Down-Regulation of the Canonical Wnt β-Catenin Pathway in the Airway Epithelium of Healthy Smokers and Smokers with COPD

Background: The Wnt pathway mediates differentiation of epithelial tissues; depending on the tissue types, Wnt can either drive or inhibit the differentiation process. We hypothesized that key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the epithelial differentiated state. Methodology/Principal Findings: Microarrays were used to assess the expression of Wnt-related genes in the small airway epithelium (SAE) obtained via bronchoscopy and brushing of healthy nonsmokers, healthy smokers, and smokers with COPD. Thirty-three of 56 known Wnt-related genes were expressed in the SAE. Wnt pathway downstream mediators b-catenin and the transcription factor 7-like 1 were down-regulated in healthy smokers and smokers with COPD, as were many Wnt target genes. Among the extracellular regulators that suppress the Wnt pathway, secreted frizzled-related protein 2 (SFRP2), was up-regulated 4.3-fold in healthy smokers and 4.9-fold in COPD smokers, an observation confirmed by TaqMan Real-time PCR, Western analysis and immunohistochemistry. Finally, cigarette smoke extract mediated up-regulation of SFRP2 and down-regulation of Wnt target genes in airway epithelial cells in vitro. Conclusions/Significance: Smoking down-regulates the Wnt pathway in the human airway epithelium. In the context that Wnt pathway plays an important role in differentiation of epithelial tissues, the down-regulation of Wnt pathway ma

Experimental evaluation of iterative reconstruction versus filtered back projection for 3D [15O]water PET activation studies using statistical parametric mapping analysis

Iterative reconstructions are increasingly used for clinical PET studies owing to the better noise properties compared with filtered backprojection (FBP). The purpose of the present study was to compare ordered subsets expectation maximization (OSEM) iterative reconstruction with FBP as input for statistical parametric mapping (SPM) analysis of PET activation studies. Two phantom studies were performed simulating both motor and cognitive tasks and acquiring data with both high and low statistics. In contrast to clinical studies, where no a priori information is known, phantom studies allow for an accurate and detailed comparison between different reconstruction techniques. The significance of "activations" during "tasks" was determined using SPM99 software. Using region of interest analysis of SPM results, it was found that the maximum and average t values within each hot spot of the phantom were higher for OSEM than for FBP. In addition, OSEM4 × 16 (4 iterations, 16 subsets) produced fewer false-positive voxels than FBP, OSEM1 × 16 and OSEM2 × 16. In conclusion, for PET activation studies use of OSEM4 × 16 seems to give the best tradeoff between signal detection and noise reduction

Alternative models for stock price dynamics

This paper evaluates the role of various volatility specifications, such as multiple stochastic volatility (SV) factors and jump components, in appropriate modeling of equity return distributions. We use estimation technology that facilitates nonnested model comparisons and use a long data set which provides rich information about the conditional and unconditional distribution of returns. We consider two broad families of models: (1) the multifactor loglinear family, and (2) the affine-jump family. Both classes of models have attracted much attention in the derivatives and econometrics literatures. There are various tradeoffs in considering such diverse specifications. If pure diffusion SV models are chosen over jump diffusions, it has important implications for hedging strategies. If logarithmic previous termmodelsnext term are chosen over affine ones, it may seriously complicate option pricing. Comparing many different specifications of pure diffusion multifactor models and jump diffusion models, we find that (1) log linear models have to be extended to two factors with feedback in the mean reverting factor, (2) affine models have to have a jump in returns, stochastic volatility or probably both. Models (1) and (2) are observationally equivalent on the data set in hand. In either (1) or (2) the key is that the volatility can move violently. As we obtain models with comparable empirical fit, one must make a choice based on arguments other than statistical goodness-of-fit criteria. The considerations include facility to price options, to hedge and parsimony. The affine specification with jumps in volatility might therefore be preferred because of the closed-form derivatives prices

Cost-Effectiveness of perioperative Vaginally Administered estrogen in postmenopausal women undergoing prolapse surgery (EVA trial):study protocol for a multicenter double-blind randomized placebo-controlled trial

