bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics in Health Care: An Overview of Current and Emerging Models
Authors: Battista R.N. , Blancquaert I. , Laberge A.-M. , van Schendel N. , Leduc N.
Published: July 2011

Background: With advances in genetic and genomic medicine, the optimal integration of genetic services into the health care system remains of major concern in many countries. Objectives: To review the current organisation of genetic services, mostly in Europe, North America and Australia, explore emerging service delivery models, and probe challenges inherent in the transition process. Methods: We conducted a literature review of genetics in clinical practice: testing, diagnosis, counselling, and treatment. We examined the basic structures of genetic services, examples of integrated networks, and existing professional resources. We investigated services belonging traditionally in medical genetics as well as those developed for more common diseases. Results: Multidisciplinary specialist clinics and coordinated services appeared to be key to delivering proper care in rare genetic disorders. For oncogenetics, neurogenetics and cardiogenetics, interprofessional collaboration between geneticists and other specialists seemed to be favoured. On the other hand, there was also a tendency toward the integration of genetic services directly into primary care. Among the most pressing challenges was the morphing of paediatric care into adult care. Conclusion: The coordination of activities between professionals in first-, second-, and third-line medical care is a primary objective calling for the reconfiguration of professional roles and responsibilities. This entails the forging of new relationships as well as an enhanced sharing of expertise and genetic information, including information regarding services. Barriers to overcome include the redistribution of roles, sharing of data and databases, and the lack of preparedness of non-genetics professionals and of the health care system in general.
Relationship between Stage of Kidney Disease and Incident Heart Failure in Older Adults
Authors: Bowling C. Barrett , Feller Margaret A. , Mujib Marjan , Pawar Pushkar P. , Zhang Yan , Ekundayo O. James , Aban Inmaculada B. , Love Thomas E. , Sanders Paul W. , Anker Stefan D. , Fonarow Gregg C. , Ahmed Ali
Published: July 2011

Background: The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear. Methods: Of the 5,795 community-dwelling adults ≧65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≧3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≧60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≧3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≧3B and 409 no CKD), respectively, balanced on 50 baseline characteristics. Results: During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≧3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≧3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027). Conclusions: Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≧3B, not CKD 3A, has a modest independent association with incident HF.
Brief Report: Phase II Multicenter Study of Temozolomide in Patients with Cisplatin-Resistant Germ Cell Tumors
Authors: Maroto P. , Huddart R. , Garcia del Muro X. , Horwich A. , Paz Ares L. , Aparicio J. , Germa-Lluch J.R.
Published: July 2011

Purpose: To determine the activity and toxicity of temozolomide in a phase II multicenter trial in patients diagnosed with relapsed or cisplatin-refractory germ cell tumors. Patients and Methods: During a recruitment period of 30 months, 20 patients received temozolomide 150 mg/m2/day p.o. for 5 days every 4 weeks, escalating to 200 mg/m2/day if grade II toxicity was not observed in the first cycle. Eligibility criteria were tumor progression or relapse after previous cisplatin and ifosfamide-containing chemotherapy, creatinine clearance of >40 ml/min, and a performance status of 0–2. Results: The median age was 38 years (range 27–56). Seventeen patients had nonseminomatous tumors, and 3 had seminomatous tumors. Six of the patients had extragonadal primary tumors (3 retroperitoneal and 3 mediastinal). The median number of prior cisplatin-containing cycles was 11 (range 7–20). Eight patients received prior high-dose chemotherapy and 14 were refractory or absolutely refractory to cisplatin. A total of 45 cycles were administered. Two partial responses lasting 9 and 3.5 months (overall response rate 10%, 95% CI 1.2–31.7) were observed. One of these responses was seen in a patient with a cisplatin-refractory tumor that had previously been treated with high-dose chemotherapy. The median time to progression and the median overall survival were 1.5 and 3.1 months, respectively. Grade III hematological toxicity consisted of thrombocytopenia in 2 patients and anemia in 1 patient. No grade IV toxicity was observed. Conclusions: Temozolomide had some activity in heavily pretreated patients resistant to cisplatin-based chemotherapy.
Combination of Gemcitabine and Doxorubicin in Rapidly Progressive Metastatic Renal Cell Carcinoma and/or Sarcomatoid Renal Cell Carcinoma
Authors: Roubaud G. , Gross-Goupil M. , Wallerand H. , de Clermont H. , Dilhuydy M.S. , Ravaud A.
Published: July 2011

