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Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2

BackgroundReceptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.MethodsWe assessedRIPK1expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patientsviaimmunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, usingRipk1S25D/S25Dkinase-deficient mice and the RIPK1 kinase inhibitor GSK′547.ResultsRIPK1expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increasedRipk1expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.ConclusionsRIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.

Asthma is the most common chronic airways disease worldwide and the severe treatment resistant subtype of asthma is responsible for the majority of disease burden. Asthma is heterogeneous in nature and can be classified according to airway infiltrates as eosinophilic or non-eosinophilic (sometimes referred to as Type 2 low), which is further divided into paucigranulocytic (low levels of granulocytes), or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in airway tissue, sputum, and bronchoalveolar lavage. Severe non-eosinophilic asthma currently has fewer effective treatment options and many of these patients fail to qualify for newer biologic monoclonal therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is a key protein whose function is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease (COPD) and has proven a valuable therapeutic target. Using human bronchial epithelial cells (hBECs) isolated differentiated at air-liquid interface we demonstrated a reduced function of the CFTR in non-eosinophilic asthma. Characterization of the cell and molecular differences in airway epithelial cells between severe asthma subtypes using single cell RNA-sequencing (scRNAseq) revealed that airway epithelial cells from non-eosinophilic asthma, and in particular neutrophilic asthma patients, fail to differentiate into CFTR-expressing ionocytes compared with eosinophilic asthma or healthy donors. We identified a novel ionocyte transcriptional signature, which was present in both bronchial and tracheal airway epithelial samples indicating conserved anatomical gene regulation. Using protein markers and immunofluorescent quantification loss of ionocytes was confirmed in non-eosinophilic asthma hBECs. Similarly, ioncytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic allergen asthma models. Furthermore, treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture, but not IL-13, led to loss of ionocytes primarily due to IFN-γ. Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target for this difficult-to-treat disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied. OBJECTIVES: This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure. METHODS: Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313. RESULTS: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO. CONCLUSIONS: A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.

The obesity paradox postulates that increased body mass index (BMI) is protective in certain patient populations. We aimed to investigate the association of BMI and different weight classes with outcomes in hospitalised patients with community-acquired pneumonia (CAP). This cohort study is a secondary data analysis of the University of Louisville Pneumonia Study database, a prospective study of hospitalised adult patients with CAP from June, 2014, to May, 2016, in Louisville, KY, USA. BMI as a predictor was assessed both as a continuous and categorical variable. Patients were categorised as weight classes based on World Health Organization definitions: BMI of, This study assessed the impact of obesity in the outcomes of patients with community-acquired pneumonia. Increasing BMI is associated with decreased long-term mortality. However, the magnitude of the protective benefit plateaus at a BMI of 35. https://bit.ly/2WrLtRo

The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.

CD4

Background We evaluated the effect of time spent in the emergency department (ED) and process of care on mortality and length of hospital stay in patients with sepsis or septic shock. Methods An observational cohort study was conducted on 117 patients who came through the University of Louisville Hospital ED and subsequently were directly admitted to the intensive care unit (ICU). Variables of interest were time in the ED from triage to physical transport to the ICU, from triage to antibiotic(s) ordered, and from triage to antibiotic(s) administered. Expected mortality was calculated according to the University Health System Consortium Database. Primary and secondary outcomes were in-hospital death and hospital length of stay in days, respectively. Results We found no significant association between time in the ED and mortality between survivors and nonsurvivors (5.5 versus 5.7 hours, P = 0.804). After adjusting for expected mortality, a 22% increase in mortality risk was found for each hour delay from triage to antibiotic(s) ordered; a 15% increase in mortality risk was observed for each hour from triage to antibiotic(s) given. Both time from triage to antibiotic(s) ordered (hazard ratio [HR] = 0.8, P = 0.044) and time from triage to antibiotic(s) delivery (HR = 0.79, P = 0.0092) were independently associated with an increased hospital stay (HR = 0.79, P = 0.0092). Conclusion Though no significant association between mortality and ED time was demonstrated, we observed a significant increase in mortality in septic patients with both delays in antibiotic(s) order and administration. Delay in care also resulted in increased hospital stays both overall and in the ICU.

