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Background: Postural stability depends on the integration of multisensory inputs to drive motor outputs. When visual and somatosensory input is available and reliable, this reduces the postural control system’s reliance on the vestibular system. Despite this, vestibular loss can still cause severe postural dysfunction (1,2). Training one or more of the three sensory systems can alter sensory weighting and change postural behavior. Vestibular activation exercises, including horizontal and vertical headshaking, influence vestibular-ocular and -motor responses and have been showed to be effective in vestibular rehabilitation (3–8). Purpose/Hypothesis: To assess sensory reweighting of postural control processing and vestibular-ocular and -motor responses after concurrent vestibular activation with postural training. It was hypothesized that the effect of this training would significantly alter the pattern of sensory weighting by changing the ratio of visual, somatosensory and vestibular dependence needed to maintain postural stability, and significantly decrease vestibular responses. Methods: Forty-two young healthy individuals (22 females; 23.0+3.9 years; 1.6+0.1 meters) were randomly assigned into four groups: 1) visual feedback weight shift training (WST) coupled with an active horizontal headshake (HHS), 2) same WST with vertical headshake (VHS), 3) WST with no headshake (NHS) and 4) no training/headshake control (CTL) groups. The headshake groups performed an intensive body WST together with horizontal or vertical rhythmic headshake at 80 to 120 beats/minute. The NHS group performed the WST with no headshake while the controls did not perform any training. Five 15-minute training sessions were performed on consecutive days for one week with the weight shift exercises involving upright limits of stability activities on a flat surface, foam or rocker board (Fig. 1). All groups performed baseline- and post-assessments including sensory organization test (SOT) and force platform ramp perturbations, coupled with electromyographic (EMG) recordings. A video head impulse test was also used to record horizontal vestibulo-ocular reflex (VOR) gain. A between- and within-group repeated measures ANOVA was used to analyze five COP sway variables, the equilibrium and composite scores and sensory ratios of the SOT as well as EMG signals and horizontal VOR gain. Similarly, COP variables, EMG, as well as vestibular reflex data (vertical VOR, vestibulo-collic reflex [VCR] and vestibulo-spinal [VSR] gains) during ramp perturbations were analyzed. Alpha level was set at p

Background Functional outcomes with early rehabilitation in the acute care setting have improved; however, an improved understanding of muscle fatigue using surface electromyography (sEMG) is warranted to better guide patient-centered exercise prescription. Objectives The objectives of this study were to assess the safety and feasibility of collecting sEMG at the acute care bedside and to determine differences in muscle fatigue during isometric and dynamic submaximal contractions among patients in the hospital, healthy younger participants, and healthy older participants. Design The study used an observational cohort design. Methods There were 37 participants. Median frequency (Fmed) of the myoelectric signal of the quadriceps femoris muscles and time to task failure (TTTF) were measured using sEMG during an isometric and dynamic fatiguing contraction. Primary analysis compared TTTF between groups for both types of contractions. Secondary analysis compared Fmed at initiation and termination of fatiguing contraction. Results High-quality sEMG measures were safe and feasible to collect at the acute care bedside with no adverse events. There was a statistically significant difference in TTTF between groups after isometric and dynamic contractions; hospitalized patients fatigued faster than healthy younger and healthy older participants after both contractions. With the exception of the vastus lateralis during a dynamic contraction in healthy younger and hospitalized patients, there was a statistically significant difference between Fmed at initiation and termination of contraction, indicating that subjects’ muscles did truly fatigue. Limitations A limitation of the study was the small sample size of patients who were hospitalized without matched controls. Conclusions sEMG is a lab quantitative technique that was found to be safe and feasible to assess muscle fatigue in the acute care environment. The protocol yielded similar results to previously published literature for healthy younger and healthy older people. Further research is needed to better understand how to integrate sEMG findings into patient-centered exercise prescriptions.

The presence of visual dependence as an influential factor on the development of functional stability in ambulatory individuals with cerebral palsy (CP) was studied in 22 adults with spastic bilateral CP, 11 of whom were considered visually dependent, and 18 healthy adults. Participants stood upright during pitch plane disturbances of the visual field and support surface. Intersegmental coordination behaviors were assessed by fitting trajectories of adjacent body segments to an ellipse. Mixed-model repeated measures ANOVAs were performed on ellipse orientation angle and area. Dissimilar stabilizing strategies adopted by the two groups with CP imply that visual dependence impacts postural control. Postural reorganization in response to visual flow in all groups indicates that we cannot ignore perceptual aspects of postural control when designing therapeutic interventions.

Particulate matter (PM) presents an environmental health risk for communities residing close to uranium (U) mine sites. However, the role of the particulate form of U on its cellular toxicity is still poorly understood. Here, we investigated the cellular uptake and toxicity of C-rich U-bearing particles as a model organic particulate containing uranyl citrate over a range of environmentally relevant concentrations of U (0-445 μM). The cytotoxicity of C-rich U-bearing particles in human epithelial cells (A549) was U-dose-dependent. No cytotoxic effects were detected with soluble U doses. Carbon-rich U-bearing particles with a wide size distribution (

Strong epidemiological evidence demonstrates an association between chronic arsenic exposure and anemia. We recently found that As(+3) impairs erythropoiesis by disrupting the function of GATA-1; however the downstream pathways impacted by the loss of GATA-1 function have not been evaluated. Additionally, our previous findings indicate that the predominant arsenical in the bone marrow of mice exposed to As(+3) in their drinking water for 30 days was MMA(+3), but the impacts of this arsenical on erythorpoisis also remain largely unknown. The goal of this study was to address these critical knowledge gaps by evaluating the comparative effects of arsenite (As(+3)) and the As(+3) metabolite, monomethyarsonous acid (MMA(+3)) on two critical regulatory pathways that control the differentiation and survival of early erythroid progenitor cells. We found that 500 nM As(+3) and 100 and 500 nM MMA(+3) suppress erythropoiesis by impairing the differentiation of early stage erythroid progenitors. The suppression of early erythroid progenitor cell development was attributed to combined effects on differentiation and survival pathways mediated by disruption of GATA-1 and STAT5. Our results show that As(+3) primarily disrupted GATA-1 function; whereas, MMA(+3) suppressed both GATA-1 and STAT5 activity. Collectively, these findings provide novel mechanistic insights into arsenic-induced dyserythropoiesis and suggest that MMA(+3) may be more toxic than As(+3) to early developing erythroid cells.

