Assessment of the Cutaneous Hormone Landscapes and Microbiomes in Vulvar Lichen Sclerosus.

Vulvar lichen sclerosus (VLS) is a progressive skin disease of unknown etiology. In this longitudinal case-control exploratory study, we evaluated the hormonal and microbial landscapes in 18 postmenopausal females (mean [SD] age: 64.4 [8.4] years) with VLS and controls. We reevaluated the patients with VLS after 10-14 weeks of daily topical class I steroid. We found that groin cutaneous estrone was lower in VLS than in controls (-22.33, 95% confidence interval [CI] = -36.96 to -7.70; P = .006); cutaneous progesterone was higher (5.73, 95% CI = 3.74-7.73; P < .0001). Forehead 11-deoxycortisol (-0.24, 95% CI = -0.42 to -0.06; P = .01) and testosterone (-7.22, 95% CI = -12.83 to -1.62; P = .02) were lower in disease. With treatment, cutaneous estrone (-7.88, 95% CI = -44.07 to 28.31; P = .62), progesterone (2.02, 95% CI = -2.08 to 6.11; P = .29), and 11-deoxycortisol (-0.13, 95% CI = -0.32 to 0.05; P = .15) normalized; testosterone remained suppressed (-7.41, 95% CI = -13.38 to -1.43; P = .02). 16S ribosomal RNA V1-V3 and ITS1 amplicon sequencing revealed bacterial and fungal microbiome alterations in disease. Findings suggest that cutaneous sex hormone and bacterial microbiome alterations may be associated with VLS in postmenopausal females.

Vulvar Lichen Sclerosus Clinical Severity Scales and Histopathologic Correlation: A Case Series.

ABSTRACT: Several vulvar lichen sclerosus (VLS) clinical severity scales have recently been proposed. In this prospective case series, we characterized histopathology in the context of clinical severity in 6 treatment-naïve postmenopausal patients with VLS. The Vulvar Quality of Life Index (VQLI) and an adaptation of the 2018 International Society for the Study of Vulvovaginal Disease Delphi consensus VLS severity score were administered. Vulvar skin punch biopsies were obtained to measure inflammatory density, constituent inflammatory cells, thickness of the stratum corneum and other epidermal layers, dermal edema, and dermal sclerosis. Clinicopathologic correlations were assessed. Two cases demonstrated sparse inflammatory densities, 1 case demonstrated patchy and nodular inflammatory density, 1 case demonstrated dense lichenoid inflammatory density, and 2 cases demonstrated dense lichenoid and epitheliotropic inflammatory densities. Those patients who reported severe pruritus demonstrated the greatest lymphocytic inflammatory densities on histopathological examination. Both cases of ulceration or erosion were associated with severe VQLI scores. Severe VQLI scores were also associated with trends for higher average thickness of the epidermal layers and of dermal sclerosis. Altogether, histopathologic grading of biopsy sites may reflect clinical severity in patients with VLS.

Is there a role for referral of high-risk patients seen in preoperative medical consultation for postoperative inpatient follow-up?

The potential benefit of referring select high-risk surgical patients who are seen during a preoperative medical consultation for postoperative inpatient medical follow-up is uncertain. Over a seven-year period, our internal medicine perioperative clinic referred 5% of 4642 preoperative consults for postoperative follow-up. A retrospective chart review found that although reasons for referral were heterogeneous, those assessed by the medical consult team postoperatively were more comorbid, had more adverse medical complications and had longer hospital admissions compared to those not referred. Physicians were best able to predict adverse cardiac and diabetes-related complications. Half of the patients who were referred for postoperative assessment were lost to follow-up, and there was a trend towards increased hospital readmissions in this group. Further research is required to identify the subset of patients who might benefit from postoperative inpatient medical assessment.

Comparative compositions of metabolites and dietary fibre components in doughs and breads produced from bread wheat, emmer and spelt and using yeast and sourdough processes.

