Vulvar pythiosis in two captive camels (Camelus dromedarius).
Two camels (Camelus dromedarius), 3- and 4-years-old, respectively, from an eastern Tennessee wildlife farm presented with persistent weight loss and large vulvar masses. An initial biopsy of the vulvar mass of one of the camels performed by a local veterinarian showed eosinophilic dermatitis. An allergic or parasitic dermatitis was suspected. The two camels were treated with one dose of sodium iodide (66 mg/kg, in 1.0 L of normosolR, IV) and ivermectin 1% (200 ug/kg PO). Upon presentation at the Veterinary Teaching Hospital, University of Tennessee, additional biopsies of the masses again revealed eosinophilic dermatitis. Microscopic examination of a Gomori methenamine silver (GMS)-stained section prepared from the biopsy of one of the camels revealed the presence of fungal-like hyphae of a mold which was suspected to be Pythium insidiosum. The vulvar masses were surgically debulked in both animals and sodium iodide and Pythium-immunotherapy prescribed. Pythium insidiosum was isolated in culture and hyphae elements were detected in histological sections confirming the diagnosis of pythiosis in both animals. Despite signs of progressive healing of the vulvar surgical areas, postoperative persistent weight lost in one of the camels suggested the possibility of gastro intestinal (GI) tract pythiosis. This camel died 5 months after the first onset of clinical signs and unfortunately a necropsy was not performed. The other camel responded well to the combination of surgery, iodides, and immunotherapy and has currently rejoined the other members of the herd.


CLEASE: a versatile and user-friendly implementation of cluster expansion method.
Materials exhibiting a substitutional disorder such as multicomponent alloys and mixed metal oxides/oxyfluorides are of great importance in many scientific and technological sectors. Disordered materials constitute an overwhelmingly large configurational space, which makes it practically impossible to be explored manually using first-principles calculations such as density functional theory due to the high computational costs. Consequently, the use of methods such as cluster expansion (CE) is vital in enhancing our understanding of the disordered materials. CE dramatically reduces the computational cost by mapping the first-principles calculation results on to a Hamiltonian which is much faster to evaluate. In this work, we present our implementation of the CE method, which is integrated as a part of the atomic simulation environment (ASE) open-source package. The versatile and user-friendly code automates the complex set up and construction procedure of CE while giving the users the flexibility to tweak the settings and to import their own structures and previous calculation results. Recent advancements such as regularization techniques from machine learning are implemented in the developed code. The code allows the users to construct CE on any bulk lattice structure, which makes it useful for a wide range of applications involving complex materials. We demonstrate the capabilities of our implementation by analyzing the two example materials with varying complexities: a binary metal alloy and a disordered lithium chromium oxyfluoride.


REPEATABILITY AND LONGITUDINAL ASSESSMENT OF FOVEAL CONE STRUCTURE IN CNGB3-ASSOCIATED ACHROMATOPSIA.
Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia. Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed. ONL thickness increased slightly compared with baseline (0.184 μm/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126). Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6-26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.


Systematic approach to understanding macrolide-ribosome interactions: NMR and modeling studies of oleandomycin and its derivatives.
The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.


Identification of depression in an inner-city population using a simple screen.
The purpose of this study was to compare a brief screening tool with physicians' usual practice in detecting depressive symptoms in patients presenting with somatic complaints to an inner-city emergency department. Depression is a major cause of morbidity and mortality in the United States. Underprivileged patients who rely on emergency departments for primary care remain at risk for undetected depression. This prospective observational study included all patients older than 18 years presenting to an urgent care clinic staffed by emergency physicians in an urban public hospital during an eight-week period. Clinically unstable patients and those with a chief complaint of depression were excluded. After consenting, patients completed a previously validated two-question screening tool for depression. Patients identified as having depressive symptoms were referred to social workers for evaluation for possible psychiatric intervention. Of the 226 patients enrolled, 55% (124/226; 95% confidence interval [CI] = 48% to 61%) screened positive for depressive symptoms. Physicians identified 14% (31/226; 95% CI = 10% to 19%) as having depressive symptoms. The kappa value was 0.22 (95% CI = 0.14 to 0.29). All patients but one identified as positive by the physicians screened positive on the screening tool. Patients who screened positive were referred to social workers. The physicians failed to identify 19 of the patients who needed further psychiatric care. Depressive symptoms are common among patients in urgent care settings with somatic complaints. A simple screening tool identified more patients for further evaluation than does physicians' usual practice.


The co-occurrence of reading disorder and ADHD: epidemiology, treatment, psychosocial impact, and economic burden.
The co-occurrence of reading disorder (RD) and attention-deficit/hyperactivity disorder (ADHD) has received increasing attention. This review summarizes the epidemiology, treatment strategies, psychosocial impact, and economic burden associated with the co-occurrence of these conditions. Common genetic and neuropsychological deficits may partially explain the high degree of overlap between RD and ADHD. Children who face the additive problems of both disorders are at greater risk for academic failure, psychosocial consequences, and poor long-term outcomes that persist into adulthood. However, few studies have evaluated interventions targeted to this patient population, underscoring the importance of identifying effective multimodal treatments that address the neuropsychological deficits of RD and ADHD through carefully planned clinical research.


IMI 2021 Reports and Digest - Reflections on the Implications for Clinical Practice.
The International Myopia Institute's (IMI) mission is to advance research, education, and management of myopia to decrease future vision impairment and blindness associated with increasing myopia. Its approach is to bring together scientists, clinicians, policymakers, government members, and educators into the field of myopia to stimulate collaboration and sharing of knowledge. The latest reports are on pathologic myopia, the impact of myopia, risk factors for myopia, accommodation and binocular vision in myopia development and progression, and the prevention of myopia and its progression. Together with the digest updating the 2019 International Myopia Institute white papers using the research published in the last 18 months, these evidence-based consensus white papers help to clarify the imperative for myopia control and the role of environmental modification initiatives, informing an evidence-based clinical approach. This guidance includes who to treat and when to start or stop treatment, and the advantages and limitations of different management approaches.


Non-Small Cell Lung Cancer, Version 6.2015.
These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.


Outcomes and Factors Associated With Reduced Symptoms in Patients With Gastroparesis.
Gastroparesis is a chronic clinical syndrome characterized by delayed gastric emptying. However, little is known about patient outcomes or factors associated with reduction of symptoms. We studied adult patients with gastroparesis (of diabetic or idiopathic type) enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Gastroparesis Registry, seen every 16 weeks and treated according to the standard of care with prescribed medications or other therapies at 7 tertiary care centers. Characteristics associated with reduced symptoms, based on a decrease of 1 or more in the gastroparesis cardinal symptom index (GCSI) score after 48 weeks of care, were determined from logistic regression models. Data were collected from patients for up to 4 years (median, 2.1 y). Of 262 patients, 28% had reductions in GCSI scores of 1 or more at 48 weeks. However, there were no significant reductions in GCSI score from weeks 48 through 192. Factors independently associated with reduced symptoms at 48 weeks included male sex, age 50 years and older, initial infectious prodrome, antidepressant use, and 4-hour gastric retention greater than 20%. Factors associated with no reduction in symptoms included overweight or obesity, a history of smoking, use of pain modulators, moderate to severe abdominal pain, a severe gastroesophageal reflex, and moderate to severe depression. Over a median follow-up period of 2.1 years, 28% of patients treated for gastroparesis at centers of expertise had reductions in GCSI scores of 1 or greater, regardless of diabetes. These findings indicate the chronic nature of gastroparesis. We identified factors associated with reduced symptoms that might be used to guide treatment. ClinicalTrials.gov no: NCT00398801.


Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives.
The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.


