Procedural application of mode-of-action and human relevance analysis: styrene-induced lung tumors in mice.

Risk assessment of human health hazards has traditionally relied on experiments that use animal models. Although exposure studies in rats and mice are a major basis for determining risk in many cases, observations made in animals do not always reflect health hazards in humans due to differences in biology. In this critical review, we use the mode-of-action (MOA) human relevance framework to assess the likelihood that bronchiolar lung tumors observed in mice chronically exposed to styrene represent a plausible tumor risk in humans. Using available datasets, we analyze the weight-of-evidence 1) that styrene-induced tumors in mice occur through a MOA based on metabolism of styrene by Cyp2F2; and 2) whether the hypothesized key event relationships are likely to occur in humans. This assessment describes how the five modified Hill causality considerations support that a Cyp2F2-dependent MOA causing lung tumors is active in mice, but only results in tumorigenicity in susceptible strains. Comparison of the key event relationships assessed in the mouse was compared to an analogous MOA hypothesis staged in the human lung. While some biological concordance was recognized between key events in mice and humans, the MOA as hypothesized in the mouse appears unlikely in humans due to quantitative differences in the metabolic capacity of the airways and qualitative uncertainties in the toxicological and prognostic concordance of pre-neoplastic and neoplastic lesions arising in either species. This analysis serves as a rigorous demonstration of the framework's utility in increasing transparency and consistency in evidence-based assessment of MOA hypotheses in toxicological models and determining relevance to human health.

A battery dataset for electric vertical takeoff and landing aircraft.

Electric vertical takeoff and landing aircraft have a unique duty cycle characterized by high discharge currents at the beginning and end of the mission (corresponding to takeoff and landing of the aircraft) and a moderate power requirement between them with no rest periods during the mission. Here, we generated a dataset of battery duty profiles for an electric vertical takeoff and landing aircraft using a cell typical for that application. The dataset features 22 cells, comprising a total of 21,392 charge and discharge cycles. 3 of the cells use the baseline cycle while each of the other cells vary either charge current, discharge power, discharge duration, ambient cooling conditions, or end of charge voltage. While it was designed to mimic the expected duty cycle of an electric aircraft, this dataset is relevant for training machine learning models on battery life, fitting physical or empirical models for battery performance and/or degradation, and countless other applications.

An occupational exposure limit (OEL) approach to protect home healthcare workers exposed to common nebulized drugs.

Home healthcare is a growing area of employment. Assessment of occupational health risks to home health care workers (HHCWs) is important because in many cases the unique characteristics of the home environment do not facilitate the level of exposure control afforded to caregivers in hospitals and other fixed patient care sites. This assessment is focused on health risks to HHCWs from exposure to pharmaceutical drugs used to treat asthma and other respiratory diseases, which are commonly administered to patients in aerosolized form via nebulizers. We developed risk-based exposure limits for workers in the form of occupational exposure limits (OEL) values for exposure to nebulized forms of the three most common drugs administered by this method: albuterol, ipratropium, and budesonide. The derived OEL for albuterol was 2 µg/day, for ipratropium was 30 µg/day, and for budesonide was 11 µg/day. These OELs were derived based on human effect data and adjusted for pharmacokinetic variability and areas of uncertainty relevant to the underlying data (human and non-human) available for each drug. The resulting OEL values provide an input to the occupational risk assessment process to allow for comparisons to HHCW exposure that will guide risk management and exposure control decisions.

Modulation of in vitro phagocytic uptake and immunogenicity potential of modified Herceptin®-conjugated PLGA-PEG nanoparticles for drug delivery.

There is an increasing interest in engineered nanoparticle (NP) conjugates for targeted and controlled drug delivery. However, the practical applications of these NP delivery vehicles remain constrained because of their reactivity with the body's immune system defenses resulting in undesirable off-target effects. In this study, poly(D,L lactide-co-glycolide) (PLGA)-b-polyethylene glycol (PEG) NPs conjugated to different quantities of the commercial antibody Herceptin® meant to target HER2-positive breast cancer cells were studied for their immune cell uptake and immunogenic properties (using murine macrophages and human dendritic cells). We further modified the Herceptin®-NP conjugates with short PEG linkers with an aim to increase their biocompatibility. The 50% Herceptin®-NP conjugate group with short PEG modification to Herceptin® showed the best reduction in immune cell uptake by 82% along with the reduction by >50% for proinflammatory cytokine response (TNF-α and IL-6). In conclusion, optimum Herceptin® coverage with improved hydrophilic profile results in reduced phagocytic uptake and immunogenicity of engineered NP-antibody conjugates, potentially minimizing their undesirable off-target effects as a drug delivery vehicle.

Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks.

The risk of human exposure to fiber nanoparticles has risen in recent years due to increases in the manufacture and utilization of carbon nanotubes (CNTs). CNTs are present as airborne particulates in occupational settings and their hazard potential has been demonstrated in experimental lung exposure studies using inbred mouse strains. However, it is not known whether different inbred strains differ in lung responses to CNTs by virtue of their genetics. In this work, common inbred strains (BALB/c, C57Bl/6, DBA/2, and C3H/He) were exposed to CNTs via oropharyngeal aspiration and lung histology and bronchoalveolar lavage (BAL) samples were evaluated over 28days with the objective of evaluating sensitivity/resistance among strains. C57Bl/6 mice developed significantly more extensive type II pneumocyte (T2P) hyperplasia and alveolar infiltrate compared to DBA/2 mice, which were resistant. Surprisingly, DBA/2 but not C57Bl/6 mice were extremely sensitive to increases in leukocytes recovered in BAL fluid. Underlying global gene expression patterns in the two strains were compared using mRNA sequencing to investigate regulatory networks associated with the different effects. The impact of exposure on gene networks regulating various aspects of immune response and cell survival was limited in DBA/2 mice compared to C57Bl/6. Investigation of B6D2F1 (C57Bl/6×DBA/2 hybrid) mice demonstrated inheritance of sensitivity to CNT exposures in regard to toxicologic lung pathology and BAL leukocyte accumulations. These findings demonstrate a genetic basis of susceptibility to CNT particle exposures and both inform the use of inbred mouse models and suggest the likelihood of differences in genetic susceptibility among humans.

Carbon Nanotube and Asbestos Exposures Induce Overlapping but Distinct Profiles of Lung Pathology in Non-Swiss Albino CF-1 Mice.

Carbon nanotubes (CNTs) are emerging as important occupational and environmental toxicants owing to their increasing prevalence and potential to be inhaled as airborne particles. CNTs are a concern because of their similarities to asbestos, which include fibrous morphology, high aspect ratio, and biopersistence. Limitations in research models have made it difficult to experimentally ascertain the risk of CNT exposures to humans and whether these may lead to lung diseases classically associated with asbestos, such as mesothelioma and fibrosis. In this study, we sought to comprehensively compare profiles of lung pathology in mice following repeated exposures to multiwall CNTs or crocidolite asbestos (CA). We show that both exposures resulted in granulomatous inflammation and increased interstitial collagen; CA exposures caused predominantly bronchoalveolar hyperplasia, whereas CNT exposures caused alveolar hyperplasia of type II pneumocytes (T2Ps). T2Ps isolated from CNT-exposed lungs were found to have upregulated proinflammatory genes, including interleukin 1ß (IL-1ß), in contrast to those from CA exposed. Immunostaining in tissue showed that while both toxicants increased IL-1ß protein expression in lung cells, T2P-specific IL-1ß increases were greater following CNT exposure. These results suggest related but distinct mechanisms of action by CNTs versus asbestos which may lead to different outcomes in the 2 exposure types.

MyD88 mediates in vivo effector functions of alveolar macrophages in acute lung inflammatory responses to carbon nanotube exposure.

Carbon nanotubes (CNTs) are rapidly emerging as high-priority occupational toxicants. CNT powders contain fibrous particles that aerosolize readily in places of manufacture and handling, posing an inhalation risk for workers. Studies using animal models indicate that lung exposure to CNTs causes prolonged inflammatory responses and diffuse alveolar injury. The mechanisms governing CNT-induced lung inflammation are not fully understood but have been suggested to involve alveolar macrophages (AMs). In the current study, we sought to systematically assess the effector role of AMs in vivo in the induction of lung inflammatory responses to CNT exposures and investigate their cell type-specific mechanisms. Multi-wall CNTs characterized for various physicochemical attributes were used as the CNT type. Using an AM-specific depletion and repopulation approach in a mouse model, we unambiguously demonstrated that AMs are major effector cells necessary for the in vivo elaboration of CNT-induced lung inflammation. We further investigated in vitro AM responses and identified molecular targets which proved critical to pro-inflammatory responses in this model, namely MyD88 as well as MAPKs and Ca(2+)/CamKII. We further demonstrated that MyD88 inhibition in donor AMs abrogated their capacity to reconstitute CNT-induced inflammation when adoptively transferred into AM-depleted mice. Taken together, this is the first in vivo demonstration that AMs act as critical effector cell types in CNT-induced lung inflammation and that MyD88 is required for this in vivo effector function. AMs and their cell type-specific mechanisms may therefore represent potential targets for future therapeutic intervention of CNT-related lung injury.