This paper compares the performance of chip seals constructed with polymer-modified emulsion (PME; CRS-2L) versus those constructed with unmodified emulsion (CRS-2). The overall performance evaluation is based on aggregate retention performance. The adhesion of the emulsions is examined using the Vialit test with various curing times and temperature conditions. To evaluate the aggregate retention performance of the chip seals, we used the Vialit test, the flip-over test and the third-scale Model Mobile Loading Simulator (MMLS3). The results from these tests indicate that the PME (CRS-2L) enhances aggregate retention performance, and does so more significantly in the early stages and at low temperatures.

A viscoelastoplastic continuum damage model has been derived and characterized for describing the behavior of asphalt concrete subject to an all-around confining pressure and deviatoric tension loading. The primary application of this model is to better understand the fatigue damage process in asphalt concrete pavements. As a result of this application and because of the bimodal behavior of this material outside the linear viscoelastic range, the modeling effort has focused primarily on the tensile characteristics. The developed model uses the elastic-viscoelastic correspondence principle, work-potential theory with damage mechanics, time-temperature superposition with growing damage, and strain-hardening viscoplasticity to arrive at a constitutive relationship. This relationship considers the experimentally observed transformation of asphalt concrete from an initially isotropic material to a transversely isotropic one by using a single-state parameter and three different damage functions. The relationship between these damage functions and the more conventional values of the modulus and Poisson’s ratio is shown to gain further physical insight into the material. Characterization of the model is performed by using constant crosshead rate monotonic tension tests with and without confinement and low strain temperature and frequency sweep complex modulus tests. The model is found to adequately describe the response of asphalt concrete under constant crosshead rate tension tests at various rates and two temperatures, the conditions that are not used in characterization.

Purpose Volar and percutaneous techniques of screw fixation for scaphoid fractures usually do not involve direct visualization of the dorsoproximal scaphoid articular surface. Intra-articular screw penetration may be overlooked if the proper fluoroscopic views are not obtained. The hypothesis of this study is that the pronated oblique fluoroscopic view of the scaphoid is the most sensitive in detecting dorsal articular screw penetration of the scaphoid when compared with other views. Methods A 3.6-mm Steinmann pin was inserted along the central axis of the scaphoid using an open dorsal technique in 10 embalmed cadaver wrists. The pin was then withdrawn from the palmar side until it was flush with the dorsal articular surface of the scaphoid. Five fluoroscopic views of the wrist were then obtained by rotating the forearm, keeping the image beam parallel to the floor: (1) anteroposterior, (2) supinated lateral, (3) pronated lateral, (4) 60° supinated oblique (60° supinated from wrist neutral), and (5) 60° pronated oblique (60° pronated from wrist neutral). The Steinmann pin was then allowed to visually protrude proximally from the articular surface in 0.5-mm increments, and all views were repeated. The view in which articular violation was first observed was recorded, as was the corresponding amount of pin protrusion. Results The pronated oblique was the fluoroscopic view in which articular penetration was first observed in all 10 specimens before it was evident on the other views. The amount of pin penetrating the articular surface before it was detected on the other views was 1 mm in 6 wrists and 2 mm in 4 wrists. Statistical analysis using Fischer's exact test was performed to determine whether the radiographic projection had an effect on the determination of articular penetration. The pronated oblique view was the first view to demonstrate articular penetration, with an average radiographically measured articular penetration of 1.4 mm ± 0.5. Conclusions This study confirms our hypothesis that the pronated oblique view is the most important fluoroscopic image to obtain when evaluating penetration of the proximal scaphoid articular surface.

The laboratory characterization of reflective crack-mitigating interlayer systems has been challenging due to the difficulty in establishing loading conditions that can simulate field behavior. Due to their widespread use in characterizing the fatigue resistance of single-layered asphalt concrete (AC) specimens, four-point beam fatigue tests are considered to be possible index tests for evaluating the behavior of various systems. However, the boundary conditions of the beam fatigue test and the criteria used to determine failure of the system with interlayers must be taken into account or else the results can be misleading. In this study, notched layered AC beams with various interlayer systems were subjected to four-point bending fatigue tests. The interlayer systems included three geosynthetics (two paving mats and one paving fabric), a chip seal layer, and a tack coat-only sample. Digital Image Correlation (DIC) was used to monitor deformation and crack propagation within these beams, and the results from the DIC analysis were compared with traditional beam fatigue failure criteria to evaluate their ability to rank the relative performance of the samples. This study found that commonly used beam fatigue failure criteria are inadequate measures of performance for layered beam tests, as they are incapable of quantifying all of the damage mechanisms that occur within layered samples, and that rankings obtained using these criteria can be misleading. Future research is needed to develop improved failure criteria and a better understanding of the correlation between the behavior of the interlayer systems tested in the four-point bending test and behavior in the field.

