Amyloid-␤ (A␤) is a major constituent of the neuritic plaque found in the brain of Alzheimer's disease patients, and a great deal of evidence suggests that the neuronal loss that is associated with the disease is a consequence of the actions of A␤. In the past few years, it has become apparent that activation of c-Jun N-terminal kinase (JNK) mediates some of the effects of A␤ on cultured cells; in particular, the evidence suggests that A␤-triggered JNK activation leads to cell death. In this study, we investigated the effect of intracerebroventricular injection of A␤ (1-40) on signaling events in the hippocampus and on long term potentiation in Schaffer collateral CA1 pyramidal cell synapses in vivo. We report that A␤ One of the pathological hallmarks of Alzheimer's disease (AD) 1 is an accumulation of plaques consisting predominately of amyloid-␤ (A␤) peptide, which is processed from amyloid precursor protein by the action of ␤-and ␥-secretase (1). Neuronal cell loss is one feature of AD, and evidence from analysis of changes in cultured cells suggests that A␤ acts as the executioner. Thus, neuronal cultures exposed to A␤ demonstrate signs of apoptosis (2-4), and previous evidence from this laboratory has revealed that cultured cortical neurons exposed to A␤ exhibited increased expression of the tumor suppressor p53; increased activation of caspase-3, a marker of apoptotic cell death; and increased TUNEL reactivity (5). The evidence is consistent with the idea that activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK) played a significant role, because depletion of JNK1 following exposure to antisense oligonucleotide prevented the effects of A␤ (5). Similarly, Morishima et al. (6) reported that A␤ increased phosphorylation of JNK and c-Jun in cultured cortical neurons and that these changes were associated with expression of the death inducer Fas ligand (FasL). Others have reported findings that support a role for JNK activation in mediating at least certain effects of A␤. For instance, A␤-induced parallel increases in JNK activation and TUNEL reactivity in PC12 cells (7), whereas activation of JNK was shown to be localized to amyloid deposits in 7-and 12-month-old mice that overexpress amyloid precursor protein (8).It has emerged in several experimental models that increased JNK phosphorylation is associated with deficits in synaptic function; for instance, increased activation of JNK has been reported in the hippocampi of aged rats (9, 10), rats exposed to whole body irradiation (11), and rats injected with the proinflammatory cytokine, interleukin (IL)-1␤ (12) or lipopolysaccharide (13), and in all cases glutamate release was decreased. In each of these experimental conditions, long term potentiation (LTP), a model of synaptic plasticity, was markedly impaired, and this impairment was coupled with an increased hippocampal concentration of IL-1␤.A number of groups have reported that A␤ administration exerts an inhibitory effect on LTP. For instance, A␤ peptides (14 -16) and natu...

Suboptimal adherence to maintenance therapy contributes to poor asthma control and exacerbations. This study evaluated the effect of different elements of a connected inhaler system (CIS), comprising clip-on inhaler sensors, a patient-facing app, and a healthcare professional (HCP) dashboard, on adherence to asthma maintenance therapy.This was an open-label, parallel-group, 6-month, randomised controlled trial in adults with uncontrolled asthma (Asthma Control Test (ACT) score <20) on fixed-dose inhaled corticosteroid/long-acting beta-agonist maintenance therapy (n=437). All received fluticasone furoate/vilanterol ELLIPTA dry powder maintenance and salbutamol/albuterol metered dose rescue inhalers with a sensor attached to each inhaler. Participants were randomised to one of five CIS study arms (1:1:1:1:1) reflecting the recipient of the data feedback from the sensors: 1) Maintenance use to participants and HCPs (N=87); 2) Maintenance use to participants (N=88); 3) Maintenance and rescue use to participants and HCPs (N=88); 4) Maintenance and rescue use to participants (N=88); 5) No feedback (control) (N=86).For the primary endpoint, observed mean adherence (sd) to maintenance therapy over months 4–6, was 82.2% (16.58) (n=83) in the “maintenance to participants and HCPs” arm and 70.8% (27.30) (n=85) in the control arm and the adjusted LS mean (se) was 80.9% (3.19) and 69.0% (3.19), respectively (study arm difference: 12.0% (95% CI: 5.2%, 18.8%; p<0.001)). Adherence was also significantly greater in the other CIS arms versus control. Mean percentage of rescue medication-free days (months 4–6) was significantly greater in participants receiving data on their rescue use compared with control. ACT scores improved in all study arms with no significant differences between groups.A CIS can improve adherence to maintenance medication and reduce rescue medication use in patients with uncontrolled asthma.

