bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of von Willebrand factor levels in young women with and without bleeding symptoms. Influence of ABO blood group and promoter haplotypes
Authors: Hillarp Andreas , Ekholm Caroline , Mattson Eva , Halldén Christer , Friberg Britt , Lethagen Stefan
Published: May 2008

The normal distribution of von Willebrand factor (VWF) levels is wide. Low levels are associated with bleeding symptoms and von Willebrand disease (VWD). We have recently described a high prevalence of bleeding symptoms in a whole age group of young females (n = 1,019) from Malmo, Sweden. It was the objective of the present study to evaluate the distribution of VWF levels in young females with or without bleeding symptoms in this population, and the influence of ABO blood group and promoter haplotypes on VWF levels and to identify a possible increased prevalence of VWD in females with bleeding symptoms. A random selection of the female age group (n = 246), into a study group (n = 176) with, and a control group (n = 70) without bleeding symptoms, was evaluated. Eighteen girls had VWF:RCo below the reference range, of which 17 belonged to the study group (17/176, 9.7%), and one to the control group (1/70, 1.4%) (p = 0.017). Blood group O was found in 14/18 girls with low VWF:RCo. There was a highly significant correlation between VWF:RCo and blood group O and non-O genotypes. Two common VWF promoter haplotypes did not contribute to the VWF:RCo variation. VWF levels did not correlate with time during menstrual cycle, or the use of oral contraceptives. No case fulfilled the diagnostic criteria for VWD. In conclusion, low VWF:RCo was significantly more frequent in females with bleeding symptoms. However, we found no case fulfilling strict diagnostic criteria for VWD. The ABO blood group was a strong modifier, but VWF promoter haplotypes had no association to VWF levels in this population.
Fibrinogen Hershey IV: A novel dysfibrinogen with a γV411I mutation in the integrin αIIbβ3 binding site
Authors: Flood Veronica , Al-Mondhiry Hamid , Rein Chantelle , Alexander Kristine , Lovely Rehana , Shackleton Kelley , David Larry , Farrell David
Published: May 2008

The carboxyl terminal segment of the fibrinogen γ chain from γ408–4ll plays a crucial role in platelet aggregation via interactions with the platelet receptor αIIbβ3. We describe here the first naturally-occurring fibrinogen point mutation affecting this region and demonstrate its effects on platelet interactions. DNA sequencing was used to sequence the proband DNA, and platelet aggregation and direct binding assays were used to quantitate the biological effects of fibrinogen Hershey IV. The Hershey IV proband was found to be heterozygous for two mutations, γV411I and γR275C. Little difference in aggregation was seen when fibrinogen Hershey IV was compared to normal fibrinogen. However, less aggregation inhibition was observed using a competing synthetic dodecapeptide containing the V411I mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet αIIbβ3 with a lower affinity than wild-type fibrinogen. These findings show that the γV411I mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available wild-type fibrinogen appears to be sufficient to support normal platelet aggregation.
Simultaneous detection and epitope mapping of anti-factor VIII antibodies
Authors: Lapalud Priscilla , Chtourou Sami , Schved Jean-François , Granier Claude , Lavigne-Lissalde Geraldine , Tarrade Catherine , Villard-Saussine Sylvie
Published: May 2008

The development of antibodies (Abs) against infused factor VIII (FVIII) is currently one of the most serious complications in the treatment of patients suffering from haemophilia A. Improved prevention and eradication of these anti-FVIII Abs remain a challenge for both clinicians and scientists. Here we describe an immunoassay to simultaneously detect and map the epitope specificity of haemophilia A patients’ inhibitors by screening plasma against both heavy and light chains (HC and LC) of human plasma-derived FVIII (pFVIII). The format used was a two-site sandwich assay, where one monoclonal antibody (mAb) specific for the HC or LC was first immobilized on beads, and then incubated with the different forms of pFVIII. After incubation with patients’ plasma samples, binding was revealed by a phycoerythrin-labeled secondary Ab. Samples from haemophilia patients with autoantibodies (autoAb) or alloantibodies (alloAb) were screened in this format. The former preferentially recognized the LC, whereas the latter were directed against both LC and HC. This technology appears attractive as it is fast and requires only 100 μl of patient’s plasma. Furthermore, not only are anti-FVIII Abs detected, but information on their epitopic specificity is also obtained.
Determinants of mean platelet volume (MPV) in an elderly population: Relevance of body fat, blood glucose and ischaemic electrocardiographic changes
Authors: Muscari Antonio , Pascalis Susanna , Ludovico Cosimo , Castaldini Nicola , Antonelli Serafina , Bianchi Giampaolo , Magalotti Donatella , Zoli Marco , Cenni Andrea
Published: May 2008

