bluuebunny/crossref_metadata_2025 huggingface dataset:
The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations
Authors: Comin-Anduix Begoña , Chodon Thinle , Sazegar Hooman , Matsunaga Douglas , Mock Stephen , Jalil Jason , Escuin-Ordinas Helena , Chmielowski Bartosz , Koya Richard C , Ribas Antoni
Published: December 2010

Purpose: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAFV600E mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma.

Experimental Design: Peripheral blood mononuclear cells (PBMC) and BRAFV600E mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigen-specific T-cell function were analyzed by specific cytokine release and cytotoxicity activity.

Results: The 50% inhibition concentration (IC50) of PLX4032 for resting human PBMC was between 50 and 150 μmol/L compared with an IC50 below 1 μmol/L for sensitive BRAFV600E mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 μmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-μmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 μmol/L.

Conclusions: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAFV600E mutant melanoma. Clin Cancer Res; 16(24); 6040–8. ©2010 AACR.
Drug Transporters and Imatinib Treatment: Implications for Clinical Practice
Authors: Eechoute Karel , Sparreboom Alex , Burger Herman , Franke Ryan M. , Schiavon Gaia , Verweij Jaap , Loos Walter J. , Wiemer Erik A.C. , Mathijssen Ron H.J.
Published: December 2010

Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as “acquired pharmacokinetic drug resistance.” This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations. Clin Cancer Res; 17(3); 406–15. ©2010 AACR.
Toward a Better Understanding of Race and Cancer
Authors: Brawley Otis W.
Published: December 2010

A better understanding of breast cancer subtypes is allowing their use as prognostic markers. For some time, it has been documented that black women with breast cancer have a poorer prognosis than white women of the same stage. Advances in immunohistochemistry and the appreciation of breast cancer subtypes are enabling investigators to study the distribution of these subtypes among populations. Clin Cancer Res; 16(24); 5920–2. ©2010 AACR.
Cost Utility of Prostate Cancer Chemoprevention with Dutasteride in Men with an Elevated Prostate Specific Antigen
Authors: Svatek Robert S. , Lotan Yair
Published: December 2010

Background: In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, dutasteride reduced the relative risk of prostate cancer (CaP) diagnosis over a 4-year period by 22.8%, but questions remain regarding the cost–effectiveness of widespread utilization. We evaluated the cost utility of chemoprevention using dutasteride in men at elevated risk for CaP.

Methods: A Markov decision analysis model with probabilistic sensitivity analysis was designed to determine the lifetime prostate-health-related costs, beginning at age 50, for men treated with dutasteride compared with placebo who are at elevated risk for CaP. Model assumptions were based on data in REDUCE; surveillance, epidemiology, and end-results program; literature review of costs, utilities, and transition rates among various prostate cancer health states; and local institutional cost data.

Results: Under the assumptions of the base case analysis, dutasteride chemoprevention is associated with a gain of 108 quality-adjusted life-years (QALYs) per 1,000 men and the quality-adjusted cost–effectiveness ratio for dutasteride compared with men not receiving chemoprevention was $140,240 per QALYs. At a cost of $626 per year, down from the current cost of $1,400, the model predicts a cost benefit from dutasteride with a willingness-to-pay threshold lower than $50 K. Assuming a 15% period prevalence renders, an incremental cost–effectiveness ratio of $576,630 per QALYs and a 30% period prevalence would yield a $98,059 per QALYs.

Conclusions: Dutasteride is unlikely to be cost effective when considering the impact on survival differences among treated versus untreated groups. However, chemoprevention may be cost effective in high-risk populations when taking into consideration adjustments for the impact on quality of life. Cancer Prev Res; 4(2); 277–83. ©2010 AACR.
Inhibition of EGFR-STAT3 Signaling with Erlotinib Prevents Carcinogenesis in a Chemically-Induced Mouse Model of Oral Squamous Cell Carcinoma
Authors: Leeman-Neill Rebecca J. , Seethala Raja R. , Singh Shivendra V. , Freilino Maria L. , Bednash Joseph S. , Thomas Sufi M. , Panahandeh Mary C. , Gooding William E. , Joyce Sonali C. , Lingen Mark W. , Neill Daniel B. , Grandis Jennifer R.
Published: December 2010

Chemoprevention of head and neck squamous cell carcinoma (HNSCC), a disease associated with high mortality rates and frequent occurrence of second primary tumor (SPT), is an important clinical goal. The epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription (STAT)-3 signaling pathway is known to play a key role in HNSCC growth, survival, and prognosis, thereby serving as a potential therapeutic target in the treatment of HNSCC. In the current study, the 4-nitroquinoline-1-oxide (4-NQO)–induced murine model of oral carcinogenesis was utilized to investigate the chemopreventive activities of compounds that target the EGFR-STAT3 signaling pathway. This model mimics the process of oral carcinogenesis in humans. The drugs under investigation included erlotinib, a small molecule inhibitor of the EGFR, and guggulipid, the extract of an Ayurvedic medicinal plant, which contains guggulsterone, a compound known to inhibit STAT3. Dietary administration of guggulipid failed to confer protection against oral carcinogenesis. On the other hand, the mice placed on erlotinib-supplemented diet exhibited a 69% decrease (P < 0.001) in incidence of preneoplastic and neoplastic lesions compared with mice on the control diet. Immunostaining of dysplastic lesions demonstrated modest decreases in STAT3 levels, with both drug treatments, that were not statistically significant. The results of the present study provide the basis for exploring the efficacy of erlotinib for prevention of HNSCC in a clinical setting. Cancer Prev Res; 4(2); 230–7. ©2010 AACR.
Renal Function in Patients with Liver Cirrhosis
Authors: Chen Yu-Wei , Wu Chih-Jen , Chang Ching-Wei , Lee Shih-Yi , Sun Fang-Ju , Chen Han-Hsiang
Published: December 2010

