) gene family. This gene family is composed of at least three members, and we describe here the developmental expression pattern and chromosomal location for one of these genes, Ptpla. In situ hybridization studies revealed that Ptpla expression was first detected at embryonic day 8.5 in muscle progenitors and later in differentiated muscle types: in the developing heart, throughout the liver and lungs, and in a number of neural crest derivatives including the dorsal root and trigeminal ganglia. Postnatally Ptpla was expressed in a number of adult tissues including cardiac and skeletal muscle, liver, testis, and kidney. The early expression pattern of this gene and its persistent expression in adult tissues suggest that it may have an important role in the development, differentiation, and maintenance of a number of different tissue types. The human homologue of Ptpla (PTPLA) was cloned and shown to map to 10p13-p14.


Chloroplast division protein ARC3 regulates chloroplast FtsZ-ring assembly and positioning in arabidopsis through interaction with FtsZ2.
Chloroplast division is initiated by assembly of a mid-chloroplast FtsZ (Z) ring comprising two cytoskeletal proteins, FtsZ1 and FtsZ2. The division-site regulators ACCUMULATION AND REPLICATION OF CHLOROPLASTS3 (ARC3), MinD1, and MinE1 restrict division to the mid-plastid, but their roles are poorly understood. Using genetic analyses in Arabidopsis thaliana, we show that ARC3 mediates division-site placement by inhibiting Z-ring assembly, and MinD1 and MinE1 function through ARC3. ftsZ1 null mutants exhibited some mid-plastid FtsZ2 rings and constrictions, whereas neither constrictions nor FtsZ1 rings were observed in mutants lacking FtsZ2, suggesting FtsZ2 is the primary determinant of Z-ring assembly in vivo. arc3 ftsZ1 double mutants exhibited multiple parallel but no mid-plastid FtsZ2 rings, resembling the Z-ring phenotype in arc3 single mutants and showing that ARC3 affects positioning of FtsZ2 rings as well as Z rings. ARC3 overexpression in the wild type and ftsZ1 inhibited Z-ring and FtsZ2-ring assembly, respectively. Consistent with its effects in vivo, ARC3 interacted with FtsZ2 in two-hybrid assays and inhibited FtsZ2 assembly in a heterologous system. Our studies are consistent with a model wherein ARC3 directly inhibits Z-ring assembly in vivo primarily through interaction with FtsZ2 in heteropolymers and suggest that ARC3 activity is spatially regulated by MinD1 and MinE1 to permit Z-ring assembly at the mid-plastid.


Risk assessment for the combinational effects of food color additives: neural progenitor cells and hippocampal neurogenesis.
In 2006, the Korea Food and Drug Administration reported that combinations of dietary colors such as allura red AC (R40), tartrazine (Y4), sunset yellow FCF (Y5), amaranth (R2), and brilliant blue FCF (B1) are widely used in food manufacturing. Although individual tar food colors are controlled based on acceptable daily intake (ADI), there is no apparent information available for how combinations of these additives affect food safety. In the current study, the potencies of single and combination use of R40, Y4, Y5, R2, and B1 were examined on neural progenitor cell (NPC) toxicity, a biomarker for developmental stage, and neurogenesis, indicative of adult central nervous system (CNS) functions. R40 and R2 reduced NPC proliferation and viability in mouse multipotent NPC, in the developing CNS model. Among several combinations tested in mouse model, combination of Y4 and B1 at 1000-fold higher than average daily intake in Korea significantly decreased numbers of newly generated cells in adult mouse hippocampus, indicating potent adverse actions on hippocampal neurogenesis. However, other combinations including R40 and R2 did not affect adult hippocampal neurogenesis in the dentate gyrus. Evidence indicates that single and combination use of most tar food colors may be safe with respect to risk using developmental NPC and adult hippocampal neurogenesis. However, the response to excessively high dose combination of Y4 and B1 is suggestive of synergistic effects to suppress proliferation of NPC in adult hippocampus. Data indicated that combinations of tar colors may adversely affect both developmental and adult hippocampal neurogenesis; thus, further extensive studies are required to assess the safety of these additive combinations.


Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts.
Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. Cross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (β (SE) = 0.064 (0.018) SD per 5 °C, p = 5.03e-4) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e-05) and leucine (0.111 (0.018) SD, p = 1.25e-09). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (-0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e-6)). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.


Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.
This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice. Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21). Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO. In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels. CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals. Collectively, the present results demonstrate that short-term CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.


Design of nanostructured plasmonic back contacts for thin-film silicon solar cells.
We report on a plasmonic light-trapping concept based on localized surface plasmon polariton induced light scattering at nanostructured Ag back contacts of thin-film silicon solar cells. The electromagnetic interaction between incident light and localized surface plasmon polariton resonances in nanostructured Ag back contacts was simulated with a three-dimensional numerical solver of Maxwell's equations. Geometrical parameters as well as the embedding material of single and periodic nanostructures on Ag layers were varied. The design of the nanostructures was analyzed regarding their ability to scatter incident light at low optical losses into large angles in the silicon absorber layers of the thin-film silicon solar cells.


Picking up the bill - improving health-care utilisation in the Democratic Republic of Congo through user fee subsidisation: a before and after study.
User fees have been shown to constitute a major barrier to the utilisation of health-care, particularly in low-income countries such as the Democratic Republic of Congo (DRC). Importantly, such barriers can lead to the exclusion of vulnerable individuals from health-care. In 2008, a donor-funded primary health-care programme began implementing user fee subsidisation in 20 health zones of the DRC. In this study, we quantified the short and long-term effects of this policy on health-care utilisation. Sixteen health zones were included for analysis. Using routinely collected health-care utilisation data before and after policy implementation, interrupted time series regression was applied to quantify the temporal impact of the user fee policy in the studied health zones. Payment of salary supplements to health-care workers and provision of free drugs - the other components of the programme - were controlled for where possible. Fourteen (88%) health zones showed an immediate positive effect in health-care utilisation rates (overall median increase of 19%, interquartile range 11 to 43) one month after the policy was introduced, and the effect was significant in seven zones (P <0.05). This initial effect was sustained or increased at 24 months in five health zones but was only significant in one health zone at P <0.05. Utilisation reduced over time in the remaining health zones (overall median increase of 4%, interquartile range -10 to 33). The modelled mean health-care utilisation rate initially increased significantly from 43 consultations/1000 population to 51 consultations/1000 population during the first month following implementation (P <0.01). However, the on-going effect was not significant (P =0.69). Our research brings mixed findings on the effectiveness of user fee subsidisation as a strategy to increase the utilisation of services. Future work should focus on feasibility issues associated with the removal or reduction of user fees and how to sustain its effects on utilisation in the longer term.


