Mometasone absorption in cultured airway epithelium

Background: Topical mometasone is frequently used as an intranasal spray, on drug-eluting stents, and compounded by specialty pharmacies as a sinus rinse. A typical sinus rinse contains 1.2 mg of mometasone dissolved in 240 mL of buffered saline and is flushed through the sinonasal cavity. The mometasone irrigation rapidly flows to the contralateral sinonasal cavity or the nasopharynx with a contact time on the order of 5 to 10 seconds. However, no information is available on the absorption rate of topical mometasone on the sinonasal surface. Methods: To determine the absorption characteristics of mometasone, we harvested nasal epithelium from 2 healthy donors and differentiated them into a mature ciliated epithelium on Millicell membranes. We applied mometasone to the apical surface for various time intervals and then rinsed off non-absorbed mometasone with phosphate-buffered saline. Millicell membranes with the adherent epithelial cells were then harvested and stored in guanidine hydrochloride for quantification using high-performance liquid chromatography–mass spectrometry. Results: Fifty percent of the maximal absorption occurred after an average of 38 minutes after application, and maximal absorption occurred after an average of 114 minutes. Conclusion: Our data provide an estimate for rates of absorption of mometasone applied to the sinonasal cavity and suggest that the absorption rates poorly match contact time during saline lavage

Interactive Marine Spatial Planning: Siting Tidal Energy Arrays around the Mull of Kintyre

The rapid development of the offshore renewable energy sector has led to an increased requirement for Marine Spatial Planning (MSP) and, increasingly, this is carried out in the context of the ‘ecosystem approach’ (EA) to management. We demonstrate a novel method to facilitate implementation of the EA. Using a real-time interactive mapping device (touch-table) and stakeholder workshops we gathered data and facilitated negotiation of spatial trade-offs at a potential site for tidal renewable energy off the Mull of Kintyre (Scotland). Conflicts between the interests of tidal energy developers and commercial and recreational users of the area were identified, and use preferences and concerns of stakeholders were highlighted. Social, cultural and spatial issues associated with conversion of common pool to private resource were also revealed. The method identified important gaps in existing spatial data and helped to fill these through interactive user inputs. The workshops developed a degree of consensus between conflicting users on the best areas for potential development suggesting that this approach should be adopted during MSP

State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

The prognostic influence of bcl-2 in malignant glioma

The bcl-2 gene is one of a complex group of genes which control programmed cell death. Bcl-2 acts to extend cell survival by blocking apoptosis, and thereby may influence tumour prognosis. This study of 187 high grade gliomas reviews clinicopathological prognostic features and the relationship to bcl-2 expression. Bcl-2 immunostaining was assessed in 159 specimens from these patients, by scoring systems of 0 to 3 for intensity of scoring and proportion of cells staining. Age, histology, pre- and post-operative performance status were found to be strongly predictive of survival (log rank test P<0.0001). The type of surgery performed did not influence survival in this group of patients. The expression of bcl-2 had a significant relationship with survival (univariate Cox model P=0.0302, hazard ratio 0.8, 95% confidence interval 0.65–0.98), with increased staining associated with improved survival. Multivariate analysis showed performance status, histology and proportion of cells staining for bcl-2 to be independently predictive of survival. Bcl-2 staining was not related to histological grade of tumours

Habitat properties are key drivers of Borrelia burgdorferi (s.l.) prevalence in Ixodes ricinus populations of deciduous forest fragments

Background: The tick Ixodes ricinus has considerable impact on the health of humans and other terrestrial animals because it transmits several tick-borne pathogens (TBPs) such as B. burgdorferi (sensu lato), which causes Lyme borreliosis (LB). Small forest patches of agricultural landscapes provide many ecosystem services and also the disservice of LB risk. Biotic interactions and environmental filtering shape tick host communities distinctively between specific regions of Europe, which makes evaluating the dilution effect hypothesis and its influence across various scales challenging. Latitude, macroclimate, landscape and habitat properties drive both hosts and ticks and are comparable metrics across Europe. Therefore, we instead assess these environmental drivers as indicators and determine their respective roles for the prevalence of B. burgdorferi in I. ricinus. Methods: We sampled I. ricinus and measured environmental properties of macroclimate, landscape and habitat quality of forest patches in agricultural landscapes along a European macroclimatic gradient. We used linear mixed models to determine significant drivers and their relative importance for nymphal and adult B. burgdorferi prevalence. We suggest a new prevalence index, which is pool-size independent. Results: During summer months, our prevalence index varied between 0 and 0.4 per forest patch, indicating a low to moderate disservice. Habitat properties exerted a fourfold larger influence on B. burgdorferi prevalence than macroclimate and landscape properties combined. Increasingly available ecotone habitat of focal forest patches diluted and edge density at landscape scale amplified B. burgdorferi prevalence. Indicators of habitat attractiveness for tick hosts (food resources and shelter) were the most important predictors within habitat patches. More diverse and abundant macro- and microhabitat had a diluting effect, as it presumably diversifies the niches for tick-hosts and decreases the probability of contact between ticks and their hosts and hence the transmission likelihood.[br/] Conclusions: Diluting effects of more diverse habitat patches would pose another reason to maintain or restore high biodiversity in forest patches of rural landscapes. We suggest classifying habitat patches by their regulating services as dilution and amplification habitat, which predominantly either decrease or increase B. burgdorferi prevalence at local and landscape scale and hence LB risk. Particular emphasis on promoting LB-diluting properties should be put on the management of those habitats that are frequently used by humans. In the light of these findings, climate change may be of little concern for LB risk at local scales, but this should be evaluated further

The Redox State of Transglutaminase 2 Controls Arterial Remodeling

While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall

Breast tumour angiogenesis

The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized

Obesity at age 20 and the risk of miscarriages, irregular periods and reported problems of becoming pregnant: the Adventist Health Study-2

In a group of 46,000 North-American Adventist women aged 40 and above, we investigated the relationships between body mass index (BMI, kg/m(2)) at age 20 and the proportion of women who reported at least one miscarriage, periods with irregular menstruation or failing to become pregnant even if trying for more than one straight year. Approximately 31, 14 and 17 %, respectively, reported the three different problems related to reproduction. Positive age- and marital status adjusted relationships were found between BMI at age 20 and periods with irregular menstruation or failing to become pregnant even if trying for more than 1 year, but not with the risk of miscarriages. Women with BMI ≥ 32.5 kg/m(2) when aged 20 had approximately 2.0 (95 % CI: 1.6, 2.4) and 1.5 (95 % CI: 1.3, 1.9) higher odds for irregular periods or failing to get pregnant, respectively, than women with BMI in the 20–24.9 kg/m(2) bracket. These relationships were consistently found in a number of strata of the population, including the large proportion of the women who never had smoked or never used alcohol. Underweight (BMI < 18.5 kg/m(2)) when aged 20 marginally (approximately 15 %) increased the risk of failing to get pregnant within a year. Thus, obesity at age 20 increases the risk of reporting some specific reproductive problems, but not the risk of miscarriages. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10654-012-9749-8) contains supplementary material, which is available to authorized users