Stochastic Framework for Addressing Chemical Partitioning and Bioavailability in Contaminated Sediment Assessment and Management.

Passive sampling to quantify net partitioning of hydrophobic organic contaminants between the porewater and solid phase has advanced risk management for contaminated sediments. Direct porewater (Cfree) measures represent the best way to predict adverse effects to biota. However, when the need arises to convert between solid-phase concentration (Ctotal) and Cfree, a wide variation in observed sediment-porewater partition coefficients (KTOC) is observed due to intractable complexities in binding phases. We propose a stochastic framework in which a given Ctotal is mapped to an estimated range of Cfree through variability in passive sampling-derived KTOC relationships. This mapping can be used to pair estimated Cfree with biological effects data or inversely to translate a measured or assumed Cfree to an estimated Ctotal. We apply the framework to both an effects threshold for polycyclic aromatic hydrocarbon (PAH) toxicity and an aggregate adverse impact on an assemblage of species. The stochastic framework is based on a "bioavailability ratio" (BR), which reflects the extent to which potency-weighted, aggregate PAH partitioning to the solid-phase is greater than that predicted by default, KOW-based KTOC values. Along a continuum of Ctotal, we use the BR to derive an estimate for the probability that Cfree will exceed a threshold. By explicitly describing the variability of KTOC and BR, estimates of risk posed by sediment-associated contaminants can be more transparent and nuanced.

Implications of fatherhood in cystic fibrosis.

Advances in fertility treatment mean that men with CF are increasingly able to become fathers. Here we report clinical outcomes in 22 men with CF who have become fathers for the first time. Overall mean (SD) FEV1% predicted declined from 60.1(18.0)% to 57.4(20.2)% from baseline to 1 year (p = 0.15). Weight declined from mean (SD) 70.6 kg (10.4) to 68.3 kg (10.2), p = 0.0001. Six men had an FEV1% predicted ≤40% at the time of birth: 50% died or received lung transplantation within the 12-15 month follow up period. Becoming a parent is a major life event, and as with new mothers, fathers with CF may be at risk of significant decline.

Clinical updates in cystic fibrosis-related diabetes.

Improved clinical care has led to a dramatic increase in life expectancy for people with cystic fibrosis (CF). As they live longer, people with CF are therefore developing secondary complications. Cystic fibrosis-related diabetes (CFRD) is the commonest extrapulmonary complication of CF. Insulin deficiency is the primary defect in CFRD, but insulin resistance and impairment of the enteroinsular axis play contributory roles. CFRD affects 9% of people with CF aged 5 to 9 years, 26% aged 10 to 20 years, and up to 50% by the age of 30. The presence of CFRD is associated with accelerated decline in pulmonary function, poorer growth and nutritional status, and increased mortality. The need for early detection of abnormal glucose handling in CF is clear since it is linked with clinical decline. Patients with CFRD may be asymptomatic for many years, so it is recommended that screening be commenced at 10 years of age. Although oral glucose tolerance test is recommended, it is well recognized that early glucose handling abnormalities will not be detected and the chance to intervene early may be missed. Many centers are therefore using continuous glucose monitoring to refine the diagnosis and investigate real-life glycemic control. Future research will hopefully widen our understanding of the pathophysiology of CFRD and therefore the treatment options available. There are clearly some promising results suggesting the use of oral agents may prove beneficial in treating CFRD but insulin should remain the mainstay of treatment until these are further evaluated.

Emerging Nonpulmonary Complications for Adults With Cystic Fibrosis: Adult Cystic Fibrosis Series.

Improved treatments for cystic fibrosis (CF)-related lung disease have resulted in increased longevity, but also increased prevalence and severity of extrapulmonary manifestations of CF, treatment-related complications, age-related conditions, and psychosocial effects of longstanding chronic disease. Likewise, the recognition of mild CF phenotypes has changed the landscape of CF disease. This review outlines our current understanding of the common extrapulmonary complications of CF, as well as the changing landscape and future directions of the extrapulmonary complications experienced by patients with CF.

Using metabolomic profiling to inform use of surrogate species in ecological risk assessment practices.

