Immune Responses and Risk of Triple-negative Breast Cancer: Implications for Higher Rates among African American Women.
The etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor-negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women.


The early Upper Paleolithic human skeleton from the Abrigo do Lagar Velho (Portugal) and modern human emergence in Iberia.
The discovery of an early Upper Paleolithic human burial at the Abrigo do Lagar Velho, Portugal, has provided evidence of early modern humans from southern Iberia. The remains, the largely complete skeleton of a approximately 4-year-old child buried with pierced shell and red ochre, is dated to ca. 24,500 years B.P. The cranium, mandible, dentition, and postcrania present a mosaic of European early modern human and Neandertal features. The temporal bone has an intermediate-sized juxtamastoid eminence. The mandibular mentum osseum and the dental size and proportions, supported by mandibular ramal features, radial tuberosity orientation, and diaphyseal curvature, as well as the pubic proportions align the skeleton with early modern humans. Body proportions, reflected in femorotibial lengths and diaphyseal robusticity plus tibial condylar displacement, as well as mandibular symphyseal retreat and thoracohumeral muscle insertions, align the skeleton with the Neandertals. This morphological mosaic indicates admixture between regional Neandertals and early modern humans dispersing into southern Iberia. It establishes the complexities of the Late Pleistocene emergence of modern humans and refutes strict replacement models of modern human origins.


Outbreak of Acinetobacter baumannii bacteremia in a neonatal intensive care unit: clinical implications and genotyping analysis.
Outbreaks of sepsis associated with have been rarely reported in neonatal intensive care units (NICUs). We describe such an outbreak in a NICU, and the results of molecular epidemiologic investigations are presented. Between August and September 2000, 6 premature infants hospitalized in a pediatric NICU developed sepsis. Three additional cases had infections during November and December. For an environmental culture survey, 94 environmental specimens and hand washings of all 43 health care workers involved in this unit were examined for the presence of this organism. Two genotyping methods, pulsed field gel electrophoresis of genomic DNA digested with I and infrequent restriction site polymerase chain reaction, were used to analyze the 9 bacteremic isolates and any isolates obtained from the environmental survey and the hand washings. Another 3 bacteremic isolates of collected in the same NICU in 1999 were incorporated as controls. The 9 infants were premature and had birth weights of <1,500 g. Before onset of sepsis 9 infants had received total parenteral nutrition, and 8 infants had had central venous catheters and received intrafat emulsion. Five (5.3%) environmental specimens and 10 (23.3%) hand washing specimens were positive for the organism. Except for the strain from Case 9, the results of both genotyping methods were concordant; 11 patterns were identified by infrequent restriction site polymerase chain reaction and 10 patterns by pulsed field gel electrophoresis. One major genotype was demonstrated in the first 6 bacteremic isolates as well as 3 hand washing isolates. The genotypes of the other 3 bacteremic isolates, the 3 control strains, the 5 environmental isolates and 7 other hand washing isolates were distinct from the genotype of outbreak strains. An outbreak of bacteremia in a NICU was clearly demonstrated by the molecular epidemiologic investigation and was possibly transmitted via the hands of health care workers.


Reaction kinetics and a physical model of the charring layer by depositing Al2O3 at ultra-high temperatures.
The thermochemical ablation of insulation material caused by slag deposition in solid rocket motors has increasingly attracted researchers' attention. Understanding the ablation mechanism and the ability to calculate reaction kinetics parameters determine the height of the thermal protection design for advanced solid rocket motors. In this work, the interaction of the Al2O3-C system is determined through static ablation experiments. Using X-ray diffraction, HSC thermodynamic software, and a thermogravimetric analyser, the carbon thermal reduction of alumina is analysed and the reaction mechanism and physical model are obtained. Isothermal experiments at 1700-1850 °C and mathematical analysis provide the kinetic parameters of the overall and step-by-step reactions. The results show that the overall reaction of the Al2O3-C system involves three steps. The overall reaction kinetics are described by the contracting area model R2 with apparent activation and frequency factors estimated as 254.5 kJ mol-1 and 5.5 × 106 min-1, respectively. The distribution reaction kinetics of steps 1 and 2 are described by the first-order chemical reaction control model (F1) and that of step 3 is described by the one-dimensional diffusion control model (D1). The corresponding activation energies are 107.9 kJ mol-1, 240.3 kJ mol-1, and 567.5 kJ mol-1, and frequency factors are 625.94 min-1, 8.3 × 105 min-1, and 1.6 × 1014 min-1, respectively.


Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age.
Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol-dependent patients and population-based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing-specific process, our findings suggest that hypermethylation in alcohol-dependent patients is a consequence, rather than a cause, of the disorder.


A model based on clinical parameters to identify myocardial late gadolinium enhancement by magnetic resonance in patients with aortic stenosis: An observational study.
With increasing age, the prevalence of aortic stenosis grows exponentially, increasing left heart pressures and potentially leading to myocardial hypertrophy, myocardial fibrosis and adverse outcomes. To identify patients who are at greatest risk, an outpatient model for risk stratification would be of value to better direct patient imaging, frequency of monitoring and expeditious management of aortic stenosis with possible earlier surgical intervention. In this study, a relatively simple model is proposed to identify myocardial fibrosis in patients with a diagnosis of moderate or severe aortic stenosis. Patients with moderate to severe aortic stenosis were enrolled into the study; patient characteristics, blood work, medications as well as transthoracic echocardiography and cardiovascular magnetic resonance were used to determine potential identifiers of myocardial fibrosis. The Royal Brompton Hospital, London, UK. One hundred and thirteen patients in derivation cohort and 26 patients in validation cohort. Identification of myocardial fibrosis. Three blood biomarkers (serum platelets, serum urea, N-terminal pro-B-type natriuretic peptide) and left ventricular ejection fraction were shown to be capable of identifying myocardial fibrosis. The model was validated in a separate cohort of 26 patients. Although further external validation of the model is necessary prior to its use in clinical practice, the proposed clinical model may direct patient care with respect to earlier magnetic resonance imagining, frequency of monitoring and may help in risk stratification for surgical intervention for myocardial fibrosis in patients with aortic stenosis.


Physical multimorbidity and psychosis: comprehensive cross sectional analysis including 242,952 people across 48 low- and middle-income countries.
In people with psychosis, physical comorbidities, including cardiovascular and metabolic diseases, are highly prevalent and leading contributors to the premature mortality encountered. However, little is known about physical health multimorbidity in this population or in people with subclinical psychosis and in low- and middle-income countries (LMICs). This study explores physical health multimorbidity patterns among people with psychosis or subclinical psychosis. Overall, data from 242,952 individuals from 48 LMICs, recruited via the World Health Survey, were included in this cross-sectional study. Participants were subdivided into those (1) with a lifetime diagnosis of psychosis ("psychosis"); (2) with more than one psychotic symptom in the past 12 months, but no lifetime diagnosis of psychosis ("subclinical psychosis"); and (3) without psychotic symptoms in the past 12 months or a lifetime diagnosis of psychosis ("controls"). Nine operationalized somatic disorders were examined: arthritis, angina pectoris, asthma, diabetes, chronic back pain, visual impairment, hearing problems, edentulism, and tuberculosis. The association between psychosis and multimorbidity was assessed by multivariable logistic regression analysis. The prevalence of multimorbidity (i.e., two or more physical health conditions) was: controls = 11.4% (95% CI, 11.0-11.8%); subclinical psychosis = 21.8% (95% CI, 20.6-23.0%), and psychosis = 36.0% (95% CI, 32.1-40.2%) (P < 0.0001). After adjustment for age, sex, education, country-wise wealth, and country, subclinical psychosis and psychosis were associated with 2.20 (95% CI, 2.02-2.39) and 4.05 (95% CI, 3.25-5.04) times higher odds for multimorbidity. Moreover, multimorbidity was increased in subclinical and established psychosis in all age ranges (18-44, 45-64, ≥ 65 years). However, multimorbidity was most evident in younger age groups, with people aged 18-44 years with psychosis at greatest odds of physical health multimorbidity (OR = 4.68; 95% CI, 3.46-6.32). This large multinational study demonstrates that physical health multimorbidity is increased across the psychosis-spectrum. Most notably, the association between multimorbidity and psychosis was stronger among younger adults, thus adding further impetus to the calls for the early intervention efforts to prevent the burden of physical health comorbidity at later stages. Urgent public health interventions are necessary not only for those with a psychosis diagnosis, but also for subclinical psychosis to address this considerable public health problem.