Background/Aims: Metastatic renal cell carcinoma (mRCC) can be rapidly progressive when tumors exhibit sarcomatoid or Fuhrman grade 4 features. Efficacy of gemcitabine (Gem) with doxorubicin (Dox) in sarcomatoid or rapidly progressive mRCC has been reported. We retrospectively evaluated Gem + Dox in a consecutive cohort of this particular patient population. Patients andMethods: Patients had an Eastern Cooperative Oncology Group performance status of 2 or more and rapidly progressive mRCC or mRCC with sarcomatoid features. Gem (1,500 mg/m2) and Dox (50 mg/m2) were given every 2 weeks with granulocyte colony-stimulating factor. Results: Twenty-nine patients were treated. Sarcomatoid features were predominant in 6 patients, while 14 tumors were Fuhrman grade 4. All patients had progressive mRCC within 4 months. No grade 4 toxicity or drug-related death was reported. One partial response (7 months), 1 mixed response, and 14 stable diseases (≧4 months for 9 patients) were observed and no response was seen in sarcomatoid tumors. The median disease-free survival was 3.7 months (≧6 months for 8 patients) and the median overall survival was 4.8 months (>12 months for 5 patients). Conclusion: This study showed a lower response rate than previously reported. Nevertheless, some patients had prolonged survival outcomes. This combination could be an option in sarcomatoid histology (NCCN guidelines) or rapidly progressive disease, but this population represents an unmet medical need.
Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells
Authors: Wang W.M. , Chen H. , Zhong F. , Lu Y. , Han L. , Chen N.
Published: July 2011

Background: Inflammation may play an important role in the pathogenesis of kidney disease. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators. The purpose of this study was to examine the effects of rosiglitazone on lipopolysaccharide (LPS)-induced kidney inflammation and to explore the mechanism of its renoprotection. Methods: Mice were treated with LPS with or without pretreatment with rosiglitazone. Blood urea nitrogen (BUN), creatinine levels, the urinary albumin-to-creatinine ratio, macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, PPAR-γ expression, and NF-ĸB and PPAR-γ activity were investigated. HK-2 cells were maintained under defined in vitro conditions, treated with either rosiglitazone and/or the PPAR-γ antagonist GW9662, and then stimulated with LPS. MCP-1, IL-8, IL-6, NF-ĸB activity and PPAR-γ expression were investigated. Results: Compared to the LPS only group, pretreatment with rosiglitazone in vivo significantly attenuated the BUN levels macrophage infiltration, MCP-1 overexpression and NF-ĸB activity (p < 0.05). Rosiglitazone also restored PPAR-γ expression and protein activity, which were reduced significantly in the LPS only group (p < 0.05). Furthermore, in the LPS-stimulated HK-2 cells, rosiglitazone downregulated MCP-1, IL-8 and IL-6 expression as well as NF-ĸB activation and increased PPAR-γ expression (p < 0.05). These effects were diminished by GW9662. Conclusion: These results showed that pretreatment with rosiglitazone could attenuate kidney inflammation through the activation of PPAR-γ, suppression of MCP-1 overproduction and NF-ĸB activation. Rosiglitazone had a protective effect via a PPAR-γ-dependent pathway in LPS-treated HK-2 cells.
Arteriogenesis Is Modulated By Bradykinin Receptor Signaling
Authors: Hillmeister Philipp , Gatzke Nora , Dülsner André , Bader Michael , Schadock Ines , Hoefer Imo , Hamann Isabell , Infante-Duarte Carmen , Jung Georg , Troidl Kerstin , Urban Daniel , Stawowy Philipp , Frentsch Marco , Li Meijing , Nagorka Stephanie , Wang Haitao , Shi Yu , le Noble Ferdinand , Buschmann Ivo
Published: July 2011

Rationale:

Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear.

Objective:

The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis.

Methods and Results:

Bradykinin receptors positively affected arteriogenesis, with the contribution of B1R being more pronounced than B2R. In mice, arteriogenesis upon femoral artery occlusion was significantly reduced in B1R mutant mice as evidenced by reduced microspheres and laser Doppler flow perfusion measurements. Transplantation of wild-type bone marrow cells into irradiated B1R mutant mice restored arteriogenesis, whereas bone marrow chimeric mice generated by reconstituting wild-type mice with B1R mutant bone marrow showed reduced arteriogenesis after femoral artery occlusion. In the rat brain 3-vessel occlusion arteriogenesis model, pharmacological blockade of B1R inhibited arteriogenesis and stimulation of B1R enhanced arteriogenesis. In the rat, femoral artery ligation combined with arterial venous shunt model resulted in flow-driven arteriogenesis, and treatment with B1R antagonist R715 decreased vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue. In monocyte migration assays, in vitro B1R agonists enhanced migration of monocytes.

Conclusions:

Kinin receptors act as positive modulators of arteriogenesis in mice and rats. B1R can be blocked or therapeutically stimulated by B1R antagonists or agonists, respectively, involving a contribution of peripheral immune cells (monocytes) linking hemodynamic conditions with inflammatory pathways.
Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease
Authors: Noureddine Hibo , Gary-Bobo Guillaume , Alifano Marco , Marcos Elisabeth , Saker Mirna , Vienney Nora , Amsellem Valérie , Maitre Bernard , Chaouat Ari , Chouaid Christos , Dubois-Rande Jean-Luc , Damotte Diane , Adnot Serge
Published: July 2011

Rationale:

Senescence of pulmonary artery smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension associated with chronic lung diseases.

