Evolutionary relationships among Massospora spp. (Entomophthorales), obligate pathogens of cicadas.
The fungal genus Massospora (Zoopagomycota: Entomophthorales) includes more than a dozen obligate, sexually transmissible pathogenic species that infect cicadas (Hemiptera) worldwide. At least two species are known to produce psychoactive compounds during infection, which has garnered considerable interest for this enigmatic genus. As with many Entomophthorales, the evolutionary relationships and host associations of Massospora spp. are not well understood. The acquisition of M. diceroproctae from Arizona, M. tettigatis from Chile, and M. platypediae from California and Colorado provided an opportunity to conduct molecular phylogenetic analyses and morphological studies to investigate whether these fungi represent a monophyletic group and delimit species boundaries. In a three-locus phylogenetic analysis including the D1-D2 domains of the nuclear 28S rRNA gene (28S), elongation factor 1 alpha-like (EFL), and beta-tubulin (BTUB), Massospora was resolved in a strongly supported monophyletic group containing four well-supported genealogically exclusive lineages, based on two of three methods of phylogenetic inference. There was incongruence among the single-gene trees: two methods of phylogenetic inference recovered trees with either the same topology as the three-gene concatenated tree (EFL) or a basal polytomy (28S, BTUB). Massospora levispora and M. platypediae isolates formed a single lineage in all analyses and are synonymized here as M. levispora. Massospora diceroproctae was sister to M. cicadina in all three single-gene trees and on an extremely long branch relative to the other Massospora, and even the outgroup taxa, which may reflect an accelerated rate of molecular evolution and/or incomplete taxon sampling. The results of the morphological study presented here indicate that spore measurements may not be phylogenetically or diagnostically informative. Despite recent advances in understanding the ecology of Massospora, much about its host range and diversity remains unexplored. The emerging phylogenetic framework can provide a foundation for exploring coevolutionary relationships with cicada hosts and the evolution of behavior-altering compounds.


Functional Magnetic Resonance Imaging Biomarkers Predicting Cognitive Progression in Parkinson Disease: Protocol for a Prospective Longitudinal Cohort Study.
Cardinal features of Parkinson disease (PD) are motor symptoms, but nonmotor features such as mild cognitive impairment (MCI) are common early in the disease process. MCI can progress and convert to dementia in advanced stages, creating significant disability and reduced quality of life. The primary pathological substrate for cognitive decline in PD is unclear, and there are no reliable biomarkers predicting the risk of conversion to dementia. A subgroup of PD patients with visual hallucinations may display more rapid conversion to dementia, suggesting that regional markers of visuoperceptual dysfunction may be sensitive to pathologic density in posterior cortical regions. The purpose of this project is to characterize PD-MCI and evaluate the utility of genetic and neuroimaging biomarkers in predicting cognitive outcomes with a prospective longitudinal study. We will evaluate whether accelerated cognitive progression may be reflected in biomarkers of early posterior cortical changes reflective of α-synuclein deposition. We will evaluate a cohort of early-stage PD patients with the following methods to predict cognitive progression: (1) serial neuropsychological evaluations including detailed visuoperceptual functioning across 4 years; (2) genetic analysis of SNCA (α-synuclein), MAPT (microtubule-associated tau), and APOE (apolipoprotein E); (3) an event-related functional magnetic resonance imaging paradigm of object recognition memory; and (4) anatomical and regional brain activation changes (resting-state functional magnetic resonance imaging) across 4 years. The project received funding from the National Institutes of Health in August 2017, and data collection began in February 2018. Enrollment is ongoing, and subjects will be evaluated annually for 4 years extended across a 5-year project including data analysis and image processing. Cognitive, genetic, and structural and functional magnetic resonance imaging will characterize neural network changes predictive of cognitive progression in PD across 4 years. Identification of biomarkers with sensitivity for early prediction and estimation of risk for conversion to dementia in PD will pave the way for effective intervention with neuroprotective therapies during the critical stage when treatment can have the greatest impact. DERR1-10.2196/12870.


Sex and environmental sensitivity in blue tit nestlings.
In birds and mammals with sexual size dimorphism (SSD), the larger sex is typically more sensitive to adverse environmental conditions, such as food shortage, during ontogeny. However, some recent studies of altricial birds have found that the larger sex is less sensitive, apparently because large size renders an advantage in sibling competition. Still, this effect is not an inevitable outcome of sibling competition, because several studies of other species of altricial birds have found the traditional pattern. We investigated if the sexes differ in environmental sensitivity during ontogeny in the blue tit, a small altricial bird with c. 6% SSD in body mass (males larger than females). We performed a cross-fostering and brood size manipulation experiment during 2 years to investigate if the sexes were differently affected as regards body size (body mass, tarsus and wing length on day 14 after hatching) and pre-fledging survival. We also investigated if the relationship between body size and post-fledging survival differed between the sexes. Pre-fledging mortality was higher in enlarged than in reduced broods, representing poor and good environments, respectively, but the brood size manipulation did not affect the mortality rate of males and females differently. In both years, both males and females were smaller on day 14 after hatching in enlarged as compared to reduced broods. In one of the years, we also found significant Sex x Experiment interactions for body size, such that females were more affected by poor environmental conditions than that of males. Body size was positively correlated with post-fledging survival, but we found no interactive effects of sex and morphological traits on survival. We conclude that in the blue tit, females (the smaller sex) are more sensitive to adverse environmental conditions which, in our study, was manifest in terms of fledgling size. A review of published studies of sex differences in environmental sensitivity in sexually size-dimorphic altricial birds suggests that the smaller sex is more sensitive than the larger sex in species with large brood size and vice versa.


Ubiquitin-specific protease 11 Aggravates Ischemia-reperfusion-induced Cardiomyocyte Pyroptosis and Injury by Promoting TRAF3 Deubiquitination
In myocardial ischemia-reperfusion injury, myocardial damage is aggravated when blood perfusion is restored in myocardial infarction. Ubiquitin-specific protease 11 (USP11), a deubiquitinating enzyme, could remove the ubiquitination of substrate proteins and regulate protein stability, thereby affecting multiple pathological processes. To investigate the potential function of USP11 in myocardial ischemia-reperfusion injury and its underlying mechanisms. In vivo and in vitro experimental study. The ischemia-reperfusion rat model in vivo was evolved, wherein the left anterior descending coronary artery was ligated for 30 min, followed by ligature release for 120 min. Meanwhile, H9C2 cells were brought to hypoxia for 6 h and then reoxygenated for 18 h to establish a cell hypoxia-reoxygenation (H/R) injury in vitro. Then, the loss-of-function experiments of USP11 were performed. Triphenyltetrazolium chloride and hematoxylin and eosin staining were performed to observe myocardial injury. The MTT assay was utilized to detect H9C2 cell viability. Pyroptosis was analyzed by TUNEL staining and flow cytometry. Pyroptosis-related protein expression and TRAF3 were analyzed via Western blot. The content of inflammatory factors was examined by enzyme-linked immunoassay. Co-immunoprecipitation and ubiquitination assays were performed to analyze for USP11 interacting with TRAF3. USP11 was upregulated in the ischemic heart tissue. Ischemia-reperfusion and H/R injuries increased USP11 expression. USP11 loss-of-function assays showed that USP11 knockdown alleviated ischemia-reperfusion- and H/R-induced myocardial cell damage, pyroptosis, pro-inflammatory factor secretion, and IKKβ/NF-κB pathway activation. In H9C2 cells, USP11 stabilized TRAF3 by deubiquitination. Furthermore, rescue experiments revealed that TRAF3 overexpression reversed the protection of silencing USP11 on H/R-induced H9C2 cell injury. This study confirmed that USP11 knockdown ameliorated myocardial ischemia-reperfusion injury by downregulating TRAF3, suggesting that USP11 silencing can be a novel target of myocardial infarction.


Eemian interglacial reconstructed from a Greenland folded ice core.
Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 ± 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 ± 250 metres, reaching surface elevations 122,000 years ago of 130 ± 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.


Cep97 and CP110 suppress a cilia assembly program.
Mammalian centrioles play a dynamic role in centrosome function, but they also have the capacity to nucleate the assembly of cilia. Although controls must exist to specify these different fates, the key regulators remain largely undefined. We have purified complexes associated with CP110, a protein that plays an essential role in centrosome duplication and cytokinesis, and have identified a previously uncharacterized protein, Cep97, that recruits CP110 to centrosomes. Depletion of Cep97 or expression of dominant-negative mutants results in CP110 disappearance from centrosomes, spindle defects, and polyploidy. Remarkably, loss of Cep97 or CP110 promotes primary cilia formation in growing cells, and enforced expression of CP110 in quiescent cells suppresses their ability to assemble cilia, suggesting that Cep97 and CP110 collaborate to inhibit a ciliogenesis program. Identification of Cep97 and other genes involved in regulation of cilia assembly may accelerate our understanding of human ciliary diseases, including renal disease and retinal degeneration.


A meta-analysis of genetic correlations between plant resistances to multiple enemies.
Genetic correlations between plant resistances to multiple natural enemies are important because they have the potential to determine the mode of selection that natural enemies impose on a host plant, the structure of herbivore and pathogen communities, and the success of plant breeding for resistance to multiple diseases and pests. We conducted a meta-analysis of 29 published studies of 16 different plant species reporting a total of 467 genetic correlations between resistances to multiple herbivores or pathogens. In general, genetic associations between resistances to multiple natural enemies tended to be positive regardless of the breeding design, type of attacker, and type of host plant. Positive genetic correlations between resistances were stronger when both attackers were pathogens or generalist herbivores and when resistance to different enemies was tested independently, suggesting that generalists may be affected by the same plant resistance traits and that interactions among natural enemies are common. Although the mean associations between resistances were positive, indicating the prevalence of diffuse selection and generalized defenses against multiple enemies, the large variation in both the strength and the direction of the associations suggests a continuum between pairwise and diffuse selection.


