bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunoliposomal Delivery of 213Bi for α-Emitter Targeting of Metastatic Breast Cancer
Authors: Lingappa Mohanambe , Song Hong , Thompson Sarah , Bruchertseifer Frank , Morgenstern Alfred , Sgouros George
Published: July 2010

Current treatment for late-stage metastatic breast cancer is largely palliative. α-Particles are highly potent, short-range radiation emissions capable of sterilizing individual cells with one to three traversals of the cell nucleus. The α-emitter, 213Bi (T1/2 = 45.6 min), was conjugated to a 100-nm diameter liposomal-CHX-A″-DTPA construct, upon which the rat HER2/neu reactive antibody, 7.16.4, was grafted. A conjugation time of 10 minutes was achieved giving a specific activity corresponding to 0.1 213Bi atom per liposome; stability in vitro and in vivo was confirmed. Efficacy in a rat/neu transgenic mouse model of metastatic mammary carcinoma was investigated. Three days after left cardiac ventricular injection of 105 rat HER-2/neu–expressing syngeneic tumor cells, macrophage-depleted Neu-N mice were treated by i.v. injection with (a) 19.2 MBq (520 μCi) of liposome-CHX-A″-DTPA-213Bi, (b) 19.2 MBq of liposome-CHX-A″-DTPA-213Bi-7.16.4, (c) 4.44 MBq (120 μCi) of 213Bi-7.16.4, and (d) cold (nonradioactive) liposome-CHX-A″-DTPA-7.16.4 as control. Treatment with (a) increased median survival time to 34 days compared with 29 days for the untreated controls (P = 0.013) and 27 days for treated cold controls. Treatment with the radiolabeled antibody–conjugated liposome (b) increased median survival time to 38 days (P = 0.0002 relative to untreated controls). The radiolabeled antibody–treated group (c) gave a median survival of 39 days, which was similar to that for the radiolabeled antibody–conjugated liposome-treated group (P = 0.5). We have shown that the 213Bi radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of 213Bi in this animal model. Cancer Res; 70(17); 6815–23. ©2010 AACR.
Biomarkers Predicting Outcome in Patients with Advanced Renal Cell Carcinoma: Results from Sorafenib Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial
Authors: Peña Carol , Lathia Chetan , Shan Minghua , Escudier Bernard , Bukowski Ronald M.
Published: July 2010

Purpose: Plasma proteins [vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), carbonic anhydrase IX (CAIX), tissue inhibitor of metalloproteinase 1 (TIMP-1), and Ras p21] and one tumor gene (VHL) were analyzed to identify prognostic biomarkers or indicators of response to sorafenib in a subset of patients enrolled in the Treatment Approaches in Renal Cancer Global Evaluation Trial.

Experimental Design: Nine hundred three patients with advanced renal cell carcinoma (RCC) were randomized to 400 mg sorafenib twice a day or placebo. Samples collected at baseline and after 3 and 12 weeks were subjected to enzyme-linked immunosorbent assays. VHL exons were sequenced from tumor biopsies.

Results: Baseline biomarker data were available for VEGF (n = 712), sVEGFR-2 (n = 713), CAIX (n = 128), TIMP-1 (n = 123), Ras p21 (n = 125), and VHL mutational status (n = 134). Higher Eastern Cooperative Oncology Group performance status (ECOG PS) score correlated with elevated baseline VEGF (P < 0.0001) and a higher incidence of VHL mutations (P = 0.008), whereas higher Memorial Sloan-Kettering Cancer Center (MSKCC) score correlated with elevated VEGF (P < 0.0001), CAIX (P = 0.027), and TIMP-1 (P = 0.0001).

Univariable analyses of baseline levels in the placebo cohort identified VEGF (P = 0.0024), CAIX (P = 0.034), TIMP-1 (P = 0.001), and Ras p21 (P = 0.016) as prognostic biomarkers for survival. TIMP-1 remained prognostic for survival in a multivariable analysis model (P = 0.002) that also included ECOG PS, MSKCC score, and the other biomarkers assayed. In the placebo cohort, TIMP-1 (P < 0.001) and Ras p21 (P = 0.048) levels increased at 12 weeks. In the sorafenib cohort, VEGF levels increased at 3 and 12 weeks of treatment (both weeks P < 0.0001), whereas sVEGFR-2 (both weeks P < 0.0001) and TIMP-1 levels (P = 0.002, week 3; P = 0.006, week 12) decreased.

Conclusions: VEGF, CAIX, TIMP-1, and Ras p21 levels were prognostic for survival in RCC patients. Of these, TIMP-1 has emerged as being independently prognostic. Clin Cancer Res; 16(19); 4853–63. ©2010 AACR.
The Effectiveness of Off-Protocol Adjuvant Chemotherapy for Patients with Urothelial Carcinoma of the Urinary Bladder
Authors: Svatek Robert S. , Shariat Shahrokh F. , Lasky Robert E. , Skinner Eila C. , Novara Giacomo , Lerner Seth P. , Fradet Yves , Bastian Patrick J. , Kassouf Wassim , Karakiewicz Pierre I. , Fritsche Hans-Martin , Müller Stefan C. , Izawa Jonathan I. , Ficarra Vincenzo , Sagalowsky Arthur I. , Schoenberg Mark P. , Siefker-Radtke Arlene O. , Millikan Randall E. , Dinney Colin P.N.
Published: July 2010

Purpose: The role of adjuvant chemotherapy for patients with high-risk urothelial carcinoma of the bladder (UCB) is not well defined. Here we address the value of adjuvant chemotherapy in patients undergoing radical cystectomy for UCB in an off-protocol routine clinical setting.

