bluuebunny/crossref_metadata_2025 huggingface dataset:
A Simplified Synthesis of Novel Dictyostatin Analogues with In Vitro Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos
Authors: Vollmer Laura L. , Jiménez Maria , Camarco Daniel P. , Zhu Wei , Daghestani Hikmat N. , Balachandran Raghavan , Reese Celeste E. , Lazo John S. , Hukriede Neil A. , Curran Dennis P. , Day Billy W. , Vogt Andreas
Published: April 2011

The natural product (−)-dictyostatin is a microtubule-stabilizing agent that potently inhibits the growth of human cancer cells, including paclitaxel-resistant clones. Extensive structure–activity relationship studies have revealed several regions of the molecule that can be altered without loss of activity. The most potent synthetic dictyostatin analogue described to date, 6-epi-dictyostatin, has superior in vivo antitumor activity against human breast cancer xenografts compared with paclitaxel. In spite of their encouraging activities in preclinical studies, the complex chemical structure of the dictyostatins presents a major obstacle for their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26-dihydrodictyostatins and found several agents that, when compared with 6-epi-dictyostatin, retained nanomolar activity in cellular microtubule-bundling assays but had lost activity against paclitaxel-resistant cells with mutations in β-tubulin. Extending these studies, we applied the new, highly convergent synthesis to generate 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin. Both compounds were potent microtubule-perturbing agents that induced mitotic arrest and microtubule assembly in vitro and in intact cells. In vitro radioligand binding studies showed that 25,26-dihydrodictyostatin and its C6-epimer were capable of displacing [3H]paclitaxel and [14C]epothilone B from microtubules with potencies comparable to (−)-dictyostatin and discodermolide. Both compounds inhibited the growth of paclitaxel- and epothilone B–resistant cell lines at low nanomolar concentrations, synergized with paclitaxel in MDA-MB-231 human breast cancer cells, and had antiangiogenic activity in transgenic zebrafish larvae. These data identify 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin as candidates for scale-up synthesis and further preclinical development. Mol Cancer Ther; 10(6); 994–1006. ©2011 AACR.
A New Target for Therapy in Squamous Cell Carcinoma of the Lung
Authors: Ohashi Kadoaki , Pao William
Published: April 2011

Investigators report the identification of novel somatic mutations in the DDR2 kinase gene in squamous cell carcinoma of the lung. Cellular, biochemical, and human data suggest that tumor cells harboring DDR2 mutations have increased sensitivity to existing tyrosine kinase inhibitors, providing rationale for clinical trials of agents that inhibit DDR2 kinase in the disease. Cancer Discovery; 1(1); 23–4. ©2011 AACR.
Optimal Approach for Small Bowel Capsule Endoscopy Using Polyethylene Glycol and Metoclopramide with the Assistance of a Real-Time Viewer
Authors: Hosono Kunihiro , Endo Hiroki , Sakai Eiji , Sekino Yusuke , Uchiyama Takashi , Watanabe Seitaro , Iida Hiroshi , Sakamoto Yasunari , Koide Tomoko , Takahashi Hirokazu , Yoneda Masato , Tokoro Chikako , Abe Yasunobu , Inamori Masahiko , Kobayashi Noritoshi , Kubota Kensuke , Nakajima Atsushi
Published: April 2011

Aim: Capsule endoscopy is limited by the poor image quality of the distal bowel and incomplete small bowel transit. The aim of this study was to establish an optimal medication protocol for capsule endoscopy performed using a real-time viewer. Methods: A total of 80 patients were prospectively recruited. The patients were randomized into two groups: the ‘conventional group’ (without any preparation) and the ‘real-time group’ (in which a real-time viewer was attached). At 60 min after swallowing the capsule, if the capsule hadreached the small bowel, 500 ml of polyethylene glycol was administered; if the capsule was still located in the stomach, 10 mg of metoclopramide was given intramuscularly, followed by 500 ml of polyethylene glycol solution. Results: The completion rate was significantly higher in the real-time group as compared with that in the conventional group (72.5 vs. 90.0%). Our protocol yielded a significantly improved image quality of the distal small bowel [image quality score = 1.6 vs. 3.0 (max 4.0)]. The detection rate of lesions in the distal small bowel was higher in the real-time group than in the conventional group. Conclusions: The present study clearly showed that our protocol yielded an improved completion rate and also improved image quality.
Bilateral Subthalamic Nucleus Stimulation in the Treatment of Neurodegeneration with Brain Iron Accumulation Type 1
Authors: Ge Ming , Zhang Kai , Ma Yu , Meng Fan-gang , Hu Wen-han , Yang An-chao , Zhang Jian-guo
Published: April 2011