Generalities in grazing and browsing ecology: using across-guild comparisons to control contingencies.
In community ecology, broad-scale spatial replication can accommodate contingencies in patterns within species groups, but contingencies in processes across species groups remain problematic. Here, based on a focused review of grazing and browsing by large mammals, we use one trophic guild as a "control" for the other to identify generalities that are not contingent upon specific consumer-resource interactions. An example of such a generality is the Jarman-Bell principle, which explains how allometries of metabolism and digestion influence dietary tolerance and thereby enable resource partitioning within both guilds at multiple scales. By comparing the grazing succession with browsing stratification we show how competition from smaller herbivores, rather than facilitation from larger ones, is the underlying process structuring ungulate assemblages when shared resources become limiting. Also, grazing lawns and browsing hedges are functionally similar. In each case, plants expressing tolerance traits can withstand chronic grazing or browsing in sites where the nutritive value of the local food resource is enhanced in positive feedback to the actions of its consumers. The debate over whether ungulates accelerate or decelerate nutrient cycling can be resolved by comparing grazing and browsing effects in the same ecosystem type. Evidence from African savannas points to the rate of nutrient cycling being controlled by the mix of tolerance and resistance traits in plants; not the relative dominance of grazing or browsing by local herbivores. We recommend this across-guild comparative approach as a novel solution with widespread utility for resolving contingencies in community processes.


The influence of head motion on intrinsic functional connectivity MRI.
Functional connectivity MRI (fcMRI) has been widely applied to explore group and individual differences. A confounding factor is head motion. Children move more than adults, older adults more than younger adults, and patients more than controls. Head motion varies considerably among individuals within the same population. Here we explored the influence of head motion on fcMRI estimates. Mean head displacement, maximum head displacement, the number of micro movements (>0.1 mm), and head rotation were estimated in 1000 healthy, young adult subjects each scanned for two resting-state runs on matched 3T scanners. The majority of fcMRI variation across subjects was not linked to head motion. However, head motion had significant, systematic effects on fcMRI network measures. Head motion was associated with decreased functional coupling in the default and frontoparietal control networks--two networks characterized by coupling among distributed regions of association cortex. Other network measures increased with motion including estimates of local functional coupling and coupling between left and right motor regions--a region pair sometimes used as a control in studies to establish specificity. Comparisons between groups of individuals with subtly different levels of head motion yielded difference maps that could be mistaken for neuronal effects in other contexts. These effects are important to consider when interpreting variation between groups and across individuals.


Exploring midwives' perception of confidence around facilitating water birth in Western Australia: A qualitative descriptive study.
the option of labouring and/or birthing immersed in warm water has become widely available throughout hospitals in the United Kingdom and Europe over the last two decades. The practice, which also occurs in New Zealand and interstate in Australia, has until recently only been available in Western Australia for women birthing at home with a small publically funded Community Midwifery Program. Despite its popularity and acceptance elsewhere, birth in water has only recently become an option for women attending some public health services in Western Australia. The Clinical Guidelines developed for the local context that support water birth require that the midwives be confident and competent to care for these women. The issue of competency can be addressed with relative ease by maternity care providers; however confidence is rather more difficult to teach, foster and attain. Clinical confidence is an integral element of clinical judgement and promotes patient safety and comfort. For this reason confident midwives are an essential requirement to support the option of water birth in Western Australia. The aim of this study was to capture midwives' perceptions of becoming and being confident in conducting water birth in addition to factors perceived to inhibit and facilitate the development of that confidence. a modified grounded theory methodology with thematic analysis. four public maternity services offering the option of water birth in the Perth metropolitan area. registered midwives employed at one of the four publicly funded maternity services that offered the option of water birth between June 2011 and June 2013. Sixteen midwives were interviewed on a one to one basis. An additional 10 midwives participated in a focus group interview. three main categories emerged from the data analysis: what came before the journey, becoming confident - the journey and staying confident. Each contained between three and five subcategories. Together they depicted how midwives describe the journey to becoming confident to support women who have chosen the option to water birth and how they are able to retain that confidence once achieved. three key implications emerged from this study, the first was that students and graduate midwives could benefit from the opportunity to work in midwifery led maternity settings that support normal physiological child birth and that accessing such practical placements should be encouraged. Secondly, maternity services would benefit from learning opportunities directed specifically at experienced midwives addressing their particular requirements. Finally, midwives are the custodians of normal physiological birth, attendance at educational days with a focus on supporting this primary role should be mandatory, to inform midwives on current evidence found to support normal birth which includes options such as water birth.


A zebrafish model of nondystrophic myotonia with sodium channelopathy.
Nondystrophic myotonias are disorders of Na+ (Nav1.4 or SCN4A) and Cl- (CLCN1) channels in skeletal muscles, and frequently show phenotype heterogeneity. The molecular mechanism underlying their pathophysiology and phenotype heterogeneity remains unclear. As zebrafish models have been recently exploited for studies of the pathophysiology and phenotype heterogeneity of various human genetic diseases, a zebrafish model may be useful for delineating nondystrophic myotonias. Here, we generated transgenic zebrafish expressing a human mutant allele of SCN4A, referred to as Tg(mylpfa:N440K), and needle electromyography revealed increased number of myotonic discharges and positive sharp waves in the muscles of Tg(mylpfa:N440K) than in controls. In addition, forced exercise test at a water temperature of 24 °C showed a decrease in the distance moved, time spent in and number of visits to the zone with stronger swimming resistance. Finally, a forced exercise test at a water temperature of 18 °C exhibited a higher number of dive-bombing periods and drifting-down behavior than in controls. These findings indicate that Tg(mylpfa:N440K) is a good vertebrate model of exercise- and cold-induced human nondystrophic myotonias. This zebrafish model may contribute to provide insight into the pathophysiology of myotonia in sodium channelopathy and could be used to explore a new therapeutic avenue.


Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction.
Previous studies have demonstrated a role for voltage-gated K+ (Kv) channel alpha subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K+ current, I(to,f), channels. Biochemical studies suggest that mouse ventricular I(to,f) channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kvbeta1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I(to,f) densities. Interestingly, the phenotypic consequences of manipulating I(to,f) expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2(-/-)) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2(-/-) ventricular myocytes revealed that I(to,f) is eliminated. In addition, the slow transient outward K+ current, I(to,s), and the Kv1.4 protein (which encodes I(to,s)) are upregulated in Kv4.2(-/-) ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2(-/-) ventricles. Similar to Kv4.3, expression of Kvbeta1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2(-/-) ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I(to,f) in Kv4.2(-/-) mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I(to,f) channels but also that the loss of I(to,f) per se does not have overt pathophysiological consequences.