Addition of Berberine to 5-Aminosalicylic Acid for Treatment of Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice.
Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5-aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-α as well as NFκB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-α secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy.


Second Trimester Fetal and Maternal Epicardial Fat Thickness in Gestational Diabetic Pregnancies.
Our aim was to evaluate the association between gestational diabetes mellitus and sonographically measured fetal epicardial fat thickness between 24-28 weeks' gestation. This was a cross-sectional study that included 40 pregnancies with gestational diabetes mellitus, matched with 40 normal pregnancies with similar maternal age, body-mass index, gestational age, fetal gender, and fetal abdominal circumference on ultrasound. Fetal epicardial fat thickness was measured and recorded during ultrasonography at 24-28 weeks of gestation. Maternal evaluation included measurement of maternal epicardial fat thickness, using echocardiography. Fetal and maternal epicardial fat thickness values were compared across the groups. Ultrasound views of fetal epicardial fat thickness were evaluated independently by 3 perinatology fellows to determine inter- and intra-observer variability. Partial and intraclass correlation analyses were used. Fetal and maternal epicardial fat thickness measurements were moderately correlated (r=0.63). Mean fetal and maternal epicardial fat thickness values were higher in gestational diabetes mellitus pregnancies (p=0.004 and p<0.0001, respectively) compared to controls. Fetal epicardial fat thickness was positively correlated (r=0.43) with postchallenge 2-h glucose values. Inter- and intra-observer agreement was high, demonstrated by strong correlations (r=0.99 and r=0.99, respectively) across fetal epicardial fat thickness measurements of the examiners. Fetuses from gestational diabetes mellitus pregnancies have significantly higher fetal and maternal epicardial fat thickness values compared to nongestational diabetes mellitus pregnancies. Fetal epicardial fat thickness obtained during second trimester fetal anatomy ultrasound may potentially be a reliable indicator for gestational diabetes mellitus. However, clinical validation studies are needed.


Spatial and temporal dynamics in the ionic driving force for GABA(A) receptors.
It is becoming increasingly apparent that the strength of GABAergic synaptic transmission is dynamic. One parameter that can establish differences in the actions of GABAergic synapses is the ionic driving force for the chloride-permeable GABA(A) receptor (GABA(A)R). Here we review some of the sophisticated ways in which this ionic driving force can vary within neuronal circuits. This driving force for GABA(A)Rs is subject to tight spatial control, with the distribution of Cl⁻ transporter proteins and channels generating regional variation in the strength of GABA(A)R signalling across a single neuron. GABA(A)R dynamics can result from short-term changes in their driving force, which involve the temporary accumulation or depletion of intracellular Cl⁻. In addition, activity-dependent changes in the expression and function of Cl⁻ regulating proteins can result in long-term shifts in the driving force for GABA(A)Rs. The multifaceted regulation of the ionic driving force for GABA(A)Rs has wide ranging implications for mature brain function, neural circuit development, and disease.


Temporal variation in incidence of IDDM in Canterbury, New Zealand.
To establish the statistical significance of observed variations over the last decade in the incidence of insulin-dependent diabetes mellitus (IDDM) in the 0- to 19-yr-old age-group and to determine whether incidence has increased in Canterbury, New Zealand. The Canterbury, New Zealand, Diabetes Registry has recorded all incidence cases of diabetes mellitus prospectively since 1982. All IDDM subjects aged 0-19 yr at diagnosis and using insulin are included in the study. Ascertainment is believed to be 100%. Prevalence was recorded at 1 January 1982 and 1 January 1990. Annual incidence for 1982-1990 was determined using age and sex cross-sectional census population denominators. The statistical significance of temporal, age, sex, and seasonal variations in incidence rates was ascertained by Poisson regression models (GLIM statistical software). Prevalence on 1 January 1990 was 115/100,000. Incidence rates during the 9 yr were periodic, with two major peaks--one in the early 1980s, the other in 1989 continuing into 1990. The temporal variation (P less than 0.02) was not age or sex specific. Incidence rates for boys were three- to fourfold higher during peak versus trough years, with a peak level of 20.7/100,000 in 1990. For girls, there was less variation, with a peak rate of 21.6/100,000 in 1990. There has been no significant increase in IDDM incidence over time. The mean rate of incidence across all age-groups for 1982-1990 was 12.7/100,000 person-yr. A significant seasonal association to the onset of IDDM was found only in boys, with incidence rates being significantly higher in winter than in summer (P less than 0.01). IDDM in Canterbury, New Zealand, presents in cycles of incidence peaks and troughs, each spanning 2-3 yr.


Centriolar SAS-7 acts upstream of SPD-2 to regulate centriole assembly and pericentriolar material formation.
The centriole/basal body is a eukaryotic organelle that plays essential roles in cell division and signaling. Among five known core centriole proteins, SPD-2/Cep192 is the first recruited to the site of daughter centriole formation and regulates the centriolar localization of the other components in C. elegans and in humans. However, the molecular basis for SPD-2 centriolar localization remains unknown. Here, we describe a new centriole component, the coiled-coil protein SAS-7, as a regulator of centriole duplication, assembly and elongation. Intriguingly, our genetic data suggest that SAS-7 is required for daughter centrioles to become competent for duplication, and for mother centrioles to maintain this competence. We also show that SAS-7 binds SPD-2 and regulates SPD-2 centriolar recruitment, while SAS-7 centriolar localization is SPD-2-independent. Furthermore, pericentriolar material (PCM) formation is abnormal in sas-7 mutants, and the PCM-dependent induction of cell polarity that defines the anterior-posterior body axis frequently fails. We conclude that SAS-7 functions at the earliest step in centriole duplication yet identified and plays important roles in the orchestration of centriole and PCM assembly.


Pseudo-Casimir interactions across nematic films with disordered anchoring axis.
We study the effective pseudo-Casimir interaction forces mediated by a nematic liquid-crystalline film bounded by two planar surfaces, one of which imposes a random (disordered) distribution of the preferred anchoring axis in the so-called easy direction. We consider both the case of a quenched as well as an annealed disorder for the easy direction on the disordered surface and analyze the resultant fluctuation-induced interaction between the surfaces. In the case of quenched disorder, we show that the disorder effects appear additively in the total interaction and are dominant at intermediate inter-surface separations. Disorder effects are shown to be unimportant at both very small and very large separations. In the case of annealed disorder its effects are non-additive in the total inter-surface interaction and can be rationalized in terms of a renormalized extrapolation length.


Melioidosis in lower provincial Cambodia: A case series from a prospective study of sepsis in Takeo Province.
Melioidosis is a severe infectious disease caused by the gram-negative soil bacterium Burkholderia pseudomallei. Melioidosis is well known to be a major cause of morbidity and mortality in Southeast Asia, particularly in Thailand. However, melioidosis remains underreported in surrounding areas such as Cambodia. We report a case series of melioidosis in seven patients from Takeo Province, Cambodia. The patients, aged 24-65 years, were enrolled from May 2014 to May 2015 during a one year prospective study of sepsis at Takeo Provincial Hospital. They presented with fever, rigors, dyspnea, fatigue, diaphoresis, productive cough, and skin abscesses. Six of the seven patients were also hyponatremic. B. pseudomallei was cultured from the blood of six patients and the sputum of one patient. In this manuscript, we provide a detailed description of the clinical presentation, case management and laboratory confirmation of B. pseudomallei, as well as discuss the difficulties of identifying and treating melioidosis in low resource settings.


Large-scale phylogenomic analyses reveal that two enigmatic protist lineages, telonemia and centroheliozoa, are related to photosynthetic chromalveolates.
Understanding the early evolution and diversification of eukaryotes relies on a fully resolved phylogenetic tree. In recent years, most eukaryotic diversity has been assigned to six putative supergroups, but the evolutionary origin of a few major "orphan" lineages remains elusive. Two ecologically important orphan groups are the heterotrophic Telonemia and Centroheliozoa. Telonemids have been proposed to be related to the photosynthetic cryptomonads or stramenopiles and centrohelids to haptophytes, but molecular phylogenies have failed to provide strong support for any phylogenetic hypothesis. Here, we investigate the origins of Telonema subtilis (a telonemid) and Raphidiophrys contractilis (a centrohelid) by large-scale 454 pyrosequencing of cDNA libraries and including new genomic data from two cryptomonads (Guillardia theta and Plagioselmis nannoplanctica) and a haptophyte (Imantonia rotunda). We demonstrate that 454 sequencing of cDNA libraries is a powerful and fast method of sampling a high proportion of protist genes, which can yield ample information for phylogenomic studies. Our phylogenetic analyses of 127 genes from 72 species indicate that telonemids and centrohelids are members of an emerging major group of eukaryotes also comprising cryptomonads and haptophytes. Furthermore, this group is possibly closely related to the SAR clade comprising stramenopiles (heterokonts), alveolates, and Rhizaria. Our results link two additional heterotrophic lineages to the predominantly photosynthetic chromalveolate supergroup, providing a new framework for interpreting the evolution of eukaryotic cell structures and the diversification of plastids.