Experimental Design: We collected and analyzed data from 11 centers contributing retrospective cohorts of patients with UCB treated with radical cystectomy without neoadjuvant chemotherapy. Patients were grouped into quintiles based on their risk of disease progression using estimates from a fitted multivariable Cox proportional hazards model. The association of adjuvant chemotherapy with survival was explored across separate quintiles.

Results: The cohort consisted of 3,947 patients, 932 (23.6%) of whom received adjuvant chemotherapy. Adjuvant chemotherapy was independently associated with improved survival (hazard ratio, 0.83; 95% confidence interval, 0.72-0.97%, P = 0.017). However, the effect of adjuvant chemotherapy was significantly modified by the individual's risk of disease progression such that an increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (P < 0.001). There was a significant improvement in survival between the treated and nontreated patients in the highest-risk quintile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.90; P = 0.002). This group was characterized by an estimated 32.8% 5-year probability of cancer-specific survival, with 86.6% of patients having both advanced pathologic stage (≥T3) and nodal involvement.

Conclusion: Adjuvant chemotherapy is associated with a significant improvement in survival for patients treated in an off-protocol clinical setting. Selective administration in patients at the highest risk for disease progression, such as those with advanced pathologic stage and nodal involvement, may optimize the therapeutic benefit of adjuvant chemotherapy. Clin Cancer Res; 16(17); 4461–7. ©2010 AACR.
Genome-Wide Catalogue of Chromosomal Aberrations in Barrett's Esophagus and Esophageal Adenocarcinoma: A High-Density Single Nucleotide Polymorphism Array Analysis
Authors: Gu Jian , Ajani Jaffer A. , Hawk Ernest T. , Ye Yuanqing , Lee Jeffrey H. , Bhutani Manoop S. , Hofstetter Wayne L. , Swisher Stephen G. , Wang Kenneth K. , Wu Xifeng
Published: July 2010

To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism arrays to profile chromosomal aberrations at each of the four sequential progression stages, Barrett's metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend = 4.82 × 10−7), and the mean percentages of single nucleotide polymorphisms with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC. Loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site regions in the human genome. However, RUNX1 at 21q22 seemed to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage. Cancer Prev Res; 3(9); 1176–86. ©2010 AACR.
Relationships Between Sleep Duration and von Willebrand Factor, Factor VII, and Fibrinogen
Authors: Miller Michelle A. , Kandala Ngianga-Bakwin , Kumari Meena , Marmot Michael G. , Cappuccio Francesco P.
Published: July 2010

Objective—

To examine the relationship between sleep duration and hemostatic factors in a well-characterized cohort.

Methods and Results—

The relationship between self-reported sleep duration and von Willebrand factor (vWF), fibrinogen, and factor VII was examined in approximately 6400 individuals from the Whitehall II Study. The analysis was stratified by sex (interaction
P
<0.001). After multiple adjustments, vWF levels were significantly higher in men with both short sleep duration (≤6 hours per night; 1.05 [95% CI, 1.01 to 1.08] [data given as geometric mean]) and long sleep duration (≥8 hours per night; 1.05 [95% CI, 1.02 to 1.08]) compared with those who slept 7 hours (
P
<0.05 for both). In women, levels of vWF were significantly higher in individuals who slept 8 hours or longer (1.11 [95% CI, 1.06 to 1.16]) compared with 7 hours (
P
<0.05). This difference was observed in premenopausal and postmenopausal women. In women, the association was nonlinear (
P
=0.02), but not in men (
P
=0.09). No statistically significant associations between sleep duration and fibrinogen or factor VII were observed.

Conclusion—

Men who slept for short and long durations had higher vWF levels. In women, there was a significant nonlinear association. The highest levels were observed in long sleepers, irrespective of menopausal status. No major associations between sleep and factor VII or fibrinogen were observed. Longitudinal studies are required to investigate causality.
C-Reactive Protein, Interleukin 6, Fibrinogen and Risk of Sudden Death in European Middle-Aged Men: The PRIME Study
Authors: Empana Jean-Philippe , Jouven Xavier , Canouï-Poitrine Florence , Luc Gerald , Tafflet Muriel , Haas Bernadette , Arveiler Dominique , Ferrieres Jean , Ruidavets Jean-Bernard , Montaye Michèle , Yarnell John , Morange Pierre , Kee Frank , Evans Alun , Amouyel Philippe , Ducimetiere Pierre
Published: July 2010

Objective—

To examine prospectively the association of high-sensitivity C-reactive protein, interleukin 6, and fibrinogen with sudden death in asymptomatic European men.

