bluuebunny/crossref_metadata_2025 huggingface dataset:
Flash Storage Today
Authors: Leventhal Adam
Published: September 2008

The past few years have been an exciting time for flash memory. The cost has fallen dramatically as fabrication has become more efficient and the market has grown; the density has improved with the advent of better processes and additional bits per cell; and flash has been adopted in a wide array of applications. The flash ecosystem has expanded and continues to expand especially for thumb drives, cameras, ruggedized laptops, and phones in the consumer space.
Developing a Child Friendly Text-to-Speech System
Authors: Jacob Agnes , Mythili P.
Published: September 2008

This paper discusses the implementation details of a child friendly, good quality, English text-to-speech (TTS) system that is phoneme-based, concatenative, easy to set up and use with little memory. Direct waveform concatenation and linear prediction coding (LPC) are used. Most existing TTS systems are unit-selection based, which use standard speech databases available in neutral adult voices. Here reduced memory is achieved by the concatenation of phonemes and by replacing phonetic wave files with their LPC coefficients. Linguistic analysis was used to reduce the algorithmic complexity instead of signal processing techniques. Sufficient degree of customization and generalization catering to the needs of the child user had been included through the provision for vocabulary and voice selection to suit the requisites of the child. Prosody had also been incorporated. This inexpensive TTS system was implemented in MATLAB, with the synthesis presented by means of a graphical user interface (GUI), thus making it child friendly. This can be used not only as an interesting language learning aid for the normal child but it also serves as a speech aid to the vocally disabled child. The quality of the synthesized speech was evaluated using the mean opinion score (MOS).
Three-Dimensional Residue-Free Volume Removal inside Sapphire by High-Temperature Etching after Irradiation of Femtosecond Laser Pulses
Authors: Matsuo Shigeki , Tokumi Kensuke , Tomita Takuro , Hashimoto Shuichi
Published: September 2008

We applied the femtosecond laser-assisted etching technique, that is, irradiation of focused femtosecond
laser pulses followed by selective chemical etching, to volume removal inside sapphire.
At room temperature, volume etching only slightly advanced while residue remained inside the
volume. By increasing the etching temperature, complete volume etching without residue was
achieved. Complete etching was, however, accompanied by undesirable phenomena of surface pits
or cracks, which are expected to be excluded through further improvement of processing.
Long-Term Outcomes of Coronary-Artery Bypass Graft Surgery Versus Percutaneous Coronary Intervention for Multivessel Coronary Artery Disease in the Bare-Metal Stent Era
Authors: Kimura Takeshi , Morimoto Takeshi , Furukawa Yutaka , Nakagawa Yoshihisa , Shizuta Satoshi , Ehara Natsuhiko , Taniguchi Ryoji , Doi Takahiro , Nishiyama Kei , Ozasa Neiko , Saito Naritatsu , Hoshino Kozo , Mitsuoka Hirokazu , Abe Mitsuru , Toma Masanao , Tamura Toshihiro , Haruna Yoshisumi , Imai Yukiko , Teramukai Satoshi , Fukushima Masanori , Kita Toru
Published: September 2008

Background—

Observational registries comparing coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have reported long-term survival results that are discordant with those of randomized trials.

Methods and Results—

We conducted a multicenter study in Japan enrolling consecutive patients undergoing first CABG or PCI between January 2000 and December 2002. Among 9877 patients enrolled, 5420 (PCI: 3712, CABG: 1708) had multivessel disease without left main involvement. Because age is an important determinant when choosing revascularization strategies, survival analysis was stratified by either age ≥75 or <75 years. Analyses were also performed in other relevant subgroups. Median follow-up interval was 1284 days with 95% follow-up rate at 2 years. At 3 years, unadjusted survival rates were 91.7% and 89.6% in the CABG and PCI groups, respectively (log rank
P
=0.26). After adjustment for baseline characteristics, survival outcome tended to be better after CABG (hazard ratio for death after PCI versus CABG [HR], 95% confidence interval [CI]: 1.23 [0.99-1.53],
P
=0.06). Adjusted survival outcomes also tended to be better for CABG among elderly patients (HR [95%CI]: 1.37 [0.98-1.92]
P
=0.07), but not among nonelderly patients (HR [95% CI]: 1.09 [0.82-1.46],
P
=0.55). Unadjusted and adjusted survival outcome for CABG and PCI were not significantly different in any subgroups when elderly patients were excluded from analysis.