The production of warm mix asphalt (WMA) mixtures with high percentages of reclaimed asphalt pavement (RAP) is gaining attention as a way to save costs and efficiently utilize existing resources. However, WMA must perform at least as well as hot mix asphalt (HMA) before it can be used as a replacement for HMA. In this study, the performance of a WMA mixture with a high percentage of RAP (40 % RAP) and a WMA additive (1.5 % of binder weight) that works as a rejuvenator was evaluated and compared with the performance of a HMA mixture with the same amount of RAP in order to evaluate the effects of the WMA rejuvenator. These mixtures were evaluated in terms of fatigue cracking using the simplified viscoelastic continuum damage (S-VECD) model and in terms of rutting using the triaxial stress sweep (TSS) test. In addition, layered viscoelastic pavement analysis for critical distresses (LVECD) was used to predict the fatigue resistance of these mixtures for future use. The WMA rejuvenator was found to improve the mixing and compaction ability of the WMA mixture. Also, compared to the HMA mixture, the WMA mixture showed better fatigue resistance, but the rejuvenator found to have an adverse effect on the rutting resistance of the mixture.

Background/Aims Cyclic vomiting syndrome (CVS) is a disabling migraine variant manifesting as severe episodes of nausea and vomiting and often refractory to many therapies. Gastric electrical stimulation (GES), which can reduce nausea and vomiting in gastroparesis, may provide symptomatic relief for drug-refractory CVS. This study assessed the utility GES in reducing the symptoms of CVS and improving the quality of life. Methods A one-year, non-randomized, clinical study was conducted. Eleven consecutive patients with drug refractory, cyclic vomiting syndrome based on Rome III criteria and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), underwent treatment with temporary GES (Temp GES) and permanent GES (Perm GES). Post-treatment follow up was done up to one year after permanent gastric electrical stimulation therapy. Results Total symptom score decreased by 68% and 40% after temporary and permanent GES therapies, respectively. Hospital admission events significantly decreased to 1.50 (± 1.00) events from 9.14 (± 7.21) annual admissions prior to treatment with permanent GES. Vomiting episodes fell by 83% post Temp GES and 69% after Perm GES treatments. Mucosal electrogram values also changed after temporary stimulation. Conclusions In a small group of drug-refractory CVS patients, treatments with temporary and permanent GES significantly reduced the severity of gastrointestinal symptoms and frequency of hospital admissions.

The immune processes involved in the clearance and immunopathology of Chlamydia infection in the female reproductive tract (FRT) are not well understood. In previous ground-breaking studies we showed that IFN-ɛ, a novel type I IFN that is exclusively and constitutively expressed in the FRT, plays an important role in protecting against Chlamydia infections. Here, we examined the effects of IFN-ɛ on innate immune processes in the FRT in order to elucidate the mechanisms by which IFN-ɛ protects against Chlamydia infections. Female WT and IFN-ɛ−/− C57BL/6 mice were pre-treated with progesterone and infected intra-vaginally with Chlamydia muridarum or sham-infected. Uterine horns were harvested and the effects of IFN-ɛ deficiency on immune factor expression and cellular infiltration were assessed using microarray/bioinformatics analyses, real-time qPCR and flow cytometry. IFN-ɛ uniquely regulated the expression of 744 genes at baseline and 802 genes during Chlamydia infection, and universally regulated the transcription of 61 genes, regardless of infection status. Of note, pathways associated with protective innate responses, such as IFN regulatory factor activation and pattern recognition receptor signalling were down-regulated in Chlamydia-infected IFN-ɛ−/− mice compared to WT controls. These changes correlate with a decrease in the expression of many important IFN-γ signalling molecules and number of IFN-γ-producing NK cells in the FRT during infection. These findings suggest that IFN-ɛ may protect against Chlamydia FRT infections by potentiating innate immune processes important for the clearance of infection, particularly pathways associated with IFN-γ signalling and the activation of NK cell responses.