Wholemeal flours from blends of bread wheat, emmer and spelt were processed into bread using yeast-based and sourdough fermentation. The bread wheat flour contained significantly higher concentrations of total dietary fibre and fructans than the spelt and emmer flours, the latter having the lowest contents. Breadmaking using sourdough and yeast systems resulted in changes in composition from flour to dough to bread including increases in organic acids and mannitol in the sourdough system and increases in amino acids and sugars (released by hydrolysis of proteins and starch, respectively) in both processing systems. The concentrations of fructans and raffinose (the major endogenous FODMAPs) were reduced by yeast and sourdough fermentation, with yeast having the greater effect. Both systems resulted in greater increases in sugars and glycerol in emmer than in bread wheat and spelt, but the significance of these differences for human health has not been established.

RNAi suppression of xylan synthase genes in wheat starchy endosperm.

The xylan backbone of arabinoxylan (AX), the major cell wall polysaccharide in the wheat starchy endosperm, is synthesised by xylan synthase which is a complex of three subunits encoded by the GT43_1, GT43_2 and GT47_2 genes. RNAi knock-down of either GT43_1 or all three genes (triple lines) resulted in decreased AX measured by digestion with endoxylanase (to 33 and 34.9% of the controls) and by monosaccharide analysis (to 45.9% and 47.4% of the controls) with greater effects on the amount of water-extractable AX (to 20.6 and 19.9% of the controls). Both sets of RNAi lines also had greater decreases in the amounts of substituted oligosaccharides released by digestion of AX with endoxylanase than in fragments derived only from the xylan backbone. Although the GT43_1 and triple lines had similar effects on AX they did differ in their contents of soluble sugars (increased in triple only) and on grain size (decreased in triple only). Both sets of transgenic lines had decreased grain hardness, indicating effects on cell wall mechanics. These results, and previously published studies of RNAi suppression of GT43_2 and GT47_2 and of a triple mutant of GT43_2, are consistent with the model of xylan synthase comprising three subunits one of which (GT47_2) is responsible for catalysis with the other two subunits being required for correct functioning but indicate that separate xylan synthase complexes may be responsible for the synthesis of populations of AX which differ in their structure and solubility.

Risk of Antibiotic-Resistant Staphylococcus aureus Dispersion from Hog Farms: A Critical Review.

The World Health Organization has declared antibiotic resistance "one of the biggest threats to global health." Mounting evidence suggests that antibiotic use in industrial-scale hog farming is contributing to the spread of antibiotic-resistant Staphylococcus aureus. To capture available evidence on these risks, we searched peer-reviewed studies published before June 2017 and conducted a meta-analysis of these studies' estimates of the prevalence of swine-associated, antibiotic-resistant S. aureus in animals, humans, and the environment. The 166 relevant studies revealed consistent evidence of livestock-associated methicillin-resistant S. aureus (MRSA) in hog herds (55.3%) raised with antibiotics. MRSA prevalence was also substantial in slaughterhouse pigs (30.4%), industrial hog operation workers (24.4%), and veterinarians (16.8%). The prevalence of swine-associated, multidrug-resistant S. aureus (MDRSA)-with resistance to three or more antibiotics-is not as well documented. Nonetheless, sufficient studies were available to estimate MDRSA pooled prevalence in conventional hog operation workers (15.0%), workers' household members (13.0%), and community members (5.37%). Evidence also suggests that antibiotic-resistant S. aureus can be present in air, soil, water, and household surface samples gathered in or near high-intensity hog operations. An important caveat is that prevalence estimates for humans reflect colonization, not active infection, and the health risks of colonization remain poorly understood. In addition, these pooled results may not represent risks in specific locations, due to wide geographic variation. Nonetheless, these results underscore the need for additional preventive action to stem the spread of antibiotic-resistant pathogens from livestock operations and a streamlined reporting system to track this risk.

Regulation of virulence and antibiotic resistance in Gram-positive microbes in response to cell wall-active antibiotics.