A porous metal-organic framework based on an asymmetric angular diisophthalate for selective adsorption of C2H2 and CO2 over CH4.
A new copper-based metal-organic framework [Cu2L(H2O)2]·5DMF·2H2O (ZJNU-56) has been solvothermally synthesized using a custom-designed asymmetric rigid bent diisophthalate ligand, 5,5'-(1-amine-naphthyl-2,4-diyl) diisophthalic acid (H4L), and structurally determined by single-crystal X-ray diffraction. ZJNU-56 features a three-dimensional (3D) open framework incorporating three different types of metal-organic cages and two distinct types of one-dimensional channels. With a moderate BET surface area of 1655 m2 g-1, optimized pore structure, and functional sites (open copper sites and Lewis basic amine groups) on the cage surface, ZJNU-56 after desolvation exhibits highly selectively adsorptive separation of C2H2 and CO2 over CH4 under ambient conditions. At 298 K, the predicted IAST selectivities are 35.7-72.9 for an equimolar C2H2/CH4 gas mixture and 6.8-7.0 for an equimolar CO2/CH4 gas mixture at pressures varying from 1 to 109 kPa, respectively, which are among the highest reported to date for copper-based MOFs.


A North-South-South partnership in higher education to develop health research capacity in the Democratic Republic of the Congo: the challenge of finding a common language.
Globally, increasing numbers of higher education institutions (HEIs) in non-English-speaking countries have adopted English as a medium of instruction (EMI), because of the perception that this provides opportunities to attract high-calibre students and academic staff, and engage with the international research community. We report an evaluation of a North-South-South collaboration to develop health research capacity in the Democratic Republic of the Congo (DRC) by establishing a postgraduate programme in nutritional epidemiology at the Kinshasa School of Public Health (KSPH), where EMI was adopted. We report experiences and perceptions of stakeholders, facilitators and students about using EMI. In-depth qualitative interviews were conducted between October and December 2019 among convenience sampled stakeholders (8), facilitators (11) and students (12) involved in the programme from all three partner institutions (University of Kinshasa; University of KwaZulu-Natal, South Africa; University of Bergen, Norway). Interviews were conducted in participants' language of preference (English or French), audio-recorded, transcribed verbatim and translated into English when required. Analysis employed a thematic approach. Most participants viewed EMI positively, reporting that studying in English created opportunities to access relevant literature, improve interactions with the scientific community and advance their careers. As a result of adopting EMI, some students had opportunities to present research findings at international conferences and publish their research in English. English-speaking researchers from partner institutions were able to participate in supervision of students' research. However, inadequate English competency, particularly among students, was challenging, with some students reporting being unable to understand or interact in class, which negatively affected their academic performance. Further, EMI created barriers at KSPH among academic staff who were not proficient in English, leading to poor participation among non-English-speaking staff and lack of integration with other postgraduate programmes. Participants suggested additional English language support for EMI. Partnerships between HEIs could be a powerful tool to develop research capacity in low-income countries in line with United Nations Sustainable Development Goals. EMI could be a solution to language barriers faced by many such partnerships, but wide-ranging support to develop English proficiency among staff and students is essential to ensure that the challenges do not outweigh the benefits.


A framework model using multifilter feature selection to enhance colon cancer classification.
Gene expression profiles can be utilized in the diagnosis of critical diseases such as cancer. The selection of biomarker genes from these profiles is significant and crucial for cancer detection. This paper presents a framework proposing a two-stage multifilter hybrid model of feature selection for colon cancer classification. Colon cancer is being extremely common nowadays among other types of cancer. There is a need to find fast and an accurate method to detect the tissues, and enhance the diagnostic process and the drug discovery. This paper reports on a study whose objective has been to improve the diagnosis of cancer of the colon through a two-stage, multifilter model of feature selection. The model described deals with feature selection using a combination of Information Gain and a Genetic Algorithm. The next stage is to filter and rank the genes identified through this method using the minimum Redundancy Maximum Relevance (mRMR) technique. The final phase is to further analyze the data using correlated machine learning algorithms. This two-stage approach, which involves the selection of genes before classification techniques are used, improves success rates for the identification of cancer cells. It is found that Decision Tree, K-Nearest Neighbor, and Naïve Bayes classifiers had showed promising accurate results using the developed hybrid framework model. It is concluded that the performance of our proposed method has achieved a higher accuracy in comparison with the existing methods reported in the literatures. This study can be used as a clue to enhance treatment and drug discovery for the colon cancer cure.


Addition of Caffeine to a Carbohydrate Feeding Strategy Prior to Intermittent Exercise.
The ergogenic effect of caffeine is well established, although no investigations providing a high carbohydrate feeding strategy (pre-exercise meal=2 g/kg BM) co-ingested with caffeine exist for soccer. This investigation examines the effect of caffeine in addition to a pre-exercise carbohydrate meal and drink mid-way through a soccer simulation. Eight recreational soccer players completed an 85-minute soccer simulation followed by an exercise capacity test (Yo-yo Intermittent Endurance test level 2) on two occasions. Prior to exercise participants consumed a high carbohydrate meal, with placebo or 5 mg/kg BM-1 caffeine. No significant performance effect was identified (p=0.099) despite a 12.8% (109 m) improvement in exercise capacity following caffeine. Rates of carbohydrate and fat oxidation did not differ between conditions and nor were differences apparent for plasma glucose, fatty acids, glycerol, β-hydroxybutyrate (p>0.05). However, an increase in lactate was observed for caffeine (p=0.039). A significant condition effect on rating of perceived exertion was identified (p<0.001), with the overall mean for the protocol lowered to 11.7±0.9 au for caffeine compared to 12.8±1.3 au. Caffeine supplementation with a carbohydrate feeding strategy failed to affect metabolic and metabolite responses, although reductions in perception of exercise were observed. While a 12.8% increase in exercise capacity was noted the findings were not significant, possibly due to the small sample size.