Polar expeditions--provisioning the centrosome for mitosis.
It is now clear that both centrioles and their surrounding pericentriolar material (PCM) are capable of self-assembly. Whereas centrioles are normally duplicated during G1-S phase, PCM components may be loaded onto centrosomes in both a microtubule-dependent and -independent manner at all stages of the cell cycle. Centrosomes enlarge dramatically after mitotic entry, when both Aurora A and Polo-like kinases cooperate to recruit additional gamma-tubulin ring complexes and microtubule-associated proteins to assist spindle formation.


Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells.
Regulation and induction of anergy in NKT cells of the liver can inhibit autoimmune and antitumor responses by mechanisms that are poorly understood. We investigated the effects of PGE2, delivered by intestinal, mucus-derived, exosome-like nanoparticles (IDENs), on NKT cells in mice. In this study, we demonstrate that IDENs migrate to the liver where they induce NKT cell anergy. These effects were mediated by an IDENs' PGE2. Blocking PGE2 synthesis attenuated IDENs inhibition of induction of IFN-γ and IL-4 by α-galactosylceramide (α-GalCer)-stimulated liver NKT cells in a PGE2 E-type prostanoid 2/E-type prostanoid 4 receptor-mediated manner. Proinflammatory conditions enhanced the migration of IDENs to the liver where α-GalCer and PGE2 induced NKT anergy in response to subsequent α-GalCer stimulation. These findings demonstrate that IDENs carrying PGE2 can be transferred from the intestine to the liver, where they act as immune modulators, inducing an anergic-like state of NKT cells. These reagents might be developed as therapeutics for autoimmune liver diseases.


Missed opportunities: poor linkage into ongoing care for HIV-positive pregnant women in Mwanza, Tanzania.
Global coverage of prevention of mother-to-child (PMTCT) services reached 53% in 2009. However the number of pregnant women who test positive for HIV in antenatal clinics and who link into long-term HIV care is not known in many resource-poor countries. We measured the proportion of HIV-positive pregnant women in Mwanza city, Tanzania, who completed the cascade of care from antenatal HIV diagnosis to assessment and engagement in care in adult HIV clinics. Thirty antenatal and maternity ward health workers were interviewed about PMTCT activities. Nine antenatal HIV education sessions were observed. A prospective cohort of 403 HIV-positive women was enrolled by specially-trained clinicians and nurses on admission to delivery and followed for four months post-partum. Information was collected on referral and attendance at adult HIV clinics, eligibility for highly active antiretroviral therapy (HAART) and reasons for lack of attendance. Overall, 70% of PMTCT health workers referred HIV-positive pregnant women to the HIV clinic for assessment and care. Antenatal HIV education sessions did not cover on-going care for HIV-infected women. Of 310 cohort participants tested in pregnancy, 51% had received an HIV clinic referral pre-delivery. Only 32% of 244 women followed to four months post-partum had attended an HIV clinic and been assessed for HAART eligibility. Non-attendance for HIV care was independently associated with fewer antenatal visits, poor PMTCT prophylaxis compliance, non-disclosure of HIV status, and non-Sukuma ethnicity. Most women identified as HIV-positive during pregnancy were not assessed for HAART eligibility during pregnancy or in the first four months post-partum. Initiating HAART at the antenatal clinic, improved counselling and linkages to care between PMTCT and adult HIV treatment services and reducing stigma surrounding disclosure of HIV results would benefit on-going care of HIV-positive pregnant women.


LocalZProjector and DeProj: a toolbox for local 2D projection and accurate morphometrics of large 3D microscopy images.
Quantitative imaging of epithelial tissues requires bioimage analysis tools that are widely applicable and accurate. In the case of imaging 3D tissues, a common preprocessing step consists of projecting the acquired 3D volume on a 2D plane mapping the tissue surface. While segmenting the tissue cells is amenable on 2D projections, it is still very difficult and cumbersome in 3D. However, for many specimen and models used in developmental and cell biology, the complex content of the image volume surrounding the epithelium in a tissue often reduces the visibility of the biological object in the projection, compromising its subsequent analysis. In addition, the projection may distort the geometry of the tissue and can lead to strong artifacts in the morphology measurement. Here we introduce a user-friendly toolbox built to robustly project epithelia on their 2D surface from 3D volumes and to produce accurate morphology measurement corrected for the projection distortion, even for very curved tissues. Our toolbox is built upon two components. LocalZProjector is a configurable Fiji plugin that generates 2D projections and height-maps from potentially large 3D stacks (larger than 40 GB per time-point) by only incorporating signal of the planes with local highest variance/mean intensity, despite a possibly complex image content. DeProj is a MATLAB tool that generates correct morphology measurements by combining the height-map output (such as the one offered by LocalZProjector) and the results of a cell segmentation on the 2D projection, hence effectively deprojecting the 2D segmentation in 3D. In this paper, we demonstrate their effectiveness over a wide range of different biological samples. We then compare its performance and accuracy against similar existing tools. We find that LocalZProjector performs well even in situations where the volume to project also contains unwanted signal in other layers. We show that it can process large images without a pre-processing step. We study the impact of geometrical distortions on morphological measurements induced by the projection. We measured very large distortions which are then corrected by DeProj, providing accurate outputs.


Surgery versus surveillance in ulcerative colitis patients with endoscopically invisible low-grade dysplasia: a cost-effectiveness analysis.
There is uncertainty regarding the optimal management of endoscopically invisible (flat) low-grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis. A Markov model was used to evaluate the costs and health outcomes of surveillance and surgery over a 20-year timeframe. Outcomes evaluated were life years gained and quality-adjusted life years (QALYs). Cohorts of patients aged 25 to 75 were modeled, including estimates from a validated surgical risk calculator and considering none, 1, or both of 2 key comorbidities: heart failure and obstructive airway disease. Surveillance is associated with more life years and QALYs compared with surgery from age 61 for those with no comorbidities, age 51 for those with 1 comorbidity and age 25 for those with 2 comorbidities. At the current United Kingdom National Institute for Health and Care Excellence threshold of $25,800 per QALY, ongoing surveillance was cost-effective at age 65 in those without comorbidities and at age 60 in those with either 1 or more comorbidities. Surveillance can be recommended from age 65 for those with no comorbidities; however, in younger patients with typical postsurgical quality of life, colectomy may be more effective clinically and more cost-effective. The results were sensitive to the colorectal cancer incidence rate in patients under surveillance and to quality of life after surgery.


Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.
Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.


Protocadherin γ A3 is expressed in follicular lymphoma irrespective of BCL2 status and is associated with tumor cell growth.
Protocadherin genes (PCDHs) have been suggested to act as tumor suppressor genes in various tumor types. Previous studies have demonstrated the upregulation of certain PCDH‑γ subfamily genes in nodal and duodenal follicular lymphoma (FL) using gene expression analyses. However, the mechanisms and associated molecular function of PCDH‑γ subfamily gene upregulation in FL remain to be elucidated. The present study examined the expression of PCDHGA3, an upregulated PCDH‑γ gene subfamily member, in B‑cell lymphoma 2 (BCL2)‑positive and ‑negative FL, and evaluated its association with tumor cell proliferation in an FL‑derived cell line. Immunohistochemical analysis demonstrated that the majority of FL grade 1‑2 samples (19/20; 95%) and over half of grade 3A FL samples (5/9; 56%) were PCDHGA3‑positive, whereas only 1/17 reactive lymphoid hyperplasia samples was positive. Notably, this positivity was widely observed in samples of BCL2‑negative FL (13/15; 87%) and FL with diffuse area (10/10; 100%). The FL‑derived cell line FL18 exhibited strong PCDHGA3 expression, similar to the patient samples, and its proliferation was suppressed by PCDHGA3 gene knockdown. Genes expressed concomitantly with PCDHGA3 were selected from gene expression data, and TNFRSF6B, a member of the tumor necrosis factor receptor superfamily, was among the top five most strongly correlated genes. Coexpression of TNFRSF6B and PCDHGA3 was observed immunohistochemically in FL18 cells, suggesting potential cooperation in tumor cell maintenance. In conclusion, the results of the present study indicated that PCDHGA3 was expressed in FL irrespective of BCL2 status and grading and was associated with cell proliferation. Further studies involving molecular genetic analyses are required to elucidate the mechanisms underlying the activity of PCDHGA3 in FL.


