Mouse-INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy.

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p > 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p > 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Contrast-Enhanced Sonography in Patients with Hyposplenia: A Retrospective Analysis in Forty-Three Patients.

PURPOSE: In contrast to splenomegaly, the clinical value of a small spleen (hyposplenia) is unclear. Contrast-enhanced ultrasound (CEUS) has not been investigated systematically in hyposplenia. METHODS: Between February 2005 and January 2017, 43 patients with hyposplenia (< 7 × 3 cm) were examined by B-mode ultrasound (US) and CEUS. A retrospective data analysis was performed. RESULTS: A total of 39 (91%) patients had an underlying disease (UD; allogenic stem cell transplantation, n = 16; autoimmune-diseases, n = 7; sickle cell anemia, n = 5; solid tumors, n = 5; others, n = 6). In 4 (9%) cases, hyposplenia was an incidental finding. The echogenicity of the spleen was normal (homogeneous, isoechogenic) in 17 (39.5%) and abnormal in 26 (60.5%) cases (inhomogeneous, n = 26 and hyperechoic, n = 9). In CEUS, 21 (49%) patients presented a normal isoenhancement. An abnormal enhancement was detected in 22 (51%) patients with UD (arterial/parenchymal inhomogeneous, n = 1; no [arterial, n = 3 and parenchymal, n = 6]; reduced [arterial, n = 8 and parenchymal, n = 15]). CONCLUSIONS: Hyposplenia is a rare pathologic finding and often associated with hematological/oncological and autoimmune diseases. Furthermore, altered B-mode US appearance and a pathological CEUS pattern are frequently found. However, the clinical implication, especially regarding splenic function remains obscure to date.

Enhancement of Meditation Analgesia by Opioid Antagonist in Experienced Meditators.

OBJECTIVE: Studies have consistently shown that long-term meditation practice is associated with reduced pain, but the neural mechanisms by which long-term meditation practice reduces pain remain unclear. This study tested endogenous opioid involvement in meditation analgesia associated with long-term meditation practice. METHODS: Electrical pain was induced with randomized, double-blind, cross-over administration of the opioid antagonist naloxone (0.15-mg/kg bolus dose, then 0.2-mg/kg per hour infusion dose) with 32 healthy, experienced meditation practitioners and a standardized open monitoring meditation. RESULTS: Under saline, pain ratings were significantly lower during meditation (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17) than at baseline (pain intensity: 6.86 ±1.04, t(31) = 2.476, p = .019, Cohen's d = 0.46; pain unpleasantness: 4.96 ±1.75, t(31) = 3.746, p = .001, Cohen's d = 0.68), confirming the presence of meditation analgesia. Comparing saline and naloxone revealed significantly lower pain intensity (t(31) = 3.12, p = .004, d = 0.56), and pain unpleasantness (t(31) = 3.47, p = .002, d = 0.62), during meditation under naloxone (pain intensity: 5.53 ± 1.54; pain unpleasantness: 2.95 ± 1.88) than under saline (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17). Naloxone not only failed to eliminate meditation analgesia but also made meditation analgesia stronger. CONCLUSIONS: Long-term meditation practice does not rely on endogenous opioids to reduce pain. Naloxone's blockade of opioid receptors enhanced meditation analgesia; pain ratings during meditation were significantly lower under naloxone than under saline. Possible biological mechanisms by which naloxone-induced opioid receptor blockade enhances meditation analgesia are discussed.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT: Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.

INTRODUCTION: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated ß-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. METHODS: Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. RESULTS: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. CONCLUSION: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.

Evidence for a fixed capacity limit in attending multiple locations.