PURPOSE OF REVIEW: Antibiotic stress can evoke considerable genotypic and phenotypic changes in Gram-positive bacteria. Here, we review recent studies describing altered virulence expression in response to cell wall-acting antibiotics and discuss mechanisms that coordinate regulation of the antibiotic response. RECENT FINDINGS: Pleiotropic effects induced by antibiotic exposure include alterations to bacterial metabolism, cell wall structure and antibiotic resistance. In addition, subinhibitory concentrations of cell wall-active (CWA) antibiotics have increasingly been shown to induce the production of exotoxins and biofilm formation that may influence virulence. Remarkably, phenotypes associated with comparable antibiotic stresses can vary considerably, emphasizing the need to better understand the response to CWA antibiotics. Recent studies support both direct antibiotic recognition and recognition of antibiotic-induced stress to the bacterial cell wall. Specifically, bacterial two-component systems, penicillin-binding protein and serine/threonine kinase-associated kinases and conserved oxidative-stress sensors each contribute to modulating the antibiotic stress response. SUMMARY: Bacterial sensory systems and global regulators coordinate signaling in response to CWA antibiotics. Regulation of the antibiotic response is complex and involves integration of signals from multiple response pathways. A better definition of the antibiotic stress response among Gram-positive pathogens may yield novel therapeutic targets to counter antibiotic resistance and virulence factor expression.

Frailty Cost: Economic Impact of Frailty in the Elective Surgical Patient.

BACKGROUND: Frailty in the surgical patient has been associated with increased morbidity, mortality, and failure to rescue. However, there is little understanding of the economic impact of frailty. STUDY DESIGN: A prospective database of elective surgery patients at an academic medical center was used to create a modified version of the Risk Analysis Index (RAI), a validated frailty index. This included 10,257 patients undergoing elective operations from 2016 to 2017. Patients were classified as not frail (RAI = 0), somewhat frail (RAI = 1 to 10), or significantly frail (RAI > 10). Cost, revenue, and income data were procured from the finance department. Univariate and multivariate analyses were performed. RESULTS: Frail patients were more likely to be older (65 years vs 50 years; p < 0.001) and inpatient (19% vs 36%; p < 0.001). General surgical, gynecologic, urologic, and cardiothoracic services operated on a higher percentage of significantly frail patients compared with orthopaedic, neurosurgical, and vascular (p < 0.001). On univariate analysis, frail patients were more likely to die (0% vs 0.4%; p < 0.001) and have increased length of stay (0.8 vs 2.1 days; p < 0.001), higher total cost ($6,934 vs $13,319), and lower net hospital income ($5,447 vs $3,129) (p < 0.001). On multivariate analysis, frailty was independently associated with increased direct cost (odds ratio [OR] 2.2; p < 0.001), indirect cost (OR 1.9; p < 0.001), total cost (OR 2.2; p < 0.001), and net income (OR 0.8; p < 0.001). Stratified by service line and inpatient vs outpatient status, frailty continued to be associated with increased direct cost, indirect cost, total cost, and decreased hospital income. CONCLUSIONS: Although a significant number of data exist on the impact of frailty in the surgical patient, the economic impacts have only limited description in the literature. Here we demonstrate that frailty, independent of age, has a detrimental financial impact on cost and hospital income in elective surgery.

Biomechanical, Anthropometric, and Psychological Determinants of Barbell Back Squat Strength.

Vigotsky, AD, Bryanton, MA, Nuckols, G, Beardsley, C, Contreras, B, Evans, J, and Schoenfeld, BJ. Biomechanical, anthropometric, and psychological determinants of barbell back squat strength. J Strength Cond Res 33(7S): S26-S35, 2019-Previous investigations of strength have only focused on biomechanical or psychological determinants, while ignoring the potential interplay and relative contributions of these variables. The purpose of this study was to investigate the relative contributions of biomechanical, anthropometric, and psychological variables to the prediction of maximum parallel barbell back squat strength. Twenty-one college-aged participants (male = 14; female = 7; age = 23 ± 3 years) reported to the laboratory for 2 visits. The first visit consisted of anthropometric, psychometric, and parallel barbell back squat 1 repetition maximum (1RM) testing. On the second visit, participants performed isometric dynamometry testing for the knee, hip, and spinal extensors in a sticking point position-specific manner. Multiple linear regression and correlations were used to investigate the combined and individual relationships between biomechanical, anthropometric, and psychological variables and squat 1RM. Multiple regression revealed only 1 statistically predictive determinant: fat-free mass normalized to height (standardized estimate ± SE = 0.6 ± 0.3; t(16) = 2.28; p = 0.037). Correlation coefficients for individual variables and squat 1RM ranged from r = -0.79 to 0.83, with biomechanical, anthropometric, experiential, and sex predictors showing the strongest relationships, and psychological variables displaying the weakest relationships. These data suggest that back squat strength in a heterogeneous population is multifactorial and more related to physical rather than psychological variables.