Arsenic exposure is well established to impair the function of zinc finger proteins, including PARP-1. Previous studies from our lab show that early developing T cells in the thymus are very sensitive to arsenite (As(+3))-induced genotoxicity mediated through PARP-1 inhibition. Additionally, it has been shown that uranium (in the form of uranyl acetate, UA) also suppresses PARP-1 activity in HEK cells. However, very little is known about whether the As(+3) metabolite, monomethylarsonous acid (MMA(+3)), also inhibits PARP-1 activity and if this is modified by combined exposures with other metals, such as uranium. In the present study, we found that MMA(+3) significantly suppressed PARP-1 function, whereas UA at high concentrations significantly increased PARP-1 activity. To evaluate whether the effects on PARP-1 activity were mediated through oxidative stress, we measured the induction of hemoxygenase-1 (Hmox-1) expression by qPCR. MMA(+3), but not UA, significantly induced oxidative stress; however, the inhibition of PARP-1 produced by MMA(+3) was not reversed by the addition of the antioxidant, Tempol. Further evaluation revealed minimal interactive effects of MMA(+3) and UA on PARP-1 function. Collectively, our results show that contrary to As(+3), the suppressive effects of MMA(+3) on PARP-1 were not substantially driven by oxidative stress in mouse thymus cells. Results for this study provide important insights into the effects of MMA(+3) and uranium exposures on PARP-1 function, which is essential for future studies focused on understanding the effects of complex environmentally relevant metal mixtures.

Anemia is a hematological disorder that adversely affects the health of millions of people worldwide. Although many variables influence the development and exacerbation of anemia, one major contributing factor is the impairment of erythropoiesis. Normal erythropoiesis is highly regulated by the zinc finger transcription factor GATA-1. Disruption of the zinc finger motifs in GATA-1, such as produced by germline mutations, compromises the function of this critical transcription factor and causes dyserythropoietic anemia. Herein, we utilize a combination of in vitro and in vivo studies to provide evidence that arsenic, a widespread environmental toxicant, inhibits erythropoiesis likely through replacing zinc within the zinc fingers of the critical transcription factor GATA-1. We found that arsenic interacts with the N- and C-terminal zinc finger motifs of GATA-1, causing zinc loss and inhibition of DNA and protein binding activities, leading to dyserythropoiesis and an imbalance of hematopoietic differentiation. For the first time, we show that exposures to a prevalent environmental contaminant compromises the function of a key regulatory factor in erythropoiesis, producing effects functionally similar to inherited GATA-1 mutations. These findings highlight a novel molecular mechanism by which arsenic exposure may cause anemia and provide critical insights into potential prevention and intervention for arsenic-related anemias.

There is limited evidence on the effects of environmental exposure to arsenic (As) on the immune system in adults. In a population-based study, we have found that urinary As (UAs), and its metabolites [inorganic As (InAs), monomethylated arsenicals (MMA+3/+5), and dimethylated arsenicals (DMA+3/+5)] modulate or influence the number of T-helper 17 (Th17) cells and IL-17A cytokine production. In non-smoking women, we observed that UAs and DMA+3/+5were associated with changes in Th17 cell numbers in a nonlinear fashion. In smoking males, we found that UAs was associated with a significant decrease of Th17 cell numbers. Similar association was observed among non-smoking males. Likewise, UAs, DMA+3/+5and MMA+3/+5were associated with diminished production of IL-17A among non-smoking males. When stratified by Vitamin D levels defined as sufficient (≥20 ng/ml) and insufficient (

Drinking water exposure to arsenic is known to cause immunotoxicity. Our previous studies demonstrated that monomethylarsonous acid (MMA+3) was the major arsenical species presented in mouse thymus cells after a 30 d drinking water exposure to arsenite (As+3). MMA+3 was also showed to be ten times more toxic than As+3 on the suppression of IL-7/STAT5 signaling in the double negative (DN) thymic T cells. In order to examine the genotoxicity induced by low to moderate doses of MMA+3, isolated mouse thymus cells were treated with 5, 50 and 500nMMMA+3 for 18h in vitro. MMA+3 suppressed the proliferation of thymus cells in a dose dependent manner. MMA+3 at 5nM induced DNA damage in DN not double positive (DP) cells. Differential sensitivity to double strand breaks and reactive oxygen species generation was noticed between DN and DP cells at 50nM, but the effects were not seen at the high dose (500nM). A stronger apoptotic effect induced by MMA+3 was noticed in DN cells than DP cells at low doses (5 and 50nM), which was negated by the strong apoptosis induction at the high dose (500nM). Analysis of intracellular MMA+3 concentrations in DN and DP cells, revealed that more MMA+3 accumulated in the DN cells after the in vitro treatment. Collectively, these results suggested that MMA+3 could directly induce strong genotoxicity in the early developing T cells in the thymus. The DN cells were much more sensitive to MMA+3 induced genotoxicity and apoptosis than DP cells, probably due to the higher intracellular levels of MMA+3.