Background: Neurodegeneration with brain iron accumulation type 1 (NBIA1), previously called Hallervorden-Spatz disease, is a rare neurodegenerative condition with abnormal brain iron accumulation. There have been some reports of deep brain stimulation (DBS) in the treatment of NBIA1. However, the target was usually the globus pallidus internus or thalamus. Objectives/Methods: We present a case of NBIA1 in a 16-year-old male who was treated with bilateral subthalamic nucleus (STN)-DBS and explored its efficacy in the treatment of NBIA1. The patient presented with severe generalized dystonia and marked dysarthria and had previously had unsuccessful ablation surgery. MRI confirmed the diagnosis of NBIA1. Results: He had significant improvement postoperatively, and the benefit of surgery was maintained for 3 years during follow-up. Burke-Fahn-Marsden Dystonia Rating Scale score was 114/120 preoperatively, and dropped to 60/120 at 14 days, 35/120 at 1 month, 28/120 at 3 months, 14/120 at 1 year and 18/120 at 3 years postoperatively. Conclusions: Our results suggest that bilateral STN-DBS might be considered as an effective treatment for selective NBIA1 patients.
Evaluation of Functional and Structural Alterations in Muscle Tissue after Short-Term Cold Storage in a New Tissue Preservation Solution
Authors: Wille Timo , Gonder Sascha , Thiermann Horst , Seeger Thomas , Rauen Ursula , Worek Franz
Published: April 2011

Storage of muscle preparations in vitro is required for the diagnosis of neuromuscular disorders and for electrophysiological tests. The current standard protocols for muscle storage or transport, i.e. placement on 0.9% NaCl-moistened gauze, lead to impaired function and structural alterations. For other tissues, however, improved preservation methods and solutions have recently been described. In this study, functional and structural alterations in the murine diaphragm were compared after storage on 0.9% NaCl-moistened gauze and after storage in different modifications of the new vascular preservation solution TiProtec®. Muscle force generation after nerve stimulation, histological parameters and ATP levels were investigated after 2.5 h of cold storage at 4°C in the different media and 0.5 h of rewarming at 25°C in Tyrode buffer. Murine diaphragms were injured during cold storage and rewarming, with the degree of the alteration being dependent on the type of solution used. There were no histological alterations and no caspase 3 activation in all groups. In contrast, diaphragms stored in the modified TiProtec solution showed markedly better performance concerning force generation after nerve stimulation (7.1 ± 1.1 cN · s) as well as higher ATP content (2.4 ± 0.7 µmol/g) and were superior to storage on 0.9% NaCl-moistened gauze (1.4 ± 0.4 cN · s; 0.3 ± 0.1 µmol/g). In conclusion, the modified TiProtec preservation solution showed promising results for short-term cold storage of murine diaphragms. For further evaluation, the transferability of these positive findings to storage conditions for muscles of other species, especially human muscle tissue, needs to be investigated.
High Hepatitis B Virus DNA Level in Serum before Liver Transplantation Increases the Risk of Hepatocellular Carcinoma Recurrence
Authors: Li Min-ru , Chen Gui-hua , Cai Chang-jie , Wang Guo-ying , Zhao Hui
Published: April 2011

Aim: To analyze the relationship between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) recurrence in orthotopic liver transplantation (OLT) patients. Methods: 340 HBV patients with OLT were included in the study; among them were 148 patients with HBV-associated HCC. Results: HCC recurrence rates at 1, 3 and 5 years were 21, 29, and 46%, respectively. Exceeding Milan criteria (hazard ratio, HR = 12.35; 95% confidence interval, CI, 2.80–54.49; p = 0.001), HBV DNA level >5 log10 copies/ml before transplant (HR = 2.45; 95% CI 1.10–5.45; p = 0.03) and HBV recurrence (HR = 2.27; 95% CI 1.10–4.75; p = 0.03) were significant independent predictors of HCC recurrence. HBV DNA >5 log10 copies/ml before transplant (HR = 8.65; 95% CI 3.40–21.98; p < 0.001) and concomitance with HCC (HR = 2.79; 95% CI 1.33–5.87; p = 0.007) were predictors of HBV recurrence. Further stratified analysis showed that HBV recurrence was more prevalent in the HCC recurrence group (HR = 4.58; 95% CI 1.88–11.12; p = 0.001). Conclusions: There is a close relationship between HBV and HCC recurrence after transplant. High HBV DNA levels before transplant are associated with HCC recurrence after transplant.
Prediction of the Outcome of Inpatient Opiate Detoxification Treatment: Results from a Multicenter Study
Authors: Specka Michael , Buchholz Angela , Kuhlmann Thomas , Rist Fred , Scherbaum Norbert
Published: April 2011

Background: Monocentric studies of inpatient opiate detoxification treatment show considerable variability regarding treatment success rates. This multicentric study investigates whether patient characteristics explain the different rates of regular discharge between treatment units. Methods: 1,017 opiate-dependent patients from 12 detoxification units with similar treatment programs, funding, staffing and equipment were analyzed. Patient data and outcomes were documented by treatment staff using a standard form. Results: Controlling for center, regular discharge (range: 14–49% between centers) was significantly associated with pre-existing plans for follow-up treatment, previous completed long-term residential and detoxification treatments, fewer unsuccessful detoxification treatments, higher age, later onset of opiate use, and longer duration of use. Controlling for patient characteristics, the center variable was significantly associated with outcome in a multiple logistic regression analysis. Conclusions: Regular discharge could best be predicted by patients’ plans for follow-up treatment and previous treatment outcomes. Although treatment units had equivalent resources and regulations, and although patient effects were statistically controlled for, there were still considerable center effects. Setting factors as well as actual drop-out processes should be investigated more closely in the future.
Characterization of a Three-Dimensional Mucosal Equivalent: Similarities and Differences with Native Oral Mucosa
Authors: Tra Wendy M.W. , van Neck Johan W. , Hovius Steven E.R. , van Osch Gerjo J.V.M. , Perez-Amodio Soledad
Published: April 2011

