Azulene-based compounds for targeting orexin receptors

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved.Peer reviewe

Stapled truncated orexin peptides as orexin receptor agonists

The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an α‐helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the α‐helical conformation of orexin‐A15–33 via peptide stapling at four different sites. At a suggested hinge region, we varied the length of the cross-linker as well as replaced the staple with two α-aminoisobutyric acid residues. Modifications close to the peptide C‐terminus, which is crucial for activity, were not allowed. However, central and N‐terminal modifications yielded bioactive peptides, albeit with decreased potencies. This provides evidence that the orexin receptors can accommodate and be activated by α-helical peptides. The decrease in potency is likely linked to a stabilization of suboptimal peptide conformation or blocking of peptide backbone–receptor interactions at the hinge region by the helical stabilization or the modified amino acids.Peer reviewe

Synthesis of carboxyimidamide-substituted benzo[c][1,2,5]oxadiazoles and their analogs, and evaluation of biological activity against Leishmania donovani

A facile synthesis route to carboxyimidamide-substituted benzoxadiazoles and related derivatives was developed. A total of 25 derivatives were synthesized. They were evaluated for antileishmanial activity by inhibition of Leishmania donovani axenic amastigote growth using a fluorescent viability microplate assay. The most promising derivative (14) demonstrated an antileishmanial EC50 of 4.0 mu M, and it also showed activity in infected macrophages (EC50 5.92 mu M) without signs of cytotoxicity.Peer reviewe

Minimal important difference and patient acceptable symptom state for common outcome instruments in patients with a closed humeral shaft fracture - analysis of the FISH randomised clinical trial data

Background: Two common ways of assessing the clinical relevance of treatment outcomes are the minimal important difference (MID) and the patient acceptable symptom state (PASS). The former represents the smallest change in the given outcome that makes people feel better, while the latter is the symptom level at which patients feel well.Methods: We recruited 124 patients with a humeral shaft fracture to a randomised controlled trial comparing surgery to nonsurgical care. Outcome instruments included the Disabilities of Arm, Shoulder, and Hand (DASH) score, the Constant-Murley score, and two numerical rating scales (NRS) for pain (at rest and on activities). A reduction in DASH and pain scores, and increase in the Constant-Murley score represents improvement. We used four methods (receiver operating characteristic [ROC] curve, the mean difference of change, the mean change, and predictive modelling methods) to determine the MID, and two methods (the ROC and 75th percentile) for the PASS. As an anchor for the analyses, we assessed patients'satisfaction regarding the injured arm using a 7-item Likert-scale.Results: The change in the anchor question was strongly correlated with the change in DASH, moderately correlated with the change of the Constant-Murley score and pain on activities, and poorly correlated with the change in pain at I rest (Spearman's rho 0.51, -0.40, 0.36, and 0.15, respectively).Depending on the method, the MID estimates for DASH ranged from -6.7 to -11.2, pain on activities from -0.5 to -1.3, and the Constant-Murley score from 6.3 to 13.5.The ROC method provided reliable estimates for DASH (-6.7 points, Area Under Curve [AUC] 0.77), the Constant-Murley Score (7.6 points, AUC 0.71), and pain on activities (-0.5 points, AUC 0.68).The PASS estimates were 14 and 10 for DASH, 2.5 and 2 for pain on activities, and 68 and 74 for the Constant-Murley score with the ROC and 75th percentile methods, respectively.Conclusion: Our study provides credible estimates for the MID and PASS values of DASH, pain on activities and the Constant-Murley score, but not for pain at rest. The suggested cut-offs can be used in future studies and for assessing treatment success in patients with humeral shaft fracture.Peer reviewe

What is a disease? Perspectives of the public, health professionals and legislators

Peer reviewe

Association of income and educational levels on initiation of oral anticoagulant therapy in patients with incident atrial fibrillation: A Finnish nationwide cohort study

Aims: Socioeconomic disparities have been reported in the outcomes of patients with atrial fibrillation (AF). We assessed the hypothesis that AF patients with higher income or educational level are more frequently initiated with oral anticoagulant (OAC) therapy for stroke prevention.Methods: The nationwide registry-based Finnish AntiCoagulation in Atrial Fibrillation cohort covers all patients with AF from all levels of care in Finland. Patients were divided into income quartiles according to their highest annual income during 2004-2018 and into three categories based on educational attainment. The outcome was the first redeemed OAC prescription.Results: We identified 239 222 patients (mean age 72.7 ± 13.2 years, 49.8% female) with incident AF during 2007-2018. Higher income was associated with higher OAC initiation rate: compared to the lowest income quartile the adjusted SHRs (95% CI) for OAC initiation were 1.09 (1.07-1.10), 1.13 (1.11-1.14) and 1.13 (1.12-1.15) in the second, third and fourth income quartiles, respectively. Patients in the highest educational category had a slightly lower OAC initiation rate than patients in the lowest educational category (adjusted SHR 0.92 [95% CI 0.90-0.93]). Income-related disparities were larger and education-related disparities only marginal among patients at high risk of ischemic stroke. The socioeconomic disparities in OAC initiation within 1-year follow-up decreased from 2007 to 2018. The adoption of direct OACs as the initial anticoagulant was faster among patients with higher income or educational levels.Conclusion: These findings highlight potential missed opportunities in stroke prevention, especially among AF patients with low income, whereas the education-related disparities in OAC initiation appear controversial.</p

Multiple primary tumours: incidence estimation in the presence of competing risks