There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.

In a cohort of approximately 200 Bangladeshi men, equally divided into smokers and nonsmokers and equally divided by exposure to high and low levels of drinking water arsenic, we examined ex vivo a series of immune markers and immune function tests in peripheral blood mononuclear cells (PBMC). These immune parameters included PBMC cell surface markers (CSM) for B, T, monocytes, and NK cells, activated T and B cell markers, cytokine production in vitro, and analysis of CD4 subsets (Th1, Th2, Treg, and Th17 cells). We found that the effects of cigarette smoke were quite different than those associated with arsenic or polycyclic aromatic hydrocarbon (PAH)-DNA adducts. Cigarette smoking was associated with a significant increase in the number of PAH-DNA adducts as well as an increase in urinary levels of 1-hydropxypyrene (1-OHP). After correcting for arsenic exposure and PAH-DNA adducts, we found that cigarette smoking was associated with an increase in the percentage of CD19+ B cells, as well as the percentage of activated B cells (CD19+, HLA-DR(bright) cells) found in PBMC. These findings demonstrate activation of the immune system during chronic exposure to cigarette smoke, which is a known risk factor for autoimmune diseases.

The progress of digitalization enables new potentials to supply chain management by available data and analysis methods. This paper focuses on the master production planning for a midterm time horizon in a volatile, diverse and capacity constrained environment. In this context, a framework for measuring quantity-and set-up-plan instability is outlined. Afterwards, a random forest machine learning approach is developed and applied on real data of a semiconductor manufacturer. The algorithm predicts the production targets and a sensitivity analysis enables an improvement of the input parameters decreasing the instability. The results foster the concept and the application field, but request extensions for capacity constraints, for algorithm comparisons and for prescriptive optimizations.

Exposures to environmental arsenic (As) and polycyclic aromatic hydrocarbons (PAH) have been shown to independently cause dysregulation of immune function. Little data exists on the associations between combined exposures to As and PAH with immunotoxicity in humans. In this work we examined associations between As and PAH exposures with lymphoid cell populations in human peripheral blood mononuclear cells (PBMC), as well as alterations in differentiation and activation of B and T cells. Two hundred men, participating in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, were selected for the present study based on their exposure to As from drinking water and their cigarette smoking status. Blood and urine samples were collected from study participants. We utilized multiparameter flow cytometry in PBMC to identify immune cells (B, T, monocytes, NK) as well as the T-helper (Th) cell subsets (Th1, Th2, Th17, and Tregs) following ex vivo activation. We did not find evidence of interactions between As and PAH exposures. However, individual exposures (As or PAH) were associated with changes to immune cell populations, including Th cell subsets. Arsenic exposure was associated with an increase in the percentage of Th cells, and dose dependent changes in monocytes, NKT cells and a monocyte subset. Within the Th cell subset we found that Arsenic exposure was also associated with a significant increase in the percentage of circulating proinflammatory Th17 cells. PAH exposure was associated with changes in T cells, monocytes and T memory (Tmem) cells and with changes in Th, Th1, Th2 and Th17 subsets all of which were non-monotonic (dose dependent). Alterations of immune cell populations caused by environmental exposures to As and PAH may result in adverse health outcomes, such as changes in systemic inflammation, immune suppression, or autoimmunity.

Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As+3) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As+3 and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As+3 induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As+3 and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As + 3 + 100 nM BP-diol and 50 nM As + 3 + 100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4-dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As+3 and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/CYP1B1 may act together to increase DNA damage produced by As+3 and PAHs.

Environmental arsenic exposure is a public health issue. Immunotoxicity induced by arsenic has been reported in humans and animal models. The purpose of this study was to evaluate mechanisms of As(+3) and MMA(+3) toxicity in mouse thymus cells. Because we know that MMA(+3) inhibits IL-7 signaling in mouse bone marrow pre-B cells, we studied the influence of As(+3) and MMA(+3) on T cell development in the thymus at the earliest stage of T cell development (CD4-CD8-, double negative, DN) which requires IL-7 dependent signaling. We found in a DN thymus cell line (D1) that a low concentration of MMA(+3) (50 nM) suppressed IL-7 dependent JAK1, 3 and STAT5 signaling. As(+3) suppressed STAT5 and JAK3 at higher concentrations (500 nM). Cell surface expression of the IL-7 receptor (CD127) was also suppressed by 50 nM MMA(+)3, but was increased by 500 NM As(+3), indicating possible differences in the mechanisms of action of these agents. A decrease in cyclin D1 protein expression was observed in D1 cells exposed to As(+3) at 500 nM and MMA(+3) starting at 50 nM, suggesting that arsenic at these environmentally-relevant doses suppresses early T cell development through the inhibition of IL-7 signaling pathway.

Human exposures to environmental metals, including uranium (U) and arsenic (As) are a global public health concern. Chronic exposures to U and As are linked to many adverse health effects including, immune suppression and autoimmunity. The gastrointestinal (GI) tract is home to many immune cells vital in the maintenance of systemic immune health. However, very little is known about the immunotoxicity of U and As at this site. The present study examined the burden of U and As exposure in the GI tract as well as the resultant immunotoxicity to intraepithelial lymphocytes (IELs) and innate immune cells of the small intestine following chronic drinking water exposures of male and female mice to U (in the form of uranyl acetate, UA) and As (in the form of sodium arsenite, As(3+)). Exposure to U or As(3+) resulted in high levels of U or As in the GI tract of male and female mice, respectively. A reduction of small intestinal CD4(+) IELs (TCRαβ(+), CD8αα(+)) was found following As(3+) exposure, whereas U produced widespread suppression of CD4(−) IEL subsets (TCRαβ(+) and TCRγδ(+)). Evaluation of innate immune cell subsets in the small intestinal lamina propria revealed a decrease in mature macrophages, along with a corresponding increase in immature/proinflammatory macrophages following As(3+) exposures. These data show that exposures to two prevalent environmental contaminants, U and As produce significant immunotoxicity in the GI tract. Collectively, these findings provide a critical framework for understanding the underlying immune health issues reported in human populations chronically exposed to environmental metals.