The aim of this study was to create and characterize a tissue-engineered mucosal equivalent (TEM) that closely resembles native mucosa. TEM consists of human primary keratinocytes and fibroblasts isolated from biopsies taken from healthy donors and seeded onto a de-epidermized dermis and cultured for 14 days at the air/liquid interface. The structure of TEM was examined and compared with native nonkeratinizing oral mucosa (NNOM). The various components of the newly formed epidermal layer, basement membrane and underlying connective tissue were analyzed using immunohistochemistry. The mucosal substitute presented in this study showed a mature stratified squamous epithelium that was similar to that of native oral mucosa, as demonstrated by K19, desmoglein-3 and involucrin staining. In addition, the expression of basement membrane components collagen type IV, laminin-5 and integrin α6 and β4 in TEM proved to be consistent with native oral mucosa. The expression of PAS, Ki67, K10 and K13, however, appeared to be different in TEM compared to NNOM. Nevertheless, the similarities with native oral mucosa makes TEM a promising tool for studying the biology of mucosal pathologies such as oral mucositis or fibrosis as well as the development of new therapies.
Mixture of Fibroblasts and Adipose Tissue-Derived Stem Cells Can Improve Epidermal Morphogenesis of Tissue-Engineered Skin
Authors: Lu Wei , Yu Jinhua , Zhang Yongjie , Ji Kun , Zhou Yalei , Li Yuan , Deng Zhihong , Jin Yan
Published: April 2011

Many studies demonstrate that the type of adjacent mesenchymal cells can affect epidermal morphogenesis of bilayered tissue-engineered skin. However, whether a mixture of different mesenchymal cell types can improve epidermal morphogenesis of bioengineered skin remains unknown. In this study, keratinocytes, dermal fibroblasts and adipose tissue-derived stem cells (ADSCs) were isolated and purified from human skin and subcutaneous fat. Conditioned medium generated from a mixture of dermal fibroblasts and ADSCs at the ratio of 1:1 was superior to that from fibroblasts or ADSCs alone in promoting keratinocyte proliferation, as indicated by MTT assay. Furthermore, ELISA results showed that the cytokine levels of human hepatocyte growth factor and keratinocyte growth factor (also known as FGF7) in the mixed fibroblasts/ADSC group were higher than those in the ADSC or dermal fibroblasts group. To examine the potential roles of mixed fibroblasts and ADSCs on epidermal morphogenesis, a three-dimensional tissue engineered skin system was applied. Histological analyses demonstrated that keratinocytes proliferated extensively over the mixture of fibroblasts and ADSCs, and formed a thick epidermal layer with well-differentiated structures. Keratin 10 (epidermal differentiation marker) was expressed in the suprabasal layer of bilayered tissue-engineered skin in the mixed fibroblasts and ADSCs group. Desmosomes and hemidesmosomes were detected in the newly formed epidermis by transmission electron microscopy analysis. Together, these findings revealed for the first time that a mixture of fibroblasts and ADSCs in bilayered tissue-engineered skin can improve epidermal morphogenesis.
Urine Cystatin C as a Biomarker of Proximal Tubular Function Immediately after Kidney Transplantation
Authors: Hall Isaac E. , Koyner Jay L. , Doshi Mona D. , Marcus Richard J. , Parikh Chirag R.
Published: April 2011

Background/Aims: Clinical methods to predict allograft function soon after kidney transplantation are ineffective. Methods: We analyzed urine cystatin C (CyC) in a prospective multicenter observational cohort study of deceased-donor kidney transplants to determine its peritransplant excretion pattern, utility for predicting delayed graft function (DGF) and association with 3-month graft function. Serial urine samples were collected for 2 days following transplant and analyzed blindly for CyC. We defined DGF as any hemodialysis in the first week after transplant, slow graft function (SGF) as a serum creatinine reduction <70% by the first week and immediate graft function (IGF) as a reduction ≧70%. Results: Of 91 recipients, 33 had DGF, 34 had SGF and 24 had IGF. Urine CyC/urine creatinine was highest in DGF for all time-points. The area under the curve (95% CI) for predicting DGF at 6 h was 0.69 (0.57–0.81) for urine CyC, 0.74 (0.62–0.86) for urine CyC/urine creatinine and 0.60 (0.45–0.75) for percent change in urine CyC. On the first postoperative day, urine CyC/urine creatinine and percent change in urine CyC were associated with 3-month graft function. Conclusion: Urine CyC on the day after transplant differs between degrees of perioperative graft function and modestly corresponds with 3-month function.
The Association between Parathyroid Hormone Levels and the Cardiorenal Metabolic Syndrome in Non-Diabetic Chronic Kidney Disease
Authors: Saab Georges , Whaley-Connell Adam , Bombeck Andrew , Kurella Tamura Manjula , Li Suying , Chen Shu-Cheng , McFarlane Samy I. , Sowers James R. , Norris Keith , Bakris George L. , McCullough Peter A. ,   for the Kidney Early Evaluation Program Investigators
Published: April 2011