Mean platelet volume (MPV) is increased in patients with coronary heart disease or at risk for stroke. However, MPV determinants have never been assessed in a population study. The present investigation is a cross-sectional study involving 366 non-selected subjects (both sexes, mean age 72.9 ± 5.5 [1 SD] years). The main cardiovascular risk factors, several indexes of adiposity (including percent body fat as estimated by skinfold measurement, and ultrasound detection of hepatic steatosis and thickness of abdominal subcutaneous and visceral fat) and ischaemic electrocardiographic (ECG) changes were assessed in all subjects. Platelet parameters were determined by a Bayer ADVIA 120 counter. In addition to being associated directly with platelet distribution width (PDW) and inversely with platelet count (p<0.0001 for both), MPV values were associated with subcutaneous abdominal fat (p=0.02), fasting blood glucose (p=0.002) and the prevalence of ischaemic ECG changes (p=0.004), and tended to be higher in the subjects with a greater prevalence of hepatic steatosis (p=0.07) and higher Homeostasis Model Assessment (HOMA) index (p=0.09). In multiple logistic regression, of the non-platelet parameters only percent body fat (p=0.006), ischaemic ECG changes (p=0.01) and blood glucose (p=0.03) remained independently associated with an MPV ≥8.4 fl (high tertile). The relative risk (odds ratio) of having ischaemic ECG changes for the subjects with MPV ≥8.4 fl was 4.2 (95% confidence interval: 2.5–7.1; p=0.006) with respect to the subjects with lower MPV values. Blood glucose, percent body fat and ischaemic ECG changes were the main MPV determinants in our elderly population.
Efficacy of extended thrombo-prophylaxis in major abdominal surgery: What does the evidence show?
Authors: Elizondo Maria , Doti Carlos , Bruetman Julio , Moreno Pablo , Bullorsky Eduardo , Ceresetto Jose , Bottaro Federico
Published: May 2008

Venous thromboembolism (VTE) is a frequent complication following major abdominal surgery. The use of low-molecular-weight heparins (LMWH) to prevent thrombotic events in these patients is a common and well documented practice. However, there is some controversy surrounding the duration of the prophylaxis, as it has been suggested that the risk persists for several weeks after surgery.The objective of this meta-analysis is to systematically review the clinical studies that compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis. An electronic data base search was performed. Only randomized, controlled studies were eligible. Data on the incidence of deep vein thrombosis (DVT), VTE and bleeding were extracted. Only three studies fulfilled the inclusion criteria. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% (23/388) versus 13.6% (55/405), RR 0.44 (CI 95% 0.28 – 0.7); DVT 5.93% (23/388) versus 12.9% (52/402), RR 0.46 (CI 95% 0,29 – 0,74); proximal DVT 1% (4/388) versus 4.72% (19/402), RR 0.24 (CI 95% 0.09 – 0,67). We found no significant difference in major or minor bleeding between the two groups: 3.85% (21/545) in the extended thrombo-prophylaxis (ETP) group versus 3.48% (19/559) in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 – 2.06). There was no heterogeneity between the studies. We conclude that ETP with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal surgery.
Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis
Authors: Matsumoto Masanori , Ishizashi Hiromichi , Kato Seiji , Matsuyama Tomomi , Isonishi Ayami , Ishikawa Masatoshi , Yagita Masato , Morioka Chie , Yoshiji Hitoshi , Tsujimoto Tatsuhiro , Kurumatani Norio , Fukui Hiroshi , Uemura Masahito , Fujimura Yoshihiro
Published: May 2008

Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimer (UL-VWFM) and the formation of platelet thrombi. It remains controversial whether or not plasma ADAMTS13:AC decreases in patients with liver cirrhosis (LC), and its relationship to clinical features has not been fully investigated. We measured ADAMTS13:AC and its related parameters in plasma in 33 patients with chronic hepatitis (CH) and in 109 patients with LC. ADAMTS13:AC decreased with increasing severity of liver disease (controls means 100%, CH 87%, Child A-LC 79%, Child B-LC 63%, and Child C-LC 31%), and showed severe deficiency (<3% of controls) in five end-stage LC. Activities measured by act-ELISA strongly correlated with those determined by the VWFM assay and ADAMTS13 antigen. Multivariate analysis showed Child-Pugh score and spleen volume independent factors contributing to ADAMTS13:AC. VWFM patterns were normal in 53% of cases, degraded in 31%, and unusually large in 16%. Patients with unusually large VWFM had the lowest ADAMTS13:AC as well as the highest Child-Pugh score, serum creatinine and blood ammonia levels. Plasma inhibitor against ADAMTS13 detected in 83% of patients with severe to moderate ADAMTS13:AC deficiency mostly showed marginal zone between 0.5 and 1.0 BU/ml. The IgG-type autoantibodies specific to plasma derived-ADAMTS13 was detected by Western blot in only five end-stage LC with severe ADAMTS13:AC deficiency. In conclusion, both plasma ADAMTS13 activity and antigen levels decreased with increasing severity of cirrhosis. An imbalance between the decreased ADAMTS13:AC and its increased substrate may reflect the predisposing state for platelet thrombi formation in patients with advanced LC.
Deep vein thrombosis in patients with chronic kidney disease
Authors: Daneschvar H. , Seddighzadeh Ali , Piazza Gregory , Goldhaber Samuel
Published: May 2008

Deep vein thrombosis (DVT) is a poorly understood complication of chronic kidney disease (CKD). The objective of our analysis was to profile DVT patients with and without CKD. We defined CKD as patients requiring dialysis or patients having nephrotic syndrome.We compared 268 patients with CKD (184 patients with dialysis-dependent renal disease and 84 with nephrotic syndrome) to 4,307 patients with preserved renal function from a prospective United States multicenter deep venous thrombosis (DVT) registry. Compared with non-CKD patients, CKD patients with DVT were younger (median age 62 vs. 69 years, p<0.0001), more often African- American (p<0.0001), and more often Hispanic (p=0.0003). CKD patients underwent surgery more frequently in the three months prior to developing DVT (48.9% vs. 39.0%, p=0.001) and more often had concomitant congestive heart failure (20.9% vs. 14.6%, p=0.005). CKD patients suffered upper extremity DVT more frequently (30.0% vs. 10.8%, p<0.0001). Patients with CKD presented less often with typical DVT symptoms of extremity discomfort (42.9% vs. 52.4%, p=0.003) and difficulty ambulating (5.4% vs. 10.1%, p=0.01). Prophylaxis rates prior to DVT were similarly low in CKD and non-CKD patients (44.2% vs. 38.0%, p=0.06). Future studies of DVT in CKD patients should explore novel strategies for improving prophylaxis utilization and the detection of DVT in this special population.
Limited diagnostic workup for deep vein thrombosis after major joint surgery
Authors: Peidro Luis , Resines Carlos , Garcés Carlos , Fernández José , Garagorri Eduardo , González Juan , Monreal Manuel ,   for the NETCOT Investigators
Published: May 2008