Historical uranium (U) mining in the Southwestern United States resulted in significant environmental contamination throughout this region and presents a significant risk of chronic metal exposure and toxicity for communities living in close proximity to mine waste sites. Uranium exposure is associated with numerous deleterious health effects including immune dysfunction; however, its effects on the immune system have yet to be fully characterized. We recently published that drinking water exposure to U, in the form of uranyl acetate (UA), results in low overall tissue retention of U (

Arsenic and polycyclic aromatic hydrocarbons (PAH) are environmental pollutants to which people around the world are exposed through water, food and air. In mouse and in vitro studies of human cells, both of these chemicals have been shown to modulate the immune system. In some experimental studies, a synergistic disruption of immune function was observed by a combined exposure to arsenic and PAH. However, a joint effect of arsenic and PAH on immune function has not been studied in humans. We have conducted an epidemiological investigation to examine effects of chronic arsenic and PAH exposures on immune function. We assessed T-cell proliferation (TCP) and cytokine production of anti-CD3/anti-CD28 stimulated lymphocytes in human peripheral blood mononuclear cells (HPBMC) among 197 healthy men enrolled to the Health Effects of Arsenic Longitudinal (HEALS) cohort in Bangladesh. By design, approximately half were active smokers and the rest were never smokers. Our analyses demonstrated that IL-1b, IL-2, IL-4 and IL-6 were significantly stimulated as a function of urinary arsenic levels in models adjusted for age, body mass index (BMI), smoking status and PAH-DNA adducts. After correcting for false detection rate (FDR), only IL-1b remained statistically significant. We found a U-shaped dose response relationship between urinary arsenic and IL-1b. On the other hand, PAH-DNA adducts were associated with an inhibition of TCP and appeared as an inverted U-shape curve. Dose response curves were non-monotonic for PAH-DNA adduct exposures and suggested that cytokine secretion of IFNg, IL-1b, IL-2, IL-10 and IL17A followed a complex pattern. In the majority of donors, there was a trend towards a decrease in cytokine associated with PAH-DNA adducts. We did not observe any interaction between urinary arsenic and PAH-DNA adducts on immune parameters. Our results indicate that long-term exposures to arsenic and PAH have independent, non-monotonic associations with TCP and cytokine production.

Inhibition of DNA repair and oxidative stress are 2 common mechanisms associated with arsenic-induced genotoxicity. The purpose of this study was to examine mechanisms of genotoxicity induced by environmentally relevant doses of arsenite (As(+3)) in mouse thymus cells. An increase in DNA damage and a decrease in poly(ADP-ribose) polymerase (PARP) activity were seen in vitro following exposure to 50 nM As(+3) in primary mouse thymus cells and a murine thymus pre-T cell line, D1. 3,4-Dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline, a well-characterized PARP inhibitor, also produced DNA damage in D1 cells, confirming the correlation between PARP inhibition and DNA damage increase. As(+3) at 500 nM induced double strand breaks (DSBs) in DNA and oxidative stress at 4 h in D1 cells, which was reversed at 18 h. No apoptosis or decrease of viability was observed in these exposures. 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, a widely-used antioxidant, was utilized to confirm that oxidative stress is partially responsible for the increase of strand breaks in 500 nM As(+3) exposure at 4 h. Expression of As(+3) exporters, Mdr1 and Mrp1, were found to be induced by 500 nM As(+3) in D1 cells, suggesting a possible mechanism for reversal of oxidative stress and DSBs at the 18-h timepoint. Finally, we showed that DNA damage and PARP inhibition by As(+3) were reversed by zinc (Zn(+2)) at approximate equimolar doses. Collectively, these results demonstrate that As(+3) at doses within the nanomolar range induce genotoxicity by inhibiting PARP, and produces oxidative stress at higher concentrations, which can be reversed by a Zn(+2) treatment.

Arsenite (As+3) and dibenzo[def,p]chrysene (DBC), a polycyclic aromatic hyrdrocarbon (PAH), are found in nature as environmental contaminants. Both are known to individually suppress the immune system of humans and mice. In order to determine their potential interactive and combined immunosuppressive effects, we examined murine bone marrow (BM) immune progenitor cells’ responses following combined oral exposures at very low levels of exposure to As+3 and DBC. Oral 5-day exposure to DBC at 1 mg/kg (cumulative dose) was found to suppress mouse BM lymphoid progenitor cells, but not the myeloid progenitors. Previously established no-effect doses of As+3 in drinking water (19 and 75 ppb for 30 days) produced more lymphoid suppression in the bone marrow when mice were concomitantly fed a low dose of DBC during the last 5 days. The lower dose (19 ppb) As+3 had a stronger suppressive effect with DBC than the higher dose (75 ppb). Thus, the interactive toxicity of As+3 and DBC in vivo could be As+3 dose dependent. In vitro, the suppressive interaction of As+3 and DBC was also evident at low concentrations (0.5 nM), but not at higher concentrations (5 nM) of As+3. These studies show potentially important interactions between As+3 and DBC on mouse BM at extremely low levels of exposure in vivo and in vitro.