The U.S. EPA frequently uses avian or fish toxicity data to set protective standards for amphibians in ecological risk assessments. However, this approach does not always adequately represent aquatic-dwelling and terrestrial-phase amphibian exposure data. For instance, it is accepted that early life stage tests for fish are typically sensitive enough to protect larval amphibians, however, metamorphosis from tadpole to a terrestrial-phase adult relies on endocrine cues that are less prevalent in fish but essential for amphibian life stage transitions. These differences suggest that more robust approaches are needed to adequately elucidate the impacts of pesticide exposure in amphibians across critical life stages. Therefore, in the current study, methodology is presented that can be applied to link the perturbations in the metabolomic response of larval zebrafish (Danio rerio), a surrogate species frequently used in ecotoxicological studies, to those of African clawed frog (Xenopus laevis) tadpoles following exposure to three high-use pesticides, bifenthrin, chlorothalonil, or trifluralin. Generally, D. rerio exhibited greater metabolic perturbations in both number and magnitude across the pesticide exposures as opposed to X. laevis. This suggests that screening ecological risk assessment surrogate toxicity data would sufficiently protect amphibians at the single life stage studied but care needs to be taken to understand the suite of metabolic requirements of each developing species. Ultimately, methodology presented, and data gathered herein will help inform the applicability of metabolomic profiling in establishing the risk pesticide exposure poses to amphibians and potentially other non-target species.

Extrapolating In Vitro Screening Assay Data for Thyroperoxidase Inhibition to Predict Serum Thyroid Hormones in the Rat.

Thyroperoxidase (TPO) is an enzyme essential for thyroid hormone (TH) synthesis and a target site for a number of xenobiotics that disrupt TH homeostasis. An in vitro high-throughput screening assay for TPO inhibition, the Amplex UltraRed-TPO (AUR-TPO), has been used to screen the ToxCast chemical libraries for this action. Output from this assay would be most useful if it could be readily translated into an in vivo response, namely a reduction of TH in serum. To this end, the relationship between TPO inhibition in vitro and serum TH decreases was examined in rats exposed to 2 classic TPO inhibitors, propylthiouracil (PTU) and methimazole (MMI). Serum and gland PTU, MMI, and TH levels were quantified using tandem liquid chromatography mass spectrometry. Thyroperoxidase activity was determined in thyroid gland microsomes treated with PTU or MMI in vitro and ex vivo from thyroid gland microsomes prepared from exposed animals. A quantitative model was constructed by contrasting in vitro and ex vivo AUR-TPO results and the in vivo time-course and dose-response analysis. In vitro:ex vivo correlations of AUR-TPO outputs indicated that less than 30% inhibition of TPO in vitro was sufficient to reduce serum T4 by 20%, a degree of regulatory significance. Although further testing of model estimates using other TPO inhibitors is essential for verification of these initial findings, the results of this study provide a means to translate in vitro screening assay results into predictions of in vivo serum T4 changes to inform risk assessment.

Energy balance and obesity in individuals with cystic fibrosis.

This article reviews the significance of nutritional status in patients with cystic fibrosis (CF), and sheds light on the reasons behind the intense focus placed on perpetual weight gain and increased caloric intake by CF patients and their providers. The manuscript explores the potential mechanisms by which aberrant CFTR may contribute to increased resting energy expenditure (REE), and how correcting and potentiating its activity, possibly by reducing REE, among other intended and off-target effects, can contribute to weight gain in this patient population. The commentary also examines what is currently known about metabolic and vascular complications of obesity in patients with CF, and presents dietary, nutritional, pharmacologic and surgical approaches that may help obese patients with CF lose weight and build more lean body mass.

Cystic fibrosis related diabetes: Medical management.

Cystic Fibrosis Related Diabetes Mellitus (CFRD) drives excess pulmonary morbidity and mortality in patients with cystic fibrosis (CF). The recommended treatment is insulin therapy. Insulin therapy in CF should be customized to the specific patient. CF patients typically require intensive insulin regimens such as multiple daily injections or insulin pump therapy, but frequently require lower doses than in type 1 diabetes mellitus. Patients with CF may also need insulin to cover intravenous or enteral feedings. Pre-diabetic glycaemic abnormalities are also associated with clinical decline in cystic fibrosis prior to the diagnosis of CFRD, however, whether and how this should be treated is not fully determined. There is also interest, but inadequate data regarding other treatments besides insulin (i.e., oral medications) for treatment of pre-diabetes or CFRD. CFTR potentiator and corrector therapy has yet to demonstrate an effect on the rate of CFRD, but may improve insulin secretion. There is great opportunity for further research to better understand when and how best to treat glycaemic abnormalities in cystic fibrosis.