A classic question concerns whether humans can attend multiple locations or objects at once. Although it is generally agreed that the answer to this question is "yes," the limits on this ability are subject to extensive debate. According to one view, attentional resources can be flexibly allocated to a variable number of locations, with an inverse relationship between the number of selected locations and the quality of information processing at each location. Alternatively, these resources might be quantized in a "discrete" fashion that enables concurrent access to a small number of locations. Here, we report a series of experiments comparing these alternatives. In each experiment, we cued participants to attend a variable number of spatial locations and asked them to report the orientation of a single, briefly presented target. In all experiments, participants' orientation report errors were well-described by a model that assumes a fixed upper limit in the number of locations that can be attended. Conversely, report errors were poorly described by a flexible-resource model that assumes no fixed limit on the number of locations that can be attended. Critically, we showed that these discrete limits were predicted by cue-evoked neural activity elicited before the onset of the target array, suggesting that performance was limited by selection processes that began prior to subsequent encoding and memory storage. Together, these findings constitute novel evidence supporting the hypothesis that human observers can attend only a small number of discrete locations at an instant.

CMR reveals myocardial damage from cardiotoxic oncologic therapies in breast cancer patients.

BACKGROUND: Breast cancer is a common and increasingly treatable disease. However, survivors have a significantly elevated risk of cardiac events afterwards. This study aimed to characterise cardiac changes during cardiotoxic cancer therapy using cardiovascular magnetic resonance (CMR) imaging. METHODS: This study involved 34 patients with histologically proven breast cancer and planned cardiotoxic therapy. All patients underwent CMR before starting therapy, and 6 and 12 months thereafter. The CMR protocol included volumetric and functional analyses, parametric mapping, and deformation analysis using feature tracking. As the control group, 10 healthy female volunteers were scanned using the same protocol. RESULTS: With therapy, there was a significant reduction of left ventricular and right ventricular ejection fractions (both p < 0.05) without reaching pathologic values. Left ventricular radial (p = 0.008), circumferential (p = 0.010), and longitudinal strain (p = 0.036) were also reduced at follow-up. In the parametric mapping, there was a significant increase in native T1 time (start: 1037 ± 41 ms vs. 6 months: 1068 ± 51 ms vs. 12 months: 1017 ± 57 ms, p < 0.001) and T2 time (start: 55 ± 4 ms vs. 6 months: 59 ± 3 ms vs. 12 months: 57 ± 3 ms, p = 0.001), with unchanged extracellular volume and relative late gadolinium enhancement. Twelve months after cancer diagnosis, the breast cancer patients exhibited significant impairments in left ventricular global radial (p = 0.001), circumferential (p = 0.001), and longitudinal strain (p = 0.002) and T2 time (p = 0.008) compared to the healthy controls. DISCUSSION: Breast cancer patients receiving cardiotoxic chemotherapy show persistent deterioration in left ventricular strain values. This is accompanied by inflammatory changes in non-invasive tissue characterisation. Larger studies with longer follow-up periods are needed to identify patients at risk and establish preventive and therapeutic approaches.

Acute turbidity exposures with Port of Miami sediments impact Orbicella faveolata tissue regeneration.

We evaluated acute turbidity effects on a threatened coral species (Orbicella faveolata) under three short-term challenge scenarios using a Port of Miami sediment homogenate to simulate turbid conditions during dredging. For these experiments we designed a simple coral challenge test system that kept turbidity stable, without adverse effects to the coral. A 96-h coral challenge experiment demonstrated that low turbidity levels (≥4 NTU) have negative effects on O. faveolata tissue regeneration. A 48-h turbidity exposure (maximum 30 NTU) had no effect on O. faveolata tissue regeneration, showing that short term turbidity exposures may not be detrimental to coral health. In a 13-day test, treated coral fragments (maximum 30 NTU) exhibited significant delays in tissue regeneration, but recovery was observed after approximately one week. The results presented here can be used to inform management decisions for proposed dredging activities proximal to coral reef habitats.

Assessment of sediment porewater toxicity in Biscayne National Park with sea urchin (Lytechinus variegatus) embryos.