While deep vein thrombosis (DVT) may be clinically suspected at several time points after major orthopedic surgery, clinical examination is often unreliable, and compression ultrasonography (CUS) screening at discharge is of limited value. A prospective cohort study was carried out in 1,033 consecutive patients who had undergone major hip or knee surgery, aimed to assess the accuracy of a strategy consisting of clinical investigation followed by CUS in the detection of proximal DVT before discharge. The circumferences of both legs were measured in all patients; those exhibiting >2 cm difference between them were considered to have suspected DVT, and underwent bilateral CUS. The same diagnostic workup was repeated on days 45 and 90 after surgery. Three patients developed pulmonary embolism (PE) during admission (one died). Five additional patients died before discharge. Routine clinical evaluation before discharge was done in 1,025 patients, and 105 (10%) had suspected DVT. CUS confirmed the diagnosis in 24 (2.3% of the overall series). After discharge, 59 patients had suspected DVT on day 45, 53 on day 90. DVT diagnosis was confirmed by CUS in 27 (26%).Three additional patients developed PE (1 fatal). This translates into a sensitivity of the routine examinations at discharge of 44%. A limited diagnostic workup for DVT before discharge has the capacity to identify 44% of those patients who will become symptomatic afterwards.
Catheter Ablation for Atrial Fibrillation in Patients With Obesity
Authors: Cha Yong-Mei , Friedman Paul A. , Asirvatham Samuel J. , Shen Win-Kuang , Munger Thomas M. , Rea Robert F. , Brady Peter A. , Jahangir Arshad , Monahan Kristi H. , Hodge David O. , Meverden Ryan A. , Gersh Bernard J. , Hammill Stephen C. , Packer Douglas L.
Published: May 2008

Background—

Obesity is a risk factor for atrial fibrillation and other cardiovascular conditions. Our objective was to determine whether catheter-based ablation effectively treated atrial fibrillation in obese patients.

Methods and Results—

Five hundred twenty-three consecutive patients with symptomatic, medication-refractory atrial fibrillation underwent catheter ablation. Patients were grouped by body mass index (lean, <25 kg/m
2
; overweight, 25 to 29.9 kg/m
2
; obese, ≥30 kg/m
2
). Outcome and quality of life were measured with a general health survey (Medical Outcomes Study 36-item Short-Form General Health Survey [SF-36]); patients were assessed before ablation and at 3 and 12 months after the procedure. Two hundred twenty-eight study patients (44%) were overweight, and 201 (38%) were obese. Twelve months after curative ablation, 72% of patients were free of atrial fibrillation without the use of antiarrhythmic agents; 84% were arrhythmia free when those receiving medication were included. Atrial fibrillation was eliminated in 75%, 72%, and 70% of the lean, overweight, and obese patients, respectively, at 12 months (
P
=0.41, trend test). SF-36 scores were lower for patients with higher body mass index (
P
<0.05) at baseline. SF-36 scores improved in every functional domain for all body mass index groups after ablation. The mean SF-36 total physical score increased from 59±20 at baseline to 77±19 in 12 months (
P
<0.001). The total mental health score improved from 66±18 to 79±16 in 12 months (
P
<0.001).

Conclusions—

Catheter ablation of atrial fibrillation was effective in obese patients. Coexistence of atrial fibrillation and obesity indicated lower SF-36 scores, but the improvement in quality of life was consistent across all body mass index categories.
Comparison of Echocardiographic Dyssynchrony Assessment by Tissue Velocity and Strain Imaging in Subjects With or Without Systolic Dysfunction and With or Without Left Bundle-Branch Block
Authors: Miyazaki Chinami , Powell Brian D. , Bruce Charles J. , Espinosa Raul E. , Redfield Margaret M. , Miller Fletcher A. , Hayes David L. , Cha Yong-Mei , Oh Jae K.
Published: May 2008

Background—

Several echocardiographic dyssynchrony indexes have been proposed to identify responders to cardiac resynchronization therapy using tissue velocity and strain. The present study aimed to compare tissue velocity–derived and strain-derived dyssynchrony indexes in patients with or without systolic dysfunction and left bundle-branch block.