C. elegans germ cells divide and differentiate in a folded tissue.

Knowing how stem cells and their progeny are positioned within their tissues is essential for understanding their regulation. One paradigm for stem cell regulation is the C. elegans germline, which is maintained by a pool of germline stem cells in the distal gonad, in a region known as the 'progenitor zone'. The C. elegans germline is widely used as a stem cell model, but the cellular architecture of the progenitor zone has been unclear. Here we characterize this architecture by creating virtual 3D models of the progenitor zone in both sexes. We show that the progenitor zone in adult hermaphrodites is organized like a folded epithelium. The progenitor zone in males is not folded. Analysis of germ cell division shows that daughter cells are born side-by-side along the epithelial-like surface of the germline tissue. Analysis of a key regulator driving differentiation, GLD-1, shows that germ cells in hermaphrodites differentiate along a folded path, with previously described "steps" in GLD-1 expression corresponding to germline folds. Our study provides a three-dimensional view of how C. elegans germ cells progress from stem cell to overt differentiation, with critical implications for regulators driving this transition.

Tumor mitotic rate is an independent predictor of survival for nonmetastatic melanoma.

BACKGROUND: Tumor mitotic rate is a known prognostic variable in Stage I melanoma; however, its importance is unclear in Stages II and III. METHODS: Patients diagnosed with nonmetastatic cutaneous melanoma from 2010 to 2014 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry. RESULTS: Of a total of 71,235 patients, the majority were white (94.7%), male (58.5%), and had a Stage I tumor (79.0%). On univariable analysis, 5-year disease-specific survival decreased with each increasing tumor mitotic rate category of 0-3, 4-10, and >10 mitoses/mm2 (Stage I 98.3%, 90.9%, 79.7%; Stage II 86.1%, 74.2%, 72.9%; and Stage III 72.5%, 58.6%, 49.7%). In multivariable models, tumor mitotic rate as both a continuous and categorical variable was associated with disease-specific survival for Stages I-III melanoma. Each unit increase in tumor mitotic rate increased the risk of death by 23% in Stage I, 5% in Stage II, and 3% in Stage III. Compared with the 0-3 tumor mitotic rate category, the risk of disease-specific mortality increased for tumors in the 4-10 and >10 categories for Stage I (RR 3.07 and 6.74, P < .0001), Stage II (RR 1.37 and 1.62, P = .0002), and Stage III (RR 1.24 and 1.35, P = .0004). CONCLUSION: In this cohort study, tumor mitotic rate is an independent predictor of survival for localized melanoma.

Factors affecting use of ballistics gelatin in laboratory studies of bacterial contamination in projectile wounds.

BACKGROUND: Ballistics gelatin is a common tissue surrogate used in bacterial contamination models for projectile wounds. Although these studies have demonstrated that bacteria are transferred from the surface of the gelatin to the wound track by a projectile, quantifiable results have been inconsistent and not repeatable in successive tests. METHODS: In this study, five areas of a typical contamination model in which bacterial recovery or survival are affected were identified for optimization. The first was a contaminated "skin" surrogate, where the novel use of vacuum filtration of a bacterial culture and buffer onto filter paper was employed. The other possibly problematic areas of the bacterial distribution model included the determination of bacterial survival when the contamination model is dried, survival in solid and molten gelatin, and the effect of high-intensity lights used for recording high-speed video. RESULTS: Vacuum filtration of bacteria and buffer resulted in a consistent bacterial distribution and recovery. The use of phosphate buffer M9 (pH 7) aided in neutralizing the ballistics gelatin and improving bacterial survival in solid gelatin. Additionally, the use of high-intensity lights to record high-speed video and the use of a 42°C water bath to melt the gelatin were found to be bactericidal for gram-positive and gram-negative bacteria. CONCLUSIONS: Multiple areas of a typical contamination model in which bacterial survival may be impeded were identified, and methods were proposed to improve survival in each area. These methods may be used to optimize the results of bacterial contamination models for medical applications, such as understanding the progression of infection in penetrating wounds and to identify possible sources of contamination for forensic purposes.

Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.

Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling. Myristate significantly increased C14-ceramide levels, whereas palmitate increased several long-chain ceramides. To define the role of ceramide synthases (CerSs) in myristate-induced ER stress, we used the pharmacologic inhibitor, fumonisin B1 (FB1), and small interfering RNA (siRNA) for CerS5 and 6, the primary isoforms that are involved in C14-ceramide generation. FB1 and siRNA for CerS5 or 6 suppressed myristate-induced C14-ceramide generation and XBP1 splicing (XBP1s). Moreover, increased XBP1s induced the downstream expression of IL-6 in a CerS5/6-dependent manner. In addition, a myristate-enriched milk fat-based diet, but not a lard-based diet, increased C14-ceramide, XBP1s, and IL-6 expression in vivo. Taken together, our data suggest that myristate modulates ER stress and cytokine production in the intestinal epithelium via CerS5/6 and C14-ceramide generation.-Choi, S., Snider, J. M., Olakkengil, N., Lambert, J. M., Anderson, A. K., Ross-Evans, J. S., Cowart, L. A., Snider, A. J. Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.

Divergent Roles of RPA Homologs of the Model Archaeon Halobacterium salinarum in Survival of DNA Damage.

The haloarchaea are unusual in possessing genes for multiple homologs to the ubiquitous single-stranded DNA binding protein (SSB or replication protein A, RPA) found in all three domains of life. Halobacterium salinarum contains five homologs: two are eukaryotic in organization, two are prokaryotic and are encoded on the minichromosomes, and one is uniquely euryarchaeal. Radiation-resistant mutants previously isolated show upregulation of one of the eukaryotic-type RPA genes. Here, we have created deletions in the five RPA operons. These deletion mutants were exposed to DNA-damaging conditions: ionizing radiation, UV radiation, and mitomycin C. Deletion of the euryarchaeal homolog, although not lethal as in Haloferax volcanii, causes severe sensitivity to all of these agents. Deletion of the other RPA/SSB homologs imparts a variable sensitivity to these DNA-damaging agents, suggesting that the different RPA homologs have specialized roles depending on the type of genomic insult encountered.

Frailty Predicts Failure to Rescue after Thoracoabdominal Operation.

BACKGROUND: An association between frailty and mortality exists; we hypothesized this is secondary to failure to rescue (F2R). STUDY DESIGN: Data were obtained from the NSQIP (2005 to 2012) for patients undergoing thoracoabdominal operations. Using the Modified Frailty Index, patients were classified as not (0 points), mildly (1 point), moderately (2 points), and severely (≥3) frail. RESULTS: There were 962,913 patients included; a majority were non-frail (52.2%), followed by mildly frail (33.8%). Complications were noted in 15.3%, major complications in 9.5%, mortality in 1.8%, and F2R in 1.3% of patients. On multivariate analysis, increases in frailty were associated with an increase in the risk of major complications (mildly: risk ratio [RR] 1.51; moderately: RR 2.69; and severely frail: RR 5.63 compared with non-frail; p < 0.0001), and death (mildly frail: RR 1.84; moderately frail: RR 4.44; and severely frail: RR 12.4). On univariate analysis, older patients, males, those undergoing small bowel interventions, gastric operations, or other procedures, and the frail were more likely to experience F2R (p < 0.0001). On multivariate analysis, males (RR 1.07), those undergoing small bowel intervention (RR 1.91), gastric operation (RR 1.83), and other procedures (RR 2.43) compared with hernia repair were more likely to experience F2R. As frailty increases F2R increases (mildly frail: RR 1.48; moderately frail: RR 2.41; and severely frail: RR 4.41) (p < 0.0001). Components of the Modified Frailty Index were analyzed separately; measures of impaired functional status were independently associated with increased F2R (RR 2.91; p < 0.0001), and those measuring comorbid medical conditions were not. CONCLUSIONS: Increases in frailty independently predict risk for F2R. The greatest predictors of F2R in the Modified Frailty Index are those associated with disability and not comorbidities.

The impact of reducing intensive care unit length of stay on hospital costs: evidence from a tertiary care hospital in Canada.

