bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Antifungal Prophylaxis with Daily Oral Fluconazole Reduce the Risk of Fungal Peritonitis in Peritoneal Dialysis Patients? The Pan Thames Renal Audit
Authors: Davenport Andrew , Wellsted David ,   on behalf of the Pan Thames Renal Audit Peritoneal Dialysis Group
Published: July 2011

Background and Objectives: Fungal peritonitis increases the risk of transfer to haemodialysis and mortality. Methods: We audited the effect of co-prescription of daily oral fluconazole with antibiotics in the Pan Thames centres on fungal peritonitis. Results: We found 49 (1.5%) fungal peritonitis cases in 3,322 episodes of peritonitis. Two centres co-prescribed prophylactic fluconazole with antibiotics, with a fungal peritonitis rate of 0.0032/patient year, compared to 0.0099 from centres not using prophylaxis. However, centres using fungal prophylaxis had lower peritonitis rates of 0.036, compared to 0.05 for the other centres. Correcting for background peritonitis rates, there was no significant difference in the incidence of fungal peritonitis. Conclusions: In centres with a low incidence of fungal peritonitis, additional co-prescription of fluconazole with antibiotics appeared to reduce the risk of fungal peritonitis. However, variation in practice between centres is the main determinant of the observed incidence of fungal peritonitis rather than the use of antifungal prophylaxis.
Long-Term Treatment with Infliximab in Patients with Sarcoidosis
Authors: Hostettler Katrin E. , Studler Ueli , Tamm Michael , Brutsche Martin H.
Published: July 2011

Background: Long-term benefit and safety of infliximab treatment in patients with chronic sarcoidosis remain unclear. Objectives: It was the aim of this study to assess the clinical benefit and safety of long-term infliximab treatment in patients with chronic steroid-resistant sarcoidosis. Methods: We conducted a retrospective chart review of all patients with chronic steroid-resistant sarcoidosis who received infliximab between January 2003 and November 2010. Pulmonary function tests and index lesions before and after infliximab therapy were assessed. Results: Between January 2003 and November 2010, 28 patients received in-fliximab, 16 of them for more than 12 months. Five (31%) of these 16 patients with long-term infliximab treatment had a predominantly pulmonary disease, whereas 11 (69%) had a predominantly extrapulmonary involvement. Mean duration of treatment for the 16 patients was 29 months (range 12-62). Six of 11 (55%) patients with mainly extrapulmonary sarcoidosis showed a complete remission of their index lesion, 4/11 (36%) had a partial remission and 1/11 (9%) showed no response. One out of 5 patients with predominantly pulmonary sarcoidosis showed a >10% improvement in percentage predicted forced vital capacity, 3/5 showed a 0-10% improvement, and in 1/5 patients, percentage predicted forced vital capacity declined during infliximab treatment. Thus, overall, 14/16 (88%) patients profited from long-term infliximab treatment. Suspected adverse effects which lead to a temporary withdrawal of infliximab therapy were noticed in 1/16 (6%) patients. Conclusions: This retrospective study indicates that long-term infliximab is very efficient and safe in patients with chronic steroid-resistant sarcoidosis when assessed with individualized treatment targets. Patients with predominantly extrapulmonary sarcoidosis seem to profit more than patients with a predominantly pulmonary disease.
Relative Efficiency of Trend Tests with Misspecified Genetic Models in Stratified Analyses of Case-Control or Cohort Data
Authors: Sitlani Colleen M. , McKnight Barbara
Published: July 2011

Background/Aims: Genetic single-nucleotide polymorphism (SNP) data are often analyzed using trend tests that rely on a specific assumption about the way that disease frequency varies across genotypes, but the validity of this assumption is not typically known. We explore the relative efficiency of trend tests in which the assumed model may or may not correspond to the true genetic model. Methods: We derive formulae for the asymptotic relative efficiencies (AREs) comparing tests that assume different genetic models. We consider both unstratified and stratified tests, using both case-control and cohort data. We illustrate these formulae using realistic parameters and compare the calculated AREs to simulated relative efficiencies in finite samples. Results: The AREs are identical for unstratified tests using case-control and cohort data, but differ for stratified tests. Loss of efficiency can be substantial, given specific combinations of high-risk allele frequencies, disease frequencies, and assumed versus actual genetic models. Given reasonably large sample sizes, asymptotic calculations align well with finite sample simulations of relative efficiency. Conclusions: ARE is a useful estimate of the relative efficiency of statistics using different underlying genetic models. ARE calculations reveal that additive gene doses, which are most commonly used, lead to large losses in power in some settings.
Continuation and Maintenance Electroconvulsive Therapy for Mood Disorders: Review of the Literature
Authors: Petrides Georgios , Tobias Kristen G. , Kellner Charles H. , Rudorfer Matthew V.
Published: July 2011