Methods and Results—

Tissue Doppler imaging was performed in 120 subjects divided into 4 groups: group 1 (n=40), normal subjects; group 2 (n=20), normal left ventricular ejection fraction and left bundle-branch block; group 3 (n=20), left ventricular ejection fraction <35% and normal conduction; and group 4 (n=40), left ventricular ejection fraction <35% and left bundle-branch block. Dyssynchrony indexes based on time to peak tissue velocity (septal-lateral delay, anteroseptal-posterior delay, and SD in time to peak systolic velocity in the 12 left ventricular segments) and strain (SD of time to peak strain in 12 segments) were measured. The SD in time to peak systolic velocity in the 12 left ventricular segments was greater in group 4 (54 ms; 25th and 75th percentiles, 46 to 64 ms) than group 1 (44 ms; 25th and 75th percentiles, 28 to 53 ms;
P
=0.006), but there was a considerable overlap of all tissue velocity–derived indexes among 4 groups, with 40% to 68% of group 1 having values proposed for predicting the responders of cardiac resynchronization therapy. The SD of time to peak strain in 12 segments distinguished these groups with much less overlap (
P
<0.01 for all pairwise comparisons).

Conclusions—

A substantial proportion of normal subjects have tissue velocity–derived dyssynchrony indexes higher than the cutoff value proposed for predicting beneficial effect of cardiac resynchronization therapy. Strain-derived timing index appears to be more specific for dyssynchrony in patients with systolic dysfunction and left bundle-branch block. Identifying an optimal tissue velocity– or strain-derived dyssynchrony index requires a large prospective clinical trial.
Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin
Authors: Moens An L. , Takimoto Eiki , Tocchetti Carlo G. , Chakir Khalid , Bedja Djahida , Cormaci Gianfranco , Ketner Elizabeth A. , Majmudar Maulik , Gabrielson Kathleen , Halushka Marc K. , Mitchell James B. , Biswal Shyam , Channon Keith M. , Wolin Michael S. , Alp Nicholas J. , Paolocci Nazareno , Champion Hunter C. , Kass David A.
Published: May 2008

Background—

Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction.

Methods and Results—

C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (−46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts.

Conclusions—

NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.
Independent Prognostic Importance of a Restrictive Left Ventricular Filling Pattern After Myocardial Infarction
Authors:   Meta-Analysis Research Group in Echocardiography (MeRGE) AMI Collaborators
Published: May 2008

Background—

Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved. We undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI.

Methods and Results—

Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20;
P
<0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF. The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (<39%) and lowest (9%) in patients with the highest LVEF (>53%;
P
<0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (
P
=0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome.

Conclusions—

Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.
Novel Role for Inhibitor of Differentiation 2 in the Genesis of Angiotensin II–Induced Hypertension
Authors: Gratze Petra , Dechend Ralf , Stocker Carolin , Park Joon-Keun , Feldt Sandra , Shagdarsuren Erdenechimeg , Wellner Maren , Gueler Faikah , Rong Song , Gross Volkmar , Obst Michael , Plehm Ralph , Alenina Natalia , Zenclussen Ana , Titze Jens , Small Kersten , Yokota Yoshifumi , Zenke Martin , Luft Friedrich C. , Muller Dominik N.
Published: May 2008

Background—

Angiotensin (Ang) II–induced target-organ damage involves innate and acquired immunity. Mice deficient for the helix-loop-helix transcription factor inhibitor of differentiation (Id2
−/−
) lack Langerhans and splenic CD8a+ dendritic cells, have reduced natural killer cells, and have altered CD8 T-cell memory. We tested the hypothesis that an alteration in the number and quality of circulating blood cells caused by Id2 deletion would ameliorate Ang II–induced target-organ damage.