Comparison of 30-day mortality models for profiling hospital performance in acute ischemic stroke with vs without adjustment for stroke severity.
There is increasing interest in reporting risk-standardized outcomes for Medicare beneficiaries hospitalized with acute ischemic stroke, but whether it is necessary to include adjustment for initial stroke severity has not been well studied. To evaluate the degree to which hospital outcome ratings and potential eligibility for financial incentives are altered after including initial stroke severity in a claims-based risk model for hospital 30-day mortality for acute ischemic stroke. Data were analyzed from 782 Get With The Guidelines-Stroke participating hospitals on 127,950 fee-for-service Medicare beneficiaries with ischemic stroke who had a score documented for the National Institutes of Health Stroke Scale (NIHSS, a 15-item neurological examination scale with scores from 0 to 42, with higher scores indicating more severe stroke) between April 2003 and December 2009. Performance of claims-based hospital mortality risk models with and without inclusion of NIHSS scores for 30-day mortality was evaluated and hospital rankings from both models were compared. Model discrimination, hospital 30-day mortality outcome rankings, and value-based purchasing financial incentive categories. Across the study population, the mean (SD) NIHSS score was 8.23 (8.11) (median, 5; interquartile range, 2-12). There were 18,186 deaths (14.5%) within the first 30 days, including 7430 deaths (5.8%) during the index hospitalization. The hospital mortality model with NIHSS scores had significantly better discrimination than the model without (C statistic, 0.864; 95% CI, 0.861-0.867, vs 0.772; 95% CI, 0.769-0.776; P < .001). Among hospitals ranked in the top 20% or bottom 20% of performers by the claims model without NIHSS scores, 26.3% were ranked differently by the model with NIHSS scores. Of hospitals initially classified as having "worse than expected" mortality, 57.7% were reclassified to "as expected" by the model with NIHSS scores. The net reclassification improvement (93.1%; 95% CI, 91.6%-94.6%; P < .001) and integrated discrimination improvement (15.0%; 95% CI, 14.6%-15.3%; P < .001) indexes both demonstrated significant enhancement of model performance after the addition of NIHSS. Explained variance and model calibration was also improved with the addition of NIHSS scores. Adding stroke severity as measured by the NIHSS to a hospital 30-day risk model based on claims data for Medicare beneficiaries with acute ischemic stroke was associated with considerably improved model discrimination and change in mortality performance rankings for a substantial portion of hospitals.


Sex chromosome mosaicism and hybrid speciation among tiger swallowtail butterflies.
Hybrid speciation, or the formation of a daughter species due to interbreeding between two parental species, is a potentially important means of diversification, because it generates new forms from existing variation. However, factors responsible for the origin and maintenance of hybrid species are largely unknown. Here we show that the North American butterfly Papilio appalachiensis is a hybrid species, with genomic admixture from Papilio glaucus and Papilio canadensis. Papilio appalachiensis has a mosaic phenotype, which is hypothesized to be the result of combining sex-linked traits from P. glaucus and P. canadensis. We show that P. appalachiensis' Z-linked genes associated with a cooler thermal habitat were inherited from P. canadensis, whereas its W-linked mimicry and mitochondrial DNA were inherited from P. glaucus. Furthermore, genome-wide AFLP markers showed nearly equal contributions from each parental species in the origin of P. appalachiensis, indicating that it formed from a burst of hybridization between the parental species, with little subsequent backcrossing. However, analyses of genetic differentiation, clustering, and polymorphism based on molecular data also showed that P. appalachiensis is genetically distinct from both parental species. Population genetic simulations revealed P. appalachiensis to be much younger than the parental species, with unidirectional gene flow from P. glaucus and P. canadensis into P. appalachiensis. Finally, phylogenetic analyses, combined with ancestral state reconstruction, showed that the two traits that define P. appalachiensis' mosaic phenotype, obligatory pupal diapause and mimicry, evolved uniquely in P. canadensis and P. glaucus, respectively, and were then recombined through hybridization to form P. appalachiensis. These results suggest that natural selection and sex-linked traits may have played an important role in the origin and maintenance of P. appalachiensis as a hybrid species. In particular, ecological barriers associated with a steep thermal cline appear to maintain the distinct, mosaic genome of P. appalachiensis despite contact and occasional hybridization with both parental species.


Rapeseed Stand Count Estimation at Leaf Development Stages With UAV Imagery and Convolutional Neural Networks.
Rapeseed is an important oil crop in China. Timely estimation of rapeseed stand count at early growth stages provides useful information for precision fertilization, irrigation, and yield prediction. Based on the nature of rapeseed, the number of tillering leaves is strongly related to its growth stages. However, no field study has been reported on estimating rapeseed stand count by the number of leaves recognized with convolutional neural networks (CNNs) in unmanned aerial vehicle (UAV) imagery. The objectives of this study were to provide a case for rapeseed stand counting with reference to the existing knowledge of the number of leaves per plant and to determine the optimal timing for counting after rapeseed emergence at leaf development stages with one to seven leaves. A CNN model was developed to recognize leaves in UAV-based imagery, and rapeseed stand count was estimated with the number of recognized leaves. The performance of leaf detection was compared using sample sizes of 16, 24, 32, 40, and 48 pixels. Leaf overcounting occurred when a leaf was much bigger than others as this bigger leaf was recognized as several smaller leaves. Results showed CNN-based leaf count achieved the best performance at the four- to six-leaf stage with F-scores greater than 90% after calibration with overcounting rate. On average, 806 out of 812 plants were correctly estimated on 53 days after planting (DAP) at the four- to six-leaf stage, which was considered as the optimal observation timing. For the 32-pixel patch size, root mean square error (RMSE) was 9 plants with relative RMSE (rRMSE) of 2.22% on 53 DAP, while the mean RMSE was 12 with mean rRMSE of 2.89% for all patch sizes. A sample size of 32 pixels was suggested to be optimal accounting for balancing performance and efficiency. The results of this study confirmed that it was feasible to estimate rapeseed stand count in field automatically, rapidly, and accurately. This study provided a special perspective in phenotyping and cultivation management for estimating seedling count for crops that have recognizable leaves at their early growth stage, such as soybean and potato.


Cardiac evaluation of the patient with stroke.
Coronary artery disease and ischemic cerebrovascular disease are leading causes of morbidity and mortality in the United States. Coronary artery disease often coexists with asymptomatic carotid artery atherosclerosis, transient ischemic attacks, or ischemic stroke. Numerous studies have shown that mortality from all forms of ischemic cerebrovascular disease is primarily due to coronary artery disease. Thus, there is increasing interest in identifying coronary artery disease in patients with cerebrovascular disease, including those without clinical manifestations of heart disease. We review the use of current noninvasive techniques to detect coronary artery disease and present practical approaches to screen for ischemic heart disease. Current diagnostic imaging methods for potential cardioembolic sources of cerebral infarction are also discussed.


Association study of lipoprotein(a) genetic markers, traditional risk factors, and coronary heart disease in HIV-1-infected patients.
General population studies have shown associations between copy number variation (CNV) of the LPA gene Kringle-IV type-2 (KIV-2) coding region, single-nucleotide polymorphism (SNP) rs6415084 in LPA and coronary heart disease (CHD). Because risk factors for HIV-infected patients may differ from the general population, we aimed to assess whether these potential associations also occur in HIV-infected patients. A unicenter, retrospective, case-control (1:3) study. Eighteen HIV-patients with confirmed diagnosis of acute myocardial infarction (AMI) were adjusted for age, gender, and time since HIV diagnosis to 54 HIV-patients without CHD. After gDNA extraction from frozen blood, both CNV and SNP genotyping were performed using real-time quantitative PCR. All genetic and non-genetic variables for AMI were assessed in a logistic regression analysis. Our results did not confirm any association in terms of lipoprotein(a) LPA structural genetic variants when comparing KIV-2 CNV (p = 0.67) and SNP genotypes (p = 0.44) between AMI cases and controls. However, traditional risk factors such as diabetes mellitus, hypertension, and CD4(+) T cell count showed association (p < 0.05) with CHD. Although significant associations of AMI with diabetes, hypertension and CD4(+) T cell count in HIV-patients were found, this study could not confirm the feasibility neither of KIV-2 CNV nor rs6415084 in LPA as genetic markers of CHD in HIV-infected patients. ● Individuals with HIV infection are at higher risk of coronary heart disease (CHD) than the non-infected population.● Our results showed no evidence of LPA structural genetic variants associated with CHD in HIV-1-infected patients.● Associations were found between diabetes mellitus, arterial hypertension, CD4(+) T cell count, and CHD.● The clinical usefulness of these biomarkers to predict CHD in HIV-1-infected population remains unproven.● Further studies are needed to assess the contribution of common genetic variations to CHD in HIV-infected individuals.


Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.
The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.


The effect of diabetes on neuropeptide content in the rat cornea and iris.
To determine the effect of diabetes mellitus on the levels of substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP) in the rat cornea and iris. Corneas and irides from control and diabetic rats were processed for neuropeptide radioimmunoassay 3 months after induction of diabetes with streptozotocin. Corneas and irides also were processed for SP and CGRP immunohistochemistry and were evaluated qualitatively. The radioimmunoassay data revealed no significant differences in either the content or concentration of SP, CGRP, and VIP between control and diabetic corneas. In contrast, iridial levels of CGRP and SP were significantly increased by 38% and 256%, respectively, in the diabetic animals. Iridial VIP levels were unchanged in the diabetic versus control groups. Immunohistochemical demonstrations of corneal and iridial SP- and CGRP-immunoreactive fiber plexuses were indistinguishable on the basis of purely qualitative criteria. The results of this study have demonstrated a target- and peptide-specific effect of short-term diabetes on SP and CGRP expression in ocular nerves of the anterior eye segment. The absence of demonstrable changes in corneal neuropeptide levels argue against the theory that corneal abnormalities seen in clinical diabetes are caused, in part, by deficits in synthesis or axonal transport of "trophic" peptides in corneal sensory nerves. In contrast, elevated iridial SP and CGRP levels may be responsible for reported clinical deficits in pupillary diameter regulation.