Objective:

To investigate whether cell senescence contributes to pulmonary vessel remodeling and pulmonary hypertension in chronic obstructive pulmonary disease (COPD).

Methods and Results:

In 124 patients with COPD investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and pulmonary hypertension severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16-positive and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age-matched and sex-matched control subjects who smoke. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell population doublings, an increased percentage of β-galactosidase–positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors.

Conclusion:

PA-SMC senescence is an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension in chronic lung disease.
Impairment of Speech Production Predicted by Lesion Load of the Left Arcuate Fasciculus
Authors: Marchina Sarah , Zhu Lin L. , Norton Andrea , Zipse Lauryn , Wan Catherine Y. , Schlaug Gottfried
Published: July 2011

Background and Purpose—

Previous studies have suggested that patients' potential for poststroke language recovery is related to lesion size; however, lesion location may also be of importance, particularly when fiber tracts that are critical to the sensorimotor mapping of sounds for articulation (eg, the arcuate fasciculus) have been damaged. In this study, we tested the hypothesis that lesion loads of the arcuate fasciculus (ie, volume of arcuate fasciculus that is affected by a patient's lesion) and of 2 other tracts involved in language processing (the extreme capsule and the uncinate fasciculus) are inversely related to the severity of speech production impairments in patients with stroke with aphasia.

Methods—

Thirty patients with chronic stroke with residual impairments in speech production underwent high-resolution anatomic MRI and a battery of cognitive and language tests. Impairment was assessed using 3 functional measures of spontaneous speech (eg, rate, informativeness, and overall efficiency) as well as naming ability. To quantitatively analyze the relationship between impairment scores and lesion load along the 3 fiber tracts, we calculated tract–lesion overlap volumes for each patient using probabilistic maps of the tracts derived from diffusion tensor images of 10 age-matched healthy subjects.

Results—

Regression analyses showed that arcuate fasciculus lesion load, but not extreme capsule or uncinate fasciculus lesion load or overall lesion size, significantly predicted rate, informativeness, and overall efficiency of speech as well as naming ability.

Conclusions—

A new variable, arcuate fasciculus lesion load, complements established voxel-based lesion mapping techniques and, in the future, may potentially be used to estimate impairment and recovery potential after stroke and refine inclusion criteria for experimental rehabilitation programs.
Natural Vitamin E α-Tocotrienol Protects Against Ischemic Stroke by Induction of Multidrug Resistance-Associated Protein 1
Authors: Park Han-A , Kubicki Natalia , Gnyawali Surya , Chan Yuk Cheung , Roy Sashwati , Khanna Savita , Sen Chandan K.
Published: July 2011

Background and Purpose—

α-Tocotrienol (TCT) represents the most potent neuroprotective form of natural vitamin E that is Generally Recognized As Safe certified by the U.S. Food and Drug Administration. This work addresses a novel molecular mechanism by which α-TCT may be protective against stroke in vivo. Elevation of intracellular oxidized glutathione (GSSG) triggers neural cell death. Multidrug resistance-associated protein 1 (MRP1), a key mediator of intracellular oxidized glutathione efflux from neural cells, may therefore possess neuroprotective functions.

Methods—

Stroke-dependent brain tissue damage was studied in MRP1-deficient mice and α-TCT-supplemented mice.

Results—

Elevated MRP1 expression was observed in glutamate-challenged primary cortical neuronal cells and in stroke-affected brain tissue. MRP1-deficient mice displayed larger stroke-induced lesions, recognizing a protective role of MRP1. In vitro, protection against glutamate-induced neurotoxicity by α-TCT was attenuated under conditions of MRP1 knockdown; this suggests the role of MRP1 in α-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of α-TCT protected against murine stroke. MRP1 expression was elevated in the stroke-affected cortical tissue of α-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of microRNA (miR)-199a-5p. In α-TCT-supplemented mice, miR-199a-5p was downregulated in stroke-affected brain tissue.

Conclusions—

This work recognizes MRP1 as a protective factor against stroke. Furthermore, findings of this study add a new dimension to the current understanding of the molecular bases of α-TCT neuroprotection in 2 ways: by identifying MRP1 as a α-TCT-sensitive target and by unveiling the general prospect that oral α-TCT may regulate miR expression in stroke-affected brain tissue.
Correlation of Inpatient and Outpatient Measures of Stroke Care Quality Within Veterans Health Administration Hospitals
Authors: Ross Joseph S. , Arling Greg , Ofner Susan , Roumie Christianne L. , Keyhani Salomeh , Williams Linda S. , Ordin Diana L. , Bravata Dawn M.
Published: July 2011

Background and Purpose—

Quality of care delivered in the inpatient and ambulatory settings may be correlated within an integrated health system such as the Veterans Health Administration. We examined the correlation between stroke care quality at hospital discharge and within 6 months postdischarge.

