Prospects For Early Investigational Therapies For Sickle Cell Disease.

Sickle cell disease (SCD) is a genetic disorder characterized by the production of abnormal hemoglobin that polymerizes at low oxygen concentrations, causing the erythrocyte to adopt a sickle-shaped morphology. SCD pathophysiology is extremely complex and can lead to numerous clinical complications, including painful vaso-occlusive crises (VOC), end-organ damage, and a shortened lifespan. An impressive number of investigational drugs are currently in early stages of clinical development with prospects for use either as chronic therapies to reduce VOC frequency and end-organ damage in SCD or for use at the time of VOC onset. Many of these agents have been developed using a pathophysiological-based approach to SCD, targeting one or more of the mechanisms that contribute to the disease process. It is plausible that a multi-drug approach to treating the disease will evolve in the coming years, whereby hydroxyurea (HU) (the only drug currently FDA-approved for SCD) is used in combination with drugs that amplify nitric oxide signaling and/or counteract hemolytic effects, platelet activation and inflammation.

As diferenças rítmicas entre o português europeu e o português brasileiro: uma abordagem otimalista e minimalista

The aim of this paper is to discuss some rhythmic differences between European and Brazilian Portuguese and their relationship to pretonic vowel reduction phenomena. After the basic facts of PE and PB are presented, we show that the issue cannot be discussed without taking into account secondary stress placement, and we proceed to present the algorithm-based approach to secondary stress in Portuguese, representative of Metrical Phonology analyses. After showing that this deterministic approach cannot adequately explain the variable position of secondary stress in both languages regarding words with an even number of pretonic syllables, we argue for the interpretation of secondary stress and therefore for the construction of rhythmic units at the PF interface, as suggested in Chomsky s Minimalist Program. We also propose, inspired by the constrain hierarchies as proposed in Optimality Theory, that such interpretation must take into account two different constraint rankings, in EP and BP. These different rankings would ultimately explain the rhythmic differences between both languages, as well as the different behavior of pretonic vowels with respect to reduction processes.