Aims: The relationship between parathyroid hormone (PTH) and the cardiorenal metabolic syndrome was examined among non-diabetic persons with chronic kidney disease (CKD). Methods: In a cross-sectional analysis, the relationship between PTH levels and the cardiorenal metabolic syndrome was investigated in 3,215 non-diabetic participants in the National Kidney Foundation-Kidney Early Evaluation Program (KEEP 2.0) found to have CKD (eGFR <60 ml/min/1.73 m2). Results: In unadjusted analyses, the prevalence of the cardiorenal metabolic syndrome increased along increasing PTH quartiles (31.7, 33.8, 37.3, and 48.7%, respectively, p for trend <0.0001). After multivariate adjustment, as compared to the first PTH quartile, odds of the cardiorenal metabolic syndrome were 16% (p = 0.18), 35% (p = 0.006), and 80% (p < 0.0001) higher for the second, third, and fourth quartiles, respectively. When taken as a continuous predictor, each standard deviation increase of natural log transformed PTH was associated with 26% (p < 0.0001) higher odds of the cardiorenal metabolic syndrome. The association of PTH with the cardiorenal metabolic syndrome was not modified by age or gender (p for interaction was not significant for both modifiers). Conclusions: Among an outpatient non-diabetic population with CKD, higher PTH levels were associated with a higher prevalence of the cardiorenal metabolic syndrome.
Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL
Authors: Nus Meritxell , MacGrogan Donal , Martínez-Poveda Beatriz , Benito Yolanda , Casanova Jesús C. , Fernández-Avilés Francisco , Bermejo Javier , de la Pompa José Luis
Published: April 2011

Objective—

Calcific aortic valve disease is similar to atherosclerosis in that both diseases result from chronic inflammation and endothelial dysfunction. Heterozygous
NOTCH1
mutations have been associated to calcific aortic disease and a bicuspid aortic valve. We investigated whether mice with genetic inactivation of the Notch signaling pathway are prone to develop valve disease when exposed to a predisposing diet.

Methods and Results—

Using Doppler echocardiography, histology, immunohistochemistry, quantitative gene expression analysis, and cell culture assays, we examined the effect of a hypercholesterolemic diet supplemented with vitamin D on mice heterozygous for null mutations in the
Notch1
receptor or the effector transcription factor gene
RBPJk
. After 16 weeks on the hyperlipidemic diet, calcific aortic disease was detected in heterozygous
RBPJk
mice. Analysis of valve leaflets revealed macrophage infiltration, enhanced collagen deposition, proosteogenic protein expression, and calcification. Heterozygous null
Notch1
mice displayed milder histopathologic changes and did not develop any significant hemodynamic disturbance. Valvular disease correlated with reduced expression of the Notch target gene
Hey1
in valves of
RBPJk
heterozygous mice fed the hyperlipidemic diet. Consistent with the in vivo data, Notch signaling inhibition in porcine valve interstitial cells led to downregulation of
HEY1
transcription, activation of osteogenic markers, and increased calcified nodule formation.

Conclusion—

We show that Notch signaling disruption via
RBPJk
heterozygous inactivation results in aortic valve disease.
Notch1
heterozygous mice do not show functional impairment, suggesting that additional Notch receptors may be involved in aortic valve homeostasis and disease. Our data establish a genetic mouse model of calcific aortic valve disease and may help to identify a patient population with reduced valvular NOTCH signaling at risk for developing this disease.
Safety of Pacemaker Reuse
Authors: Baman Timir S. , Meier Pascal , Romero Joshua , Gakenheimer Lindsey , Kirkpatrick James N. , Sovitch Patricia , Oral Hakan , Eagle Kim A.
Published: April 2011

Background—

A large disparity in medical health care is clearly evident between developed and underserved nations in the field of cardiac electrophysiology, specifically pacemaker implantation. This study aimed to assess the safety of pacemaker reuse.

Methods and Results—

A computerized search from January 1, 1970, to September 1, 2010, identified 18 studies with outcomes of pacemaker reuse. The primary outcome was pacemaker infection or device erosion as defined by each individual study protocol. Secondary end points were device malfunction defined as a defect in the structural or electric integrity of the pulse generator. Pooled individual patient data (n=2270) from 18 trials were included in the analysis. The proportion of patients in whom an infection developed after pacemaker reuse was 1.97% (1.15% to 3.00%). There was no significant difference in infection rate between pacemaker reuse and new device implantation (odds ratio, 1.31 [0.50 to 3.40],
P
=0.580). The proportion of patients in whom device malfunction developed after pacemaker reuse was 0.68% (0.27% to 1.28%). Compared with new device implantation, there was an increased risk for malfunction in the reuse group (odds ratio, 5.80 [1.93 to 17.47],
P
=0.002). This difference was mainly driven by abnormalities in set screws, which possibly occurred during device extraction, as well as nonspecific device “technical errors.”

Conclusions—

This study suggests that pacemaker reuse has an overall low rate of infection and device malfunction and may be a safe and efficacious means of treating patients in underserved nations with symptomatic bradyarrhythmias and no other method of obtaining a device. However, the results also denote a higher rate of device malfunction as compared with new device implantation. Patients with highly symptomatic conduction disease may benefit from pacemaker reuse; however, they should be closely monitored for device malfunction, especially during implantation.
Kinesin-Like Protein 6 (KIF6) Polymorphism and the Efficacy of Rosuvastatin in Primary Prevention
Authors: Ridker Paul M , MacFadyen Jean G. , Glynn Robert J. , Chasman Daniel I.
Published: April 2011

Background—

Hypothesis-generating data raise the possibility that carriers of the kinesin-like protein 6 (
KIF6
)
719 arginine (Arg) allele preferentially benefit from statin therapy, and, on this basis, a commercial assay for
KIF6
has been developed.