Methods—

We conducted a cross-sectional hospital-level correlation analyses of chart-abstracted data for 3467 veterans discharged alive after an acute ischemic stroke from 108 Veterans Health Administration medical centers and 2380 veterans with postdischarge follow-up within 6 months in fiscal year 2007. Four risk-standardized processes of care represented discharge care quality: prescription of antithrombotic and antilipidmic therapy, anticoagulation for atrial fibrillation, and tobacco cessation counseling along with a composite measure of defect-free care. Five risk-standardized intermediate outcomes represented postdischarge care quality: achievement of blood pressure, low-density lipoprotein, international normalized ratio, and glycosylated hemoglobin target levels, and delivery of appropriate treatment for poststroke depression along with a composite measure of achieved outcomes.

Results—

Median risk-standardized composite rate of defect-free care at discharge was 79%. Median risk-standardized postdischarge rates of achieving goal were 56% for blood pressure, 36% for low-density lipoprotein, 41% for international normalized ratio, 40% for glycosylated hemoglobin, and 39% for depression management and the median risk-standardized composite 6-month outcome rate was 44%. The hospital composite rate of defect-free care at discharge was correlated with meeting the low-density lipoprotein goal (
r
=0.31;
P
=0.007) and depression management (
r
=0.27;
P
=0.03) goal but was not correlated with blood pressure, international normalized ratio, glycosylated hemoglobin goals, nor with the composite measure of achieved postdischarge outcomes (probability values >0.13).

Conclusions—

Hospital discharge care quality was not consistently correlated with ambulatory care quality.
Racial Disparities in Tissue Plasminogen Activator Treatment Rate for Stroke
Authors: Hsia Amie W. , Edwards Dorothy F. , Morgenstern Lewis B. , Wing Jeffrey J. , Brown Nina C. , Coles Regina , Loftin Sarah , Wein Andrea , Koslosky Sara S. , Fatima Sabiha , Sánchez Brisa N. , Fokar Ali , Gibbons M. Chris , Shara Nawar , Jayam-Trouth Annapurni , Kidwell Chelsea S.
Published: July 2011

Background and Purpose—

Some prior studies have shown that racial disparities exist in intravenous tissue plasminogen activator (tPA) use for acute ischemic stroke. We sought to determine whether race was associated with tPA treatment for stroke in a predominantly black urban population.

Methods—

Systematic chart abstraction was performed on consecutive hospitalized patients with ischemic stroke from all 7 acute care hospitals in the District of Columbia from February 1, 2008, to January 31, 2009.

Results—

Of 1044 patients with ischemic stroke, 74% were black, 19% non-Hispanic white, and 5% received intravenous tPA. Blacks were one third less likely than whites to receive intravenous tPA (3% versus 10%,
P
<0.001). However, blacks were also less likely than whites to present within 3 hours of symptom onset (13% versus 21%,
P
=0.004) and also less likely to be tPA-eligible (5% versus 13%,
P
<0.001). Of those who presented within 3 hours, blacks were almost half as likely to be treated with intravenous tPA than whites (27% versus 46%,
P
=0.023). The treatment rate for tPA-eligible patients was similar for blacks and whites (70% versus 76%,
P
=0.62).

Conclusions—

In this predominantly black urban population hospitalized for acute ischemic stroke, blacks were significantly less likely to be treated with intravenous tPA due to contraindications to treatment, delayed presentation, and stroke severity. Effective interventions designed to increase treatment in this population need to focus on culturally relevant education programs designed to address barriers specific to this population.
Early Ischemic Change on CT Versus Diffusion-Weighted Imaging for Patients With Stroke Receiving Intravenous Recombinant Tissue-Type Plasminogen Activator Therapy
Authors: Nezu Tomohisa , Koga Masatoshi , Nakagawara Jyoji , Shiokawa Yoshiaki , Yamagami Hiroshi , Furui Eisuke , Kimura Kazumi , Hasegawa Yasuhiro , Okada Yasushi , Okuda Satoshi , Kario Kazuomi , Naganuma Masaki , Maeda Koichiro , Minematsu Kazuo , Toyoda Kazunori
Published: July 2011

Background and Purpose—

Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitative topographical score to evaluate early ischemic change in the middle cerebral arterial territory on CT as well as on diffusion-weighted imaging (DWI). The aim of the present study was to elucidate the relationship between CT-ASPECTS and DWI-ASPECTS for patients with hyperacute stroke and their associations with outcomes after recombinant tissue-type plasminogen activator therapy based on a multicenter registry.

Methods—

ASPECTS was assessed on both CT and DWI before intravenous 0.6 mg/kg alteplase in 360 patients with stroke (119 women, 71±11 years old). The outcomes were symptomatic intracerebral hemorrhage within 36 hours and independence at 3 months defined by a modified Rankin Scale score of 0 to 2.