Impacts from above-ground activities in the eagle ford shale play on landscapes and hydrologic flows, La Salle County, Texas.
We assess the spatial and geomorphic fragmentation from the recent Eagle Ford Shale play in La Salle County, Texas, USA. Wells and pipelines were overlaid onto base maps of land cover, soil properties, vegetation assemblages, and hydrologic units. Changes to continuity of different ecoregions and supporting landscapes were assessed using the Landscape Fragmentation Tool (a third-party ArcGIS extension) as quantified by land area and continuity of core landscape areas (i.e., those degraded by "edge effects"). Results show decreases in core areas (8.7%; ~33,290 ha) and increases in landscape patches (0.2%; ~640 ha), edges (1.8%; ~6940 ha), and perforated areas (4.2%; ~16230 ha). Pipeline construction dominates landscape disturbance, followed by drilling and injection pads (85, 15, and 0.03% of disturbed area, respectively). An increased potential for soil loss is indicated, with 51% (~5790 ha) of all disturbance regimes occurring on soils with low water-transmission rates (depth to impermeable layer less than 50 cm) and a high surface runoff potential (hydrologic soil group D). Additionally, 88% (~10,020 ha) of all disturbances occurred on soils with a wind erodibility index of approximately 19 kt/km(2)/year (0.19 kt/ha/year) or higher, resulting in an estimated potential of 2 million tons of soil loss per year. Results demonstrate that infrastructure placement is occurring on soils susceptible to erosion while reducing and splitting core areas potentially vital to ecosystem services.


Levels of PCBs in wild bird eggs: considering toxicity through enzyme induction potential and molecular structure.
Polychlorinated biphenyls (PCBs) were analysed in wild bird eggs from industrialised areas in South Africa. The concentration, congener profile, feeding guild, potential associated risk and biology were investigated. PCBs were detected in all eggs with 30 congeners present in more than 80% of the samples. Σ(34)PCB concentrations ranged between 0.9 and 296 ng g(-1) wet weight (ww). The metabolic potential of the PCB metabolic groups showed good agreement with the biodegradability of the individual congeners. Phenobarbital-type (PB-type) inducer PCBs were prevalent, indicating the predominance of less toxic PCB congeners. However, non-ortho PCBs which were not included in the current analyses, could affect the toxic potential of the PCBs in the eggs requiring more investigation. Although the current levels of PCBs measured do not indicate a health risk to the birds assessed, the presence of mono-ortho PCBs at appreciable levels motivates for the assessment of dioxin-like chemicals in wild bird eggs.


Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia.
Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical-subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.


SESAMI study of employment support for people with severe mental health problems: 12-month outcomes.
In the context of UK policy to promote employment for people with disability as a means to greater social inclusion, this study investigated how people with severe mental health problems fare in existing supported employment agencies. The aim of the study was to identify factors associated with successful placement in work and to test the impact of working on psychological well-being in this group. One hundred and fifty-five users of six English agencies were followed up for 1 year (2005-2006). Information was collected about their employment status, job-seeking behaviour, perceived obstacles to work, self-esteem and hope, and the employment support received. Eighty-two per cent of those working at baseline were still in work a year later. The support agencies helped 25% of unemployed clients into work, a statistically significant increase in the proportion of clients in employment. Gaining employment was associated with improvements in financial satisfaction and self-esteem. There was a trend towards working half time. People who had been out of work longer were less likely to secure employment. No significant associations were found between getting a job and personal characteristics, the quantity of employment support given, nor the recipient's rating of the support offered. The odds of moving into work were nearly four times higher for those people who visited a job centre prior to the start of the study. Clients of specialist agencies rated their provision more highly than clients of pan-disability agencies. These results demonstrate the benefits of working for this group and support the development of employment services with an individualised, rapid placement approach, linked to job centre advice and expert mental health service input. This is consistent with the Individual Placement and Support model, and highlights in addition the importance of job centres for its implementation in England.


First mitochondrial genomes of five hoverfly species of the genus Eristalinus (Diptera: Syrphidae).
The hoverfly genus Eristalinus (Diptera, Syrphidae) contains many widespread pollinators. The majority of the species of Eristalinus occur in the Afrotropics and their molecular systematics still needs to be investigated. This study presents the first complete and annotated mitochondrial genomes for five species of Eristalinus. They were obtained by high-throughput sequencing of total genomic DNA. The total length of the mitogenomes varied between 15 757 and 16 245 base pairs. Gene composition, positions, and orientation were shared across species, and were identical to those observed for other Diptera. Phylogenetic analyses (maximum likelihood and Bayesian inference) based on the 13 protein coding and both rRNA genes suggested that the subgenus Eristalinus was paraphyletic with respect to the subgenus Eristalodes. An analysis of the phylogenetic informativeness of all protein coding and rRNA genes suggested that NADH dehydrogenase subunit 5 (nad5), cytochrome c oxidase subunit 1, nad4, nad2, cytochrome b, and 16S rRNA genes are the most promising mitochondrial molecular markers to result in supported phylogenetic hypotheses of the genus. In addition to the five complete mitogenomes currently available for hoverflies, the five mitogenomes published here will be useful for broader molecular phylogenetic analyses among hoverflies.


Williamsia faeni sp. nov., an actinomycete isolated from a hay meadow.
The taxonomic status of an actinomycete isolated from soil collected from a hay meadow was determined using a polyphasic approach. The strain, designated N1350(T), had morphological and chemotaxonomic properties consistent with its classification in the genus Williamsia and formed a distinct phyletic line within the clade comprising the type strains of species of the genus Williamsia in the 16S rRNA gene tree. Strain N1350(T) shared highest 16S rRNA gene sequence similarities with Williamsia marianensis MT8(T) (98.1 %) and Williamsia muralis MA140-96(T) (98.3 %). However, strain N1350(T) was readily distinguished from the type strains of Williamsia species using a combination of phenotypic properties. On the basis of these data, strain N1350(T) is considered to represent a novel species of the genus Williamsia. The name proposed for this taxon is Williamsia faeni sp. nov., with the type strain N1350(T) (=DSM 45372(T) =NCIMB 14575(T) =NRRL B-24794(T)).


[Portal vein thrombosis in patients undergoing to liver transplantation].
Portal venous thrombosis (PVT) is common in patients with liver cirrhosis, undergoing liver transplantation (LT); in our setting, this is the first publication with an emphasis on results and surgical strategies. Was to review the case history of the Guillermo Almenara Irigoyen National Hospital, determine characteristics, types of PVT and surgical management. We analyzed patients undergoing LT who presented PVT between March 2000 and Jun 2018. Of 255 liver transplants in 239 patients, 229 adults and 26 pediatric, these last were excluded. We found 27 patients had PVT (12.2%) diagnosed in pre and during LT, none with malignant PVT, the most frequent etiologies of cirrhosis were non-alcoholic steatohepatitis (37.4%), alcoholic steatohepatitis (22%), autoimmune hepatitis (AIH) (11%), virus B hepatitis (VBH) (7.4%) and others (11.5%). According to PVT grade: Yerdel I in ten patients (37%), Yerdel II in te patients (37%), Yerdel III in four patients (15%) and Yerdel IV in three patients (11%). Surgical strategy used: thrombectomy in 23 cases (85.2%), hemitransposition cavoportal in 2 cases (7.4%), reno-porto anastomosis with interposition of venous graft in 1 case (3.7%) and thrombectomy with interposition of venous graft in 1 case (3.7%). The re - PVT was present in two cases (7.5%). The PVT decreased patient survival after LT 1 year (81.2%), 3 years (78.4%) and 5 years (78.4%) compared with patients without PVT 1 year (84.6%) 3 years (82.3%) and 5 years (82.3%) respectively. Cirrhosis with PVT was clinically more unbalanced, survival decreased to a higher degree of PVT. Surgical behavior similar to other transplant centers. Early diagnosis is essential to take early surgical action and decrease morbidity and mortality after LT.


Improved performance of polarization-stable VCSELs by monolithic sub-wavelength gratings produced by soft nano-imprint lithography.
We present a novel method for fabricating polarization-stable oxide-confined single-mode GaAs based vertical cavity surface emitting lasers (VCSELs) emitting at 850 nm using a new soft-lithography nano-imprint technique. A monolithic surface grating is etched in the output mirror of the laser cavity using a directly imprinted silica-based sol-gel imprint resist as an etch mask. The opto-electronic performance of these devices is compared to VCSELs fabricated by state-of-the-art electron-beam lithography. The lasers made using the soft nano-imprint technique show single-mode TM lasing at a threshold and laser slope similar to that of devices made by e-beam lithography. The soft nano-imprint technique also enables the fabrication of gratings with sub-wavelength pitch, which avoids diffraction losses in the laser cavity. The resulting single-mode VCSEL devices exhibit 29% enhanced efficiency compared to devices equipped with diffractive gratings.


