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The 24-ha Abrams Creek Wetlands (Winchester City and Frederick County, Virginia) is an array of fen, swamp, and disturbed transitional ecosystems underlain by limestone and dolostone bedrock. Soils of the area are generally characterized by exceptionally high levels of calcium (>10,000 ppm). Floristic data were collected through monthly surveys during the 2012–14 growing seasons and plot sampling in representative locations. We documented 296 vascular plant species during the inventory period; eight species found previously were not relocated. The 304 total species comprised 206 genera in 78 families. Of these, 55 species were graminoids (27 grasses, 21 sedges, 7 rushes). Obligate or facultative wetland species comprised 43% of the list. The 216 native species represented 71% of the total and included 20 listed as rare in Virginia. Plot data revealed that native species represented 72–99% of the total vegetative cover in the communities sampled. Floristic quality of the 12 constituent sites was ...

Seaweeds are an important component of human diets, especially in Asia and the Pacific islands, and have shown chemopreventive as well as anti-inflammatory properties. However, structural characterization and mechanistic insight of seaweed components responsible for their biological activities are lacking. We isolated cymopol and related natural products from the marine green alga Cymopolia barbata and demonstrated their function as activators of transcription factor Nrf2-mediated antioxidant response to increase the cellular antioxidant status. We probed the reactivity of the bioactivation product of cymopol, cymopol quinone, which was able to modify various cysteine residues of Nrf2's cytoplasmic repressor protein Keap1. The observed adducts are reflective of the polypharmacology at the level of natural product, due to multiple electrophilic centers, and at the amino acid level of the cysteine-rich target protein Keap1. The non-polar C. barbata extract and its major active component cymopol, reduced inflammatory gene transcription in vitro in macrophages and mouse embryonic fibroblasts in an Nrf2-dependent manner. Cymopol-containing extracts attenuated neutrophil migration in a zebrafish tail wound model. RNA-seq analysis of colonic tissues of mice exposed to non-polar extract or cymopol showed an antioxidant and anti-inflammatory response, with more pronounced effects exhibited by the extract. Cymopolia extract reduced DSS-induced colitis as measured by fecal lipocalin concentration. RNA-seq showed that mucosal-associated bacterial composition and transcriptional profile in large intestines were beneficially altered to varying degrees in mice treated with either the extract or cymopol. We conclude that seaweed-derived compounds, especially cymopol, alter Nrf2-mediated host and microbial gene expression, thereby providing polypharmacological effects.

Nematodes parasitize ∼1/3 of humans worldwide, and effective treatment via administration of anthelmintics is threatened by growing resistance to current therapies. The nematode transcription factor SKN-1 is essential for development of embryos and upregulates the expression of genes that result in modification, conjugation, and export of xenobiotics, which can promote resistance. Distinct differences in regulation and DNA binding relative to mammalian Nrf2 make SKN-1 a promising and selective target for the development of anthelmintics with a novel mode of action that targets stress resistance and drug detoxification. We report 17 (ML358), a first in class small molecule inhibitor of the SKN-1 pathway. Compound 17 resulted from a vanillamine-derived hit identified by high throughput screening that was advanced through analog synthesis and structure-activity studies. Compound 17 is a potent (IC50 = 0.24 μM, Emax = 100%) and selective inhibitor of the SKN-1 pathway and sensitizes the model nematode C. elegans to oxidants and anthelmintics. Compound 17 is inactive against Nrf2, the homologous mammalian detoxification pathway, and is not toxic to C. elegans (LC50 > 64 μM) and Fa2N-4 immortalized human hepatocytes (LC50 > 5.0 μM). In addition, 17 exhibits good solubility, permeability, and chemical and metabolic stability in human and mouse liver microsomes. Therefore, 17 is a valuable probe to study regulation and function of SKN-1 in vivo. By selective targeting of the SKN-1 pathway, 17 could potentially lead to drug candidates that may be used as adjuvants to increase the efficacy and useful life of current anthelmintics.

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups’ new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases). © 2017, Serdi and Springer-Verlag France.