Methods and Results—

Among the 9771 men from the Etude PRospective de l’Infarctus du Myocarde (PRIME) Study, 664 had a first coronary heart disease over 10 years, including 50 sudden deaths, 34 nonsudden coronary deaths, and 580 nonfatal coronary heart disease events. For each outcome, 2 matched controls, who were free of coronary heart disease at the index date, were randomly selected from the initial cohort (nested case control study design). There was a 3-fold increased risk (95% CI, 1.20 to 7.81) of sudden death between the upper and the lower third of interleukin 6 after adjustment for baseline confounders in conditional logistic regression analysis. Neither high-sensitivity C-reactive protein (hazard ratio
third versus first tertile
=1.27; 95% CI, 0.51 to 3.17) nor fibrinogen (hazard ratio
third versus first tertile
=1.90; 95% CI, 0.76 to 4.75) was associated with sudden death. For comparison, there was a 6-fold increased risk of nonsudden coronary death from the highest compared with the lowest tertile of fibrinogen and a trend toward an association with higher C-reactive protein and higher interleukin 6. All 3 inflammatory biomarkers were moderately, but significantly, associated with nonfatal coronary heart disease.

Conclusion—

Interleukin 6, but not high-sensitivity C-reactive protein or fibrinogen, is an independent predictor of sudden death in asymptomatic European men.
Kruppel-Like Factor 2 Regulates Endothelial Barrier Function
Authors: Lin Zhiyong , Natesan Viswanath , Shi Hong , Dong Fei , Kawanami Daiji , Mahabeleshwar Ganapati H. , Atkins G. Brandon , Nayak Lalitha , Cui Yingjie , Finigan James H. , Jain Mukesh K.
Published: July 2010

Objective—

A central function of the endothelium is to serve as a selective barrier that regulates fluid and solute exchange. Although perturbation of barrier function can contribute to numerous disease states, our understanding of the molecular mechanisms regulating this aspect of endothelial biology remains incompletely understood. Accumulating evidence implicates the Kruppel-like factor 2 (KLF2) as a key regulator of endothelial function. However, its role in vascular barrier function is unknown.

Methods and Results—

To assess the role of KLF2 in vascular barrier function in vivo, we measured the leakage of Evans blue dye into interstitial tissues of the mouse ear after treatment with mustard oil. By comparison with KLF2
+/+
mice, KLF2
+/−
mice exhibited a significantly higher degree of vascular leak. In accordance with our in vivo observation, adenoviral overexpression of KLF2 in human umbilical vein endothelial cells strongly attenuated the increase of endothelial leakage by thrombin and H
2
O
2
as measured by fluorescein isothiocyanate dextrans (FITC-dextran) passage. Conversely, KLF2 deficiency in human umbilical vein endothelial cells and primary endothelial cells derived from KLF2
+/−
mice exhibited a marked increase in thrombin and H
2
O
2
-induced permeability. Mechanistically, our studies indicate that KLF2 confers barrier-protection via differential effects on the expression of key junction protein occludin and modification of a signaling molecule (myosin light chain) that regulate endothelial barrier integrity.

Conclusion—

These observations identify KLF2 as a novel transcriptional regulator of vascular barrier function.
Neuregulin 1 Sustains the Gene Regulatory Network in Both Trabecular and Nontrabecular Myocardium
Authors: Lai Donna , Liu Xifu , Forrai Ariel , Wolstein Orit , Michalicek Jan , Ahmed Ishtiaq , Garratt Alistair N. , Birchmeier Carmen , Zhou Mingdong , Hartley Lynne , Robb Lorraine , Feneley Michael P. , Fatkin Diane , Harvey Richard P.
Published: July 2010

Rationale:

The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide.

Objective:

To understand the role of Nrg1 in heart development through analysis of null and hypomorphic
Nrg1
mutant mice.

Methods and Results:

Chamber domains were correctly specified in
Nrg1
mutants, although chamber-restricted genes
Hand1
and
Cited1
failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2–dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants.

Conclusions:

The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1–ErbB1/4–Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.
Sarcoplasmic Reticulum Ca
2+
Pumping Kinetics Regulates Timing of Local Ca
2+
Releases and Spontaneous Beating Rate of Rabbit Sinoatrial Node Pacemaker Cells
Authors: Vinogradova Tatiana M. , Brochet Didier X.P. , Sirenko Syevda , Li Yue , Spurgeon Harold , Lakatta Edward G.
Published: July 2010

Rationale:

Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca
2+
releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na
+
-Ca
2+
exchange current (
I
NCX
), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca
2+
transient and LCR appearance, defines the time of late diastolic depolarization
I
NCX
activation. Mechanisms that control the LCR period, however, are still unidentified.

Objective:

To determine dependence of the LCR period on SR Ca
2+
refilling kinetics and establish links between regulation of SR Ca
2+
replenishment, LCR period, and spontaneous cycle length.

Methods and Results:

Spontaneous APs and SR luminal or cytosolic Ca
2+
were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca
2+
following AP-induced Ca
2+
transient was highly correlated with the time to 90% decay of cytosolic Ca
2+
transient (T-90
C
). Local SR Ca
2+
depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca
2+
refilling. Inhibition of SR Ca
2+
pump by cyclopiazonic acid dose-dependently suppressed spontaneous SANCs firing up to ≈50%. Cyclopiazonic acid and graded changes in phospholamban phosphorylation produced by β-adrenergic receptor stimulation, phosphodiesterase or protein kinase A inhibition shifted T-90
C
and proportionally shifted the LCR period and spontaneous cycle length (
R
2
=0.98).