Conclusions—

In the CREDO-Kyoto registry, survival outcomes among patients <75 years of age were similar after PCI and CABG, a result that is consistent with those of randomized trials.
Local Delivery of Imatinib Mesylate (STI571)-Incorporated Nanoparticle Ex Vivo Suppresses Vein Graft Neointima Formation
Authors: Kimura Satoshi , Egashira Kensuke , Nakano Kaku , Iwata Eiko , Miyagawa Miho , Tsujimoto Hiroyuki , Hara Kaori , Kawashima Yoshiaki , Tominaga Ryuji , Sunagawa Kenji
Published: September 2008

Background—

Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure attributable to neointima formation. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of vein graft failure. Therefore, we hypothesized that nanoparticle (NP)-mediated drug delivery system of PDGF-receptor (PDGF-R) tyrosine kinase inhibitor (imatinib mesylate: STI571) could be an innovative therapeutic strategy.

Methods and Results—

Uptake of STI571-NP normalized PDGF-induced cell proliferation and migration. Excised rabbit jugular vein was treated ex vivo with PBS, STI571 only, FITC-NP, or STI571-NP, then interposed back into the carotid artery position. NP was detected in many cells in the neointima and media at 7 and 28 days after grafting. Significant neointima was formed 28 days after grafting in the PBS group; this neointima formation was suppressed in the STI571-NP group. STI571-NP treatment inhibited cell proliferation and phosphorylation of the PDGF-R-β but did not affect inflammation and endothelial regeneration.

Conclusions—

STI571-NP-induced suppression of vein graft neointima formation holds promise as a strategy for preventing vein graft failure.
Factors Associated With Prolonged Recovery After the Fontan Operation
Authors: Salvin Joshua W. , Scheurer Mark A. , Laussen Peter C. , Mayer John E. , del Nido Pedro J. , Pigula Frank A. , Bacha Emile A. , Thiagarajan Ravi R.
Published: September 2008

Background—

Mortality and major morbidity after the Fontan operation is low in the current era. However, factors contributing to prolonged postoperative recovery are not clearly understood.

Methods and Results—

Data on all patients admitted to the cardiac intensive care unit (CICU) after a Fontan operation between June 2001 and December 2005 were retrospectively analyzed. We excluded all patients who died, required Fontan takedown, or required ECMO. The study cohort was further divided into a prolonged recovery group that included patients with >75%ile for duration of mechanical ventilation or pleural drainage, and a standard recovery group which included all other patients. A multivariable logistic regression model was used to compare demographic, anatomic, and physiological variables between the prolonged and standard recovery groups. There were 226 Fontan operations performed. Of the study population (n=218), the median age was 2.61 years (1.0 to 31.9 years) and weight was 12.45 kg (8.4 to 77.5 kg). The most common diagnosis was hypoplastic left heart syndrome (n=80, 36.7%). A systemic right atrioventricular valve was present in 139 (63.7%). The lateral tunnel fenestrated Fontan was the most common surgery (n=195, 89.4%). Within the study population, 81 (38%) patients meet criteria for prolonged recovery. Univariate risk factors for prolonged recovery included higher preoperative PVR (
P
=0.033), longer bypass times (
P
=0.009), higher postbypass lactate level (
P
=0.017), higher postoperative central venous (
P
<0.001) common atrial pressure (
P
=0.042), inotropic score (
P
<0.001), and need for greater volume resuscitation during the 24 postoperative hours (>75% for the entire group;
P
<0.001). In a multivariable model, need for greater volume resuscitation (OR 2.81, 95% CI 1.30, 6.05) was the only independent risk factor for prolonged outcome after the Fontan operation.

Conclusions—

High volume expansion in the early postoperative period is an independent risk factor for prolonged recovery. The need for high volume expansion may represent the compound effects of multiple risk factors including preoperative hemodynamics and a marked systemic inflammatory response to surgery and cardiopulmonary bypass, which in turn may mediate prolonged recovery.
Tight Heart Rate Control Reduces Secondary Adverse Events in Patients With Type B Acute Aortic Dissection
Authors: Kodama Kazuhisa , Nishigami Kazuhiro , Sakamoto Tomohiro , Sawamura Tadashi , Hirayama Touitsu , Misumi Hiroyasu , Nakao Koichi
Published: September 2008

Background—

Although type B aortic dissection has been treated with β blockers to lower the arterial blood pressure (BP), there has been little evidences about reduction in heart rate (HR). We assessed whether tight HR control improved the outcome of medical treatment in patients with aortic dissection.