Women's employment status and mortality: the atherosclerosis risk in communities study.
As women's labor force participation in the United States has increased over the past decades, there has been an interest in the potential health effects of employment. To date, however, research findings have been contradictory. Thus, the aim of this study was to investigate the association between employment status and mortality among 7361 middle-aged African American and white women who participated in the Atherosclerosis Risk in Communities (ARIC) Study. Women were classified as employed or homemakers at the baseline examination (1987-1989) and were followed for approximately 11 years. Proportional hazards regression was used to estimate unadjusted and adjusted hazard ratios. After adjusting for sociodemographic factors and selected risk factors for mortality, employed women had a lower risk of mortality than homemakers (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.49, 0.86). This decreased risk of mortality persisted in additional analyses that excluded those who died within the first 2 years of follow-up or, alternatively, those with a history of coronary heart disease (CHD), stroke, cancer, hypertension, diabetes, or a perception of fair or poor health at baseline. In cause of death-specific analyses, the mortality advantage among employed women persisted for circulatory system-related deaths; however, the association for cancer-related deaths was weaker, and the CI included one. As the association between employment status and mortality was not explained by known risk factors for mortality, additional research is needed to identify other potential factors that may help to explain this relationship.


[Environment, Trauma and Technical Innovations: Three Links Between Donald W. Winnicott and Sándor Ferenczi].
Throughout this paper, the theoretical and clinical approaches of D.W. Winnicott are reviewed in order to reread the written production of Sándor Ferenczi. Winnicott's clinical and theoretical concepts allow returning to Ferenczi and rescuing aspects of his work that had been silenced in the psychoanalytic community. Ferenczi, in turn, is one that holds his presence in Winnicott's thought. Even though there are few times in which he cites Ferenczi in his work, it is possible to draw clear relationships between both theories. Three main issues are addressed: the role of the environment as active; the primitive traumatic event in which there is no one that has experience of it, and psychoanalysis as the place to experience that which happened in the first months of life for the first time; and, finally, severe pathologies and psychoses: technical innovations in Winnicott and Ferenczi for the treatment of psychotic and borderline patients. It is concluded that the theoretical and technical developments of Winnicott serve to illuminate a retrospective reading of Ferenczi.


Health and safety hazards associated with subways: a review.
Subway systems are key components in mass transportation networks worldwide, providing rapid and affordable transportation to urban communities in 58 different countries. The benefits afforded by subway transit are numerous and mainly derived from the reduction in automobile use, thereby limiting environmental and health hazards associated with exhaust-air emissions. Additionally, by limiting congestion and providing vital transportation links within a city, subways also improve the overall quality of life of urban communities. However, to best maximize the positive impact on the urban environment, subway systems need to provide a safe and healthy environment for both passengers and subway transit workers. Periodically, safety concerns are raised, most recently in relation to the vulnerability of subways to terrorist attacks. To examine this issue more carefully, we conducted a structured review of the literature to identify and characterize potential health and safety hazards associated with subways. A secondary goal was to identify various risk management strategies designed to minimize the risk of these hazards. This information may be helpful to urban communities, urban planners, public health specialists, and others interested in subway safety.


Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization.
Recently, it was revealed that the inhibition of nonproteolytic activation of prorenin led to significant suppression of ocular inflammation in endotoxin-induced uveitis. The purpose of the present study was to investigate whether nonproteolytically activated prorenin plays a role in ischemia-induced retinal neovascularization. C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal (P) day 7 to P12, followed by room-air breathing to P17 to induce ischemia-initiated retinal neovascularization. Tissue localization of activated prorenin and prorenin receptor was examined by immunohistochemistry. Animals received intraperitoneal injections of handle-region peptide (HRP), a decoy peptide corresponding to the handle region of prorenin, which inhibits prorenin receptor-mediated upregulation of the renin-angiotensin system (RAS). A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiologic and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA expression and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA. Retinal vessels in ischemic retinopathy eyes were positive for activated prorenin and prorenin receptor. Pathologic, but not physiologic, retinal neovascularization was significantly attenuated in HRP-treated mice compared with vehicle- or control peptide-treated animals. The number of adherent leukocytes was also significantly reduced. Retinal mRNA expression and protein levels of ICAM-1, VEGF, VEGFR-1, and VEGFR-2 in ischemic retinopathy were also significantly suppressed by the application of HRP. The present findings suggest that nonproteolytic activation of prorenin selectively promotes pathologic, but not physiologic, retinal neovascularization through the inflammatory processes related to pathologic neovascularization.


N,N-dialkylaniline-substituted tetraethynylethenes: a new class of chromophores possessing an emitting charge-transfer state. Experimental and computational studies.
The photophysical properties of N,N-dimethylaniline- (DMA) substituted tetraethynylethene (TEE; 3,4-diethynylhex-3-ene-1,5-diyne) and related derivatives were investigated in a joint experimental and computational study. Measurements of the electronic emission spectra showed that these novel chromophores display a dual fluorescence which strongly depends on solvent polarity. Computational studies suggest that the twisted intramolecular charge-transfer state (TICT) model offers a possible explanation for the experimentally observed dual fluorescence. Time-dependent density functional calculations revealed that the initial excited state reached upon photoirradiation relaxes to a lower-energy TICT state in which either the dimethylamino group is twisted into an orthogonal position with respect to the remaining planar arylated TEE moiety or the entire DMA donor group takes an orthogonal orientation with respect to the rigid, planar TEE acceptor moiety. For the compounds investigated, the charge-transfer state responsible for the strongly solvent-dependent luminescence is directly connected with the initial excited state, namely, no crossing of states is involved.


Who knows best? Awareness of divided attention difficulty in a neurological rehabilitation setting.
To explore whether patients relearning to walk after acquired brain injury and showing cognitive-motor interference were aware of divided attention difficulty; whether their perceptions concurred with those of treating staff. Patients and neurophysiotherapists (from rehabilitation and disabled wards) completed questionnaires. Factor analyses were applied to responses. Correlations between responses, clinical measures and experimental decrements were examined. Patient/staff responses showed some agreement; staff reported higher levels of perceived difficulty; responses conformed to two factors. One factor (staff/patients alike) reflected expectations about functional/motor status and did not correlate with decrements. The other factor (patients) correlated significantly with dual-task motor decrement, suggesting some genuine awareness of difficulty (cognitive performance prioritized over motor control). The other factor (staff) correlated significantly with cognitive decrement (gait prioritized over sustained attention). Despite some inaccurate estimation of susceptibility; patients and staff do exhibit awareness of divided attention difficulty, but with a limited degree of concurrence. In fact, our results suggest that patients and staff may be sensitive to different aspects of the deficit. Rather than 'Who knows best?', it is a question of 'Who knows what?'


Snapshots of dynamics in synthesizing N(6)-isopentenyladenosine at the tRNA anticodon.
Bacterial and eukaryotic tRNAs that decode codons starting with uridine have a hydrophobically hypermodified adenosine at position 37 (A(37)) adjacent to the 3'-end of the anticodon, which is essential for efficient and highly accurate protein translation by the ribosome. However, it remains unclear as to how the corresponding tRNAs are selected to be modified by alkylation at the correct position of the adenosine base. We have determined a series of crystal structures of bacterial tRNA isopentenyltransferase (MiaA) in apo- and tRNA-bound forms, which completely render snapshots of substrate selections during the modification of RNA. A compact evolutionary inserted domain (herein swinging domain) in MiaA that exhibits as a highly mobile entity moves around the catalytic domain as likely to reach and trap the tRNA substrate. Thereby, MiaA clamps the anticodon stem loop of the tRNA substrate between the catalytic and swinging domains, where the two conserved elongated residues from the swinging domain pinch the two flanking A(36) and A(38) together to squeeze out A(37) into the reaction tunnel. The site-specific isopentenylation of RNA is thus ensured by a characteristic pinch-and-flip mechanism and by a reaction tunnel to confine the substrate selection. Furthermore, combining information from soaking experiments with structural comparisons, we propose a mechanism for the ordered substrate binding of MiaA.


Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis.
Cancer stem cells (CSCs) are believed to be resistant to currently available therapies and may be responsible for relapse of cancer in patients. Measuring circulating tumor cells (CTCs) in the blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers or relapse of the cancer disease. However, accurate detection of CTCs has remained a problem, as epithelial-cell markers used to date are not always reliable for detecting CTCs, especially during epithelial-mesenchymal transition. As CSCs are required to initiate metastatic tumors, our goal was to optimize and standardize a method for identifying circulating CSCs (CCSCs) in patients, using established CSC markers. Here, we report for the first time the detection of CCSCs in the blood of athymic nude mice, bearing metastatic tumors, and in the blood of patients positive for colonic adenocarcinomas. Using a simple and non-expensive method, we isolated a relatively pure population of CSCs (CD45-/CK19+), free of red blood cells and largely free of contaminating CD45+ white blood cells. Enriched CCSCs from patients with colon adenocarcinomas had a malignant phenotype and co-expressed CSC markers (DCLK1/LGR5) with CD44/Annexin A2. CSCs were not found in the blood of non-cancer patients, free of colonic growths. Enriched CCSCs from colon cancer patients grew primary spheroids, suggesting the presence of tumor-initiating cells in the blood of these patients. In conclusion, we have developed a novel diagnostic assay for detecting CSCs in circulation, which may more accurately predict the risk of relapse or metastatic disease in patients. As CSCs can potentially initiate metastatic growths, patients positive for CCSCs can be treated with inhibitory agents that selectively target CSCs, besides conventional treatments, to reduce the risk of relapse/metastatic disease for improving clinical outcomes.


Molecular phylogeny of Diabrotica beetles (Coleoptera: Chrysomelidae) inferred from analysis of combined mitochondrial and nuclear DNA sequences.
The phylogenetic relationships of thirteen Diabrotica (representing virgifera and fucata species groups) and two outgroup Acalymma beetle species (Coleoptera: Chrysomelidae) were inferred from the phylogenetic analysis of a combined data set of 1323 bp of mitochondrial DNA (mtDNA) cytochrome oxidase subunit 1 (COI) and the entire second internal transcribed spacer region (ITS-2) of nuclear ribosomal DNA of 362 characters. Species investigated were D. adelpha, D. balteata, D. barberi, D. cristata, D. lemniscata, D. longicornis, D. porracea, D. speciosa, D. undecimpunctata howardi, D. u. undecimpunctata, D. virgifera virgifera, D. v. zeae, D. viridula, and outgroup A. blandulum and A. vittatum. Maximum parsimony (MP), minimum evolution (ME), and maximum likelihood (ML) analyses of combined COI and ITS-2 sequences clearly place species into their traditional morphological species groups with MP and ME analyses resulting in identical topologies. Results generally confer with a prior work based on allozyme data, but within the virgifera species group, D. barberi and D. longicornis strongly resolve as sister taxa as well as monophyletic with the neotropical species, D. viridula, D. cristata and D. lemniscata also resolve as sister taxa. Both relationships are not in congruence with the prior allozyme-based hypothesis. Within the fucata species group, D. speciosa and D. balteata resolve as sister taxa. Results also strongly supported the D. virgifera and D. undecimpunctata subspecies complexes. Our proposed phylogeny provides some insight into current hypotheses regarding distribution status and evolution of various life history traits for Diabrotica.


In vitro production of alkaloids: Factors, approaches, challenges and prospects.
The wide diversity of plant secondary metabolites is largely used for the production of various pharmaceutical compounds. In vitro cell tissue or organ culture has been employed as a possible alternative to produce such industrial compounds. Tissue culture techniques provide continuous, reliable, and renewable source of valuable plant pharmaceuticals and might be used for the large-scale culture of the plant cells from which these secondary metabolites can be extracted. Alkaloids are one of the most important secondary metabolites known to play a vital role in various pharmaceutical applications leading to an increased commercial importance in recent years. The tissue culture techniques may be utilized to improve their production of alkaloids via somaclonal variations and genetic transformations. The focus of this review is toward the application of different tissue culture methods/techniques employed for the in vitro production of alkaloids with a systematic approach to improve their production.


Boronic acid-modified magnetic materials for antibody purification.
Aminophenyl boronic acids can form reversible covalent ester interactions with cis-diol-containing molecules, serving as a selective tool for binding glycoproteins as antibody molecules that possess oligosaccharides in both the Fv and Fc regions. In this study, amino phenyl boronic acid (APBA) magnetic particles (MPs) were applied for the magnetic separation of antibody molecules. Iron oxide MPs were firstly coated with dextran to avoid non-specific binding and then with 3-glycidyloxypropyl trimethoxysilane to allow further covalent coupling of APBA (APBA_MP). When contacted with pure protein solutions of human IgG (hIgG) and bovine serum albumin (BSA), APBA_MP bound 170 ± 10 mg hIgG g(-1) MP and eluted 160 ± 5 mg hIgG g(-1) MP, while binding only 15 ± 5 mg BSA g(-1) MP. The affinity constant for the interaction between hIgG and APBA_MP was estimated as 4.9 × 10(5) M(-1) (Ka) with a theoretical maximum capacity of 492 mg hIgG adsorbed g(-1) MP (Qmax), whereas control particles bound a negligible amount of hIgG and presented an estimated theoretical maximum capacity of 3.1 mg hIgG adsorbed g(-1) MP (Qmax). APBA_MPs were also tested for antibody purification directly from CHO cell supernatants. The particles were able to bind 98% of IgG loaded and to recover 95% of pure IgG (purity greater than 98%) at extremely mild conditions.


The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes.
Parathyroid hormone-related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lacking PTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57(Kip2) is the opposite of the PTHrP-null phenotype, we hypothesized that PTHrP's proliferative actions in chondrocytes might be mediated by opposing p57. We generated p57/PTHrP-null embryos, which showed partial rescue of the PTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in the PTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment of p57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression of p57 expression.


The reopening rate of the fingers domain is a determinant of base selectivity for RB69 DNA polymerase.
Two divalent metal ions are required for nucleotide incorporation by DNA polymerases. Here we use the bacteriophage RB69 DNA polymerase (RB69 pol) and the metal ion exchange-inert nucleotide analogue rhodium(III) deoxythymidine triphosphate (Rh.dTTP) to investigate the requirements of metal binding to the "A" site and to the "B" site, independently. We show that while binding of a metal ion to the A site is required for the nucleotidyl transfer reaction to occur, this metal binding is insufficient to initiate the prechemistry enzyme isomerization that has been observed with this polymerase. Moreover, we show that binding of a deoxynucleoside triphosphate (dNTP), in the absence of a catalytic metal ion, is sufficient to induce this conformational change. In this report, we also present several lines of evidence (from pulse-chase, rapid chemical quench-flow, and stopped-flow fluorescence experiments) for the reverse rate of the enzyme isomerization, closed to open, of a DNA polymerase complex. The implications of these data for the fidelity of DNA polymerization by RB69 pol are discussed.


Evidence that a septin diffusion barrier is dispensable for cytokinesis in budding yeast.
Septins are essential for cytokinesis in Saccharomyces cerevisiae, but their precise roles remain elusive. Currently, it is thought that before cytokinesis, the hourglass-shaped septin structure at the mother-bud neck acts as a scaffold for assembly of the actomyosin ring (AMR) and other cytokinesis factors. At the onset of cytokinesis, the septin hourglass splits to form a double ring that sandwiches the AMR and may function as diffusion barriers to restrict diffusible cytokinesis factors to the division site. Here, we show that in cells lacking the septin Cdc10 or the septin-associated protein Bud4, the septins form a ring-like structure at the mother-bud neck that fails to re-arrange into a double ring early in cytokinesis. Strikingly, AMR assembly and constriction, the localization of membrane-trafficking and extracellular-matrix-remodeling factors, cytokinesis, and cell-wall-septum formation all occur efficiently in cdc10Δ and bud4Δ mutants. Thus, diffusion barriers formed by the septin double ring do not appear to be critical for S. cerevisiae cytokinesis. However, an AMR mutation and a septin mutation have synergistic effects on cytokinesis and the localization of cytokinesis proteins, suggesting that tethering to the AMR and a septin diffusion barrier may function redundantly to localize proteins to the division site.


THE ACTION OF ETHYLHYDROCUPREIN (OPTOCHIN) ON TYPE STRAINS OF PNEUMOCOCCI IN VITRO AND IN VIVO, AND ON SOME OTHER MICROORGANISMS IN VITRO.
1. Ethylhydrocuprein hydrochloride in very high dilution inhibits the growth of, and in 18 hours kills, representatives of all four groups of pneumococci in vitro. The killing effect is generally seen in somewhat lower dilutions than the inhibiting effect. No constant or considerable difference is seen in these actions on representatives of the four groups of the pneumococci. The action of ethylhydrocuprein hydrochloride on the pneumococci in vitro is so strongly specific that it may possibly be used as a test for a true pneumococcus. 2. The inhibitory or killing effects of ethylhydrocuprein hydrochloride in vitro on bacteria other than pneumococci are slight or absent. The effects are greater on streptococci than on any other organisms examined, but are still much less than on the pneumococci. This action distinguishes between the streptococcus group, including Streptococcus mucosus sometimes found in normal mouths, on the one hand, and the true pneumococcus (including Pneumococcus mucosus), on the other. 3. Quinine hydrochloride inhibits the growth of, and kills the pneumococcus in vitro; much stronger concentrations, however, are necessary than in the case of ethylhydrocuprein. This effect of quinine hydrochloride is also seen on other organisms, but in a less degree. 4. Ethylhydrocuprein (optochin base) has a well marked protective action against experimental pneumococcal infection in mice in the case of type strains of all four groups of pneumococci; this protective action may be efficient against many multiples of the minimum lethal dose.