Background: Despite the poor prognosis of patients with both cirrhosis and renal failure, most reports on renal function and outcomes of cirrhosis have come from liver transplant registries. The present study aimed to investigate the association between renal function and cirrhosis in a broader population. Methods: 3,857 patients were enrolled after the exclusion of patients with incomplete data. The most recent demographic data after the latest laboratory measurements obtained at outpatient or inpatient department were collected. Results: In predicting renal function, estimated glomerular filtration rate (eGFR) was found to be dissociated from Child-Pugh points (β = –0.01, p = 0.691), different causes of cirrhosis, and presence of diabetes (β = –0.03, p = 0.112). In terms of predicting in-hospital mortality, the sensitivity (60–82%) and specificity (70–90%) of the model for end-stage liver disease (MELD) score increased with the decrease in eGFR. However, the blood urea nitrogen (BUN)/creatinine ratio was better than the MELD score in patients with normal eGFR. Conclusion: In contrast to prerenal causes of kidney injury, the underlying causes of cirrhosis or diabetes had relatively minor effects on renal function in cirrhotic patients. The BUN/creatinine ratio was a better index than the MELD score in predicting in-hospital mortality in cirrhotic patients with normal renal function.
Association between Very Low PTH Levels and Poor Survival Rates in Haemodialysis Patients: Results from the French ARNOS Cohort
Authors: Jean G. , Lataillade D. , Genet L. , Legrand E. , Kuentz F. , Moreau-Gaudry X. , Fouque D. ,   on behalf of the ARNOS study investigators
Published: December 2010

Introduction: A very low parathyroid hormone (PTH) level (VLPL) is associated with an increased risk of adynamic bone disease, vascular calcification, and mortality in haemodialysis (HD) patients. The aim of the study was to assess the frequency, the associated factors, and the prognosis of non-surgical VLPL in a cohort of prevalent HD patients. Methods: In July 2005, a cross-sectional study was performed on the French ARNOS cohort in 1,348 prevalent HD patients from 24 dialysis centres in the Rhône-Alpes area. Patients with a baseline intact PTH level <50 pg/ml (VLPL, Group 1) and ≧50 pg/ml (Group 2) were compared and a 42-month survival analysis was performed. Patients with prevalent or incident parathyroidectomy were excluded. Results: We studied 1,138 prevalent HD patients. As compared to patients of Group 2 (n = 1,019), patients with VLPL (Group 1, n = 119) had lower serum albumin levels (34.5 ± 5 vs. 36.4 ± 5 g/l, p < 0.0001), less protein intake (nPCR 0.99 ± 0.28 vs. 1.1 ± 0.28 g/kg/day, p = 0.01), higher calcaemia (2.30 ± 0.2 vs. 2.26 ± 0.2 mmol/l, p = 0.01) and were more frequently treated with calcium carbonate (67 vs. 54%, p < 0.001). Patients with VLPL had a higher mortality rate (HR: 1.4 (1.07–1.8), p = 0.006) after adjustment for age, gender, diabetes, and dialysis vintage. The odds ratios of mortality for patients with VLPL remained higher in all calcaemia and serum albumin quartiles. Only 3/119 patients in Group 1 did not receive any PTH-lowering therapies (i.e. calcium carbonate (67%), alfacalcidol (38%), cinacalcet (10.1%), and dialysate calcium ≧1.5 mmol/l (94%)). Conclusion: In this observational French cohort, VLPL was observed in 10% of prevalent HD patients and was associated with poor survival rates. An inadequate therapeutic strategy could be responsible for this observation. The real consequences of this iatrogenic adynamic bone disease remain hypothetical, but it may be related to the risk of developing vascular calcification. It is hypothesized that a more adequate strategy, using fewer PTH-lowering therapies in cases of VLPL, may help in improving the poor prognosis.
CD22 Regulates Adaptive and Innate Immune Responses of B Cells
Authors: Kawasaki Norihito , Rademacher Christoph , Paulson James C.
Published: December 2010