Colorectal cancer (CRC) is a genetic disease, due to progressive accumulation of mutations in oncogenes and tumor suppressor genes. Large scale genomic sequencing projects revealed >100 mutations in any individual CRC. Many of these mutations are likely passenger mutations and fewer are driver mutations. Of these, activating mutations in RAS proteins are essential for cancer initiation, progression, and/or resistance to therapy. There has been significant interest in developing drugs targeting mutated cancer gene products or downstream signaling pathways. Due to the number of mutations involved and inherent redundancy in intracellular signaling, drugs targeting one mutation or pathway have been either ineffective or led to rapid resistance. We have devised a strategy whereby multiple cancer pathways may be simultaneously targeted for drug discovery. For proof-of-concept, we targeted the oncogenic KRAS, and HIF pathways, since oncogenic KRAS has been shown to be required for cancer initiation and progression, and HIF-1α and HIF-2α are induced by the majority of mutated oncogenes and tumor suppressor genes in CRC. We have generated isogenic cell lines defective in either oncogenic KRAS or both HIF-1α and HIF-2α, and subjected them to multiplex genomic, siRNA, and high-throughput small molecule screening. We have identified potential drug targets and compounds for preclinical and clinical development. Screening of our marine natural product library led to the rediscovery of the microtubule agent dolastatin 10 and the class I histone deacetylase (HDAC) inhibitor largazole to inhibit oncogenic KRAS and HIF pathways. Largazole was further validated as an anti-angiogenic agent in a HIF-dependent manner in human cells and in vivo in zebrafish using a genetic model with activated HIF. Our general strategy, coupling functional genomics with drug susceptibility or chemical-genetic interaction screens, enables the identification of potential drug targets and candidates with requisite selectivity. Molecules prioritized in this manner can easily be validated in suitable zebrafish models due to the genetic tractability of the system. Our multidimensional platform with cellular and organismal components can be extended to larger scale multiplex screens that include other mutations and pathways.

The authors would like to change and use the correct name of M. Khaitov which is M. Kaitov on this manuscript. The authors have incorrectly used her other name during the finalization of this research. With this, the authors hereby publish the correct author names as presented above. © 2016 Serdi and Springer-Verlag France

Subarachnoid haemorrhage (SAH) accounts for 1 to 7% of all strokes. In France, the range of incidence of SAH varies between 3 and 8/100,000 inhabitants. Global mortality lies around 40%, including 70% during the first week. The size of more than 90% of all aneurysms is less than 10 mm. In more than 90% of the patients; SAH is sporadic and a familial screening is warranted only after SAH occurring in 2 first-degree relatives. The main risk factors of SAH are tobacco, arterial hypertension and alcohol abuse. Genetic susceptibility may exist: it could involve several genes, the expression of which would characterize pathophysiological pathways implicated in the disease. This could be identified using genomic technique of microarrays, which could explore all the genome, simply using a sample of peripheral venous blood. For example, in the future, this approach could help to identify patients who are at high risk to develop vasospasm after SAH.

Background: Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. Methods: As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis. Results: Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed. Conclusion: A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis. © 2015 Dustri-Verlag Dr. Karl Feistle.

In this paper, correlations between the elongation at break and the oxidation of chlorosulfonated polyethylene and ethylene propylene rubber (EPR) polymers in instrumentation and control cables irradiated at different dose rates are brought to evidence. During irradiation, the following phenomena are observed: an increase of oxygen consumption, a degradation of the mechanical properties and a reduction of the oxidation induction time (OIT) measured for EPR. A correlation between the mechanical properties and the OIT of the EPR has only been established in the case of irradiation at low dose rate. This reveals a difference in the oxidative degradation process at low and high dose rates. This study shows the possibility to assess the ageing of electric cables installed inside nuclear power plants by OIT measurements.

Background: The number of allergens to be tested in order to identify sensitized patients is important in order to have the most cost-effective approach in epidemiological studies. Objective: To define the minimal number and the type of skin prick test (SPT) allergens required to identify a patient as sensitized using results of the new Pan-European GA2LEN skin prick test study. Method: In a large Pan-European multicenter (17 centers in 14 countries) patient based study, a standardized panel of 18 allergens has been prick tested using a standardized procedure. Conditional approach allowed to determine the allergens selection. Result: Among the 3034 patients involved, 1996 (68.2%) were sensitized to at least one allergen. Overall, eight allergens (grass pollen, Dermatophagoides pteronyssinus, birch pollen, cat dander, Artemisia, olive pollen, Blatella and Alternaria) allowed to identified more than 95% of sensitized subjects. However, differences were observed between countries, two allergens being sufficient for Switzerland (grass pollen and cat dander) as opposed to nine for France (grass pollen, Dermatophagoides pteronyssinus, olive pollen, cat dander, Blatella, cypress, dog dander, alder and [Artemisia or Alternaria]). According to country, up to 13 allergens were needed to identify all sensitized subjects. Conclusion: Eight to ten allergens allowed the identification of the majority of sensitized subjects. For clinical care of individual patients, the whole battery of 18 allergens is needed to appropriately assess sensitization across Europe. © 2009 John Wiley & Sons A/S.