Methods and Results—

In the recently completed JUPITER trial, men and women without prior cardiovascular disease or diabetes who had baseline low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg daily or to placebo and followed for first major vascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or vascular death) and for all-cause mortality. We evaluated the effect of polymorphism at rs20455 encoding the
KIF6
719Arg allele on outcomes in this primary prevention trial, both among Caucasian participants and in the trial as a whole. Among 8781 Caucasian trial participants, we observed no increase in vascular event rates among carriers of the
KIF6
719Arg allele as compared with noncarriers (hazard ratio, 0.91; 95% confidence interval, 0.66 to 1.26) nor any difference in percent low-density lipoprotein cholesterol reduction with rosuvastatin according to genotype (−52 versus −52 mg/dL,
P
=0.11). Rosuvastatin allocation was associated with an almost identical reduction in the trial primary end point among carriers (hazard ratio, 0.61; 95% confidence interval, 0.43 to 0.87) as among noncarriers (hazard ratio, 0.59; 95% confidence interval, 0.39 to 0.88) (
P
-interaction=0.90). Genotype had no impact on rosuvastatin efficacy in further analyses that included all-cause mortality, in analyses conducted in the total trial cohort that adjusted for race, or in analyses using generalized models of inheritance rather than recessive models.

Conclusions—

In the large primary prevention JUPITER trial, rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the
KIF6
719Arg allele. Thus, at least for rosuvastatin, there appears to be no clinical utility to screening for
KIF6
genotype as a method to determine vascular risk or to predict statin efficacy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00239681.
Small Heat Shock Protein 20 Interacts With Protein Phosphatase-1 and Enhances Sarcoplasmic Reticulum Calcium Cycling
Authors: Qian Jiang , Vafiadaki Elizabeth , Florea Stela M. , Singh Vivek P. , Song Weizhong , Lam Chi Kung , Wang Yigang , Yuan Qunying , Pritchard Tracy J. , Cai Wenfeng , Haghighi Kobra , Rodriguez Patricia , Wang Hong-Sheng , Sanoudou Despina , Fan Guo-Chang , Kranias Evangelia G.
Published: April 2011

Background:

Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling.

Methods and Results:

Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1–PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1.

Conclusions:

Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1–PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.
Delayed Administration of Human Umbilical Tissue-Derived Cells Improved Neurological Functional Recovery in a Rodent Model of Focal Ischemia
Authors: Zhang Li , Li Yi , Zhang Chunling , Chopp Michael , Gosiewska Anna , Hong Klaudyne
Published: April 2011

Background and Purpose—

The short time window required by neuroprotective strategies for successful treatment of patients with ischemic stroke precludes treatment for most. However, clinical therapies based on neuroregeneration might extend this therapeutic time window and thus address a significant unmet need. Human umbilical tissue-derived cells have shown great potential as neuroregenerative candidates for stroke treatment.

Methods—

The effectiveness of intravenous administration of human umbilical tissue-derived cells was tested in a rodent middle cerebral artery stroke model in a dose escalation study (doses tested: 3×10
5
, 1×10
6
, 3×x10
6
, or 1×10
7
cells/injection) followed by a time-of-administration study (time after stroke: Day 1, Day 7, Day 30, and Day 90 at a dose of 5×10
6
cells/injection). Controls were phosphate-buffered saline injections and human bone marrow-derived mesenchymal stromal cell injections. Post-treatment outcome tools included the modified neurological severity score and the adhesive removal tests. Histology was performed on all cases to evaluate synaptogenesis, neurogenesis, angiogenesis, and cell apoptosis.

Results—

Statistically significant improvements of human umbilical tissue-derived cell treatment versus phosphate-buffered saline in modified neurological severity scores and adhesive test results were observed for doses ≥3×10
6
cells up to 30 days poststroke. At doses ≥3×10
6
, histological evaluations confirmed enhanced synaptogenesis, vessel density, and reduced apoptosis in the ischemic boundary zone and increased proliferation of progenitor cells in the subventricular zone of human umbilical tissue-derived cell-treated animals versus phosphate-buffered saline controls.

Conclusions—

These results indicate effectiveness of intravenous administration of human umbilical tissue-derived cells in a rodent stroke model compared with phosphate-buffered saline control and warrant further investigation for possible use in humans.
Burden of Stroke in Indigenous Western Australians
Authors: Katzenellenbogen Judith M. , Vos Theo , Somerford Peter , Begg Stephen , Semmens James B. , Codde James P.
Published: April 2011

Background and Purpose—

Despite the disproportionate burden of cardiovascular disease among indigenous Australians, information on stroke is sparse. This article documents the incidence and burden of stroke (in disability-adjusted life years) in indigenous and non-indigenous people in Western Australia (1997–2002), a state resident to 15% of indigenous Australians comprising 3.4% of the population of Western Australia.