B cells sense microenvironments through the B cell receptor (BCR) and Toll-like receptors (TLRs). While signals from BCR and TLRs synergize to distinguish self from nonself, inappropriate regulation can result in development of autoimmune disease. Here we show that CD22, an inhibitory co-receptor of BCR, also negatively regulates TLR signaling in B cells. CD22-deficient (Cd22–/–) B cells exhibit hyperactivation in response to ligands of TLRs 3, 4 and 9. Evidence suggests that this results from impaired induction of suppressors of cytokine signaling 1 and 3, well-known suppressors of TLR signaling. Antibody-mediated sequestration of CD22 on wild-type (WT) B cells augments proliferation by TLR ligands. Conversely, expression of CD22 in a Cd22–/– B cell line blunts responses to TLR ligands. We also show that lipopolysaccharide-induced transcription by nuclear factor-ĸB is inhibited by ectopic expression of CD22 in a TLR4 reporter cell line. Taken together, these results suggest that negative regulation of TLR signaling is an intrinsic property of CD22. Since TLRs and BCR activate B cells through different signaling pathways, and are differentially localized in B cells, CD22 exhibits a broader regulation of receptors that mediate adaptive and innate immune responses of B cells than previously recognized.
Interventions to Reduce Late Referrals to Nephrologists
Authors: Fischer Michael J. , Ahya Shubhada N. , Gordon Elisa J.
Published: December 2010

Background: Despite the adverse health outcomes with late nephrology referral for patients with chronic kidney disease (CKD), little is known about the underlying mechanisms and reasons for late referral patterns. Methods: We conducted a Medline search for peer-reviewed articles focused on nephrology referral among adults with CKD. We critically reviewed this literature in regard to late nephrology referral, highlighted its shortcomings, and provided a theoretically based framework for future research. Results: Late referral has been attributed to three key types of factors: primary care provider (PCP), patient, and healthcare system factors. Limited empirical research has pointed to knowledge deficits, perceptions, and preferences by PCPs as well as to knowledge deficits, psychological concerns, and economic concerns by patients. The existing literature is severely limited by retrospective designs, closed-ended surveys, and the absence of a theoretically driven conceptual framework to fully evaluate root causes of this ongoing problem. Social Cognitive Theory may be a particularly well-suited conceptual model for late nephrology referral because important PCP and patient factors correspond to key constructs of this theory. Conclusion: Future research is needed to delineate pathways underlying reasons for PCPs’ late referral patterns and CKD patients’ referral nonadherence. Interventions are urgently needed to reduce late referrals and improve the health of patients with CKD.
Haemodiafiltration versus High-Flux Haemodialysis: Effects on Phosphate Control and Erythropoietin Response
Authors: Oates Thomas , Pinney Jennifer H. , Davenport Andrew
Published: December 2010

Introduction: Haemodiafiltration (HDF) has been reported to improve erythropoietin (EPO) responsiveness and phosphate clearance. We prospectively audited the effect of HDF on EPO dosages, weight and serum phosphate. Methods: 34 patients dialyzing on Tu/Th/Sa switched to HDF, and 44 dialyzing on M/W/F remained on high-flux haemodialysis (HD) and were followed for 12 months. Results: Dialysis adequacy (Kt/V start HDF 1.56 ± 0.03 vs. HD 1.58 ± 0.04 and 12 months 1.55 ± 0.03 vs. 1.59 ± 0.03), haemoglobin (start 11.7 ± 0.3 vs. 11,8 ± 0.2 g/dl and end 11.5 ± 0.1 vs. 11.3 ± 0.3 g/dl), weight (start 69.8 ± 2.4 vs. 67.8 ± 2.5 kg and end 67.4 ± 2.5 vs. 66.1 ± 2.3 kg), or EPO prescription (start 83 (61–186) vs. 123 (71–225) IU/kg/weeks and 12 months 142 (48–188) vs. 124 (59–223) IU/kg/weeks) did not differ. There were no differences in serum albumin, CRP, calcium and parathyroid hormone. Serum beta-2-microglobulin (B2M) decreased with HDF (32.7 ± 1.9 vs. 28.1 ± 1.1 mg/l, p < 0.01), but not with HD (31.6 ± 1.4 vs. 31.5 ± 1.1 mg/l). Serum phosphate fell with HDF (start 1.48 ± 0.08 vs. 1.57 ± 0.07 mmol/l (p = NS); 3 months 1.35 ± 0.07 vs. 1.61 ± 0.08; 6 months 1.34 ± 0.06 vs. 1.57 ± 0.06, and 12 months 1.36 ± 0.07 vs. 1.67 ± 0.07, all p < 0.05). Conclusion: HDF did not lead to weight gain or improved EPO responsiveness in this prospective observational study. However, predialysis serum phosphate and B2M fell with HDF.
p53-Mediated Oxidative Stress and Tubular Injury in Rats with Glycerol-Induced Acute Kidney Injury
Authors: Homsi Eduardo , Mota da Silva, Jr. Sergio , Machado de Brito Silvano , Bouçada Inácio Peixoto Elisa , Butori Lopes de Faria Jose , Janino Patrícia
Published: December 2010