Supplementation of Lactobacillus plantarum Improves Markers of Metabolic Dysfunction Induced by a High Fat Diet.
Obesity is a prevalent chronic condition in many developed and developing nations that raises the risk for developing heart disease, stroke, and diabetes. Previous studies have shown that consuming particular probiotic strains of Lactobacillus is associated with improvement in the obese and diabetic phenotype; however, the mechanisms of these beneficial effects are not well understood. In this study, C57BL/6J male mice were fed a lard-based high fat diet for 15 weeks with Lactobacillus plantarum supplementation NCIMB8826 (Lp) between weeks 10 and 15 ( n = 10 per group). Systemic metabolic effects of supplementation were analyzed by NMR metabolomics, protein expression assays, gene transcript quantification, and 16S rRNA marker gene sequencing. Body and organ weights were not significantly different with Lp supplementation, and no microbiota community structure changes were observed in the cecum; however, L. plantarum numbers were increased in the treatment group according to culture-based and 16S rRNA gene quantification. Significant differences in metabolite and protein concentrations (serum, liver, and colon), gene expression (ileum and adipose), and cytokines (colon) were observed between groups with increases in the gene expression of tight junction proteins in the ileum and cecum and improvement of some markers of glucose homeostasis in blood and tissue with Lp supplementation. These results indicate Lp supplementation impacts systemic metabolism and immune signaling before phenotypic changes and without large-scale changes to the microbiome. This study supports the notion that Lp is a beneficial probiotic, even in the context of a high fat diet.


Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.
Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.


Immunobiology of solid organ transplantation.
The field of organ transplantation is entering a very exciting phase in which tolerance induction may become a therapeutic possibility. The induction of tolerance would allow patients to enjoy the benefits of their transplanted organ without risking the mortality and morbidity associated with long-term pharmacological immunosuppression. In this review, we explore the immunobiology of solid organ transplantation, discussing the immunological mechanisms responsible for allograft rejection, and outlining the rational behind a range of successful experimental tolerance induction strategies.


The relationships between alcoholic beverage use and other traits to blood pressure: a new Kaiser Permanente study.
In a new study controlled for many factors, we reconfirmed the relationship of higher blood pressure to alcohol use. This relationship was slightly stronger in men, whites, and persons 55 years of age or older. A slight increase in blood pressure appeared in men who drank one to two drinks daily, and a continuous increase occurred at all higher drinking levels among white men who had constant drinking habits. Among women, an increase occurred only at three or more drinks daily. The data suggest complete regression, beginning within days, of alcohol-associated hypertension upon abstinence. Blood pressure showed minor differences with beverage preference: those who preferred liquor had higher adjusted mean blood pressure than those preferring wine or beer. The results of this study contribute to the likelihood that the alcohol-blood pressure association is causal. Smoking, coffee use, and tea use showed no association with higher blood pressure. Systolic pressure showed a positive relationship to total serum calcium and an inverse relationship to serum potassium, but diastolic pressure showed little relationship to these blood constituents; the explanations include a possible direct effect on regulation of blood pressure.


Quantitative Ultrasound Spectroscopy for Differentiation of Hepatocellular Carcinoma from At-Risk and Normal Liver Parenchyma.
Quantitative ultrasound approaches can capture tissue morphologic properties to augment clinical diagnostics. This study aims to clinically assess whether quantitative ultrasound spectroscopy (QUS) parameters measured in hepatocellular carcinoma (HCC) tissues can be differentiated from those measured in at-risk or healthy liver parenchyma. This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the Institutional Review Board. Fifteen patients with HCC, 15 non-HCC patients with chronic liver disease, and 15 healthy volunteers were included (31.1% women; 68.9% men). Ultrasound radiofrequency data were acquired in each patient in both liver lobes at two focal depths (3/9 cm). Region of interests (ROIs) were drawn on HCC and liver parenchyma. The average normalized power spectrum for each ROI was extracted, and a linear regression was fit within the -6 dB bandwidth, from which the midband fit (MBF), spectral intercept (SI), and spectral slope (SS) were extracted. Differences in QUS parameters between the ROIs were tested by a mixed-effects regression. There was a significant intraindividual difference in MBF, SS, and SI between HCC and adjacent liver parenchyma (P < 0.001), and a significant interindividual difference between HCC and at-risk and healthy non-HCC parenchyma (P < 0.001). In patients with HCC, cirrhosis (n = 13) did not significantly change any of the three parameters (P > 0.8) in differentiating HCC from non-HCC parenchyma. MBF (P = 0.12), SI (P = 0.33), and SS (P = 0.57) were not significantly different in non-HCC tissue among the groups. The QUS parameters are significantly different in HCC versus non-HCC liver parenchyma, independent of underlying cirrhosis. This could be leveraged for improved HCC detection with ultrasound in the future.


Unilateral pallidotomy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets exhibiting levodopa-induced dyskinesia.
Pallidotomy paradoxically reduces the intensity of levodopa-induced dyskinesia without worsening motor symptoms. The reasons for this are not clear and no experimental study has investigated this phenomenon. The objective of this investigation was to evaluate the effects of unilateral pallidotomy on locomotor activity, motor disability and levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated levodopa-primed common marmosets. Animals were primed to exhibit dyskinesia by daily administration of levodopa until stable dyskinesia was evoked by each dose. Locomotor activity, motor disability and dyskinesia were assessed weekly at baseline and following an acute levodopa challenge. Prior to pallidotomies, two distinct groups of animals emerged: poor responders to levodopa with mild dyskinesia (Group 1) and those exhibiting a marked increase in motor activity and pronounced dyskinesia (Group 2). Electrolytic lesions were placed in the left internal segment of the globus pallidus. Pallidotomy had no effect on basal or levodopa-induced motor activity in either group but significantly improved basal motor disability in Group 2. Following pallidotomy, the ability of levodopa to reduce motor disability was significantly increased in both groups. Pallidotomy improved dyskinesia in both Groups 1 and 2 but it was more effective in reducing dystonia compared with chorea. The effect of pallidotomy on dyskinesia in Group 2 was transient, with the intensity of involuntary movements reverting to presurgery levels 4 weeks later. This study shows that in levodopa-primed, parkinsonian marmosets, placement of discrete globus pallidus lesions can ameliorate levodopa-induced dyskinesia but not akinesia. This model allows the evaluation of pallidotomy-induced biochemical changes in dyskinetic primates.


[Postnatal depression in Colombian women: secondary analysis of the 2010 Colombian Demographic and Health Survey].
Examining the prevalence of self-reported postpartum depression (PD) in a representative sample of Colombian women. A secondary analysis was made of the Colombian Demographic and Health Survey 2010; the survey included 53 521 women aged 13 to 49 years-old. A clinical diagnosis of depression by self-report, during the first six months' postpartum as a perinatal complication, was defined as the dependent variable by interview. Logistic regression was used, taking into account the multistage study design and adjusting for potential confounders. The results were presented as adjusted odds ratios (OR) with 95 % confidence intervals (95 % CI). Overall PD prevalence was 12.9 %, being higher in urban areas (15.1 %) than in rural areas (6.8 %) and in women aged 20-34 years-old (13.4 %). The Amazonas and Guainía departments had lower PD prevalence (3.1 % and 3.5 % respectively), while the city of Bogotá and the Quindío department had higher prevalence (18.1 % and 22.1 % PD, respectively). After adjustment, women aged 20 to 34 years-old (OR=1.15: 1.03 to 1.28 95 % CI), primigravidae (OR=1.42: 1.28-1.57 95 % CI), residing in urban areas (OR=2.43: 2.06 to 2.87 95 % CI) and having had university level education (OR=2.22: 1.98 to 2.48 95 % CI) were associated with PD. A high prevalence of postpartum depression was found in the study population. Socio-demographic and geographic factors contributed towards depression according to self-report. More research is needed to enable early identification of and intervention in women suffering from depression.


An inhibitor of sodium transport in the urine of dogs with normal renal function.
The urine and serum of chronically uremic patients and dogs contain an inhibitor of sodium transport that reduces short-circuit current (SCC) in the toad bladder and produces natriuresis in the rat. The present studies represent an effort to determine whether the same inhibitor is detectable in urine of normal dogs maintained on a dosium intake varying from 3 to 258 meq/day. Observations were made with and without fludrocortisone. The same Sephadex G-25 gel filtration fraction previously shown to contain the "uremic" inhibitor was tested in both the isolated toad bladder and rat bioassay systems. The fraction from dogs maintained on 258 meq qodium plus 0.2 mg fludrocortisone/day consistently inhibited SCC in the toad bladder and induced a natriuresis in the rat (P less than 0.001). The fraction from dogs on the same sodium intake without fludrocortisone was also natriuretic (P less than 0.01) but did not inhibit SCC significantly. In contrast, the fraction from dogs fed 3 meq sodium with fludrocortisone or 91 meq sodium without fludrocortisone had no significant effect in either assay system. Thus, an inhibitor of sodium transport has been found in the urine of nonuremic dogs. Both the degree of natriuresis in the rat and the degree of inhibition of SCC in the toad bladder correlated with the state of sodium balance which ensued in the dog.