Anatomical traces of vocabulary acquisition in the adolescent brain.

A surprising discovery in recent years is that the structure of the adult human brain changes when a new cognitive or motor skill is learned. This effect is seen as a change in local gray or white matter density that correlates with behavioral measures. Critically, however, the cognitive and anatomical mechanisms underlying these learning-related structural brain changes remain unknown. Here, we combined brain imaging, detailed behavioral analyses, and white matter tractography in English-speaking monolingual adolescents to show that a critical linguistic prerequisite (namely, knowledge of vocabulary) is proportionately related to relative gray matter density in bilateral posterior supramarginal gyri. The effect was specific to the number of words learned, regardless of verbal fluency or other cognitive abilities. The identified region was found to have direct connections to other inferior parietal areas that separately process either the sounds of words or their meanings, suggesting that the posterior supramarginal gyrus plays a role in linking the basic components of vocabulary knowledge. Together, these analyses highlight the cognitive and anatomical mechanisms that mediate an essential language skill.

Effect of sediment-associated pyrethroids, fipronil, and metabolites on Chironomus tentans growth rate, body mass, condition index, immobilization, and survival.

Pyrethroids and fipronil insecticides partition to sediment and organic matter in aquatic systems and may pose a risk to organisms that use these matrices. It has been suggested that bioavailability of sediment-sorbed pesticides is reduced, but data on toxicity of sediment-associated pesticides for pyrethroids and fipronil are limited. In the current study, 10-d sediment exposures were conducted with larval Chironomus tentans for bifenthrin, lambda-cyhalothrin, permethrin, fipronil, fipronil-sulfide, and fipronil-sulfone, the last two being common fipronil metabolites. Sublethal endpoints included immobilization, instantaneous growth rate (IGR), body condition index, and growth estimated by ash-free dry mass (AFDM). Pyrethroid lethal concentrations to 50% of the population (LC50s) were 6.2, 2.8, and 24.5 microg/g of organic carbon (OC) for bifenthrin, lambda-cyhalothrin, and permethrin, respectively; with the former two lower than previously published estimates. Fipronil, fipronil-sulfide, and fipronil-sulfone LC50 values were 0.13, 0.16, and 0.12 microg/g of OC, respectively. Ratios of LC50s to sublethal endpoints (immobilization, IGR, and AFDM) ranged from 0.90 to 9.03. The effects on growth observed in the present study are important because of the unique dipteran life cycle involving pupation and emergence events. Growth inhibition would likely lead to ecological impacts similar to mortality (no emergence and thus not reproductively viable) but at concentrations up to 4.3 times lower than the LC50 for some compounds. In addition, C. tentans was highly sensitive to fipronil and metabolites, suggesting that dipterans may be important for estimating risk and understanding effects of phenylpyrazole-class insecticides on benthic macroinvertebrate communities.

The utility of solid-phase microextraction in evaluating polycyclic aromatic hydrocarbon bioavailability during habitat restoration with dredged material at moderately contaminated sites.