Methods and Results—

We used gene-deleted and transgenic mice. We conducted kidney and bone marrow transplants. In contrast to Ang II–infused Id2
+/−
, Id2
−/−
mice infused with Ang II remained normotensive and failed to develop albuminuria or renal damage. Bone marrow transplant of Id2
+/−
bone marrow to Id2
−/−
mice did not restore the blunted blood pressure response to Ang II. Transplantation of Id2
−/−
kidneys to Id2
+/−
mice also could not prevent Ang II–induced hypertension and renal damage. We verified the Ang II resistance in Id2
−/−
mice in a model of local tissue Ang II production by crossing hypertensive mice transgenic for rat angiotensinogen with Id2
−/−
or Id2
+/−
mice. Angiotensinogen-transgenic Id2
+/−
mice developed hypertension, albuminuria, and renal injury, whereas angiotensinogen-transgenic Id2
−/−
mice did not. We also found that vascular smooth muscle cells from Id2
−/−
mice showed an antisenescence phenotype.

Conclusions—

Our bone marrow and kidney transplant experiments suggest that alterations in circulating immune cells or Id2 in the kidney are not responsible for Ang II resistance. The present studies identify a previously undefined role for Id2 in the pathogenesis of Ang II–induced hypertension.
Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II–Induced Adventitial Myofibroblast Migration
Authors: Haurani Mounir J. , Cifuentes M. Eugenia , Shepard Alexander D. , Pagano Patrick J.
Published: May 2008

The vascular adventitia is emerging as an important modulator of vessel remodeling. Adventitial myofibroblasts migrate to the neointima after balloon angioplasty, contributing to restenosis. We postulated that angiotensin II (Ang II) enhances adventitial myofibroblast migration in vitro via reduced nicotinamide-adenine dinucleotide phosphate oxidase–derived H
2
O
2
and that Nox4-based oxidase promotes migration. Ang II increased myofibroblast migration in a concentration-dependent manner, with a peak increase of 1023±83%. Rat adventitial myofibroblasts were cotransfected with human Nox4 and human p22-phox plasmids or an empty vector. PCR showed an 8-fold increase in human Nox4 and human p22-phox plasmid expression. Using RT-PCR with primers specifically designed for rat reduced nicotinamide-adenine dinucleotide phosphate oxidases, endogenous Nox levels were determined. Ang II decreased endogenous Nox4 and Nox1 mRNA to 41% and 27% of control, respectively, but had no effect on Nox2. Cotransfection with human Nox4 and human p22-phox plasmids combined with Ang II reduced endogenous Nox4 mRNA levels (37±5% of control;
P
<0.05), whereas it had no significant effect on Nox1 or Nox2. In empty vector–transfected cells, Ang II increased myofibroblast migration by 192±32% versus vehicle (
P
<0.01) while increasing H
2
O
2
(473±22% versus control;
P
<0.001). Cotransfection with human Nox4 and human p22-phox plasmids decreased Ang II-induced migration (46±6%;
P
<0.001) in parallel with attenuation of H
2
O
2
production (23±8% versus empty vector;
P
<0.05). Our data suggest that Nox4 promotes Ang II-induced myofibroblast migration via an H
2
O
2
-dependent pathway. The data also suggest that Nox4 causes feedback inhibition of its own expression in adventitial myofibroblasts.
Postnatal Intermittent Hypoxia and Developmental Programming of Hypertension in Spontaneously Hypertensive Rats
Authors: Soukhova-O'Hare Galia K. , Ortines Roger V. , Gu Yan , Nozdrachev Alexander D. , Prabhu Sumanth D. , Gozal David
Published: May 2008

