Curing hemoglobinopathies : challenges and advances of conventional and new gene therapy approaches

Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier frequency of over 5%.1 With migration, they are becoming more common worldwide, making their management and care an increasing concern for health care systems. BT is characterized by an imbalance in the \u3b1/\u3b2-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Globally, there are over 25,000 births each year with transfusion-dependent thalassemia (TDT). The currently available treatment for TDT is lifelong transfusions and iron chelation therapy or allogenic bone marrow transplantation as a curative option. SCD affects 300 million people worldwide2 and severely impacts the quality of life of patients who experience unpredictable, recurrent acute and chronic severe pain, stroke, infections, pulmonary disease, kidney disease, retinopathy, and other complications. While survival has been dramatically extended, quality of life is markedly reduced by disease- and treatment-associated morbidity. The development of safe, tissue-specific and efficient vectors, and efficient gene-editing technologies has led to the development of several gene therapy trials for BT and SCD. However, the complexity of the approach presents its hurdles. Fundamental factors at play include the requirement for myeloablation on a patient with benign disease, the age of the patient, and the consequent bone marrow microenvironment. A successful path from proof-of-concept studies to commercialization must render gene therapy a sustainable and accessible approach for a large number of patients. Furthermore, the cost of these therapies is a considerable challenge for the health care system. While new promising therapeutic options are emerging,3,4 and many others are on the pipeline,5 gene therapy can potentially cure patients. We herein provide an overview of the most recent, likely potentially curative therapies for hemoglobinopathies and a summary of the challenges that these approaches entail

Torulaspora delbrueckii Yeast Strains for Small-scale Chenin blanc and Pinotage Vinifications

Nine Torulaspora delbrueckii yeast strains, a commercial T. delbrueckii strain and a commercial Saccharomyces cerevisiae yeast strain were used in the production of small‑scale Chenin blanc and Pinotage vinifications. The fermentations were carried out at 15°C and 24°C respectively. Four T. delbrueckii yeasts were used as single inoculants, while the remainder were inoculated sequentially. The commercial S. cerevisiae yeast strains were added at zero, 24 and 48 hours after the T. delbrueckii strain. The wines were evaluated chemically and sensorially and the data was analysed statistically. The results for the white wine vinification trial showed that two T. delbrueckii treatments could produce novel wines, either on their own or as a component of co‑inoculated fermentations. These compared well with, and even exceeded, the quality of wine produced by the S. cerevisiae reference treatment regarding chemical composition and overall sensory quality. One T. delbrueckii strain showed its robustness by being re-isolated from the yeast lees at the end of fermentation. The red wine vinifications were less conclusive, and no distinctive T. delbrueckii “fingerprint” was observed in the chemical and sensory data, neither was a pattern observed regarding the different inoculation times

Effect of Torulaspora delbrueckii Yeast on the Anthocyanin and Flavanol Concentrations of Cabernet franc and Pinotage Wines

Pinotage and Cabernet franc grape must were inoculated with Saccharomyces cerevisiae and Torulasporadelbrueckii yeasts. Differences in colour were observed between Pinotage (S. cerevisiae) and Pinotage (T.delbrueckii) wines, whereas differences in berry and herbaceous character were observed between Cabernetfranc (S. cerevisiae) and Cabernet franc (T. delbrueckii) wines. Mouthfeel properties between treatmentsfor both wines were not significantly different. Overall quality was slightly higher in wines inoculatedwith T. delbrueckii compared to wines inoculated with S. cerevisiae. Anthocyanins and flavanols measuredin Pinotage wines made with T. delbrueckii were higher compared to Pinotage must inoculated with S.cerevisiae. Cabernet franc wines made with S. cerevisiae were higher in anthocyanin glycoside and flavanolconcentrations compared to Cabernet franc wines made with T. delbrueckii. Insignificant differencesin acetylated and coumarylated anthocyanins were evident between Cabernet franc (S. cerevisiae) andCabernet franc (T. delbrueckii) wines. Principal component analysis showed that epigallocatechin gallate,epicatechin gallate, procyanidin B2, peonidin 3-O-glucoside, delphinidin 3-(6-acetyl) glucoside, petunidin3-(6-acetyl) glucoside, malvidin 3-(6-acetyl) glucoside and malvidin 3-O-glucoside concentrationswere highest in Pinotage wines inoculated with T. delbrueckii. Cabernet franc wines inoculated with S.cerevisiae yeasts were highest in malvidin 3-(6-p-coumaroyl) glucoside, petunidin 3-(6-p-coumaroyl)glucoside, petunidin 3-O-glucoside, epicatechin gallate and epigallocatechin gallate concentrations. Totalanthocyanins were highest in Pinotage (S. cerevisiae) wines and Cabernet franc (T. delbrueckii) wines.Flavanols were highest in Pinotage (T. delbrueckii) and Cabernet franc (S. cerevisiae) wines. It is evidentfrom the results that yeast species has an impact on the flavonoid concentrations within a grape variety

Electron-Phonon Coupling in Charged Buckminsterfullerene

A simple, yet accurate solution of the electron-phonon coupling problem in C_{60} is presented. The basic idea behind it is to be found in the parametrization of the ground state electronic density of the system calculated making use of ab-initio methods, in term of sp$^{2+x}$ hybridized orbitals. This parametrization allows for an economic determination of the deformation potential associated with the fullerene's normal modes. The resulting electron-phonon coupling constants are used to calculate Jahn-Teller effects in C_{60}^-, and multiple satellite peaks in the corresponding photoemission reaction. Theory provides an accurate account of the experimental findings.Comment: 11 pages, 3 figures. Accepted for publication in Chem. Phys. Let