Basal cold but not heat tolerance constrains plasticity among Drosophila species (Diptera: Drosophilidae).
Thermal tolerance and its plasticity are important for understanding ectotherm responses to climate change. However, it is unclear whether plasticity is traded-off at the expense of basal thermal tolerance and whether plasticity is subject to phylogenetic constraints. Here, we investigated associations between basal thermal tolerance and acute plasticity thereof in laboratory-reared adult males of eighteen Drosophila species at low and high temperatures. We determined the high and low temperatures where 90% of flies are killed (ULT(90) and LLT(90) , respectively) and also the magnitude of plasticity of acute thermal pretreatments (i.e. rapid cold- and heat-hardening) using a standardized, species-specific approach for the induction of hardening responses. Regression analyses of survival variation were conducted in ordinary and phylogenetically informed approaches. Low-temperature pretreatments significantly improved LLT(90) in all species tested except for D. pseudoobscura, D. mojavensis and D. borealis. High-temperature pretreatment only significantly increased ULT(90) in D. melanogaster, D. simulans, D. pseudoobscura and D. persimilis. LLT(90) was negatively correlated with low-temperature plasticity even after phylogeny was accounted for. No correlations were found between ULT(90) and LLT(90) or between ULT(90) and rapid heat-hardening (RHH) in ordinary regression approaches. However, after phylogenetic adjustment, there was a positive correlation between ULT(90) and RHH. These results suggest a trade-off between basal low-temperature tolerance and acute low-temperature plasticity, but at high temperatures, increased basal tolerance was accompanied by increased plasticity. Furthermore, high- and low-temperature tolerances and their plasticity are clearly decoupled. These results are of broad significance to understanding how organisms respond to changes in habitat temperature and the degree to which they can adjust thermal sensitivity.


Extra dimensions and warped geometries.
The field of extra dimensions, as well as the hypothesized sizes of extra dimensions, have grown by leaps and bounds over the past few years. I summarize the new results and the reasons for the recent activity in this field. These include the observations that extra dimensions can be macroscopic or even infinite in size. Another new development is the application of extra dimensions to the determination of particle physics parameters and properties.


Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation.
The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-d-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M.


Modeling perceived relationships between melody, harmony, and key.
Perceptual relationships between four-voice harmonic sequences and single voices were examined in three experiments. In Experiment 1, listeners rated the extent to which single voices were musically consistent with harmonic sequences. When harmonic sequences did not change key, judgments were influenced by three sources of congruency: melody (whether the single voice was the same as the soprano voice of the harmonic sequence), chord progression (whether the single voice could be harmonized to give rise to the chord progression of the harmonic sequence), and key structure (whether or not the single voice implied modulation). When key changes occurred, sensitivity to sources of congruency was reduced. In Experiment 2, another interpretation of the results was examined: that consistency ratings were based on congruency in well-formedness. Listeners provided well-formedness ratings of the single voices and harmonic sequences. A multiple regression analysis suggested that consistency ratings were based not merely on well-formedness but on congruency in melody, chord progression, and key structure. In Experiment 3, listeners rated the extent of modulation in harmonic sequences and in each voice of the sequences. Discrimination between modulation conditions was greater for single voices than for harmonic sequences, suggesting that abstraction of key from melody may occur without reference to implied harmony. A partially hierarchical system for processing melody, harmony, and key is proposed.


One-year follow-up comparison of the effectiveness of McKenzie treatment and strengthening training for patients with chronic low back pain: outcome and prognostic factors.
A randomized controlled trial with multivariable analyses of prognostic factors. To report the long-term outcome of McKenzie treatment compared with strengthening training. Further, to determine patient-related factors associated with poor outcome 14 months after completion of treatment. Exercise therapy is widely recommended for patients with chronic low back pain. However, reports vary considerably concerning characteristics of patients who will not respond to treatment. Knowledge of factors associated with poor outcome may assist identification of patients requiring special attention. A total of 260 patients with chronic low back pain were included in a previously reported randomized controlled trial of McKenzie therapy versus strengthening training. Outcome variables were: functional status, pain level, work status, and use of healthcare services during follow-up. Also, factors associated with withdrawal during the intervention were sought identified. The following factors of possible prognostic significance were determined: levels of pain and disability, pain-distribution, duration of symptoms, smoking habits, leisure activities, workload, job satisfaction, treatment preference, outcome expectations, treatment modality received, compliance with home exercises during follow-up, and demographic variables such as age, gender, work status, and application for pension. Association between variables was examined by multiple logistic regression analysis and odds ratios. No differences in outcomes were found between the treatment groups at 14 months of follow-up. Low level of pain intensity and disability, sick leave at entry, low pretreatment expectations of future work ability, withdrawal during treatment, and discontinuance of exercises after the end of the treatment period were associated with poor outcome. Poor long-term outcome of exercise therapy for chronic low back pain can be explained by a number of patient-related factors. Different prognostic factors were associated with different outcomes. These factors were more important in determining outcome than the exercise-programs studied.


Effect of biological and coagulation pre-treatments to control organic and biofouling potential components of ultrafiltration membrane in the treatment of lake water.
Biological aerated filter (BAF), sand filtration (SF), alum and Moringa oleifera coagulation were investigated as a pre-treatment for reducing the organic and biofouling potential component of an ultrafiltration (UF) membrane in the treatment of lake water. The carbohydrate content was mainly responsible for reversible fouling of the UF membrane compared to protein or dissolved organic carbon (DOC) content. All pre-treatment could effectively reduce these contents and led to improve the UF filterability. Both BAF and SF markedly led to improvement in flux than coagulation processes, and alum gave greater flux than M. oleifera. This was attributed to the effective removal and/or breakdown of high molecular weight (MW) organics by biofilters. BAF led to greater improvement in flux than SF, due to greater breakdown of high MW organics, and this was also confirmed by the attenuated total reflection-Fourier transform infrared spectroscopy analysis. Coagulation processes were ineffective in removing biofouling potential components, whereas both biofilters were very effective as shown by the reduction of low MW organics, biodegradable dissolved organic carbon and assimilable organic carbon contents. This study demonstrated the potential of biological pre-treatments for reducing organic and biofouling potential component and thus improving flux for the UF of lake water treatment.


Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine.
Methamphetamine (MA) and cocaine induce behavioral effects primarily through modulation of dopamine neurotransmission. However, the genetic regulation of sensitivity to these two drugs may be similar or disparate. Using selective breeding, lines of mice were produced with extreme sensitivity (high MA activation; HMACT) and insensitivity (low MA activation; LMACT) to the locomotor stimulant effects of acute MA treatment. Studies were performed to determine whether there is pleiotropic genetic influence on sensitivity to the locomotor stimulant effect of MA and to other MA- and cocaine-related behaviors. The HMACT line exhibited more locomotor stimulation in response to several doses of MA and cocaine, compared to the LMACT line. Both lines exhibited locomotor sensitization to 2 mg/kg of MA and 10 mg/kg of cocaine; the magnitude of sensitization was similar in the two lines. However, the lines differed in the magnitude of sensitization to a 1 mg/kg dose of MA, a dose that did not produce a ceiling effect that may confound interpretation of studies using higher doses. The LMACT line consumed more MA and cocaine in a two-bottle choice drinking paradigm; the lines consumed similar amounts of saccharin and quinine, although the HMACT line exhibited slightly elevated preference for a low concentration of saccharin. These results suggest that some genes that influence sensitivity to the acute locomotor stimulant effect of MA have a pleiotropic influence on the magnitude of behavioral sensitization to MA and sensitivity to the stimulant effects of cocaine. Further, extreme sensitivity to MA may protect against MA and cocaine self-administration.