Obstructive and central apneas during sleep are associated with chronic intermittent hypoxia (CIH) and increased cardiovascular morbidity. Spontaneously hypertensive rats exposed to CIH during postnatal days 4 to 30 develop exaggerated hypertension as adults. We hypothesized that reactive oxygen species and altered L-Ca
2+
channel activity may underlie the postnatal programming of exaggerated blood pressure and cardiac remodeling. Newborn male spontaneously hypertensive rats were exposed to CIH (10% and 21% O
2
alternating every 90 seconds, 12 h/d, for postnatal days 4 to 30) or normoxia (room air). In each condition, spontaneously hypertensive rats received daily (SC) 1 of 3 treatments:
l
-calcium channel blocker nifedipine (5 mg/kg), superoxide dismutase mimetic MnTMPyP pentachloride (10 mg/kg), or vehicle (polyethylene glycol). Blood pressure was evaluated monthly for 6 months after birth, and echocardiographic assessments were conducted at 6 months of age. CIH vehicle-treated rats presented higher systolic blood pressure (187±5 mm Hg) as compared with normoxic vehicle treated controls (163±2 mm Hg;
P
<0.001). Postnatal CIH elicited marked increases in left ventricular wall thickness in a pattern of concentric hypertrophy with augmented systolic contractility. The treatment with nifedipine in the CIH group attenuated blood pressure (159±2 mm Hg;
P
<0.001) and normalized left ventricular wall thickness and systolic function, whereas the treatment with SOD mimetic decreased blood pressure (165±2 mm Hg;
P
<0.001) and reduced left ventricular wall thickness without changes in the systolic function. We conclude that Ca
2+
and reactive oxygen species–mediated signaling during intermittent hypoxia are critical mechanisms underlying postnatal programming of an increased severity of hypertension and hypertrophic cardiac remodeling in a genetically susceptible rodent model.
Left Ventricular Filling Pressure by Doppler Echocardiography in Patients With End-Stage Renal Disease
Authors: Wang Angela Y-M. , Wang Mei , Lam Christopher W-K. , Chan Iris H-S. , Zhang Yan , Sanderson John E.
Published: May 2008

Left ventricular hypertrophy and systolic dysfunction predict mortality in patients with end-stage renal disease. However, the prognostic value of left ventricular filling pressure has remained uncertain in this population. We evaluated whether the early mitral inflow velocity to peak mitral annulus velocity (E/Em) ratio, an estimate of left ventricular filling pressure by tissue Doppler imaging, has significant additional prognostic value to conventional echocardiographic parameters and other clinical and biochemical parameters in 220 patients with end-stage renal disease. The E/Em ratio was elevated (>15) in 62% of the patients. Multivariate analysis showed that an elevated E/Em ratio had the highest correlation with left ventricular volume index, followed by loss of residual glomerular filtration rate, increasing age, worsening ejection fraction, and diabetes. During the median follow-up of 48 months, the E/Em ratio emerged as an independent predictor of all-cause mortality (adjusted hazard ratio: 1.027; 95% CI: 1.003 to 1.051;
P
=0.026) and cardiovascular death (adjusted hazard ratio: 1.033; 95% CI: 1.002 to 1.065;
P
=0.035) in the multivariable Cox regression analysis. In addition, the E/Em ratio added significant incremental prognostic value for all-cause mortality (
P
=0.035) and cardiovascular death (
P
=0.035) beyond the standard clinical, biochemical, and dialysis parameters and echocardiographic measurements. In conclusion, the E/Em ratio displayed important additional long-term prognostic information above and beyond that of left ventricular mass and systolic function. Our data suggest that left ventricular filling pressure should be estimated during echocardiographic examination for additional prognostication in patients with end-stage renal disease.
Toward the Non-(Re)presentational Actor: From Grotowski to Richards
Authors: Salata Kris
Published: May 2008

Situating Apocalypsis cum figuris as a turning point in Grotowski's efforts to move beyond theatrical representation, Salata considers the trajectory in Grotowski's work from acting to doing. Emphasizing the centrality of Buber's concept of the I-Thou, Salata examines the implications of Grotowski's search for unmediated perception through the lens of such theorists as Heidegger, Deleuze, and Levinas.
On the Functional Neuroanatomy of Visual Word Processing: Effects of Case and Letter Deviance
Authors: Kronbichler Martin , Klackl Johannes , Richlan Fabio , Schurz Matthias , Staffen Wolfgang , Ladurner Gunther , Wimmer Heinz
Published: May 2008