Methods and Results—

From 1997 to 2005, 171 patients with acute aortic dissection medically treated and controlled to lower BP under 120 mm Hg were enrolled. Based on the average HR at 3, 5, and 7 days after the onset, patients were divided into tight HR (<60 beat per minute) control group (32 patients; mean HR of 56.6±3.1 beat per minute) and conventional HR (≥60 beat per minute) control group (139 patients; mean HR of 71.7±8.2 beat per minute). We compared the frequency of aortic events including late organ or limb ischemia, aortic rupture, recurrent dissection, and aortic expansion of >5 mm, and surgical requirement between two groups. During a median follow-up of 27.0 months, late organ or limb ischemia, aortic rupture, recurrent dissection, pathological aortic expansion, and aortic surgery occurred in 0, 8, 14, 39, and 26 patients, respectively. Reduction in aortic events was observed in tight HR control group (12.5%) compared to conventional HR control group (36.0%), (Odds ratio: 0.25, C.I.: 0.08 to 0.77,
P
<0.01).

Conclusions—

The present study demonstrated that tight heart rate control improved the outcome of medical treatment in patients with aortic dissection.
Calcium-Activated Potassium Channels Contribute to Human Coronary Microvascular Dysfunction After Cardioplegic Arrest
Authors: Feng Jun , Liu Yuhong , Clements Richard T. , Sodha Neel R. , Khabbaz Kamal R. , Senthilnathan Venkatachalam , Nishimura Katherine K. , Alper Seth L. , Sellke Frank W.
Published: September 2008

Background—

Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (K
Ca
) channels in this dysfunction in the human coronary microvasculature.

Methods and Results—

Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 μm in diameter) in a pressurized no-flow state were examined in the presence of K
Ca
channel activators/blockers and several other vasodilators. We also examined expression and localization of K
Ca
channel gene products in the coronary microvasculature using reverse transcriptase-polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance K
Ca
channels (IK
Ca
/SK
Ca
), NS309 (10
−5
M), and to the endothelium-dependent vasodilators, substance P (10
−8
M) and adenosine 5diphosphate (10
−5
M), were significantly reduced compared with pre-CP responses (
P
<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance K
Ca
channels (BK
Ca
), NS1619 (10
−5
M), and to the endothelium-independent vasodilator, sodium nitroprusside (10
−4
M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5 diphosphate-induced relaxation (
P
<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BK
Ca
, IK
Ca
, and SK
Ca
and the expression of IK
Ca
mRNA were not altered post-CP reperfusion.

Conclusion—

Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SK
Ca
and IK
Ca
channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.
The Effects of Mitral Regurgitation Alone Are Sufficient for Leaflet Remodeling
Authors: Stephens Elizabeth H. , Nguyen Tom C. , Itoh Akinobu , Ingels Neil B. , Miller D. Craig , Grande-Allen K. Jane
Published: September 2008

Background——

Although chronic mitral regurgitation results in adverse left ventricular remodeling, its effect on the mitral valve leaflets per se is unknown. In a chronic ovine model, we tested whether isolated mitral regurgitation alone was sufficient to remodel the anterior mitral leaflet.

Methods and Results—

Twenty-nine sheep were randomized to either control (CTRL, n=11) or experimental (HOLE, n=18) groups. In HOLE, a 2.8- to 4.8-mm diameter hole was punched in the middle scallop of the posterior mitral leaflet to create “pure” mitral regurgitation. At 12 weeks, the anterior mitral leaflet was analyzed immunohistochemically to assess markers of collagen and elastin synthesis as well as matrix metalloproteinases and proteoglycans. A semiquantitative grading scale for characteristics such as intensity and delineation of stain between layers was used to quantify differences between HOLE and CTRL specimens across the heterogeneous leaflet structure. At 12 weeks, mitral regurgitation grade was greater in HOLE versus CTRL (3.0±0.8 versus 0.4±0.4,
P
<0.001). In HOLE anterior mitral leaflet, saffron-staining collagen (Movat) decreased, consistent with an increase in matrix metalloproteases throughout the leaflet. Type III collagen expression was increased in the midleaflet and free edge and expression of prolyl-4-hydroxylase (indicating collagen synthesis) was increased in the spongiosa layer. The proteoglycan decorin, also involved in collagen fibrillogenesis, was increased compared with CTRL (all
P
≤0.05).

Conclusions—

In HOLE anterior mitral leaflet, the increased expression of proteins related to collagen synthesis and matrix degradation suggests active matrix turnover. These are the first observations showing that regurgitation alone can stimulate mitral leaflet remodeling. Such leaflet remodeling needs to be considered in reparative surgical techniques.
Skeletal Myoblasts Preserve Remote Matrix Architecture and Global Function When Implanted Early or Late After Coronary Ligation Into Infarcted or Remote Myocardium
Authors: Farahmand Patrick , Lai Teresa Y.Y. , Weisel Richard D. , Fazel Shafie , Yau Terrence , Menasche Philippe , Li Ren-Ke
Published: September 2008

Background—

The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes suggests that their beneficial effects on cardiac function after a myocardial infarction are mediated by paracrine effects. We evaluated the roles of these factors in the preservation of matrix architecture (in the infarct and remote regions) by varying the timing (postmyocardial infarction) and delivery site of the implanted cells.