Background: Electroconvulsive therapy (ECT) is a highly effective treatment for mood disorders. Continuation ECT (C-ECT) and maintenance ECT (M-ECT) are required for many patients suffering from severe and recurrent forms of mood disorders. This is a review of the literature regarding C- and M-ECT. Methods: We conducted a computerized search using the words continuation ECT, maintenance ECT, depression, mania, bipolar disorder and mood disorders. We report on all articles published in the English language from 1998 to 2009. Results: We identified 32 reports. There were 24 case reports and retrospective reviews on 284 patients. Two of these reports included comparison groups, and 1 had a prospective follow-up in a subset of subjects. There were 6 prospective naturalistic studies and 2 randomized controlled trials. Conclusions: C-ECT and M-ECT are valuable treatment modalities to prevent relapse and recurrence of mood disorders in patients who have responded to an index course of ECT. C-ECT and M-ECT are underused and insufficiently studied despite positive clinical experience of more than 70 years. Studies which are currently under way should allow more definitive recommendations regarding the choice, frequency and duration of C-ECT and M-ECT following acute ECT.
Transient Left Ventricular Systolic Dysfunction with Thrombus and Subsequent Cardioembolic Stroke in Short-Term Overt Hypothyroidism
Authors: Yang Jeong Hoon , Jang Hye Won , Park Sung-Ji , Park Seung Woo
Published: July 2011

A 57-year-old woman was referred for cardiomegaly on a chest X-ray taken during thyroxine withdrawal for radioiodine therapy after total thyroidectomy. Baseline transthoracic echocardiography showed left ventricular (LV) wall motion abnormalities and an LV apical mural thrombus. Coronary angiography revealed normal epicardial coronary arteries. Despite anticoagulation treatment, the patient developed abrupt aphasia, agraphia and acalculia. The distal branch of the inferior segmental branch on the left middle cerebral artery was not well visualized on magnetic resonance angiography. Three days later, the patient had made a near full neurological recovery. After 4 weeks of anticoagulation therapy, the apical mural thrombus and wall motion abnormalities resolved. This is the first reported case in the medical literature of transient LV systolic dysfunction with thrombus and subsequent cardioembolic stroke in a patient with short-term overt hypothyroidism.
Docetaxel plus Oxaliplatin in Combination with Capecitabine as First-Line Treatment for Advanced Gastric Cancer
Authors: Amarantidis K. , Xenidis N. , Chelis L. , Chamalidou E. , Dimopoulos P. , Michailidis P. , Tentes A. , Deftereos S. , Karanikas M. , Karayiannakis A. , Kakolyris S.
Published: July 2011

Objective: In the present phase II study, we evaluated the efficacy and safety of a docetaxel-oxaliplatin-capecitabine combination as a first-line treatment in patients with advanced gastric cancer. Patients and Methods: A total of 27 patients (18 males) with histologically confirmed inoperable gastric adenocarcinoma were recruited. Docetaxel was given (50 mg/m2 i.v.) on day 1 followed by oxaliplatin (75 mg/m2 i.v.) also on day 1. Capecitabine (2,750 mg/m2) was given orally as two daily divided doses from days 1 to 7. Cycles were repeated every 2 weeks. All patients had measurable disease and 18 of them had a performance status (WHO) of 0. Results: A total of 240 treatment cycles were administered. All patients were evaluable for toxicity. Four patients who discontinued treatment early (having received only 3 chemotherapy cycles) were included as non-responders in an intention-to-treat response analysis. Complete response, partial response, stable disease and progressive disease were observed in 4 (15%), 12 (44%), 3 (11%) and 8 (30%) patients, respectively. The observed response rate was 59%, and the disease control rate (complete response + partial response + stable disease) was 70%. At the time of analysis, 6 patients were still alive and the median survival was 18.0 months. The most common grade III/IV toxicities observed were neutropenia (5%), diarrhea (2%), palmar-plantar erythrodysesthesia (2%) and neurotoxicity (1%). All other toxicities were mostly of grade I/II and easily manageable. Conclusion: The combination of docetaxel, oxaliplatin and capecitabine in the described mode of administration represents a relatively active and well-tolerated regimen in patients with advanced gastric cancer and warrants further evaluation.
FXIII-A Leu34 genetic variant in premature coronary artery disease: A genotype – phenotype case control study
Authors: Silvain Johanne , Pena Ana , Vignalou Jean-Baptiste , Hulot Jean-Sébastien , Galier Sophie , Cayla Guillaume , Bellemain-Appaix Anne , Barthélémy Olivier , Beygui Farzin , Bal-dit-Sollier Claire , Drouet Ludovic , Weisel John , Collet Jean-Phillippe , Montalescot Gilles
Published: July 2011

The FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (<45 years old) who survived a myocardial infarction (MI) and 242 healthy controls matched for age and gender. We evaluated its effect on longterm clinical outcome defined as a composite of cardiovascular death, recurrent MI and urgent revascularisation. In addition, fibrin clot stiffness (elastic modulus or EM) and response to rt-PA-mediated fibrinolysis (fibrinolysis rate) were measured ex vivo using the Hemodyne analyser and confocal microscopy as surrogate endpoint. FXIII-A Leu34 genetic variant was not associated with premature CAD (adj. odds ratio 0.83 [0.49–1.4]) nor did it influence clinical outcome in patients, during a median follow-up of 6.3 (± 2.4) years. Patients produced stiffer fibrin clots (median [IQR] EM =20.3 [14.9–28.1] vs. 12.8 [9.6–17.1] kdynes/ cm2; p<0.0001) and displayed reduced response to fibrinolysis with lower fibrinolysis rate (6.7 [3.4–11.0] vs. 9.0 [5.0–16.7] sec-1x10−4; p<0.0001) than healthy controls. Carriage of factor XIII-A Leu34 led to a stepwise decrease in fibrinolysis rate with a significant gene–dose-effect in patients (7.7 [4.1–12.2] vs. 4.8 [3.0–8.5] vs. 4.3 [2.4–8.1] sec-1x10−4, for wild-type, heterozygous and homozygous, p for trend =0.003) and a non-significant trend in controls (p=0.01). In conclusion, FXIII-A Leu34 is a polymorphism which provides a strong resistance to fibrinolysis with a gene-dose effect, but does not relate to premature CAD or to recurrent coronary events in this study.
Malignant transformation in melanocytes is associated with increased production of procoagulant microvesicles
Authors: Lima Luize , Oliveira Andreia , Campos Luiza , Bonamino Martin , Chammas Roger , Werneck Claudio , Vicente Cristina , Barcinski Marcello , Petersen Lars , Monteiro Robson
Published: July 2011

Shedding of microvesicles (MVs) by cancer cells is implicated in a variety of biological effects, including the establishment of cancer-associated hypercoagulable states. However, the mechanisms underlying malignant transformation and the acquisition of procoagulant properties by tumour-derived MVs are poorly understood. Here we investigated the procoagulant and prothrombotic properties of MVs produced by a melanocyte-derived cell line (melan-a) as compared to its tumourigenic melanoma counterpart Tm1. Tumour cells exhibit a two-fold higher rate of MVs production as compared to melan-a. Melanoma MVs display greater procoagulant activity and elevated levels of the clotting initiator protein tissue factor (TF). On the other hand, tumour- and melanocyte- derived MVs expose similar levels of the procoagulant lipid phosphatidylserine, displaying identical abilities to support thrombin generation by the prothrombinase complex. By using an arterial thrombosis model, we observed that melanoma- but not melanocyte-derived MVs strongly accelerate thrombus formation in a TF-dependent manner, and accumulate at the site of vascular injury. Analysis of plasma obtained from melanoma-bearing mice showed the presence of MVs with a similar procoagulant pattern as compared to Tm1 MVs produced in vitro. Remarkably, flow-cytometric analysis demonstrated that 60% of ex vivo MVs are TF-positive and carry the melanoma-associated antigen, demonstrating its tumour origin. Altogether our data suggest that malignant transformation in melanocytes increases the production of procoagulant MVs, which may contribute for a variety of coagulation- related protumoural responses.
Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus
Authors: Alessi Marie-Christine , Nicaud Viviane , Scroyen Ilse , Lange Celine , Saut Noemie , Fumeron Frederic , Marre Michel , Lantieri Olivier , Fontaine-Bisson Benedicte , Juhan-Vague Iréne , Balkau Beverley , Tregouet David-Alexandre , Morange Pierre-Emmanuel ,   D.E.S.I.R. Study Group
Published: July 2011

It was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.S.I.R. cohort who subsequently developed MetS (n=487) and T2DM (n=182) over a nine-year follow-up (42 presented both) and who were matched with two healthy control subjects each by use of a nested case-control design. Parameters composing the MetS explained about 20% of plasma vitronectin levels. An increase of one standard deviation of vitronectin was associated with increased risks of both the MetS (odds ratio [OR] = 1.21 [1.07 – 1.37], p = 0.003) and T2DM (OR = 1.24 [1.01 – 1.53], p = 0.045). Corresponding ORs for PAI-1 levels were 1.46 [1.27 – 1.68] (p < 10−4) and 1.40 [1.14 – 1.72] (p = 0.0012). However, the effects of vitronectin and PAI-1 levels on outcomes were not independent. The vitronectin–MetS association was restricted to individuals with low to modest PAI-1 levels (OR = 1.33 [1.14 – 1.54], p = 0.0003) while no association was observed in individuals with high PAI-1 levels (OR = 0.87 [0.68 – 1.10], p = 0.24), the test for interaction being highly significant (p = 0.0009). In conclusion, baseline plasma vitronectin is a marker of incident MetS at nine years. Its predictive ability for MetS and T2DM should not be assessed independently of PAI-1 levels.
Fibrinogen concentration and its role in CVD risk in black South Africans – effect of urbanisation
Authors: Maat Moniek , Jerling Johann , Hoekstra Tiny , Kruger Annamarie , Pieters Marlien
Published: July 2011