Background/Aims: p53 is a transcriptional factor that responds to severe cell damage promoting the transcription of proapoptotic and prooxidant genes. In this study, we evaluated the role of p53 activation in glycerol-induced acute kidney injury (Gly-AKI). Methods: Rats were treated with p53 inhibitor (pifithrin-α) in the moment we injected glycerol. Renal function, renal histology (HE), TUNEL labeling, cleaved caspase-3 staining, renal p53, Bax, PUMA, Bcl-2, p21 and survivin expressions, renal lipid and DNA oxidative markers, and the expression of antioxidant enzymes (Mn-SOD, HO-1, and NAD(P)H:quinone-oxidoreductase-1) were evaluated. Results: Gly-AKI rats showed an increased renal expression of phosphorylated-p53. The p53 inhibitor attenuated renal impairment and significantly reduced tubular injury. The expression of the oxidative markers was significantly reduced in treated rats. Proapoptotic and prooxidant proteins Bax and PUMA were overexpressed in Gly-AKI rats and reduced in treated rats. On the contrary, antiapoptotic Bcl-2, p21, and survivin showed a tendency to increase in treated rats. The antioxidant enzymes’ expression remained elevated or increased in treated rats. Conclusion: On the whole, p53 inhibition was protective in the short term. The oxidative stress subsided and the transcription tipped toward prosurvival genes; consequently tubular injury was attenuated in treated rats.
Genetic Influences on Peripheral Arterial Disease in a Twin Population
Authors: Wahlgren Carl Magnus , Magnusson Patrik K.E.
Published: December 2010

Objective—

To analyze the contribution of genetic and environmental factors to the development of peripheral arterial disease (PAD) in a large population-based sample of twins.

Methods and Results—

The understanding of genetics in PAD is still limited. From the Swedish Twin Registry and the national patient discharge registry, 1464 twins with PAD were identified, including 33 monozygotic (MZ) and 42 dizygotic (DZ) concordant pairs and 298 MZ and 1008 DZ discordant pairs. Traditional cardiovascular risk factors were significantly more prevalent in twins with PAD than in those without PAD. Concordances and correlations were higher in MZ compared with DZ twins, indicating genetic influences in PAD. The risk of PAD for persons whose twin had PAD compared with persons whose twin did not have PAD, estimated as an odds ratio, was 17.7 (95% CI, 11.7 to 26.6) for MZ twins and 5.7 (95% CI, 4.1 to 7.9) for DZ twins. In the structural equation models, Mx analyses, genetic effects accounted for 58% (95% CI, 50% to 64%) and nonshared environmental effects for 42% (95% CI, 36% to 50%) of the phenotypic variance among twins.

Conclusion—

Heritability is an important component, along with unique environmental factors, for the development of PAD. The proportion of the overall PAD heritability attributed to the heritability of cardiovascular risk factors needs to be resolved. Traditional risk factors could explain a major proportion of PAD heritability. A better understanding of the genetics in PAD could identify individuals at increased risk who may benefit from targeted therapies.
Mitral Valve Endothelial Cells With Osteogenic Differentiation Potential
Authors: Wylie-Sears Jill , Aikawa Elena , Levine Robert A. , Yang Jeong-Hee , Bischoff Joyce
Published: December 2010

Objective—

Cardiac valvular endothelium is unique in its ability to undergo endothelial-to-mesenchymal transformation, a differentiation process that is essential for valve development and has been proposed as mechanism for replenishing the interstitial cells of mature valves. We hypothesized that the valvular endothelium contains endothelial cells that are direct precursors to osteoblastic valvular interstitial cells (VICs).

Methods and Results—

Clonal cell populations from ovine mitral valve leaflets were isolated by single cell plating. Mitral valvular endothelial and mesenchymal clones were tested for osteogenic, adipogenic, and chondrogenic differentiation, determined by the expression of lineage-specific markers. Mitral valvular endothelial clones showed a propensity for osteogenic, as well as chondrogenic differentiation that was comparable to a mitral valvular VIC clone and to bone marrow–derived mesenchymal stem cells. Osteogenic differentiation was not detected in nonvalvular endothelial cells. Regions of osteocalcin expression, a marker of osteoblastic differentiation, were detected along the endothelium of mitral valves that had been subjected in vivo to mechanical stretch.

Conclusion—

Mitral valve leaflets contain endothelial cells with multilineage mesenchymal differentiation potential, including osteogenic differentiation. This unique feature suggests that postnatal mitral valvular endothelium harbors a reserve of progenitor cells that can contribute to osteogenic and chondrogenic VICs.
Enhanced Dispersion of Repolarization Explains Increased Arrhythmogenesis in Severe Versus Therapeutic Hypothermia
Authors: Piktel Joseph S. , Jeyaraj Darwin , Said Tamer H. , Rosenbaum David S. , Wilson Lance D.
Published: December 2010

Background—

Hypothermia is proarrhythmic, and, as the use of therapeutic hypothermia (TH) increases, it is critically important to understand the electrophysiological effects of hypothermia on cardiac myocytes and arrhythmia substrates. We tested the hypothesis that hypothermia-enhanced transmural dispersion of repolarization (DOR) is a mechanism of arrhythmogenesis in hypothermia. In addition, we investigated whether the degree of hypothermia, the rate of temperature change, and cooling versus rewarming would alter hypothermia-induced arrhythmia substrates.

Methods and Results—

Optical action potentials were recorded from cells spanning the transmural wall of canine left ventricular wedge preparations at baseline (36°C), during cooling and during rewarming. Electrophysiological parameters were examined while varying the depth of hypothermia. On cooling to 26°C, DOR increased from 26±4 ms to 93±18 ms (
P
=0.021); conduction velocity decreased from 35±5 cm/s to 22±5 cm/s (
P
=0.010). On rewarming to 36°C, DOR remained prolonged, whereas conduction velocity returned to baseline. Conduction block and reentry was observed in all severe hypothermia preparations. Ventricular fibrillation/ventricular tachycardia was seen more during rewarming (4/5) versus cooling (2/6). In TH (n=7), cooling to 32°C mildly increased DOR (31±6 to 50±9,
P
=0.012), with return to baseline on rewarming and was associated with decreased arrhythmia susceptibility. Increased rate of cooling did not further enhance DOR or arrhythmogenesis.