PURPOSE: To use theoretical modelling exercises to determine the effect of reduced intensive care unit (ICU) length of stay (LOS) on total hospital costs at a Canadian centre. METHODS: We conducted a retrospective cost analysis from the perspective of one tertiary teaching hospital in Canada. Cost, demographic, clinical, and LOS data were retrieved through case-costing, patient registry, and hospital abstract systems of The Ottawa Hospital Data Warehouse for all new in-patient ward (30,483) and ICU (2,239) encounters between April 2012 and March 2013. Aggregate mean daily variable direct (VD) costs for ICU vs ward encounters were summarized by admission day number, LOS, and cost centre. RESULTS: The mean daily VD cost per ICU patient was $2,472 (CAD), accounting for 67.0% of total daily ICU costs per patient and $717 for patients admitted to the ward. Variable direct cost is greatest on the first day of ICU admission ($3,708), and then decreases by 39.8% to plateau by the fifth day of admission. Reducing LOS among patients with ICU stays ≥ four days could potentially result in an annual hospital cost saving of $852,146 which represents 0.3% of total in-patient hospital costs and 1.2% of ICU costs. CONCLUSION: Reducing ICU LOS has limited cost-saving potential given that ICU costs are greatest early in the course of admission, and this study does not support the notion of reducing ICU LOS as a sole cost-saving strategy.

Comparison between MRI and pathology in the assessment of tumour regression grade in rectal cancer.

BACKGROUND: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. METHODS: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan-Meier method was used to estimate survival outcomes. RESULTS: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7-4.7) and 6.6 weeks (IQR: 5.9-7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (κ=0.24) or modified three-tier systems (κ=0.25). Sensitivity and specificity of mrTRG 1-2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8-86.5) and 62.8% (95% CI: 54.5-70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1-2) compared to poor regression (mrTRG 3-5) (5-year recurrence-free survival 76.9% vs 65.9%, P=0.18; 5-year overall survival 80.6% vs 68.8%, P=0.22). CONCLUSIONS: The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.

Defective postsecretory maturation of MUC5B mucin in cystic fibrosis airways.

In cystic fibrosis (CF), airway mucus becomes thick and viscous, and its clearance from the airways is impaired. The gel-forming mucins undergo an ordered "unpacking/maturation" process after granular release that requires an optimum postsecretory environment, including hydration and pH. We hypothesized that this unpacking process is compromised in the CF lung due to abnormal transepithelial fluid transport that reduces airway surface hydration and alters ionic composition. Using human tracheobronchial epithelial cells derived from non-CF and CF donors and mucus samples from human subjects and domestic pigs, we investigated the process of postsecretory mucin unfolding/maturation, how these processes are defective in CF airways, and the probable mechanism underlying defective unfolding. First, we found that mucins released into a normal lung environment transform from a compact granular form to a linear form. Second, we demonstrated that this maturation process is defective in the CF airway environment. Finally, we demonstrated that independent of HCO3- and pH levels, airway surface dehydration was the major determinant of this abnormal unfolding process. This defective unfolding/maturation process after granular release suggests that the CF extracellular environment is ion/water depleted and likely contributes to abnormal mucus properties in CF airways prior to infection and inflammation.

Ecoimmunology and microbial ecology: Contributions to avian behavior, physiology, and life history.

Bacteria have had a fundamental impact on vertebrate evolution not only by affecting the evolution of the immune system, but also generating complex interactions with behavior and physiology. Advances in molecular techniques have started to reveal the intricate ways in which bacteria and vertebrates have coevolved. Here, we focus on birds as an example system for understanding the fundamental impact bacteria have had on the evolution of avian immune defenses, behavior, physiology, reproduction and life histories. The avian egg has multiple characteristics that have evolved to enable effective defense against pathogenic attack. Microbial risk of pathogenic infection is hypothesized to vary with life stage, with early life risk being maximal at either hatching or fledging. For adult birds, microbial infection risk is also proposed to vary with habitat and life stage, with molt inducing a period of increased vulnerability. Bacteria not only play an important role in shaping the immune system as well as trade-offs with other physiological systems, but also for determining digestive efficiency and nutrient uptake. The relevance of avian microbiomes for avian ecology, physiology and behavior is highly topical and will likely impact on our understanding of avian welfare, conservation, captive breeding as well as for our understanding of the nature of host-microbe coevolution.