Conclusions:

The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca
2+
replenishment, which is critically dependent on SR pumping rate, Ca
2+
available for pumping, supplied by L-type Ca
2+
channel, and ryanodine receptor Ca
2+
release flux, each of which is modulated by cAMP-mediated protein kinase A–dependent phosphorylation.
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage
Authors: Morgenstern Lewis B. , Hemphill J. Claude , Anderson Craig , Becker Kyra , Broderick Joseph P. , Connolly E. Sander , Greenberg Steven M. , Huang James N. , Macdonald R. Loch , Messé Steven R. , Mitchell Pamela H. , Selim Magdy , Tamargo Rafael J.
Published: July 2010

Purpose—

The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.

Methods—

A formal literature search of MEDLINE was performed. Data were synthesized with the use of evidence tables. Writing committee members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Council’s Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statements Oversight Committee and Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years’ time.

Results—

Evidence-based guidelines are presented for the care of patients presenting with intracerebral hemorrhage. The focus was subdivided into diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence, and future considerations.

Conclusions—

Intracerebral hemorrhage is a serious medical condition for which outcome can be impacted by early, aggressive care. The guidelines offer a framework for goal-directed treatment of the patient with intracerebral hemorrhage.
Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction
Authors: Allen Claire , Srivastava Kirtiman , Bayraktutan Ulvi
Published: July 2010

Background and Purpose—

Enhanced vascular permeability attributable to disruption of blood–brain barrier results in the development of cerebral edema after stroke. Using an in vitro model of the brain barrier composed of human brain microvascular endothelial cells and human astrocytes, this study explored whether small GTPase RhoA and its effector protein Rho kinase were involved in permeability changes mediated by oxygen-glucose deprivation (OGD), key pathological phenomena during ischemic stroke.

Methods and Results—

OGD increased RhoA and Rho kinase protein expressions in human brain microvascular endothelial cells and human astrocytes while increasing or unaffecting that of endothelial nitric oxide synthase in respective cells. Reperfusion attenuated the expression and activity of RhoA and Rho kinase in both cell types compared to their counterparts exposed to equal periods of OGD alone while selectively increasing human brain microvascular endothelial cells endothelial nitric oxide synthase protein levels. OGD compromised the barrier integrity as confirmed by decreases in transendothelial electric resistance and concomitant increases in flux of permeability markers sodium fluorescein and Evan’s blue albumin across cocultures. Transfection of cells with constitutively active RhoA also increased flux and reduced transendothelial electric resistance, whereas inactivation of RhoA by anti-RhoA Ig electroporation exerted opposite effects. In vitro cerebral barrier dysfunction was accompanied by myosin light chain overphosphorylation and stress fiber formation. Reperfusion and treatments with a Rho kinase inhibitor Y-27632 significantly attenuated barrier breakdown without profoundly altering actin structure.

Conclusions—

Increased RhoA/Rho kinase/myosin light chain pathway activity coupled with changes in actin cytoskeleton account for OGD-induced endothelial barrier breakdown.
Real-Time Continuous Monitoring of Cerebral Blood Flow Autoregulation Using Near-Infrared Spectroscopy in Patients Undergoing Cardiopulmonary Bypass
Authors: Brady Kenneth , Joshi Brijen , Zweifel Christian , Smielewski Peter , Czosnyka Marek , Easley R. Blaine , Hogue Charles W.
Published: July 2010

Background and Purpose—

Individualizing mean arterial blood pressure targets to a patient’s cerebral blood flow autoregulatory range might prevent brain ischemia for patients undergoing cardiopulmonary bypass (CPB). This study compares the accuracy of real-time cerebral blood flow autoregulation monitoring using near-infrared spectroscopy with that of transcranial Doppler.

Methods—

Sixty adult patients undergoing CPB had transcranial Doppler monitoring of middle cerebral artery blood flow velocity and near-infrared spectroscopy monitoring. The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of middle cerebral artery blood flow velocity and mean arterial blood pressure. The cerebral oximetry index was calculated as a similar coefficient between slow waves of cerebral oximetry and mean arterial blood pressure. When cerebral blood flow is autoregulated, Mx and cerebral oximetry index vary around zero. Loss of autoregulation results in progressively more positive Mx and cerebral oximetry index.

Results—

Mx and cerebral oximetry index showed significant correlation (
r
=0.55,
P
<0.0001) and good agreement (bias, 0.08±0.18, 95% limits of agreement: −0.27 to 0.43) during CPB. Autoregulation was disturbed in this cohort during CPB (average Mx 0.38, 95% CI 0.34 to 0.43). The lower cerebral blood flow autoregulatory threshold (defined as incremental increase in Mx >0.45) during CPB ranged from 45 to 80 mm Hg.

Conclusions—

Cerebral blood flow autoregulation can be monitored continuously with near-infrared spectroscopy in adult patients undergoing CPB. Real-time autoregulation monitoring may have a role in preventing injurious hypotension during CPB.