The current study aimed to explore the impact of visual dependence on sensorimotor coupling of postural sway and visual motion in adults and teens with spastic cerebral palsy (CP). We hypothesized that individuals with CP would exhibit greater magnitudes of sway than healthy individuals, and the presence of visual dependence (VD) would produce instability in the direction of visual motion. Participants stood in a virtual environment in which the visual scene remained static or continuously rotated 30 degree/second in pitch-up or pitch-down. Increased center of pressure and center of mass responses were observed in the direction of visual scene motion in those with CP. Those with VD exhibited reduced frequency responses in anterior-posterior direction than those who were visually independent. VD suggests deficient sensorimotor integration that could contribute to postural instability and reduced motor function. Individuals with CP who are visually dependent may benefit from more sensory focused rehabilitation strategies.AP, anterior-posterior; CP, cerebral palsy; COM, center of mass; COP, center of pressure; MDF, median frequency; ML, mediolateral; PD, pitch down (nose down) rotation; PU, pitch up (nose up) rotation; RFT, rod and frame test; RMS, root mean square; SLP, slope of the fitted line; TD, typical development; VD, visual dependence; VI, visual independence; VOR, vestibulo-ocular reflex; VPI, visual perceptual impairment.

This unit describes procedures for the isolation, cryopreservation, and thawing of human peripheral blood mononuclear cells (HPBMC) and analysis of cell surface markers (CSM) for immunophenotyping using polychromatic flow cytometry. This methodology can be used to ensure that cell integrity and phenotype stability are not altered through cryopreservation and extended storage. For this analysis, HPBMC were isolated from 7 healthy individuals, and 11-color flow cytometry was performed on freshly isolated samples as well as samples cryopreserved for short- and long-term periods. There is no significant difference in the percentage of cells expressing the CSM CD3, CD4, CD8, CD45RO, CD16, CD19, or CD56 between freshly isolated and cryopreserved HPBMC. Hence, cryopreservation of HPBMC does not influence the phenotype of distinct cellular subsets in isolated mononuclear cells. This protocol for HPBMC isolation, cryopreservation, and thawing of HPBMC is intended for long-term studies of large cohorts requiring sample shipment and subsequent batch analysis. © 2017 by John Wiley & Sons, Inc.

In a recent unit in this series, protocols for the isolation, cryopreservation, thawing, and immunophenotyping of HPBMC isolated from peripheral whole blood using cell surface marker (CSM) staining and multi-color flow cytometry analysis were presented. The current procedure describes the detection and quantification of CSM and intracellular markers (ICM), including transcription factors and cytokines, following activation and differentiation of CD4+ T-cells using multi-color flow cytometry. Results indicated that repeatable and robust detection of ICM could be obtained in surface marker-defined T cells that identify functional subsets of cells. There were no observed differences between fresh and cryopreserved HPBMC in eight phenotypes analyzed (T-CD3, Th-CD4, Tmem-CD45RO, activated T-CD3/CD25, Treg- Foxp3/CD25, Th1-IFNγ, Th2- IL-4, Th17-IL-17A). There was an observed difference in activated T- CD3/CD69 in the short term (30-90 days) cryopreserved samples as compared to the freshly isolated samples, which may have resulted from the variance in controls or small sample size. © 2017 by John Wiley & Sons, Inc.

Drinking water exposure to arsenic is known to cause immunotoxicity. Our previous studies demonstrated that monomethylarsonous acid (MMA(+3)) was the major arsenical species presented in mouse thymus cells after a 30 d drinking water exposure to arsenite (As(+3)). MMA(+3) was also showed to be ten times more toxic than As(+3) on the suppression of IL-7/STAT5 signaling in the double negative (DN) thymic T cells. In order to examine the genotoxicity induced by low to moderate doses of MMA(+3), isolated mouse thymus cells were treated with 5, 50 and 500 nM MMA(+3) for 18 h in vitro. MMA(+3) suppressed the proliferation of thymus cells in a dose dependent manner. MMA(+3) at 5 nM induced DNA damage in DN not double positive (DP) cells. Differential sensitivity to double strand breaks and reactive oxygen species generation was noticed between DN and DP cells at 50 nM, but the effects were not seen at the high dose (500 nM). A stronger apoptotic effect induced by MMA(+3) was noticed in DN cells than DP cells at low doses (5 and 50 nM), which was negated by the strong apoptosis induction at the high dose (500 nM). Analysis of intracellular MMA(+3) concentrations in DN and DP cells, revealed that more MMA(+3) accumulated in the DN cells after the in vitro treatment. Collectively, these results suggested that MMA(+3) could directly induce strong genotoxicity in the early developing T cells in the thymus. The DN cells were much more sensitive to MMA(+3) induced genotoxicity and apoptosis than DP cells, probably due to the higher intracellular levels of MMA(+3).

Arsenite (As+3) exposure is known to cause immunotoxicity in human and animal models. Our previous studies demonstrated that As+3 at 50-500 nM concentrations induced both genotoxicity and nongenotoxicity in mouse thymus cells. Developing T cells at CD4-CD8- double negative (DN) stage, the first stage after early T cells are transported from bone marrow to thymus, were found to be more sensitive to As+3 toxicity than the T cells at CD4 + CD8 + double positive (DP) stage in vitro. Induction of Mdr1 (Abcb1) and Mrp1 (Abcc1), 2 multidrug resistance transporters and exporters of As+3, was associated with the reversal of As+3-induced double strand breaks and DNA damage. In order to confirm that the thymus cell populations have different sensitivity to As+3in vivo, male C57BL/6J mice were exposed to 0, 100, and 500 ppb As+3 in drinking water for 30 d. A significant decrease in DN cell percentage was observed with exposure to 500 ppb As+3. Low to moderate concentrations of As+3 were shown to induce higher genotoxicity in sorted DN than DP cells in vitro. Calcein AM uptake and Mdr1/Mrp1 mRNA quantification results revealed that DN cells not only had limited As+3 exporter activity, but also lacked the ability to activate these exporters with As+3 treatments, resulting in a higher accumulation of intracellular As+3. Knockdown study of As+3 exporters in the DN thymic cell line, D1 using siRNA, demonstrated that Mdr1 and Mrp1 regulate intracellular As+3 accumulation and genotoxicity. Taken together, the results indicate that transporter regulation is an important mechanism for differential genotoxicity induced by As+3 in thymocytes at different developmental stages.