Methods and Results—

Skeletal myoblasts (5×10
6
) or control media were injected into the infarct or noninfarcted myocardium at 5 or 30 days after coronary artery ligation in rats. Function was assessed by echocardiography before transplantation and 14 and 30 days thereafter and with a Millar catheter at 30 days after transplantation. Ventricular geometry, remote fibrillar collagen architecture, and changes in the matrix metalloproteinase-TIMP system were evaluated. Myoblast implantation in both sites and at both times preserved matrix architecture (length and width of collagen fibers) in the remote myocardium (in association with some decreases in remote myocardial matrix metalloprotease activity), improved global cardiac function, and attenuated the progressive increase in end diastolic volume (
P
<0.05 for all measures compared with medium controls). Cells delivered into the infarct region preserved scar thickness; cells delivered into the noninfarcted myocardium preserved wall thickness.

Conclusions—

Regardless of whether the cells were injected into the infarct or the noninfarcted myocardium early after an myocardial infarction or later, skeletal myoblasts improved cardiac function by preventing ventricular dilation and preserving matrix architecture in the remote region, likely mediated by paracrine effects.
Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age
Authors: Mahmoodi Bakhtawar K. , Brouwer Jan-Leendert P. , Veeger Nic J.G.M. , van der Meer Jan
Published: September 2008

Background—

Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined.

Methods and Results—

On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2;
P
=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S–, protein C–, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2).

Conclusions—

Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.
Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E2Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress
Authors: Jia Zhanjun , Guo Xiaohua , Zhang Hui , Wang Mong-Heng , Dong Zheng , Yang Tianxin
Published: September 2008

Prostaglandin (PG) E2has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1+/+mice but induced a marked hypertensive response in mPGES-1−/−mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47phox, gp91phox, and Nox1. The hypertension in mPGES-1−/−mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure–lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47phox, gp91phox, and Nox1 that were all inhibited by PGE2. The −/− mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1–derived PGE2buffers Ang II–induced vasoconstriction via inhibition of NADPH oxidase–dependent reactive oxygen species production.
Assessing the Dangers of Illicit Networks: Why al-Qaida May Be Less Threatening Than Many Think
Authors: Eilstrup-Sangiovanni Mette , Jones Calvert
Published: September 2008

Theoretical work on networked organization informs a large swathe of the current literature on international organized crime and terrorism in the field of international relations. Clandestine networks are portrayed as large, fluid, mobile, highly adaptable, and resilient. Many analysts have concluded that this makes them difficult for more stable, hierarchical states to combat. The prevailing mood of pessimism about the ability of states to combat illicit networks, however, may be premature. International relations scholars working in the area have often been too quick to draw parallels to the world of the firm, where networked organization has proven well adapted to the fast-moving global marketplace. They have consequently overlooked not only issues of community and trust but also problems of distance, coordination, and security, which may pose serious organizational difficulties for networks in general and for illicit networks in particular. Closer attention to a wider body of historical and contemporary research on dynamics of participation in underground movements, the life cycle of terrorism and insurgency, and vulnerabilities in organized crime reveals that clandestine networks are often not as adaptable or resilient as they are made out to be. An analysis of the al-Qaida network suggests that as al-Qaida adopts a more networked organization, it becomes exposed to a gamut of organizational dilemmas that threatens to reduce its unity, cohesion, and ability to act collectively.
Climate Impacts of Making Evapotranspiration in the Community Land Model (CLM3) Consistent with the Simple Biosphere Model (SiB)
Authors: Lawrence Peter J. , Chase Thomas N.
Published: September 2008