Background: Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy subjects and patients with asthma or chronic obstructive pulmonary disease (COPD) through a moderate-resistance dry powder inhaler (DPI). Correlations between inhaler-specific inhalation characteristics and inhaler-independent lung function parameters were investigated.Methods: Healthy subjects (n = 15), patients with mild, moderate, or severe asthma (n = 45), and patients with mild, moderate, severe, or very-severe COPD (n = 60) were included in the studies. Inhalation pressure drop versus time profiles were recorded using an instrumented ELLIPTA® DPI or bespoke resistor component with equivalent resistivity. Inhaler-independent lung function assessments included pharyngometry, spirometry, plethysmography, and diffusion.Results: For the inhaler-specific inhalation profiles, the mean maximal effort peak inspiratory flow rates (PIFRs) varied across the subgroups from 65.8–110.6 L/min (range: 41.6–142.9). Peak pressure drop, PIFR, inhaled volume, and average inhalation flow rate (primary endpoints) did not differ markedly between healthy subjects and patients with asthma or mild COPD. Moderate, severe, and very-severe COPD patients demonstrated lower mean peak pressure drops, PIFRs and inhaled volumes, which tended to decrease with increasing COPD severity. Severe and very-severe COPD patients demonstrated shorter mean inhalation times compared with all other participants. Inhaler-independent lung function parameters were consistent with disease severity, and statistically significant (p < 0.05) strong correlations (R > 0.7) with components of the inhaler-specific inhalation profiles were observed in the COPD cohort; correlations in the asthma cohort tended to be weaker.Conclusions: All participants achieved a maximal effort PIFR ≥ 41.6 L/min through the moderate resistance of the ELLIPTA inhaler. Patients with asthma achieved similar inhalation profiles to healthy subjects, but increasing COPD severity tended to reduce a patient's inhalation capability. Correlation analyses suggest that some lung function parameters may be a useful indicator of ability to inhale efficiently through a moderate-resistance DPI, such as the ELLIPTA inhaler.

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ObjectiveTo compare the effects of switching from a pressurised metered dose inhaler (pMDI)-based to a dry powder inhaler (DPI)-based maintenance therapy versus continued usual care on greenhouse gas emissions (carbon dioxide equivalents, CO2e) and asthma control.MethodsThis post-hoc analysis was based on a subset of 2236 (53%) patients from the Salford Lung Study in Asthma who at baseline were using a pMDI-based controller therapy. During the study patients were randomised to fluticasone furoate/vilanterol (FF/VI) via the ELLIPTA DPI (switched from pMDI to DPI) (n=1081) or continued their usual care treatment (n=1155), and were managed in conditions close to everyday clinical practice. Annual CO2e (kg) was calculated for the total number of maintenance and rescue inhalers prescribed. Asthma control was assessed by the proportion of ACT responders (composite of ACT total score ≥20 and/or increase from baseline ≥3).ResultsThe groups were well matched for demographic characteristics and baseline Asthma Control Test (ACT) total score (mean age: 49 years; mean ACT score: usual care, 16.6; FF/VI, 16.5). Annual CO2e kg per patient (maintenance plus rescue therapy) was significantly lower with FF/VI DPI treatment (‘switch’ group) than usual care (least squares geometric mean 108 kg (95% CI 102 to 114) vs 240 kg (95% CI 229 to 252), p<0.001). Asthma control was consistently superior over the 12 months in the FF/VI DPI group compared with usual care.ConclusionsPatients switching from a pMDI-based to a DPI-based maintenance therapy more than halved their inhaler carbon footprint without loss of asthma control. The remaining inhaler carbon footprint could be reduced through switches from pMDI to DPI rescue medications or alternative lower-carbon footprint rescue inhalers if available. Asthma control improved in both groups, with greater control demonstrated in those initiated on FF/VI DPI.Trial registration numberNCT01706198.