Clinical Trials Registration—

at www.clinicaltrials.gov (NCT00769691).
Continuous Assessment of Cerebral Autoregulation With Near-Infrared Spectroscopy in Adults After Subarachnoid Hemorrhage
Authors: Zweifel Christian , Castellani Gianluca , Czosnyka Marek , Carrera Emmanuel , Brady Kenneth M. , Kirkpatrick Peter J. , Pickard John D. , Smielewski Peter
Published: July 2010

Background and Purpose—

In patients with subarachnoid hemorrhage, the assessment of cerebral autoregulation aids in prognosis as well as detection of vasospasm. Mx is a validated index of cerebral autoregulation based on measures of cerebral perfusion pressure and mean flow velocity on transcranial Doppler but is impractical for longer-term monitoring. Near-infrared spectroscopy is noninvasive and suitable for continuous monitoring of cerebral tissue oxygenation using the Tissue Oxygenation Index. In this study, we compared near-infrared spectroscopy-based indices of cerebral autoregulation (TOx) with Mx in patients with subarachnoid hemorrhage.

Methods—

Arterial blood pressure, intracranial pressure, mean flow velocity, and Tissue Oxygenation Index were recorded. Mx and TOx were calculated as moving correlation coefficients between 10-second averaged values of cerebral perfusion pressure and mean flow velocity and between cerebral perfusion pressure and Tissue Oxygenation Index. We also calculated TOxA, the moving correlation coefficient between arterial blood pressure and Tissue Oxygenation Index.

Results—

Fifty-one recording sessions were performed in 27 patients with subarachnoid hemorrhage with a total duration of 62.5 hours. Correlations of Mx and TOx over time varied markedly among individual recordings. However, time-averaging over the entire recording interval in each of the 51 recordings, we found correlations between Mx and TOx and between Mx and TOxA were highly significant. This correlation was even stronger after correction for multiple sampling for each patient, reaching
r
=0.81 for Mx and TOx and
r
=0.72 for Mx and TOxA.

Conclusion—

Near-infrared spectroscopy can be used to continuously assess cerebral autoregulation in adults after subarachnoid hemorrhage.
Gender Differences in Treatment of Severe Carotid Stenosis After Transient Ischemic Attack
Authors: Poisson Sharon N. , Johnston S. Claiborne , Sidney Stephen , Klingman Jeffrey G. , Nguyen-Huynh Mai N.
Published: July 2010

Background and Purpose—

Gender differences in carotid endarterectomy (CEA) rates after transient ischemic attack are not well studied, although some reports suggest that eligible men are more likely to have CEA than women after stroke.

Methods—

We retrospectively identified all patients diagnosed with transient ischemic attack and ≥70% carotid stenosis on ultrasound in 2003 to 2004 from 19 emergency departments. Medical records were abstracted for clinical data; 90-day follow-up events, including stroke, cardiovascular events, or death; CEA within 6 months; and postoperative 30-day outcomes. We assessed gender as a predictor of CEA and its complications adjusting for demographic and clinical variables as well as time to CEA between groups.

Results—

Of 299 patients identified, 47% were women. Women were older with higher presenting systolic blood pressure and less likely to smoke or to have coronary artery disease or diabetes. Fewer women (36.4%) had CEA than men (53.8%;
P
=0.004). Reasons for withholding surgical treatment were similar in women and men, and there were no differences in follow-up stroke, cardiovascular event, postoperative complications, or death. Time to CEA was also significantly delayed in women.

Conclusions—

Women with severe carotid stenosis and recent transient ischemic attack are less likely to undergo CEA than men, and surgeries are more delayed.
Differential Patterns of Cognitive Decline in Anterior and Posterior White Matter Hyperintensity Progression
Authors: Marquine María J. , Attix Deborah K. , Goldstein Larry B. , Samsa Gregory P. , Payne Martha E. , Chelune Gordon J. , Steffens David C.
Published: July 2010

Background and Purpose—

White matter hyperintensities (WMHs) found on brain MRI in elderly individuals are largely thought to be due to microvascular disease, and its progression has been associated with cognitive decline. The present study sought to determine patterns of cognitive decline associated with anterior and posterior WMH progression.

Methods—

Subjects included 110 normal controls, aged ≥60 years, who were participants in the Duke Neurocognitive Outcomes of Depression in the Elderly study. All subjects had comprehensive cognitive evaluations and MRI scans at baseline and after 2 years. Cognitive composites were created in 5 domains: complex processing speed, working memory, general memory, visual-constructional skills, and language. Change in cognition was calculated using standard regression-based models accounting for variables known to impact serial testing. A semiautomated segmentation method was used to measure WMH extent in anterior and posterior brain regions. Hierarchical multiple linear regression models were used to evaluate which of the 5 measured cognitive domains was most strongly associated with regional (anterior and posterior) and total WMH progression after adjusting for demographics (age, sex, and education).

Results—

Decline in complex processing speed was independently associated with both anterior (

r
2

=0.06,
P
=0.02) and total WMH progression (

r
2

=0.05,
P
=0.04). In contrast, decline in visual-constructional skills was uniquely associated with posterior progression (

r
2

=0.05,
P
<0.05).