In recent climate sensitivity experiments with the Community Climate System Model, version 3 (CCSM3), a wide range of studies have found that the Community Land Model, version 3 (CLM3), simulates mean global evapotranspiration with low contributions from transpiration (15%), and high contributions from soil and canopy evaporation (47% and 38%, respectively). This evapotranspiration partitioning is inconsistent with the consensus of other land surface models used in GCMs. To understand the high soil and canopy evaporation and the low transpiration observed in the CLM3, select individual components of the land surface parameterizations that control transpiration, canopy and soil evaporation, and soil hydrology are compared against the equivalent parameterizations used in the Simple Biosphere Model, versions 2 and 3 (SiB2 and SiB3), and against more recent developments with CLM. The findings of these investigations are used to develop new parameterizations for CLM3 that would reproduce the functional dynamics of land surface processes found in SiB and other alternative land surface parameterizations. Global climate sensitivity experiments are performed with the new land surface parameterizations to assess how the new SiB, consistent CLM land surface parameterizations, influence the surface energy balance, hydrology, and atmospheric fluxes in CLM3, and through that the larger-scale climate modeled in CCSM3. It is found that the new parameterizations enable CLM to simulate evapotranspiration partitioning consistently with the multimodel average of other land surface models used in GCMs, as evaluated by Dirmeyer et al. (2005). The changes in surface fluxes also resulted in a number of improvements in the simulation of precipitation and near-surface air temperature in CCSM3. The new model is fully coupled in the CCSM3 framework, allowing a wide range of climate modeling investigations without the surface hydrology issues found in the current CLM3 model. This provides a substantially more robust framework for performing climate modeling experiments investigating the influence of land cover change and surface hydrology in CLM and CCSM than the existing CLM3 parameterizations. The study also shows that changes in land surface hydrology have global scale impacts on model climatology.
Interaction of Typhoon Shanshan (2006) with the Midlatitude Trough from both Adjoint-Derived Sensitivity Steering Vector and Potential Vorticity Perspectives
Authors: Wu Chun-Chieh , Chen Shin-Gan , Chen Jan-Huey , Chou Kun-Hsuan , Lin Po-Hsiung
Published: September 2008

Targeted observation is one of the most important research and forecasting issues for improving tropical cyclone predictability. A new parameter [i.e., the adjoint-derived sensitivity steering vector (ADSSV)] has been proposed and adopted as one of the targeted observing strategies in the Dropwindsonde Observations for Typhoon Surveillance near the Taiwan Region (DOTSTAR). The ADSSV identifies the sensitive areas at the observing time to the steering flow at the verifying time through the adjoint calculation. In this study, the ADSSV is calculated from the nonlinear forecast model of the fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5) and its adjoint to interpret the dynamical processes in the interaction between Typhoon Shanshan (2006) and the midlatitude trough. The ADSSV results imply that high-sensitivity regions affecting the motion of Typhoon Shanshan are located at the edge of the subtropical high and the 500-hPa midlatitude trough over northern central China. These ADSSV signals are in very good agreement with the quantitative evaluation based on the potential vorticity (PV) diagnosis. The vertical structure of the ADSSV is also shown for more physical insights into the typhoon–trough interaction. The maximum ADSSV occurs at 800–500 hPa to the southeast of Shanshan (associated with the subtropical high), while distinct ADSSV signals are located upstream of the storm center at about 500–300 hPa (associated with the mid- to upper-tropospheric midlatitude trough). Overall, it is demonstrated that the ADSSV features can well capture the signal of the large-scale trough feature affecting the motion of Shanshan, which can also be well validated from the PV analysis.
Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis
Authors: Barnard Adele L. , Chidgey Ann P. , Bernard Claude C. , Boyd Richard L.
Published: September 2008

Bone marrow transplantation (BMT) potentially represents a novel therapy for the amelioration and even cure for multiple sclerosis (MS). It has important advantages over immunosuppressive drug treatments because, while effecting broad-based ablation of the immune system and autoreactive cells, it provides an important means for overcoming the resultant immunodeficiency, while possibly restoring self-tolerance. However, both of these benefits are predicated on a functional thymus that undergoes profound age-induced atrophy from puberty. Reversal of thymic atrophy has been achieved by several procedures, including removal of sex steroids by surgical or chemical (LHRH agonist) castration. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we combined BMT with androgen depletion to induce immune regeneration, and investigated the kinetics of increased thymic function on immune reconstitution and disease reduction. We show that androgen depletion significantly increased the efficacy of BMT to ameliorate the clinical signs of EAE while concurrently restoring the periphery with increased naive and regulatory lymphocytic populations. Upon rechallenge, mice with a regenerated thymus had a slower onset of clinical symptoms compared with mice undergoing BMT only. These results suggest that thymic regeneration strategies may be used as a complement to conventional BMT protocols for the treatment of MS.
Cross-species comparison of biological themes and underlying genes on a global gene expression scale in a mouse model of colorectal liver metastasis and in clinical specimens
Authors: Bandapalli Obul Reddy , Kahlert Christoph , Hellstern Victoria , Galindo Luis , Schirmacher Peter , Weitz Jürgen , Brand Karsten
Published: September 2008

Background

Invasion-related genes over-expressed by tumor cells as well as by reacting host cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models.

