Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

The Darlington and Northallerton Long Term Asthma Study: pulmonary function

BACKGROUND: The Darlington and Northallerton Asthma Study is an observational cohort study started in 1983. At that time little was published about long term outcome in asthma and the contribution of change in reversible disease or airway remodelling to any excess deterioration in function. The study design included regular review of overall and fixed function lung. We report the trends over fifteen years. METHODS: All asthmatics attending secondary care in 1983, 1988 and 1993 were recruited. Pulmonary function was recorded at attendance and potential best function estimated according to protocol. Rate of decline was calculated over each 5-year period and by linear regression analysis in those seen every time. The influence of potential explanatory variables on this decline was explored. RESULTS: 1724 satisfactory 5-year measurements were obtained in 912 subjects and in 200 subjects on all occasions. Overall rate of decline (ml/year (95%CI)) calculated from 5-year periods was FEV1 ♂41.0 (34.7–47.3), ♀28.9 (23.2–34.6) and best FVC ♂63.1 (55.1–71.2)ml/year, ♀45.8 (40.0–51.6).The principal association was with age. A dominant cubic factor suggested fluctuations in the rate of change in middle life with less rapid decline in youth and more rapid decline in the elderly. Rapid decline was possibly associated with short duration. Treatment step did not predict rate of deterioration. CONCLUSIONS: Function declined non-linearly and more rapidly than predicted from normal subjects. It reports for the first time a cubic relationship between age and pulmonary function. This should be taken into account when interpreting other articles reporting change in function over time

Increased Migration of Monocytes in Essential Hypertension Is Associated with Increased Transient Receptor Potential Channel Canonical Type 3 Channels

Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in patients with essential hypertension. In the present study we tested the hypothesis that increased monocyte migration is associated with increased TRPC3 expression. Monocyte migration assay was performed in a microchemotaxis chamber using chemoattractants formylated peptide Met-Leu-Phe (fMLP) and tumor necrosis factor-α (TNF-α). Proteins were identified by immunoblotting and quantitative in-cell Western assay. The effects of TRP channel-inhibitor 2–aminoethoxydiphenylborane (2-APB) and small interfering RNA knockdown of TRPC3 were investigated. We observed an increased fMLP-induced migration of monocytes from hypertensive patients compared with normotensive control subjects (246±14% vs 151±10%). The TNF-α-induced migration of monocytes in patients with essential hypertension was also significantly increased compared to normotensive control subjects (221±20% vs 138±18%). In the presence of 2-APB or after siRNA knockdown of TRPC3 the fMLP-induced monocyte migration was significantly blocked. The fMLP-induced changes of cytosolic calcium were significantly increased in monocytes from hypertensive patients compared to normotensive control subjects. The fMLP-induced monocyte migration was significantly reduced in the presence of inhibitors of tyrosine kinase and phosphoinositide 3-kinase. We conclude that increased monocyte migration in patients with essential hypertension is associated with increased TRPC3 channels

Tennis play intensity distribution and relation with aerobic fitness in competitive players

15 p.Los objetivos de este estudio fueron (1) describir la intensidad relativa del juego de tenis simulado en función del tiempo acumulado en tres zonas de intensidad metabólica y (2) determinar las relaciones entre esta distribución de intensidad de juego y la aptitud aeróbica de un grupo de jugadores competitivos. 20 jugadores masculinos de nivel avanzado a élite (ITN) realizaron una prueba de tenis de resistencia específica en el campo incremental hasta el agotamiento para determinar el consumo máximo de oxígeno (VO2max) y los umbrales de ventilación primero y segundo (VT1, VT2). Los parámetros de ventilación y de intercambio de gases se monitorizaron utilizando un analizador de gas portátil telemétrico (K4 b2, Cosmed, Roma, Italia). Dos semanas después, los participantes jugaron un juego de tenis simulado contra un oponente de nivel similar. Las zonas de intensidad (1: baja, 2: moderada y 3: alta) fueron delimitadas por los valores individuales de VO2 correspondientes a VT1 y VT2, y se expresaron como porcentaje del VO2 máximo y la frecuencia cardíaca. Cuando se expresó en relación con el VO 2 máx. El porcentaje de tiempo de juego en la zona 1 (77 ± 25%) fue significativamente mayor (p <0,001) que en la zona 2 (20 ± 21%) y la zona 3 (3 ± 5%). Se encontraron correlaciones positivas de moderadas a altas entre VT1, VT2 y VO2max, y el porcentaje del tiempo de juego transcurrido en la zona 1 (r = 0,68-0,75), así como las correlaciones inversas de bajas a altas entre las variables metabólicas y el porcentaje de tiempo empleado en las zonas 2 y 3 (r = -0.49–0.75). Los jugadores con mejor aptitud aeróbica juegan a intensidades relativamente más bajas. Concluimos que los jugadores pasaron más del 75% del tiempo en su zona de baja intensidad, con menos del 25% del tiempo dedicado a intensidades moderadas a altas. La aptitud aeróbica parece determinar la intensidad metabólica que los jugadores pueden mantener durante todo el juegoS

Improving the Management of COPD in Women

COPD is a highly debilitating disease that represents a substantial and growing health burden in women. There is increasing evidence for sex-related differences in COPD risk, progression, and outcomes. However, the disease receives scant attention as a women's health issue. Thus, a multifaceted approach is required to address COPD in women, including greater awareness, minimization of risk, and further elucidation of the sex-specific factors (biological and cultural) that affect risk, disease progression, and treatment success. This article reviews the current literature on the topic and provides suggestions for achieving better outcomes for the millions of women with COPD worldwide

Perlindungan Hukum Atas Hak Pengguna Nama Domain Ditinjau dari Undang-undang Nomor 11 Tahun 2008 Tentang Informasi dan Transaksi Elektronik Serta Undang-undang Nomor 8 Tahun 19999 Tentang Perlindungan Konsumen

Kemajuan teknolgi yang berkembang begitu cepat telah membawa Perubahan berbagi aspek kehidupan manusia, salah satu perkembangan yang nampak adalah perkembangan yang nampak adalah perkembangan dalam dunia internet. Internet telah menjadi sarana yang lekat dengan masyarakat, berbagai kegiatan masyarakat yang digunakan dapat dilakukan melalui media internet, salah satunya dalam bidang perdagangan. Sistem perdagangan yang ada dalam media internet telah memudahkan bagi seseorang dikarenakan tidak adanya batasan ruang dan waktu. Seorang dapat melakukan perdagangan yang ada dalam media internet dengan mudah, sistem pendaftaran yang cepat, dan penggunaannya yang mudah, dikarenakan kemudahan yang diberikan memberikan celah bagi seseorang untuk melakukan pelanggaran, salah satu pelanggaran yang muncul adalah tindakan Domain Name Hijacking. Pelanggaran tersebut telah menimbulkan kerugian bagi seorang pelaku usaha, dikarenakan kesamaan yang dimiliki dari nama domain tersebut sehingga menyebabkan kerugian bagi pemilik nama domain, namun juga kerugian bagi konsumen. Sebelum menjelaskan mengenai permasalahan tersebut, apakah itu domain? Apakah itu Domain Name Hijacking? Bagaimanakah perlindungan atas pemilik nama domain tersebut? Permasalahan yang ada tersebut berguna untuk memberikan wawasan bagi masyarakat dan berguna untuk melindungi pengguna dari nama domain yang dirugikan.Kata Kunci: internet, nama domain, perlindungan konsume