The Impact of Nylon-3 Copolymer Composition on the Efficiency of siRNA Delivery to Glioblastoma Cells.
Glioblastoma multiforme is a devastating disease that has attracted enormous attention due to poor prognosis and high recurrence. Small interfering RNA (siRNA) in principle offers a promising therapeutic approach by the downregulation of disease-related genes via RNA interference. For efficient siRNA delivery to target sites, cationic polymers are often used in preclinical studies for the protection of siRNA and complex formation based on electrostatic interactions. In an effort to develop biocompatible and efficient nanocarriers with a translational outlook for optimal gene silencing at reduced toxicity, we synthesized two sets of nylon-3 copolymers with variable cationic content (DM or NM monomer) and hydrophobic subunits (CP monomer) and evaluated their suitability for in vitro siRNA delivery into glioblastoma cells. DM0.4/CP0.6 and NM0.4/CP0.6 polymers with similar subunit ratios were synthesized to compare the effect of different cationic subunits. Additionally, we utilized NM0.2/CP0.8 polymers to evaluate the impact of the different hydrophobic content in the polymer chain. The siRNA condensation ability and polymer-siRNA complex stability was evaluated by unmodified and modified SYBR gold assays, respectively. Further physicochemical characteristics, e.g., particle size and surface charge, were evaluated by dynamic light scattering and laser Doppler anemometry, whereas a relatively new method for polyplex size distribution analysis-tunable resistive pulse sensing-was additionally developed and compared to DLS measurements. Transfection efficiencies, the route of cell internalization, and protein knockdown abilities in glioblastoma cells were investigated by flow cytometry. Furthermore, cellular tolerability was evaluated by MTT and LDH assays. All the polymers efficiently condensed siRNA at N/P ratios of three, whereas polymers with NM cationic subunits demonstrated smaller particle size and lower polyplex stability. Furthermore, NM0.2/CP0.8 polyplexes with the highest hydrophobic content displayed significantly higher cellular internalization in comparison to more cationic formulations and successful knockdown capabilities. Detailed investigations of the cellular uptake route demonstrated that these polyplexes mainly follow clathrin-mediated endocytotic uptake mechanisms, implying high interaction capacity with cellular membranes. Taken together with conducive toxicity profiles, highly hydrophobic nylon-3 polymers provide an appropriate siRNA delivery agent for the potential treatment of glioblastoma.


Antibacterial effects and action modes of asiatic acid.
In this study, the antibacterial effects and action modes of asiatic acid against the foodborne bacterial pathogens Escherichia coli O157:H7, Salmonella Typhimurium DT104, Pseudomonas aeruginosa, Listeria monocytogenes, Staphylococcus aureus, Enterococcus faecalis, and Bacillus cereus were examined. Minimal inhibitory concentrations (MICs) of asiatic acid against these bacteria were in the range of 20-40 μg/mL. Minimum bactericidal concentrations of asiatic acid were in the range of 32-52 μg/mL. Asiatic acid at 2X MIC effectively reduced bacterial numbers from 6 log10 to < 2 log10 in all test bacteria within 6 h (P < 0.05). The antibacterial activity of asiatic acid was not affected by heat treatments from 25 to 100°C. Asiatic acid at 1 or 2X MICs caused 40-56% and 71-89% membrane damage in test bacteria within 2 h, respectively In addition, asiatic acid at 1 or 2X MICs led to 1.5-2.4 ppm and 2.9-4.1 ppm K(+) release within 2 hr, respectively. Asiatic acid treatments dose-dependently increased bacterial nucleotide leakage (P < 0.05). After 3 days of storage at 25°C, the addition of asiatic acid dose-dependently inhibited the growth of test bacteria in ground beef (P < 0.05), in which 8 mg asiatic acid treatments led to bacterial levels (log CFU/g) in said ground beef lower than 2. These findings suggest that asiatic acid might be a potent antibacterial agent to prevent food contamination.


Efficacy of prophylactic antibiotic administration for breast cancer surgery in overweight or obese patients: research highlight.
The rate of surgical site infection (SSI) after breast surgery is higher than expected for a 'clean procedure'. There is currently no consensus on the use of antibiotics, and as a result there is variation in use. An infection may compromise cosmesis and delay the start of adjuvant therapy. This research highlight reviews a recent paper by Gulluoglu and colleagues investigating the use of antibiotics in overweight and obese patients undergoing breast cancer surgery and also reviews the current literature on this important topic.


The ColRS-Regulated Membrane Protein Gene XAC1347 Is Involved in Copper Homeostasis and hrp Gene Expression in Xanthomonas citri subsp. citri.
Xanthomonas citri subsp. citri (Xcc) is the major causal agent of citrus canker disease. The XAC1347 gene, which encodes a conserved membrane protein in Xcc, is required for virulence during infection. However, the molecular events mediated by XAC1347 remain unclear. In this study, we reported that XAC1347 gene is positively regulated by two component regulatory system ColRS and required for type III secretion system function. A non-polar deletion mutant of the XAC1347 gene resulted in a Hrp minus phenotype in plants and reduced copper homeostasis. Real-time PCR experiments indicated that XAC1347 gene is induced by copper ions. The expression levels of representative genes from four hrp operons, including hrpB1, hrcV, hrpF, and hrpD6, were reduced in XAC1347 mutant, indicating that XAC1347 is involved hrp gene expression.


Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 - 2013.
Tumor testing for mutations in the epidermal growth factor receptor (EGFR) gene is indicated for all newly diagnosed, metastatic lung cancer patients, who may be candidates for first-line treatment with an EGFR tyrosine kinase inhibitor. Few studies have analyzed population-level testing. We identified clinical, demographic, and regional predictors of EGFR & KRAS testing among Medicare beneficiaries with a new diagnosis of lung cancer in 2011-2013 claims. The outcome variable was whether the patient underwent molecular, EGFR and KRAS testing. Independent variables included: patient demographics, Medicaid status, clinical characteristics, and region where the patient lived. We performed multivariate logistic regression to identify factors that predicted testing. From 2011 to 2013, there was a 19.7% increase in the rate of EGFR testing. Patient zip code had the greatest impact on odds to undergo testing; for example, patients who lived in the Boston, Massachusetts hospital referral region were the most likely to be tested (odds ratio (OR) of 4.94, with a 95% confidence interval (CI) of 1.67-14.62). Patient demographics also impacted odds to be tested. Asian/Pacific Islanders were most likely to be tested (OR 1.63, CI 1.53-1.79). Minorities and Medicaid patients were less likely to be tested. Medicaid recipients had an OR of 0.74 (CI 0.72-0.77). Hispanics and Blacks were also less likely to be tested (OR 0.97, CI 0.78-0.99 and 0.95, CI 0.92-0.99), respectively. Clinical procedures were also correlated with testing. Patients who underwent transcatheter biopsies were 2.54 times more likely to be tested (CI 2.49-2.60) than those who did not undergo this type of biopsy. Despite an overall increase in EGFR testing, there is widespread underutilization of guideline-recommended testing. We observed racial, income, and regional disparities in testing. Precision medicine has increased the complexity of cancer diagnosis and treatment. Targeted interventions and clinical decision support tools are needed to ensure that all patients are benefitting from advances in precision medicine. Without such interventions, precision medicine may exacerbate racial disparities in cancer care and health outcomes.


Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage.
The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.