Background Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. Methods As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis. Results Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed. Conclusion A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Background: Within a large prospective study, the Global Asthma and Allergy European Network (GA2LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. Objective: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. Methods: The GA2LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Results: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. Conclusion: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. © 2013 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

This study evaluates pollution from a former tannery by examining soils containing high concentrations of chromium (between 138 and 720 mg/kg dry matter according to the sample). This study presents an original methodology for characterizing chromium according to its two possible origins in soils: natural or anthropogenic. Conducting both a mineralogical study and a physicochemical study made it possible to clearly understand these origins. Natural chromium is particularly linked to pyroxenes, a primary mineral of the Massif Central, France, and found in large quantities in the samples studied. Anthropogenic chromium is adsorbed by vermiculites on their interfoliary sites. These clays possess a high capacity of cationic exchange and can thus attract chromium easily. In all of the samples studied, the naturally chromiferous mineral contribution was high (97 to 519 mg/kg dry matter), whereas that of the clays was low (41 to 201 mg/kg dry matter), indicating a smaller proportion of chromium introduced by humans. Natural chromium values are approximately 70 to 80%, whereas those for anthropogenic chromium are approximately 20 to 30%. This approach makes it possible to set realistic objectives for the cleanup of chromium-contaminated soils.

International audience; Despite the strong reduction in rainfall observed after 1968, the water table of some endorheic areas in the Sahel has been found to be rising over the last several decades. It has been previously demonstrated that this is due to land use changes which have led to a severe increase in runoff and erosion. In such areas, the excess in runoff causes a strong increase in the number of ponds, their sizes and thus, their duration. Ponds have been identified as the main zones of deep infiltration of water. The aim of this study was to investigate whether other areas of the Sahelian region could also be defined as deep infiltration ones as well, and then, whether they were contributing to aquifer recharge. Soil water content was surveyed for five consecutive years (2004-2008) by implementing a set of measurement devices at different depths. The hydrologic water balance was monitored at stream flow gauge stations located upstream and downstream of two small endorheic catchments. A temporal increase in runoff and erosion induced by the soil degradation following the replacement of bush vegetation by cultivated crops and fallow land areas was observed. This process led to the appearance of extended bare soil areas due to both aeolian and hydric erosion, triggering a strong reduction in soil infiltrability under millet fields and fallow lands as well as in the soil water holding capacity. It also resulted in the formation of a great number of gullies and sand sediment deposits in the endorheic areas. Measurements showed that sandy deposits correspond in fact to large areas of deep infiltration: tens of thousands of cubic meters of water infiltrated catchments of less than 1 km2. Runoff decreased by up to 50% in the sandy deposit areas, while infiltration (close to 1300 mm h-1) was observed up to depths of 10 m. These factors would raise the water table and significantly modify the surface and sub-surface components of the water cycle.

This paper presents in details the fatigue life prediction models developed for lead-free assemblies in harsh environments during the 3-year European LIFE project GEAMCOS. The approach uses advanced finite element modelling as well as experimental fatigue data. It is also based on a complete material characterisation for a wide range of stress conditions. It focuses on the most critical packages of the full lead-free GEAMCOS test board and of the functional demonstrator developed for military communication.

Background: Skin prick testing is the standard for diagnosing IgE-mediated allergies. However, different allergen extracts and different testing procedures have been applied by European allergy centres. Thus, it has been difficult to compare results from different centres or studies across Europe. It was, therefore, crucial to standardize and harmonize procedures in allergy diagnosis and treatment within Europe. Aims: The Global Asthma and Allergy European Network (GALEN), with partners and collaborating centres across Europe, was in a unique position to take on this task. The current study is the first approach to implement a standardized procedure for skin prick testing in allergies against inhalant allergens with a standardized pan-European allergen panel. Methods: The study population consisted of patients who were referred to one of the 17 participating centres in 14 European countries (n = 3034, median age = 33 years). Skin prick testing and evaluation was performed with the same 18 allergens in a standardized procedure across all centres. Results: The study clearly shows that many allergens previously regarded as untypical for some regions in Europe have been underestimated. This could partly be related to changes in mobility of patients, vegetation or climate in Europe. Conclusion: The results of this large pan-European study demonstrate for the first time sensitization patterns for different inhalant allergens in patients across Europe. The standardized skin prick test with the standardized allergen battery should be recommended for clinical use and research. Further EU-wide monitoring of sensitization patterns is urgently needed. © 2009 John Wiley & Sons A/S.