The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines

Neutrophils are often exclusively considered as first line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seem to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilisation and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies. This article is protected by copyright. All rights reserved

A Narrative Review about Prosocial and Antisocial Behavior in Childhood: The Relationship with Shame and Moral Development

We conducted a literature review aimed at identifying the origins of shame as well as its effects on moral development, especially in terms of behavioral outcomes, and we reflected on the practical implications of our findings. We explored the role of shame in moral development through cultural differences and parental influences, collecting evidence of psychopathological consequences of primary moral emotion dysregulation. These studies showed a dichotomous feature of shame, as a prosocial behavior enhancer in morally relevant situations and, simultaneously, a risk factor for aggressive and antisocial behaviors on other occasions. Dysregulated shame leads to maladaptive interpersonal behaviors, which could evolve towards psychopathological paths. Therefore, an integrated intervention is recommended in children with emotional/behavioral problems

Cultivares e sistemas de cultivo de cebola no verão.

O presente trabalho foi realizado em São José do Rio Pardo. com o objetivo de avaliar o comportamento de cultivares de cebola Alfa Tropical, Alfa São Francisco e Mercedes em quatro sistemas de cultivo no verão. O experimento foi conduzido no delineamento de blocos casualizados, com quatro repetições e arranjo em parcelas subdivididas. Muda's de cebola produzidas em canteiros ou em bandejas de 200 células foram transplantadas em sistema convencional e direto na palha. A interação entre sistemas de cultivo e ,cultivares foi significativa na produtividade e incidência do mal-das-sete-voltas. A produtividade total variou entre 0.7 e 55.1 t ha-1. sendo as mais baixas produtividades obtidas com a cultivar Mercedes em todos os sistemas de cultivo. Foi observado que a produtividade e a precocidade de colheita foram maiores ou a incidência do mal-das-sete-voltas menor com as mudas de bandejas/ Em geral, a produtividade ou a precocidade de colheita tenderam a aumentar com a redução do preparo do solo. O transplantio direto na palha de mudas de bandejas é uma opção viável para a produção de cebola com sustentabilidade ambiental no verão.Suplemento. Edição dos resumos expandidos do 46. Congresso Brasileiro de Olericultura, Goiânia, ago. 2006

Breakthrough pain in oncology: a longitudinal study.

Abstract CONTEXT: Existing studies on breakthrough pain (BP) have reported different prevalence rates because of different settings, populations, and assessment methods. These studies have used cross-sectional designs, and the relationship of BP with analgesic treatment has not been evaluated. OBJECTIVES: The aim of this study was to longitudinally assess BP in cancer patients admitted to oncology units. METHODS: A consecutive sample of patients admitted to oncology centers was selected. At admission (T0), three months after admission (T3), and six months after admission (T6), data on background pain and BP were recorded. BP was assessed in terms of its intensity, duration, number of episodes, onset with movement, spontaneous relief after stopping activity, limitation of physical activity, and effectiveness of analgesics. RESULTS: Three hundred two patients completed the study. At T0, T3, and T6, 39%, 38%, and 33% patients, respectively, had continuous pain (P=0.294). Pain intensity significantly decreased (P=0.004 and 0.027 at T3 and T6, respectively). Most patients had BP at T0 (87.1%), T3 (80.9%), and T6 (73.2%), and there was a significant decrease in the prevalence of BP over time (P=0.016). Of 149 patients with BP, pain on movement was recorded in 43.6%, 43.4%, and 32.4% at T0, T3, and T6, respectively (P=0.228). Pain spontaneously decreased or ceased when stopping physical activity in 66%, 56%, and 62% at T0, T3, and T6, respectively (P=0.537). Pain on movement strongly limited physical activity in most patients. CONCLUSION: These data expand current information about BP and underline the need for a longitudinal assessment of a phenomenon that is invariably dependent on stage of disease, patient, and therapeutic factors

Influência de cultivares de feijão-caupi no crescimento populacional de Callosobruchus maculatus (FABR., 1775) (Coleoptera: Chrysomelidae: Bruchinae).

Na região Nordeste do Brasil a cultura do feijão-caupi tem grande importância socioeconômica, exercendo função no suprimento das necessidades nutricionais e fixação de mão-de-obra. Dentre as pragas que atacam os grãos de feijão-caupi durante o armazenamento, destaca-se Callosobruchus maculatus, por provocar perdas quantitativas e qualitativas. O controle deste inseto é feito principalmente com inseticidas sintéticos, no entanto, com os problemas decorrentes da intoxicação de aplicadores e seleção de insetos resistentes, formas alternativas de controle têm sido buscadas. Neste contexto, o objetivo deste trabalho foi avaliar a influência de cultivares de caupi no crescimento populacional de C. maculatus. Para realização do experimento utilizou-se cultivares de caupi provenientes da Embrapa Semiárido: BRS Guariba, BRS Maratoã, BRS Milênio, BRS Paraguaçu e BRS Pujante, além da testemunha Sempre Verde. Realizou-se teste sem chance de escolha, avaliando-se número de insetos emergidos e a taxa instantânea de crescimento populacional. A cultivar BRS Pujante apresentou os melhores resultados em relação aos parâmetros biológicos testados, apresentando possivelmente resistência do tipo antibiose.CONAC 2012. Disponível em: http://www.conac2012.org/resumos/pdf/241a.pdf. Acesso em: 08 ago. 2013