The aim of this study was to investigate correlates of fibrinogen concentration in black South Africans, as well as its association with cardiovascular disease (CVD) risk and whether urbanisation influences this association. A total of 1,006 rural and 1,004 urban black South Africans from the PURE study were cross-sectionally analysed. The association of fibrinogen with CVD risk was determined by investigating the association of fibrinogen with other CVD risk markers as well as with predicted CVD risk using the Reynolds Risk score. The rural group had a significantly higher fibrinogen concentration than the urban group, despite higher levels of risk factors and increased predicted CVD risk in the urban group. Increased levels of CVD risk factors were, however, still associated with increased fibrinogen concentration. Fibrinogen correlated significantly, but weakly, with overall predicted CVD risk. This correlation was stronger in the urban than in the rural group. Multiple regression analysis showed that a smaller percentage of the variance in fibrinogen is explained by the traditional CVD risk factors in the rural than in the urban group. In conclusion, fibrinogen is weakly associated with CVD risk (predicted overall risk as well with individual risk factors) in black South Africans, and is related to the degree of urbanisation. Increased fibrinogen concentration, in black South Africans, especially in rural areas, is largely unexplained, and likely not strongly correlated with traditional CVD-related lifestyle and pathophysiological processes. This does, however, not exclude the possibility that once increased, the fibrinogen concentration contributes to future development of CVD.
Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications
Authors: Spectre Galia , Arnetz Lisa , Östenson Claes-Göran , Brismar Kerstin , Li Nailin , Hjemdahl Paul
Published: July 2011

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in plateletrich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p=0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p=0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12–14%; p=0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p=0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p=0.002), but not 75 mg BID (p=0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2=0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.
Sustained impact of electronic alerts on rate of prophylaxis against venous thromboembolism
Authors: Beeler Patrick , Kucher Nils , Blaser Jürg
Published: July 2011

Advanced electronic alerts (eAlerts) and computerised physician order entry (CPOE) increase adequate thromboprophylaxis orders among hospitalised medical patients. It remains unclear whether eAlerts maintain their efficacy over time, after withdrawal of continuing medical education (CME) on eAlerts and on thromboprophylaxis indications from the study staff. We analysed 5,317 hospital cases from the University Hospital Zurich during 2006–2009: 1,854 cases from a medical ward with eAlerts (intervention group) and 3,463 cases from a surgical ward without eAlerts (control group). In the intervention group, an eAlert with hospital-specific venous thromboembolism (VTE) prevention guidelines was issued in the electronic patient chart 6 hours after admission if no pharmacological or mechanical thromboprophylaxis had been ordered. Data were analysed for three phases: pre-implementation (phase 1), eAlert implementation with CME (phase 2), and post-implementation without CME (phase 3). The rates of thromboprophylaxis in the intervention group were 43.4% in phase 1 and 66.7% in phase 2 (p<0.001), and increased further to 73.6% in phase 3 (p=0.011). Early thromboprophylaxis orders within 12 hours after admission were more often placed in phase 2 and 3 as compared to phase 1 (67.1% vs. 52.1%, p<0.001). In the surgical control group, the thromboprophylaxis rates in the three phases were 88.6%, 90.7%, 90.6% (p=0.16). Advanced eAlerts may provide sustained efficacy over time, with stable rates of thromboprophylaxis orders among hospitalised medical patients.
Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay
Authors: Bartsch Ingrid , Sandrock Kirstin , Lanza Francois , Nurden Paquita , Hainmann Ina , Pavlova Anna , Greinacher Andreas , Tacke Uta , Barth Michael , Busse Anja , Oldenburg Johannes , Bommer Martin , Strahm Brigitte , Superti-Furga Andrea , Zieger Barbara
Published: July 2011

The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ibβ (GP1BB) but also the SEPT5 gene, located 5’ to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIbβ and SEPT5 proteins in the patient’s platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealedimpaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleedingepisodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect.
Progression of the Prothrombotic State in Aging Bmal1-Deficient Mice
Authors: Hemmeryckx Bianca , Van Hove Cor E. , Fransen Paul , Emmerechts Jan , Kauskot Alexandre , Bult Hidde , Lijnen H. Roger , Hoylaerts Marc F.
Published: July 2011

Objective—

The goal of this study was to examine the functional relationship between aging endothelium and thrombogenicity in a mouse model of premature aging.

Methods and Results—

Coagulation tests and factors, blood cell counts, aorta endothelial function, aorta gene expression, and FeCl
3
-induced thrombosis in mesenteric blood vessels were analyzed in 10- to 30-week-old brain and muscle ARNT-like protein-1 (Bmal1)–deficient (knockout [KO]) mice and wild-type littermates. Ten-week-old KO mice manifested shortened prothrombin times (9.7 versus 11.3 seconds in wild-type) and elevated plasma fibrinogen (264 versus 172 mg/dL). At 30 weeks, factor VII (198% versus 149%), and platelet counts (2049 versus 1354 K/μL) were increased in KO mice. Gene deficiency reduced the vasoactive nitric oxide production at 10 and 30 weeks and tended to reduce and increase the protein expression of thrombomodulin and von Willebrand factor, respectively, with aging. Shortened venular and arteriolar occlusion times on FeCl
3
-induced injury in 10-week-old KO mice confirmed higher thrombogenicity, culminating in priapism, observed in 60% of 25- to 30-week-old KO males.