Age-related brain structural alterations in children with specific language impairment.
Previous neuroimaging studies have suggested that children with specific language impairment (SLI) may show subtle anatomical alterations in specific brain regions. We aimed to characterize structural abnormalities in children with SLI using a voxel-wise analysis over the whole brain. Subjects covered a wide age range (5-17 years) in order to assess the dynamic nature of the disorder across childhood. Three-dimensional MRIs were collected from 36 children with SLI and from a comparable group of healthy controls. Global gray and white matter measurements were obtained for each subject, and voxel-based morphometry (VBM) was used to evaluate between-group differences in regional brain anatomy. Possible age-related changes were assessed in separate analyses of younger (below 11 years of age) and older children. SLI patients showed larger global gray and white matter volumes, particularly in the younger subgroup. Voxel-wise analyses of the whole sample showed two regions of increased gray matter volume in SLI: the right perisylvian region and the occipital petalia. Age-group analyses suggested a more extended pattern of volume increases in the younger subjects, which included entorhinal, temporopolar, caudate nucleus, motor-precentral and precuneus gray matter, and white matter of the frontal and temporal lobes. Our results suggest that in the SLI brain there are enduring anatomical alterations that exist across a wide age range, as well as a distributed pattern of abnormalities that appear to normalize with development. They also suggest that the neuroanatomical basis of SLI may be better characterized by considering the dynamic course of the disorder throughout childhood.


Induction of glutamine synthetase in embryonic retina: its dependence on cell interactions.
A relation between enzyme induction in embryonic cells and cellular organization is indicated by the finding that the levels of glutamine synthetase induced by hydrocortisone in the embryonic neural retina in vitro are dependent on the associations between the retina cells. Intact retina tissue, aggregates of dissociated cells, and cells in monolayer culture showed a decreasing response, in this order, to glutamine synthetase induction. With time of culture, the enzyme activity continued to rise in the intact retina and in cell aggregates, but activity declined in monolayer cultures even though the inducer was continuously present. Dispersed cells cultured in monolayer without the inducer showed after 24 hours a loss of inducibility which could not be reversed by reaggregating such modified cells but could be prevented by maintaining the freshly dispersed cells at a low temperature.


Safety evaluation of the food enzyme endo-1,4-β-xylanase from the genetically modified Trichoderma reesei strain RF5427.
The food enzyme endo-1,4-β-xylanase (4-β-D-xylan xylanohydrolase; EC 184.108.40.206) is produced with the genetically modified Trichoderma reesei strain RF5427 by AB Enzymes GmbH. The genetic modifications do not give rise to safety concerns. The food enzyme is free from viable cells of the production organism and recombinant DNA. It is intended to be used in baking, brewing and cereal-based processes, distilled alcohol production and grain treatment for the production of starch and gluten fractions. Since residual amounts of the food enzyme are removed by distillation and during grain treatment, dietary exposure was only calculated for baking, brewing and cereal-based processes. Based on the proposed maximum use levels, dietary exposure to the food enzyme-Total Organic Solids (TOS) was estimated to be up to 0.119 mg TOS/kg body weight (bw) per day. Genotoxicity tests did not raise a safety concern. The Panel identified a no observed adverse effect level at the highest dose tested of 939 mg TOS/kg bw per day in a repeated dose 90-day oral toxicity study in rats, resulting in a margin of exposure of at least 7,890. Similarity of the amino acid sequence of the food enzyme to those of known allergens was searched and no matches were found. The Panel considered that allergenicity can be excluded for distilled alcohol production. The risk of allergic sensitisation and elicitation reactions cannot be excluded for baking, brewing and cereal-based processes, and for grain treatment for the production of starch and gluten fractions, but the likelihood of such reactions to occur is considered to be low. Based on the data provided, the removal of TOS during the production of distilled alcohol and grain treatment, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


Quality of interaction between at-risk infants and caregiver at 12-15 months is associated with 3-year autism outcome.
Recent models of the early emergence of autism spectrum disorder (ASD) propose that infant intrinsic risk susceptibilities in behaviour may be amplified by interaction within the early social environment into an increasingly atypical developmental trajectory. This study examines whether 6- and 12-month parent-infant interactions in at-risk siblings differ from those with low-risk and whether--in at-risk siblings--such interactions predict later 3-year classification of ASD or no ASD. Within the British Autism Study of Infant Siblings (BASIS), 6-min videotaped episodes of parent-infant free play in infants at 6-10 months (45 at-risk siblings and 47 low-risk siblings) and 12-15 months (43 at-risk siblings and 48 low-risk siblings) in a laboratory setting were rated on the Manchester Assessment of Caregiver-Infant Interaction (MACI), blind to participant information. Standard tests were administered for concurrent behavioural signs of ASD features and developmental level. Systematic consensus diagnostic classification of ASD was made at 3 years for the at-risk siblings. Parent nondirectiveness and sensitive responsiveness differed in relation to ASD/risk status (at-risk ASD, at-risk no-ASD and low-risk) at both 6 and 12 months. At 6 months, infant liveliness was lower in the at-risk groups; at 12 months, infant attentiveness to parent and positive affect were lower in the at-risk group later diagnosed with ASD. Dyadic mutuality and intensity of engagement showed a group effect at 12 months. Dyadic mutuality, infant positive affect and infant attentiveness to parent at 12 months (but not 6 months) predicted 3-year ASD outcome, whereas infant ASD-related behavioural atypicality did not. This is the first prospective evidence that early dyadic interaction between at-risk infants and their parents is associated with later diagnostic outcome in ASD. Possible explanations for these findings and their theoretical implications are considered.


Self-assertive interdependence in Arab culture.
Arabs represent a major cultural group, yet one that is relatively neglected in cultural psychology. We hypothesized that Arab culture is characterized by a unique form of interdependence that is self-assertive. Arab cultural identity emerged historically in regions with harsh ecological and climatic environments, in which it was necessary to protect the survival of tribal groups. Individuals in Arabian cultures were honour-bound to be respectable and trustworthy group members. Supporting this hypothesis, study 1 found that Arabs were interdependent and holistic (like East Asians), but also self-assertive (like Westerners). This psychological profile was observed equally for both Muslim and Christian Arabs, thus ruling out Islamic religion as an alternative explanation for our findings. Studies 2 and 3 showed that the self-assertive tendency of Arabs is in service of interdependence, whereas that of Westerners is in service of independence. Our work contributes to the current effort by cultural psychologists to go beyond the prevailing East versus West, interdependence versus independence paradigm. It also speaks to the emerging socioecological perspective in cultural research.


Reversible unfolding of individual titin immunoglobulin domains by AFM.
Single-molecule atomic force microscopy (AFM) was used to investigate the mechanical properties of titin, the giant sarcomeric protein of striated muscle. Individual titin molecules were repeatedly stretched, and the applied force was recorded as a function of the elongation. At large extensions, the restoring force exhibited a sawtoothlike pattern, with a periodicity that varied between 25 and 28 nanometers. Measurements of recombinant titin immunoglobulin segments of two different lengths exhibited the same pattern and allowed attribution of the discontinuities to the unfolding of individual immunoglobulin domains. The forces required to unfold individual domains ranged from 150 to 300 piconewtons and depended on the pulling speed. Upon relaxation, refolding of immunoglobulin domains was observed.


PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding.
Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.


Goal-directed therapy improves the outcome of high-risk cardiac patients undergoing off-pump coronary artery bypass.
There has been a constant emphasis on developing management strategies to improve the outcome of high-risk cardiac patients undergoing surgical revascularization. The performance of coronary artery bypass surgery on an off-pump coronary artery bypass (OPCAB) avoids the risks associated with extra-corporeal circulation. The preliminary results of goal-directed therapy (GDT) for hemodynamic management of high-risk cardiac surgical patients are encouraging. The present study was conducted to study the outcome benefits with the combined use of GDT with OPCAB as compared to the conventional hemodynamic management. Patients with the European System for Cardiac Operative Risk Evaluation ≥3 scheduled for OPCAB were randomly divided into two groups; the control and GDT groups. The GDT group included the monitoring and optimization of advanced parameters, including cardiac index (CI), systemic vascular resistance index, oxygen delivery index, stroke volume variation; continuous central venous oxygen saturation (ScVO 2 ), global end-diastolic volume, and extravascular lung water (EVLW), using FloTrac™ , PreSep™ , and EV-1000 ® monitoring panels, in addition to the conventional hemodynamic management in the control group. The hemodynamic parameters were continuously monitored for 48 h in Intensive Care Unit (ICU) and corrected according to GDT protocol. A total of 163 patients consented for the study. Seventy-five patients were assigned to the GDT group and 88 patients were in the control group. In view of 9 exclusions from the GDT group and 12 exclusions from control group, 66 patients in the GDT group and 76 patients in control group completed the study. The length of stay in hospital (LOS-H) (7.42 ± 1.48 vs. 5.61 ± 1.11 days, P < 0.001) and ICU stay (4.2 ± 0.82 vs. 2.53 ± 0.56 days, P < 0.001) were significantly lower in the GDT group as compared to control group. The duration of inotropes (3.24 ± 0.73 vs. 2.89 ± 0.68 h, P = 0.005) was also significantly lower in the GDT group. The two groups did not differ in duration of ventilated hours, mortality, and other complications. The parameters such as ScVO 2 , CI, and EVLW had a strong negative and positive correlation with the LOS-H with r values of - 0.331, -0.319, and 0.798, respectively. The study elucidates the role of a goal-directed hemodynamic optimization for improved outcome in high-risk cardiac patients undergoing OPCAB.


