MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress.

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress.

Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: a Chronic Effects of Neurotrauma Consortium Study.

Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI).

Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury.

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE.

Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study.

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI.

Patterns of Twitter Behavior Among Networks of Cannabis Dispensaries in California.

Background: Twitter represents a social media platform through which medical cannabis dispensaries can rapidly promote and advertise a multitude of retail products. Yet, to date, no studies have systematically evaluated Twitter behavior among dispensaries and how these behaviors influence the formation of social networks.

Objectives: This study sought to characterize common cyberbehaviors and shared follower networks among dispensaries operating in two large cannabis markets in California.

Predictors of Neurocognitive Syndromes in Combat Veterans.

Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability.

Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy.

Purpose: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis.

Social and medical vulnerability factors of emergency department frequent users in a universal health insurance system.

Objectives: The objectives were to identify the social and medical factors associated with emergency department (ED) frequent use and to determine if frequent users were more likely to have a combination of these factors in a universal health insurance system.

Methods: This was a retrospective chart review case-control study comparing randomized samples of frequent users and nonfrequent users at the Lausanne University Hospital, Switzerland. The authors defined frequent users as patients with four or more ED visits within the previous 12 months.

Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial.

Objective: To evaluate whether early mobilization after acute ischaemic stroke is better than delayed mobilization with regard to medical complications and if it is safe in relation to neurological function and cerebral blood flow.

Design: Randomized controlled pilot trial of early versus delayed mobilization out of bed with incidence of severe complications as the primary outcome.

Setting: Acute stroke unit in the neurology department of a University Hospital.

Acute life-threatening extrinsic allergic alveolitis in a paint controller.

Background: Occupational diisocyanate-induced extrinsic allergic alveolitis (EAA) is a rare and probably underestimated diagnosis. Two acute occupational EAA cases have been described in this context, but neither of them concerned hexamethylene diisocyanate (HDI) exposure.

Aims: To investigate the cause of a life-threatening EAA arising at work in a healthy 30-year-old female paint quality controller.

Estimating model-adjusted risks, risk differences, and risk ratios from complex survey data.

There is increasing interest in estimating and drawing inferences about risk or prevalence ratios and differences instead of odds ratios in the regression setting. Recent publications have shown how the GENMOD procedure in SAS (SAS Institute Inc., Cary, North Carolina) can be used to estimate these parameters in non-population-based studies.

CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma.

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue.

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive.

Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways.

Background: Recent evidence indicates that zoledronate, a nitrogen-containing bisphosphonate used to treat conditions of increased bone resorption, may have anti-angiogenic activity. The endothelial cells signaling events modulated by zoledronate remain largely elusive.

Objectives: The aim of this work was to identify signaling events suppressed by zoledronate in endothelial cells and responsible for some of its biological effects.

Prenatal developmental toxicity evaluation of 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T) co-administered to Swiss Albino (CD-1) mice.

Background: In pregnant women, antiretroviral drugs improve maternal health and reduce vertical transmission of human immunodeficiency virus to the infant. However, few nonclinical studies have examined the potential for adverse drug interactions.

Methods: On gestational days (GD) 6-16, mice were dosed with vehicle, ddI (360, 1440, or 2,880 mg/kg/day, p.

Expressed isolated integrin beta1 subunit cytodomain induces endothelial cell death secondary to detachment.

Expression of isolated beta integrin cytoplasmic domains in cultured endothelial cells was reported to induce cell detachment and death. To test whether cell death was the cause or the consequence of cell detachment, we expressed isolated integrin beta1 cytoplasmic and transmembrane domains (CH1) in cultured human umbilical vein endothelial cells (HUVEC), and monitored detachment, viability, caspase activation and signaling. CH1 expression induced dose-dependent cell detachment.

Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt.

Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis.

Urokinase-type plasminogen activator inhibits alpha 4 beta 1 integrin-mediated T lymphocyte adhesion to fibronectin independently of its catalytic activity.

The urokinase-type plasminogen activator (u-PA)/plasmin system plays an important role in promoting cell migration and invasion, an effect which is largely ascribed to the proteolytic activity of these enzymes. We investigated whether u-PA modulates integrin-dependent T lymphocyte migration and adhesion on fibronectin independently of its plasminogen activator function. Here we report that u-PA reduced the spontaneous and phorbol 12-myristate 13-acetate-induced migration of peripheral blood T lymphocytes on fibronectin by 20-50%, decreased the T lymphocyte and alpha4beta1(+)/alpha5beta1(+) K562 cell adhesion on fibronectin by 30-40%, and completely suppressed integrin alpha4beta1-dependent T lymphocyte and alpha4beta1(+)/alpha5beta1(+) K562 cell adhesion to the LDV-containing 40-kDa fibronectin fragment.

Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon-gamma results in simultaneous synergistic and reversible effects on proliferation and morphology.

Regional administration of high doses of tumor necrosis factor (TNF), interferon gamma (IFNgamma) and melphalan to patients with advanced cancers of the limbs, results in rapid and specific tumor necrosis, while the normal adjacent tissues remain unaffected. The tumor vasculature is selectively destroyed by this treatment, and neovascular endothelial cells appear to be an early and specific target of TNF and IFNgamma. To further understand some of the cellular events underlying these in vivo effects, we have investigated the response of human macro- and microvascular endothelial cells in vitro, after exposure to high doses of TNF and IFNgamma (up to 40 x 10(3) U/ml each).

Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma.

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma.

Analysis of prevention program effectiveness with clustered data using generalized estimating equations.

Experimental studies of prevention programs often randomize clusters of individuals rather than individuals to treatment conditions. When the correlation among individuals within clusters is not accounted for in statistical analysis, the standard errors are biased, potentially resulting in misleading conclusions about the significance of treatment effects. This study demonstrates the generalized estimating equations (GEE) method, focusing specifically on the GEE-independent method, to control for within-cluster correlation in regression models with either continuous or binary outcomes.

Cluster sampling techniques in quantal response teratology and developmental toxicity studies.

This paper presents a model-free approach for evaluating teratology and developmental toxicity data involving clustered binary responses. In teratology studies, a major statistical problem arises from the effect of intralitter correlation, or the potential for littermates to respond similarly. Some statistical methods impose strict distributional assumptions to account for extra-binomial variation, while others rely on nonparametric resampling and empirical variance estimation techniques.

Long-term evaluation of drug abuse resistance education.

Project DARE (Drug Abuse Resistance Education) is the most prevalent school-based drug-use prevention program in the United States, but there is little evidence of its effectiveness. Results from a longitudinal evaluation of the program in 36 schools in Illinois provide only limited support for DARE's impact on student's drug use immediately following the intervention, and no support for either continued or emerging impact on drug use 1 or 2 years after receiving DARE instruction. In addition, DARE had only limited positive effects on psychological variables (i.

Developmental neurotoxicity evaluation of orally administered isopropanol in rats.

Isopropanol was administered by gavage to timed-mated rats from Gestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administered were 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg. The dams were allowed to deliver and body weights and food consumption were recorded during gestation and lactation.

Ratio estimates, the delta method, and quantal response tests for increased carcinogenicity.

This paper demonstrates the use of the delta method for estimating the variance of ratio statistics derived from animal carcinogenicity experiments. The Cochran-Armitage test (Cochran, 1954, Biometrika 10, 417-451; and Armitage, 1955, Biometrics 11, 375-386) is routinely applied to carcinogenicity data as a test for linear trend in lifetime tumor incidence rates. The computing formula for this test derives from the assumption that the denominators of the quantal response rates are fixed.