A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants

Influenza virus has a high mutation rate, such that within one host different viral variants can emerge. Evidence suggests that influenza virus variants are more prevalent in pregnant and/or obese individuals due to their impaired interferon response. We have recently shown that the non-allergic, paucigranulocytic subtype of asthma is associated with impaired type I interferon production. Here, we seek to address if this is associated with an increased emergence of influenza virus variants. Compared to controls, mice with paucigranulocytic asthma had increased disease severity and an increased emergence of influenza virus variants. Specifically, PB1 mutations exclusively detected in asthmatic mice were associated with increased polymerase activity. Furthermore, asthmatic host-derived virus led to increased disease severity in wild-type mice. Taken together, these data suggest that at least a subset of patients with asthma may be more susceptible to severe influenza and may be a possible source of new influenza virus variants

One step forward, one step sideways? Expanding research capacity for neglected diseases

<p>Abstract</p> <p>Background</p> <p>There is general agreement, including from the pharmaceutical industry, that current market based methods of generating research into the development of pharmaceutical products that are relevant for developing countries do not work. This conclusion is relevant not just for the most neglected diseases such as leishmaniasis but even for global diseases such as cancer and cardiovascular disease.</p> <p>Discussion</p> <p>Stimulating research will mean overcoming barriers such as patent thickets, poor coordination of research activities, exclusive licensing of new technologies by universities and the structural problems that inhibit conducting appropriate clinical trials in developing countries. In addition, it is necessary to ensure that the priorities for research reflect the needs of developing countries and not just donors. This article will explore each of these issues and then look at three emerging approaches to stimulating research -paying for innovation, priority review sales or vouchers and public-private partnerships, - and evaluate their strengths and weaknesses.</p> <p>Summary</p> <p>All of the stakeholders agree that there is a pressing need for a major expansion in the level of R&D. Whatever that new model turns out to be, it will have to deal with the 5 barriers outlined in this paper. Finally, none of the three proposals considered here for expanding research is free from major limitations.</p

Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice

Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr42/2 mice by 6 months of age, the lungs of Tlr22/2 mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr42/2 mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal2/2 mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal2/2 mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr42/2 mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema

HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling.

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling

Reconstrução abdominal tardia sem tensão após laparostomia: uma nova técnica

OBJETIVO: A reconstrução abdominal tardia após laparostomia é sempre um procedimento desafiador para o cirurgião devido à necessidade de se corrigir um grande defeito na parede abdominal anterior, o que habitualmente demanda a lise de extensas aderências entre alças intestinais e o tecido cicatricial, sem que a hérnia incisional seja o resultado final. Neste trabalho, propomos uma técnica simples e inédita para esta reconstrução abdominal, sem tensão, utilizando tela de polipropileno sobre o tecido de granulação, sem necessidade de qualquer dissecção intra-peritoneal. MÉTODO: Descrição da técnica e estudo prospectivo de 17 pacientes submetidos à mesma entre 1998 e 2005. Foram analisados; a causa da laparostomia, o tempo entre a laparostomia e a reconstrução, o tempo operatório e a evolução pós-operatória imediata e tardia incluindo a incidência de hérnias incisionais. RESULTADOS: A idade média dos pacientes foi de 41 anos. As indicações da laparostomia foram; peritonite em oito pacientes, trauma abdominal em outros oito e pancreatite necrotizante em um. O tempo médio até a reconstrução abdominal foi de 14 meses. O tempo médio do procedimento cirúrgico foi de 130 minutos. O período médio de internação hospitalar foi de 2,6 dias para os 15 pacientes sem complicações pós-operatórias. Não houveram óbitos ou ocorrência de síndrome de compartimento abdominal relacionados à técnica. A média do período de acompanhamento pós-operatório é de 24 meses e até o momento não há ocorrência de hérnia incisional em todo o grupo. CONCLUSÕES: A técnica aqui proposta é de fácil execução e reprodutibilidade, torna desnecessária a manipulação da cavidade abdominal com conseqüente diminuição do risco de lesão de vísceras abdominais e proporciona o fechamento definitivo da laparostomia sem tensão. Esta técnica não acarretou síndrome de compartimento abdominal e nenhum paciente desenvolveu hérnia incisional até o momento