Full-band absorption enhancement in ultrathin-film solar cells through the excitation of multiresonant guided modes.
We demonstrate the optimization of plasmonic thin-film solar cells with broadband absorption enhancements. The solar cells model system consists of a three-dimensional, periodic array of Ag/silica cylinders on a Si film supported by a silica substrate. Particle swarm optimization (PSO) and the finite-difference time domain (FDTD) are combined to achieve the maximum absorption enhancement (Ehm). Through optimization, the optimal system parameters, such as the height and diameter of Ag and the silica cylinder, and the period of periodic array, were obtained. Following this approach, we can attain a 321% enhancement in the integrated quantum efficiency as compared to a cell without metallic structures. The full-band absorption enhancement arises from the near-field enhancement and multiresonant guided modes in the Si waveguide.


Envenoming by Bothrops jararaca in Brazil: association between venom antigenaemia and severity at admission to hospital.
The association between the clinical severity of Bothrops jararaca envenoming at admission and serum venom and plasma fibrinogen concentrations before antivenom administration is reported in 137 patients admitted to Hospital Vital Brazil, Instituto Butantan, São Paulo, Brazil, between 1989 and 1990. Other variables such as age, gender, site of the bite, use of tourniquet and the time interval between the bite and start of antivenom therapy, spontaneous systemic bleeding, and the 20 minute whole blood clotting test (20WBCT) at admission showed no association with either severity or serum venom antigen concentration (SVAC). Mean SVAC in patients with mild envenoming was significantly lower than in the group with moderate envenoming (P = 0.0007). Patients with plasma fibrinogen concentrations > 1.5 g/L had a lower mean SVAC than patients with plasma fibrinogen concentrations < or = 1.5 g/L (P = 0.02). Those admitted with a tourniquet in place had significantly higher plasma fibrinogen concentrations than those without a tourniquet (P = 0.002). A multiple logistic regression model showed independent risk factors for severity: bites at sites other than legs or forearms, SVACs > or = 400 ng/mL, and the use of a tourniquet. Rapid quantification of SVAC before antivenom therapy might improve initial evaluation of severity in B. jararaca bites.


Effects of NG-monomethyl-L-arginine and L-arginine on acetylcholine renal response.
Intrarenal infusion of acetylcholine in meclofenamate-treated dogs significantly increased renal blood flow, diuresis, and natriuresis. Intrarenal infusions of either NG-monomethyl-L-arginine (inhibitor of endothelium-derived relaxing factor formation), or L-arginine (precursor of endothelium-derived relaxing factor formation) did not modify basal levels of those parameters. However, the infusion of NG-monomethyl-L-arginine inhibited the acetylcholine-induced increases in renal blood flow and diuresis without affecting natriuresis, which increased significantly. The infusion of L-arginine failed to further enhance hemodynamic and excretory effects elicited by acetylcholine. The concomitant infusion of L-arginine and NG-monomethyl-L-arginine did not change renal blood flow, urine flow, or sodium excretion rate. L-Arginine administration prevented the inhibitory effect of NG-monomethyl-L-arginine on acetylcholine-induced renal vasodilatation and diuresis. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. The results indicate that the vasodilatory and diuretic responses to intrarenal acetylcholine in meclofenamate-treated dogs are largely dependent on endothelium-derived relaxing factor.


Adaptations to a new physical training program in the combat controller training pipeline.
The United States Air Force combat controller (CCT) training pipeline is extremely arduous and historically has a high attrition rate of 70 to 80%. The primary objective of this study was to evaluate the impact of incorporating a 711 Human Performance Wing (HPW) / Biobehavior, Bioassessment, and Biosurveillance Branch (RHPF)-developed physical fitness-training program into the combat controller (CCT) 5-level training physical fitness program. One-hundred-nine CCT trainees were tested and trained during their initial eight weeks at the 720th Special Tactics Training Squadron (STTS) at Hurlburt Field. Modifications to their physical training program were principally aimed at reducing overtraining and overuse injury, educating trainees and cadre on how to train smarter, and transitioning from traditional to "functional" PT. A battery of physiological measurements and a psychological test were administered prior to and immediately after trainees undertook an 8-week modified physical fitness training program designed to reduce overtraining and injury and improve performance. We performed multiple physical tests for cardiovascular endurance (VO₂max and running economy), "anaerobic" capacity (Wingate power and loaded running tests), body composition (skinfolds), power (Wingate and vertical jump), and reaction time (Makoto eye-hand test). We used the Mental Toughness Questionnaire 48 (MTQ-48) for the psychological test. We observed several significant improvements in physical and physiological performance over the eight weeks of training. Body composition improved by 16.2% (p < 0.05). VO₂max, time-to-exhaustion, and ventilatory threshold were all significantly higher after implementation of the new program than before it. We observed strong trends towards improvement in work accomplished during loaded running (p = 0.07) and in average power per body mass during lower body Wingate (p = 0.08). Other measures of lower body power did not change significantly over the training period, but did show mild trends towards improvement. Upper body average and peak power per kilogram of body mass both improved significantly by 5.8% and 8.1%, respectively. Reaction time was significantly better posttraining as demonstrated by a 7% improvement during the reactive test. Reactive accuracy also improved significantly with the post test accuracy percentage jumping from 61% to 76%. Furthermore, overuse injuries, a major source of attrition fell by a dramatic 67%. The modifications resulted in significant improvement in trainees? graduation rate. In the eight classes prior to implementation of these changes, average CCT graduating class size was nine trainees. For the eight classes following the changes, average CCT graduating class rose to 16.5 trainees, an increase of 83%. Due to its success, STTS leadership expanded the modifications from the eight weeks prior to CDS to include the entire second year of the pipeline.


Rupture of the distal tendon of the biceps brachii. A biomechanical study.
In biomechanical studies on ten patients who had had a rupture of the distal tendon of the biceps brachii, we compared the results of immediate anatomical reattachment, delayed reattachment, and conservative treatment. When the tendon was simply attached to the brachialis muscle (one patient), there was nearly normal strength in elbow flexion but about 50 per cent loss of forearm supination. Late reinsertion (one patient) improved strength of both flexion and supination, but not to normal. Immediate reattachment (four patients) restored normal strength in flexion and supination at one year but not at four months (one patient). With conservative treatment (three patients) there was a mean loss of 40 per cent of supination strength and variable loss of flexion strength, averaging 30 per cent. These data suggest that immediate surgical reinsertion of the biceps tendon into the radial tuberosity, compared with other modes of treatment, restores more strength of flexion and supination.


Ecological interactions shape the adaptive value of plant defence: Herbivore attack versus competition for light.
Plants defend themselves against diverse communities of herbivorous insects. This requires an investment of limited resources, for which plants also compete with neighbours. The consequences of an investment in defence are determined by the metabolic costs of defence as well as indirect or ecological costs through interactions with other organisms. These ecological costs have a potentially strong impact on the evolution of defensive traits, but have proven to be difficult to quantify.We aimed to quantify the relative impact of the direct and indirect or ecological costs and benefits of an investment in plant defence in relation to herbivory and intergenotypic competition for light. Additionally, we evaluated how the benefits of plant defence balance its costs in the context of herbivory and intergenotypic competition.To this end, we utilised a functional-structural plant (FSP) model of Brassica nigra that simulates plant growth and development, morphogenesis, herbivory and plant defence. In the model, a simulated investment in defences affected plant growth by competing with other plant organs for resources and affected the level and distribution of herbivore damage.Our results show that the ecological costs of intergenotypic competition for light are highly detrimental to the fitness of defended plants, as it amplifies the size difference between defended and undefended plants. This leads to herbivore damage counteracting the effects of intergenotypic competition under the assumption that herbivore damage scales with plant size. Additionally, we show that plant defence relies on reducing herbivore damage rather than the dispersion of herbivore damage, which is only beneficial under high levels of herbivore damage.We conclude that the adaptive value of plant defence is highly dependent on ecological interactions and is predominantly determined by the outcome of competition for light. plain language summary is available for this article.


Examining the impact of a crime gun intelligence center.
With gun crime on the rise, efforts to curb this form of violence have captured the attention of government agencies and police departments alike. One form of such efforts is the proliferation of Crime Gun Intelligence Centers (CGICs) in police departments across the country. However, with only three non-peer-reviewed evaluations of these CGICs to date, our understanding of their effectiveness is limited. The present study aims to fill this gap by examining the impact of the Phoenix Police Department's (PPD) CGIC on clearance rates and prosecutorial outcomes for gun crimes. The data for this study come from PPD's Records Management System (RMS), computer-aided dispatch (CAD) system, impounded evidence, National Integrated Ballistics Information Network (NIBIN) lead data, and arrest data. Prosecutorial data were supplied by the Maricopa County Attorney's Office (MCAO). This study examined pretest and posttest differences that occurred over the study period. Difference-in-difference (DID) models were calculated to assess the impact of the CGIC on the outcome measures of interest. We found that from the year prior to the CGIC to 2 years post-CGIC, NIBIN inputs increased by 115%, NIBIN leads increased by 163%, timeliness of entry (of ballistics evidence) improved with 32% of processed items entered within 24-48 h in the second year of the CGIC compared with only 3% the year preceding the CGIC, and clearance rates for arrests increased significantly. These findings have implications for the continued adoption of CGIC, as well as the utility of NIBIN.


Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.
Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.


Evidence for functional alpha 2-adrenoceptors on vascular sympathetic nerve endings in the human forearm.
The role of alpha 2-adrenoceptors on vascular sympathetic nerve endings in modulating release of the sympathetic neurotransmitter norepinephrine (NE) in humans was examined by measuring the regional rate of appearance of NE in forearm venous plasma (forearm NE spillover [FSO]) in 32 healthy volunteers during intra-arterial infusion of drugs acting at adrenoceptors or directly on vascular smooth muscle. Simultaneous intra-arterial infusions of tracer amounts of [3H]NE were used to calculate the extraction rate of NE in the forearm. Methoxamine or propranolol with epinephrine (PRO + EPI) was used to stimulate alpha-adrenoceptors, yohimbine was used to inhibit alpha-adrenoceptors, and sodium nitroprusside (NIP) was used to produce increases in forearm blood flow directly. Sympathetic efferent activity was manipulated by systemic intravenous infusions of NIP or trimethaphan. Yohimbine and NIP increased and PRO + EPI and methoxamine decreased NE FSO, without effects on systemic blood pressure, heart rate, or arterial levels of catechols. Changes in FSO were flow dependent; therefore, the slope of the relation between the changes in FSO and forearm blood flow was used to evaluate the effects of each drug on regional sympathoneural activity. During administration of yohimbine, the mean slope of the relation between the change in estimated FSO and the change in forearm blood flow was about four times that of the mean slope during administration of NIP (F = 6.35, p less than 0.05). The slopes of the relations between changes in FSO and forearm blood flow were unaffected by systemic trimethaphan or NIP infusion, indicating that the activity of alpha 2-adrenoceptors was not altered during inhibition or reflexive stimulation of sympathetic outflow. The results suggest that alpha 2-adrenoceptors modulate release of NE from vascular sympathetic nerve endings in humans and that the function of these receptors is unchanged during acute changes in junctional NE concentrations.


Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB.
MicroRNAs regulate pathways contributing to oncogenesis, and thus the mechanisms causing dysregulation of microRNA expression in cancer are of significant interest. Mature mir-29b levels are decreased in malignant cells, and this alteration promotes the malignant phenotype, including apoptosis resistance. However, the mechanism responsible for mir-29b suppression is unknown. Here, we examined mir-29 expression from chromosome 7q32 using cholangiocarcinoma cells as a model for mir-29b downregulation. Using 5' rapid amplification of cDNA ends, the transcriptional start site was identified for this microRNA locus. Computational analysis revealed the presence of two putative E-box (Myc-binding) sites, a Gli-binding site, and four NF-kappaB-binding sites in the region flanking the transcriptional start site. Promoter activity in cholangiocarcinoma cells was repressed by transfection with c-Myc, consistent with reports in other cell types. Treatment with the hedgehog inhibitor cyclopamine, which blocks smoothened signaling, increased the activity of the promoter and expression of mature mir-29b. Mutagenesis analysis and gel shift data are consistent with a direct binding of Gli to the mir-29 promoter. Finally, activation of NF-kappaB signaling, via ligation of Toll-like receptors, also repressed mir-29b expression and promoter function. Of note, activation of hedgehog, Toll-like receptor, and c-Myc signaling protected cholangiocytes from TRAIL-induced apoptosis. Thus, in addition to c-Myc, mir-29 expression can be suppressed by hedgehog signaling and inflammatory pathways, both commonly activated in the genesis of human malignancies.


Prevalence and effectiveness of treatment of hypertension on cardiovascular morbidity and mortality in an elderly population aged 70 years and over.
The prevalence of hypertension, effectiveness of blood pressure control and compliance, and the effectiveness of treatment on 18-month overall mortality and development of cardiovascular disease in an elderly Chinese population were studied. The study group examined were aged 70 years and over, and consisted of a random sample of subjects on the Old Age and Disability Allowance register. They were stratified by sex and 5-year age groups from 70-74 to 90+ years. Information obtained at baseline included medical history, use of drugs, and measurement of blood pressure. Subjects with a blood pressure > 160/90 were classified as hypertensive. The overall prevalence of hypertension was 48%, 19% being undiagnosed. Among subjects with a known history of hypertension and taking drugs, only approximately half had adequate control (BP < or = 160/90). One fifth of those with a known diagnosis of hypertension were not taking drugs. Subjects who developed stroke had a higher mean systolic and pulse pressure at baseline; no difference in mean pressures was observed for overall mortality or development of heart disease. No difference in mortality or development of cardiovascular disease was observed between the following groups: known history of hypertension and taking medication with controlled blood pressure, known history and taking medication and blood pressure poorly controlled or not taking drugs, and normal blood pressure with no history of hypertension.


EUS: a meta-analysis of test performance in suspected choledocholithiasis.
EUS has been proposed as a less invasive means of diagnosing choledocholithiasis and may eliminate the need for ERCP and its associated risks. The literature pertaining to EUS for the diagnosis of choledocholithiasis reports widely varying sensitivities and specificities. To more precisely estimate the diagnostic accuracy of EUS in suspected choledocholithiasis. MEDLINE and EMBASE databases were used to identify prospective cohort studies in which the results of EUS were compared with the results of an acceptable criterion standard, including ERCP, intraoperative cholangiography, or surgical exploration. Two independent reviewers extracted standardized data and assessed trial quality. A random effects model was used to estimate the sensitivity, specificity, likelihood, and diagnostic odds ratio (DOR), and a summary receiver operating characteristic curve was constructed. All predefined potential sources of heterogeneity were explored by subgroup analysis and meta-regression. A total of 2673 patients with suspected choledocholithiasis were reported in 27 studies that satisfied the inclusion criteria. EUS had a high overall pooled sensitivity of 0.94 (95% CI, 0.93-0.96), a specificity of 0.95 (95% CI, 0.94-0.96), and an area under the curve of 0.98. Three variables appeared to yield a higher DOR: a higher disease prevalence, an adequate time interval between index test and criterion standards, and the presence of verification bias. Misclassification of patients by imperfect criterion standards could potentially underestimate the performance of an EUS. An EUS is a noninvasive test, with excellent overall sensitivity and specificity for diagnosing choledocholithiasis. An EUS should, therefore, be used to select patients for a therapeutic ERCP to minimize the risk of complications associated with unnecessary diagnostic ERCP.


Neutron diffraction and gravimetric study of the manganese nitriding reaction under ammonia decomposition conditions.
Manganese and its nitrides have recently been shown to co-catalyse the ammonia decomposition reaction. The nitriding reaction of manganese under ammonia decomposition conditions is studied in situ simultaneously by thermogravimetric analysis and neutron diffraction. Combining these complementary measurements has yielded information on the rate of manganese nitriding as well as the elucidation of a gamut of different manganese nitride phases. The neutron diffraction background was shown to be related to the extent of the ammonia decomposition and therefore the gas composition. From this and the sample mass, implications about the rate-limiting steps for nitriding by ammonia and nitriding by nitrogen are discussed.


Clinical implementation of intensity-modulated radiation therapy.
The clinical implementation of intensity-modulated radiation therapy (IMRT) is a complex process because of the introduction of new treatment planning algorithms and beam delivery systems compared to conventional 3-dimensional conformal radiation therapy (3D-CRT) and the lack of established national performance protocols. IMRT uses an inverse-planning algorithm to create nonuniform fields that are only deliverable through a newly designed beam-modulating delivery system. The intent of this paper is to describe our experience and to elucidate the new clinical procedures that must be executed to have a successful IMRT program. Patients who undergo IMRT at our institution are immobilized and simulated before proceeding to computed tomography scan for patient data acquisition. Treatment planning involves the use of different prescription dose formats and different planning techniques compared to 3D-CRT. The desired dose goals for the target and sensitive structures must be specified before initiating the planning process, which is computer intensive. After the plan is completed, the delivery instructions are transferred to the delivery system via either a floppy disk for MIMiC-based IMRT or through the network for MLC-based IMRT. Target localizations are carried out using orthogonal radiographs. Ultrasound imaging system (BAT) is used to localize the prostate. Dose validation is performed using films, ion chambers or dose-calculation-based techniques.