<p>Abstract</p> <p>Background</p> <p>Estimating the risk of developing subsequent primary tumours in a population is difficult since the occurrence probability is conditioned to the survival probability.</p> <p>Methods</p> <p>We proposed to apply Markov models studying the transition intensities from first to second tumour with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In a simulation study we applied the proposed method in different settings with constant or varying underlying intensities and applying age standardisation. In addition, we illustrated the method with data on breast cancer from the Piedmont Cancer Registry.</p> <p>Results</p> <p>The simulation study showed that the person-years approach led to a sensibly wider bias than the AJ estimators. The largest bias was observed assuming constantly increasing incidence rates. However, this situation is rather uncommon dealing with subsequent tumours incidence. In 9233 cases with breast cancer occurred in women resident in Turin, Italy, between 1985 and 1998 we observed a significant increased risk of 1.91 for subsequent cancer of corpus uteri, estimated with the age-standardised Aalen-Johansen incidence ratio (AJ-IR^stand), and a significant increased risk of 1.29 for cancer possibly related to the radiotherapy of breast cancer. The peak of occurrence of those cancers was observed after 8 years of follow-up.</p> <p>Conclusion</p> <p>The increased risk of a cancer of the corpus uteri, also observed in other studies, is usually interpreted as the common shared risk factors such as low parity, early menarche and late onset of menopause. We also grouped together those cancers possibly associated to a previous local radiotherapy: the cumulative risk at 14 years is still not significant, however the AJ estimators showed a significant risk peak between the eighth and the ninth year. Finally, the proposed approach has been shown to be reliable and informative under several aspects. It allowed for a correct estimation of the risk, and for investigating the time trend of the subsequent cancer occurrence.</p

Faktori rizika od karcinoma larinksa u Crnoj Gori

Laryngeal cancer is the most common head and neck cancer. There might be many risk factors for laryngeal cancer. Smoking, especially cigarette smoking and alcohol are indisputable risk factors. The authors of this paper assessed the presumed risk factors in order to identify possible aetiological agents of the disease. A hospital-based case-control study was conducted. The study group consisted of 108 histologically verified laryngeal cancer patients and 108 hospital controls matched by sex, age (±3 years) and place of residence. Laryngeal cancer patients and controls were interviewed during their hospital stay using a structured questionnaire. According to multiple logistic regression analysis six variables were independently related to laryngeal cancer: hard liquor consumption (Odd Ratio /OR/=2.93, Confidence Interval /CI/ 95 % = 1.17 to 7.31), consumption more than 2 alcoholic drinks per day (OR=4.96, CI 95 % = 2.04 to12.04), cigarette smoking for more than 40 years (OR=4.32, CI 95 % = 1.69 to 11.06), smoking more than 30 cigarettes per day (OR=4.24, CI 95 % = 1.75 to 10.27), coffee consumption more than 5 cups per day (OR=4.52, CI 95 % = 1.01 to 20.12) and carbonated beverage consumption (OR=0.38, CI 95 %= 0.16 to 0.92). The great majority of laryngeal cancers could be prevented by eliminating tobacco smoking and alcohol consumption.Maligni tumori larinksa najčešći su tumori glave i vrata. Glavni faktori rizika od razvoja malignih tumora grkljana su pušenje i konzumiranje alkoholnih pića. Cilj rada bio je ispitivanje potencijalnih faktora rizika od nastanka malignih tumora larinksa. Sprovedena je studija slučaj-kontrola. Studijsku grupu činilo je 108 pacijenata s histološki verificiranim rakom larinksa i 108 kontrola individualno izjednačenih po spolu, dobi (± 3 godine) i mjestu stanovanja. Svi ispitanici su anketirani ciljanim epidemiološkim upitnikom a u analizi podataka korištena je multivarijantna logistička regresijska analiza. Koristeći se multivarijantnom logističkom regresijskom analizom, statistički značajnu povezanost s rakom larinksa dobili smo za sljedeće varijable: konzumiranje žestokih pića (omjer izgleda /OR/=2.93, interval pouzdanosti /CI/ 95 % = 1.17 do 7.31), konzumiranje više od 2 alkoholna pića na dan (OR = 4.96, CI 95 % = 2.04 do 12.04), konzumiranje cigareta duže od 40 godina (OR = 4.32, CI 95 % = 1.69 do 11.06), konzumiranje više od 30 cigareta na dan (OR = 4.24, CI 95 % = 1.75 do 10.27), konzumiranje više od 5 šalica kave na dan (OR = 4.52, CI 95 % = 1.01 do 20.12) i konzumiranje gaziranih pića (OR = 0.38, CI 95 % = 0.16 do 0.92). Obolijevanje zbog malignih tumora larinksa moglo bi se značajno smanjiti prestankom konzumiranja duhana i alkohola

Panama and the WTO : new constitutionalism of trade policy and global tax governance

"Corrigendum" in Review of International Political Economy, 24(4), p. 738 (DOI: 10.1080/09692290.2017.1332547).Tax havens and tax flight have lately received increasing attention, while interest toward multilateral trade policies has somewhat diminished. We argue that more attention needs to be paid exactly to the interrelations between trade and tax policies. Drawing from two case studies on Panama's trade disputes, we show how World Trade Organization (WTO) rules can be used both to resist attempts to sanction secrecy structures and to promote measures against tax flight. The theory of new constitutionalism can help to explain how trade treaties can 'lock in' tax policies. However, our case studies show that trade policy not only 'locks in' democratic policy-making, but also enables tax havens to use their commercialized sovereignty to resists anti-secrecy measures. What is being 'locked in' are the policy tools, not necessarily the policies. The changing relationship between trade and tax policies can also create new and unexpected tools for tackling tax evasion, underlining the importance of epistemic arbitrage in the context of new constitutionalism. In principle, political actors with sufficient technical and juridical knowledge can shape global tax governance to various directions regardless of their formal position in the world political hierarchies. This should be taken into account when trade treaties are being negotiated or revised.Peer reviewe