No difference between micro- and macroprolactinomas in the prolactin responsiveness to metoclopramide and dopamine administration.
Differences between micro- and macroprolactinomas, as regards the prolactin secretory pattern in response to pharmacological challenges, have been reported in in vivo and in vitro models, and interpreted as being due to different dopaminergic regulation of prolactin release. In 32 patients with prolactin-secreting tumors, 19 with microprolactinomas and 13 with macroprolactinomas, and ten healthy volunteers, we evaluated the prolactin secretion in response to pharmacological manipulations of central dopaminergic tone. To this end, three tests were performed, in random order: (1) 4-h saline infusion; (2) 10 mg metoclopramide as i.v. bolus; (3) 4-h dopamine infusion (0.01 microgram/kg/min) with a 10-mg metoclopramide bolus given after the second hour of infusion. Dopamine infusion, compared to saline, caused a significant prolactin decrease in all the three groups of subjects, without significant difference between micro- and macroprolactinoma patients. In prolactinoma patients, administration of metoclopramide induced a significant rise in plasma prolactin which, however, was significantly lower than the one displayed by controls. Again, no difference was observed between the two groups of hyperprolactinemic patients. Dopamine infusion induced a significant and comparable increase in the prolactin response to metoclopramide in micro- and macroprolactinoma patients, while it was ineffective in control subjects. In conclusion, no differences appear to exist between micro- and macroprolactinoma patients as regards the prolactin secretory pattern during pharmacological modifications of the dopaminergic tone. A central dopaminergic defect and an increased prolactin turnover with attendant reduction of the intracellular hormone pool may both be involved in the reduced prolactin release following provocative stimuli in patients with prolactinoma.


Automated analysis of free speech predicts psychosis onset in high-risk youths.
Psychiatry lacks the objective clinical tests routinely used in other specializations. Novel computerized methods to characterize complex behaviors such as speech could be used to identify and predict psychiatric illness in individuals. In this proof-of-principle study, our aim was to test automated speech analyses combined with Machine Learning to predict later psychosis onset in youths at clinical high-risk (CHR) for psychosis. Thirty-four CHR youths (11 females) had baseline interviews and were assessed quarterly for up to 2.5 years; five transitioned to psychosis. Using automated analysis, transcripts of interviews were evaluated for semantic and syntactic features predicting later psychosis onset. Speech features were fed into a convex hull classification algorithm with leave-one-subject-out cross-validation to assess their predictive value for psychosis outcome. The canonical correlation between the speech features and prodromal symptom ratings was computed. Derived speech features included a Latent Semantic Analysis measure of semantic coherence and two syntactic markers of speech complexity: maximum phrase length and use of determiners (e.g., which). These speech features predicted later psychosis development with 100% accuracy, outperforming classification from clinical interviews. Speech features were significantly correlated with prodromal symptoms. Findings support the utility of automated speech analysis to measure subtle, clinically relevant mental state changes in emergent psychosis. Recent developments in computer science, including natural language processing, could provide the foundation for future development of objective clinical tests for psychiatry.


Analysis of VOT in Turkish speakers with aphasia.
Studies investigating voicing onset time (VOT) production by speakers with aphasia have shown that nonfluent aphasics show a deficit in the articulatory programming of speech sounds based on the range of VOT values produced by aphasic individuals. If the VOT value lies between the normal range of VOT for the voiced and voiceless categories, then it is a phonetic distortion, thus a phonetic/articulatory deficit. A number of studies in different languages (French, English, Thai, Taiwanese) have investigated VOT in aphasic subjects in which their VOT values have been compared to those of normal speakers. This study investigates the VOT productions of voiced and voiceless stops by Turkish speakers with aphasia. Six patients with different aetiologies but similar language characteristics participated in this study. The results suggest that although Turkish nonfluent aphasics exhibit unimodal distribution of VOT production, the VOT values and ranges show language-specific properties.


Attention-deficit/hyperactivity disorder: identifying high priority future research needs.
With onset often occurring before 6 years of age, attention-deficit/hyperactivity disorder (ADHD) involves attention problems, impulsivity, overactivity, and sometimes disruptive behavior. Impairment usually persists into adulthood, with an estimated worldwide prevalence in adults of 2.5%. Existing gaps in evidence concerning ADHD hinder decision-making about treatment. This article describes and prioritizes future research needs for ADHD in three areas: treatment effectiveness for at-risk preschoolers; long-term treatment effectiveness; and variability in prevalence, diagnosis, and treatment.Using a recent systematic review concerning ADHD completed by a different evidence-based practice center as a foundation, we worked with a diverse group of 12 stakeholders, who represented researchers, funders, healthcare providers, patients, and families, to identify and prioritize research needs. From an initial list of 29 evidence gaps, we enumerated 8 high-priority research needs: a) accurate, brief standardized diagnosis and assessment; b) comparative effectiveness and safety of pharmacologic treatments for children under 6 years of age; c) comparative effectiveness of different combinations of psychosocial and pharmacologic treatments for children under 6 years of age; d) case identification and measurement of prevalence and outcomes; e) comparative effectiveness of psychosocial treatment alone versus pharmacologic and combination treatments for children under 6 years of age; f) comparative long-term treatment effectiveness for people 6 years of age and older; g) relative efficacy of specific psychosocial program components for children under 6 years of age; and h) identification of person-level effect modifiers for people 6 years of age and older. In this article, we describe these future research needs in detail and discuss study designs that could be used to address them.


Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.
Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.


Wharton's Jelly Mesenchymal Stromal Cells from Human Umbilical Cord: a Close-up on Immunomodulatory Molecules Featured In Situ and In Vitro.
Therapeutic options for end-stage organ failure are often limited to whole organ transplantation. The tolerance or rejection of the transplanted organ is driven by both early non-specific innate and specific adaptive responses. The use of mesenchymal stromal cells (MSCs) is considered a promising tool in regenerative medicine. Human umbilical cord (HUC) is an easily available source of MSCs, without relevant ethical issues. Moreover, Wharton's jelly-derived MSCs (WJ-MSCs), showed consistent immunomodulatory features that may be useful to promote immune tolerance in the host after transplantation. Few data are available on the phenotype of WJ-MSCs in situ. We investigated the expression of immune-related molecules, such as HLAs, IDO, CD276/B7-H3, and others, both in situ (HUC) and in in vitro-cultured WJ-MSCs. Morphological and biochemical techniques were used to define the expression of such molecules. In addition, we focused on the possible role of CD276/B7-H3 on T cells proliferation inhibition. We assessed CD276/B7-H3 expression by WJ-MSCs both in situ and alongside cell culture. WJ-MSCs were able to suppress T cell proliferation in mixed lymphocyte reaction (MLR). Moreover, we describe for the first time a specific role for CD276/B7-H3, since the immunomodulatory ability of WJ-MSCs was abolished upon anti-CD276/B7-H3 antibody addition to the MLR. These results further detail the immune regulation properties and tolerance induction exerted by human WJ-MSCs, in particular pointing to CD276/B7-H3 as one of the main involved factors. These data further suggest WJ-MSCs as potent tools to modulate local immune response in "support-type" regenerative medicine approaches.


Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation.
Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microglia, astrocytes, or oligodendrocyte lineage cells (i.e., NG2-glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review, we will give a detailed summary on different glial ablation studies, focusing on the adult mouse central nervous system and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future.


Fair credit reporting medical information regulations. Final rules.
The OCC, Board, FDIC, OTS, and NCUA (Agencies) are publishing final rules to implement section 411 of the Fair and Accurate Credit Transactions Act of 2003 (FACT Act). The final rules create exceptions to the statute's general prohibition on creditors obtaining or using medical information pertaining to a consumer in connection with any determination of the consumer's eligibility, or continued eligibility, for credit for all creditors. The exceptions permit creditors to obtain or use medical information in connection with credit eligibility determinations where necessary and appropriate for legitimate purposes, consistent with the Congressional intent to restrict the use of medical information for inappropriate purposes. The final rules also create limited exceptions to permit affiliates to share medical information with each other without becoming consumer reporting agencies. The final rules are substantially similar to the rules adopted by the Agencies on an interim final basis in June 2005.


Improved recovery from spinal cord injury in rats with chronic parvovirus serotype-1a infection.
A vendor informed us that rats shipped to us and used by us in a spinal cord contusion injury experiment were infected by rat parvovirus type 1a (RPV-1a). Our aim was therefore to determine whether this infection may have altered locomotor recovery or tissue pathology. Stockholm, Sweden. We induced a moderate contusion injury of the spinal cord in rats received from an (unknown to us) RPV-1a-contaminated facility. We compared the hind limb locomotor function between RPV-1a-infected rats and non-infected controls with the same spinal cord lesions, obtained before (historical control), as well as after infection (future controls). Histologically, we assessed spinal tissue sparing, astrocyte reactivity and the amount of macrophages/activated microglia. RPV-1a-infected rats had significantly better hind limb locomotor recovery compared with both 'historical' and 'future' controls. We also observed significantly better tissue sparing and axonal sparing around the injury site, as well as significant reductions in macrophages/activated microglia and astrocyte reactivity in the spinal cords of RPV-1a-infected rats. The results stress the importance of knowing the health status of animals used to study central nervous system trauma and support the notion that acquired infections, even if asymptomatic, may alter response to injury in mammals. Furthermore, the results demonstrate that virus infections may have positive effects on functional recovery after spinal cord injury and indicate that RPV-1a infection may be neuroprotective by dampening secondary damage.


