Visible Type Application

The Hindley-Milner HM type system automatically infers the types at which polymorphic functions are used. In HM, the inferred types are unambiguous, and every expression has a principal type. Type annotations make HM compatible with extensions where complete type inference is impossible, such as higher-rank polymorphism and type-level functions. However, programmers cannot use annotations to explicitly provide type arguments to polymorphic functions, as HM requires type instantiations to be inferred. We describe an extension to HM that allows visible type application. Our extension requires a novel type inference algorithm, yet its declarative presentation is a simple extension to HM. We prove that our extended system is a conservative extension of HM and admits principal types. We then extend our approach to a higher-rank type system with bidirectional type-checking. We have implemented this system in the Glasgow Haskell Compiler and show how our approach scales in the presence of complex type system features

Concept and Development of a Potent Topical Corticosteroid

In a rational approach to identify an ultrapotent compound for the treatment of therapy-resistant dermatoses, Weirich's modification of McKenzie's skin vasoconstriction assay (HVK test) has been used as the essential selection criteria. In a primary phase, a quantitative relationship between the HVK activity of 25 derivatives of corticosterone substituted in various positions of the skeleton, and their lipophilicity (log P) was established. The specific lipophilicity-independent interactions were accounted for by the inclusion of 'indicator variables' into the regression analysis. The highly significant results allowed to localize an optimal log P range and to identify the influence of various substituents. In a next phase, the evidence of the first HVK analysis was refined by considering 28 additional compounds. On the basis of the confirmed facts, six 21-chloro-6α-fluoro compounds were specifically synthesized and submitted to dermatopharmacological testing. Finally, CGP 14458 (= 2l-chloro-6α,9-difluoro-11β-hydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-17α-yl propionate) which was predicted to be the most potent representative of these series, whose synthesis is described in detail, showed indeed to be the most effective compound. Clinical trials with this compound – halobetasol propionate/Ultravate® (ulobetasol/Miracorten®) – confirmed its unique efficacy, especially in the treatment of severe, chronic plaque psoriasis

Veno-occlusive disease of the liver in children treated for Wilms tumor

Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) +/- other drugs +/- radiotherapy according to surgical stage and histology. Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during preoperative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6-180 days using supportive therapy only. (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patient

Termination Casts: A Flexible Approach to Termination with General Recursion

This paper proposes a type-and-effect system called Teqt, which distinguishes terminating terms and total functions from possibly diverging terms and partial functions, for a lambda calculus with general recursion and equality types. The central idea is to include a primitive type-form "Terminates t", expressing that term t is terminating; and then allow terms t to be coerced from possibly diverging to total, using a proof of Terminates t. We call such coercions termination casts, and show how to implement terminating recursion using them. For the meta-theory of the system, we describe a translation from Teqt to a logical theory of termination for general recursive, simply typed functions. Every typing judgment of Teqt is translated to a theorem expressing the appropriate termination property of the computational part of the Teqt term.Comment: In Proceedings PAR 2010, arXiv:1012.455

Sclerosing Epithelioid Fibrosarcoma of the Bone: A Case Report of High Resistance to Chemotherapy and a Survey of the Literature

Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue sarcoma mostly occurring in extraosseous sites. SEF represents a clinically challenging entity especially because no standardized treatment regimens are available. Intraosseous localization is an additional challenge with respect to the therapeutical approach. We report on a 16-year-old patient with SEF of the right proximal tibia. The patient underwent standardized neoadjuvant chemotherapy analogous to the EURAMOS-1 protocol for the treatment of osteosarcoma followed by tumor resection and endoprosthetic reconstruction. Histopathological analysis of the resected tumor showed >90% vital tumor cells suggesting no response to chemotherapy. Therefore, therapy was reassigned to the CWS 2002 High-Risk protocol for the treatment of soft tissue sarcoma. To date (22 months after diagnosis), there is no evidence of relapse or metastasis. Our data suggest that SEF may be resistant to a chemotherapy regimen containing Cisplatin, Doxorubicin, and Methotrexate, which should be considered in planning treatment for patients with SEF

Selectivity of saflufenacil applied alone or mixed to glyphosate in maize.

The use of selective herbicides is important for weed management in agricultural crops. Selectivity studies of new molecules are really important to expand the control options of glyphosate-resistant and -tolerant eudicotyledons in corn. The objective of this work was to evaluate the selectivity of the herbicide saflufenacil applied alone in different doses in post-emergence of corn and in a mixture with glyphosate. The design used was randomized blocks, with four replications, with treatments consisting of five doses of saflufenacil, applied alone and in a mixture with a fixed dose of glyphosate, in addition to the weeded control and only glyphosate. At 7, 14, 21 and 28 days after application (DAT), the phytotoxicity of the herbicides to the crop was evaluated. The physiological variables were measured at 35 DAT. At harvest, yield components were determined, in addition to the mass of 1,000 grains and grain yield. The application of the mixture of glyphosate with saflufenacil increases phytotoxicity symptoms and yield losses. Doses of up to 70 g ha-1, applied alone, caused low phytotoxicity to corn and did not interfere in yield. The use of glyphosate + saflufenacil tank mixtures caused decreases in yield of 43.96 and 40.81% when compared, respectively, with the weeded control and the averages of the applications of the herbicides alone. Saflufenacil has the potential to be used in the management of eudicotyledonous weeds, as long as it is not mixed with glyphosate and the dose limit is respected

Efficacy and safety of N-acetyl-GED-0507-34-LEVO gel in patients with moderate-to severe facial acne vulgaris: A phase 2B randomised double-blind, vehicle-controlled trial.