Altered iron levels and/or dysregulated iron homeostasis have been associated with a number of lung diseases, however, the mechanisms that underpin these associations, and whether iron plays a role in the pathogenesis of disease, are yet to be fully elucidated. In this study, systemic and pulmonary iron and lung structure and function were assessed in transferrin receptor (TFR)2 mutant and wild-type (WT) BALB/c mice fed a high-iron diet (containing 2% carbonyl iron) compared to normal diet controls, respectively. The effects of increased iron loading on murine models of ovalbumin- and house dust mite-induced allergic airways disease (AAD) were also assessed. Excess iron accumulation was observed in the lungs in both the genetic and diet-induced models of iron overloading. Increased iron levels in the lung were associated with emphysema-like alveolar enlargement, small airways collagen deposition, alterations in baseline lung function and increased airways hyper-responsiveness (AHR). Increased iron loading also resulted in altered type 1, 2 and 17 cytokine production, increased eosinophilic inflammation and severe, steroid-resistant AHR in AAD. Interestingly, AAD also results in altered systemic and pulmonary iron levels and iron regulatory molecule expression. These data show that increased iron levels in the lung results in emphysema and airways fibrosis that corresponds with reduced lung function. We also show that lung disease may be closely associated with changes in iron homeostasis. These models will be used to characterize the interplay between iron and immunity in the pathogenesis of lung disease and determine the therapeutic effectiveness of correcting dysregulated iron homeostasis for the treatment of lung disease.

There is a critical window in early-life where the lung is still maturing and susceptible to infection. Indeed, severe respiratory infections in early-life are a risk factor for the development of chronic lung diseases. The aim of this study was to identify the mechanisms involved. Neonatal wild-type (WT), TLR2 deficient (−/−), IL-13−/−, MyD88−/− and STAT6−/− mice were infected with the natural mouse bacterial pathogen Chlamydia muridarum, as a model of severe respiratory tract infection in early-life. In some experiments WT mice were treated with miR-21 antagomirs, PI3K inhibitors, or relevant controls during early-life infection. The impact of targeting these specific immune molecules during early-life on infection-induced impairment of lung function and structure were assessed. Neonatal Chlamydia respiratory infection increased TLR2, IL-13-receptor, miR-21 and PI3K expression and/or activity in the lung. TLR2 signalling induced IL-13-receptor expression, IL-13 signalling induced miR-21 expression and miR-21 increased PI3K activity. TLR2 signalling also increased IL-13+ ILC2s in the lung. TLR2−/− and IL-13−/− mice were protected against infection-induced airway hyperresponsiveness (AHR), but not emphysema-like alveolar enlargement. This TLR2/IL-13 mediated phenotype was independent of MyD88, but dependent on STAT6. Specific targeting of miR-21 prevented AHR but not emphysema. Pan-PI3K inhibition did not affect AHR, but protected against emphysema. Interestingly, early-life infection-induced AHR was steroid insensitive. This study identifies a novel signalling network that may be targeted for the prevention of the long-term deleterious effects of early-life infection on lung function and structure.

Real-time assessment of high-value targets is an ongoing challenge for the defense community. Many automatic target recognition (ATR) approaches exist, each with specific advantages and limitations. An ATR system is presented here that integrates machine learning, expert systems, and other advanced image understanding concepts. The ATR system employs a hierarchical strategy relying primarily on abductive polynomial networks at each level of recognition. Advanced feature extraction algorithms are used at each level for pixel characterization and target description. Polynomial networks process feature data and situational information, providing input for subsequent levels of processing. An expert system coordinates individual recognition modules. Heuristic processing of object likelihood estimates is also discussed. Here, separate estimators determine the likelihood that an object belongs to a particular class. Heuristic knowledge to resolve ambiguities that occur when more than one class appears likely is discussed. In addition, a comparison of model-based recognition with the primary polynomial network approach is presented. Model-based recognition is a goal-driven approach that compares a representation of the unknown target to a reference library of known targets. Each approach has advantages and limitations that should be considered for a specific implementation. This ATR approach can potentially overcome limitations of current systems such as catastrophic degradation during unanticipated operating conditions, while meeting strict processing requirements. These benefits result from implementation of robust feature extraction algorithms that do not take explicit advantage of peculiar characteristics of the sensor imagery; and the compact, real-time processing capability provided by abductive polynomial networks.