Methods—

Indigenous and non-indigenous stroke incidence and excess mortality rates were estimated from linked hospital and mortality data, with adjustment for nonadmitted events. Nonfatal burden was calculated from nonfatal incidence, duration (modeled from incidence, excess mortality, and remission), and disability weights. Stroke death counts formed the basis of fatal burden. Nonfatal and fatal burden were summed to obtain disability-adjusted life years, by indigenous status.

Results—

The total burden was 55 099 and 2134 disability-adjusted life years in non-indigenous and indigenous Western Australians, respectively. The indigenous to non-indigenous age-standardized stroke incidence rate ratio (≥15 years) was 2.6 in males (95% CI, 2.3–3.0) and 3.0 (95% CI, 2.6–3.5) in females, with similar rate ratios of disability-adjusted life years. The burden profile differed substantially between populations, with rate ratios being highest at younger ages.

Conclusions—

The differential between indigenous and non-indigenous stroke burden is considerable, highlighting the need for comprehensive intersectoral interventions to reduce indigenous stroke incidence and improve outcomes. Programs to reduce risk factors and increase access to culturally appropriate stroke services are required. The results here provide the quantitative basis for policy development and monitoring of stroke outcomes.
Measurement of Cerebrovascular Reactivity in Pediatric Patients With Cerebral Vasculopathy Using Blood Oxygen Level-Dependent MRI
Authors: Han Jay S. , Mikulis David J. , Mardimae Alexandra , Kassner Andrea , Poublanc Julien , Crawley Adrian P. , deVeber Gabrielle A. , Fisher Joseph A. , Logan William J.
Published: April 2011

Background and Purpose—

Cerebrovascular reactivity (CVR) is an indicator of cerebral hemodynamics. In adults with cerebrovascular disease, impaired CVR has been shown to be associated with an increased risk of stroke. In children, however, CVR studies are not common. This may be due to the difficulties and risks associated with current CVR study methodologies. We have previously described the application of precise control of end-tidal carbon dioxide partial pressure for CVR studies in adults. Our aim is to report initial observations of CVR studies that were performed as part of a larger observational study regarding investigations in pediatric patients with cerebral vascular disease.

Methods—

Thirteen patients between the ages of 10 and 16 years (10 with a diagnosis of Moyamoya vasculopathy and 3 with confirmed, or suspected, intracranial vascular stenosis) underwent angiography, MRI, and functional blood oxygen level-dependent MRI mapping of CVR to hypercapnia. The results of the CVR study were then related to both the structural imaging and clinical status.

Results—

Sixteen blood oxygen level-dependent MRI CVR studies were performed successfully in 13 consecutive patients. Twelve of the 13 patients with angiographic abnormalities also had CVR deficits in the corresponding downstream vascular territories. CVR deficits were also seen in 8 of 9 symptomatic patients and 2 of the asymptomatic patients. Noteably, in patients with abnormalities on angiography, the reductions in CVR extended beyond the ischemic lesions identified with MR structural imaging into normal-appearing brain parenchyma.

Conclusions—

This is the first case series reporting blood oxygen level-dependent MRI CVR in children with cerebrovascular disease. CVR studies performed so far provide information regarding hemodynamic compromise, which complements traditional clinical assessment and structural imaging.
Is the Maximum Dose of 90 mg Alteplase Sufficient for Patients With Ischemic Stroke Weighing >100 kg?
Authors: Diedler Jennifer , Ahmed Niaz , Glahn Jörg , Grond Martin , Lorenzano Svetlana , Brozman Miroslav , Sykora Marek , Ringleb Peter
Published: April 2011

Background and Purpose—

Intravenous alteplase for acute ischemic stroke has a maximum dose limit of 90 mg. Consequently, patients >100 kg body weight receive a lower per-kilogram dose compared with those ≤100 kg. We investigated if the lower per-kilogram dose is associated with poor early neurological improvement and worse outcome after thrombolysis.

Methods—

Of 27 910 patients registered in Safe Implementation of Treatment in Stroke–International Stroke Thrombolysis Register (SITS-ISTR; 2002 to 2009), 1190 (4.3%) weighed >100 kg. Major neurological improvement was used to estimate recanalization (National Institutes of Health Stroke Scale improvement ≥8 points or score of 0 at 24 hours). Outcome measures included symptomatic intracerebral hemorrhage (National Institutes of Health Stroke Scale deterioration ≥4 points within 24 hours and Type 2 parenchymal hemorrhage), functional independence (modified Rankin Scale 0 to 2), and mortality at 3 months.

Results—

Patients >100 kg received a lower per-kilogram alteplase dose (0.82 versus 0.90,
P
<0.001), were younger (62 versus 70 years,
P
<0.001), had a lower baseline National Institutes of Health Stroke Scale (10 versus 12,
P
<0.001), but more frequently had cardiovascular risk factors. Major neurological improvement at 24 hours occurred in 27.7% in both groups. Symptomatic intracerebral hemorrhage occurred in 2.6% versus 1.7% (
P
=0.03) in >100 kg versus ≤100 kg. Functional independence was 59.7% versus 53.6% (
P
<0.001) and mortality was 14.4% versus 15.1% (
P
=0.54). After adjustment for baseline characteristics, there was no significant difference for major neurological improvement or functional independence between >100 kg and ≤100 kg, but >100-kg patients had a higher odds ratio for symptomatic intracerebral hemorrhage (OR, 1.6; 95% CI, 1.06 to 2.41;
P
=0.02) and mortality (OR, 1.37; 95% CI, 1.08 to 1.74;
P
=0.01).