Background: Skin prick testing is the standard for diagnosing IgE-mediated allergies. A positive skin prick reaction, however, does not always correlate with clinical symptoms. A large database from a Global Asthma and Allergy European Network (GA2LEN) study with data on clinical relevance was used to determine the clinical relevance of sensitizations against the 18 most frequent inhalant allergens in Europe. The study population consisted of patients referred to one of the 17 allergy centres in 14 European countries (n = 3034, median age = 33 years). The aim of the study was to assess the clinical relevance of positive skin prick test reactions against inhalant allergens considering the predominating type of symptoms in a pan-European population of patients presenting with suspected allergic disease. Methods: Clinical relevance of skin prick tests was recorded with regard to patient history and optional additional tests. A putative correlation between sensitization and allergic disease was assessed using logistic regression analysis. Results: While an overall rate of ≥60% clinically relevant sensitizations was observed in all countries, a differential distribution of clinically relevant sensitizations was demonstrated depending on type of allergen and country where the prick test was performed. Furthermore, a significant correlation between the presence of allergic disease and the number of sensitizations was demonstrated. Conclusion: This study strongly emphasizes the importance of evaluating the clinical relevance of positive skin prick tests and calls for further studies, which may, ultimately, help increase the positive predictive value of allergy testing. © 2009 John Wiley & Sons A/S.

Nonallergic rhinitis (NAR) can be defined as a chronic nasal inflammation which is not caused by systemic IgE-dependent mechanisms. It is common and probably affects far more than 200 million people worldwide. Both children and adults are affected. However, its exact prevalence is unknown and its phenotypes need to be evaluated using appropriate methods to better understand its pathophysiology, diagnosis and management. It is important to differentiate between infectious rhinitis, allergic/NAR and chronic rhinosinusitis, as management differs for each of these cases. Characterization of the phenotype, mechanisms and management of NAR represents one of the major unmet needs in allergic and nonallergic diseases. Studies on children and adults are required in order to appreciate the prevalence, phenotype, severity and co-morbidities of NAR. These studies should compare allergic and NAR and consider different age group populations including elderly subjects. Mechanistic studies should be carried out to better understand the disease(s) and risk factors and to guide towards an improved diagnosis and therapy. These studies need to take the heterogeneity of NAR into account. It is likely that neuronal mechanisms, T cells, innate immunity and possibly auto-immune responses all play a role in NAR and may also contribute to the symptoms of allergic rhinitis. © 2008 The Authors.

Subarachnoid haemorrhage (SAH) accounts for 1 to 7% of all strokes. In France, the range of incidence of SAH varies between 3 and 8/100,000 inhabitants. Global mortality lies around 40%, including 70% during the first week. The size of more than 90% of all aneurysms is less than 10 mm. In more than 90% of the patients; SAH is sporadic and a familial screening is warranted only after SAH occurring in 2 first-degree relatives. The main risk factors of SAH are tobacco, arterial hypertension and alcohol abuse. Genetic susceptibility may exist: it could involve several genes, the expression of which would characterize pathophysiological pathways implicated in the disease. This could be identified using genomic technique of microarrays, which could explore all the genome, simply using a sample of peripheral venous blood. For example, in the future, this approach could help to identify patients who are at high risk to develop vasospasm after SAH.

