Phosphodiesterase-III Inhibitor Prevents Hemorrhagic Transformation Induced by Focal Cerebral Ischemia in Mice Treated with tPA

The purpose of the present study was to investigate whether cilostazol, a phosphodiesterase-III inhibitor and antiplatelet drug, would prevent tPA-associated hemorrhagic transformation. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone at 6 h, with combined tPA plus cilostazol at 6 h, or with vehicle at 6 h. We used multiple imaging (electron microscopy, spectroscopy), histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To further investigate the mechanism of cilostazol to beneficial effect, we also performed an in vitro study with tPA and a phosphodiesterase-III inhibitor in human brain microvascular endothelial cells, pericytes, and astrocytes. Combination therapy with tPA plus cilostazol prevented development of hemorrhagic transformation, reduced brain edema, prevented endothelial injury via reduction MMP-9 activity, and prevented the blood-brain barrier opening by inhibiting decreased claudin-5 expression. These changes significantly reduced the morbidity and mortality at 18 h and 7 days after the reperfusion. Also, the administration of both drugs prevented injury to brain human endothelial cells and human brain pericytes. The present study indicates that a phosphodiesterase-III inhibitor prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA

Targeted Sister Chromatid Cohesion by Sir2

The protein complex known as cohesin binds pericentric regions and other sites of eukaryotic genomes to mediate cohesion of sister chromatids. In budding yeast Saccharomyces cerevisiae, cohesin also binds silent chromatin, a repressive chromatin structure that functionally resembles heterochromatin of higher eukaryotes. We developed a protein-targeting assay to investigate the mechanistic basis for cohesion of silent chromatin domains. Individual silencing factors were tethered to sites where pairing of sister chromatids could be evaluated by fluorescence microscopy. We report that the evolutionarily conserved Sir2 histone deacetylase, an essential silent chromatin component, was both necessary and sufficient for cohesion. The cohesin genes were required, but the Sir2 deacetylase activity and other silencing factors were not. Binding of cohesin to silent chromatin was achieved with a small carboxyl terminal fragment of Sir2. Taken together, these data define a unique role for Sir2 in cohesion of silent chromatin that is distinct from the enzyme's role as a histone deacetylase

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

Myocardial tagging by Cardiovascular Magnetic Resonance: evolution of techniques--pulse sequences, analysis algorithms, and applications

Cardiovascular magnetic resonance (CMR) tagging has been established as an essential technique for measuring regional myocardial function. It allows quantification of local intramyocardial motion measures, e.g. strain and strain rate. The invention of CMR tagging came in the late eighties, where the technique allowed for the first time for visualizing transmural myocardial movement without having to implant physical markers. This new idea opened the door for a series of developments and improvements that continue up to the present time. Different tagging techniques are currently available that are more extensive, improved, and sophisticated than they were twenty years ago. Each of these techniques has different versions for improved resolution, signal-to-noise ratio (SNR), scan time, anatomical coverage, three-dimensional capability, and image quality. The tagging techniques covered in this article can be broadly divided into two main categories: 1) Basic techniques, which include magnetization saturation, spatial modulation of magnetization (SPAMM), delay alternating with nutations for tailored excitation (DANTE), and complementary SPAMM (CSPAMM); and 2) Advanced techniques, which include harmonic phase (HARP), displacement encoding with stimulated echoes (DENSE), and strain encoding (SENC). Although most of these techniques were developed by separate groups and evolved from different backgrounds, they are in fact closely related to each other, and they can be interpreted from more than one perspective. Some of these techniques even followed parallel paths of developments, as illustrated in the article. As each technique has its own advantages, some efforts have been made to combine different techniques together for improved image quality or composite information acquisition. In this review, different developments in pulse sequences and related image processing techniques are described along with the necessities that led to their invention, which makes this article easy to read and the covered techniques easy to follow. Major studies that applied CMR tagging for studying myocardial mechanics are also summarized. Finally, the current article includes a plethora of ideas and techniques with over 300 references that motivate the reader to think about the future of CMR tagging

Warping in New Crop Radiata Pine 100×50mm (2 by 4) Boards

ニュークロップラジアタパイン2×4材の乾燥による狂いの性状を明かにするために，生材から含水率約7％まで無拘束で乾燥した時の狂い（縦ぞり，弓ぞり，ねじれ）と狂いに影響するいくつかの因子（材の丸太内における位置，収縮率，繊維傾斜角，比重，節の大きさや分布など）を詳細に調べた。また，狂いの方向をはっきりさせるためにleading edgeという基準位置を設け，正（positive）と負（negative）の縦ぞり，弓ぞりおよびねじれを定義した。2×4材の丸太内における位置は（γ，θ）で表し，overlay法と直接法で測定した（ここで，γは丸太の髄から2×4材の中心までの距離，θは2×4材の年輪状態を示す値で，0°（柾目板）から90°（板目板）までの範囲にある）。生材の時は供試材（61本）の約60％が負の縦ぞりおよび弓ぞりを示したが，乾燥すると約80％が正の縦ぞり，弓ぞりを示した。ねじれは繊維傾斜角に強く影響される。（γ，θ）と縦ぞりおよび弓ぞりの3次元のグラフの形は未成熟材と成熟材の繊維方向収縮率の差によって説明できる。縦ぞりはγの値に関係なく，θ＝0°（柾目板）の時最大で，θ＝90°（板目板）の時最小である。縦ぞり，弓ぞりおよびねじれとそれぞれの影響因子との関係を調べたが，それぞれの因子はお互いに関連しており，ひとつだけの因子による解析では間違った結果を導くおそれがある。これをさけるためには数学モデルによる解析が必要である。The bow, crook and twist that developed during the unrestrained drying of 61 radiata pine boards were carefully measured. The boards were sawn from four carefully selected logs and the position of each board in the log was accurately specified. The shrinkage coefficients, spiral grain and several other parameters were measured for each log as a function of radial position. The position, size and associated grain deviation of all knots in each board were carefully recorded. A novel method has been developed to analyse bow, crook and twist. The concept of a leading edge has been introduced. The leading edge is the edge of a board closest to the pith while the board was still part of the log. Bow, crook and twist were measured with respect to the surfaces that contained the leading edge. Positive and negative bow, crook and twist have been carefully defined. A strong tendency has been found for boards to develop positive crook and positive bow during drying. While the average twist also became more positive during drying, only about half the boards developed positive twist. Twist was found to be strongly related to spiral grain. The data were analysed in terms of two board coordinates r and θ where r is the distance of the centroid of the board's cross-section from the pith and θ is a parameter indicating the orientation of the annual rings, where θ ranges from 0 degrees for quartersawn to 90 degrees for flatsawn. The shape of the three dimensional graphs obtained by plotting crook and bow versus r and θ can be explained in terms of differences in longitudinal shrinkage between corewood and mature wood. Crook had a minimum value at a θ value of 90° for all values of r. Bow, crook and twist were analysed in terms of single parameters such as density, ring width, and distance from the pith. It was found that analysis in terms of single parameters is at best inadequate, while in the worst case it can lead to erroneous conclusions. Multi-variant analysis would be desirable, but as many of the variables are interdependent 61 boards form too small a sample. Yet to study a greater number would be an impossible task. The recommended alternative is the development of a mathematical model against which the experimental data can be tested