Defective interfering Semliki Forest virus populations are biologically and physically heterogeneous.
This study demonstrates that populations of defective interfering Semliki Forest virus (DI SEV) are heterogeneous particularly in respect of their interference properties. Interference was quantified by two assays, one measuring inhibition of the yield of infectious progeny virus, and the other measuring reduction in virus-directed RNA synthesis; for 11 different DI SFV preparations a ratio of the two interference titres was calculated. These ratios varied up to 46-fold indicating that each DI virus preparation contained an interference activity that varied independently of the other. However, sister stocks made from the same parental inoculum had similar properties. The effects of different DI virus preparations on other parameters (virus polypeptide synthesis, yield of DI virus and yield of infectious virus) were investigated using inocula with interference titres standardized by either assay. Co-inoculation of L929 cells with 50 p.f.u. SFV showed that these parameters varied independently of each other and of the DI virus inoculum. There was no correlation with the number of undiluted passages each DI stock had received. Direct evidence of physical heterogeneity was demonstrated by metrizamide density gradient centrifugation. Although infecting virus sedimented as a narrow band, DI SFV was distributed over a broad region of the gradient. Its position on the gradient indicated that DI SFV has a higher nucleic acid: protein ratio than standard virus. DI virus progeny obtained by using fractions of the gradient as inoculum were as heterogeneous as the unfractionated parent, confirming that DI viruses retain heterogeneity on passage.


H3K9 Methyltransferases Suv39h1 and Suv39h2 Control the Differentiation of Neural Progenitor Cells in the Adult Hippocampus.
In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.


Comparing tomographic EEG neurofeedback and EMG biofeedback in children with attention-deficit/hyperactivity disorder.
Two types of biofeedback (BF), tomographic electroencephalogram (EEG) neurofeedback (NF) and electromyographic biofeedback (EMG-BF), both with phasic and tonic protocols, were compared for treatment effects and specificity in attention-deficit/hyperactivity disorder (ADHD). Thirteen children with ADHD trained their brain activity in the anterior cingulate cortex (ACC), and twelve trained activity of arm muscles involved in fine motor skills. In each training session, resting state 24-channel EEG and training performances were recorded. Both groups showed similar behavioral improvements and artifact reduction in selected conditions, with no significant advantages despite medium effect sizes on primary outcomes for NF. Only the EMG-BF group, however, showed clear improvement in training regulation performance, and specific motor coordination effects. The NF group tended to present individual normalization of trained frequency bands in the ACC during rest across training. The results provide evidence for some specific effects in our small sample, albeit only to a small extent.


Sociodemographic patterning of non-communicable disease risk factors in rural India: a cross sectional study.
To investigate the sociodemographic patterning of non-communicable disease risk factors in rural India. Cross sectional study. About 1600 villages from 18 states in India. Most were from four large states due to a convenience sampling strategy. 1983 (31% women) people aged 20-69 years (49% response rate). Prevalence of tobacco use, alcohol use, low fruit and vegetable intake, low physical activity, obesity, central adiposity, hypertension, dyslipidaemia, diabetes, and underweight. Prevalence of most risk factors increased with age. Tobacco and alcohol use, low intake of fruit and vegetables, and underweight were more common in lower socioeconomic positions; whereas obesity, dyslipidaemia, and diabetes (men only) and hypertension (women only) were more prevalent in higher socioeconomic positions. For example, 37% (95% CI 30% to 44%) of men smoked tobacco in the lowest socioeconomic group compared with 15% (12% to 17%) in the highest, while 35% (30% to 40%) of women in the highest socioeconomic group were obese compared with 13% (7% to 19%) in the lowest. The age standardised prevalence of some risk factors was: tobacco use (40% (37% to 42%) men, 4% (3% to 6%) women); low fruit and vegetable intake (69% (66% to 71%) men, 75% (71% to 78%) women); obesity (19% (17% to 21%) men, 28% (24% to 31%) women); dyslipidaemia (33% (31% to 36%) men, 35% (31% to 38%) women); hypertension (20% (18% to 22%) men, 22% (19% to 25%) women); diabetes (6% (5% to 7%) men, 5% (4% to 7%) women); and underweight (21% (19% to 23%) men, 18% (15% to 21%) women). Risk factors were generally more prevalent in south Indians compared with north Indians. For example, the prevalence of dyslipidaemia was 21% (17% to 33%) in north Indian men compared with 33% (29% to 38%) in south Indian men, while the prevalence of obesity was 13% (9% to 17%) in north Indian women compared with 24% (19% to 30%) in south Indian women. The prevalence of most risk factors was generally high across a range of sociodemographic groups in this sample of rural villagers in India; in particular, the prevalence of tobacco use in men and obesity in women was striking. However, given the limitations of the study (convenience sampling design and low response rate), cautious interpretation of the results is warranted. These data highlight the need for careful monitoring and control of non-communicable disease risk factors in rural areas of India.


Clinical practice guideline (update): adult sinusitis.
This update of a 2007 guideline from the American Academy of Otolaryngology--Head and Neck Surgery Foundation provides evidence-based recommendations to manage adult rhinosinusitis, defined as symptomatic inflammation of the paranasal sinuses and nasal cavity. Changes from the prior guideline include a consumer added to the update group, evidence from 42 new systematic reviews, enhanced information on patient education and counseling, a new algorithm to clarify action statement relationships, expanded opportunities for watchful waiting (without antibiotic therapy) as initial therapy of acute bacterial rhinosinusitis (ABRS), and 3 new recommendations for managing chronic rhinosinusitis (CRS). The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing adult rhinosinusitis and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to improve diagnostic accuracy for adult rhinosinusitis, promote appropriate use of ancillary tests to confirm diagnosis and guide management, and promote judicious use of systemic and topical therapy, which includes radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. The update group made strong recommendations that clinicians (1) should distinguish presumed ABRS from acute rhinosinusitis (ARS) caused by viral upper respiratory infections and noninfectious conditions and (2) should confirm a clinical diagnosis of CRS with objective documentation of sinonasal inflammation, which may be accomplished using anterior rhinoscopy, nasal endoscopy, or computed tomography. The update group made recommendations that clinicians (1) should either offer watchful waiting (without antibiotics) or prescribe initial antibiotic therapy for adults with uncomplicated ABRS; (2) should prescribe amoxicillin with or without clavulanate as first-line therapy for 5 to 10 days (if a decision is made to treat ABRS with an antibiotic); (3) should reassess the patient to confirm ABRS, exclude other causes of illness, and detect complications if the patient worsens or fails to improve with the initial management option by 7 days after diagnosis or worsens during the initial management; (4) should distinguish CRS and recurrent ARS from isolated episodes of ABRS and other causes of sinonasal symptoms; (5) should assess the patient with CRS or recurrent ARS for multiple chronic conditions that would modify management, such as asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia; (6) should confirm the presence or absence of nasal polyps in a patient with CRS; and (7) should recommend saline nasal irrigation, topical intranasal corticosteroids, or both for symptom relief of CRS. The update group stated as options that clinicians may (1) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation for symptomatic relief of viral rhinosinusitis; (2) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation) for symptomatic relief of ABRS; and (3) obtain testing for allergy and immune function in evaluating a patient with CRS or recurrent ARS. The update group made recommendations that clinicians (1) should not obtain radiographic imaging for patients who meet diagnostic criteria for ARS, unless a complication or alternative diagnosis is suspected, and (2) should not prescribe topical or systemic antifungal therapy for patients with CRS.