Electronic structure calculations with GPAW: a real-space implementation of the projector augmented-wave method.
Electronic structure calculations have become an indispensable tool in many areas of materials science and quantum chemistry. Even though the Kohn-Sham formulation of the density-functional theory (DFT) simplifies the many-body problem significantly, one is still confronted with several numerical challenges. In this article we present the projector augmented-wave (PAW) method as implemented in the GPAW program package (https://wiki.fysik.dtu.dk/gpaw) using a uniform real-space grid representation of the electronic wavefunctions. Compared to more traditional plane wave or localized basis set approaches, real-space grids offer several advantages, most notably good computational scalability and systematic convergence properties. However, as a unique feature GPAW also facilitates a localized atomic-orbital basis set in addition to the grid. The efficient atomic basis set is complementary to the more accurate grid, and the possibility to seamlessly switch between the two representations provides great flexibility. While DFT allows one to study ground state properties, time-dependent density-functional theory (TDDFT) provides access to the excited states. We have implemented the two common formulations of TDDFT, namely the linear-response and the time propagation schemes. Electron transport calculations under finite-bias conditions can be performed with GPAW using non-equilibrium Green functions and the localized basis set. In addition to the basic features of the real-space PAW method, we also describe the implementation of selected exchange-correlation functionals, parallelization schemes, ΔSCF-method, x-ray absorption spectra, and maximally localized Wannier orbitals.


Childhood psychological problems in school settings in rural Southern Africa.
Many children can be exposed to multiple adversities in low and middle-income countries (LMICs) placing them at potential risk of psychological problems. However, there is a paucity of research using large representative cohorts examining the psychological adjustment of children in school settings in these countries. Children's psychological adjustment has been shown to affect educational progress which is critical for their future. This study, based in a rural, socio-economically disadvantaged area of South Africa, aimed to examine the prevalence of children's psychological problems as well as possible risk and protective factors. Rates of psychological problems in 10-12 year olds were examined using teacher- and child-report questionnaires. Data on children from 10 rural primary schools, selected by stratified random sampling, were linked to individual and household data from the Agincourt health and socio-demographic surveillance system collected from households over 15 years. A total of 1,025 children were assessed. Teachers identified high levels of behavioural and emotional problems (41%). Children reported lower, but substantial rates of anxiety/depression (14%), and significant post-traumatic stress symptoms (24%); almost a quarter felt unsafe in school. Risk factors included being a second-generation former refugee and being from a large household. Protective factors highlight the importance of maternal factors, such as being more educated and in a stable partnership. The high levels of psychological problems identified by teachers are a serious public health concern, as they are likely to impact negatively on children's education, particularly given the large class sizes and limited resources in rural LMIC settings. Despite the high levels of risk, a proportion of children were managing well and research to understand resilience could inform interventions.


MRI findings guiding selection of active surveillance for prostate cancer: a review of emerging evidence.
Active surveillance (AS) for prostate cancer (PCa) is generally considered to be a safe strategy for men with low-risk, localized disease. However, as many as 1 in 4 patients may be incorrectly classified as AS-eligible using traditional inclusion criteria. The use of multiparametric magnetic resonance imaging (mpMRI) may offer improved risk stratification in both the initial diagnostic and disease monitoring setting. We performed a review of recently published studies to evaluate the utility of this imaging modality for this clinical setting. An English literature search was conducted on PubMed for original investigations on localized PCa, AS, and magnetic resonance imaging. Our Boolean criteria included the following terms: PCa, AS, imaging, MRI, mpMRI, prospective, retrospective, and comparative. Our search excluded publication types such as comments, editorials, guidelines, reviews, or interviews. Our literature review identified 71 original investigations. Among these, 52 met our inclusion criteria. Evidence suggests mpMRI improves characterization of clinically significant prostate cancer (csPCa) foci, and the enhanced detection and risk-stratification afforded by this modality may keep men from being inappropriately placed on AS. Use of serial mpMRI may also permit longer intervals between confirmatory biopsies. Multiple studies demonstrate the benefit of MRI-targeted biopsies. The use of mpMRI of the prostate offers improved confidence in risk-stratification for men with clinically low-risk PCa considering AS. While on AS, serial mpMRI and MRI-targeted biopsy aid in the detection of aggressive disease transformation or foci of clinically-significant cancer undetected on prior biopsy sessions.


The bHLH transcription factor hand2 plays parallel roles in zebrafish heart and pectoral fin development.
The precursors of several organs reside within the lateral plate mesoderm of vertebrate embryos. Here, we demonstrate that the zebrafish hands off locus is essential for the development of two structures derived from the lateral plate mesoderm - the heart and the pectoral fin. hands off mutant embryos have defects in myocardial development from an early stage: they produce a reduced number of myocardial precursors, and the myocardial tissue that does form is improperly patterned and fails to maintain tbx5 expression. A similar array of defects is observed in the differentiation of the pectoral fin mesenchyme: small fin buds form in a delayed fashion, anteroposterior patterning of the fin mesenchyme is absent and tbx5 expression is poorly maintained. Defects in these mesodermal structures are preceded by the aberrant morphogenesis of both the cardiogenic and forelimb-forming regions of the lateral plate mesoderm. Molecular analysis of two hands off alleles indicates that the hands off locus encodes the bHLH transcription factor Hand2, which is expressed in the lateral plate mesoderm starting at the completion of gastrulation. Thus, these studies reveal early functions for Hand2 in several cellular processes and highlight a genetic parallel between heart and forelimb development.


Associations of mental health and family background with opioid analgesic therapy: a nationwide Swedish register-based study.
There is evidence of greater opioid prescription to individuals in the United States with mental health conditions. Whether these associations generalize beyond the US prescription environment and to familial mental health and socioeconomic status (SES) has not been examined comprehensively. This study estimated associations of diverse preexisting mental health diagnoses, parental mental health history, and SES in childhood with opioid analgesic prescription patterns nationwide in Sweden. Using register-based data, we identified 5,071,193 (48.4% female) adolescents and adults who were naive to prescription opioid analgesics and followed them from 2007 to 2014. The cumulative incidence of any dispensed opioid analgesic within 3 years was 11.4% (95% CI, 11.3%-11.4%). Individuals with preexisting self-injurious behavior, as well as opioid and other substance use, attention-deficit/hyperactivity, depressive, anxiety, and bipolar disorders had greater opioid therapy initiation rates than did individuals without the respective conditions (hazard ratios from 1.24 [1.20-1.27] for bipolar disorder to 2.12 [2.04-2.21] for opioid use disorder). Among 1,298,083 opioid recipients, the cumulative incidence of long-term opioid therapy (LTOT) was 7.6% (7.6%-7.7%) within 3 years of initiation. All mental health conditions were associated with greater LTOT rates (hazard ratios from 1.66 [1.56-1.77] for bipolar disorder to 3.82 [3.51-4.15] for opioid use disorder) and were similarly associated with concurrent benzodiazepine-opioid therapy. Among 1,482,462 adolescents and young adults, initiation and LTOT rates were greater for those with parental mental health history or lower childhood SES. Efforts to understand and ameliorate potential adverse effects of opioid analgesics must account for these patterns.


A comparison of synaptophysin, chromogranin, and L-dopa decarboxylase as markers for neuroendocrine differentiation in lung cancer cell lines.
Synaptophysin is a Mr 38,000 integral membrane glycoprotein expressed by a variety of normal and neoplastic neuroendocrine cells. We studied synaptophysin as an immunocytochemical marker for neuroendocrine differentiation in lung cancer and compared it to the immunocytochemical expression of chromogranin A, a marker for dense core (endocrine) granules, and the biochemical activity of L-dopa decarboxylase (DDC), the key amine-handling enzyme. Of the 250 cell lines available to us, we selected examples representative of the following cell types: bronchial carcinoids (n = 4), small cell lung cancer (SCLC) (n = 7), extrapulmonary small cell carcinomas (n = 4), and non-small cell lung cancers (n = 18) whose neuroendocrine status had been previously determined on the basis of electron microscopy and DDC activity. We demonstrated (a) there was a higher incidence of synaptophysin than chromogranin A immunoreactivity in carcinoid (100 versus 75%), classic SCLC (70 versus 50%), and variant SCLC (57 versus 29%) cell lines; (b) 3 of the 4 (75%) extrapulmonary small cell lung cancer cell lines expressed synaptophysin and chromogranin A; (c) 5 of the 7 (71%) non-small cell lung cancer cell lines previously shown to express multiple neuroendocrine markers were positive for synaptophysin, chromogranin A, and DDC activity; (d) none of the other 11 non-small cell lung cancer cell lines expressed synaptophysin or chromogranin A; and (e) formalin fixation and paraffin embedding reduced synaptophysin immunoreactivity in 11 of 14 (79%) of the cell lines, as compared to freshly prepared specimens fixed in 95% ethanol. Western blot analysis using the synaptophysin antibody (SY38) demonstrated immunoreactive proteins ranging from Mr 43,000 to 45,000 in five representative cell lines. The concordance of expression of all three neuroendocrine markers was statistically significant when values for all cell lines were totalled. Synaptophysin was a more commonly expressed marker for variant SCLC cell lines, which rarely showed DDC activity. We conclude that synaptophysin may be a more sensitive and specific marker for neuroendocrine differentiation, when compared to chromogranin A and DDC in lung cancer cell lines which express only part of the neuroendocrine program.