Results

This study examined the suitability of a murine model (CT26/Balb/C) of colorectal liver metastasis to represent clinical liver metastasis specimens using a global gene expression approach. Cross-species similarity was examined between pure liver, liver invasion, tumor invasion and pure tumor compartments through overlap of up-regulated genes and gene ontology (GO)-based biological themes on the level of single GO-terms and of condensed GO-term families. Three out of four GO-term families were conserved in a compartment-specific way between the species: secondary metabolism (liver), invasion (invasion front), and immune response (invasion front and liver). Among the individual GO-terms over-represented in the invasion compartments in both species were "extracellular matrix", "cell motility", "cell adhesion" and "antigen presentation" indicating that typical invasion related processes are operating in both species. This was reflected on the single gene level as well, as cross-species overlap of potential target genes over-expressed in the combined invasion front compartments reached up to 36.5%.

Generally, histopathology and gene expression correlated well as the highest single gene overlap was found to be 44% in syn-compartmental comparisons (liver versus liver) whereas cross-compartmental overlaps were much lower (e.g. liver versus tumor: 9.7%). However, single gene overlap was surprisingly high in some cross-compartmental comparisons (e.g. human liver invasion compartment and murine tumor invasion compartment: 9.0%) despite little histolopathologic similarity indicating that invasion relevant genes are not necessarily confined to histologically defined compartments.

Conclusion

In summary, cross-species comparison on a global gene expression scale suggests the validity of an animal model representing the human situation. The actual yield of potential target genes depends on several variables including the animal model, choice of inclusion criteria, inherent species differences and histologic assessment.
The stress responsive and morphologically regulated hsp90 gene from Paracoccidioides brasiliensis is essential to cell viability
Authors: Nicola André M , Andrade Rosângela V , Dantas Alessandra S , Andrade Patrícia A , Arraes Fabrício BM , Fernandes Larissa , Silva-Pereira Ildinete , Felipe Maria Sueli S
Published: September 2008

Background

Paracoccidioides brasiliensis is a dimorphic fungus that causes the most prevalent systemic mycosis in Latin America. The response to heat shock is involved in pathogenesis, as this pathogen switches from mycelium to yeast forms in a temperature dependent fashion that is essential to establish infection. HSP90 is a molecular chaperone that helps in the folding and stabilization of selected polypeptides. HSP90 family members have been shown to present important roles in fungi, especially in the pathogenic species, as an immunodominant antigen and also as a potential antifungal therapeutic target.

Results

In this work, we decided to further study the Pbhsp90 gene, its expression and role in cell viability because it plays important roles in fungal physiology and pathogenesis. Thus, we have sequenced a Pbhsp90 cDNA and shown that this gene is present on the genome as a single copy. We have also confirmed its preferential expression in the yeast phase and its overexpression during dimorphic transition and oxidative stress. Treatment of the yeast with the specific HSP90 inhibitors geldanamycin and radicicol inhibited growth at 2 and 10 μM, respectively.

Conclusion

The data confirm that the Pbhsp90 gene encodes a morphologically regulated and stress-responsive protein whose function is essential to cell viability of this pathogen. This work also enforces the potential of HSP90 as a target for antifungal therapies, since the use of HSP90 inhibitors is lethal to the P. brasiliensis yeast cells in a dose-responsive manner.
Decrease in excitatory neurons, astrocytes and proliferating progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene
Authors: Chen Kesi , Ohkubo Yasushi , Shin Dana , Doetschman Thomas , Sanford L Philip , Li Hongqi , Vaccarino Flora M
Published: September 2008

Background

The Fgf2 gene is expressed in the brain neuroepithelium during embryonic development and in astroglial cells throughout life. Previous knockout studies suggested that FGF2 plays a role in the proliferation of neural progenitors in the embryonic cerebral cortex. These studies exclusively used knockout alleles lacking the Fgf2 exon 1. However, the description of putative alternative exons located downstream from the canonical exon 1 raised the possibility that alternatively spliced transcripts may compensate for the lack of the canonical exon 1 in the Fgf2 -/- mice.

Results

We generated and characterized a new line of Fgf2 knockout mice lacking the expression of exon 3, which is conserved in all Fgf2 transcripts and contains essential heparin and receptor binding interfaces. The expression of Fgf2 exon 3 was prevented by inserting a transcriptional STOP cassette in the Fgf2 genomic locus. These mice demonstrate a phenotype in the adult neocortex characterized by decreased density and number of cortical excitatory neurons and astrocytes, which is virtually identical to that of the Fgf2 -/- mice lacking exon 1. In addition, we also show that the Fgf2 exon 3 knockout mice have decreased proliferation of precursors in the adult cerebral cortex, which had not been previously investigated in the other mutant lines.