Conclusion—

Endothelial dysfunction and a hypercoagulable state cause early arterial and venous thrombogenicity in Bmal1 KO mice. With aging, progressive endothelial dysfunction, rising platelet counts, and high factor VII further enhance thrombogenicity, provoking priapism.
Essential Domains of A Disintegrin and Metalloprotease With Thrombospondin Type 1 Repeats-13 Metalloprotease Required for Modulation of Arterial Thrombosis
Authors: Xiao Juan , Jin Sheng-Yu , Xue Jing , Sorvillo Nicoletta , Voorberg Jan , Zheng X. Long
Published: July 2011

Objective—

A disintegrin and metalloprotease with thrombospondin type 1 repeats-13 (ADAMTS13) inhibits platelet aggregation and arterial thrombosis by cleavage of von Willebrand factor. However, the structural components of ADAMTS13 required for inhibition of arterial thrombosis are not fully defined.

Methods and Results—

Using recombinant proteins and a murine model, we demonstrated that an ADAMTS13 variant truncated after either the eighth thrombospondin type 1 repeat or the spacer domain inhibits ferric chloride–induced arterial thrombosis in
ADAMTS13
−/−
mice with efficacy similar to that of full-length ADAMTS13. The results obtained from monitoring thrombus formation in carotid and mesenteric arteries were highly concordant. Further analyses by site-directed mutagenesis and human monoclonal antibody inhibition assay revealed that the Cys-rich and spacer domains of ADAMTS13, particularly the amino acid residues between Arg559 and Glu664 in the spacer domain, may be critical for modulation of arterial thrombosis in vivo. Finally, the thrombosis-modulating function of ADAMTS13 and variants/mutants was highly correlated with the von Willebrand factor–cleavage activity under fluid shear stress.

Conclusion—

Our results suggest that the amino terminus of ADAMTS13, specifically the variable region of the spacer domain, is crucial for modulation of arterial thromboses under (patho)physiological conditions. These findings shed more light on the structure-function relationship of ADAMTS13 in vivo and may be applicable for rational design of protein- or gene-based therapy of arterial thromboses.
CD14
dim
CD16
+
and CD14
+
CD16
+
Monocytes in Obesity and During Weight Loss
Authors: Poitou Christine , Dalmas Elise , Renovato Mariana , Benhamo Vanessa , Hajduch Froogh , Abdennour Meriem , Kahn Jean-François , Veyrie Nicolas , Rizkalla Salwa , Fridman Wolf-Hervé , Sautès-Fridman Catherine , Clément Karine , Cremer Isabelle
Published: July 2011

Objective—

Studies suggest the implication of CD16
+
subpopulations (CD14
+
CD16
+
, CD14
dim
CD16
+
) in inflammatory diseases. We aimed to determine the frequency of these subpopulations during weight loss in obesity and diabetes, conditions associated with changes in systemic inflammation, and we tested the link with subclinical atherosclerosis.

Methods and Results—

CD14
dim
CD16
+
and CD14
+
CD16
+
frequencies were measured by flow cytometry in lean subjects, obese subjects before and after a hypocaloric diet or gastric surgery, and obese diabetic subjects before and after gastric surgery. Both monocyte subsets were increased in obese subjects, with a significant enrichment of the CD14
dim
CD16
+
subpopulation in obese diabetic patients. Multivariate analysis demonstrated a link between the percentages of CD14
dim
CD16
+
monocytes and glycemia, independent of fat mass. Drastic weight loss led to a sharp decrease of this subset, the variations of which were strongly related to fat mass changes. A reduction of at least 5% of fat mass was sufficient to observe a significant decrease of CD14
dim
CD16
+
monocytes. A diminution of the CD14
+
CD16
+
subset was also observed during weight loss and was associated with a decrease in intima-media thickness.

Conclusion—

This work demonstrates a major impact of fat mass variations on CD14
dim
CD16
+
monocyte subsets and that the decrease in the CD14
+
CD16
+
subpopulation is linked to a reduction of subclinical atherosclerosis.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00476658.
Netrin-4 Activates Endothelial Integrin α6β1
Authors: Larrieu-Lahargue Frederic , Welm Alana L. , Thomas Kirk R. , Li Dean Y.
Published: July 2011

Rationale:

Netrin-4 regulates vascular development. Identity of netrin-4 endothelial receptor and its subsequent cell functions is controversial. We previously demonstrated that the inhibition of netrin-1 canonical receptors, Unc5B and neogenin, expressed by lymphatic endothelial cells, do not suppress netrin-4-induced cell signaling and functions. Netrin family members were shown to signal through a range of receptors, including integrins (such as α3β1, α6β1, and α6β4) in nonendothelial cells.

Objective:

We tested whether integrins are netrin-4 receptors in the endothelium.

Methods and Results:

The α6β1 integrin is expressed by endothelial cells, and binds netrin-4 in a dose-dependent manner. Inhibition of α6 or β1 integrin subunits suppresses netrin-4-induced endothelial cell migration, adhesion, and focal adhesion contact. Netrin-4-stimulated phosphorylation of Src kinase family, effectors of endothelial cell migration, is also abolished by α6 or β1 inhibition. Finally, netrin-4 and α6β1 integrin expression colocalize in mouse embryonic, intestine, and tumor vasculature.