The Utility of a 7-Day Percutaneous Spinal Cord Stimulator Trial Measured by a Pain Diary: A Long-term Retrospective Analysis.

Objective. The purpose of this study was to investigate the utility of a 7-day percutaneous spinal cord stimulator trial using a 7-day diary to measure outcomes during the trial and at long-term follow-up. Materials and Method. Diaries completed prior to and during the trial were analyzed, as was a follow-up questionnaire. Trial and follow-up data were compared using nonparametric statistics and descriptive analyses. Result. Results revealed statistically significant differences between pretrial and long-term follow-up measures of pain, mood, anxiety, and suffering for patients with positive trials. Expected differences existed between patients with positive and negative trials during the trial. Responders to permanent implantation differed on anxiety before and after the trial compared to nonresponders. Conclusion. Patients who underwent a 7-day percutaneous trial, had a positive trial and received permanent implantation fared well long-term. The 7-day diary did not result in a superior method of determining responders vs. nonresponders at long-term follow-up. More research is needed to determine whether different quantitative measures would predict long-term outcome.

The effects of transdermal fentanyl on driving, cognitive performance, and balance in patients with chronic nonmalignant pain conditions.

OBJECTIVE: To evaluate driving performance, cognition, and balance in patients with chronic nonmalignant pain before and after the addition of transdermal fentanyl to their treatments. DESIGN: Prospective, one-group pretest-posttest design. SETTING: Outpatient pain center associated with a large, urban medical school. INTERVENTIONS: Patients taking less than a 15-mg equivalent of oxycodone per day took baseline driving performance, cognitive, and balance tests. Transdermal fentanyl was initiated and titrated in 25-microg/hour increments, weighing benefits and side effects. At the end of a 1-month period, the achieved dose was maintained for another month. After they were stabilized for 1 month, patients repeated driving, cognitive, and balance tests. RESULTS: Twenty three patients completed the study; three discontinued secondary to side effects. The median dose at the end of the titration period was 50 microg/hour (48%). No differences were found in driving simulation measures between the pretreatment and posttreatment periods. No decrements in cognitive performance were found. Improvements in visual motor tracking, visual memory, and attention were found during treatment with transdermal fentanyl. No differences in balance or body sway were found. Pain decreased over the course of treatment. CONCLUSIONS: The addition of transdermal fentanyl to a treatment regimen containing no opiates or small amounts of opiates for patients with chronic nonmalignant pain did not negatively affect their driving performances, reaction times, cognition, or balance. Future studies in this area are needed to guide treatment decisions.

Eosinophilic exudative pleural effusion after initiation of tizanidine treatment: a case report.

In this case report, we present a 42-year-old man with history of chronic low back pain after a work-related injury. The patient failed multiple therapeutic modalities both conservative and interventional, including numerous spinal injections and placement of a spinal cord stimulator. Finally, an intrathecal morphine pump was placed to control his pain in addition to oral pain medications. The course of the treatment included adding a muscle relaxant, tizanidine (Zanaflex), to control spasms in the lower extremities. Six weeks after starting tizanidine, a large pleural effusion was noted incidentally on a computerized tomography scan of the thoracic and lumbar spine. The patient underwent work-up for the pleural effusion; all tests came back negative. Finally, a drug reaction to tizanidine was suspected. The drug was discontinued, and 4 weeks later the pleural effusion resolved.

Epidural steroids, epidural morphine and epidural steroids combined with morphine in the treatment of post-laminectomy syndrome.

Epidural morphine injection followed by a steroid has been reported to be effective for the post-laminectomy pain ('failed back') syndrome. This double-blind, parallel study was undertaken to evaluate that mode of therapy. Twenty-two patients who had undergone at least one prior laminectomy, who were still symptomatic, were randomized to receive 50 mg of lidocaine epidurally with: (a) 75 mg triamcinolone diacetate (TR); or (b) 8 mg of preservative-free morphine (MP); or (c) both (TR and MP), at 1 month intervals for 3 consecutive months. The spinal interspace identified with the patients' pain complaint was the site of injection. For each treatment, patients were admitted to the Clinical Research Center for 24 h and their condition continuously monitored with a pulse oximeter and apnea monitor. Five to 7 patients in each group had pain relief for less than 1 month. No patient given morphine had pain relief for more than 1 month. Life-threatening ventilatory depression occurred in the group given triamcinolone and morphine. The use of morphine alone or combined with slow release triamcinolone does not appear to be appropriate for the treatment of the post-laminectomy pain syndrome.