Components of airway hyperresponsiveness and their associations with inflammation and remodeling in mice

BACKGROUND: Pathologic changes, including inflammation and remodeling, occur in the asthmatic airway. However, their relative contribution to the components of airway hyperresponsiveness (AHR) remains unclear. OBJECTIVE: Attempting to delineate AHR into discrete immune-mediated and structural remodeling components, we performed a detailed time course of the development, progression, and persistence of maximal respiratory system resistance, airway reactivity, and airway sensitivity. METHODS: Mice exposed to increasing durations of persistent allergen were assessed for airway function, morphometry, and inflammation. RESULTS: Allergen exposure resulted in increases for all indices of AHR that persisted for at least 4 weeks after chronic allergen exposure (P < .01 for all values). Early increases in AHR were associated with increases in immune-mediated events, including airway eosinophils (P < .01), whereas sustained AHR was associated with structural remodeling events. Increased maximal respiratory system resistance, evident by 6 weeks postallergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, was associated with an increase in collagen deposition (P < .01). Increased airway reactivity and sensitivity, each evident by 1 week after allergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, were associated with an increase in airway smooth muscle area (P < .01). CONCLUSION: Our novel observation of distinct temporal relationships in the development, progression, and persistence of the individual indices of AHR supports our hypothesis that multiple underlying factors contribute to airway dysfunction. CLINICAL IMPLICATIONS: These findings illustrate the importance of clearly addressing specific components of airway dysfunction to provide greater insight into specific pathophysiologic mechanisms in airway disease.     

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma

POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.     

A retrospective analysis of 44 implants with no rotational primary stability used for fixed prosthesis anchorage

PURPOSE: The aim of this study was to determine the osseointegration potential of implants with apical primary stability but no resistance to rotation in variable clinical conditions. MATERIALS AND METHODS: Patient records of treatment performed between October 1993 and May 2004 were reviewed for primary implant stability. Patients who exhibited implants without rotational primary stability (RPS) were reviewed further to determine patient age, gender, implant type, implant surface, loading protocol, and prosthesis type. RESULTS: Forty-four implants without RPS were reported in 12.8% of patients treated during the period reviewed. Statistical significant differences in cumulative survival rate (CSR) were seen with implant location and surface. No significant difference in CSR was observed in relation to loading protocol, despite a higher success rate (17.4% higher) for the immediate loading population. No difference in CSR was observed with respect to gender. DISCUSSION AND CONCLUSION: In the early years of machined implants, there was a higher failure rate of implants without RPS. The results for this implant population show that there are statistically significant differences in survival rate between the maxilla and mandible, and also between titanium oxide-surfaced implants and machined implants. The sample size of this study limited the statistical significance of the difference in CSR observed between loading protocols. Implants without RPS that are not removed at the time of surgery can become osseointegrated with a survival rate of 82%. Survival rates increase when testing sample is limited to titanium oxide-surfaced implants under an immediate loading protocol. Under the appropriate level of risk, implants that have apical primary stability but no resistance to rotation can become osseointegrated when incorporated in a rigid prosthesis under immediate loading circumstances.     

Re-Validating the Observational Teamwork Assessment for Surgery Tool (OTAS-D): Cultural Adaptation, Refinement, and Psychometric Evaluation

Background

The nontechnical and team skills of surgical teams are critical for safety and efficiency in the operating room. Assessment of nontechnical and team skills can facilitate improvement by encouraging both self-reflection and team reflection, identifying training needs, and informing operating room (OR) team training approaches. The observational teamwork assessment for surgery (OTAS) tool is a well-validated and robust tool for capturing teamwork in the operating room. The aims of the present study were to systematically adapt and refine the OTAS for German-speaking OR staff and to test the adapted assessment tool (OTAS-D) for psychometric properties and metric equivalence.

Methods

The study was carried out in three stages: at stage 1, OTAS was translated into German. At stage 2, experienced German OR experts (surgeons, OR nurses, anesthetists) were interviewed. At stage 3, two blinded assessors observed 11 general surgical operations (general surgical and vascular procedures) and interrater reliability was tested for refined OTAS-D behavioral exemplars and scorings.

Results

The German OR experts confirmed the applicability and content validity of the vast majority of translated behavioral exemplars. After their evaluation, 32 items were changed slightly, six were changed substantially, and one item was added. During observations, perfect and substantial interobserver agreement was found for 77 behavioral exemplars (67.1 % of the items, kappa coefficient >0.60). Rating at all OTAS behaviors showed acceptable levels of reliability (intraclass correlation coefficients >0.72).

Conclusions

The OTAS-D is a tool for valid and reliable assessment of nontechnical skills that contribute to safe and effective surgical performance in ORs staffed by German-speaking professionals. Furthermore, our study serves as an example for systematically adapting and customizing well-established observational tools across different healthcare environments.     

Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation

Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient.     

Lifecourse Health Development: Past, Present and Future

During the latter half of the twentieth century, an explosion of research elucidated a growing number of causes of disease and contributors to health. Biopsychosocial models that accounted for the wide range of factors influencing health began to replace outmoded and overly simplified biomedical models of disease causation. More recently, models of lifecourse health development (LCHD) have synthesized research from biological, behavioral and social science disciplines, defined health development as a dynamic process that begins before conception and continues throughout the lifespan, and paved the way for the creation of novel strategies aimed at optimization of individual and population health trajectories. As rapid advances in epigenetics and biological systems research continue to inform and refine LCHD models, our healthcare delivery system has struggled to keep pace, and the gulf between knowledge and practice has widened. This paper attempts to chart the evolution of the LCHD framework, and illustrate its potential to transform how the MCH system addresses social, psychological, biological, and genetic influences on health, eliminates health disparities, reduces chronic illness, and contains healthcare costs. The LCHD approach can serve to highlight the foundational importance of MCH, moving it from the margins of national debate to the forefront of healthcare reform efforts. The paper concludes with suggestions for innovations that could accelerate the translation of health development principles into MCH practice.     

A Lifecourse Approach to Health Development: Implications for the Maternal and Child Health Research Agenda

Lifecourse-informed models of health fundamentally challenge simple biomedical models, introducing new ways of thinking about how diseases develop. This paper considers the broad implications of lifecourse theory for the maternal and child health (MCH) research agenda. The Lifecourse Health Development model provides an organizing framework for a synthesis of the existing literature on lifecourse health and identification of gaps in knowledge. Priority areas identified for MCH research in order to close these knowledge gaps include: epigenetic mechanisms and their potential mutability; peri-conception as a critical and sensitive period for environmental exposures; maternal health prior to pregnancy; the role of the placenta as an important regulator of the intra-uterine environment; and ways to strengthen early mother–child interactions. Addressing knowledge gaps will require an emphasis on longitudinal rather than cross-sectional studies, long-term (lifetime) rather than short-term perspectives, datasets that include socio-demographic, biologic and genetic data on the same subjects rather than discipline-specific studies, measurement and study of positive health as well as disease states, and study of multi-rather than single generational cohorts. Adoption of a lifecourse-informed MCH research agenda requires a shift in focus from single cause-single disease epidemiologic inquiry to one that addresses multiple causes and outcomes. Investigators need additional training in effective interdisciplinary collaboration, advanced research methodology and higher-level statistical modeling. Advancing a life course health development research agenda in MCH will be foundational to the nation’s long-term health.     

Bisphenol A and Reproductive Health: Update of Experimental and Human Evidence, 2007–2013

Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction.Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action.Methods: We reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction.Discussion: Because BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development.Conclusion: Based on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant.Citation: Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. 2014. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786; http://dx.doi.org/10.1289/ehp.1307728     

Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts

Background: Prospective evidence regarding associations for exposures to bisphenol A (BPA) and phthalates with type 2 diabetes (T2D) is lacking.Objective: We prospectively examined urinary concentrations of BPA and phthalate metabolites with T2D risk.Methods: We measured BPA and eight major phthalate metabolites among 971 incident T2D case–control pairs from the Nurses’ Health Study (NHS) (mean age, 65.6 years) and NHSII (mean age, 45.6 years).Results: In the NHSII, BPA levels were not associated with incident T2D in multivariate-adjusted analysis until body mass index was adjusted: odds ratio (OR) comparing extreme BPA quartiles increased from 1.40 (95% CI: 0.91, 2.15) to 2.08 (95% CI: 1.17, 3.69; p_trend = 0.02) with such an adjustment. In contrast, BPA concentrations were not associated with T2D in the NHS (OR = 0.81; 95% CI: 0.48, 1.38; p_trend = 0.45). Likewise, urinary concentrations of total phthalate metabolites were associated with T2D in the NHSII (OR comparing extreme quartiles = 2.14; 95% CI: 1.19, 3.85; p_trend = 0.02), but not in the NHS (OR = 0.87; 95% CI: 0.49, 1.53; p_trend = 0.29). Summed metabolites of butyl phthalates or di-(2-ethylhexyl) phthalates were significantly associated with T2D only in the NHSII; ORs comparing extreme quartiles were 3.16 (95% CI: 1.68, 5.95; p_trend = 0.0002) and 1.91 (95% CI: 1.04, 3.49; p_trend = 0.20), respectively.Conclusions: These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives.Citation: Sun Q, Cornelis MC, Townsend MK, Tobias DK, Eliassen AH, Franke AA, Hauser R, Hu FB. 2014. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts. Environ Health Perspect 122:616–623; http://dx.doi.org/10.1289/ehp.1307201