Conclusions—

Our results support the current upper dose limit. There was a higher incidence of symptomatic intracerebral hemorrhage in patients >100 kg despite the lower per-kilogram recombinant tissue plasminogen activator dose. Major neurological improvement and functional independence were similar.
The Declining Significance of Race: Revisited & Revised
Authors: Wilson William Julius
Published: April 2011

Wilson reflects on the nearly eight hundred research studies that claim to provide an empirical test of the arguments presented in his book The Declining Significance of Race (1978; second edition, 1980). Wilson considers representative studies that incorrectly address his book, before discussing those publications that correctly address his thesis, including those that uphold, partially support, or challenge his arguments and basic claims. In the process, Wilson explores how some of these studies led him to revise or extend parts of his basic thesis, especially as it pertains to race and interracial relations today. Wilson also takes into account changes within the African American population since he wrote The Declining Significance of Race. He reveals how his thoughts have changed with respect to both race- and class-based solutions for the problems faced by people of color.
Destabilizing the American Racial Order
Authors: Hochschild Jennifer L. , Weaver Vesla M. , Burch Traci
Published: April 2011

Are racial disparities in the United States just as deep-rooted as they were before the 2008 presidential election, largely eliminated, or persistent but on the decline? One can easily find all of these pronouncements; rather than trying to adjudicate among them, this essay seeks to identify what is changing in the American racial order, what persists or is becoming even more entrenched, and what is likely to affect the balance between change and continuity. The authors focus on young American adults, who were raised in a distinctive racial context and who think about and practice race differently than their older counterparts. For many young Americans, racial attitudes are converging across groups and social networks are becoming more intertwined. Most important, although group-based hierarchy has not disappeared, race or ethnicity does less to predict a young adult's life chances than ever before in American history.
Intra-minority Intergroup Relations in the Twenty-First Century
Authors: Richeson Jennifer A. , Craig Maureen A.
Published: April 2011

Recent projections indicate that by the year 2050, racial minorities will comprise more than 50 percent of the U.S. population. That is, the United States is expected to become a “majority-minority” nation. This essay adopts a social psychological approach to consider how these dramatic demographic changes may affect both racial minorities and white Americans. Specifically, drawing from theoretical work on social identification, the essay examines the likely psychological meaning (if any) of a majority-minority nation for racial minorities' self-concepts and the resulting effects on their evaluations of members of other racial minority groups. In addition, the potential reactions of white Americans to the possibility of becoming a numerical minority are explored. Drawing on reactions to the election of Barack Obama as the first black president of the United States, the authors conclude by discussing the implications of America's shifting racial demographics for the U.S. racial hierarchy.
Somewhere between Jim Crow & Post-Racialism: Reflections on the Racial Divide in America Today
Authors: Bobo Lawrence D.
Published: April 2011

In 1965, when Dædalus published two issues on “The Negro American,” civil rights in the United States had experienced a series of triumphs and setbacks. The Civil Rights Act of 1964 and the Voting Rights Act of 1965 extended basic citizenship rights to African Americans, and there was hope for further positive change. Yet 1965 also saw violent confrontations in Selma, Alabama, and the Watts neighborhood of Los Angeles that were fueled by racial tensions. Against this backdrop of progress and retreat, the contributors to the Dædalus volumes of the mid-1960s considered how socioeconomic factors affected the prosperity, well-being, and social standing of African Americans. Guest editor Lawrence D. Bobo suggests that today we inhabit a similarly unsettled place: situated somewhere between the overt discrimination of Jim Crow and the aspiration of full racial equality. In his introduction, Bobo paints a broad picture of the racial terrain in America today before turning the volume over to the contributors, who take up particular questions ranging from education and family support, to racial identity and politics, to employment and immigration.
Revisiting the Restricted Growth Function Genetic Algorithm for Grouping Problems
Authors: Lewis R. , Pullin E.
Published: April 2011

An overview of the restricted growth function genetic algorithm is given. Empirically we show that the algorithm exhibits poor performance and is consistently outperformed on a range of problems by two very basic evolutionary algorithms with blind operators.
A Multifactor Winner-Take-All Dynamics
Authors: Zhu Junmei
Published: April 2011

Perceptual systems often have to disentangle different factors from mixed observations. If each factor is represented by a set of variables, each standing for a discrete value of the factor, the factor values underlying an observation can be extracted by a winner-take-all (WTA) mechanism over the direct product of the factors. Search in the product space, however, is expensive. It is computationally attractive to work on the marginal factors. In this letter we study the dynamics of a multifactor system modeled by a number of interacting WTA dynamics, one for each factor. We give theoretical results on the stable fixed points of this system and show experimental results on invariant object recognition.
Does It Take Democrats to Democratize? Lessons From Islamic and Secular Elite Values in Turkey
Authors: Somer Murat
Published: April 2011