Improving mapping and SNP-calling performance in multiplexed targeted next-generation sequencing.
Compared to classical genotyping, targeted next-generation sequencing (tNGS) can be custom-designed to interrogate entire genomic regions of interest, in order to detect novel as well as known variants. To bring down the per-sample cost, one approach is to pool barcoded NGS libraries before sample enrichment. Still, we lack a complete understanding of how this multiplexed tNGS approach and the varying performance of the ever-evolving analytical tools can affect the quality of variant discovery. Therefore, we evaluated the impact of different software tools and analytical approaches on the discovery of single nucleotide polymorphisms (SNPs) in multiplexed tNGS data. To generate our own test model, we combined a sequence capture method with NGS in three experimental stages of increasing complexity (E. coli genes, multiplexed E. coli, and multiplexed HapMap BRCA1/2 regions). We successfully enriched barcoded NGS libraries instead of genomic DNA, achieving reproducible coverage profiles (Pearson correlation coefficients of up to 0.99) across multiplexed samples, with <10% strand bias. However, the SNP calling quality was substantially affected by the choice of tools and mapping strategy. With the aim of reducing computational requirements, we compared conventional whole-genome mapping and SNP-calling with a new faster approach: target-region mapping with subsequent 'read-backmapping' to the whole genome to reduce the false detection rate. Consequently, we developed a combined mapping pipeline, which includes standard tools (BWA, SAMtools, etc.), and tested it on public HiSeq2000 exome data from the 1000 Genomes Project. Our pipeline saved 12 hours of run time per Hiseq2000 exome sample and detected ~5% more SNPs than the conventional whole genome approach. This suggests that more potential novel SNPs may be discovered using both approaches than with just the conventional approach. We recommend applying our general 'two-step' mapping approach for more efficient SNP discovery in tNGS. Our study has also shown the benefit of computing inter-sample SNP-concordances and inspecting read alignments in order to attain more confident results.


IgG4-related lung disease: a case series of 6 patients and review of the literature.
IgG4 related disease has been recently proposed as a unifying term for a group of inflammatory conditions previously referred to by a plethora of other names. The common denominator for these entities is the histopathologic finding of lymphocytic infiltrates rich in IgG4 producing plasma cells, often accompanied by storiform fibrosis and obliterative phlebitis. Many medical conditions have been attributed to IgG4-related disease,but few reports of IgG4-related lung disease have been published, and it remains a rare condition about which little is known. In this report, we describe the clinical and pathologic features of six patients with IgG4-related disease of the lung. Patients were followed 1-5 years following their diagnosis. We describe unique features of IgG4-related lung disease, including one patient who presented with alveolar hemorrhage and a positive anti-neutrophil cytoplasmic antibody and two patients whose disease improved after treatment with mycophenylate mofetil. Two patients presented with pulmonary pseudotumor. We conclude that the clinical presentation of IgG4-related lung disease varies widely, and histopathology remains the key to diagnosis.


Graded boosting of synaptic signals by low-threshold voltage-activated calcium conductance.
Low-threshold voltage-activated calcium conductances (LT-VACCs) play a substantial role in shaping the electrophysiological attributes of neurites. We have investigated how these conductances affect synaptic integration in a premotor nonspiking (NS) neuron of the leech nervous system. These cells exhibit an extensive neuritic tree, do not fire Na(+)-dependent spikes, but express an LT-VACC that was sensitive to 250 μM Ni(2+) and 100 μM NNC 55-0396 (NNC). NS neurons responded to excitation of mechanosensory pressure neurons with depolarizing responses for which amplitude was a linear function of the presynaptic firing frequency. NNC decreased these synaptic responses and abolished the concomitant widespread Ca(2+) signals. Coherent with the interpretation that the LT-VACC amplified signals at the postsynaptic level, this conductance also amplified the responses of NS neurons to direct injection of sinusoidal current. Synaptic amplification thus is achieved via a positive feedback in which depolarizing signals activate an LT-VACC that, in turn, boosts these signals. The wide distribution of LT-VACC could support the active propagation of depolarizing signals, turning the complex NS neuritic tree into a relatively compact electrical compartment.


Conserved Amino Acid Residues that Affect Structural Stability of Candida boidinii Formate Dehydrogenase.
The NAD+-dependent formate dehydrogenase (FDH; EC 22.214.171.124) from Candida boidinii (CboFDH) has been extensively used in NAD(H)-dependent industrial biocatalysis as well as in the production of renewable fuels and chemicals from carbon dioxide. In the present work, the effect of amino acid residues Phe285, Gln287, and His311 on structural stability was investigated by site-directed mutagenesis. The wild-type and mutant enzymes (Gln287Glu, His311Gln, and Phe285Thr/His311Gln) were cloned and expressed in Escherichia coli. Circular dichroism (CD) spectroscopy was used to determine the effect of each mutation on thermostability. The results showed the decisive roles of Phe285, Gln287, and His311 on enhancing the enzyme's thermostability. The melting temperatures for the wild-type and the mutant enzymes Gln287Glu, His311Gln, and Phe285Thr/His311Gln were 64, 70, 77, and 73 °C, respectively. The effects of pH and temperature on catalytic activity of the wild-type and mutant enzymes were also investigated. Interestingly, the mutant enzyme His311Gln exhibits a large shift of pH optimum at the basic pH range (1 pH unit) and substantial increase of the optimum temperature (25 °C). The present work supports the multifunctional role of the conserved residues Phe285, Gln287, and His311 and further underlines their pivotal roles as targets in protein engineering studies.