Conclusions—

Hypothermia amplifies DOR and is a mechanism for arrhythmogenesis. DOR is directly dependent on the depth of cooling and rewarming. This provides insight into the clinical observation of a low incidence of arrhythmias in TH and has implications for protocols for the clinical application of TH.
Natural History of Perihematomal Edema After Intracerebral Hemorrhage Measured by Serial Magnetic Resonance Imaging
Authors: Venkatasubramanian Chitra , Mlynash Michael , Finley-Caulfield Anna , Eyngorn Irina , Kalimuthu Rajalakshmi , Snider R.W. , Wijman Christine Anne
Published: December 2010

Background and Purpose—

Knowledge on the natural history and clinical impact of perihematomal edema (PHE) associated with intracerebral hemorrhage is limited. We aimed to define the time course, predictors, and clinical significance of PHE measured by serial magnetic resonance imaging.

Methods—

Patients with primary supratentorial intracerebral hemorrhage ≥5 cm
3
underwent serial MRIs at prespecified intervals during the first month. Hematoma (H
v
) and PHE (E
v
) volumes were measured on fluid-attenuated inversion recovery images. Relative PHE was defined as E
v
/H
v
. Neurologic assessments were performed at admission and with each MRI. Barthel Index, modified Rankin scale, and extended Glasgow Outcome scale scores were assigned at 3 months.

Results—

Twenty-seven patients with 88 MRIs were prospectively included. Median H
v
and E
v
on the first MRI were 39 and 46 cm
3
, respectively. Median peak absolute E
v
was 88 cm
3
. Larger hematomas produced a larger absolute E
v
(
r
2
=0.6) and a smaller relative PHE (
r
2
=0.7). Edema volume growth was fastest in the first 2 days but continued until 12±3 days. In multivariate analysis, a higher admission hematocrit was associated with a greater delay in peak PHE (
P
=0.06). Higher admission partial thromboplastin time was associated with higher peak rPHE (
P
=0.02). Edema volume growth was correlated with a decline in neurologic status at 48 hours (81 vs 43 cm
3
,
P
=0.03) but not with 3-month functional outcome.

Conclusions—

PHE volume measured by MRI increases most rapidly in the first 2 days after symptom onset and peaks toward the end of the second week. The timing and magnitude of PHE volume are associated with hematologic factors. Its clinical significance deserves further study.
Carotid Artery Wall Thickness and Risk of Stroke Subtypes
Authors: Ohira Tetsuya , Shahar Eyal , Iso Hiroyasu , Chambless Lloyd E. , Rosamond Wayne D. , Sharrett A. Richey , Folsom Aaron R.
Published: December 2010

Background and Purpose—

Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke.

Methods—

Between 1987 and 1989, 13 560 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities (ARIC) study. Incident strokes were ascertained by hospital surveillance.

Results—

During an average follow-up of 15.7 years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness levels. Although this positive association was observed for all stroke subtypes, the age-, gender-, and race-adjusted risk ratios were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61 mm), the adjusted risk ratios for those in the highest quintile (≥0.85 mm) of intima-media thickness were 2.55 (95% CI, 1.09–5.94) for hemorrhagic, 2.89 (95% CI, 1.50–5.54) for lacunar, 3.61 (95% CI, 2.33–5.99) for nonlacunar, and 6.12 (95% CI, 2.71–13.9) for cardioembolic stroke. The risk ratios were attenuated by additional adjustment for covariates but remained statistically significant for nonlacunar and cardioembolic strokes (
P
for trend <0.001, respectively). The association between carotid intima-media thickness and lacunar stroke was somewhat stronger in blacks than in whites (
P
for interaction=0.07).

Conclusions—

Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.
Microbleeds Are Independently Related to Gait Disturbances in Elderly Individuals With Cerebral Small Vessel Disease
Authors: de Laat Karlijn F. , van den Berg Heleen A.C. , van Norden Anouk G.W. , Gons Rob A.R. , Olde Rikkert Marcel G.M. , de Leeuw Frank-Erik
Published: December 2010

Background and Purpose—

Cerebral small vessel disease (SVD), including white matter lesions and lacunar infarcts, is related to gait disturbances. Microbleeds (MB) are another manifestation of SVD, but their clinical impact remains unclear. We therefore investigated the relation between the number and location of MB and gait, independently of white matter lesions and lacunar infarcts.

Methods—

MRI scanning was performed in 485 nondemented elderly individuals with cerebral SVD. The number and location of MB were rated. Gait was assessed with a GAITRite system and the Tinetti and Timed-Up-and-Go tests. MB were related to gait parameters by age, height, total brain volume, white matter lesions, and number of lacunar infarcts-adjusted linear regression.

Results—

A higher number of MB was independently related to a shorter stride length and poorer performance on the Tinetti and Timed-Up-and-Go tests. These relations seemed to be explained by MB in the temporal and frontal lobe and basal ganglia, including the thalamus.