The sea urchin embryo development toxicity test was used to investigate toxicity of the benthic substrate in Biscayne National Park (BISC). Twenty-five sites were selected based upon a high potential for anthropogenic stressor input (e. g., hydrocarbons, personal care products, nutrients, etc.) or proximity to coral reef habitats. We found that sediment interstitial water (porewater) was toxic to urchin embryos at 22 of 25 sites. Healthy sites included two coral reefs (Anniversary Reef and Marker 14 Reef) and Turkey Point Channel. Discrete areas of BISC have highly toxic sediments and the presence of sediment contaminants could negatively impact reproduction, growth and population density of benthic invertebrates, such as corals. Results of the sea urchin embryo development toxicity test can be used as a baseline assessment for monitoring improvements or degradation in ecosystem health and could be a valuable tool to investigate the suitability of degraded habitats for future reef restoration. Since the last comprehensive environmental assessment of BISC was performed in 1999, further investigation into the sources of toxicity at BISC is needed.

A survey of environmental pollutants and cellular-stress markers of Porites astreoides at six sites in St. John, U.S. Virgin Islands.

Coral communities along the coast of St. John, U.S. Virgin Islands have exhibited site-specific behavior in declines. In order to determine if these specific coral communities are stressed and whether a pollutant or environmental factor present at this site is a probable stressor, we surveyed six near-shore coral communities in St. John, USVI for environmental pollutants and to determine the cellular physiological condition of the coral, Porites astreoides. The six sites within St. John are Cruz Bay, Caneel Bay, Hawksnest Bay, Trunk Bay, Tektite Reef in Beehive Bay, and Red Point. Red Point was considered the reference site because of its abundance and diversity of species, and it was the furthest removed from down-stream and down-current anthropogenic activities. All sites showed distinct cellular-stress marker patterns, indicating that the physiological condition of each population was different. Populations at Cruz, Hawksnest, Trunk, and Tektite were stressed, as indicated by high levels of DNA lesions and expression of stress proteins. Hawksnest and Tektite were contaminated with polyaromatic hydrocarbons (PAHs), while Cruz was contaminated with semi-volatile organochlorines and nitrogen-based biocides. At least for Hawksnest and Tektite, stress-marker patterns were consistent with an exposure to PAHs. Fecal coliform levels were high in Cruz and Trunk, indicating fecal contamination, as well as consideration for management action. Results from this study serve as a justification for a more thorough and methodical investigation into the stressors responsible for declines of coral populations within St. John. Furthermore, this study supports the argument for the importance of local factors contributing to regional coral reef declines; that not all forces impacting coral are global.

Expression and Characterization of a Bright Far-red Fluorescent Protein from the Pink-Pigmented Tissues of Porites lobata.

Members of the anthozoan green fluorescent protein (GFP) family display a diversity of photo-physical properties that can be associated with normal and damaged coral tissues. Poritid coral species often exhibit localized pink pigmentation in diseased or damaged tissues. Our spectral and histological analyses of pink-pigmented Porites lobata lesions show co-localization of bright red fluorescence with putative amoebocytes concentrating in the epidermis, suggesting an activated innate immune response. Here we report the cloning, expression, and characterization of a novel red fluorescent protein (plobRFP) from the pink-pigmented tissues associated with lesions on Porites lobata. In vitro, the recombinant plobRFP exhibits a distinct red emission signal of 614 nm (excitation maximum: 578 nm), making plobRFP the furthest red-shifted natural fluorescent protein isolated from a scleractinian coral. The recombinant protein has a high molar extinction coefficient (84,000 M-1 cm-1) and quantum yield (0.74), conferring a notable brightness to plobRFP. Sequence analysis suggests the distinct brightness and marked red shift may be inherent features of plobRFP's chromophore conformation. While plobRFP displays a tendency to aggregate, its high pH stability, photostability, and spectral properties make it a candidate for cell imaging applications and a potential template for engineering optimized RFPs. The association of plobRFP with a possible immune response furthers its potential use as a visual diagnostic and molecular biomarker for monitoring coral health.