Autophagy orchestrates the crosstalk between cells and organs.
Over the recent years, it has become apparent that a deeper understanding of cell-to-cell and organ-to-organ communication is necessary to fully comprehend both homeostatic and pathological states. Autophagy is indispensable for cellular development, function, and homeostasis. A crucial aspect is that autophagy can also mediate these processes through its secretory role. The autophagy-derived secretome relays its extracellular signals in the form of nutrients, proteins, mitochondria, and extracellular vesicles. These crosstalk mediators functionally shape cell fate decisions, tissue microenvironment and systemic physiology. The diversity of the secreted cargo elicits an equally diverse type of responses, which span over metabolic, inflammatory, and structural adaptations in disease and homeostasis. We review here the emerging role of the autophagy-derived secretome in the communication between different cell types and organs and discuss the mechanisms involved.


Correlates of quality of life among African American and white cancer survivors.
African Americans continue to suffer disproportionately from cancer morbidity and mortality, with emerging evidence suggesting potential quality of life (QOL) disparities in the survivorship period. The objective of the study was to assess sociodemographic, clinical, and psychosocial factors associated with physical and mental health QOL (PHQOL and MHQOL) among African American and white cancer survivors. Patients were recruited from tumor registries. Telephone interviews were conducted with 248 African American and 244 white respondents with a history of breast, prostate, or colorectal cancers. Multivariate regression models were used to assess what factors were associated with PHQOL and MHQOL. Key racial differences in adjusted analyses included poorer MHQOL scores among African Americans compared with white survivors. Furthermore, race moderated the relationship between perceived social support and MHQOL, where higher social support levels were associated with increased MHQOL among African Americans. Other correlates of QOL impacted racial groups similarly. For example, factors associated with PHQOL scores included being unemployed, being uninsured, the presence of medical comorbidities, a longer time since diagnosis, and higher levels of cancer-related stress appraisals. Factors associated with MHQOL scores included being unemployed, higher levels of daily stress, higher levels of stress associated with the diagnosis, higher levels of education, higher levels of perceived social support, and higher levels of spirituality. Interventions aimed at increasing social support may have important implications for improving QOL outcomes among African Americans. Measuring and understanding factors associated with QOL have important implications for patient adjustment and clinical decision making.


Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring.
Both iron deficiency (ID) and infection are common during pregnancy and studies have described altered brain development in offspring as a result of these individual maternal exposures. Given their high global incidence, these two insults may occur simultaneously during pregnancy. We recently described a rat model which pairs dietary ID during pregnancy and prenatal immune activation. Pregnant rats were placed on iron sufficient (IS) or ID diets from embryonic day 2 (E2) until postnatal day 7, and administered the bacterial endotoxin, lipopolysaccharide (LPS) or saline on E15/16. In this model, LPS administration on E15 caused greater induction of the pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in ID dams compared to IS dams. This suggested that the combination of prenatal immune activation on a background of maternal ID might have more adverse neurodevelopmental consequences for the offspring than exposure to either insult alone. In this study we used this model to determine whether combined exposure to maternal ID and prenatal immune activation interact to affect juvenile and adult behaviors in the offspring. We assessed behaviors relevant to deficits in humans or animals that have been associated with exposure to either maternal ID or prenatal immune activation alone. Adult offspring from ID dams displayed significant deficits in pre-pulse inhibition of acoustic startle and in passive avoidance learning, together with increases in cytochrome oxidase immunohistochemistry, a marker of metabolic activity, in the ventral hippocampus immediately after passive avoidance testing. Offspring from LPS treated dams showed a significant increase in social behavior with unfamiliar rats, and subtle locomotor changes during exploration in an open field and in response to amphetamine. Surprisingly, there was no interaction between effects of the two insults on the behaviors assessed, and few observed alterations in juvenile behavior. Our findings show that long-term effects of maternal ID and prenatal LPS were additive, such that offspring exposed to both insults displayed more adult behavioral abnormalities than offspring exposed to one alone.


Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies.
As exome and genome sequencing (ES/GS) enters the clinic, there is an urgent need to understand the psychological effects of test result disclosure. Through a Clinical Sequencing Exploratory Research (CSER), phase 1 (CSER1) Consortium collaboration, we evaluated participants' psychological outcomes across multiple clinical settings. We conducted a random effects meta-analysis of state anxiety (Hospital Anxiety and Depression Scale [HADS]/Generalized Anxiety Disorder 7-item), depressive symptoms (HADS/Personal Health Questionnaire 9-item), and multidimensional impact (i.e., test-related distress, uncertainty and positive impact: modified Multidimensional Impact of Cancer Risk Assessment/Feelings About Genomic Testing Results scale). Anxiety and depression did not increase significantly following test result disclosure. Meta-analyses examining mean differences from pre- to postdisclosure revealed an overall trend for a decrease in participants' anxiety. We observed low levels of test-related distress and perceptions of uncertainty in some populations (e.g., pediatric patients) and a wide range of positive responses. Our findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results. Some populations may experience low levels of test-related distress or greater positive psychological effects. Future research should further investigate the reasons for test-related psychological response variation.


Mitochondrial Epigenetic Changes Link to Increased Diabetes Risk and Early-Stage Prediabetes Indicator.
Type 2 diabetes (T2D) is characterized by mitochondrial derangement and oxidative stress. With no known cure for T2D, it is critical to identify mitochondrial biomarkers for early diagnosis of prediabetes and disease prevention. Here we examined 87 participants on the diagnosis power of fasting glucose (FG) and hemoglobin A1c levels and investigated their interactions with mitochondrial DNA methylation. FG and A1c led to discordant diagnostic results irrespective of increased body mass index (BMI), underscoring the need of new biomarkers for prediabetes diagnosis. Mitochondrial DNA methylation levels were not correlated with late-stage (impaired FG or A1c) but significantly with early-stage (impaired insulin sensitivity) events. Quartiles of BMI suggested that mitochondrial DNA methylation increased drastically from Q1 (20 < BMI < 24.9, lean) to Q2 (30 < BMI < 34.9, obese), but marginally from Q2 to Q3 (35 < BMI < 39.9, severely obese) and from Q3 to Q4 (BMI > 40, morbidly obese). A significant change was also observed from Q1 to Q2 in HOMA insulin sensitivity but not in A1c or FG. Thus, mitochondrial epigenetic changes link to increased diabetes risk and the indicator of early-stage prediabetes. Further larger-scale studies to examine the potential of mitochondrial epigenetic marker in prediabetes diagnosis will be of critical importance for T2D prevention.


Vascular plant abundance and diversity in an alpine heath under observed and simulated global change.
Global change is predicted to cause shifts in species distributions and biodiversity in arctic tundra. We applied factorial warming and nutrient manipulation to a nutrient and species poor alpine/arctic heath community for seven years. Vascular plant abundance in control plots increased by 31%. There were also notable changes in cover in the nutrient and combined nutrient and warming treatments, with deciduous and evergreen shrubs declining, grasses overgrowing these plots. Sedge abundance initially increased significantly with nutrient amendment and then declined, going below initial values in the combined nutrient and warming treatment. Nutrient addition resulted in a change in dominance hierarchy from deciduous shrubs to grasses. We found significant declines in vascular plant diversity and evenness in the warming treatment and a decline in diversity in the combined warming and nutrient addition treatment, while nutrient addition caused a decline in species richness. The results give some experimental support that species poor plant communities with low diversity may be more vulnerable to loss of species diversity than communities with higher initial diversity. The projected increase in nutrient deposition and warming may therefore have negative impacts on ecosystem processes, functioning and services due to loss of species diversity in an already impoverished environment.


Bmp6 expression can be regulated independently of liver iron in mice.
The liver is the primary organ for storing iron and plays a central role in the regulation of body iron levels by secretion of the hormone Hamp1. Although many factors modulate Hamp1 expression, their regulatory mechanisms are poorly understood. Here, we used conditional knockout mice for the iron exporter ferroportin1 (Fpn1) to modulate tissue iron in specific tissues in combination with iron-deficient or iron-rich diets and transferrin (Tf) supplementation to investigate the mechanisms underlying Hamp1 expression. Despite liver iron overload, expression of bone morphogenetic protein 6 (Bmp6), a potent-stimulator of Hamp1 expression that is expressed under iron-loaded conditions, was decreased. We hypothesized that factors other than liver iron must play a role in controlling Bmp6 expression. Our results show that erythropoietin and Tf-bound iron do not underlie the down-regulation of Bmp6 in our mice models. Moreover, Bmp6 was down-regulated under conditions of high iron demand, irrespective of the presence of anemia. We therefore inferred that the signals were driven by high iron demand. Furthermore, we also confirmed previous suggestions that Tf-bound iron regulates Hamp1 expression via Smad1/5/8 phosphorylation without affecting Bmp6 expression, and the effect of Tf-bound iron on Hamp1 regulation appeared before a significant change in Bmp6 expression. Together, these results are consistent with novel mechanisms for regulating Bmp6 and Hamp1 expression.