Background: Preliminary in vitro and in vivo studies have supported the efficacy of the peroxisome proliferator-activated receptor-γ (PPARγ) modulator N-acetyl-GED-0507-34-LEVO (NAC-GED) for the treatment of acne-inducing sebocyte differentiation, improving sebum composition and controlling the inflammatory process. Objectives: To evaluate the efficacy and safety of NAC-GED (5% and 2%) in patients with moderate-to-severe facial acne vulgaris. Methods: This double-blind phase II randomized controlled clinical trial was conducted at 36 sites in Germany, Italy and Poland. Patients aged 12-30 years with facial acne, an Investigator Global Assessment (IGA) score of 3-4, and an inflammatory and noninflammatory lesion count of 20-100 were randomized to topical application of the study drug (2% or 5%) or placebo (vehicle), once daily for 12 weeks. The co-primary efficacy endpoints were percentage change from baseline in total lesion count (TLC) and IGA success at week 12; the safety endpoints were adverse events (AEs) and serious AEs. This study was registered with EudraCT (2018-003307-19). Results: Between Q1 in 2019 and Q1 in 2020 450 patients [n = 418 (92·9%) IGA 3; n = 32 (7·1%) IGA 4] were randomly assigned to NAC-GED 5% (n = 150), NAC-GED 2% (n = 150) or vehicle (n = 150). The percentage change in TLC reduction was statistically significantly higher in both the NAC-GED 5% [-57·1%, 95% confidence interval (CI) -60·8 to -53·4; P &lt; 0·001] and NAC-GED 2% (-44·7%, 95% CI -49·1 to -40·1; P &lt; 0·001) groups compared with vehicle (-33·9%, 95% CI -37·6 to -30·2). A higher proportion of patients treated with NAC-GED 5% experienced IGA success (45%, 95% CI 38-53) vs. the vehicle group (24%, 95% CI 18-31; P &lt; 0·001). The IGA success rate was 33% in the NAC-GED 2% group (P = not significant vs. vehicle). The percentage of patients who had one or more AEs was 19%, 16% and 19% in the NAC-GED 5%, NAC-GED 2% and vehicle groups, respectively. Conclusions: The topical application of NAC-GED 5% reduced TLC, increased the IGA success rate and was safe for use in patients with acne vulgaris. Thus, NAC-GED, a new PPARγ modulator, showed an effective clinical response. What is already known about this topic? Acne vulgaris, one of the most common dermatological diseases, affects more than 85% of adolescents. There is a medical need for innovative and safe treatment of acne vulgaris. The peroxisome proliferator-activated receptor-γ (PPARγ) is involved in lipid metabolism and specifically in cell differentiation, sebum production and the inflammatory reaction. What does this study add? N-acetyl-GED-0507-34-LEVO (NAC-GED 5%), a PPARγ modulator, significantly improves acne manifestations in patients with moderate-to-severe acne and is safe and well tolerated. The results suggest that the PPARγ receptor is a novel therapeutic target for acne. The results provide a basis for a large phase III trial to assess the effectiveness and safety profile of NAC-GED in combating a disease that afflicts 80-90% of adolescents

Adequação de propriedades rurais ao Código Florestal Brasileiro: estudo de caso no Estado do Paraná.

O Código Florestal Brasileiro de 1965 conceitua e regulamenta as Áreas de Preservação Permanente (APP) e Reserva Legal (RL). Para regulamentar a adequação das propriedades agrícolas ao código florestal, o estado do Paraná instituiu o SISLEG - Sistema de Manutenção, Recuperação e Proteção da Reserva Legal e Áreas de Preservação Permanente. Neste estudo foram quantificadas, com auxílio do sistema de posicionamento global (GPS) e programas de Sistemas de Informações Geográficas (SIG), as APPs e RLs de 147 propriedades em oito municípios das regiões centro-oriental e sudeste do Paraná, visando analisá-las frente ao Código Florestal vigente. Observou-se expressiva cobertura florestal formada por fragmentos de Floresta Ombrófila Mista; as superfícies disponíveis para definição de RL apresentam valores superiores àqueles requeridos pela legislação. Há necessidade de recomposição das APPs em 67% das propriedades; 26% das propriedades estão de acordo com as exigências do Código Florestal. A quantificação da cobertura florestal necessária e remanescente, tal como a pequena demanda de área para readequação de APP (5% da área total) permitem inferir que esses quesitos não são entraves para a regularização ambiental da agricultura familiar, nas propriedades analisadas