Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the molecular mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent reduction of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymography. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunoprecipitation assay. H(2)O(2) reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused reduction of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small molecule activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the reduction in exercise tolerance. Thus, SIRT1 is a negative regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.

Apoptotic ␤-cell death is central to the pathogenesis of type 1 diabetes and may be important in islet graft rejection. Despite this, genetic control of ␤-cell apoptosis is only poorly understood. We report that inhibition of gene transcription sensitized ␤-cells to tumor necrosis factor (TNF)-␣-induced apoptosis, indicating the presence of a regulated antiapoptotic response. Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokinestimulated human and mouse islets. Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in ␤-cells. Regulation of A20 was nuclear factor-B (NF-B)-dependent, two NF-B sites within the A20 promoter were found to be necessary and sufficient for A20 expression in ␤-cells. Activation of NF-B by TNF receptor-associated factor (TRAF) 2, TRAF6, NF-B-inducing kinase, or protein kinase D, which transduce signals downstream of Toll-like receptors, TNF receptors, and free radicals, respectively, were all potent activators of the A20 promoter. Moreover, A20 expression was induced in transplanted islets in vivo. Finally, A20 expression was sufficient to protect ␤-cells from TNFinduced apoptosis. These data demonstrate that A20 is the cardinal antiapoptotic gene in ␤-cells. Further, A20 expression is NF-B dependent, thus linking islet proinflammatory gene responses with protection from apoptosis.

No abstract

Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)(A) receptor channel (apparent IC50 = 0.040 +/- 0.001 mg mL(-1)), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL(-1)), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABA(A) antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported.

Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)(A) receptor channel (apparent IC50 = 0.040 +/- 0.001 mg mL(-1)), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL(-1)), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABA(A) antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported.

The relative importance of genetic factors and tobacco smoking intensity in the pathogenesis of the airway disease and emphysematous components of chronic obstructive pulmonary disease (COPD) is unknown. We addressed this question in a familybased study that recruited probands (FEV 1 Ͻ 60% predicted, ages 45-65 yr, and Ͼ 5 pack-year smoking history) and their current/ex-smoking siblings. The family-based design allowed us to test the relationship between COPD phenotype (emphysema or small airway disease) in a proband and his or her siblings. Subjects completed a questionnaire and underwent spirometry, and a subset of participants underwent chest computed tomography (CT) scans.Results: The number of pack-years was only weakly correlated with FEV 1 in 634 individuals with emphysema, as assessed by radiologist scoring of chest CT scans (r ϭ Ϫ0.09, p ϭ 0.02). The amount of emphysema on CT scan was inversely related to FEV 1 (p Ͻ 0.001), but there was no relationship between pack-years and amount of emphysema. Emphysema was more prevalent in the siblings of probands with emphysema (41.7%) than in siblings of nonemphysema probands (23.6%, p Ͻ 0.001); this was independent of pack-years smoked (adjusted odds ratio, 2.12; p ϭ 0.03). In 482 individuals without emphysema, FEV 1 was correlated with pack-years smoked (r ϭ Ϫ0.38, p Ͻ 0.0001). The correlation between pack-years and FEV 1 was particularly strong (r ϭ Ϫ0.58, p Ͻ 0.0001) in 48 siblings who were from families in which the proband had predominantly small airway disease.These data suggest that emphysema and airway-related COPD are distinct phenotypes and have different relationships with smoking. Moreover, differences in amount of emphysema are not explained by cumulative smoking, suggesting a complex gene-environment interaction.Conflict of Interest Statement : B.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.M., on behalf of GlaxoSmithKline (GSK), over the last 3 years has served on advisory boards and received $7,500. He spoke at GSK-sponsored programs and received $18,000. He participated in multicenter clinical trials. His institution has received unrestricted educational grants from GSK and has received research grants for participating in GSK multicenter clinical trials. H.O.C. received $11,000 in 2003 for serving on an advisory board for GSK. In addition, he is the coinvestigator on two multicenter studies sponsored by GSK and has received travel expenses to attend meetings related to the project. He has three contract service agreements with GSK to quantify the CT scans in subjects with COPD. A percentage of his salary between 2003 and 2006 ($15,000/yr) derives from contract funds provided to a colleague, Peter D. Pare, by GSK for the development of validated methods to measure emphysema and airway disease using CT. There is no financial relationship between any industry and the current study. N.L.M. has a GSK-sponsored research grant on quantification of emphysema and airway abno...

His bundle pacing (HBP) and left bundle pacing (LBP) are novel delivery methods for cardiac resynchronisation therapy (CRT) for left bundle branch block (LBBB) patients. Septal flash (SF), an abnormal pre-ejection motion of the septum towards the left ventricle (LV) arising from dyssynchronous activation, has been shown in the past to be a robust and independent predictor for CRT response. Although small-cohort studies showed the feasibility and efficacy of HBP and LBP, the effects of HBP and LBP on septal motion have yet to be investigated. In this study, we used our four-chamber heart electro-mechanics simulation framework to determine whether HBP and LBP can correct for SF. We performed simulations in four fourchamber heart models. In synchronous and LBBB activation, simulated mean lateral septal movement from the right ventricle (RV) into the LV was-0.4±0.5mm and-3.7±0.9mm (p<0.05), respectively. HBP reduced septal motion to-0.4±0.5mm (p=0.5 when compared to synchronous activation). In LBP, septal motion was reversed to 0.9±0.5mm and significantly different from synchronous activation (p<0.05). HBP was better able to recover septal function over LBP in patients with complete atrioventricular block.

Since the introduction of transvenous cardiac pacing leads, pacemaker system design has remained similar for several decades. Progressive miniaturisation of electronic circuitry and batteries has enabled a smaller, single pacing unit comprising the intracardiac electrodes, generator and computer. This review explores the development of leadless pacing, the clinical trials comparing leadless to transvenous pacing in addition to the future developments of multichamber leadless pacing.