Drinking water arsenic (WAs) exposure has been linked to a number of detrimental health outcomes including anemia, primarily among pregnant women. Little is known about the effects of arsenic (As) on hematological disorders among men. We have examined the role of As exposure on hematological indicators of anemia in a group of men exposed to a wide range of As in their drinking water. We conducted a cross-sectional investigation among 119 healthy men in the Health Effects of As Longitudinal Study (HEALS) cohort, in rural Bangladesh. The participants are part of an ongoing study focused on evaluating the influence of As and smoking on immune function. Samples were collected at recruitment and analyzed for water As, urinary As (UAs) and UAs metabolites to assess As exposure. Blood samples were also collected at recruitment and assayed immediately for hematological parameters. We found that increased WAs levels were associated with decreased red blood cell counts [β=-0.13, p

We report on the evaluation of commercial electroless nickel phosphorus (NiP) coatings for ultracold neutron (UCN) transport and storage. The material potential of 50~$\mu$m thick NiP coatings on stainless steel and aluminum substrates was measured to be $V_F = 213(5.2)$~neV using the time-of-flight spectrometer ASTERIX at the Lujan Center. The loss per bounce probability was measured in pinhole bottling experiments carried out at ultracold neutron sources at Los Alamos Neutron Science Center and the Institut Laue-Langevin. For these tests a new guide coupling design was used to minimize gaps between the guide sections. The observed UCN loss in the bottle was interpreted in terms of an energy independent effective loss per bounce, which is the appropriate model when gaps in the system and upscattering are the dominate loss mechanisms, yielding a loss per bounce of $1.3(1) \times 10^{-4}$. We also present a detailed discussion of the pinhole bottling methodology and an energy dependent analysis of the experimental results., Comment: 13 pages, 14 figures

Setting Victoria, Australia. Objective To describe the epidemiology and control of tuberculosis (TB) in Victoria, 2005-2010. Design Retrospective review of laboratory-confirmed TB in Victoria, 2005-2010. State TB reference laboratory records were matched with Department of Health notification records to obtain laboratory, demographic, clinical and treatment data. Results The incidence of TB fell in the Australian-born population but increased overall, reflecting an increase in the proportion of overseas-born cases from 88.9% to 95.8% between 2005 and 2010 (P = 0.03). Patients from India and Viet Nam accounted for over one third of all cases. For overseas-born cases, the median time between arrival and diagnosis was 4 years. Half of all diagnoses were pulmonary disease, of which 45.4% were Ziehl-Neelsen smear-positive. Treatment was most commonly self-administered (76.9%), and very few patients defaulted or failed treatment (1.1%). Only 4.1% of cases were linked to another laboratory-confirmed case. Multidrug-resistant TB remained uncommon (1.7% of cases). Conclusions TB in Victoria remains low by global standards and continues to overwhelmingly affect the overseas-born population. Current TB control strategies in Victoria are effective, but strengthened control in high-burden countries will also improve TB control locally.

Epidemiological studies report an association between chronic arsenic (As) exposure and anemia in men, and women who are predisposed to anemia. The purpose of these studies was to determine whether a 60 d drinking water exposure of adult male C57BL/6J mice to 0, 100, and 500ppb arsenite (As+3) results in anemia due to alterations in erythroid progenitor cell development in the bone marrow. Exposure to 500ppb As+3 for 60 d resulted in a reduction of mean corpuscular hemoglobin (MCH) levels, but did not significantly alter red blood cell (RBC) counts, hemoglobin (Hgb) levels, mean corpuscular Hgb concentrations (MCHC), or mean corpuscular volumes (MCV). Attenuation of burst-forming unit-erythroid (BFU-E) colony formation was observed in bone marrow cells of mice exposed to 500ppb As+3. The differentiation of late-stage bone marrow erythroblasts as defined by CD71 and Ter119 surface marker expression was reduced with the 500ppb As+3 exposure. Mice exposed to 500ppb As+3 also had elevated serum levels of erythropoietin (EPO). Collectively, these results show that exposure to low levels of As+3 attenuate the development of early BFU-E cells and reduce the differentiation of late-stage erythroblasts. This suppression of bone marrow erythropoiesis may be a contributing factor to the mild hypochromic anemia observed in 500ppb As+3 exposed mice.

At Institut Laue-Langevin (ILL) and Paul Scherrer Institute (PSI), we have measured the losses and depolarization probabilities of ultracold neutrons on various materials: (i) nickel-molybdenum alloys with weight percentages of 82/18, 85/15, 88/12, 91/9, and 94/6 and natural nickel Ni100, (ii) nickel-vanadium NiV93/7, (iii) copper, and (iv) deuterated polystyrene (dPS). For the different samples, storage-time constants up to $\ensuremath{\sim}460\phantom{\rule{0.16em}{0ex}}\mathrm{s}$ were obtained at room temperature. The corresponding loss parameters for ultracold neutrons, $\ensuremath{\eta}$, varied between $1.0\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$ and $2.2\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$. All $\ensuremath{\eta}$ values are in agreement with theory except for dPS, where anomalous losses at room temperature were established with four standard deviations. The depolarization probabilities per wall collision $\ensuremath{\beta}$ measured with unprecedented sensitivity varied between $0.7\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}6}$ and $9.0\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}6}$. Our depolarization result for copper differs from other experiments by 4.4 and 15.8 standard deviations. The $\ensuremath{\beta}$ values of the paramagnetic NiMo alloys over molybdenum content show an increase of $\ensuremath{\beta}$ with increasing Mo content. This is in disagreement with expectations from literature. Finally, ferromagnetic behavior of NiMo alloys at room temperature was found for molybdenum contents of 6.5 at.% or less and paramagnetic behavior for more than 8.7 at.%. This may contribute to solving an ambiguity in literature.