The over- or underprediction of risk in moderately contaminated sediments can have a large impact on the nature of applied management strategies given that concentrations border on being toxic or not toxic. Project managers should give significant consideration as to how moderate levels of contaminants in native sediments and dredged material used for restoration will impact recovery of habitat. Total solid-phase (Ctotal ) and porewater (Cfree ) polycyclic aromatic hydrocarbons (PAHs) were quantified in native sediments and dredged material to determine if the predictions of risk from Ctotal are consistent with those based on Cfree . The sediment matrix phase in which PAHs were quantified resulted in disparate conclusions regarding the predicted reduction in contamination following restoration. Total solid-phase PAH concentrations suggested a significant decrease following restoration, whereas little to no change was observed in measured Cfree . Risk metrics based on Ctotal gave inconclusive estimates for toxicity, whereas measured Cfree suggested toxicity is unlikely, a conclusion consistent with toxicity testing. The incorporation of black carbon (BC) into model estimates for Cfree gave predictions more consistent with measured Cfree , suggesting that geochemical conditions (especially BC) play an important part in predicting toxicity at moderately contaminated sites. In addition to the use of Cfree in toxicity evaluation, in-situ Cfree measurements provided a constraint on diffusive PAH loads from sediment relative to ongoing stream loads. If passive sampling had been employed during the sampling designs and site evaluations, the costs of toxicity testing would not have been incurred, given that Cfree suggested little to no toxicity. The results from the project highlight the benefits to be gained by moving beyond inconclusive, screening-level Ctotal metrics and implementing more sensitive and accurate Cfree metrics in assessments of risk in moderately contaminated sediments. Integr Environ Assess Manag 2018;14:212-223. © 2017 SETAC.

Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis.

In animals, glucose concentrations are 3-20 times lower in lung lining fluid than in plasma. In humans, glucose concentrations are normally low (<1 mmol/l) in nasal and bronchial fluid, but they are elevated by inflammation or hyperglycemia. Furthermore, elevated bronchial glucose is associated with increased respiratory infection in intensive care patients. Our aims were to estimate normal glucose concentrations in fluid from distal human lung sampled noninvasively and to determine effects of hyperglycemia and lung disease on lung glucose concentrations. Respiratory fluid was sampled as exhaled breath condensate, and glucose was measured by chromatography with pulsed amperometric detection. Dilution corrections, based on conductivity, were applied to estimate respiratory fluid glucose concentrations (breath glucose). We found that breath glucose in healthy volunteers was 0.40 mmol/l (SD 0.24), reproducible, and unaffected by changes in salivary glucose. Breath-to-blood glucose ratio (BBGR) was 0.08 (SD 0.05). Breath glucose increased during experimental hyperglycemia (P < 0.05) and was elevated in diabetic patients without lung disease [1.20 mmol/l (SD 0.69)] in proportion to hyperglycemia [BBGR 0.09 (SD 0.06)]. Breath glucose was elevated more than expected for blood glucose in cystic fibrosis patients [breath 2.04 mmol/l (SD 1.14), BBGR 0.29 (SD 0.17)] and in cystic fibrosis-related diabetes [breath 4.00 mmol/l (SD 2.07), BBGR 0.54 (0.28); P < 0.0001]. These data indicate that 1) this method makes a biologically plausible estimate of respiratory fluid glucose concentration, 2) respiratory fluid glucose concentrations are elevated by hyperglycemia and lung disease, and 3) effects of hyperglycemia and lung disease can be distinguished using the BBGR. This method will support future in vivo investigation of the cause and effect of elevated respiratory fluid glucose in human lung disease.

Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis.

BACKGROUND: Pulmonary decline accelerates in cystic fibrosis-related diabetes (CFRD) proportional to severity of glucose intolerance, but mechanisms are unclear. In people without CF, airway glucose (AG) concentrations are elevated when blood glucose (BG)> or =8 mmol L(-1) (airway threshold), and are associated with acquisition of respiratory infection. METHODS: To determine the relationship between BG and AG, 40 CF patients underwent paired BG and AG (nasal) measurements. Daily time with BG>airway threshold was compared in 10 CFRD, 10 CF patients with normal glucose tolerance (CF-NGT) and 10 healthy volunteers by continuous BG monitoring. The effect of glucose at airway concentrations on bacterial growth was determined in vitro by optical densitometry. RESULTS: AG was present more frequently (85%-vs.-19%, p<0.0001) and at higher concentrations (0.5-3 mmol L(-1)-vs.-0.5-1 mmol L(-1), p<0.0001) when BG was > or =8 mmol L(-1)-vs.-<8 mmol L(-1). Daily time with BG> or =8 mmol L(-1) was CFRD (49+/-25%), CF-NGT (6+/-5%), healthy volunteers (1+/-3%), p<0.0001. Staphylococcus aureus growth increased at > or =0.5 mmol L(-1) (p=0.006) and Pseudomonas aeruginosa growth above 1-4 mmol L(-1) glucose (p=0.039). CONCLUSIONS: BG> or =8 mmol L(-1) predicted elevated AG concentrations in CF, at least in nasal secretions. CFRD patients spent approximately 50% day with BG>airway threshold, implying persistently elevated AG concentrations. Further studies are required to determine whether elevated airway glucose concentrations contribute to accelerated pulmonary decline in CFRD.