Conclusions—

This study offers the first indication that MB may be associated with gait disturbances, independently of other coexisting markers of SVD.
Increased Risk of Stroke in Patients With Bullous Pemphigoid
Authors: Yang Ya-Wen , Chen Yi-Hua , Xirasagar Sudha , Lin Herng-Ching
Published: December 2010

Background and Purpose—

Although previous research reveals that cardiovascular events and thromboembolic diseases are important causes of death in patients with bullous pemphigoid (BP), the risk of stroke after the diagnosis of BP relative to the general population remains unknown. Using a randomly selected nationwide population-based sample, this study investigates the risk of stroke in patients with BP compared with unaffected individuals of a similar age.

Methods—

This study analyzes data from Taiwan's National Health Insurance Research Database. This sample included 390 patients with BP and 1950 matched subjects as a comparison group. Stratified Cox proportional hazard regressions were used to calculate the 3-year stroke risk for these 2 groups after adjusting for patient's age, sex, and comorbid medical disorders at baseline.

Results—

Of the 2340 patients in the sample, 312 patients (13.3%) had strokes during the 3-year follow-up period, 89 (22.8% of the patients with BP) in the study group and 223 (11.4% of patients without BP) in the comparison group (
P
<0.001). The hazard ratio for stroke for patients with BP was 2.37 (95% CI, 1.78 to 3.15;
P
<0.001) times as high that for patients without BP within the 3-year follow-up period after adjusting for hypertension, diabetes, hyperlipidemia, heart failure, atrial fibrillation, and coronary heart disease.

Conclusions—

Patients with BP have an increased risk of stroke and particularly ischemic stroke.
Bone Marrow-Derived Cells Contribute to Vascular Endothelial Growth Factor–Induced Angiogenesis in the Adult Mouse Brain by Supplying Matrix Metalloproteinase-9
Authors: Hao Qi , Su Hua , Palmer Daniel , Sun Baoliang , Gao Peng , Yang Guo-Yuan , Young William L.
Published: December 2010

Background and Purpose—

Our previous studies have shown that bone marrow-derived cells (BMDCs) home to a brain angiogenic focus. The angiogenic response to vascular endothelial growth factor (VEGF) stimulation is reduced in matrix metalloproteinase-9 (MMP-9) knockout mice. We hypothesized that BMDCs contribute to VEGF-induced angiogenesis by supplying MMP-9.

Methods—

Bone marrow (BM) transplantation was conducted using MMP-9 knockout (MMP-9 KO) or wild-type (WT) mice as both donors and recipients. Adeno-associated viral vectors expressing VEGF or LacZ were injected into the striatum 4 weeks after BM transplantation. Circulating white blood cells (WBCs), microvessel density, number of BMDCs, and MMP-9 activity around the injection site were analyzed.

Results—

Two weeks after vector injection, circulating WBCs increased in WT mice but not in MMP-9 KO mice. VEGF overexpression increased microvessel density by 38% in WT mice 4 weeks after vector injection (
P
=0.0001). After transplantation of MMP-9 KO BM to WT mice, microvessel density only increased 18% after VEGF stimulation (
P
=0.037), with MMP-9 activity reduced to 35% of the level of WT mice (
P
<0.01). There was minimal angiogenic response in MMP-9 KO mice with MMP-9 KO BM (
P
=0.28). Transplantation of WT BM to MMP-9 KO mice restored brain angiogenic response to 92% of the WT level, ie, a 30% increase of microvessel density with VEGF overexpression (
P
=0.0006); MMP-9 activity was similar to that in WT mice.

Conclusions—

BM-derived MMP-9 plays an important role in BM cell mobilization and focal angiogenesis in the brain in response to VEGF stimulation.
Red Meat Consumption and Risk of Stroke in Swedish Women
Authors: Larsson Susanna C. , Virtamo Jarmo , Wolk Alicja
Published: December 2010

Background and Purpose—

High red meat consumption has been associated with increased risk of some cancers and may also be a risk factor for cardiovascular diseases. However, epidemiological studies of red meat consumption in relation to risk of stroke are very limited. Our objective was to examine the association between red meat consumption and stroke incidence in the Swedish Mammography Cohort.

Methods—

We prospectively followed 34 670 women without cardiovascular disease and cancer at baseline. Participants completed a self-administered questionnaire on diet and other risk factors for cardiovascular diseases in 1997. Cox proportional hazards models were used to estimate multivariable-adjusted relative risks (RR) and 95% CI.

Results—

During a mean follow-up of 10.4 years, we ascertained 1680 incident cases of stroke, comprising 1310 cerebral infarction, 154 intracerebral hemorrhage, 79 subarachnoid hemorrhage, and 137 unspecified stroke. Total red meat and processed meat consumption was associated with a statistically significant increased risk of cerebral infarction, but not of total stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The multivariable RR of cerebral infarction for the highest versus the lowest quintile of consumption were 1.22 (95% CI, 1.01–1.46) for red meat and 1.24 (95% CI, 1.04–1.49) for processed meat. Fresh (unprocessed) meat consumption was not associated with total stroke or with any stroke subtype.

