OBJECTIVE—The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211. RESEARCH DESIGN AND METHODS—In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 μg/kg) with eight subjects per dose level at a 3:1 active:placebo randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211). RESULTS—After subcutaneous administration, the half-life of NN2211 was found to be 11–15 h. Overall, although there were no statistically significant differences compared with placebo in the area under the curve (0–9 h for insulin or glucagon), there was a borderline- significant lowering of glucose levels (P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion (P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment (notably headache, dizziness, nausea, and vomiting). CONCLUSIONS—This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans.

In vitro air-liquid interface (ALI) cell culture models can potentially be used to assess inhalation toxicology endpoints and are usually considered, in terms of relevancy, between classic (i.e., submerged) in vitro models and animal-based models. In some situations that need to be clearly defined, ALI methods may represent a complement or an alternative option to in vivo experimentations or classic in vitro methods. However, it is clear that many different approaches exist and that only very limited validation studies have been carried out to date. This means comparison of data from different methods is difficult and available methods are currently not suitable for use in regulatory assessments. This is despite inhalation toxicology being a priority area for many governmental organizations. In this setting, a 1-day workshop on ALI in vitro models for respiratory toxicology research was organized in Paris in March 2016 to assess the situation and to discuss what might be possible in terms of validation studies. The workshop was attended by major parties in Europe and brought together more than 60 representatives from various academic, commercial, and regulatory organizations. Following plenary, oral, and poster presentations, an expert panel was convened to lead a discussion on possible approaches to validation studies for ALI inhalation models. A series of recommendations were made and the outcomes of the workshop are reported.

Fullerenes represent a group of nanoparticles discovered in 1985. They are spherical molecules consisting entirely of carbon atoms (C x ) to which side chains can be added, furnishing compounds with widely different properties. Fullerenes interact with biological systems, for example, by enzyme inhibition, causing phototoxic reactions, being scavengers of reactive oxygen species and free radicals, in addition to being able to initiate free radical reactions. Absorption, distribution and excretion strongly depend on the properties of the side chains. The pristine C 60 has a very long biological half-life, whereas the most water-soluble derivatives are eliminated from the exposed animals within weeks. A long biological half-life raises concern about bioaccumulation and long-term effects. In general, the acute oral, dermal and airway toxicity is low. However, few relevant experimental studies of repeated dose toxicity, reproductive toxicity and carcinogenic effect are available. The data suggest that direct DNA damaging effects are low, but formation of reactive oxygen species may cause inflammation and genetic damage. Apparently, it is dose-dependent whether a beneficial or an adverse effect occurs.Nanoparticle-based technology is a rapidly growing area of interest [1,2], which takes advantage of the fact that the specific surface area increases dramatically at small-size particles, thus these particles may have properties that are different from corresponding particles with larger size [1][2][3]. This also applies for toxicity, which, among other factors, depends on surface area, chemical composition and shape [3]. Nanoparticles (<100 nm, at least in one dimension) comprise naturally occurring (e.g. combustion products) and engineered/ manufactured nanoparticles [3]. Nanoparticles are used, for example, in electronic equipments [1,2] In a recent publication from the German chemical industry, it appeared that the most commonly used manufactured nanoparticles are sialic acid, metal nanoparticles, metal oxides, silicate, carbon black, nanosilver, pharmaceutical products and other nanoparticles [7]. The similar bulk materials were used in the UK in addition to niche products such as fullerenes, carbon nanotubes, nanowires, quantum dots and other nanoparticles [2]. A large-scale production plant for fullerene has recently been opened in Japan, allowing a production of a high tonnage per year [2]. Due to the high electron affinity and superior ability to transport charge, fullerene-based solar cells are currently accepted as being the most effective for this purpose [8]. The in vivo biology and toxicology of fullerenes are the subjects of this MiniReview not only as fullerenes are interesting due to their technical properties, but also as they are considered candidates for new drugs, new antioxidants and new radicalscavenging compounds [5,9,10]. Further examples of in vitro effects are available from the recent review [10]. In vitro toxicity is only considered where assumed to contribute to the understanding ...

Objective: To review the literature on the relationship between obesity and sexual function. Method: A search in the medical literature from 1966 and onwards was carried out through Medline and Embase for publications on obesity, in combination with Medical Subject Heading words related to sexual function and dysfunction. Comments: Four prospective and seven cross-sectional studies were found describing association between obesity and erectile dysfunction (ED). One cross-sectional study was found describing obesity and female sexual dysfunction (FSD). The prospective studies on ED all demonstrated a direct association and so did five of the seven cross-sectional studies. The single FSD study did not find any relationship. Eight intervention studies on weight loss and sexual difficulties were identified. All included few individuals and results were mixed even if most indicated an increase of sexual activity among both men and women after weight loss intervention. Conclusion: Support for the assumption that obesity is associated with ED was found in both prospective and cross-sectional studies. FSD was not adequately described in the literature and prospective studies are needed here. Results from weight loss intervention studies are less conclusive, but also point toward improvement in sexual dysfunction with reduced weight. Keywords: body mass index; sexual function; sexual dysfunction; weight loss; metabolic syndrome; erectile dysfunction IntroductionAt present, 10-30% of all individuals from developed countries are obese. In addition, 1/3-2/3 are considered to be overweight.1 Obesity is on the increase throughout the world, and increasing trends cause concern among health authorities about the associated comorbidities, for example, type 2 diabetes, heart disease, hypertension, certain cancers, reduced life expectancy 1 and their cost to society. Other somatic and psychological malfunctions are also known to follow obesity such as fertility problems, osteoarthritis, social disabilities caused by stigmatization, sleeping problems or apnea. Sexual dysfunctions may also relate to obesity, but are rarely mentioned, and may, for both individual and partner, cause concern and constitute a great problem. Obesity is also rarely mentioned as a cofactor to sexual problems in textbooks on human sexuality, and, if so, with no reference to data in support of a causal relationship. 2,3The aim of the present review was therefore to evaluate the current evidence from the scientific literature of a possible association between obesity and sexual dysfunction among men and women.Obesity and sexual dysfunction There seems to be no available evidence that sexual dysfunction may cause obesity, but there are indicators that obesity may cause sexual dysfunction. However, it may be difficult to single out the independent effects on dysfunction of obesity from other causes, as obesity is a known independent risk factor for vascular risk factors such as dyslipidemia, hypertension, diabetes mellitus and depression, all known to be direct...

BackgroundThis work provides the first description of the bacterial population of the lung microbiota in mice. The aim of this study was to examine the lung microbiome in mice, the most used animal model for inflammatory lung diseases such as COPD, cystic fibrosis and asthma.Bacterial communities from broncho-alveolar lavage fluids and lung tissue were compared to samples taken from fecal matter (caecum) and vaginal lavage fluid from female BALB/cJ mice.ResultsUsing a customized 16S rRNA sequencing protocol amplifying the V3-V4 region our study shows that the mice have a lung microbiome that cluster separately from mouse intestinal microbiome (caecum). The mouse lung microbiome is dominated by Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes and Cyanobacteria overlapping the vaginal microbiome. We also show that removal of host tissue or cells from lung fluid during the DNA extraction step has an impact on the resulting bacterial community profile. Sample preparation needs to be considered when choosing an extraction method and interpreting data.ConclusionsWe have consistently amplified bacterial DNA from mouse lungs that is distinct from the intestinal microbiome in these mice. The gut microbiome has been extensively studied for its links to development of disease. Here we suggest that also the lung microbiome could be important in relation to inflammatory lung diseases. Further research is needed to understand the contribution of the lung microbiome and the gut-lung axis to the development of lung diseases such as COPD and asthma.