Conclusions:

The α6β1 integrin is a netrin-4 receptor in lymphatic endothelium and consequently represents a potential target to inhibit netrin-4-induced metastatic dissemination.
Serum Low-Density Lipoprotein Cholesterol Level Predicts Hematoma Growth and Clinical Outcome After Acute Intracerebral Hemorrhage
Authors: Rodriguez-Luna David , Rubiera Marta , Ribo Marc , Coscojuela Pilar , Pagola Jorge , Piñeiro Socorro , Ibarra Bernardo , Meler Pilar , Maisterra Olga , Romero Francisco , Alvarez-Sabin Jose , Molina Carlos A.
Published: July 2011

Background and Purpose—

Lower serum low-density lipoprotein cholesterol (LDL-C) levels have been associated with increased risk of death after intracerebral hemorrhage (ICH). Nevertheless, their link with hematoma growth (HG) is unknown. Therefore, we aimed to investigate the relationship between LDL-C levels, HG, and clinical outcome in patients with acute ICH.

Methods—

We prospectively studied 108 consecutive patients with primary supratentorial ICH presenting within 6 hours from symptoms onset. National Institutes of Health Stroke Scale score and ICH volume on computed tomography scan were recorded at baseline and at 24 hours. Lipid profile was obtained during the first 24 hours. Significant HG was defined as hematoma enlargement >33% or >6 mL at 24 hours. Early neurological deterioration as well as mortality and poor long-term outcome (modified Rankin Scale score >2) at 3 months were recorded.

Results—

Although LDL-C levels were not correlated with ICH volume (
r
=−0.18;
P
=0.078) or National Institutes of Health Stroke Scale score (
r
=−0.17;
P
=0.091) at baseline, lower LDL-C levels were associated with HG (98.1±33.7 mg/dL versus 117.3±25.8 mg/dL;
P
=0.003), early neurological deterioration (89.2±31.8 mg/dL versus 112.4±29.8 mg/dL;
P
=0.012), and 3-month mortality (94.9±37.4 mg/dL versus 112.5±28.5 mg/dL;
P
=0.029), but not with poor long-term outcome (109.5±31.3 mg/dL versus 108.3±30.5 mg/dL;
P
=0.875). Moreover, LDL-C levels were inversely related to the amount of hematoma enlargement at 24 hours (
r
=−0.31;
P
=0.004). In multivariate logistic regression analysis, LDL-C level <95 mg/dL emerged as an independent predictor of HG (OR, 4.24; 95% CI, 1.26–14.24;
P
=0.020), early neurological deterioration (OR, 8.27; 95% CI, 1.66–41.16;
P=
0.010), and 3-month mortality (OR, 6.34; 95% CI, 1.29–31.3;
P
=0.023).

Conclusions—

Lower serum LDL-C level independently predicts HG, early neurological deterioration, and 3-month mortality after acute ICH.
Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats
Authors: Oyama Naoki , Yagita Yoshiki , Kawamura Miki , Sugiyama Yukio , Terasaki Yasukazu , Omura-Matsuoka Emi , Sasaki Tsutomu , Kitagawa Kazuo
Published: July 2011

Background and Purpose—

It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery. Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR).

Methods—

Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser
1177
-phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N
5
-(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia.

Results—

In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N
5
-(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin.

Conclusions—

These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR.
Trends in Pregnancy Hospitalizations That Included a Stroke in the United States From 1994 to 2007
Authors: Kuklina Elena V. , Tong Xin , Bansil Pooja , George Mary G. , Callaghan William M.
Published: July 2011

Background and Purpose—

Stroke is an important contributor to maternal morbidity and mortality, but there are no recent data on trends in pregnancy-related hospitalizations that have involved a stroke. This report describes stroke hospitalizations for women in the antenatal, delivery, and postpartum periods from 1994 to 1995 to 2006 to 2007 and analyzes the changes in these hospitalizations over time.

Methods—

Hospital discharge data were obtained from the Nationwide Inpatient Sample, developed as part of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. Pregnancy-related hospitalizations with stroke were identified according to the International Classification of Diseases, Ninth Revision. All statistical analyses accounted for the complex sampling design of the data source.

Results—

Between 1994 to 1995 and 2006 to 2007, the rate of any stroke (subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, transient ischemic attack, cerebral venous thrombosis, or unspecified) among antenatal hospitalizations increased by 47% (from 0.15 to 0.22 per 1000 deliveries) and among postpartum hospitalizations by 83% (from 0.12 to 0.22 per 1000 deliveries) while remaining unchanged at 0.27 for delivery hospitalizations. In 2006 to 2007, ≈32% and 53% of antenatal and postpartum hospitalizations with stroke, respectively, had concurrent hypertensive disorders or heart disease. Changes in the prevalence of these 2 conditions from 1994 to 1995 to 2006 to 2007 explained almost all of the increase in postpartum hospitalizations with stroke during the same period.

Conclusions—

Our results have demonstrated an increasing trend in the rate of pregnancy-related hospitalizations with stroke in the United States, especially during the postpartum period, from 1994 to 1995 to 2006 to 2007.
Sex-Specific Temporal Trends in In-Hospital Mortality After Stroke Among Middle-Age Individuals in the United States
Authors: Towfighi Amytis , Tai Waimei , Markovic Daniela , Ovbiagele Bruce
Published: July 2011

Background and Purpose—

Recent studies have revealed an increase in stroke prevalence among middle-aged women in the United States. To determine whether this is due to improved survival, we assessed temporal trends in sex-specific in-hospital mortality after stroke.