Conclusion

The results demonstrate that the phenotype of two completely different Fgf2 KO mouse lines, lacking exon 1 or exon 3, is remarkably similar. The combined results from these KO models clearly indicate that FGF2 plays a role in cortical cell genesis during embryonic development as well as in adulthood. Thus, FGF2 may be required for the maintenance of the pool of adult cortical progenitor cells.
NPHS2variation in focal and segmental glomerulosclerosis
Authors: Tonna Stephen J , Needham Alexander , Polu Krishna , Uscinski Andrea , Appel Gerald B , Falk Ronald J , Katz Avi , Al-Waheeb Salah , Kaplan Bernard S , Jerums George , Savige Judy , Harmon Jennifer , Zhang Kang , Curhan Gary C , Pollak Martin R
Published: September 2008

Background

Focal and segmental glomerulosclerosis (FSGS) is the most common histologic pattern of renal injury seen in adults with idiopathic proteinuria. Homozygous or compound heterozygous mutations in the podocin gene NPHS2 are found in 10–30% of pediatric cases of steroid resistant nephrosis and/or FSGS.

Methods

We studied the spectrum of genetic variation in 371 individuals with predominantly late onset FSGS (mean age of onset 25 years) by analysis of DNA samples.

Results

We identified 15 non-synonymous alleles that changed the amino acid sequence in 63 of the subjects screened (17%). Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855–856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously. Twelve individuals of the 371 (3.2%) screened had two likely disease-causing NPHS2 alleles, present in either a homozygous or compound heterozygous state. We genotyped the two most common of the non-synonymous NPHS2 alleles (p.A242V and p.R229Q) identified by resequencing in participants from the Nurses' Health Study and also genotyped p.R229Q in 3 diabetic cohorts. We found that the presence of either of these variants does not significantly alter the risk of albuminuria in the Nurses' Health participants, nor does p.R229Q associate with "diabetic nephropathy".

Conclusion

NPHS2 mutations are a rare cause of FSGS in adults. The most common non-synonymous NPHS2 variants, p.R229Q and p.A242V, do not appear to alter the risk of proteinuria in the general population nor does p.R229Q associate with measures of kidney dysfunction in diabetic individuals. Our results help clarify the frequency of FSGS-causing NPHS2 mutations in adults and broaden our understanding of the spectrum of NPHS2 mutations that lead to human disease.
The effects of timing of fine needle aspiration biopsies on gene expression profiles in breast cancers
Authors: Wong Vietty , Wang Dong-Yu , Warren Keisha , Kulkarni Supriya , Boerner Scott , Done Susan Jane , Leong Wey Liang
Published: September 2008

Background

DNA microarray analysis has great potential to become an important clinical tool to individualize prognostication and treatment for breast cancer patients. However, with any emerging technology, there are many variables one must consider before bringing the technology to the bedside. There are already concerted efforts to standardize protocols and to improve reproducibility of DNA microarray. Our study examines one variable that is often overlooked, the timing of tissue acquisition, which may have a significant impact on the outcomes of DNA microarray analyses especially in studies that compare microarray data based on biospecimens taken in vivo and ex vivo.

Methods

From 16 patients, we obtained paired fine needle aspiration biopsies (FNABs) of breast cancers taken before (PRE) and after (POST) their surgeries and compared the microarray data to determine the genes that were differentially expressed between the FNABs taken at the two time points. qRT-PCR was used to validate our findings. To examine effects of longer exposure to hypoxia on gene expression, we also compared the gene expression profiles of 10 breast cancers from clinical tissue bank.

Results

Using hierarchical clustering analysis, 12 genes were found to be differentially expressed between the FNABs taken before and after surgical removal. Remarkably, most of the genes were linked to FOS in an early hypoxia pathway. The gene expression of FOS also increased with longer exposure to hypoxia.

Conclusion

Our study demonstrated that the timing of fine needle aspiration biopsies can be a confounding factor in microarray data analyses in breast cancer. We have shown that FOS-related genes, which have been implicated in early hypoxia as well as the development of breast cancers, were differentially expressed before and after surgery. Therefore, it is important that future studies take timing of tissue acquisition into account.
The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile
Authors: Brambilla Daria , Mancuso Cesare , Scuderi Mariagrazia Rita , Bosco Paolo , Cantarella Giuseppina , Lempereur Laurence , Di Benedetto Giulia , Pezzino Salvatore , Bernardini Renato
Published: September 2008

This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
Patient satisfaction with primary care: an observational study comparing anthroposophic and conventional care
Authors: Esch Barbara M , Marian Florica , Busato André , Heusser Peter
Published: September 2008

Background

This study is part of a cross-sectional evaluation of complementary medicine providers in primary care in Switzerland. It compares patient satisfaction with anthroposophic medicine (AM) and conventional medicine (CON).

