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Sex and age associated differences in the tumor immune microenvironment of non-muscle invasive bladder (NMIBC) cancer and associated clinical outcomes are emerging indicators of treatment outcomes. The incidence of urothelial carcinoma of the bladder is four times higher in males than females; however, females tend to present with a more aggressive disease, a poorer response to immunotherapy and suffer worse clinical outcomes. Recent findings have demonstrated sex differences in the tumor immune microenvironment of non-muscle invasive and muscle invasive bladder cancer and associated clinical outcomes. However, a significant gap in knowledge remains with respect to the current pre-clinical modeling approaches to more precisely recapitulate these differences towards improved therapeutic design. Given the similarities in mucosal immune physiology between humans and mice, we evaluated the sex and age-related immune alterations in healthy murine bladders. Bulk-RNA sequencing and multiplex immunofluorescence-based spatial immune profiling of healthy murine bladders from male and female mice of age groups spanning young to old showed a highly altered immune landscape that exhibited sex and age associated differences, particularly in the context of B cell mediated responses. Spatial profiling of healthy bladders, using markers specific to macrophages, T cells, B cells, activated dendritic cells, high endothelial venules, myeloid cells and the PD-L1 immune checkpoint showed sex and age associated differences. Bladders from healthy older female mice also showed a higher presence of tertiary lymphoid structures (TLSs) compared to both young female and male equivalents. Spatial immune profiling of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen exposed male and female bladders from young and old mice revealed a similar frequency of TLS formation, sex differences in the bladder immune microenvironment and, age associated differences in latency of tumor induction. These findings support the incorporation of sex and age as factors in pre-clinical modeling of bladder cancer and will potentially advance the field of immunotherapeutic drug development to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

On August 12, 2014, an Anchorage hospital notified the Alaska Section of Epidemiology (SOE) that a middle-aged male resident of Anchorage (patient A) had arrived in the emergency department with possible palytoxin exposure. Patient A complained of a bitter metallic taste, fever, weakness, cough, and muscle pain 7-8 hours after introduction of live zoanthid coral into his home aquarium. Palytoxin, a potent toxin known to produce the reported effects, is contained in zoanthid marine corals. [ABSTRACT FROM AUTHOR]

The article presents several case studies on suspected exposure to palytoxin due to zoanthid marine corals in aquarium shops and homes in Alaska from 2012 to 2014. Topics include the epidemiologic investigation conducted by the Alaska Section of Epidemiology (SOE) to detect palytoxin inhalation in patients exposed to zoanthid marine corals, the testing of coral samples by the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition.

Context: Epidemiological studies show positive associations between increased ambient air pollutant levels and adverse cardiopulmonary effects. These studies suggest that the elderly and those with certain genetic polymorphisms are susceptible to adverse air pollution-associated health events. Hypothesis/objective: We hypothesize that physiological responses to air pollutants vary with age and are genetically influenced. Materials and methods: To test this hypothesis, we exposed mice from three inbred strains (C57BL/6J, B6; C3H/HeJ, HeJ; C3H/HeOuJ, OuJ) to ozone (O3) and carbon black (CB) at two ages, (5 months, 12 months), for 3 consecutive days, to either filtered air (FA), CB particles, or O3 and CB sequentially (O3CB) (CB, 550 µg/m3; O3, 600 ppb). Heart rate (HR), HR variability (HRV), breathing, and core temperature (Tco) responses were analyzed. Results: We observed time-dependent physiological changes in response to O3CB exposure in each strain, relative to FA exposure for both age groups. Each mouse strain showed distinct adaptation profiles to repeated acute exposures to O3. In younger mice, several time-dependent effects (decreased HR and increased HRV) were prominent in HeJ and OuJ mice but not B6 mice. We also observed variability in adaptation in older mice. However, responses in older mice were generally attenuated when compared to the younger mice. In addition, cardiac-respiratory interactions were affected with CB and O3CB exposures albeit with patterns differing by age or exposure. Discussion/conclusion: Our results suggest that age considerably attenuates physiological responses to O3 and O3CB exposures. Age-related physiological changes such as increased oxidative stress in mouse tissue may be involved in this attenuation. [ABSTRACT FROM AUTHOR]