Narrowing down the apricot Plum pox virus resistance locus and comparative analysis with the peach genome syntenic region.
Sharka disease, caused by the Plum pox virus (PPV), is one of the main limiting factors for stone fruit crops worldwide. Only a few resistance sources have been found in apricot (Prunus armeniaca L.), and most studies have located a major PPV resistance locus (PPVres) on linkage group 1 (LG1). However, the mapping accuracy was not sufficiently reliable and PPVres was predicted within a low confidence interval. In this study, we have constructed two high-density simple sequence repeat (SSR) improved maps with 0.70 and 0.68 markers/cm, corresponding to LG1 of 'Lito' and 'Goldrich' PPV-resistant cultivars, respectively. Using these maps, and excluding genotype-phenotype incongruent individuals, a new binary trait locus (BTL) analysis for PPV resistance was performed, narrowing down the PPVres support intervals to 7.3 and 5.9 cm in 'Lito' and 'Goldrich', respectively. Subsequently, 71 overlapping oligonucleotides (overgo) probes were hybridized against an apricot bacterial artificial chromosome (BAC) library, identifying 870 single BACs from which 340 were anchored onto a map region of approximately 30-40 cm encompassing PPVres. Partial BAC contigs assigned to the two allelic haplotypes (resistant/susceptible) of the PPVres locus were built by high-information content fingerprinting (HICF). In addition, a total of 300 BAC-derived sequences were obtained, and 257 showed significant homology with the peach genome scaffold_1 corresponding to LG1. According to the peach syntenic genome sequence, PPVres was predicted within a region of 2.16 Mb in which a few candidate resistance genes were identified.


Effect of plasma from hypertensive subjects on Ca2+ transport in permeabilized human neutrophils.
1. The effects of plasma fractions from essential hypertensive subjects (n = 14) and normotensive subjects (n = 14) on Ca2+ transport in permeabilized human neutrophils was studied using an ion-selective electrode. 2. Plasma fractions were obtained by gel filtration and contained substances with a molecular mass in the range 1000-1500 daltons. This fraction isolated from essential hypertensive subjects has been shown to increase blood pressure after intravenous injection in the rat. 3. The rate of Ca2+ uptake by permeabilized neutrophils after addition of extracellular Ca2+ was significantly accelerated during incubation of the cells with the hypertensive fraction (1049.3 +/- 807.7% vs 242.5 +/- 320.9% of the control value, mean +/- SD, P less than 0.05). 4. It is concluded that the hypertensive plasma fraction increases Ca2+ accumulation in subcellular particles, so that under excitatory conditions Ca2+ release in arterial smooth muscle might be enhanced.


Sheep botfly: ophthalmomyiasis externa.
Sheep botfly (Oestrus ovis) conjunctival infestation is rare in North America but is common in other parts of the world. The author treated 30 patients with this type of conjunctivitis in Jerusalem in 1981 and 1982. The conjunctivitis may vary from mild to severe (pseudo-orbital cellulitis). Features of the conjunctivitis include pale edema, linear superficial punctate keratopathy and the presence of larvae in the conjunctival sac. Conjunctival scrapings revealed a preponderance of polymorphonucleocytes.


[Sexually-transmitted disease prevalence and the factors associated with it in sexually-exploited children in Bogota, Colombia].
Presenting the characteristics of a group of children who have been sexually exploited in Bogota, determining the prevalence of sexually-transmitted disease (STD) in this group of children and establishing the factors associated with STD in this population. This was a descriptive, cross-sectional study. The medical charts of children aged 10 to 17 years who sought medical attention at Fundación Renacer between January 2002 and June 2004 were reviewed. The analysis included descriptive statistics, correlations and binomial logistic regression. 255 children's charts were included, producing the following characteristics: being female (58.8%), average age was 15.4, 5.9% were affiliated to social security, 89.8% engaged in substance abuse, 41.2% used family planning, 3.9% used a condom during every intercourse and there were 0.86 average pregnancies per female adolescent. Sexually-transmitted disease prevalence was 30.9%. The most common diseases were condilomatosis and Neisseria gonorrhoeae infection. Substance abuse and infrequent condom use were associated with a diagnosis of STD. Child sexual exploitation is a reality in Colombia. In spite of the limitations of this study, it can be concluded that STDs are an important problem in the sexually-abused child population in Bogota. Preventing child sexual exploitation and integral attention for these children (including health service provision) must become a priority.


Antifungal pre-emptive strategy for high-risk neutropenic patients: why the story is still ongoing.
Neutropenic patients with haematological malignancies are at high risk of invasive fungal disease (IFD). Due to limitations in specific procedures to establish an early diagnosis of IFD, two historical unpowered studies suggested, three decades ago, that giving an empirical antifungal treatment to patients with persistent or recurrent fever under broad-spectrum antibacterials, could reduce the risk of IFD. For cost and toxicity reasons, this strategy became debated when modern imaging and indirect biological markers became available. Different pre-emptive strategies, either based on lung imaging, galactomannan antigenaemia, fungal PCR, or a combination of several parameters, were designed with the goal of restricting the administration of antifungals to the more at-risk patients with early signs of IFD. Almost all pre-emptive studies showed or suggested a reduction of administration and cost of antifungals during neutropenic phases. However, the clinical pertinence and safety of the strategy, and mainly its optimal design, are still pending. This paper reviews the evolution of these strategies and how they may be implemented in the haematology ward.


Meloidogyne javanica Chorismate Mutase Transcript Expression Profile Using Real-Time Quantitative RT-PCR.
A developmental expression profile of the Meloidodgyne javanica esophageal gland gene chorismate mutase-1 (Mj-cm-1) could suggest when in the lifecycle of the nematode the Mj-cm-1 product is functional. This study used real-time quantitative RT-PCR to examine the variation in Mj-cm-1 transcript levels over six timepoints in the nematode lifecycle: egg, infective second-stage juveniles (Inf-J2), 2-day post-inoculation (pi), 7-day pi, 14-day pi, and adult. The Mj-cm-1 mRNA levels peaked at 2-day pi, about 100-fold above levels expressed at the egg and Inf-J2 stages. Some expression of Mj-cm-1 remained during the 7-day pi, 14-day pi, and adult stages. High transcript levels of the beta-actin control gene M. javanica Beta-actin-1 (Mj-ba-1) demonstrated the presence of cDNA at all timepoints. The peak in Mj-cm-1 transcript expression at 2-day pi as well as the previously shown esophageal gland localization of Mj-cm-1 mRNA suggest that the product of this gene may be involved early in the establishment of parasitism.


Tailoring Interfacial Exchange Anisotropy in Hard-Soft Core-Shell Ferrite Nanoparticles for Magnetic Hyperthermia Applications.
Magnetically hard-soft core-shell ferrite nanoparticles are synthesized using an organometallic decomposition method through seed-mediated growth. Two sets of core-shell nanoparticles (S1 and S2) with different shell (Fe3O4) thicknesses and similar core (CoFe2O4) sizes are obtained by varying the initial quantities of seed nanoparticles of size 6.0 ± 1.0 nm. The nanoparticles synthesized have average sizes of 9.5 ± 1.1 (S1) and 12.2 ± 1.7 (S2) nm with corresponding shell thicknesses of 3.5 and 6.1 nm. Magnetic properties are investigated under field-cooled and zero-field-cooled conditions at several temperatures and field cooling values. Magnetic heating efficiency for magnetic hyperthermia applications is investigated by measuring the specific absorption rate (SAR) in alternating magnetic fields at several field strengths and frequencies. The exchange bias is found to have a nonmonotonic and oscillatory relationship with temperature at all fields. SAR values of both core-shell samples are found to be considerably larger than that of the single-phase bare core particles. The effective anisotropy and SAR values are found to be larger in S2 than those in S1. However, the saturation magnetization displays the opposite behavior. These results are attributed to the occurrence of spin-glass regions at the core-shell interface of different amounts in the two samples. The novel outcome is that the interfacial exchange anisotropy of core-shell nanoparticles can be tailored to produce large effective magnetic anisotropy and thus large SAR values.


Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.


Mental Health in School-Aged Children Prenatally Exposed to Alcohol and Other Substances.
Prenatal exposure to substances can possibly influence a child's neurodevelopment and may impact on subsequent mental health. We investigated the mental health status of school-aged children referred to a pediatric hospital with a history of prenatal exposure to alcohol or other substances. Mental health was assessed using the Strengths and Difficulties Questionnaire and compared with a reference group. A total of 105 of 128 (82%) eligible children prenatally exposed to substances participated in the study, with 48 children exposed to alcohol and 57 to other substances. Strengths and Difficulties Questionnaire subscale mean scores, total difficulties scores, and total impact scores were statistically significantly higher in the group of exposed children, compared with the reference group. In this hospital-based population of school-aged children prenatally exposed to alcohol or other substances, the exposed group had an increased risk of mental health problems, compared with the reference group.


Clathrin structure characterized with monoclonal antibodies. I. Analysis of multiple antigenic sites.
Three monoclonal antibodies that react with previously undefined antigenic determinants on the clathrin molecule have been produced and characterized. They were isolated from a fusion between myeloma cells and popliteal lymphocytes from SJL mice that had received footpad injections of human brain clathrin. This protocol was chosen to favor the production of antibodies to poorly immunogenic proteins and thereby increase the repertoire of anti-clathrin monoclonal antibodies. One antibody (X16) reacts preferentially with the heavier of the two clathrin light chains (LCa) when it is not associated with heavy chain. This specificity is different from that of the anti-LCa antibody, CVC.6, which has preferential reactivity with heavy chain-associated LCa. In addition, X16 and CVC.6 bound simultaneously to LCa, confirming that they react with different sites. The other two antibodies produced, X19 and X22, react with two different determinants on the clathrin heavy chain, based on immunoprecipitation, Western blot, and binding studies. Competitive binding studies with anti-clathrin monoclonal antibodies showed that they define a total of five distinct antigenic determinants on bovine clathrin.


Unusual recurrence of trigeminal neuralgia after microvascular decompression by muscle interposal.
Patients with trigeminal neuralgia (TN) and persistent or recurrent facial pain after microvascular decompression (MVD) typically undergo less invasive procedures in the hope of providing pain relief. However, re-operation should be considered in selected patients. A 48-year-old woman presented with recurrent trigeminal neuralgia (TN) 3 years following microvascular decompression (MVD). The patient underwent brain magnetic resonance angiography (MRA), which did not reveal neurovascular compression; therefore surgical re-exploration was carried out. During the operation, the fifth cranial nerve was seen without impingement from any blood vessels; however, a very firm tissue was observed and identified as the muscle fragment from the previous MVD procedure. The fifth cranial nerve was carefully separated from the muscle. Thereafter, the right SCA was dissected out from the muscle and suspended by a periosteum tape sutured to the nearby dura. Our findings, along with similar cases reported in the literature, support the development of new inert materials and alternative surgical strategies that can limit TN recurrence.


Water and myotonia in goats.
Lipid granules have been found in the cytoplasm of odontoblasts and in the odontoblastic extensions within the dentinal tubules. It is suggested that these granules represent specific activity on the part of the normal cell as well as an increase in number after injury. While they are not limited to occurrence within the vacuoles in the cytoplasm of the odontoblasts, the relationship of the granules to the vacuoles suggests that the vacuoles are also a part of the physiologic activity of the adult odontoblasts.


Sporadic inclusion-body myositis: conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau.
The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated.


An Alu retrotransposition-mediated deletion of CHD7 in a patient with CHARGE syndrome.
CHD7 mutations account for about 60-65% among more than 200 CHARGE syndrome cases. When rare whole gene deletion cases associated with chromosomal abnormalities are excluded, all mutations of CHD7 reported to date have been point mutations and small deletions and insertions, rather than exonic deletions. To test whether exonic deletions represent a common pathogenic mechanism, we assessed exon copy number by using a recently developed method, the multiplex PCR/liquid chromatography assay (MP/LC). Multiple exons were amplified using unlabeled primers, then separated by ion-pair reversed-phase high-performance liquid chromatography, and quantitated by fluorescence detection using a post-column intercalation dye under the premise that the relative peak intensities for each target directly reflect exon copy number. By using MP/LC, we identified one CHARGE syndrome patient who had a de novo deletion encompassing exons 8-12 among 13 classic CHARGE patients in whom screening by denaturing high-performance liquid chromatography (DHPLC) failed to identify point mutations and small insertions/deletions in CHD7. This is the first CHARGE patient who was documented to have exonic deletion of CHD7. The deletion closely recapitulated the Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene (CMP-Neu5Ac hydroxylase), which is regarded as a novel molecular mechanism in the evolution from non-human primates to humans. As demonstrated in this study, MP/LC is a promising method for characterizing exonic deletions, which are largely left unexamined in most routine mutation analysis.


Subclinical thyroid disease in the elderly.
The development of sensitive assays for thyrotropin (TSH) has led to the discovery that many older patients have abnormal TSH levels without other alterations in serum thyroid hormone levels, conditions termed subclinical hypothyroidism (isolated elevation of TSH levels) and subclinical hyperthyroidism (isolated suppression of TSH levels). Subclinical hypothyroidism occurs in 5% to 10% of elderly subjects, and is especially prevalent in elderly women. Subclinical hyperthyroidism is less common, affecting less than 2% of the elderly population. The causes of subclinical thyroid disease in the elderly are similar to those of thyroid disease in the general population, although medications and iodine-containing compounds may play an increased role. Potential risks of subclinical hypothyroidism in the elderly include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neurological and neuropsychiatric effects. Potential risks of subclinical hyperthyroidism in the elderly include progression to overt hyperthyroidism, cardiovascular effects (especially atrial fibrillation), and osteoporosis. Decisions to treat elderly subjects with subclinical thyroid disease should be based on a careful assessment of these risks in the individual patient.


Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.


[Villous adenoma of the rectum. Review of the literature and personal experience].
Potential malignancy of rectal villous adenomas is referred as varying from 20 to 30%; an appropriate surgical excision is required in order to insure an effective cancer prophylaxis and to improve the accuracy of the pathologic assessment. The Authors review their series concerning 15 patients with one or more polyps of villous type, located at the lower third of the rectum and with precise indications for transanal excision. In 13 cases histology demonstrated the presence of an adenoma with different grade of dysplasia, which simply entered a follow-up together with a case of an adenoma with carcinoma in situ. The latter, because of the presence of invasive carcinoma, underwent radical surgery. No postoperative morbidity was observed. Recurrence rate was 8%. After an accurate review of the Literature, a radical management of the rectal villous tumour performed on routine basis seems unjustified. The Authors suggest the indication for a modern proceeding.


Lab experiments for the study of social-ecological systems.
Governance of social-ecological systems is a major policy problem of the contemporary era. Field studies of fisheries, forests, and pastoral and water resources have identified many variables that influence the outcomes of governance efforts. We introduce an experimental environment that involves spatial and temporal resource dynamics in order to capture these two critical variables identified in field research. Previous behavioral experiments of commons dilemmas have found that people are willing to engage in costly punishment, frequently generating increases in gross benefits, contrary to game-theoretical predictions based on a static pay-off function. Results in our experimental environment find that costly punishment is again used but lacks a gross positive effect on resource harvesting unless combined with communication. These findings illustrate the importance of careful generalization from the laboratory to the world of policy.


[How do the cost bias and probability bias influence social anxiety symptoms?].
The cost and probability bias in social situations are considered to be a maintaining factor for social anxiety disorder (SAD) symptoms. However, the process by which the cost and probability bias influences other SAD symptoms, such as avoidance behavior, self-perception of autonomic responses, and anxiety in social situations has not been investigated. We developed a model of the cost and probability bias and investigated the process through which the cost and probability bias influences SAD symptoms. Undergraduate students (N=290) were administered self-report measures assessing each component of SAD symptoms. A path analysis was conducted using the cost and probability bias model, which indicated high validity for the model (goodness of fit index = .99, adjusted goodness of fit index = .92, root mean square error of approximation = .09). The results also indicated that the cost bias had a strong effect on each component of SAD symptoms, and that the probability bias mediated the relationship between fear of negative evaluation and the cost bias. These findings suggest that changing the cost and probability bias may improve SAD symptoms.