It is known in humans and mouse models, that drinking water exposures to arsenite (As +3 ) leads to immunotoxicity. Previously, our group showed that certain types of immune cells are extremely sensitive to arsenic induced genotoxicity. In order to see if cells from different immune organs have differential sensitivities to As +3 , and if the sensitivities correlate with the intracellular concentrations of arsenic species, male C57BL/6J mice were dosed with 0, 100 and 500 ppb As +3 via drinking water for 30 d. Oxidation State Specific Hydride Generation- Cryotrapping- Inductively Coupled Plasma- Mass Spectrometry (HG- CT- ICP- MS) was applied to analyze the intracellular arsenic species and concentrations in bone marrow, spleen and thymus cells isolated from the exposed mice. A dose-dependent increase in intracellular monomethylarsonous acid (MMA +3 ) was observed in both bone marrow and thymus cells, but not spleen cells. The total arsenic and MMA +3 levels were correlated with an increase in DNA damage in bone marrow and thymus cells. An in vitro treatment of 5, 50 and 500 nM As +3 and MMA +3 revealed that bone marrow cells are most sensitive to As +3 treatment, and MMA +3 is more genotoxic than As +3 . These results suggest that the differential sensitivities of the three immune organs to As +3 exposure are due to the different intracellular arsenic species and concentrations, and that MMA +3 may play a critical role in immunotoxicity.

Controlled laboratory study.To assess scapular kinematics and electromyographic signal amplitude of the shoulder musculature, before and after thoracic spine manipulation (TSM) in subjects with rotator cuff tendinopathy (RCT). Changes in range of motion, pain, and function were also assessed.There are various treatment techniques for RCT. Recent studies suggest that TSM may be a useful component in the management of pain and dysfunction associated with RCT.Thirty subjects between 18 and 45 years of age, who showed signs of RCT, participated in this study. Changes in scapular kinematics and muscle activity, as well as changes in shoulder pain and function, were assessed pre-TSM and post-TSM using paired t tests and repeated-measures analyses of variance.TSM did not lead to changes in range of motion or scapular kinematics, with the exception of a small decrease in scapular upward rotation (P = .05). The only change in muscle activity was a small but significant increase in middle trapezius activity (P = .03). After TSM, subjects demonstrated decreased pain during performance of the Jobe empty-can (mean ± SD change, 2.6 ± 1.1), Neer (2.6 ± 1.3), and Hawkins-Kennedy (2.8 ± 1.3) tests (all, P.001). Subjects also reported decreased pain with shoulder flexion (mean ± SD change, 2.0 ± 1.5; P.001) and improved shoulder function (force production, 2.5 ± 1.4 kg; Penn Shoulder Score, 7.7 ± 9.4; sports/performing arts module of the Disabilities of the Arm, Shoulder and Hand questionnaire, 16.4 ± 13.2) (all, P.001).Immediate improvements in shoulder pain and function post-TSM are not likely explained by alterations in scapular kinematics or shoulder muscle activity. For people with pain associated with RCT, TSM may be an effective component of their treatment plan to improve pain and function. However, further randomized controlled studies are necessary to better validate this treatment approach.Therapy, level 4.

We have built a device to filter ultracold neutrons with axial velocities v n ≤ 8.0 m / s from faster neutrons. The apparatus has been successfully tested at the Institut Laue-Langevin in Grenoble and is used in specific experiments, e.g., the measurement of ultracold neutron transmission through various types of neutron guides.

Breast cancer is the most common cancer and the second leading cause of cancer-related mortality worldwide. The etiology of breast cancer is very diverse and ethanol (EtOH) consumption is a well-established risk factor for breast cancer in women. However, the mechanism by which EtOH exerts its carcinogenic activity in breast tissue remains unknown. CYP2E1 is known to metabolize ethanol and produce reactive oxygen species (ROS), including superoxide in epithelial cells. Therefore, in the present studies, we investigated whether there is an increase in ROS following overexpression of CYP2E1 in MCF-10A cells. We found that 30 and 100 mM EtOH increased ROS levels after 2 h treatment in CYP2E1 overexpressing cells. Based on these results and our previous studies with ROS-producing chemicals, we also examined epidermal growth factor receptor (EGFR) activation following exposure to ethanol. We found that there was an increase in phosphorylation of pY1086 EGFR after 18 h EtOH treatment in CYP2E1 overexpressing cells. These studies support a hypothesis that EtOH might increase human mammary cell activation, via an EGFR-dependent signaling mechanism associated with oxidative stress.

Purpose The purpose of this study was to examine the relationship between spasticity and muscle volume in children with cerebral palsy (CP), using isokinetic dynamometry and magnetic resonance imaging. Methods A retrospective sample of 8 children with diplegic CP was analyzed. One set of 10 passive knee flexion movements was completed at a velocity of 180° per second with concurrent surface electromyography of the medial hamstrings (MH) and vastus lateralis (VL) to assess knee extensor spasticity. Magnetic resonance imaging was used to measure maximum cross-sectional area and muscle volume of the quadriceps femoris. Results The quadriceps femoris muscle volume was positively correlated with MH reflex activity, VL reflex activity, MH/VL co-contraction, and peak knee extensor passive torque (P Conclusion The present findings suggest that higher levels of knee extensor muscle spasticity are associated with greater quadriceps muscle volume in children with spastic diplegic CP.