Context modulation of facial emotion perception differed by individual difference.
Certain facial configurations are believed to be associated with distinct affective meanings (i.e. basic facial expressions), and such associations are common across cultures (i.e. universality of facial expressions). However, recently, many studies suggest that various types of contextual information, rather than facial configuration itself, are important factor for facial emotion perception. To examine systematically how contextual information influences individuals' facial emotion perception, the present study estimated direct observers' perceptual thresholds for detecting negative facial expressions via a forced-choice psychophysical procedure using faces embedded in various emotional contexts. We additionally measured the individual differences in affective information-processing tendency (BIS/BAS) as a possible factor that may determine the extent to which contextual information on facial emotion perception is used. It was found that contextual information influenced observers' perceptual thresholds for facial emotion. Importantly, individuals' affective-information tendencies modulated the extent to which they incorporated context information into their facial emotion perceptions. The findings of this study suggest that facial emotion perception not only depends on facial configuration, but the context in which the face appears as well. This contextual influence appeared differently with individual's characteristics of information processing. In summary, we conclude that individual character traits, as well as facial configuration and the context in which a face appears, need to be taken into consideration regarding facial emotional perception.


Metabotropic glutamate receptor type 1alpha and tubulin assemble into dynamic interacting complexes.
Metabotropic glutamate receptors (mGlu receptors) are coupled to G-protein second messenger pathways and modulate glutamate neurotransmission in the brain, where they are targeted to specific synaptic locations. Very recently, we identified tubulin as an interacting partner of the mGlu(1alpha) receptor in rat brain. Using BHK-570 cells permanently expressing the receptor we have shown that this interaction occurs predominantly with soluble tubulin, following its translocation to the plasma membrane. In addition, treatment of the cells with the agonist quisqualic acid induce tubulin depolymerization and its translocation to the plasma membrane. Immunofluorescence detection of both the receptor and tubulin in agonist-treated cells reveals a disruption of the microtubule network and an increased clustering of the receptor. Collectively these data demonstrate that the mGlu(1alpha) receptor interacts with soluble tubulin and that this association can take place at the plasma membrane.


Distribution of mast-cell precursors in hematopoeitic and lymphopoietic tissues of mice.
Two experimental systems were used to investigate the origin of precursor cells which differentiate into tissue mast cells in vivo. (a) Increase of mast cell number was examined in the skin, stomach, cecum, and mesentery of genetically mast cell-depleted WBB6F1 (WB X C57BL/6)-W/WV mice after the injection of various hematolymphoid cells of congenic +/+ mice. (b) Appearance of mast cells with giant granules was studied in irradiated C57BL/6-+/+ mice after the injection of lymphoid cells of C57BL/6-bgJ/bgJ (beige, Chediak-Higashi syndrome) mice. Concentrations of mast cell precursors in the thymus, lymph node and Peyer's patch were less than 0.1% of the concentration in the bone marrow. Neither treatment of donor bone marrow cells with anti-Thy-1.2 serum and complement nor thymectomy of the recipient mice affects the development of mast cells in the skin, stomach, cecum, and mesentery. Moreover, the number of mast cells increased to normal level when the skin of WBB6F1-W/WV mice was grafted on the back of nude athymic (BALB/c-nu/nu) mice. These results indicate that mast cell precursors are derived from hematopoietic tissues rather than lymphopoetic ones and that the differentiation of the precursor cells does not depend on T lymphocytes or the thymus.


Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice.
Physical exercise promotes glucose uptake into skeletal muscle and makes the working muscles more sensitive to insulin. To understand the role of insulin receptor (IR) signaling in these responses, we studied the effects of exercise and insulin on skeletal muscle glucose metabolism and insulin signaling in mice lacking insulin receptors specifically in muscle. Muscle-specific insulin receptor knockout (MIRKO) mice had normal resting 2-deoxy-glucose (2DG) uptake in soleus muscles but had no significant response to insulin. Despite this, MIRKO mice displayed normal exercise-stimulated 2DG uptake and a normal synergistic activation of muscle 2DG uptake with the combination of exercise plus insulin. Glycogen content and glycogen synthase activity in resting muscle were normal in MIRKO mice, and exercise, but not insulin, increased glycogen synthase activity. Insulin, exercise, and the combination of exercise plus insulin did not increase IR tyrosine phosphorylation or phosphatidylinositol 3-kinase activity in MIRKO muscle. In contrast, insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice, and prior exercise markedly enhanced this insulin effect. In conclusion, normal expression of muscle insulin receptors is not needed for the exercise-mediated increase in glucose uptake and glycogen synthase activity in vivo. The synergistic activation of glucose transport with exercise plus insulin is retained in MIRKO mice, suggesting a phenomenon mediated by nonmuscle cells or by downstream signaling events.


Effective Energy Transfer via Plasmon-Activated High-Energy Water Promotes Its Fundamental Activities of Solubility, Ionic Conductivity, and Extraction at Room Temperature.
Water is a ubiquitous solvent in biological, physical, and chemical processes. Unique properties of water result from water's tetrahedral hydrogen-bonded (HB) network (THBN). The original THBN is destroyed when water is confined in a nanosized environment or localized at interfaces, resulting in corresponding changes in HB-dependent properties. In this work, we present an innovative idea to validate the reserve energy of high-energy water and applications of high-energy water to promote water's fundamental activities of solubility, ionic conductivity, and extraction at room temperature. High-energy water with reduced HBs was created by utilizing hot electrons with energies from the decay of surface plasmon excited at gold (Au) nanoparticles (NPs). Compared to conventional deionized (DI) water, solubilities of alkali metal-chloride salts in high-energy water were significantly increased, especially for salts that release heat when dissolved. The ionic conductivity of NaCl in high-energy water was also markedly higher, especially when the electrolyte's concentration was extremely low. In addition, antioxidative components, such as polyphenols and 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (THSG) from teas, and Polygonum multiflorum (PM), could more effectively be extracted using high-energy water. These results demonstrate that high-energy water has emerged as a promising innovative solvent for promoting water's fundamental activities via effective energy transfer.


Pest categorisation of the Andean Potato Weevil (APW) complex (Coleoptera: Curculionidae).
The EFSA Panel on Plant Health performed a pest categorisation of the species within the Andean Potato Weevil (APW) complex (Coleoptera: Curculionidae) for the EU. The complex consists of 14 species, 12 belong to the genus Premnotrypes, plus Phyrdenus muriceus and Rhigopsidius tucumanus. These weevils co-occur in the Andean region, usually above 2,100 m. Eggs are deposited in plant debris close to potato plants. Upon hatching larvae immediately bore into potato tubers where they complete development. Except for R. tucumanus, which pupates inside the tuber, mature larvae leave the tuber and pupate in the soil. Adults can survive feeding on different plants but cannot deposit fertile eggs unless fed on potato foliage. P. muriceus can also complete development feeding on tomato and eggplant roots and occurs at lower altitudes from southern USA to central Argentina. Within the APW complex only species in the genus Premnotrypes are regulated in Annex IIA of Commission Implementing Regulation 2019/2072 as Premnotrypes spp. (non-EU). Within this regulation potential pathways, such as solanaceous plants for planting with foliage and growing medium, seed and ware potatoes, and soil, can be considered as closed. There are no records of interception of any of these weevils in EUROPHYT. Should these species be introduced into the EU, climatic conditions and wide availability of potato crops in the EU territory would provide conditions for establishment, spread and economic impact. Phytosanitary measures are available to reduce the likelihood of entry. The species within the APW complex satisfy with no uncertainties the criteria that are within the remit of EFSA to assess, for them to be regarded as potential Union quarantine pests. Although human-assisted movement of seed potatoes is considered the main mechanism for spread of these species, these weevils do not meet the criterion of occurring in the EU for them to be regarded as potential Union regulated non-quarantine pests.


Physical Demands of Match Play in Successful and Less-Successful Elite Rugby League Teams.
To quantify activity profiles in approximately 5-min periods to determine if the intensity of rugby league match play changes after the most intense period of play and to determine if the intensity of activity during predefined periods of match play differ between successful and less-successful teams playing at an elite standard. Movement was recorded using a MinimaxX global positioning system (GPS) unit sampling at 10 Hz during 25 rugby league matches, equating to 200 GPS files. Data for each half of match play were separated into 8 equal periods. These periods represented the most intense phase of match play (peak period), the period after the most intense phase of match play (subsequent period), and the average demands of all other periods in a match (mean period). Two rugby league teams were split into a high-success and a low-success group based on their success rates throughout their season. Compared with their less-successful counterparts, adjustables and hit-up forwards from the high-success team covered less total distance (P < .01) and less high-intensity-running distance (P < .01) and were involved in a greater number of collisions (P < .01) during the mean period of match play. Although a greater number of collisions during match play is linked with a greater rate of success, greater amounts of high-intensity running and total distance are not related to competitive success in elite rugby league. These results suggest that technical and tactical differences, rather than activity profiles, may be the distinguishing factor between successful and less-successful rugby league teams.


Increased detection sensitivity of surface plasmon sensors using oblique induced resonant coupling.
Increased detection sensitivity was achieved by adjusting the incident angle on periodic gold nanostructures that induced a resonant coupling between surface and substrate surface plasmon modes. For 500 nm-period gold nanoslits, a small incident angle, 7°, resulted in 2.64 times narrower linewidth and a 1.8 times increase in the figure of merit as compared to normal incidence. Furthermore, the intensity sensitivity was increased 4.5 times due to the change in the resonant coupling and redshift of the surface plasmon mode.