Increased ambient particulate matter (PM) is associated with adverse cardiovascular and respiratory outcomes, as demonstrated by epidemiology studies. Several studies have investigated the role of copollutants, such as ozone (O3), in this association. It is accepted that physiological adaptation involving the respiratory system occurs with repeated exposures to O3. We hypothesize that adaptation to PM and O3 varies among different inbred mouse swains, and eardiopulmonary adaptation to O3 is a synchronized response between the cardiac and respiratory systems. Heart rate (HR), HR variability (HRV), and the magnitude and pattern of breathing were simultaneously measured by implanted telemeters and by plethysmography in three inbred mouse strains: C57BI/6J (B6), C3H/HeJ (HeJ), and C3H/HeOtd (Old), Physiological responses were assessed during dual exposures to illtered air (FA), O3 (576 ± 32 parts/billion), and/or carbon black (CB; 556 ± 34 μg/m3). Exposures were repeated for 3 consecutive days. While each strain showed significant reductions in HR during CB with O3 preexposure (O3CB) on day 1, prominent HRV responses were observed in only HeJ and OuJ mice. Each strain also differed in their adaptation profile in response to repeated O3CB exposures. Whereas B6 mice showed rapid adaptation in HR after day 1, HeJ mice generally showed more moderate HR and HRV adaptation after day 2 of exposure. Unlike either B6 or HeJ strains, OuJ mice showed little evidence of HR or HRV adaptation to repeated O3CB exposure. Adaptation profiles between HR regulation and breathing characteristics were strongly correlated, but these associations also varied significantly among strains. These findings suggest that genetic factors determine the responsivity and adaptation of the cardiac and respiratory systems to repeated copollutant exposures. During O3CB exposure, adaptation of cardiac and respiratory systems is markedly synchronized, which may explain a potential mechanism for adverse effects of PM on heart function. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Increased ambient particulate matter (PM) levels are associated with cardiovascular morbidity and mortality, as shown by numerous epidemiology studies. Few studies have investigated the role of copollutants, such as ozone, in this association. Furthermore, the mechanisms by which PM affects cardiac function remain uncertain. We hypothesized that PM and O3 induce adverse cardiovascular effects in mice and that these effects are strain dependent. STUDY DESIGN: After implanting radiotelemeters to measure heart rate (HR) and HR variability (HRV) parameters, we exposed C57Bl/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ) inbred mouse strains to three different daily exposures of filtered air (FA), carbon black particles (CB), or O3 and CB sequentially [O3CB; for CB, 536 ± 24 µg/m3; for O3, 584 ± 35 ppb (mean ± SE)]. RESULTS: We observed significant changes in HR and HRV in all strains due to O3CB exposure, but not due to sequential FA and CB exposure (FACB). The data suggest that primarily acute HR and HRV effects occur during O3CB exposure, especially in HeJ and OuJ mice. For example, HeJ and OuJ mice demonstrated dramatic increases in HRV parameters associated with marked bradycardia during O3CB exposure. In contrast, depressed HR responses occurred in B6 mice without detectable changes in HRV parameters. CONCLUSIONS: These findings demonstrate that important interstrain differences exist with respect to PM- and O3-induced cardiac effects. This interstrain variation suggests that genetic factors may modulate HR regulation in response to and recuperation from acute copollutant exposures. [ABSTRACT FROM AUTHOR]