Results—

DWI-ASPECTS was positively correlated with CT-ASPECTS (ρ=0.511,
P
<0.001) and was lower than CT-ASPECTS (median 8 [interquartile range, 6 to 9] versus 9 [8 to 10],
P
<0.001). Higher baseline National Institutes of Health Stroke Scale score (standardized partial regression coefficient [β] 0.061,
P
<0.001) and cardioembolic stroke (β 0.35,
P
<0.001) were related to this discrepancy. The area under the receiver operating characteristic curve for predicting sICH (12 patients) using ASPECTS was 0.673 (95% CI, 0.503 to 0.807) by CT and 0.764 (95% CI, 0.635 to 0.858) by DWI (
P
=0.275). The area for predicting independence at 3 months (192 patients) was 0.621 (0.564 to 0.674) by CT and 0.639 (0.580 to 0.694) by DWI (
P
=0.535).

Conclusions—

For patients with hyperacute stroke, DWI-ASPECTS scored approximately 1 point lower than CT-ASPECTS. Both CT-ASPECTS and DWI-ASPECTS were useful predictors of symptomatic intracerebral hemorrhage and independence at 3 months after recombinant tissue-type plasminogen activator.
Cost-Effectiveness of Tissue-Type Plasminogen Activator in the 3- to 4.5-Hour Time Window for Acute Ischemic Stroke
Authors: Tung Christie E. , Win Sandra S. , Lansberg Maarten G.
Published: July 2011

Background and Purpose—

The aim of this study was to determine the cost-effectiveness of tissue-type plasminogen activator (tPA) treatment in the 3- to 4.5-hour time window after ischemic stroke.

Methods—

Decision-analytic and Markov state-transition models were created to determine the cost-effectiveness of treatment of ischemic stroke patients with intravenous tPA administered in the 3- to 4.5-hour time window compared with medical therapy without tPA. Health benefits were measured in quality-adjusted life-years (QALYs). The economic outcome measure of the model was the difference in estimated healthcare costs between the 2 treatment alternatives. The incremental cost-effectiveness ratio was calculated by dividing the cost difference by the difference in QALYs. One-way sensitivity and probabilistic analyses were performed to test the robustness of the model.

Results—

The administration of tPA compared with standard medical therapy resulted in a lifetime gain of 0.28 QALYs for an additional cost of $6050, yielding an incremental cost-effectiveness ratio of $21 978 per QALY. One-way sensitivity analyses demonstrated that the incremental cost-effectiveness ratio was most sensitive to the cost of hospitalization for patients who received tPA. Based on probabilistic analysis, there is an 88% probability that tPA is the preferred treatment at a willingness-to-pay threshold of $50 000 per QALY.

Conclusions—

The balance of costs and benefits favors treatment with intravenous tPA in the 3- to 4.5-hour time window. This supports, from a societal perspective, the use of tPA therapy in this treatment time window for acute ischemic stroke.
Self-Expandable Stents in the Treatment of Acute Ischemic Stroke Refractory to Current Thrombectomy Devices
Authors: Linfante Italo , Samaniego Edgar A. , Geisbüsch Philipp , Dabus Guilherme
Published: July 2011

Background and Purpose—

Vessel recanalization is a strong predictor of good outcome in acute ischemic strokes (AIS) secondary to large vessel occlusions. We report our single-center experience with self-expandable stents in the treatment of AIS.

Methods—

The stroke database of Baptist Cardiac and Vascular Institute in Miami was retrospectively reviewed from August of 2008 to September of 2010. All cases of AIS in which a self-expandable stents was deployed as acute endovascular intervention were included in the analysis. Criteria for intervention were the onset of neurological symptoms because of AIS, a National Institute of Health Stroke Scale score ≥4 at presentation, stroke attributable to a large vessel occlusion, and failure of arterial thrombolysis or mechanical thrombectomy or both. Good outcome was defined as a modified Rankin Scale score ≤2 at 1 month from hospital discharge.

Results—

Nineteen patients with AIS who underwent stenting were identified. Median National Institute of Health Stroke Scale score on admission was 19. Six Enterprise and 13 Wingspan stents were deployed. Recanalization was achieved in 95% occlusions (63% thrombolysis in myocardial infarction grade 3 and 32% thrombolysis in myocardial infarction grade 2). Good clinical outcome was achieved in 42%. No intraprocedural complications occurred and all stents were successfully deployed. Symptomatic intracerebral hemorrhage occurred in 3 (16%) patients, 2 of whom died.

Conclusions—

Use of self-expandable stents in AIS appears to be safe and may be considered when currently available thrombectomy devices and/or intraarterial thrombolysis fail.
Optimal End Points for Acute Stroke Therapy Trials
Authors: Saver Jeffrey L.
Published: July 2011

Background and Purpose—

Over the past decade, analysis of completed actual trials, model population studies, and theoretical work have improved approaches to selecting and analyzing end points in acute stroke treatment trials.

Methods—

Narrative review.