BACKGROUND: Surgery for pelvic organ prolapse (POP) is associated with high recurrence rates. The costs associated with the treatment of recurrent POP are huge, and the burden from women who encounter recurrent POP, negatively impacts their quality of life. Estrogen therapy might improve surgical outcome for POP due to its potential beneficial effects. It is thought that vaginal estrogen therapy improves healing and long-term maintenance of connective tissue integrity. Hence, this study aims to evaluate the cost-effectiveness of perioperative vaginal estrogen therapy in postmenopausal women undergoing POP surgery. METHODS: The EVA trial is a multi-center double-blind randomized placebo-controlled trial conducted in the Netherlands comparing the effectiveness and costs-effectiveness of vaginal estrogen therapy. This will be studied in 300 postmenopausal women undergoing primary POP surgery, with a POP-Q stage of ≥ 2. After randomization, participants administer vaginal estrogen cream or placebo cream from 4 to 6 weeks preoperative until 12 months postoperative. The primary outcome is subjective improvement of POP symptoms at 1 year follow-up, measured with the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes are POP-Q anatomy in all compartments, re-interventions, surgery related complications, general and disease specific quality of life, sexual function, signs and complaints of vaginal atrophy, vaginal pH, adverse events, costs, and adherence to treatment. Follow up is scheduled at 6 weeks, 6 months and 12 months postoperative. Data will be collected using validated questionnaires and out-patient visits including gynecological examination performed by an independent gynecologist. DISCUSSION: This study investigates whether perioperative vaginal estrogen will be cost-effective in the surgical treatment of POP in postmenopausal women. It is hypothesized that estrogen therapy will show a reduction in recurrent POP symptoms and a reduction in reoperations for POP, with subsequent improved quality of life among women and cost savings. Trial registrationNetherlands Trial Registry: NL6853; registered 19-02-2018, https://www.trialregister.nl/trial/6853. EudraCT: 2017-003144-21; registered: 24-07-2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12905-021-01587-9

Volume and market share of anti-epileptic drugs in The Netherlands: impact of new drugs.

Item does not contain fulltextOBJECTIVE: In the past decade, several new anti-epileptic drugs (AEDs) were introduced in The Netherlands. These new drugs, one of which is lamotrigine, are 6 to 10 times more expensive than conventional anti-convulsants. In 1997, the high cost of lamotrigine, together with a lack of clinical data supporting its superiority over conventional drugs, prompted the Dutch Health Insurance Board to release a guideline in which the use of lamotrigine was restricted to difficult-to-treat patients. Other new drugs that were marketed after 1997 also became subject to this guideline. The utilisation of new AEDs and the cost consequences are the subject of this paper. METHODS: Data from extramurally prescribed AEDs was obtained from the Dutch Drug Information Project, which is a database containing prescriptions for about 5.5 million inhabitants of the Netherlands. This data was used to study the impact of new AEDs on volume and market share of AEDs in the period from 1995 to 2001 in The Netherlands. RESULTS: Between 1995 and 2001, the total volume of AEDs increased by 130%, 60% of which consisted of new AEDs. Gabapentin, lamotrigine and oxcarbazepine were the most frequently prescribed new compounds. The volume share of new AEDs increased from 5% in 1995 to 18% in 2001. The market share amounted to 21.5 million euros in 1995 and rose to 47 million euros in 2001; 80% of this increase was due to the introduction of new AEDs. DISCUSSION: Although in 2001 the volume share of new AEDs was still modest, their introduction has led to a strong increase in the cost. New data is emerging on the effectiveness and cost-benefit sum of the new AEDs; this may change the place in therapy of these drugs. Because of their strong potential to force up cost, the positioning of new AEDs requires further attention

Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study.

BACKGROUND: Socioeconomic adversity in early life has been hypothesized to "program" a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation. METHODS AND FINDINGS: We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991-1993 until 2007-2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48-2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26-1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%-58%). CONCLUSIONS: In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible. Please see later in the article for the Editors' Summary