The goal of this study was to test the following hypotheses: (1) exposure to mobile emissions from mobile sources close to a heavily trafficked roadway will exacerbate airway inflammation and allergic airway responses in a sensitized mouse model, and (2) the magnitude of allergic airway disease responses will decrease with increasing distance from the roadway. A particle concentrator and a mobile exposure facility were used to expose ovalbumin (OVA)-sensitized BALB/c mice to purified air and concentrated fine and concentrated ultrafine ambient particles at 50 m and 150 m downwind from a roadway that was heavily impacted by emissions from heavy duty diesel-powered vehicles. After exposure, we assessed interleukin (IL)-5, IL-13, OVA-specific immunoglobulin E, OVA-specific immunoglobulin G1, and eosinophil influx as biomarkers of allergic responses and numbers of polymorphonuclear leukocytes as a marker of inflammation. The study was performed over a two-year period, and there were differences in the concentrations and compositions of ambient particulate matter across those years that could have influenced our results. However, averaged over the two-year period, exposure to concentrated ambient particles (CAPs) increased the biomarkers associated with airway allergies (IL-5, immunoglobulin E, immunoglobulin G1 and eosinophils). In addition, mice exposed to CAPs 50 m downwind of the roadway had, on the average, greater allergic responses and showed greater indications of inflammation than did mice exposed to CAPs 150m downwind. This study is consistent with the hypothesis that exposure to CAPs close to a heavily trafficked roadway influenced allergic airway responses. [ABSTRACT FROM AUTHOR]

Presents a method of moment-based formulation for the solution of the telegraphist's equations in nonuniform transmission lines. Use of entire domain basis functions that build in a frequency variation; Nonuniform lines in microstrip and coplanar technologies on monolithic microwave/millimeter wave integrated circuit and miniaturized hybrid microwave integrated circuit.

A new method of moment-based formulation for the analysis of nonuniform transmission lines is presented. Subdomain complex basis functions are used to simulate different structures over a wide range of frequencies. The results obtained using the proposed formulation are validated by comparison to those obtained by CAD packages. Strip-line and microstrip-line transitions are investigated with an application to the design of a matched microstrip taper with width and dielectric height variations. [ABSTRACT FROM AUTHOR]

O3 is a principal pollutant that coexists with PM in urban ambient air. Studies associate O3 and PM exposure with adverse health effects; however the mechanisms of action remain unclear. We implanted radiometers to measure HR, and then exposed two mouse strains (i.e. C3H/HeJ, C3 and C57Bl/6J, B6 [n=3/ strain]) to three different protocols for 3 consecutive days as follows: 1) 2 hr-filtered air (FA) + 3 hr-FA; 2) 2 hr-FA + 3 hr-carbon black (CB); and 3) 2 hr-ozone (O3, 550 ppb) + 3 hr-CB HR and VO2 were collected simultaneously on the mornings before and after exposure. We observed relative increases in O2-pulse,(VO2/HR) with FACB (4.9%±2.4), and O3CB (7.5%±6) independent of HR changes in the B6 mice. Correlations between HR and VO2 were also examined. The C3 mice did not exhibit obvious coupling of HR and VO2 (r²=0.16±0.06) at baseline or with treatment. The B6 animals, however, appear to inherently possess a high association between HR and VO2 (r²= 0.40±0.08) and this association changed dramatically with exposure: i.e., FACB (r²=0.13±0.06) and O3CB (r²=0.60±0.01) exposures. Thus, these results suggest that HR and VO2 coupling varies between inbred strains and among different pollutants. In terms of hemodynamic control, HR regulation is altered by air pollutant exposures such that a greater O2 delivery is required with each stroke of the heart. Future studies will aim to elucidate genetic factors that may modify individual responses and susceptibility to these air pollutants. [ABSTRACT FROM AUTHOR]

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted. • The Alliance for Risk Assessment developed an international collaboration to explore human half-life of perfluorooctanoate. • Independent working groups found human studies noted occurrence of unmonitored PFOA exposures, which inflate PFOA half-life. • And that few of these studies estimated the half-life of PFOA isomers, which deflate values of n-PFOA half-life. • Studies striking the best balance in addressing these uncertainties suggest a human PFOA half-life is less than 2 years. • The single best value appears to be a geometric mean of 1.3 years, however, a median value of 1.8 years was seen to add value. [ABSTRACT FROM AUTHOR]