Conclusion—

Findings from this study suggest that red and processed meat consumption may increase the risk of cerebral infarction in women.
Intracranial Atherosclerosis
Authors: Arenillas Juan F.
Published: December 2010

The most relevant ideas discussed in this article are described here. Intracranial atherosclerotic disease (ICAD) represents the most common cause of ischemic stroke worldwide. Its importance in whites may have been underestimated. New technical developments, such as high-resolution MRI, allow direct assessment of the intracranial atherosclerotic plaque, which may have a profound impact on ICAD diagnosis and therapy in the near future. Early detection of ICAD may allow therapeutic intervention while the disease is still asymptomatic. The Barcelonès Nord and Maresme Asymptomatic Intracranial Atherosclerosis Study is presented here. The main prognostic factors that characterize the patients who are at a higher risk for ICAD recurrence are classified and discussed. The best treatment for ICAD remains to be established. The Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Study is currently ongoing to address this crucial issue. These and other topics will be discussed at the Fifth International Intracranial Atherosclerosis Conference (Valladolid, Spain, autumn 2011).
Reperfusion Therapies for Acute Ischemic Stroke
Authors: Molina Carlos A.
Published: December 2010

Background and Purpose—

Arterial recanalization and subsequent reperfusion have extensively demonstrated their ability to restore the brain function when performed shortly after acute ischemic stroke. However, arterial recanalization does not necessarily lead to brain tissue reperfusion.

Summary of Report—

This review provides an update of current approaches to improve the efficacy profile of brain tissue reperfusion within and beyond the therapeutic window, including the use of novel thrombolytic agents, bridging intravenous and intra-arterial therapies, and mechanical clot retrieval or aspiration.

Conclusions—

There are still several challenges in the near future of reperfusion therapy for acute ischemic stroke, such as improving the ultra-early access to treatment within the “golden hour,” extending the therapeutic window beyond the current 4.5-hour time window, and developing novel thrombolitics or combined approaches to improve treatment efficacy.
Anatomy of Stroke Injury Predicts Gains From Therapy
Authors: Riley Jeff D. , Le Vu , Der-Yeghiaian Lucy , See Jill , Newton Jennifer M. , Ward Nick S. , Cramer Steven C.
Published: December 2010

Background and Purpose—

Many therapies are emerging that aim to improve motor function in people with stroke. Identifying key biological substrates needed for treatment gains would help to predict treatment effects and to maximize treatment impact. The current study addressed the hypothesis that behavioral gains from therapy targeting distal upper extremity are predicted by the structural integrity of key motor system white matter tracts.

Methods—

Twenty-three subjects with chronic left-sided stroke underwent robotic therapy targeting the distal right upper extremity. MRI was obtained at baseline and used to outline the infarct. For each subject, the degree to which stroke injured each of 4 descending white matter tracts (from the primary motor cortex, supplementary motor area, dorsal premotor cortex, and ventral premotor cortex, respectively) was determined. Correlations between tract-specific injury and behavioral gains from therapy were then examined.

Results—

Numerous examples were found whereby tract-specific injury predicted treatment gains. The strongest correlations pertained to stroke injury to tracts descending from the primary motor cortex and dorsal premotor cortex. Infarct volume and baseline behavior were weak predictors of treatment gains.

Conclusions—

Extent of injury to specific motor tracts predicts behavioral gains from treatment in subjects with chronic stroke. This supports a role for these tracts in mediating treatment effects and reinforces the importance of lesion location in stroke. Tract-specific injury was stronger than infarct volume or baseline clinical status at predicting gains, identifies subjects with sufficient biological substrate to improve from therapy, and so might be useful as an entry criterion in repair-based trials.
Imaging Evaluation of Acute Ischemic Stroke
Authors: Wechsler Lawrence R.
Published: December 2010

Background and Purpose—

Imaging is an important aspect of decisions regarding treatment for acute stroke. New imaging techniques using MRI and CT enable estimation of tissue viability. This information may be useful to select patients for acute stroke therapies.

Summary of Report—

Several clinical trials identified patients with penumbra based on MRI or CT imaging. The results indicate patients with penumbra by imaging improve with reperfusion, but it is not yet clear that thrombolysis is beneficial when patients are selected on this basis. New quantitative techniques for assessing perfusion and diffusion may improve these results.

Conclusion—

Identifying reversible patterns on MRI or CT perfusion imaging may ultimately yield better results than the mismatch concept that is currently under active investigation.
Hospital-Level Variation in Mortality and Rehospitalization for Medicare Beneficiaries With Acute Ischemic Stroke
Authors: Fonarow Gregg C. , Smith Eric E. , Reeves Mathew J. , Pan Wenqin , Olson DaiWai , Hernandez Adrian F. , Peterson Eric D. , Schwamm Lee H. ,   for the Get With The Guidelines Steering Committee and Hospitals
Published: December 2010

Background and Purpose—

Stroke is the second leading cause of hospital admission among older adults in the United States. However, little is known regarding contemporary ischemic stroke mortality and rehospitalization rates for Medicare beneficiaries and how they vary by hospital.

Methods—

We analyzed outcome data from 91 134 Medicare fee-for-service beneficiaries treated at 625 Get With The Guidelines–Stroke hospitals between April 2003 and December 2006. Within each hospital, 30-day and 1-year death or all-cause readmission rates were calculated with and without risk adjustment.