Results—

Because stroke affects persons in their biological, functional, social, and experiential dimensions, measures of impairment, disability, handicap, and quality of life are all desirable in pivotal trials, with disability being most important. Scales that are valid, reliable, responsive, and easy to administer are preferred; consequently, the modified Rankin Scale has become the most widely used single clinical efficacy measure. Because stroke cripples and kills, most outcome scales array patient outcome in ordered ranks, spread over the entire range from normal to disabled to dead. Generally, shift analysis, analyzing all health state transitions concurrently, is the most efficient analytic technique to detect treatment effects, with sliding dichotomy less efficient and fixed dichotomy least efficient, unless treatment effects strongly cluster at 1 or a few health state transitions that can be prespecified. Test statistics must also take into account interpretability, ie, how well they can be converted into metrics capturing all outcomes the intervention might alter in proportion to the degree they are valued by the patient; full ordinal analysis is most informative, sliding dichotomy is intermediately informative, and fixed dichotomy is least informative regarding this global outcome.

Conclusions—

Stroke trial power and interpretation can be substantially enhanced by adherence to the principles delineated in this review. Full ordinal and sliding dichotomy analysis will most often be advantageous compared with fixed dichotomous approaches.
1997/98 El Niño–Induced Changes in Rainfall Vertical Structure in the East Pacific
Authors: Li Rui , Min Qilong , Fu Yunfei
Published: July 2011

The 1997/98 El Niño–induced changes in rainfall vertical structure in the east Pacific (EP) are investigated by using collocated Tropical Rainfall Measuring Mission (TRMM) precipitation radar (PR) and associated daily SST and 6-hourly reanalysis data during January, February, March, and April of 1998, 1999, and 2000. This study shows that there are five key parameters, that is, surface rain rate, precipitation-top height (or temperature), and precipitation growth rates at upper, middle, and low layers to define a rainfall profile, and those five key parameters are strongly influenced by both SST and large-scale dynamics. Under the influence of 1997/98 El Niño, the precipitation-top heights in the EP were systematically higher by about 1 km than those under non–El Niño conditions, while the freezing level was about 0.5 km higher. Under the constraints of rain type, surface rain rate, and the precipitation top, the shape of rainfall profile still showed significant differences: the rain growth was relatively faster in the mid-layer (−5° to +2°C isotherm) but slower in the lower layer (below +2°C isotherm) under the influence of El Niño. It is also evident that the dependence of precipitation top height on SST was stronger under large-scale decent (non–El Niño) circulations but much weaker under large-scale ascent (El Niño) circulations. The combined effect of larger vertical extent and greater growth rate in the middle layer further shifted latent heating upward as compared with the impact of horizontal changes in the rain type fractions (convective versus stratiform). Such additional latent heating shift would certainly further elevate circulation centers and strengthen the upper-layer circulation.
WATCH: Current Knowledge of the Terrestrial Global Water Cycle
Authors: Harding Richard , Best Martin , Blyth Eleanor , Hagemann Stefan , Kabat Pavel , Tallaksen Lena M. , Warnaars Tanya , Wiberg David , Weedon Graham P. , Lanen Henny van , Ludwig Fulco , Haddeland Ingjerd
Published: July 2011

Water-related impacts are among the most important consequences of increasing greenhouse gas concentrations. Changes in the global water cycle will also impact the carbon and nutrient cycles and vegetation patterns. There is already some evidence of increasing severity of floods and droughts and increasing water scarcity linked to increasing greenhouse gases. So far, however, the most important impacts on water resources are the direct interventions by humans, such as dams, water extractions, and river channel modifications. The Water and Global Change (WATCH) project is a major international initiative to bring together climate and water scientists to better understand the current and future water cycle. This paper summarizes the underlying motivation for the WATCH project and the major results from a series of papers published or soon to be published in the Journal of Hydrometeorology WATCH special collection. At its core is the Water Model Intercomparison Project (WaterMIP), which brings together a wide range of global hydrological and land surface models run with consistent driving data. It is clear that we still have considerable uncertainties in the future climate drivers and in how the river systems will respond to these changes. There is a grand challenge to the hydrological and climate communities to both reduce these uncertainties and communicate them to a wider society.
The Effect of Koshu Seamount on the Formation of the Kuroshio Large Meander South of Japan
Authors: Endoh Takahiro , Tsujino Hiroyuki , Hibiya Toshiyuki
Published: July 2011

Using an inflow–outflow numerical model, the authors demonstrate that the existence of Koshu Seamount, located about 200 km to the south of Cape Shiono-misaki, is essential in creating the large meander (LM) of the Kuroshio. When Koshu Seamount is completely smoothed out, the meander trough propagates away without being amplified to form the LM. In contrast, nearly the same LM as in the case with full topography is formed when the foot of Koshu Seamount remains without being smoothed out and also when the foot of Koshu Seamount is filled in so that the upper part of Koshu Seamount remains. A linear stability analysis applied to the model output shows that the Kuroshio becomes baroclinically most unstable when the water depth decreases offshoreward. The authors therefore conclude that the enhancement of baroclinic instability over the northern slope of Koshu Seamount is a prerequisite to the formation of the LM.
Radar Backscattering from Snowflakes: Comparison of Fractal, Aggregate, and Soft Spheroid Models
Authors: Tyynelä Jani , Leinonen Jussi , Moisseev Dmitri , Nousiainen Timo
Published: July 2011