Methods—

Individuals aged 35 to 64 years hospitalized in 1997 to 2006 with a primary discharge diagnosis of stroke (N=2 537 097) in the United States were identified by the Nationwide Inpatient Sample. Temporal trends in sex-specific mortality after stroke and sex differences in mortality were assessed, before and after controlling for covariates.

Results—

From 1997 to 2006, poststroke mortality decreased in both men (6.06% to 5.15%) and women (6.02% to 4.88%) aged 35 to 64 years. Unadjusted analysis revealed that women aged 35 to 44 years (odds ratio=0.89; 95% CI, 0.83 to 0.95) and 45 to 54 years (odds ratio=0.93; 95% CI, 0.89 to 0.97) had lower mortality compared with men, whereas women aged 55 to 64 years had similar mortality compared with men. After adjustment for covariates, stroke type accounted for the better survival in women aged 35 to 44 years. After adjustment for covariates, women aged 45 to 54 years persistently had better survival than did men. Women aged 55 to 64 years had better survival than did men, once race and insurance type were accounted for.

Conclusions—

This study revealed a decline in stroke mortality rates from 1997 to 2006 among individuals aged 35 to 64 years. Better survival among women compared with men aged 35 to 54 years may partially explain the sex disparity in stroke prevalence.
Impact of Hospital Admission During Nonworking Hours on Patient Outcomes After Thrombolysis for Stroke
Authors: Haeusler Karl Georg , Gerischer Lea M. , Vatankhah Bijan , Audebert Heinrich J. , Nolte Christian H.
Published: July 2011

Background and Purpose—

Whether the time of hospital admission is relevant for short-term outcome after stroke is under debate and may depend on care facilities.

Methods—

We retrospectively analyzed medical records from patients who received thrombolytic therapy within 4.5 hours of stroke onset in a stroke unit of the Charité–University Hospital Berlin (Charité; n=291) or within the stroke telemedicine (TEMPiS) network, comprising 12 community hospitals with telestroke units in Bavaria (n=616).

Results—

Thrombolytic therapy was administered during nonworking hours in 59.5% (Charité) and 55.0% (TEMPiS) of patients. A trend toward a lower rate of symptomatic intracranial hemorrhage (3.4% versus 9.2%;
P
=0.053), clinical worsening (11.9% versus 19.7%;
P
=0.079), and 7-day mortality (3.4% versus 8.7%;
P
=0.073) after admission during working hours was seen at Charité. However, multivariable analysis did not show a significant impact of the time of admission on clinical worsening, symptomatic intracranial hemorrhage, or 7-day mortality in both cohorts. Thrombolysis based on brain computed tomography instead of magnetic resonance imaging (odds ratio=4.98, 95% CI, 1.09 to 22.7) and more severe National Institutes of Health Stroke Scale score on admission (odds ratio=1.15 per point; 95% CI, 1.07 to 1.24) were associated with 7-day mortality at Charité. National Institutes of Health Stroke Scale score on admission (odds ratio=1.13 per point; 95% CI, 1.06 to 1.19) and older age (odds ratio=1.05 per year; 95% CI, 1.004 to 1.09) were correlated with 7-day mortality in TEMPiS. National Institutes of Health Stroke Scale on admission was the only independent predictor of symptomatic intracranial hemorrhage or clinical worsening in both cohorts.

Conclusions—

The majority of stroke patients received thrombolysis during nonworking hours. The time of hospital admission did not significantly influence the short-term outcome after thrombolysis.
Progression Rate and Ipsilateral Neurological Events in Asymptomatic Carotid Stenosis
Authors: Hirt Liam S.
Published: July 2011

Background and Purpose—

Progression of asymptomatic carotid stenoses with >50% luminal narrowing is associated with an increased risk of stroke. The significance of the progression rate in these patients is unknown. The main aim of this study was to evaluate the rate of change of carotid luminal narrowing over 1 year, as a risk factor for ipsilateral ischemic events, in patients with a >50% asymptomatic carotid stenosis. Secondary aims were to establish the incidence of changes in carotid luminal narrowing and establish additional risk factors for ipsilateral neurological events.

Methods—

A retrospective analysis was conducted of data derived from the deferred endarterectomy arm of the Asymptomatic Carotid Surgery Trial. Patients were followed up for ≥5 years with serial carotid duplex examinations. Data were derived from information obtained at randomization and annual follow-up visits with carotid duplex examination. Potential risk factors for ipsilateral neurological events were analyzed in Poisson regression models.

Results—

Data from 1469 patients were included. Two hundred forty-four had ipsilateral events; 240 had ipsilateral carotid surgery; 370 died from nonstroke causes; and 82 had an asymptomatic carotid occlusion. The annual incidence of progression in the cohort as a whole was 5.2%. Ipsilateral events occurred in 17% of patients. Diabetes and previous contralateral symptoms showed a significant independent association with ipsilateral neurological events. Ipsilateral events were associated with high rates of progression over 1 year but not with low progression rates or regression.