Characteristics, management, and outcomes of cocaine-positive patients with acute coronary syndrome (from the National Cardiovascular Data Registry).
Although cocaine ingestion may cause or contribute to myocardial infarction (MI), few contemporary data are available describing cocaine-associated MI. We describe the characteristics, management, and outcomes of patients with MI and recent cocaine use from the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines (ACTION Registry-GWTG) program. The study population was 102,952 patients enrolled in the American College of Cardiology ACTION Registry-GWTG from July 2008 to March 31, 2010 from 460 sites across the United States. Cocaine exposure was defined as self-reported cocaine use within the last 72 hours or a positive urine test for cocaine. Demographics and medical history, presenting characteristics, treatments, and in-hospital outcomes were reported on a standard case record form. A total of 924 patients (0.9%) were cocaine positive. Compared with cocaine-negative patients, cocaine-positive patients were younger and predominantly men with fewer cardiovascular risk factors. There was a higher percentage of ST elevation myocardial infarction (STEMI) (46.3% vs 39.7%) and cardiogenic shock at presentation in the cocaine-positive group, but the percentage of multivessel coronary artery disease was lower (53.3% vs 64.5%). Beta blockers within 24 hours (85.8% vs 90.1%, p <0.0001) and drug-eluting stents (40.1% vs 68.8%, p <0.0001 in patients with non-STEMI; 27.6% vs 54.6%, p <0.0001 in patients with STEMI) were used less commonly in cocaine-positive patients. Multivariable-adjusted in-hospital mortality was similar between cocaine-positive and cocaine-negative patients (adjusted odds ratio 1.00, 95% confidence interval 0.69 to 1.44, p value = 0.98). In conclusion cocaine-positive patients with acute coronary syndrome are younger with fewer risk factors, multivessel coronary artery disease and lower drug-eluting stent and β-blocker usage. Cocaine use was not associated with in-hospital mortality.


Cardiovascular risk and antiangiogenic therapy for age-related macular degeneration.
The neovascular form of the age-related macular degeneration (AMD) causes most cases of severe blindness. Because vascular endothelial growth factor (VEGF) plays a leading role in this disorder, several inhibitors of this molecule are being used in its treatment. However, VEGF has important functions in vascular pathophysiology. It enhances the development of collateral vessels that may supply blood to areas whose arteries are severely affected by atherosclerotic lesions. Additionally, it may promote restoration of the damaged endothelium, a vessel layer that protects against the development of atherothrombosis, and it has hypotensive effects. In contrast, VEGF may stimulate the formation of microvessels inside the atherosclerotic plaque. These vessels may become disrupted and cause intraplaque hemorrhage, stimulating disease progression. VEGF also has a role in thrombus formation. The effects of anti-VEGF therapy may therefore compromise patient safety. When administered systemically to cancer patients, the main cardiovascular adverse effects of these compounds have been thrombosis, hemorrhage and hypertension. As patients with AMD constitute a high-risk population for cardiovascular events, the safety of new anti-VEGF therapies must be assessed. In this review we analyze the effects of VEGF on atherosclerosis and the cardiovascular safety of anti-VEGF therapies in AMD.


Ozone dose mapping and the utility of models.
In Europe the monitoring of ozone doses to growing crops is based on measurement of AOT40, the annual accumulated excess ozone concentration over a threshold of 40 ppb, aggregated over the growing season. To show the extent of ozone pollution it is desirable to construct maps of AOT40. However, data are limited and there is large inter-annual variation, so what is to be mapped is very variable, and our knowledge of it is limited. This paper describes a spatially referenced random effects model which appears able to describe many features of the data and our uncertainty about them. The problem of translating this or similar models into a map faithfully representing our knowledge is considered, as are some questions it raises about decision-makers' and the public's need for and use of technical models.


Substance P and beta-endorphin mediate electro-acupuncture induced analgesia in mouse cancer pain model.
Opioid analgesics are generally used to combat the pain associated with cancerous conditions. These agents not only inhibit respiratory function and cause constipation, but also induce other significant side effects such as addiction and tolerance, all of which further contribute to a reduced quality of life for cancer patients. Thus, in the present study, the effects of electro-acupuncture treatment (EA) on mechanical allodynia were examined in a cancer pain mouse model. In order to produce a neuropathic cancer pain model, S-180 sarcoma cells were inoculated around the sciatic nerve of left legs of Balb/c mice. Magnetic Resonance Imaging (MRI) scanning confirmed the mass of S-180 cancer cells embedded around the sciatic nerve. Mechanical allodynia was most consistently induced in the mouse sarcoma cell line S-180 (2 x 10(6)sarcoma cells)-treated group compared to all the other groups studied. EA stimulation (2 Hz) was administered daily to ST36 (Zusanli) of S-180 bearing mice for 30 min for 9 days after S-180 inoculation. EA treatment significantly prolonged paw withdrawal latency from 5 days after inoculation. It also shortened the cumulative lifting duration from 7 days after inoculation, compared to the tumor control. Also, the overexpression of pain peptide substance P in the dorsal horn of the spinal cord was significantly decreased in the EA-treated group compared to the tumor control on Day 9 post inoculation. Furthermore, EA treatment effectively increased the concentration of beta-endorphin in blood and brain samples of the mice to a greater extent than that of the tumor control as well as the normal group. The concentration of beta-endorphin for EA treatment group increased by 51.457% in the blood and 12.6% in the brain respectively, compared to the tumor control group. The findings of this study suggest that a S-180 cancer pain model is useful as a consistent and short time animal model. It also indicated that EA treatment could be used as an alternative therapeutic method for cancer pain due to a consequent decrease in substance P and increase in beta-endorphin levels.


Role construction and boundaries in interprofessional primary health care teams: a qualitative study.
The move towards enhancing teamwork and interprofessional collaboration in health care raises issues regarding the management of professional boundaries and the relationship among health care providers. This qualitative study explores how roles are constructed within interprofessional health care teams. It focuses on elucidating the different types of role boundaries, the influences on role construction and the implications for professionals and patients. A comparative case study was conducted to examine the dynamics of role construction on two interprofessional primary health care teams. The data collection included interviews and non-participant observation of team meetings. Thematic content analysis was used to code and analyze the data and a conceptual model was developed to represent the emergent findings. The findings indicate that role boundaries can be organized around interprofessional interactions (giving rise to autonomous or collaborative roles) as well as the distribution of tasks (giving rise to interchangeable or differentiated roles). Different influences on role construction were identified. They are categorized as structural (characteristics of the workplace), interpersonal (dynamics between team members such as trust and leadership) and individual dynamics (personal attributes). The implications of role construction were found to include professional satisfaction and more favourable wait times for patients. A model that integrates these different elements was developed. Based on the results of this study, we argue that autonomy may be an important element of interprofessional team functioning. Counter-intuitive as this may sound, we found that empowering team members to develop autonomy can enhance collaborative interactions. We also argue that while more interchangeable roles could help to lessen the workloads of team members, they could also increase the potential for power struggles because the roles of various professions would become less differentiated. We consider the conceptual and practical implications of our findings and we address the transferability of our model to other interprofessional teams.


Phosphorylation of dopamine transporter serine 7 modulates cocaine analog binding.
As an approach to elucidating dopamine transporter (DAT) phosphorylation characteristics, we examined in vitro phosphorylation of a recombinant rat DAT N-terminal peptide (NDAT) using purified protein kinases. We found that NDAT becomes phosphorylated at single distinct sites by protein kinase A (Ser-7) and calcium-calmodulin-dependent protein kinase II (Ser-13) and at multiple sites (Ser-4, Ser-7, and Ser-13) by protein kinase C (PKC), implicating these residues as potential sites of DAT phosphorylation by these kinases. Mapping of rat striatal DAT phosphopeptides by two-dimensional thin layer chromatography revealed basal and PKC-stimulated phosphorylation of the same peptide fragments and comigration of PKC-stimulated phosphopeptide fragments with NDAT Ser-7 phosphopeptide markers. We further confirmed by site-directed mutagenesis and mass spectrometry that Ser-7 is a site for PKC-stimulated phosphorylation in heterologously expressed rat and human DATs. Mutation of Ser-7 and nearby residues strongly reduced the affinity of rat DAT for the cocaine analog (-)-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (CFT), whereas in rat striatal tissue, conditions that promote DAT phosphorylation caused increased CFT affinity. Ser-7 mutation also affected zinc modulation of CFT binding, with Ala and Asp substitutions inducing opposing effects. These results identify Ser-7 as a major site for basal and PKC-stimulated phosphorylation of native and expressed DAT and suggest that Ser-7 phosphorylation modulates transporter conformational equilibria, shifting the transporter between high and low affinity cocaine binding states.


TIME to reduce agitation in persons with dementia in nursing homes. A process evaluation of a complex intervention.
The Targeted Intervention Interdisciplinary Model for Evaluation and Treatment of Neuropsychiatric Symptoms (TIME) has recently in a three-month cluster randomised controlled trial demonstrated reduction in agitation in nursing home residents with dementia. To ease replication and future implementation, and to clarify possible causal mechanisms, we performed a process evaluation of the intervention based on the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). An exploratory and a quasi-experimental design with mixed methods were used. The RE-AIM dimensions were explored by questionnaires to 807 staff members and 46 leading ward nurses in both the intervention nursing homes (INH) and the control nursing homes (CNH), before the start of the trial (baseline), and six and 12 months later. These questionnaires assessed data regarding the reach, effectiveness (staff level) and adoption dimensions. To assess implementation, we used a checklist for performance of the main components in TIME and analysed the minutes from 84 case conferences in the INH. To explore adoption and maintenance, five focus group interviews with 32 participants from the staff in the INH were conducted three to 6 months after the end of the trial. Reach: On average 61% (SD 22) of the staff in each ward in the INH attended the training sessions. Effectiveness at staff level: There were no between-group differences throughout the study period for attitudes towards dementia, perceived competence or perception of mastery and social interaction. Adoption: 16 of the 17 INH completed the intervention. 75% or more of the components of TIME were performed for 91% of the included residents. Maintenance: Most of the nursing homes used TIME three to 6 months after the end of the trial. An easy to grasp model and an engaged leadership facilitated the intervention and maintenance. A high degree of reach, adoption, implementation and maintenance contributed to the effectiveness of TIME at resident level. One other causal assumption of the effectiveness of TIME is the development in the staff of a new, shared and situated knowledge about each individual resident, not reflected by measurements in general knowledge and attitudes. The trial was registered January 6, 2016 with ClinicalTrials.gov ( NCT02655003 ).


Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid.
Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.


Usefulness of the virtual monochromatic image in dual-energy spectral CT for decreasing renal cyst pseudoenhancement: a phantom study.
The purpose of this study was to determine the effect that dual-energy spectral CT has on renal cyst pseudoenhancement with a renal cyst phantom. Two renal compartments within a CT phantom were filled with 40- and 240-HU solutions of diluted contrast material, mimicking the nonenhanced phase and nephrographic phase of MDCT, respectively. A saline-filled tapering cylindric cyst model was used, simulating cysts of varying diameters (range, 0.7-3.0 cm) suspended in the renal compartments. The phantom was scanned using dual-energy CT (DECT) (80 and 140 kVp) and conventional, single-energy CT (120 kVp) with the same 64-MDCT scanner. Attenuation increase was measured for a cyst model within 40- and 240-HU dilutions. We compared the attenuation increase obtained on virtual monochromatic images from DECT with conventional, single-energy MDCT images using a paired Student t test. Pseudoenhancement occurred in the conventional single-energy CT acquisitions, with water attenuation increase of 42.44 ± 4.03 HU measured at 120 kVp. In virtual monochromatic images of DECT, we observed less pseudoenhancement with water attenuation increase of 21.51 ± 6.18 HU at 70 keV. Both acquisitions yielded a p value less than 0.0001. We achieved less pseudoenhancement of renal cysts with virtual monochromatic images of DECT compared with conventional single-energy CT. This method may be useful when an accurate differentiation between small renal cysts and solid masses is critical.


Cardiac Arrest Disrupts Caspase-1 and Patterns of Inflammatory Mediators Differently in Skin and Muscle Following Localized Tissue Injury in Rats: Insights from Data-Driven Modeling.
Trauma often cooccurs with cardiac arrest and hemorrhagic shock. Skin and muscle injuries often lead to significant inflammation in the affected tissue. The primary mechanism by which inflammation is initiated, sustained, and terminated is cytokine-mediated immune signaling, but this signaling can be altered by cardiac arrest. The complexity and context sensitivity of immune signaling in general has stymied a clear understanding of these signaling dynamics. We hypothesized that advanced numerical and biological function analysis methods would help elucidate the inflammatory response to skin and muscle wounds in rats, both with and without concomitant shock. Based on the multiplexed analysis of inflammatory mediators, we discerned a differential interleukin (IL)-1α and IL-18 signature in skin vs. muscle, which was suggestive of inflammasome activation in the skin. Immunoblotting revealed caspase-1 activation in skin but not muscle. Notably, IL-1α and IL-18, along with caspase-1, were greatly elevated in the skin following cardiac arrest, consistent with differential inflammasome activation. Tissue-specific activation of caspase-1 and the NLRP3 inflammasome appear to be key factors in determining the type and severity of the inflammatory response to tissue injury, especially in the presence of severe shock, as suggested via data-driven modeling.


Convergent evolution in human and domesticate adaptation to high-altitude environments.
Humans and their domestic animals have lived and thrived in high-altitude environments worldwide for thousands of years. These populations have developed a number of adaptations to survive in a hypoxic environment, and several genomic studies have been conducted to identify the genes that drive these adaptations. Here, we discuss the various adaptations and genetic variants that have been identified as adaptive in human and domestic animal populations and the ways in which convergent evolution has occurred as these populations have adapted to high-altitude environments. We found that human and domesticate populations have adapted to hypoxic environments in similar ways. Specific genes and biological pathways have been involved in high-altitude adaptation for multiple populations, although the specific variants differ between populations. Additionally, we found that the gene EPAS1 is often a target of selection in hypoxic environments and has been involved in multiple adaptive introgression events. High-altitude environments exert strong selective pressures, and human and animal populations have evolved in convergent ways to cope with a chronic lack of oxygen. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'.


Should patents for antiretrovirals be waived in the developing world? Annual Varsity Medical Debate--London, 21 January 2011.
The 2011 Varsity Medical Debate, between Oxford and Cambridge Universities, brought students and faculty together to discuss the waiving of patents for antiretroviral therapies in the developing world. With an estimated 29.5 million infected by Human Immunodeficiency Virus (HIV) in low- and middle-income countries and only 5.3 million of those being treated, the effective and equitable distribution of anti-retroviral therapy (ART) is an issue of great importance. The debate centred around three areas of contention. Firstly, there was disagreement about whether patents were the real barrier to the access of anti-retroviral therapy in the developing world. Secondly, there were differing views on the effectiveness of a patent pool. Thirdly, concerns were raised over the impact of waiving patents on research to produce new and better anti retro-viral drugs.


Effect of tibolone pretreatment on kinases and phosphatases that regulate the expression and phosphorylation of Tau in the hippocampus of rats exposed to ozone.
Oxidative stress (OS) is a key process in the development of many neurodegenerative diseases, memory disorders, and other pathological processes related to aging. Tibolone (TIB), a synthetic hormone used as a treatment for menopausal symptoms, decreases lipoperoxidation levels, prevents memory impairment and learning disability caused by ozone (O3) exposure. However, it is not clear if TIB could prevent the increase in phosphorylation induced by oxidative stress of the microtubule-associated protein Tau. In this study, the effects of TIB at different times of administration on the phosphorylation of Tau, the activation of glycogen synthase kinase-3β (GSK3β), and the inactivation of Akt and phosphatases PP2A and PTEN induced by O3 exposure were assessed in adult male Wistar rats. Rats were divided into 10 groups: control group (ozone-free air plus vehicle [C]), control + TIB group (ozone-free air plus TIB 1 mg/kg [C + TIB]); 7, 15, 30, and 60 days of ozone exposure groups [O3] and 7, 15, 30, and 60 days of TIB 1 mg/kg before ozone exposure groups [O3 + TIB]. The effects of O3 exposure and TIB administration were assessed by western blot analysis of total and phosphorylated Tau, GSK3β, Akt, PP2A, and PTEN proteins and oxidative stress marker nitrotyrosine, and superoxide dismutase activity and lipid peroxidation of malondialdehyde by two different spectrophotometric methods (Marklund and TBARS, respectively). We observed that O3 exposure increases Tau phosphorylation, which is correlated with decreased PP2A and PTEN protein levels, diminished Akt protein levels, and increased GSK3β protein levels in the hippocampus of adult male rats. The effects of O3 exposure were prevented by the long-term treatment (over 15 days) with TIB. Malondialdehyde and nitrotyrosine levels increased from 15 to 60 days of exposure to O3 in comparison to C group, and superoxide dismutase activity decreased. Furthermore, TIB administration limited the changes induced by O3 exposure. Our results suggest a beneficial use of hormone replacement therapy with TIB to prevent neurodegeneration caused by O3 exposure in rats.


The combination of β-caryophyllene, baicalin and catechin synergistically suppresses the proliferation and promotes the death of RAW267.4 macrophages in vitro.
β-caryophyllene, which is a constituent of many essential oils, has been known to be a selective agonist of the cannabinoid receptor type-2 and to exert cannabimimetic anti-inflammatory effects in animals. The effects of β-caryophyllene on macrophages have not been investigated to date. This study was undertaken to determine whether β-caryophyllene exerts suppressive effects on mouse RAW267.4 macrophages in vitro in comparison with other botanical molecules that exert antioxidant and anti-inflammatory effects. The proliferation of RAW267.4 cells was suppressed by culture with β-caryophyllene (50, 100 and 200 µg/ml of medium) or curcumin (100 and 200 µg/ml). Culture with baicalin (1-200 µg/ml) or (+)-catechin (1-200 µg/ml) did not exert an effect on RAW267.4 cells. The combination of β-caryophyllene (1 or 10 µg/ml) with either curcumin (1 or 10 µg/ml), baicalin (1 or 10 µg/ml) or (+)-catechin (1 or 10 µg/ml) did not exert any suppressive effects on cell proliferation. Of note, the combination of all three agents, β-caryophyllene, baicalin and (+)-catechin at the concentration of either 1 or 10 µg/ml was found to exert synergistic suppressive effects on cell proliferation. Moreover, the combination of β-caryophyllene, baicalin and (+)-catechin synergistically promoted the death of RAW267.4 cells. Such an effect was blocked by culture with caspase-3 inhibitor. The combination of the three agents decreased the protein levels of Akt, mitogen-activated protein kinase (MAPK) and cyclooxygenase (COX)-1 or -2. On the whole, this study demonstrates that the combination of β-caryophyllene, baicalin and (+)-catechin exerts synergistic suppressive effects on macrophages in vitro. This composition may be a useful as an anti-inflammatory treatment strategy.