The sensitivity of radar backscattering cross sections on different snowflake shapes is studied at C, Ku, Ka, and W bands. Snowflakes are simulated using two complex shape models, namely, fractal and aggregate, and a soft spheroid model. The models are tuned to emulate physical properties of real snowflakes, that is, the mass–size relation and aspect ratio. It is found that for particle sizes up to 5 mm and for frequencies from 5 to 35 GHz, there is a good agreement in the backscattering cross section for all models. For larger snowflakes at the Ka band, it is found that the spheroid model underestimates the backscattering cross sections by a factor of 10, and at W band by a factor of 50–100. Furthermore, there is a noticeable difference between spheroid and complex shape models in the linear depolarization ratios for all frequencies and particle sizes.
Experimental Tropical Cyclone Prediction Using the GFDL 25-km-Resolution Global Atmospheric Model
Authors: Gall Jeffrey S. , Ginis Isaac , Lin Shian-Jiann , Marchok Timothy P. , Chen Jan-Huey
Published: July 2011

This paper describes a forecasting configuration of the Geophysical Fluid Dynamics Laboratory (GFDL) High-resolution Atmospheric Model (HiRAM). HiRAM represents an early attempt in unifying, within a global modeling framework, the capabilities of GFDL’s low-resolution climate models for Intergovernmental Panel on Climate Change (IPCC) type climate change assessments and high-resolution limited-area models for hurricane predictions. In this study, the potential of HiRAM as a forecasting tool is investigated by applying the model to the near-term and intraseasonal hindcasting of tropical cyclones (TCs) in the Atlantic basin from 2006 to 2009. Results demonstrate that HiRAM provides skillful near-term forecasts of TC track and intensity relative to their respective benchmarks from t = 48 h through t = 144 h. At the intraseasonal time scale, a simple HiRAM ensemble provides skillful forecasts of 21-day Atlantic basin TC activity at a 2-day lead time. It should be noted that the methodology used to produce these hindcasts is applicable in a real-time forecasting scenario. While the initial experimental results appear promising, the HiRAM forecasting system requires various improvements in order to be useful in an operational setting. These modifications are currently under development and include a data assimilation system for forecast initialization, increased horizontal resolution to better resolve the vortex structure, 3D ocean model coupling, and wave model coupling. An overview of these ongoing developments is provided, and the specifics of each will be described in subsequent papers.
A Primer on Research Ethics in the Field of Gifted Education
Authors: Moon Tonya R.
Published: July 2011

Most organizations (e.g., institutions of higher education, K-12 school systems) that engage in research with human subjects have institutional review boards (IRBs; also known as research committees) responsible for the oversight of research activities to ensure the ethical treatment of participants. Professional societies such as American Educational Research Association (AERA) and the American Psychological Association (APA) have also developed ethical codes for research activities involving human subjects. Many journals, including GCQ, require that all research considered for publication is accompanied by documentation of review and approval by an IRB or other similar committee. The purpose of this Methodological Brief is to provide researchers, new and experienced, within the field of gifted education a brief introduction to the ethical principles that guide the decision making process of IRBs, to provide examples of what might be considered ethical code violations, and to offer suggestions for working through the review and approval process with IRB officials. 1
Giftedness and Metacognition
Authors: Snyder Kate E. , Nietfeld John L. , Linnenbrink-Garcia Lisa
Published: July 2011

The current study investigated differences in metacognition between high school gifted ( n = 44) and typical ( n = 23) students and examined local calibration accuracy as a potential mechanism for partially explaining superior exam performance by gifted students. Metacognition was measured using student self-reports of metacognitive awareness, acquired at the start of a semester-long course on biology, and students’ global (pre- and posttest) and local (item-by-item) confidence judgments to assess monitoring across four biology exams over the course of one semester. Gifted students outperformed typical students on both local and global postdictive measures of calibration. However, there were no statistically significant differences in global predictive judgments or calibration bias. Local, item-by-item calibration accuracy partially mediated the relation between giftedness and exam performance. Implications for both theory and practice are discussed.
Markets in eighteenth century Bengal economy
Authors: Mukherjee Tilottama
Published: July 2011

This article explores the emergence, functioning and growth of markets in early modern Bengal and suggests the existence of decentralised interlinked exchange sites whose numbers increased over the course of the eighteenth century, with founders from diverse social groups and clearly delineated rules about establishment and resolution of conflict. Markets were both extensive as well as efficient with panoply of market regulations to ensure the smooth functioning of these sites. Investment made by different strata of society, guiding principles determining the spatial and temporal distribution of market places, the pervasive and robust service industry, internal consumption and mercantile penetration, in agriculture as well as other sectors, consolidated the process of commercialisation and shaped the provincial economy. A differentiated merchant community, with differing scales of operation, area and profit margin, serviced this economy. Both the indigenous and the early Company state were beneficiaries of the taxes but they were not the prime movers. The Nizamat of Bengal played a facilitating role in the smooth functioning of the market places, but the state even in the later part of the eighteenth century did not or could not act as the sole unilateral arbiter of all that was happening in the economic sphere.
Pharmacodynamic Effects on Biochemical Markers of Bone Turnover and Pharmacokinetics of the Cathepsin K Inhibitor, ONO‐5334, in an Ascending Multiple‐Dose, Phase 1 Study
Authors: Nagase Shinichi , Ohyama Michiyo , Hashimoto Yoshitaka , Small Maria , Kuwayama Tomohiro , Deacon Steve
Published: July 2011

Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO‐5334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15‐ and 28‐day multiple‐dosing cohorts. Plasma ONO‐5334 concentration reached steady state within 2 days. Twenty‐four hours after the last dose in the 15‐day multiple‐dose cohort, 100, 300, and 600 mg once daily reduced urinary C‐terminal telopeptide of type I collagen by a mean (± standard deviation) 44.9% ± 13.6%, 84.5% ± 4.4%, and 92.5% ± 1.3%, respectively. The 28‐day cohort showed similar effects. There were far smaller effects on bone‐specific alkaline phosphatase (B‐ALP), tartrate‐resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO‐5334 was well tolerated up to 600 mg/d and for up to 28 days of multiple dosing. Multiple dosing with ONO‐5334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B‐ALP, OC) or osteoclast number (TRAP5b).
Pharmacokinetics and Safety of the Lopinavir/Ritonavir Tablet 500/125 mg Twice Daily Coadministered With Efavirenz in Healthy Adult Participants
Authors: Ng Juki , Chiu Yi‐Lin , Awni Walid , Bernstein Barry , Causemaker Sonja J. , Klein Cheri E.
Published: July 2011

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (Cmax), plasma concentration prior to morning dosing (Ctrough), and area under the plasma concentration‐time curve over a dosing interval (AUC12) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.
Active or passive bio-coating: does it matters in extracorporeal circulation?
Authors: Jacobs S , De Somer F , Vandenplas G , Van Belleghem Y , Taeymans Y , Van Nooten G
Published: July 2011

Background: Two types of surface coating for cardiopulmonary bypass (CPB) are used: bioactive (heparin, nitric oxide) and biopassive (albumin, polyethyleneoxide (PEO), phosphorylcholine). When haemocompatible coatings are combined with the separation of pleuro-pericardial aspiration, attenuation of both the coagulation and complement cascades, as well as better platelet preservation, has been demonstrated. This study wants to investigate if the combination of a bioactive with a biopassive coating (unfractionated heparin embedded in a phosphorylcholine matrix) combines the beneficial effects of both approaches.

Materials and methods: Thirty patients undergoing elective CABG were prospectively randomized into two groups of 15 patients. The sole exclusion criterion was an ejection fraction of less than 40%. In the control group (PC), the whole CPB circuit was coated with phosphorylcholine (PC). In the study group (XPC), unfractionated heparin was embedded in the PC matrix of the oxygenator and arterial line filter.

Results: No differences were found for haemolytic index, thrombin-anti-thrombin complex (TAT), IL-6, IL-10 and blood loss. PF4 plasma concentration increased from 27.6±22.0 IU/mL to 165.7±43.9 IU/mL (p<0.001) at 15 minutes of CPB in the PC and from 16.0±9.7 IU/mL to 150.9 ± 61.3 IU/mL (p<0.001) in the XPC group. Terminal complement complex (TCC) increased over time in both groups until the end of CPB (Figure 2A). Within each group, TCC generation was statistically significantly higher after the release of the aortic cross-clamp (p<0.001) and at the end of CPB (p<0.001). Total TCC generation was statistically significantly higher in the XPC group compared to the PC group (p=0.026). The difference was statistically significant after the release of the aortic cross-clamp (p=0.005) and at the end of CPB (p=0.001).

Conclusions: Based on our results, there is no additional benefit in combining phosphorylcholine with unfractionated heparin in elective patients undergoing coronary artery bypass grafting (CABG). Massive haemodilution leads to enhanced complement activation.
Multi-scale fractal dimension based on morphological covering for gear fault diagnosis
Authors: Li B , Zhang P-L , Mi S-S , Zhang Y-T , Liu D-S
Published: July 2011

Fractal dimension (FD) is one of the most utilized parameters for characterizing and discriminating vibration signals in gear fault detection. However, most of the natural signals are not critical self-similar fractals; the assumption of a constant FD at all scales may not be appropriate. Motivated by this fact, this article explores the capacity of the multi-scale fractal dimension (MFD) to represent the complexity of vibration signals for gear fault diagnosis. We select the morphological covering method to calculate the MFD. Vibration signals measured from a gear test rig with five states are employed to evaluate the effectiveness of the presented method. Experimental results reveal that the vibration signals acquired from gear with five states demonstrate different fractal structures when the visualization scales are changed. The MFD can provide more information about the signals and yield a higher classification rate than the FD and traditional statistical parameters. It is very reasonable to apply the MFD to vibration signal analysis for improving the performance of the gear fault diagnosis.