Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition.

One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53-induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24-/- progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24-/- mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.

Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia.

Dinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including chronic lymphocytic leukaemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB, p38, PI3K/AKT and RAF/MEK/ERK. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL2 family such as MCL1 and BCL-xL (also termed BCL2L1). Finally, we showed that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and the BCL2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin-dependent kinase inhibitors in CLL in combination with other relevant targeted therapies.

Effects of CPAP on clinical variables and autonomic modulation in children during an asthma attack.

Continuous positive airway pressure (CPAP) causes changes in alveolar and intrathoracic pressure and the activation of pulmonary stretch receptors affects the balance of the autonomic nervous system. The acute effects of CPAP on autonomic modulation have been demonstrated in different diseases, but no studies have been carried out addressing CPAP in patients with asthma. The hypothesis tested in the present study is that CPAP can produce an autonomic effect beyond a mechanical effect of bronchial dilatation in children with asthma. The results demonstrated improvements in clinical variables and an increase in vagal tone with the administration of CPAP during an asthma attack, as demonstrated by a diminished respiratory rate and a reduction in signs of respiratory distress. Regarding autonomic modulation, an increase in parasympathetic variables was found, indicating non-cholinergic activation stemming from the persistent increase in peak flow.

Estudo comparativo entre substâncias químicas utilizadas na descontaminação de instrumentais cirúrgicos / Comparative study between chemicals used to decontaminate surgical instruments

A eficácia da descontaminação tem sido questionada na literatura por isso foi desenvolvido o estudo com o objetivo de verificar a ação microbicida do processo de descontaminação. Foram avaliados instrumentais de 54 cirurgias de grande porte correspondendo a 216 culturas, distribuídas em: Grupo 1 - após término da cirurgia, Grupo 2 - após detergente enzimático, Grupo 3 - após fenóis sintéticos, Grupo 4 - após detergente enzimático e fenóis sintético. Os resultados mostraram crescimento de grande variedade de bactérias, no entanto não houve identificação de fungos. No grupo 1 houve positividade de 44,44 por cento, No grupo 2, 3 e 4 foram respectivamente 25,92 por cento, 12,96 por cento e 7,4 por cento. sendo o grupo 4 o de melhor desempenho. Das 54 amostras, houve crescimento compatível em apenas 5(26,32 por cento) das amostras, sendo 4 com Staphylococcus coagulase negativo e uma pseudomonas não aeruginosa. Crescimento incompatível ocorreu em 14 amostras sendo identificadas 18 bactérias, a maioria Gram negativa não fermentadora.