Conclusions—

Distinct cognitive profiles are associated with anterior and posterior WMH progression among normal elders. These differing profiles need to be considered when evaluating the cognitive correlates of WMHs.
Thrombolysis With 0.6 mg/kg Intravenous Alteplase for Acute Ischemic Stroke in Routine Clinical Practice
Authors: Nakagawara Jyoji , Minematsu Kazuo , Okada Yasushi , Tanahashi Norio , Nagahiro Shinji , Mori Etsuro , Shinohara Yukito , Yamaguchi Takenori ,   for J-MARS Investigators
Published: July 2010

Background and Purpose—

In Japan, alteplase at 0.6 mg/kg was approved in October 2005 for use within 3 hours of stroke onset by the Ministry of Health, Labor and Welfare (MHLW). The aim of the Japan post-Marketing Alteplase Registration Study (J-MARS), which was requested by MHLW at the time of approval, was to assess the safety and efficacy of 0.6 mg/kg alteplase in routine clinical practice for the Japanese.

Methods—

A total of 7492 patients from 942 centers were enrolled in the J-MARS, an open-label, nonrandomized, observational study, from October 2005 to October 2007. Primary outcome measures were symptomatic intracranial hemorrhage (a deterioration in NIHSS score ≥4 from baseline) and favorable outcome (modified Rankin Scale score, 0–1) at 3 months after stroke onset.

Results—

The proportion of patients with symptomatic intracranial hemorrhage in 7492 patients (safety analysis) was 3.5% (95% confidence interval [CI], 3.1%–3.9%) within 36 hours and 4.4% (95% CI, 3.9%–4.9%) at 3 months. The overall mortality rate was 13.1% (95% CI, 12.4%–13.9%) and the proportion of patients with fatal symptomatic intracranial hemorrhage was 0.9% (95% CI, 0.7%–1.2%). The outcomes at 3 months were available for 4944 patients and the proportion of favorable outcome (efficacy analysis) was 33.1% (95% CI, 31.8%–34.4%). The subgroup analysis in patients between 18 and 80 years with a baseline NIHSS score <25 demonstrated that favorable outcome at 3 months was 39.0% (95% CI, 37.4%–40.6%).

Conclusions—

These data suggest that 0.6 mg/kg intravenous alteplase within 3 hours of stroke onset could be safe and effective in routine clinical practice for the Japanese.
Responding to Norm Indeterminacy outside the Nation-State Frame
Authors: White Jonathan
Published: July 2010

I examine responses to norm indeterminacy in the transnational context, focusing on regional integration in post-War Europe. I argue that the development of the European Union has been facilitated by the use of a legitimizing device whereby policy decisions at a European level are cast as beyond the scope of reasonable political disagreement and therefore distinct from the conditions which make democracy a desirable political form at the national level. This rejection of the political significance of norm indeterminacy has led to a widely diagnosed trend of “depoliticization” in European politics. The paper examines how best to understand this trend, and explores how an adapted account of “enlightened localism” might offer better ways of coping with indeterminate norms.
“Virtuous Citizenship”:Ethnicity and Encapsulation among Akan-Speaking Ghanaian Methodists in London
Authors: Fumanti Mattia
Published: July 2010

Akan-speaking Methodists in London make sense of their diasporic experience by claiming ‘virtuous’ citizenship. Regardless of their legal and formal status, they feel themselves to be citizens of Britain as Methodists, workers and law-abiding subjects. Active membership in the British Methodist church, conceived as an English transnational polity extending to Ghana, allows for this alternative construction, rooted in Methodist Christian ideology of universal and selfless love, and the Akan concept of tema ‐ empathy for the pain of others, expressed in moral and material obligations to humanity at large, and family or fellowship members. Encapsulation in ethnically exclusive fellowships has become, however, highly problematic for the British Methodist Church whose internal conversation mirrors wider debates in Britain on multiculturalism and immigrant citizenship. Ghanaians themselves are increasingly aware of this critique, but for them ethnic fellowships do not imply exclusion or exclusiveness: they are the loci where people’s agency is experienced, and where they gain recognition and distinction.
Identity Politics, Social Movement and the State: ‘Pan-African’ Associations and the Making of an ‘African community’ in Belgium
Authors: Grégoire Nicole
Published: July 2010

Drawing on a social movement theoretical framework, the paper explores the collective action desires and attempts expressed within the African associational milieu in Belgium to improve the social, economic and political being of the African-rooted people in Belgium. It thus focuses on the emergence of non-profit organisations aiming at mobilising people of sub-Saharan African descent under a common ‘Pan-African’ banner. It analyses the link between the context for the emergence of these associations ‐ in which the state played an important role ‐ their working modes and their members’ affiliation strategies, as a way to address a ‘lack of mobilisation’ frequently deplored by many African associational leaders. Secondly, it shows how a certain African elite tries to go beyond old rivalries and previous failures, by shaping a Pan-African community, symbolically located both in the African life ‘here’ (in Belgium and by extension Europe) and ‘there’ (in Africa).
The impact of a psychoeducational intervention on family members’ views about schizophrenia: Results from the OASIS Italian multi-centre study
Authors: Fiorillo Andrea , Bassi Mariano , de Girolamo Giovanni , Catapano Francesco , Romeo Fabio
Published: July 2010

Background: The opinions of relatives of patients with schizophrenia about this disorder can influence its course and outcome.

Aims: In 2003, the Italian Psychiatric Association promoted a study on family psychoeducational intervention to explore its effectiveness in improving relatives’ opinions and beliefs about schizophrenia.