Association between neutrophil-lymphocyte & platelet lymphocyte ratios with prognosis & mortality in rapidly progressive glomerulonephritis.
Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome manifested by features of nephritic syndrome and progressive loss of renal function over a short time. The objective of this study was to investigate the relationship between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and prognostic factors and pathological findings of renal biopsy in RPGN. Consecutive newly diagnosed RPGN patients who had follow up for at least six months were retrospectively analyzed. The estimated glomerular filtration rate (eGFR) was calculated. Albumin, C-reactive protein (CRP) levels and CRP/albumin ratio were also calculated. Fifty four patients were included in the study. The mean age was 48.92±20.12 years. Clinicopathological diagnosis was pauci-immune glomerulonephritis (GN) in 40 while two had postinfectious GN, six systemic lupus erythematosus, three IgA nephropathy, two Henoch-Schönlein purpura and one membranoproliferative GN. The mean NLR was 7.02±6.34 and mean PLR was 273.90±39.15. Positive correlations between NLR and CRP levels (P=0.009, r=0.511) and CRP/albumin ratios (P=0.005, r=0.542) were observed. PLR and CRP/albumin ratios (P=0.041, r=0.412) were correlated positively. The per cent of fibrocellular crescents was negatively correlated with NLR (P=0.019, r=-0.291), and positively correlated with the lymphocyte count (P=0.05, r=0.256). In secondary crescentic subgroup, the per cent of fibrinoid necrosis had a positive correlation with PLR (P=0.013, r=0.642). Both NLR (P=0.036) and PLR (P=0.051) detected at the first month of the treatment period, were observed to be significantly correlated with mortality. This study showed that NLR could predict mortality in patients with RPGN; correlated with systemic inflammation; showed a negative correlation with the per cent of fibrocellular crescents and could be regarded as a measure of glomerular inflammatory state. Moreover, PLR may be considered to be an indicator of disease severity in acute phase of crescentic GN.


The Role of Bacteria and Its Derived Metabolites in Chronic Pain and Depression: Recent Findings and Research Progress.
Chronic pain is frequently comorbid with depression in clinical practice. Recently, alterations in gut microbiota and metabolites derived therefrom have been found to potentially contribute to abnormal behaviors and cognitive dysfunction via the "microbiota-gut-brain" axis. PubMed was searched and we selected relevant studies before October 1, 2019. The search keyword string included "pain OR chronic pain" AND "gut microbiota OR metabolites"; "depression OR depressive disorder" AND "gut microbiota OR metabolites". We also searched the reference lists of key articles manually. This review systematically summarized the recent evidence of gut microbiota and metabolites in chronic pain and depression in animal and human studies. The results showed the pathogenesis and therapeutics of chronic pain and depression might be partially due to gut microbiota dysbiosis. Importantly, bacteria-derived metabolites, including short-chain fatty acids, tryptophan-derived metabolites, and secondary bile acids, offer new insights into the potential linkage between key triggers in gut microbiota and potential mechanisms of depression. Studying gut microbiota and its metabolites has contributed to the understanding of comorbidity of chronic pain and depression. Consequently, modulating dietary structures or supplementation of specific bacteria may be an available strategy for treating chronic pain and depression.


Characterization of the Kv1.1 I262T and S342I mutations associated with episodic ataxia 1 with distinct phenotypes.
Episodic ataxia type 1 (EA-1) is an autosomal dominant neurological disorder caused by mutations in the potassium channel Kv1.1. Two EA-1 mutations, I262T and S342I, have been identified with unique clinical phenotypes, but their functional and biochemical properties have not been fully investigated. Here we characterized these two mutations in transfected mammalian cells both electrophysiologically and biochemically. We found that the I262T mutation resulted in a ∼7-fold reduction in the K+ current amplitude compared with wild type channels, whereas the S342I mutation produced an apparent nonfunctional channel when expressed alone. Co-expression of wild type and mutant channels showed that both I262T and S342I exerted dominant-negative effects on wild type function. The protein expression analysis showed that I262T resulted in ∼2-fold decrease in surface protein levels of Kv1.1, which partially contributed to the decreased surface conductance density, whereas the S342I mutation showed no effects on surface protein expression. Conservative amino acid substitution experiments suggest that the wild type amino acids at these two positions are required for normal channel function. Our results broaden the knowledge of EA-1 mutations and the underlying mechanisms of the associated disorder.


Self-Administered Computer Therapy for Apraxia of Speech: Two-Period Randomized Control Trial With Crossover.
There is currently little evidence on effective interventions for poststroke apraxia of speech. We report outcomes of a trial of self-administered computer therapy for apraxia of speech. Effects of speech intervention on naming and repetition of treated and untreated words were compared with those of a visuospatial sham program. The study used a parallel-group, 2-period, crossover design, with participants receiving 2 interventions. Fifty participants with chronic and stable apraxia of speech were randomly allocated to 1 of 2 order conditions: speech-first condition versus sham-first condition. Period 1 design was equivalent to a randomized controlled trial. We report results for this period and profile the effect of the period 2 crossover. Period 1 results revealed significant improvement in naming and repetition only in the speech-first group. The sham-first group displayed improvement in speech production after speech intervention in period 2. Significant improvement of treated words was found in both naming and repetition, with little generalization to structurally similar and dissimilar untreated words. Speech gains were largely maintained after withdrawal of intervention. There was a significant relationship between treatment dose and response. However, average self-administered dose was modest for both groups. Future software design would benefit from incorporation of social and gaming components to boost motivation. Single-word production can be improved in chronic apraxia of speech with behavioral intervention. Self-administered computerized therapy is a promising method for delivering high-intensity speech/language rehabilitation. URL: http://orcid.org/0000-0002-1278-0601. Unique identifier: ISRCTN88245643.


Recreating an aesthetic smile: multidisciplinary and metal-free approach using CAD/CAM technology.
The aesthetic rehabilitation of patients with functionally compromised dentition frequently involves a multidisciplinary approach. A correct aesthetic diagnosis, treatment plan, and careful material selection are critical factors in successful restoration. A team approach that includes the clinicians, the laboratory technician, and the patient is essential to achieve the desired result. The following case presentation demonstrates a successful multidisciplinary approach used to recreate an aesthetic smile in a young patient with functionally and aesthetically compromised anterior maxillary dentition.


Can Genetic Testing Identify Talent for Sport?
Elite athlete status is a partially heritable trait, as are many of the underpinning physiological, anthropometrical, and psychological traits that contribute to elite performance. In recent years, our understanding of the specific genetic variants that contribute to these traits has grown, such that there is considerable interest in attempting to utilise genetic information as a tool to predict future elite athlete status. In this review, we explore the extent of the genetic influence on the making of a sporting champion and we describe issues which, at present, hamper the utility of genetic testing in identifying future elite performers. We build on this by exploring what further knowledge is required to enhance this process, including a reflection on the potential learnings from the use of genetics as a disease prediction tool. Finally, we discuss ways in which genetic information may hold utility within elite sport in the future, including guiding nutritional and training recommendations, and assisting in the prevention of injury. Whilst genetic testing has the potential to assist in the identification of future talented performers, genetic tests should be combined with other tools to obtain an accurate identification of those athletes predisposed to succeed in sport. The use of total genotype scores, composed of a high number of performance-enhancing polymorphisms, will likely be one of the best strategies in the utilisation of genetic information to identify talent in sport.


Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis.
A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data. We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86-1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81-1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41-0.88). Substantial statistical heterogeneity was evident for the case-control studies (I(2)=66%, P=0.01), but not for the cohort studies (I(2)=0%, P=0.48) or randomized trials (I(2)=30%, P=0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results. We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.