Do political-Islamic elites need to be democrats for participation in democracy, how do their values compare to secular elites’, and how do their values change through participation and affect democratization itself? A comparative-systematic content analysis of three Islamic-conservative and two pro-secular Turkish newspapers over nine years shows that, overall, political-Islamic elites adopt democratic political values. Furthermore, they began to view that liberal-democratic rights and freedoms serve their interests. However, value democratization, and, thus, moderation and democratization, is not a linear and inexorable process automatically resulting from participation or socioeconomic development. It occurs through ruptures such as conflicts with secular actors, and interdependently through the interactions of secular and religious actors. Hence, religious actors’ adoption of more democracy may paradoxically make some secular actors less democratic. The consolidation of pluralistic democracy requires the emergence of both religious and secular democrats by resolving complex problems of commitment, and of clashes in areas like social pluralism where Islamic values are less open to change.
Modification of the edge crack torsion specimen for mode III delamination testing. Part II – experimental study
Authors: Browning Grant , Carlsson Leif A. , Ratcliffe James G.
Published: April 2011

Experimental studies of carbon/epoxy edge crack torsion specimen have been conducted using a specially designed twist test fixture. Of particular concern was verification of the recommendations expressed in the analytical part of this study (Part 1), where it was suggested that overhang (sections of specimen laying outside of the loading and support pins) in the x- and y-directions should be minimized, and fracture testing at longer delamination lengths should be avoided. The experimental test results verified that the specimens with the smallest overhang produced the most consistent delamination toughness data, GIIIc. Specimens with large overhangs exhibited high apparent GIIIc values at long delamination lengths. This was most likely due to nonuniform loading and associated nonuniform delamination extension.
Peace of Cemeteries: Civil War Dynamics in Postwar States’ Repression
Authors: Herreros Francisco
Published: April 2011

This article analyzes whether state repression in post—civil war situations can be explained by dynamics associated with previous civil wars. It claims that in post—civil war situations the state can more easily resort to indiscriminate repression against social groups, relying on information related to the civil war. Two civil war dynamics are tested: preemptive indiscriminate violence to eliminate opposition by the defeated population and retaliation for crimes committed during the war. Using data from the first decade of the Francoist regime in Spain, the author found that civil war dynamics, and not actual dissent, explain most of the country’s postwar violence.
La ville africaine d’après la production de langue française. Conditions économiques, migration urbaine et protestation religieuse
Authors: Ollagnon Matthieu
Published: April 2011

La prime organisation de la ville africaine est souvent indissociable de la période coloniale, période où elle a constitué une médiation privilégiée entre colonisateurs et indigènes, soit dans le registre de la domination, soit dans celui de transactions sociales variées. Dans ce bouillonnement, entre recomposition des liens sociaux et persistance des solidarités anciennes, l’accent peut être mis sur la question des groupements chrétiens minoritaires, messianiques, comme agents de protestation et de socialisation. L’École de Chicago, appréhendant la ville comme un processus continu d’organisation et de désorganisation sociales géographiquement marqué, apparaît alors comme la matrice adaptée pour en interroger la spécificité historique et les enjeux. Dans cette perspective, C. Collantes Diez met en relation une revue de la production de langue française et à la lumière d’une réflexion nourrie de l’observation participante.
Are Sin Stocks Paying the Price for Accounting Sins?
Authors: Kim Irene , Venkatachalam Mohan
Published: April 2011

Recent empirical evidence suggests that sin stocks—publicly traded stocks in the gaming, tobacco, alcohol, and adult entertainment industries—are neglected by stock market participants because of social norms, regulatory scrutiny, and litigation risk. Consequently, these firms experience low institutional ownership, low analyst following, and higher expected returns. This paper examines whether higher information risk in the form of poor financial reporting quality offers an explanation for the higher expected returns of sin firms. Inconsistent with this explanation, we find that the financial reporting quality of sin firms is superior relative to a variety of control groups along two dimensions: predictability of earnings for future cash flows and timely loss recognition. These results imply that, despite superior returns and higher financial reporting quality, investors are willing to neglect sin stocks and instead bear a financial cost in order to comply with societal norms and reflect non-financial tastes in their portfolio.
Association between symptoms and their severity with survival time in hospitalized patients with far advanced cancer
Authors: Liu Yong , Xi Qing-song , Xia Shu , Zhuang Liang , Zheng Wei , Yu Shiying
Published: April 2011

Objective: To assess the significance of symptoms and their severity for predicting survival of hospitalized patients with far advanced cancer.

Methods: Two hundred fifty-six patients with far advanced cancer at the Cancer Center of Tongji Hospital, China were assessed by the Chinese version of the M.D. Anderson Symptom Inventory (MDASI-C). A Cox regression model was used to determine symptoms that could predict survival time. The log-rank test was used to compare the survival of patients accompanied by significant symptoms at different intensities.

Results: Median survival was 49 days. Fatigue was the most common and severe symptom, followed by lack of appetite, disturbed sleep, and pain. Multivariate analysis showed that fatigue, shortness of breath, lack of appetite, and feeling sad were independent prognostic factors for survival time ( p < 0.05), with a hazard ratio of dying of 1.39, 1.13, 1.33, and 1.16, respectively. The survival time for patients with different intensities of the four symptoms showed significant differences ( p < 0.01).

Conclusions: Fatigue, lack of appetite, feeling sad, and shortness of breath could be predictive factors for survival time of hospitalized patients with far advanced cancer. The more severe these symptoms are, the shorter will be survival time.