Conclusions—

Fast rates of progression of carotid luminal narrowing should be interpreted as a sign of significantly increased risk of future ipsilateral neurological events.
Arterial Spin-Labeling MRI Can Identify the Presence and Intensity of Collateral Perfusion in Patients With Moyamoya Disease
Authors: Zaharchuk Greg , Do Huy M. , Marks Michael P. , Rosenberg Jarrett , Moseley Michael E. , Steinberg Gary K.
Published: July 2011

Background and Purpose—

Determining the presence and adequacy of collateral blood flow is important in cerebrovascular disease. Therefore, we explored whether a noninvasive imaging modality, arterial spin labeling (ASL) MRI, could be used to detect the presence and intensity of collateral flow using digital subtraction angiography (DSA) and stable xenon CT cerebral blood flow as gold standards for collaterals and cerebral blood flow, respectively.

Methods—

ASL and DSA were obtained within 4 days of each other in 18 patients with Moyamoya disease. Two neurointerventionalists scored DSA images using a collateral grading scale in regions of interest corresponding to ASPECTS methodology. Two neuroradiologists similarly scored ASL images based on the presence of arterial transit artifact. Agreement of ASL and DSA consensus scores was determined, including kappa statistics. In 15 patients, additional quantitative xenon CT cerebral blood flow measurements were performed and compared with collateral grades.

Results—

The agreement between ASL and DSA consensus readings was moderate to strong, with a weighted kappa value of 0.58 (95% confidence interval, 0.52–0.64), but there was better agreement between readers for ASL compared with DSA. Sensitivity and specificity for identifying collaterals with ASL were 0.83 (95% confidence interval, 0.77–0.88) and 0.82 (95% confidence interval, 0.76–0.87), respectively. Xenon CT cerebral blood flow increased with increasing DSA and ASL collateral grade (
P
<0.05).

Conclusions—

ASL can noninvasively predict the presence and intensity of collateral flow in patients with Moyamoya disease using DSA as a gold standard. Further study of other cerebrovascular diseases, including acute ischemic stroke, is warranted.
Charlson Comorbidity Index Adjustment in Intracerebral Hemorrhage
Authors: Bar Barak , Hemphill J. Claude
Published: July 2011

Background and Purpose—

Previous studies of intracerebral hemorrhage (ICH) outcome prediction models have not systematically included adjustment for comorbid conditions. The purpose of this study was to assess whether the Charlson Comorbidity Index (CCI) was associated with early mortality and long-term functional outcome in patients with intracerebral hemorrhage.

Methods—

We performed a retrospective analysis on a prospective observational cohort of patients with ICH admitted to 2 University of California San Francisco hospitals from June 1, 2001 to May 31, 2004. Components of the ICH score and use of early care limitations were recorded. Outcome was assessed using the modified Rankin Scale to 12 months. The CCI was derived using hospital discharge International Classification of Diseases, revision 9 codes and patient history obtained from standardized case report forms.

Results—

In this cohort of 243 ICH patients, comorbid conditions were common, with CCI scores ranging from 0 to 12. Only 29% of patients with high CCI scores (≥3) achieved a 12-month modified Rankin Scale score of ≥3 compared with 48% of patients with CCI scores of 0 (
P
=0.02). CCI score was independently predictive of 12-month functional outcome, with higher CCI having a greater impact (CCI=2: odds ratio, 2.3;
P
=0.06; CCI=≥3: odds ratio, 3.5;
P
=0.001).

Conclusions—

Comorbid medical conditions as measured by the CCI independently influence outcome after ICH. Future ICH outcome studies should account for the impact of comorbidities on patient outcome.
Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome
Authors: Becker Kyra J. , Kalil Angela J. , Tanzi Pat , Zierath Dannielle K. , Savos Anna V. , Gee J. Michael , Hadwin Jessica , Carter Kelly T. , Shibata Dean , Cain Kevin C.
Published: July 2011

Background and Purpose—

Immune responses to brain antigens occur after stroke, and experimental studies show that the likelihood of developing a detrimental autoimmune response to these antigens is increased by systemic inflammation at the time of stroke. The aim of this study was to determine if patients who developed infection in the poststroke period would be similarly predisposed to develop autoimmune responses to central nervous system antigens.

Methods—

We enrolled 114 patients within 72 hours of ischemic stroke. Clinical and demographic data were obtained, and cellular immune responses to a panel of central nervous system antigens were assessed during the initial week and again at Day 90. Outcome was assessed using the modified Rankin Scale.

Results—

Patients who developed an infection, especially pneumonia, in the 15 days after stroke were more likely to evidence a Th1(+) response to myelin basic protein and glial fibrillary acidic protein (
P
=0.019 and
P
=0.039, respectively) at 90 days after stroke. Further, more robust Th1 responses to myelin basic protein at 90 days were associated with a decreased likelihood of good outcome, even after adjusting for baseline stroke severity and patient age (OR, 0.477; 95% CI, 0.244 to 0.935;
P
=0.031).

Conclusions—

This study demonstrates that immune responses to brain antigens occur after stroke. Although these responses are likely to be an epiphenomenon of ischemic brain injury, the response to myelin basic protein appears to have clinical consequences. The potential role of postischemic autoimmune-mediated brain injury deserves further investigation.