Effect of Louisiana sweet crude oil on a Pacific coral, Pocillopora damicornis.

Recent oil spill responses such as the Deepwater Horizon event have underscored the need for crude oil ecotoxicological threshold data for shallow water corals to assist in natural resource damage assessments. We determined the toxicity of a mechanically agitated oil-seawater mixture (high-energy water-accommodated fraction, HEWAF) of a sweet crude oil on a branched stony coral, Pocillopora damicornis. We report the results of two experiments: a 96 h static renewal exposure experiment and a "pulse-chase" experiment of three short-term exposure durations followed by a recovery period in artificial seawater. Five endpoints were used to determine ecotoxicological values: 1) algal symbiont chlorophyll fluorescence, 2) a tissue regeneration assay and a visual health metric with three endpoints: 3) tissue integrity, 4) tissue color, and 5) polyp behavior. The sum of 50 entrained polycyclic aromatic hydrocarbons (tPAH50) was used as a proxy for oil exposure. For the 96 h exposure dose response experiment, dark-adapted maximum quantum yield (Fv/Fm) of the dinoflagellate symbionts was least affected by crude oil (EC50 = 913 µg/L tPAH50); light-adapted effective quantum yield (EQY) was more sensitive (EC50 =  428 µg/L tPAH50). In the health assessment, polyp behavior (EC50 = 27 µg/L tPAH50) was more sensitive than tissue integrity (EC50 = 806 µg/L tPAH50) or tissue color (EC50 = 926 µg/L tPAH50). Tissue regeneration proved to be a particularly sensitive measurement for toxicity effects (EC50 = 10 µg/L tPAH50). Short duration (6-24 h) exposures using 503 µg/L tPAH50 (average concentration) resulted in negative impacts to P. damicornis and its symbionts. Recovery of chlorophyll a fluorescence levels for 6-24 h oil exposures was observed in a few hours (Fv/Fm) to several days (EQY) following recovery in fresh seawater. The coral health assessments for tissue integrity and tissue color were not affected following short-term oil exposure durations, but the 96 h treatment duration resulted in significant decreases for both. A reduction in polyp behavior (extension) was observed for all treatment durations, with recovery observed for the short-term (6-24 h) exposures within 1-2 days following placement in fresh seawater. Wounded and intact fragments exposed to oil treatments were particularly sensitive, with significant delays observed in tissue regeneration. Estimating ecotoxicological values for P. damicornis exposed to crude oil HEWAFs provides a basis for natural resource damage assessments for oil spills in reef ecosystems. These data, when combined with ecotoxicological values for other coral reef species, will contribute to the development of species sensitivity models.

CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases.

Background: Analysis of cerebrospinal fluid (CSF) is a frequently used diagnostic tool in a variety of neurological diseases. Recent studies suggested that investigating membrane particles enriched with the stem cell marker CD133 may offer new avenues for studying neurological disease. In this study, we evaluated the amount of membrane particle-associated CD133 in human CSF in neuroinflammatory and degenerative diseases. Methods: We compared the amount of membrane particle-associated CD133 in CSF samples collected from 45 patients with normal pressure hydrocephalus, parkinsonism, dementia, and cognitive impairment, chronic inflammatory diseases and 10 healthy adult individuals as controls. After ultracentrifugation of CSF, gel electrophoresis and immunoblotting using anti-CD133 monoclonal antibody 80B258 were performed. Antigen-antibody complexes were detected using chemiluminescence. Results: The amount of membrane particle-associated CD133 was significantly increased in patients with normal pressure hydrocephalus (p < 0.001), parkinsonism (p = 0.011) as well as in patients with chronic inflammatory disease (p = 0.008). Analysis of CSF of patients with dementia and cognitive impairment revealed no significant change compared with healthy individuals. Furthermore, subgroup analysis of patients with chronic inflammatory diseases demonstrated significantly elevated levels in individuals with relapsing-remitting multiple sclerosis (p = 0.023) and secondary progressive multiple sclerosis (SPMS; p = 0.010). Conclusion: Collectively, our study revealed elevated levels of membrane particle-associated CD133 in patients with normal pressure hydrocephalus, parkinsonism as well as relapsing-remitting and SPMS. Membrane glycoprotein CD133 may be of clinical value for several neurological diseases.

NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802-13. ©2017 AACR.

Military deployment human exposure assessment: urine total and isotopic uranium sampling results.

Currently the Department of Defense (DoD) does not use exposure biomarkers to measure service members' exposure to environmental chemicals. Blood and urine exposure biomarkers for volatile organic compounds (VOC), selected heavy metals, depleted uranium (DU), and chemical warfare agents are currently available but have not been field tested or validated by the DoD in military deployments as a tool to document exposures. The Military Deployment Human Exposure Assessment Study, a prospective cohort of 46 soldiers deployed to Bosnia, was designed to field test blood and urine exposure biomarkers as a mechanism to document exposures to these chemicals during military deployments. Blood and urine were collected before, during, and after deployment. Standard questionnaire, environmental, and occupational monitoring data collection methods were conducted for comparison to the exposure biomarker results. This article compares and reports the pre-, during, and postdeployment urine total and isotopic uranium measurements and compares them to perceived exposures captured on questionnaire, to environmental data collected by the United Nations Environmental Program in Bosnia, and to standard U.S. urine uranium reference levels (CDC, 2003). Additionally, the questionnaire and environmental and occupational measurements are reported. The results of the study indicate that exposure biomarkers may be a valuable tool to the DoD in exposure and risk assessment with regard to environmental and occupational exposures to uranium.

Derivation of risk based wipe surface screening levels for industrial scenarios.

The environmental characterization of building interiors and other surfaces has generally been performed with wipe-sampling because it is a non-destructive technique. There is no consensus, however, as to the interpretation of the results of wipe-sampling. Specifically, there is not a standardized method to determine if chemicals found at sampled levels pose a threat to human health. A methodology was developed, based on acceptable health risk levels, to derive screening levels for evaluating wipe-sampling results pertaining to industrial scenarios. The methodology was based on the United States Environmental Protection Agency (USEPA) Region IX Preliminary Remediation Goal (PRG) approach; a multi-exposure methodology commonly used for evaluating soil concentrations. PRGs are the USEPA determined health based goals for soil preliminary remediation efforts. Probabilistic techniques were used to conduct a sensitivity analysis of the methodology to determine which variables drive the ultimate screening levels. Discrete values were then selected based on standard industrial scenarios common to the US Army. The wipe surface screening levels reported are for use as preliminary guidelines which help to determine whether further sampling or cleanup are necessary. The levels are not meant as cleanup or compliance criteria.

The recommended role of exposure biomarkers for the surveillance of environmental and occupational chemical exposures in military deployments: policy considerations.

A lack of individual exposure information limited the evaluation of exposure-outcome relationships after the Gulf War. Exposure concerns during Operation Enduring Freedom and Iraqi Freedom deployments have increased interest in individual environmental and occupational chemical exposure assessment. Currently, deployment assessments are conducted using intermittent ambient air monitoring, occasional focused evaluations based on these results, and postdeployment questionnaire documentation of exposure and/or health concerns. Although this strategy is an improvement over previous practice, it has limitations, including a reliance on evidence of an acute problem, to initiate in-depth health evaluation. Exposure biomarkers may have the potential to overcome some of the limitations of current environmental and occupational exposure assessment tools. This article examines current exposure assessment methods, reviews emerging technologies, and recommends a phased approach to introducing exposure biomarkers into a comprehensive occupational and environmental health surveillance program.

A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain.

