Molecular origin of enhanced proton conductivity in anhydrous ionic systems

YesIonic systems with enhanced proton conductivity are widely viewed as promising electrolytes in fuel cells and batteries. Nevertheless, a major challenge toward their commercial applications is determination of the factors controlling the fast proton hopping in anhydrous conditions. To address this issue, we have studied novel proton-conducting materials formed via a chemical reaction of lidocaine base with a series of acids characterized by a various number of proton-active sites. From ambient and high pressure experimental data, we have found that there are fundamental differences in the conducting properties of the examined salts. On the other hand, DFT calculations revealed that the internal proton hopping within the cation structure strongly affects the pathways of mobility of the charge carrier. These findings offer a fresh look on the Grotthuss-type mechanism in protic ionic glasses as well as provide new ideas for the design of anhydrous materials with exceptionally high proton conductivity

Molecular dynamics and physical stability of amorphous nimesulide drug and its binary drug-polymer systems

yesIn this paper we study the effectiveness of three well known polymers: inulin, Soluplus and PVP in stabilizing amorphous form of nimesulide (NMS) drug. The re-crystallization tendency of pure drug as well as measured drug-polymer systems were examined at isothermal conditions by using broadband dielectric spectroscopy (BDS), and at non-isothermal conditions by differential scanning calorimetry (DSC). Our investigation has shown that the crystallization half-life time of pure NMS at 328 K is equal to 33 minutes. We found that this time can be prolonged to 40 years after adding to NMS 20% of PVP polymer. This polymer proved to be the best NMS’s stabilizer, while the worst stabilization effect was found after adding the inulin to NMS. Additionally, our DSC, BDS and FTIR studies indicate that for suppression of NMS’s re-crystallization in NMS-PVP system, the two mechanisms are responsible: the polymeric steric hindrances as well as the antiplastization effect excerted by the excipient.The authors J.K., Z.W., K.G. and M.P., are grateful for the financial support received within the Project No. 2015/16/W/NZ7/00404 (SYMFONIA 3) from the National Science Centre, Poland. H.M. and L.T. are supported by Science Foundation Ireland under grant No. 12/RC/2275 (Synthesis and Solid State Pharmaceuticals Centre)

Capacitance of thin films containing polymerized ionic liquids

Electrode-polymer interfaces dictate many of the properties of thin films such as capacitance, the electric field experienced by polymers, and charge transport. However, structure and dynamics of charged polymers near electrodes remain poorly understood, especially in the high concentration limit representative of the melts. To develop an understanding of electric field–induced transformations of electrode-polymer interfaces, we have studied electrified interfaces of an imidazolium-based polymerized ionic liquid (PolyIL) using combinations of broadband dielectric spectroscopy, specular neutron reflectivity, and simulations based on the Rayleigh’s dissipation function formalism. Overall, we obtained the camel-shaped dependence of the capacitance on applied voltage, which originated from the responses of an adsorbed polymer layer to applied voltages. This work provides additional insights related to the effects of molecular weight in affecting structure and properties of electrode-polymer interfaces, which are essential for designing next-generation energy storage and harvesting devices

アトガキ

Background: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomised controlled trial (RCT). Objectives: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. Methods: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis used bivariate regression of costs and QALYs, with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective Results: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline-initiated therapy with prednisolone-initiated therapy (net cost: £959, 95% CI –£24 to £1941; net QALYs: –0.024, 95% CI –0.088 to 0.041). However, findings varied by baseline blister severity. For patients with mild or moderate blistering (≤30) net costs and outcomes were similar. For patients with severe blistering (>30) net costs were higher (£2558, 95% CI –£82 to £5198) and quality of life poorer (–0.090 QALYs, 95% CI–0.222 to 0.042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1.5% at a willingness to pay of £20,000/QALY. Conclusions: Consistent with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of NHS resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering

Early invasive vulvar squamous cell carcinoma arising in a woman with vulvar pemphigus vulgaris and systemic lupus erythematosus

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucous membranes. Genital involvement occurs when most other common sites are concurrently affected or are in remission. Systemic lupus erythematosus (SLE) is an autoimmune disease that may affect many parts of the body and the skin with occasional bullous lesions. Pemphigus vulgaris and SLE may be associated, albeit rarely. Here, we report the first case of a woman affected with SLE presenting with early invasive squamous cell carcinoma (SCC) arising from Pemphigus Vulgaris of the vulva

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk

Doxycycline compared to prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomised controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. METHODS: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis used bivariate regression of costs and QALYs, with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective RESULTS: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline-initiated therapy with prednisolone-initiated therapy (net cost: £959, 95% CI -£24 to £1941; net QALYs: -0.024, 95% CI -0.088 to 0.041). However, findings varied by baseline blister severity. For patients with mild or moderate blistering (≤30) net costs and outcomes were similar. For patients with severe blistering (>30) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0.090 QALYs, 95% CI-0.222 to 0.042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1.5% at a willingness to pay of £20,000/QALY. CONCLUSIONS: Consistent with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of NHS resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering

Feedback within the Inter-Cellular Communication and Tumorigenesis in Carcinomas

The classical somatic mutation theory (SMT) of carcinogenesis and metastasis postulates that malignant transformation occurs in cells that accumulate a sufficient amount of mutations in the appropriate oncogenes and/or tumor suppressor genes. These mutations result in cell-autonomous activation of the mutated cell and a growth advantage relative to neighboring cells. However, the SMT cannot completely explain many characteristics of carcinomas. Contrary to the cell-centered view of the SMT with respect to carcinogenesis, recent research has revealed evidence that the tumor microenvironment plays a role in carcinogenesis as well. In this review, we present a new model that accommodates the role of the tumor microenvironment in carcinogenesis and complements the classical SMT. Our “feedback” model emphasizes the role of an altered spatiotemporal communication between epithelial and stromal cells during carcinogenesis: a dysfunctional intracellular signaling in tumorigenic epithelial cells leads to inappropriate cellular responses to stimuli from associated stromal or inflammatory cells. Thus, a positive feedback loop of the information flow between parenchymal and stromal cells results. This constant communication between the stromal cells and the tumor cells causes a perpetually activated state of tumor cells analogous to resonance disaster

Modelling prognostic factors in advanced pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial

Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001). Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term