Results—

In this cohort, mean age was 79.3 years, 58% were female, and 82% were white. In-hospital, 30-day, and 1-year unadjusted mortality from admission were 6.1%, 14.1%, and 31.1%, respectively, for participating hospitals. The median hospital-level 30-day unadjusted death or readmission rate after discharge was 21.4% (10th to 90th 14.4% to 28.6%). The overall rate of death or rehospitalization within 1 year of hospital discharge was 61.9%. Risk-adjusted rates varied widely by hospital at each time point. There were no improvements in death or rehospitalization from 2003 to 2006. Hospital-level performance in risk-adjusted outcomes did not significantly differ by size or primary stroke center designation, but academic hospitals and those in the Northeast or West had slightly more favorable outcomes.

Conclusions—

Nearly two thirds of the Medicare beneficiaries discharged after ischemic stroke died or were rehospitalized within 1 year, but hospital-level outcomes varied considerably. These findings underscore the need to better understand the patterns and causes of deaths and readmission after ischemic stroke and to develop strategies aimed at avoiding those that are preventable.
Role of Iron in Brain Injury After Intraventricular Hemorrhage
Authors: Chen Zhi , Gao Chao , Hua Ya , Keep Richard F. , Muraszko Karin , Xi Guohua
Published: December 2010

Background and Purpose—

Intraventricular extension of hemorrhage is a predictor of poor outcome in intracerebral hemorrhage, and iron overload contributes to brain injury after intracerebral hemorrhage. The current study investigated the role of iron in ventricular dilatation and neuronal death in a rat model of intraventricular hemorrhage (IVH).

Methods—

There were 2 parts in this study. First, male Sprague-Dawley rats had a 200-μL injection of either autologous blood or saline into the right lateral ventricle and were euthanized at different time points. Rats had MRI and brains were used for Western blot analysis, immunohistochemistry, histology, and brain tissue nonheme iron measurements. Second, rats had IVH and were treated with deferoxamine or vehicle, and rats were euthanized 4 weeks later for brain tissue loss and lateral ventricle size measurements.

Results—

IVH resulted in brain iron accumulation, bilateral enlargement of the lateral ventricles, and hippocampal brain tissue loss. Iron accumulation was associated with upregulation of heme oxygenase-1 and ferritin. Systemic deferoxamine treatment reduced IVH-induced ventricular enlargement (eg, day 28: 32.7±10.6 vs 43.8±9.7 mm
3
in vehicle-treated group, n=8 to 9;
P
<0.05) and hippocampal brain tissue loss (hippocampal volume: 89.0±2.7 vs 85.2±4.1 mm
3
in the vehicle-treated group;
P
<0.05).

Conclusions—

Iron has a role in brain injury after IVH. Deferoxamine may be a therapy for patients with IVH or intraventricular extension after intracerebral hemorrhage.
Citicoline Preclinical and Clinical Update 2009–2010
Authors: Dávalos Antoni , Secades Julio
Published: December 2010

Citicoline is a neuroprotectant and neurorestorative drug that is used in the treatment of acute ischemic stroke in some countries. The research with this compound continues. In this review, we focus on the latest publications or communications or both and on the major ongoing experimental and clinical projects involving citicoline in stroke recovery.
Where Did the Mullahs Go? Oral Histories from Rural Uzbekistan
Authors: Kamp Marianne
Published: December 2010

Oral histories with elderly collective farmers in Uzbekistan, who recalled the establishment of their collective farms in the 1930s, depict the closing of village mosques and the disappearance of many rural mullahs. Anti-religious policies focused on Islamic institutions and paid functionaries; however, mullahs were left in many villages, and they continued to lead Islamic practices clandestinely. Religious leaders who had never been closely tied to Islamic institutions, such as otins (women religious leaders) were not targeted for arrest and removal. Our respondents remembered times when it was difficult to engage in any practice of Islam publicly, but they emphasized that nonetheless, community members fulfilled the ritual that they deemed most essential: the funeral prayer.
Red Orientalism: Mikhail Pavlovich and Marxist Oriental Studies In Early Soviet Russia
Authors: Kemper Michael
Published: December 2010

Marxist Oriental Studies in early Soviet Russia emerged in opposition to the 'bourgeois' Russian tradition of classical Oriental scholarship; rather than studying texts and history, Bolshevik Orientalists saw their task in providing the Soviet government with the necessary political and socio-economic knowledge to support the liberation of the contemporary East from colonialism and imperialism. After a failed attempt to stir revolutions in the Muslim World via a 'Congress of the Peoples of the East' in Baku in 1920 and a 'University of Social Sciences for Workers of the Orient' in the same city, the Bolsheviks established an Oriental Studies teaching institute as well as an Oriental Studies Association in Moscow, both under Stalin's Commissariat for Nationalities. The article traces the biography of the key figure in these organizations, Mikhail P. Pavlovich (1871-1927). Pavlovich was not a professional Orientalist but a prolific Marxist writer and propaganda lecturer on military affairs, world transportation lines, imperialism and colonialism—arguably the issues that made the Bolsheviks interested in the Orient. While Pavlovich's Marxist Oriental Studies (and his journal Novyi Vostok, 'The New Orient') were 'anti-Orientalist' in their rhetoric, it can be shown that they used the same notions and methods for which they condemned Western Oriental Studies.