As part of the European LIFE project GEAMCOS, this paper presents the simulation evaluation of lead-free electronic assemblies submitted to harsh environments encountered in aeronautical and military communication applications. It addresses the following questions: (1) the determination of an optimal accelerated test condition in the temperature range of -40degC/100degC for assemblies with SnAgCu alloy, (2) the evaluation of the life-time of five assemblies with SnAgCu and SnPb, (3) a sensitivity analysis on design and serigraphy parameter variations, (4) the determination of a test protocol in vibration environments. All the results give relevant life-time predictions. The CSP and PQFP components should have longer time-to- failure with SnAgCu solder joints than with SnPb joints. The contrary is expected for 1st and 2nd level interconnects of large BGA packages. In any case, the factor is found to remain less than about 2. The PCB thermal expansion coefficient has the highest impact, followed by the solder joint height. The first level interconnect reliability is not impacted by any of the parameter changes. Simulation work in GEAMCOS project shall go on in 2007-2008 with an experimental validation of the thermo- mechanical simulations. This will require to identify a new constitutive material model for SnAgCu and to calibrate the simulations with experimental test results.

Skin prick testing (SPT) is the standard method for diagnosing allergic sensitization but is to some extent performed differently in clinical centres across Europe. There would be advantages in harmonizing the standard panels of allergens used in different European countries, both for clinical purposes and for research, especially with increasing mobility within Europe and current trends in botany and agriculture. As well as improving diagnostic accuracy, this would allow better comparison of research findings in European allergy centres. We have compared the different SPT procedures operating in 29 allergy centres within the Global Allergy and Asthma European Network (GA2LEN). Standard SPT is performed similarly in all centres, e.g. using commercial extracts, evaluation after 15-20 min exposure with positive results defined as a wheal > 3 mm diameter. The perennial allergens included in the standard SPT panel of inhalant allergens are largely similar (e.g. cat: pricked in all centres; dog: 26 of 29 centres and Dermatophagoides pteronyssinus: 28 of 29 centres) but the choice of pollen allergens vary considerably, reflecting different exposure and sensitization rates for regional inhalant allergens. This overview may serve as reference for the practising doctor and suggests a GA2LEN Pan-European core SPT panel. Copyright © Blackwell Munksgaard 2005.

A rapid method for the diagnosis of the most frequent cystic fibrosis mutations in the Reunion Island is described based on a coamplification polymerase chain reaction (PCR) followed by a single digestion using MseI. We have used this strategy to detect the two most frequent mutations in this area: ΔF508 (in exon 10) and Y122X (in exon 4). These two mutations account for 70% of the CF chromosomes. This diagnosis method, which is rapid, easy, direct, and inexpensive, allows adult and neonatal carrier screening in this population. © 1993 Wiley-Liss, Inc.

Congenital bilateal absence of the vas deferens (CBAVD) with obstructive azoospermia is a congenital reproductive disorder that affects one in 10000 male individuals. The observation that many men presenting with CBAVD have mutations in their CFTR genes had led to the proposal that CBAVD may be a primary genital form of cystic fibrosis. We report here one novel mutation located in exon 10 of the CFTR gene. This mutation, named D513G (A--G at position 1670), has been found in one of 83 patients with CBAVD from France, the analysis of exon 10 using a chemical clamp DGGE assay allowed us to identify three CF mutations AEF508 (37/166; 22%), AE1507 (1/166; 0/6%) and D513G (1/166; 0.6%), and two variants M470V and E528E (1716 GA). The novel D513G mutation has not been found in more than 200 non-CF chromosomes and in a sample of 300 CF chromosomes from French classical CF patients.

The relationship between circadian rhythms in the pharmacological actions of meperidine and hexobarbital and similar rhythms in the hepatic metabolism of these drugs was examined in mice under a variety of environmental alterations to determine whether such rhythms may be causally related. The rate of metabolism of p-nitroanisole and hexobarbital by hepatic 9000 X g supernatant fractions was found to be higher at 2400 hours (middark phase) compared to 1200 hours (midlight phase). The rhythms in in vitro hexobarbital and in vivo merperidine metabolism were inversely related in time with similar rhythms in duration of hexobarbital sleep time and meperidine analgesia. Exposure of mice to continuous lighting abolished the rhythms in metabolism and response to meperidine and hexobarbital. Reversal of the usual lighting cycle inverted the rhythm in hexobarbital metablism while abolishing the rhythm in pharmacological response to hexobarbital; meperidine was similarly affected. Adrenalectomy abolished the rhythm in hexobarbital metabolism, diminished the amplitude of the circadian variation in meperidine metabolism and abolished the rhythm in hexobarbital hypnosis and meperidine analgesia. These results indicate that circadian rhythms in the action of hexobarbital and meperidine are well correlated with similar rhythms in the disposition of these drugs.