Identification of high-risk cutaneous melanoma tumors is improved when combining the online American Joint Committee on Cancer Individualized Melanoma Patient Outcome Prediction Tool with a 31-gene expression profile-based classification.
A significant proportion of patients with American Joint Committee on Cancer (AJCC)-defined early-stage cutaneous melanoma have disease recurrence and die. A 31-gene expression profile (GEP) that accurately assesses metastatic risk associated with primary cutaneous melanomas has been described. We sought to compare accuracy of the GEP in combination with risk determined using the web-based AJCC Individualized Melanoma Patient Outcome Prediction Tool. GEP results from 205 stage I/II cutaneous melanomas with sufficient clinical data for prognostication using the AJCC tool were classified as low (class 1) or high (class 2) risk. Two 5-year overall survival cutoffs (AJCC 79% and 68%), reflecting survival for patients with stage IIA or IIB disease, respectively, were assigned for binary AJCC risk. Cox univariate analysis revealed significant risk classification of distant metastasis-free and overall survival (hazard ratio range 3.2-9.4, P < .001) for both tools. In all, 43 (21%) cases had discordant GEP and AJCC classification (using 79% cutoff). Eleven of 13 (85%) deaths in that group were predicted as high risk by GEP but low risk by AJCC. Specimens reflect tertiary care center referrals; more effective therapies have been approved for clinical use after accrual. The GEP provides valuable prognostic information and improves identification of high-risk melanomas when used together with the AJCC online prediction tool.


Perceived discrimination and cancer screening behaviors in US Hispanics: the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study.
Perceived discrimination has been associated with lower adherence to cancer screening guidelines. We examined whether perceived discrimination was associated with adherence to breast, cervical, colorectal, and prostate cancer screening guidelines in US Hispanic/Latino adults. Data were obtained from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study, including 5,313 Hispanic adults aged 18–74 from Bronx, NY, Chicago, IL, Miami, FL, and San Diego, CA, and those who were within appropriate age ranges for specific screening tests were included in the analysis. Cancer screening behaviors were assessed via self-report. Perceived discrimination was measured using the Perceived Ethnic Discrimination Questionnaire. Confounder-adjusted multivariable polytomous logistic regression models assessed the association between perceived discrimination and adherence to cancer screening guidelines. Among women eligible for screening, 72.1 % were adherent to cervical cancer screening guidelines and 71.3 %were adherent to breast cancer screening guidelines. In participants aged 50–74, 24.6 % of women and 27.0 % of men were adherent to fecal occult blood test guidelines; 43.5 % of women and 34.8 % of men were adherent to colonoscopy/sigmoidoscopy guidelines; 41.0 % of men were adherent to prostate-specific antigen screening guidelines. Health insurance coverage, rather than perceived ethnic discrimination,was the variable most associated with receiving breast, cervical,colorectal, or prostate cancer screening. The influence of discrimination as a barrier to cancer screening may be modest among Hispanics/Latinos in urban US regions. Having health insurance facilitates cancer screening in this population. Efforts to increase cancer screening in Hispanics/Latinos should focus on increasing access to these services, especially among the uninsured.


Functional heterogeneity of a large family of human LTR-like promoters and enhancers.
The human genome contains a variety of elements similar in structure to retroviruses and retrotransposons. We have shown that the long terminal repeat (LTR) sequences of a large family of human retrovirus-like elements, RTVL-H, are heterogeneous in their ability to regulate the expression of linked genes. Although all of five LTRs tested could promote expression of the chloramphenicol acetyltransferase (CAT) gene, their relative promoter activities as well as range of activities varied widely. Several of the LTRs tested also exhibited bidirectional promoter activity either alone or when activated by an SV40 early enhancer. One LTR, H6, displayed strong promoter activity in human (NTera2D1, 293, Hep2), monkey (COS-1), and mouse (3T3) cells. In fact, the activity of this LTR was similar to that of the SV40 early promoter/enhancer in 293, COS-1, and 3T3 cells. RNA mapping studies have localized the transcription start site to the expected location in the H6 LTR. RTVL-H LTRs were also shown to contain sequences which could increase transcription from the human beta-globin promoter and be influenced by SV40 enhancer sequences. As the human genome contains several hundred related RTVL-H sequences and a similar number of solitary LTRs, these findings raise the possibility that RTVL-H LTRs could have diverse effects on the expression of adjacent cellular genes.


Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence.
Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.


Peer-assessed outcomes in the multimodal treatment study of children with attention deficit hyperactivity disorder.
Peer-assessed outcomes were examined at the end of treatment (14 months after study entry) for 285 children (226 boys, 59 girls) with attention deficit hyperactivity disorder (ADHD) who were rated by their classmates (2,232 classmates total) using peer sociometric procedures. All children with ADHD were participants in the Multimodal Treatment Study of Children with ADHD (MTA). Treatment groups were compared using the orthogonal treatment contrasts that accounted for the largest amount of variance in prior MTA outcome analyses: Medication Management + Combined Treatment versus Behavior Therapy + Community Care; Medication Management versus Combined Treatment; Behavior Therapy versus Community Care. There was little evidence of superiority of any of the treatments for the peer-assessed outcomes studied, although the limited evidence that emerged favored treatments involving medication management. Post hoc analyses were used to examine whether any of the four treatment groups yielded normalized peer relationships relative to randomly selected-classmates. Results indicated that children from all groups remained significantly impaired in their peer relationships.


Negative symptoms and hypofrontality in chronic schizophrenia.
Frontal lobe dysfunction is widely suspected to underlie negative symptoms of schizophrenia. This hypothesis is based largely on long-standing observations of the similarities between the effects of frontal lobe lesions and negative symptoms. However, there is little direct evidence specifically for such an association in schizophrenic patients. We measured the relationship between decreased relative prefrontal cortex glucose metabolism (hypofrontality) using positron emission tomography and evaluated the severity of negative symptoms in 20 chronic schizophrenics who underwent scanning while not receiving neuroleptic drugs. We found a close relationship between negative symptoms and prefrontal hypometabolism, particularly in the right dorsolateral convexity. This association was regionally specific. Furthermore, there was no evidence that this relationship was an artifact of age, cerebral atrophy, or severity of positive symptoms.


Communication with Family and Friends across the Life Course.
Each stage of the human life course is characterised by a distinctive pattern of social relations. We study how the intensity and importance of the closest social contacts vary across the life course, using a large database of mobile communication from a European country. We first determine the most likely social relationship type from these mobile phone records by relating the age and gender of the caller and recipient to the frequency, length, and direction of calls. We then show how communication patterns between parents and children, romantic partner, and friends vary across the six main stages of the adult family life course. Young adulthood is dominated by a gradual shift of call activity from parents to close friends, and then to a romantic partner, culminating in the period of early family formation during which the focus is on the romantic partner. During middle adulthood call patterns suggest a high dependence on the parents of the ego, who, presumably often provide alloparental care, while at this stage female same-gender friendship also peaks. During post-reproductive adulthood, individuals and especially women balance close social contacts among three generations. The age of grandparenthood brings the children entering adulthood and family formation into the focus, and is associated with a realignment of close social contacts especially among women, while the old age is dominated by dependence on their children.


Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa.
To determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a subset of the detected RP1 heterozygotes using electroretinography (ERG), psychophysics, and optical coherence tomography (OCT). Seventeen adRP families had heterozygous RP1 changes. Thirteen families had the Arg677ter mutation, whereas four others had one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better preserved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to those with the Arg677ter mutation. Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerability of retinopathy with more pronounced effects in the inferonasal peripheral retina. At other disease stages, cone function is also affected, and severe retina-wide degeneration can occur. The nonpenetrance or minimal disease expression in some Arg677ter mutation-positive heterozygotes suggests important roles for modifier genes or environmental factors in RP1-related disease.


Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence.
Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission-associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development.


[Progressive dysphagia with peculiar laryngeal movement induced by tardive dystonia].
Recently, patients receiving the long-term administration of typical antipsychotics have been recognized to be at risk of developing intractable tardive dystonia. A 44-year-old man was referred to our hospital because of progressive dysphagia for about 5 years. He had received several typical antipsychotic medications since at age of 24 years for the treatment of chronic schizophrenia. The patient had been suffering from an abnormal sensation in his throat and progressive dysphagia for five years, and nasal escape on deglutition for one year. A videotape recorder esophago pharyngography revealed that his larynx was positioned low, at the level of the 6th cervical vertebra, before swallowing, and was not elevated but rather descended to the level of the 7th vertebra upon swallowing. When the larynx was in this lower position, a small amount of swallowed material was transported to the esophagus. The remaining material in the pyriform sinus overflowed into the laryngeal cavity and lower airway after swallowing. However, the patient was able to eat with ease when he was with a girl friend, eating in a restaurant, and was hungry. The peculiar downward movement of the larynx was not observed during speech production, only during deglutition. Based on these findings, we suspected that his peculiar swallowing disorder might have been induced by tardive dystonia arising from the long-term administration of typical antipsychotics.


Testosterone deficiency: a historical perspective.
The biological effects of the testes and testosterone are known since antiquity. Aristotle knew the effects of castration and his hypothesis on fertilization is one of the first scientific encounters in reproductive biology. Over centuries, castration has been performed as punishment and to produce obedient slaves, but also to preserve the soprano voices of prepubertal boys. The Chinese imperial (and other oriental) courts employed castrates as overseers in harems who often obtained high-ranking political positions. The era of testis transplantation and organotherapy was initiated by John Hunter in London who transplanted testes into capons in 1786. The intention of his experiments was to prove the 'vital principle' as the basis for modern transplantation medicine, but Hunter did not consider endocrine aspects. Arnold Adolph Berthold postulated internal secretion from his testicular transplantation experiments in 1849 in Göttingen and is thus considered the father of endocrinology. Following his observations, testicular preparations were used for therapy, popularized by self-experiments by Charles-Edouard Brown-Séquard in Paris (1889), which can at best have placebo effects. In the 1920s Sergio Voronoff transplanted testes from animals to men, but their effectiveness was disproved. Today testicular transplantation is being refined by stem cell research and germ cell transplantation. Modern androgen therapy started in 1935 when Enrest Lacquer isolated testosterone from bull testes in Amsterdam. In the same year testosterone was chemically synthesized independently by Adolf Butenandt in Göttingen and Leopold Ruzicka in Basel. Since testosterone was ineffective orally it was either compressed into subcutaneous pellets or was used orally as 17α-methyl testosterone, now obsolete because of liver toxicity. The early phases of testosterone treatment coincide with the first description of the most prominent syndromes of hypogonadism by Klinefelter, by Kallmann, DelCastillo and Pasqualini. In the 1950s longer-acting injectable testosterone enanthate became the preferred therapeutic modality. In the 1950s and 1960s, research concentrated on the chemical modification of androgens in order to emphasize their anabolic effects. Although anabolic steroids have largely disappeared from clinical medicine, they continue to live an illegal life for doping in athletics. In the 1970s the orally effective testosterone undecanoate was added to the spectrum of preparations. Recent transdermal gels and long-acting injectable preparations provide options for physiological testosterone substitution therapy.


Ovine brain natriuretic peptide in cardiac tissues and plasma: effects of cardiac hypertrophy and heart failure on tissue concentration and molecular forms.
Whereas numerous studies have examined the cardiac tissue content and secretion of atrial natriuretic peptide (ANP), the response of brain natriuretic peptide (BNP) in states of experimental cardiac overload is less well documented. Our recent partial cloning of the ovine BNP gene has enabled us to study changes in cardiac tissue concentration, together with tissue and circulating molecular forms of ANP and BNP, in response to cardiac overload induced by rapid ventricular pacing (n = 7) and aortic coarctation (n = 6). In normal sheep, although highest levels of BNP were found in atrial tissue (15-fold those of the ventricle), the BNP/ANP concentration ratio in the ventricles was 10- to 20-fold higher than the ratio calculated for atrial tissue. Compared with normal sheep, significant depletion of both ANP and BNP concentrations within the left ventricle occurred after rapid ventricular pacing. Size exclusion and reverse phase HPLC analysis of atrial and ventricular tissue extracts from normal and overloaded sheep showed a single peak of high molecular weight BNP consistent with the proBNP hormone. In contrast, immunoreactive BNP extracted from plasma drawn from the coronary sinus was all low molecular weight material. Further analysis of plasma BNP using ion exchange HPLC disclosed at least 3 distinct immunoreactive peaks consistent with ovine BNP forms 26-29 amino acid residues in length. These findings show that BNP is stored as the prohormone in sheep cardiac tissues and that complete processing to mature forms occurs at the time of secretion. The capacity to process the prohormone at secretion is not impaired by chronic heart failure.


Placental ischemia and breast cancer risk after preeclampsia: tying the knot.
Although hypertensive disorders of pregnancy, such as preeclampsia, continue to be a significant source of maternal and fetal morbidity and mortality, there is emerging evidence that effects of the preeclamptic syndrome persist into later life. In contrast to recent studies that have reported that formerly preeclamptic women are at increased risk for cardiovascular disease, it appears that preeclampsia may be associated with a decreased risk of breast cancer. Recent investigations have provided exciting new insights into potential mechanisms underlying the pathogenesis of preeclampsia and some of these findings may bear relevance to the anticancer effects reported in the epidemiological literature. Placental ischemia is regarded to be a primary factor in preeclampsia and the ischemic placenta produces a variety of factors that generate profound effects on endothelial cell function and the cardiovascular system during pregnancy. Moreover, several of these factors are reportedly elevated many years after preeclamptic pregnancies. This group of molecules includes factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin/CD105 (sEng) and various cytokines. Many of these factors have been strongly associated with cancer incidence and, hence, could contribute to the modification of cancer risk observed in these women. Therefore, identifying potential connections between placental dysfunction and future cancer risk is an important endeavor towards realizing novel therapeutic regimens for cancer patients.