Relationship between glycosylated haemoglobin and mean plasma glucose concentration in cystic fibrosis.

BACKGROUND: HbA(1c) is recommended for monitoring glycaemic control in people with cystic fibrosis-related diabetes (CFRD). However the relationship between HbA(1c) and mean plasma glucose concentration (MPG) has not been established in CFRD, as in other forms of diabetes mellitus. METHODS: 20 people (13 male, 29.7+/-8.8 years, 10 CFRD) with cystic fibrosis (CF) underwent HbA(1c) measurement and 48 h continuous glucose monitoring for estimation of MPG. The relationship between HbA(1c) and MPG was established and compared to the reported relationship for type 1 diabetes. RESULTS: HbA(1c) was strongly correlated with MPG (R(2)=0.888, p<0.0001) in CF. The relationship of MPG to HbA(1c) was described by the equation MPG=(1.47xHbA(1c))-1.15, giving a 1.47 mmol L(-1) change in MPG per 1% change in HbA(1c). This equation predicts that MPG in people with CF and HbA(1c) <7.0% will be similar to MPG in people with type 1 diabetes who achieve the same HbA(1c) target. CONCLUSIONS: These results imply that HbA(1c)<7.0% will predict good blood glucose control in CF as in type 1 diabetes. However, although HbA(1c) predicts complications in type 1 diabetes, further studies are required to establish the relationship between HbA(1c) and diabetic complications in people with CFRD.

Clinical importance of cystic fibrosis-related diabetes.

The prevalence of cystic fibrosis-related diabetes (CFRD) and glucose intolerance (IGT) has risen dramatically over the past 20 years as survival has increased for people with cystic fibrosis (CF). Diabetes is primarily caused by pancreatic damage, which reduces insulin secretion, but glucose tolerance is also modified by factors that alter insulin resistance, such as intercurrent illness and infection. CFRD not only causes the symptoms and micro and macrovascular complications seen in type 1 and type 2 diabetes in the general population, but also is associated with accelerated pulmonary decline and increased mortality. Pulmonary effects are seen some years before the diagnosis of CFRD, implying that impaired glucose tolerance may be detrimental. Current practice is to screen for changes in glucose tolerance by regular measurement of fasting blood glucose, by oral glucose tolerance test or a combination of these approaches with symptom review and measurement of HbA1C. Treatment is clearly indicated for those with CFRD and fasting hyperglycaemia to control symptoms and reduce complications. As nutrition is critical in people with CF to maintain body mass and lung function, blood glucose should be controlled in CFRD by adjusting insulin doses to the requirements of adequate food intake and not by calorie restriction. It is less clear whether blood glucose control will have clinical benefits in the management of patients with CFRD without fasting hyperglycaemia or with impaired glucose tolerance and further studies are required to establish the best treatment for this patient group.

Bringing new treatments to the bedside in cystic fibrosis.

The discovery of the cystic fibrosis transmembrane conductance regulator gene in 1989 led to a dramatic increase in the understanding of the molecular basis of CF. Increased knowledge has provided the opportunity to target drug development at correcting the basic defect either by gene therapy or pharmacological modulation of the abnormal physiological processes. Development of new medications for the CF population poses many challenges. The discovery and development of new medications is always time consuming and expensive. Since CF affects a small population worldwide, the potential for a drug company to profit from a new treatment is limited. In addition, each new therapy must have an additional and proven benefit to be attractive to clinicians and consumers, otherwise it will not be commercially viable. Demonstrating clinical benefit is problematic as a limited number of patients are available to participate in clinical trails and outcome measures, such as length of life, are hard to measure. In this review we will illustrate these challenges by discussing the development of treatments which have successfully reached the bedside and those that were unsuccessful.