Methods: In each of the 10 Italian mental health centres, 30 patients with schizophrenia and 30 key relatives were randomly recruited to receive the experimental intervention or the standard care. The experimental intervention consisted of 12 manual-based informative sessions on schizophrenia. Each relative filled in the self-reported questionnaire on family opinions about schizophrenia.

Results: The treated sample included 107 patients and 112 relatives; the control group consisted of 105 patients and 118 relatives. In both groups, stress, traumas, heredity and family difficulties were most frequently mentioned as causing the disorder. Relatives’ opinions about patients’ civil rights and social competence, in particular the right to get married, to have children and to vote, improved and the belief that patients with schizophrenia are unpredictable decreased at the end of the intervention.

Conclusions: These results confirm that relatives of patients with schizophrenia should receive psychoeducational interventions, particularly in Italy where family involvement in schizophrenia care is particularly frequent.
Terrorism in the Worlds of Welfare Capitalism
Authors: Krieger Tim , Meierrieks Daniel
Published: July 2010

This contribution argues that social policies ameliorate poor short-run and long-run socioeconomic conditions (e.g., unemployment, poverty, inequality, and dissatisfaction), thereby indirectly reducing terrorist activity. The authors empirically assess the influence of social policies (indicated by social spending and welfare regime variables) on homegrown terrorism for fifteen Western European countries during the 1980—2003 period. The authors find that higher social spending in certain fields (health, unemployment benefits, and active labor market programs) is associated with a significant reduction in homegrown terrorism, while spending in other fields (e.g., public housing) is not. Moderate evidence furthermore indicates that the different worlds of welfare capitalism differently affect homeland terrorism. Social democratic welfare regimes that create low levels of market dependence are on average less prone to domestic terrorist activity. The findings suggest that homegrown terrorism in Western Europe may also be fought by higher spending in certain fields and more generous welfare regimes.
Predicting Conflict in Space and Time
Authors: Weidmann Nils B. , Ward Michael D.
Published: July 2010

The prediction of conflict constitutes a challenge to social scientists. This article explores whether the incorporation of geography can help us make our forecasts of political violence more accurate. The authors describe a spatially and temporally autoregressive discrete regression model, following the framework of Geyer and Thompson. This model is applied to geo-located data on attributes and conflict events in Bosnia over the period from March 1992 to October 1995. Results show that there is a strong spatial as well as temporal dimension to the outbreak of violence in Bosnia. The authors then explore the use of this model for predicting future conflict. Using a simulation approach, the predictive accuracy of the spatial—temporal model is compared to a standard regression model that only includes time lags. The results show that even in a difficult out-of-sample prediction task, the incorporation of space improves our forecasts of future conflict.
Knowing Your Enemy: Information and Commitment Problems in Civil Wars
Authors: Kirschner Shanna A.
Published: July 2010

When do civil wars last especially long? Commitment problems can stymie conflict resolution but they are not homogeneous across all civil wars. Indeed, combatants’ perceptions of their adversaries significantly affect the severity of commitment problems. Intergroup interactions provide combatants with one crucial type of information about their adversaries and about the risks associated with signing a peace settlement, shaping strategic decisions. The argument is tested against a new data set of all ethnic civil wars between 1945 and 2004. The results demonstrate that intergroup interactions prolong wars when they indicate that a peace deal will be especially fragile or that the costs of it breaking down will be especially high. This is true, regardless of the combatants’ goals or their capabilities. In sum, information shapes perceptions and the severity of commitment problems, in turn affecting the duration of civil wars.
Sequential versus Simultaneous Schelling Models: Experimental Evidence
Authors: Benito Juan Miguel , Brañas-Garza Pablo , Hernández Penélope , Sanchis Juan A.
Published: July 2010

This article shows the results of experiments where subjects play the Schelling’s spatial proximity model. Two types of experiments are conducted: one in which choices are made sequentially and a variation of the first where the decision making is simultaneous. The results of the sequential experiments are identical to Schelling’s prediction: subjects finish in a segregated equilibrium. Likewise, in the variant of the simultaneous decision experiment, the same result is reached: segregation. Subjects’ heterogeneity generates a series of focal points in the first round. To locate themselves, subjects use these focal points immediately, and as a result, the segregation takes place again. Furthermore, simultaneous experiments with commuting costs allow us to conclude that introducing positive moving costs does not affect segregation.
PAR2 and Temporomandibular Joint Inflammation in the Rat
Authors: Denadai-Souza A. , Cenac N. , Casatti C.A. , de Souza Câmara P.R. , Yshii L.M. , Costa S.K.P. , Vergnolle N. , Muscará M.N.
Published: July 2010