Virulence properties of Escherichia coli faecal strains isolated in Poland from healthy children and strains belonging to serogroups O18, O26, O44, O86, O126 and O127 isolated from children with diarrhoea.
Four hundred and twenty-seven Escherichia coli isolates from 427 cases of infantile diarrhoea in Poland, belonging to serogroups O18, O26, O44, O86, O126 and O127 and 150 E. coli isolates from 52 healthy children were examined for selected virulence properties. The presence of the plasmid pAA, a plasmid encoding enterohaemolysin, the genes encoding intimin (eae), bundle-forming pili (bfp), Shiga toxins I and II (stxI, stxII) and cytotoxic necrotising factor types 1 and 2 (cnfl, cnf2) was investigated by PCR. Adhesion to HEp-2 cell monolayers was also tested and selected strains were investigated for the presence of P-fimbriae and haemolytic activity. Typical enteropathogenic E. coli isolates (typical EPEC, strains possessing eae and bfp, but not stx) were not found. The particular classes of E. coli among 427 isolates from ill children were: atypical EPEC (eae+ bfp, stx-), 21.3%; Shiga toxin-producing E. coli (STEC), 0.7%; diffusely adherent E. coli (DAEC), 4%; enteroaggregative E. coli (EAEC), 16.9%; necrotoxic E. coli type 1 (NTEC1), 0.2%; and cell-detaching E. coli (CDEC), 29%. With the exception of STEC, all the above classes of E. coli were found among the isolates from healthy children which comprised: atypical EPEC 8.0%, DAEC 6.7%, EAEC 17.3%, NTEC1 14.0% and CDEC 40.0%. Cell detachment (CD) was significantly associated with 3-h haemolytic activity. There was also strong correlation between haemolytic activity (Hly) and the presence of P-fimbriae. No correlation was found between the presence of the cnf1 gene and CD, Hly or P-fimbriae.


Why is a landscape perspective important in studies of primates?
With accelerated deforestation and fragmentation through the tropics, assessing the impact that landscape spatial changes may have on biodiversity is paramount, as this information is required to design and implement effective management and conservation plans. Primates are expected to be particularly dependent on the landscape context; yet, our understanding on this topic is limited as the majority of primate studies are at the local scale, meaning that landscape-scale inferences are not possible. To encourage primatologists to assess the impact of landscape changes on primates, and help future studies on the topic, we describe the meaning of a "landscape perspective" and evaluate important assumptions of using such a methodological approach. We also summarize a number of important, but unanswered, questions that can be addressed using a landscape-scale study design. For example, it is still unclear if habitat loss has larger consistent negative effects on primates than habitat fragmentation per se. Furthermore, interaction effects between habitat area and other landscape effects (e.g., fragmentation) are unknown for primates. We also do not know if primates are affected by synergistic interactions among factors at the landscape scale (e.g., habitat loss and diseases, habitat loss and climate change, hunting, and land-use change), or whether landscape complexity (or landscape heterogeneity) is important for primate conservation. Testing for patterns in the responses of primates to landscape change will facilitate the development of new guidelines and principles for improving primate conservation.


Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.
Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase.


Cigarette graphic warning labels and smoking prevalence in Canada: a critical examination and reformulation of the FDA regulatory impact analysis.
The estimated effect of cigarette graphic warning labels (GWL) on smoking rates is a key input to the Food and Drug Administration's (FDA) regulatory impact analysis (RIA), required by law as part of its rule-making process. However, evidence on the impact of GWLs on smoking prevalence is scarce. The goal of this paper is to critically analyse FDA's approach to estimating the impact of GWLs on smoking rates in its RIA, and to suggest a path forward to estimating the impact of the adoption of GWLs in Canada on Canadian national adult smoking prevalence. A quasi-experimental methodology was employed to examine the impact of adoption of GWLs in Canada in 2000, using the USA as a control. We found a statistically significant reduction in smoking rates after the adoption of GWLs in Canada in comparison with the USA. Our analyses show that implementation of GWLs in Canada reduced smoking rates by 2.87-4.68 percentage points, a relative reduction of 12.1-19.6%; 33-53 times larger than FDA's estimates of a 0.088 percentage point reduction. We also demonstrated that FDA's estimate of the impact was flawed because it is highly sensitive to the changes in variable selection, model specification, and the time period analysed. Adopting GWLs on cigarette packages reduces smoking prevalence. Applying our analysis of the Canadian GWLs, we estimate that if the USA had adopted GWLs in 2012, the number of adult smokers in the USA would have decreased by 5.3-8.6 million in 2013. Our analysis demonstrates that FDA's approach to estimating the impact of GWLs on smoking rates is flawed. Rectifying these problems before this approach becomes the norm is critical for FDA's effective regulation of tobacco products.


The vaccinia virus superoxide dismutase-like protein (A45R) is a virion component that is nonessential for virus replication.
A characterization of the A45R gene from vaccinia virus (VV) strain Western Reserve is presented. The open reading frame is predicted to encode a 125-amino-acid protein (M(r), of 13,600) with 39% amino acid identity to copper-zinc superoxide dismutase (Cu-Zn SOD). Sequencing of the A45R gene from other orthopoxviruses, here and by others, showed that the protein is highly conserved in all viruses sequenced, including 16 strains of VV, 2 strains of cowpox virus, camelpox virus, and 4 strains of variola virus. In all cases the protein lacks key residues involved in metal ion binding that are important for the catalytic activity. The A45R protein was expressed in Escherichia coli, purified, and tested for SOD activity, but neither enzymatic nor inhibitory SOD activity was detected. Additionally, no virus-encoded SOD activity was detected in infected cells or purified virions. A monoclonal antibody raised against the A45R protein expressed in E. coli identified the A45R gene product as a 13.5-kDa protein that is expressed late during VV infection. Confocal microscopy of VV-infected cells indicated that the A45R protein accumulated predominantly in cytoplasmic viral factories. Electron microscopy and biochemical analyses showed that the A45R protein is incorporated into the virion core. A deletion mutant lacking the majority of the A45R gene and a revertant virus in which the deleted gene was restored were constructed and characterized. The growth properties of the deletion mutant virus were indistinguishable from those of wild-type and revertant viruses in all cell lines tested, including macrophages. Additionally, the virulence and pathogenicity of the three viruses were also comparable in murine and rabbit models of infection. A45R is unusual in being the first VV core protein described that affects neither virus replication nor virulence.


Primary care provider utilization and satisfaction with a health system navigation program for adolescents with behavioral health needs.
Approximately 49.5% of the adolescents report a mental health disorder; only about half of the children and adolescents with mental health disorders seek treatment from a mental health professional. Stigma and poor access to behavioral health providers are leading barriers to care. A large ambulatory health system implemented a BH navigation program to facilitate referrals from primary care physicians (PCPs), including pediatricians and family physicians, to BH providers. We studied PCP adoption of BH navigation services over a 4-year period, from July 2014 to June 2018. We retrieved operational data regarding service utilization, patient information from electronic health records and PCP information from administrative data, and surveyed PCPs for their appraisals of navigation services. Four thousand five hundred and fifty-five referrals were made for 3,912 patients from 290 PCPs (71% of PCPs in the health system). Depression (39%), anxiety (25%), and attention-deficit hyperactivity disorder (7%) were the most frequent reasons for referral. Referrals increased dramatically in the first half of the study period and decreased afterwards. Ninety-one percent of the PCPs agreed or strongly agreed that navigation enhanced their clinical care at 12-month survey. More than 90% of the PCPs rated the referral process, communication with navigation staff, and the overall experience as above average or excellent at 12 months. There was a decrease in these evaluation indicators after 2.5 years. The initial high referral volume reflects a need for BH navigation services. However, challenges remain to maintain positive PCP assessment in the face of such demand.


Acute hemodynamic changes following high load and very low load lower body resistance exercise with and without the restriction of blood flow.
To examine the acute changes in blood flow and blood pressure of very low load knee extensor exercise (15% one repetition maximum (1RM)) with and without different levels of applied pressure to determine how these effects might differ from high load exercise. We also sought to examine if this differed between men and women. A total of 90 participants (45 men, 45 women) were randomized into a very low load condition with no restriction 15/0, (n = 21), a very low load condition with 40% arterial occlusion pressure (15/40, n = 23), a very low load condition with 80% arterial occlusion pressure (15/80, n = 22), and a traditional high load condition (70/0, n = 24). Pre-post change in blood flow and blood pressure were compared across conditions. Evidence for or against the null hypothesis was quantified using Bayes factors (BF10). For blood flow, there was no evidence that the changes were different across conditions (BF10: 0.902). However, only the very low load free flow condition (15/0) had evidence to suggest a change (mean, (standard deviation)) from baseline (5.3 (9.1) ml · min-1; BF10: 3.687). Systolic pressure increased ~17 mmHg for the 15/0, 15/40, and 70/0 conditions, with no change in the 15/80 condition. There was no effect of sex for any variable. There was substantial variability in our blood flow measurements, making conclusions difficult for this variable. Of note, the blood pressure response was not augmented by blood flow restriction. The hemodynamic changes were also similar between sexes, indicating that men and women were not changing differently.