BACKGROUND: Although acetaminophen is one of the oldest and most widely used of all analgesic drugs, the incremental benefit of the 1000-mg dose compared with the 650-mg dose has been questioned. OBJECTIVE: The aim of this study was to assess the relative efficacy of acetaminophen 1000 mg versus acetaminophen 650 mg over a 6-hour period in patients experiencing at least moderate postsurgical dental pain. METHODS: This single-center, randomized, double-blind, placebo-controlled, single-dose study enrolled patients aged 16 to 50 years who experienced at least moderate pain after surgical removal of impacted third molars. Each patient received either acetaminophen 1000 mg (n = 239), acetaminophen 650 mg (n = 241), or placebo (n = 60) when they had at least moderate pain and a score ≥50 on the 100-mm Visual Analog Scale (VAS) postsurgically. Pain intensity and pain relief were measured over 6 hours (VAS 0-100 mm). RESULTS: All 540 patients (52% female; age range, 16-30 years; 95% white) were included in the efficacy analysis. For the primary efficacy endpoint (weighted sum of the pain intensity difference from baseline [PID] and pain relief [PAR] scores over 6 hours [SPRID6]), acetaminophen 1000 mg demonstrated a 24% improvement compared with acetaminophen 650 mg (529.4 vs 427.3; P = 0.001). In addition, acetaminophen 650 mg was significantly superior compared with placebo (P < 0.001). The weighted sum of PID over 6 hours (SPID6), the weighted total pain relief over 6 hours (TOTPAR6), and the percentage of patients with >50% of the maximum possible TOTPAR6 score were significantly greater for patients treated with acetaminophen 1000 mg compared with those receiving acetaminophen 650 mg (P ≤ 0.006) or placebo (P < 0.001) and for patients treated with acetaminophen 650 mg compared with placebo (P < 0.001). Time to rescue, rescue rates through 4 and 6 hours, and patient global assessment demonstrated similar findings. Patients treated with acetaminophen 1000 mg or 650 mg had a significantly different distribution in times to confirmed perceptible and meaningful pain relief compared with those receiving placebo (P < 0.001). Adverse events were reported by 18.5% of patients, with no clinically important difference between active treatment groups and placebo. CONCLUSIONS: Acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo. The outcomes of this study are limited to the single-dose design of this study. ClinicalTrials.gov identifier: NCT01115673.

Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic.

The neurotensin hexapapetide fragment NT(8-13) is a potent analgesic when administered directly to the central nervous system but does not cross the blood-brain barrier. A total of 43 novel derivatives of NT(8-13) were evaluated, with one, ABS212 (1), being most active in four rat models of pain when administered peripherally. Compound 1 binds to human neurotensin receptors 1 and 2 with IC(50) of 10.6 and 54.2 nM, respectively, and tolerance to the compound in a rat pain model did not develop after 12 days of daily administration. When it was administered peripherally, serum levels and neurotensin receptor binding potency of 1 peaked within 5 min and returned to baseline within 90-120 min; however, analgesic activity remained near maximum for >240 min. This could be due to its metabolism into an active fragment; however, all 4- and 5-mer hydrolysis products were inactive. This pharmacokinetic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic.

Detection and quantitation of curcumin in mouse lung cell cultures by matrix-assisted laser desorption ionization time of flight mass spectrometry.

A method to detect and quantify curcumin and two curcuminoid metabolites in biological matrices, including mouse serum and mouse lung cell cultures, was developed. Standard curves between 0.04 and 10.00 nmol curcumin were prepared in serum, giving correlation coefficients of 0.94-0.99. Alcoholic extraction, concentration, and addition of dilute hydrochloric acid to stabilize the curcumin were essential to the reproducibility of the protocol. Untreated and curcumin-treated mouse lung fibrotic and nonfibrotic cell cultures were analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry utilizing this method. Curcumin uptake was calculated to be 7.0-11.6% for the saline-treated cells and 7.4-11.9% for the bleomycin-treated cultures. Curcumin was not detected in untreated cells. Two additional peaks (m/z=399 and 429) were observed in the curcumin-treated cells. These may be curcumin-derived products resulting from HCl treatment of the tissue samples.