Investigations of thin film depositions of silicon carbide (SiC) from pulse sputtering a hollow cathode SiC target are presented. The unique feature of the hollow cathode technique is that germanium can be added to the films. This changes the properties of the SiC. Such changes include evidence of Ge C bonds, lowering of the resistivity, and lowering of the bandgap. The analysis includes crystallographic and morphological studies of the deposited films and their quality using X-ray diffraction, transmission electron microscopy, scanning electron microscopy, and Raman spectroscopy data. Basic electrical properties are also presented along with optical bandgap information gathered from spectroscopic ellipsometry data.

Foliar tissue of turkey oak trees, Quercus laevis Walter (Fagales: Fagaceae), were manually damaged in an attempt to investigate their wounding response. Leaves were damaged with a hole punch early in the growing season to simulate herbivory. To another group of trees, the hormone, jasmonic acid, was applied to leaves in situ to determine if this volatile compound associated with wounding could elicit a defensive response in non-damaged trees. Foliar tannin concentration increased in both control and treated trees within 2 weeks after the experiment had been begun. Damaged trees exhibited a 56.5% increase in foliar tannin concentration and trees applied with jasmonic acid showed a 62.4% increase while control trees had only a 35.9% increase; however, these differences were not significant. Interestingly, manually damaged leaves demonstrated a 72.5% increase in crude tannin levels, whereas non-damaged leaves on damaged trees showed only a 42.3% increase. These differences approached significance and suggest that damage to leaves induced an increase in tannins, but this increase was not systemic. Moreover, damaged and jasmonate-treated trees had significantly fewer insects compared with control trees. Manually damaged leaves had the highest tannin concentration after treatment, and this was interpreted to be an induced defense or wounding response. Jasmonic acid appeared to have no effect on foliar tannin concentration; however, the number of herbivorous insects on jasmonic acid treated trees was similar to the number on damaged trees.

Aim To compare the effects of a supported speed treadmill training exercise program (SSTTEP) with exercise on spasticity, strength, motor control, gait spatiotemporal parameters, gross motor skills, and physical function. Method Twenty-six children (14 males, 12 females; mean age 9y 6mo, SD 2y 2mo) with spastic cerebral palsy (CP; diplegia, n=12; triplegia, n=2; quadriplegia n=12; Gross Motor Function Classification System levels II–IV) were randomly assigned to the SSTTEP or exercise (strengthening) group. After a twice daily, 2-week induction, children continued the intervention at home 5 days a week for 10 weeks. Data collected at baseline, after 12-weeks’ intervention, and 4 weeks after the intervention stopped included spasticity, motor control, and strength; gait spatiotemporal parameters; Gross Motor Function Measure (GMFM); and Pediatric Outcomes Data Collection Instrument (PODCI). Results Gait speed, cadence, and PODCI global scores improved, with no difference between groups. No significant changes were seen in spasticity, strength, motor control, GMFM scores, or PODCI transfers and mobility. Post-hoc testing showed that gains in gait speed and PODCI global scores were maintained in the SSTTEP group after withdrawal of the intervention. Interpretation Although our hypothesis that the SSTTEP group would have better outcomes was not supported, results are encouraging as children in both groups showed changes in function and gait. Only the SSTTEP group maintained gains after withdrawal of intervention.

Thin SiC buffer layers have been grown by sputtering a graphite C target onto both (111) and (110) Si substrates. Converting the graphitic C into SiC is highly temperature dependent and relies on free silicon atoms that sublime from voids in the substrate at higher temperatures. Morphological and structural investigations were performed by Field Emission Scanning Electron Microscopy (FESEM) and X-ray Diffraction (XRD).

International audience; We describe the status of the new measurement of the neutron electric dipole moment (nEDM) to be performed at the strong source of ultra-cold neutrons at the Paul Scherrer Institut. The experimental technique is based on Ramsey's method of separated oscillatory fields, applied to UCN stored in vacuum in a chamber at room temperature. Our approach is performed in three phases: in phase one, new components have been developed and tested at the Institut Laue-Langevin. Phase two is being performed at PSI, where the apparatus was moved in 2009. Here, together with the optimization of the magnetic environment, the prospective UCN density of not, vert, similar 100 cm-3 should enable an improvement of the currently best limit by a factor of five within two years of data taking. In the third phase, a new spectrometer will then gain another order of magnitude in sensitivity. The improvements will be mainly due to (1) much higher UCN intensity, (2) improved magnetometry and magnetic field control, and (3) a double chamber configuration with opposite electric field directions.

High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to uranyl acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (

Die aktuelle Leitlinie der ESC stellt ein hilfreiches und im klinischen Alltag praktikables Instrument in der Risikostratifizierung von Patienten im Kontext eines geplanten operativen Eingriffes als auch im perioperativen Management dar. Besonders wertvoll erscheinen die klare Strukturierung der Risikostratifizierung von Patienten und geplantem operativem Eingriff in den 3 Risikokategorien niedrig, mittel und hoch und die sich daraus ableitenden Konsequenzen im medikamentosen als auch diagnostischen und interventionellen pra-, peri- und postoperativen Management. Der grundlegende Algorithmus und Entscheidungsbaum wird auch in den parallel zu diesem Kommentar publizierten Pocket-Leitlinien der Deutschen Gesellschaft fur Kardiologie eine zentrale Stellung einnehmen.