Methods

We collected baseline data on structural characteristics of the physicians and their practices and health status and demographics of the patients. Four weeks later patients assessed their satisfaction with the received treatment (five items, four point rating scale) and evaluated the praxis care (validated 23-item questionnaire, five point rating scale). 1946 adult patients of 71 CON and 32 AM primary care physicians participated.

Results

1. Baseline characteristics: AM patients were more likely female (75.6% vs. 59.0%, p < 0.001) and had higher education (38.6% vs. 24.7%, p < 0.001). They suffered more often from chronic illnesses (52.8% vs. 46.2%, p = 0.015) and cancer (7.4% vs. 1.1%). AM consultations lasted on average 23,3 minutes (CON: 16,8 minutes, p < 0.001).

2. Satisfaction: More AM patients expressed a general treatment satisfaction (56.1% vs. 43.4%, p < 0.001) and saw their expectations completely fulfilled at follow-up (38.7% vs. 32.6%, p < 0.001). AM patients reported significantly fewer adverse side effects (9.3% vs. 15.4%, p = 0.003), and more other positive effects from treatment (31.7% vs. 17.1%, p < 0.001).

Europep: AM patients appreciated that their physicians listened to them (80.0% vs. 67.1%, p < 0.001), spent more time (76.5% vs. 61.7%, p < 0.001), had more interest in their personal situation (74.6% vs. 60.3%, p < 0.001), involved them more in decisions about their medical care (67.8% vs. 58.4%, p = 0.022), and made it easy to tell the physician about their problems (71.6% vs. 62.9%, p = 0.023). AM patients gave significantly better rating as to information and support (in 3 of 4 items p [less than or equal to] 0.044) and for thoroughness (70.4% vs. 56.5%, p < 0.001).

Conclusion

AM patients were significantly more satisfied and rated their physicians as valuable partners in the treatment. This suggests that subject to certain limitations, AM therapy may be beneficial in primary care. To confirm this, more detailed qualitative studies would be necessary.
Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines
Authors: Eustace Alex J , Crown John , Clynes Martin , O'Donovan Norma
Published: September 2008

Background

Metastatic melanoma is a highly chemotherapy resistant tumour. The use of newer targeted therapies alone and in combination with chemotherapy may offer new hope of improving response to treatment. Dasatinib, a multi-target kinase inhibitor, is currently approved for the treatment of chronic myeloid leukaemia and has shown promising results in preclinical studies in a number of solid tumours.

Methods

We examined the effects of dasatinib on proliferation, chemo-sensitivity, cell cycle arrest, apoptosis, migration and invasion in human melanoma cell lines. Expression and activation of Src kinase, FAK and EphA2 were also examined in the melanoma cells.

Results

Dasatinib inhibited growth of three of the five melanoma cell lines. Comparison with sorafenib showed that in these three cell lines dasatinib inhibited growth at lower concentrations than sorafenib. Dasatinib in combination with the chemotherapy drug temozolomide showed greater efficacy than either drug alone. Dasatinib induced cell cycle arrest and apoptosis and significantly inhibited cell migration and invasion of melanoma cells. Dasatinib inhibition of proliferation was associated with reduced phosphorylation of Src kinase, while decreased phosphorylation of FAK was implicated in dasatinib-mediated inhibition of migration and invasion in melanoma cells.

Conclusion

Dasatinib has both anti-proliferative and anti-invasive effects in melanoma cells and combined with chemotherapy may have clinical benefit in the treatment of malignant melanoma.
Takayasu arteritis in children
Authors: Al abrawi Safia , Fouillet-Desjonqueres Marine , David Louis , Barral Xavier , Cochat Pierre , Cimaz Rolando
Published: September 2008

Takayasu arteritis (TA) is a large vessel vasculitis that usually affects young female patients during the second and third decades of life, but has been reported in children as young as 24 months of age. Aim of this report was to describe four children (two girls) with TA, as well as summarizing main published studies. The mean age at presentation of our cases was 11 years (range 8–15). Three patients were Caucasians and one Asian. Arterial hypertension was the commonest mode of presentation followed by systemic symptoms. Other related symptoms were due to ischemia and consisted of abdomen, chest, and limb pain. An abdominal bruit was noted in only one patient. Inflammation markers were always abnormal. Angiography was performed in all cases; left subclavian artery and common carotid artery were more frequently involved. Renal artery stenosis was observed in two patients. One boy was diagnosed as having an associated immune deficiency (Wiskott-Aldrich syndrome). Treatment modalities included prednisone (n = 4), methotrexate (n = 3), and mycophenolate mofetil (MMF) (n = 1). Surgery was required in two patients. Follow-up ranged from 3 to 10 years since diagnosis. In three cases antihypertensive drugs and methotrexate were stopped, and prednisone was reduced to 7.5 mg/day.