The proteinase-activated receptor 2 (PAR2) is a putative therapeutic target for arthritis. We hypothesized that the early pro-inflammatory effects secondary to its activation in the temporomandibular joint (TMJ) are mediated by neurogenic mechanisms. Immunofluorescence analysis revealed a high degree of neurons expressing PAR2 in retrogradely labeled trigeminal ganglion neurons. Furthermore, PAR2 immunoreactivity was observed in the lining layer of the TMJ, co-localizing with the neuronal marker PGP9.5 and substance-P-containing peripheral sensory nerve fibers. The intra-articular injection of PAR2 agonists into the TMJ triggered a dose-dependent increase in plasma extravasation, neutrophil influx, and induction of mechanical allodynia. The pharmacological blockade of natural killer 1 (NK1) receptors abolished PAR2-induced plasma extravasation and inhibited neutrophil influx and mechanical allodynia. We conclude that PAR2 activation is pro-inflammatory in the TMJ, through a neurogenic mechanism involving NK1 receptors. This suggests that PAR2 is an important component of innate neuro-immune response in the rat TMJ.
Surface Integrity Governs the Proteome of Hypomineralized Enamel
Authors: Mangum J.E. , Crombie F.A. , Kilpatrick N. , Manton D.J. , Hubbard M.J.
Published: July 2010

Growing interest in the treatment and prevention of Molar/Incisor Hypomineralization (MIH) warrants investigation into the protein composition of hypomineralized enamel. Hypothesizing abnormality akin to amelogenesis imperfecta, we profiled proteins in hypomineralized enamel from human permanent first molars using a biochemical approach. Hypomineralized enamel was found to have from 3- to 15-fold higher protein content than normal, but a near-normal level of residual amelogenins. This distinguished MIH from hypomaturation defects with high residual amelogenins (amelogenesis imperfecta, fluorosis) and so typified it as a hypocalcification defect. Second, hypomineralized enamel was found to have accumulated various proteins from oral fluid and blood, with differential incorporation depending on integrity of the enamel surface. Pathogenically, these results point to a pre-eruptive disturbance of mineralization involving albumin and, in cases with post-eruptive breakdown, subsequent protein adsorption on the exposed hydroxyapatite matrix. These insights into the pathogenesis and properties of hypomineralized enamel hold significance for prevention and treatment of MIH.
Effects of Regular and Low-fluoride Dentifrices on Plaque Fluoride
Authors: Pessan J.P. , Alves K.M.R.P. , Ramires I. , Taga M.F.L. , Sampaio F.C. , Whitford G.M. , Buzalaf M.A.R.
Published: July 2010

Previous studies have indicated that the use of low-fluoride dentifrices could lead to proportionally higher plaque fluoride levels when compared with conventional dentifrices. This double-blind, randomized, crossover study determined the effects of placebo, low-fluoride, and conventional dentifrices on plaque fluoride concentrations ([F]) in children living in communities with 0.04, 0.72, and 3.36 ppm F in the drinking water. Children used the toothpastes twice daily, for 1 wk. Samples were collected 1 and 12 hrs after the last use of dentifrices and were analyzed for fluoride and calcium. Similar increases were found 1 hr after the children brushed with low-fluoride ( ca. 1.9 mmol F/kg) and conventional ( ca. 2.4 mmol F/kg) dentifrices in the 0.04- and 0.72-ppm-F communities. Despite the fact that the increases were less pronounced in the 3.36-ppm-F community, our results indicate that the use of a low-fluoride dentifrice promotes a proportionally higher increase in plaque [F] when compared with that achieved with a conventional dentifrice, based on dose-response considerations.
Sphingosine-1-phosphate Signaling in Human Submandibular Cells
Authors: Seo J. , Koo N.-Y. , Choi W.-Y. , Kang J.-A. , Min J.H. , Jo S.-H. , Lee S.J. , Oh S.-B. , Kim J.-S. , Lee J.-H. , Choi S.-Y. , Park K.
Published: July 2010

Sphingosine-1-phosphate (S1P) is a significant lipid messenger modulating many physiological responses. S1P plays a critical role in autoimmune disease and is suggested to be involved in Sjögren’s syndrome pathology. However, the mechanism of S1P signaling in salivary glands is unclear. Here we studied the effects of S1P on normal human submandibular gland cells. S1P increased levels of the intracellular Ca2+ concentration ([Ca2+]i), which was inhibited by pre-treatment with U73122 or 2-aminoethoxydiphenyl borate (2-APB). Pre-treated S1P did not inhibit subsequent carbachol-induced [Ca2+]i increase, which suggests that S1P and muscarinic signaling are independent of each other. S1P1, S1P2, and S1P3 receptors SphK1 and SphK2 were commonly expressed in human salivary gland cells. S1P, but not carbachol, induces the expression of interleukin-6 and Fas. Our results suggest that S1P triggers Ca2+ signaling and the apoptotic pathway in normal submandibular gland cells, which suggests in turn that S1P affects the progression of Sjögren’s syndrome.
The Impact of Military Spending on the Likelihood of Democratic Transition Failure: Testing Two Competing Theories
Authors: Clardie Justin
Published: July 2010

Many countries complete tenuous transitions to democracy and must work to prevent an authoritarian reversal, which is often at the hands of the military. One of the most important tools the new government has in dealing with the military is the amount of money allocated to the military. This leads to the question, how does government military spending in post-transition democratic countries affect the chances of democratic transition failure? The extant literature provides two answers. The first is to increase military spending to placate the military; the second is to decrease military spending to weaken the military and address social welfare needs. The article tests these two hypotheses by examining democratic transitions from 1967 to 1999 using both logit and survival analysis methods. The results of the study provide robust support for the hypothesis that decreasing military spending decreases the likelihood of a democratic transition failure.