When adequate fracture reduction cannot be achieved with closed techniques, internal fixation can restore anatomy and improve functional outcomes. Volar plating, dorsal plating, and radial plating are well-described techniques that are useful in isolation or in combination, depending on the specific fracture pattern. In this article, we review each of these techniques and provide case examples to illustrate their applicability.

This paper focuses on the application of moment invariants as pixel-level characterization features. An innovative machine learning paradigm used to automatically learn information fusion models is briefly presented.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Detection, classification, and identification of high-value targets are ongoing challenges for the defense research community. Many automatic target recognition approaches exist, each with specific advantages and limitations. This approach first segments potential targets at the pixel level, followed by several hierarchical levels of object classification and identification. This paper discusses a specific aspect of this paradigm--the heuristic assessment of object classification likelihood estimates.

Model-based and data-driven approaches to automatic target recognition each provide a methodology to determine the class of an unknown target. Model-based recognition is a goal-driven approach that compares a representation of the unknown target to a reference library of unknown targets. A comparator algorithm determines a degree of `match' to each reference target. Data-driven approaches use a numeric algorithm to process a set of characterization features to produce a class likelihood estimate. Each approach has advantages and limitations that should be considered for a specific implementation. This research compares a specific implementation of each of these approaches developed for an automatic target recognition system that processes multi- spectral imagery representing military targets. To provide a valid baseline to compare the performance of each approach, a common target set, characterization feature set, and performance metrics are considered.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Successful object classification is highly dependent upon initial segmentation of an object from its background. For complex, real-world imaging applications, this task is extremely challenging and critical to the success of the recognition system. Traditional object segmentation techniques often rely heavily upon noise removal during preprocessing and subsequently employ image-level segmentation strategies. Because effective noise-removal strategies are often difficult to develop for real-world imagery, alternate methods are required for object segmentation. An alternate approach is to determine target/nontarget status of image regions at the pixel level. In this manner, noise removal and object segmentation are performed in a single process. The approach takes advantage of the large amount of information contained in present-day, multispectral imagery. The key issues associated with this approach are a robust pixel information representation and an information fusion algorithm to process pixel-level information.

Chlamydial respiratory tract infections are associated with the development and exacerbation of asthma in both children and adults, but the mechanisms underpinning this association remain unknown. We investigated the effect of the age of chlamydial infection on key features of asthma in later life using mouse models of Ovalbumin-induced allergic airways disease (AAD). Neonatal and infant, but not adult infection resulted in differential and permanent alterations in airway eosinophils, T-cell cytokines and dendritic cells (DCs). Infection of neonates suppressed eosinophil influx into the airways and reduced T-cell cytokine release which correlated with a significant reduction in the number and activation of DCs. In stark contrast, infant infection augmented eosinophil influx and increased T-cell cytokine release which correlated with increased DC numbers and activation. Importantly, both neonatal and infant infections enhanced physiological (mucus secreting cell hyperplasia and airways hyper-responsiveness) responses in AAD in later life, which correlated with enhanced IL-13 expression in the lung. Furthermore, neonatal infection induced substantial alterations in lung structure which was linked with increased TGF-β in lung tissue. Thus, early life infection enhances pivotal features of AAD through age dependent, differential affects on immune responses and lung structure.

The relative risk of breast cancer is very high among women who were exposed to ionizing radiation during or before puberty. In the current studies, the surviving fractions of clonogenic mammary cells of groups of virgin rats were estimated after single exposures to {sup 137}Cs {gamma} rays at intervals from 1 to 12 weeks after birth. The radiosensitivity of clonogens from prepubertal rats was high and changed with the onset of puberty at between 4 and 6 weeks of age. By this time, the increase in the size of the clonogenic cell subpopulation was slowing and differentiation of terminal mammary end buds and alveolar structures was occurring. Analysis of the relationship of clonogen survival and radiation dose according to the {alpha}/{beta} model showed that the exponential {alpha}D term predominated at the second and fourth weeks of age. By the eighth week of age, the {beta}D{sup 2} term had come to predominate and the survival curve had a pronounced initial convex shoulder. Further experiments are required to determine whether there is an association between the high sensitivity of the prepubertal and pubertal mammary clonogens to radiation killing and a high susceptibility to radiogenic initiation of cancer. 24 refs., 4 figs., 1more » tab.« less