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde''s reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case for a causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding. [ABSTRACT FROM AUTHOR]

Engineered nanoparticles (ENPs) are increasingly tested in cellular and laboratory-animal experiments for hazard potential, but there is a lack of health effects data for humans exposed to ENPs. However, human data for another source of nanoparticle (NP) exposure are available, notably for the NPs contained in diesel exhaust particulate (DEP). Studies of human volunteers exposed to diesel exhaust (DE) in research settings report DEP-NP number concentrations (i.e., >106 particles/cm3) that exceed number concentrations reported for worst-case exposure conditions for workers manufacturing and handling ENPs. Recent human DE exposure studies, using sensitive physiological instrumentation and well-characterized exposure concentrations and durations, suggest that elevated DE exposures from pre-2007 engines may trigger short-term changes in, for example, lung and systemic inflammation, thrombogenesis, vascular function, and brain activity. Considerable uncertainty remains both as to which DE constituents underlie the observed responses (i.e., DEP NPs, DEP mass, DE gases), and as to the implications of the observed short-term changes for the development of disease. Even so, these DE human clinical data do not give evidence of a unique toxicity for NPs as compared to other small particles. Of course, physicochemical properties of toxicological relevance may differ between DEP NPs and other NPs, yet overall, the DE human clinical data do not support the idea that elevated levels of NPs per se (at least in the DEP context) must be acutely toxic by virtue of their nano-sized nature alone. [ABSTRACT FROM AUTHOR]

Nitrogen dioxide (NO2) is a ubiquitous atmospheric pollutant due to the widespread prevalence of both natural and anthropogenic sources, and it can be a respiratory irritant when inhaled at elevated concentrations. Evidence for health effects of ambient NO2 derives from three types of studies: observational epidemiology, human clinical exposures, and animal toxicology. Our review focuses on the human clinical studies of adverse health effects of short-term NO2 exposures, given the substantial uncertainties and limitations in interpretation of the other lines of evidence... [ABSTRACT FROM AUTHOR]

Motor vehicle exhaust emissions are known to exacerbate asthma and other respiratory diseases. Several studies have demonstrated significant associations between living near highly trafficked roadways and increased incidence of asthma and increased severity of asthma-related symptoms, medication usage, and physician visits. This study tested the hypotheses that (1) exposure to particulate matter (PM) near a heavily trafficked Los Angeles freeway would enhance inflammatory and allergic responses in ovalbumin (OVA)-sensitized BALB/c mice compared to sensitized, clean air controls, and (2) there would be differences in response at two distances downwind of heavily traveled freeways because of greater toxicity of PM closest to the freeway. An ambient particle concentrator was used to expose ovalbumin (OVA)-treated BALB/c mice to purified air, to concentrated fine ambient particles, and to concentrated ultrafine airborne particles (CAPs) at 2 distances, 50 m and 150 m, downwind of a roadway that is impacted by emissions from both heavy-duty diesel and light duty gasoline vehicles. Tissues and biological fluids from the mice were analyzed after exposures for 5 days/wk in 2 consecutive weeks. The biomarkers of allergic or inflammatory responses that were assessed included cytokines released by Type 2 T-helper cells (interleukin [IL]-5 and IL-13), OVA-specific immunoglobulin E (IgE), OVA-specific immunoglobulin G1 (IgG1), and pulmonary infiltration of polymorphonuclear leukocytes and eosinophils. IL-5 and IgG1 were significantly increased in mice exposed to CAPs 50 m downwind of the road, compared to responses in mice exposed to purified air, providing evidence of allergic response. No significant increases in allergy-related responses were observed in mice exposed to CAPs 150 m downwind of the road. The biological responses at the 50-m site were significantly associated with organic and elemental carbon components of fine and ultrafine particles (p ≤ .05). The primary source of these contaminants at the roadway sites was motor vehicle emissions, suggesting that particulate matter from motor vehicle fuel combustion could exert adjuvant effects and promote the development of allergic airway diseases. [ABSTRACT FROM AUTHOR]