This functional magnetic resonance imaging study contrasted case-deviant and letter-deviant forms with familiar forms of the same phonological words (e.g., TaXi and Taksi vs. Taxi) and found that both types of deviance led to increased activation in a left occipito-temporal region, corresponding to the visual word form area (VWFA). The sensitivity of the VWFA to both types of deviance may suggest that this region represents well-known visual words not only as sequences of abstract letter identities but also includes information on the typical case-format pattern of visual words. Case-deviant items, in addition, led to increased activation in a right occipito-temporal region and in a left occipital and a left posterior occipito-temporal region, which may reflect increased demands on letter processing posed by the case-deviant forms.
What is “Odd” in Posner's Location-cueing Paradigm? Neural Responses to Unexpected Location and Feature Changes Compared
Authors: Vossel Simone , Weidner Ralph , Thiel Christiane M. , Fink Gereon R.
Published: May 2008

Within the parietal cortex, the temporo-parietal junction (TPJ) and the intraparietal sulcus (IPS) seem to be involved in both spatial and nonspatial functions: Both areas are activated when misleading information is provided by invalid spatial cues in Posner's location-cueing paradigm, but also when infrequent deviant stimuli are presented within a series of standard events. In the present study, we used functional magnetic resonance imaging to investigate the distinct and shared brain responses to (i) invalidly cued targets requiring attentional reorienting, and (ii) to target stimuli deviating in color and orientation leading to an oddball-like distraction effect. Both unexpected location and feature changes were accompanied by a significant slowing of manual reaction times. Bilateral TPJ and right superior parietal lobe (SPL) activation was observed in response to invalidly as compared to validly cued targets. In contrast, the bilateral inferior occipito-temporal cortex, the left inferior parietal cortex, right frontal areas, and the cerebellum showed stronger activation in response to deviant than to standard targets. Common activations were observed in the right angular gyrus along the IPS and in the right inferior frontal gyrus. We conclude that the superior parietal and temporo-parietal activations observed here as well as previously in location-cueing paradigms do not merely reflect the detection and processing of unexpected stimuli. Furthermore, our data suggest that the right IPS and the inferior frontal gyrus are involved in attentional selection and distractor processing of both spatial and nonspatial features.
Induced Gamma-band Activity Elicited by Visual Representation of Unattended Objects
Authors: Martinovic Jasna , Gruber Thomas , Ohla Kathrin , Müller Matthias M.
Published: May 2008

Object recognition is achieved through neural mechanisms reliant on the activity of distributed neural assemblies that are thought to be coordinated by synchronous firing in the gamma-band range (>20 Hz). An outstanding question focuses on the extent to which the role of gamma oscillations in object recognition is dependent on attention. Attentional mechanisms determine the allocation of perceptual resources to objects in complex scenes biasing the outcome of their mutual competitive interactions. Would object-related enhancements in gamma activity also occur for unattended objects when perceptual resources are traded off to the processing of concurrent visual material? The present electroencephalogram study investigated event-related potentials and evoked (time- and phase-locked) and induced (non-time- and phase-locked to stimulus onset) gamma-band activity (GBA) using a visual discrimination task of low or high perceptual load at fixation. The task was performed while task-irrelevant familiar or unfamiliar objects coappeared in the surrounding central area. Attentional focus was kept at fixation by varying perceptual load between trials; in such conditions, only holistic object processing or low-level perceptual processing, requiring little or no attention, are thought to occur. Although evoked GBA remained unmodulated, induced GBA enhancements, specific to familiar object presentations, were observed, thus providing evidence for cortical visual representation of unattended objects. In addition, the effect was mostly driven by object-specific activity under low load, implying that, in cluttered or complex scenes, attentional selection likely plays a more significant role in object representation.
In the Eye of the Beholder: Individual Differences in Perceived Social Isolation Predict Regional Brain Activation to Social Stimuli
Authors: Cacioppo John T. , Norris Catherine J. , Decety Jean , Monteleone George , Nusbaum Howard
Published: May 2008

Prior research has shown that perceived social isolation (loneliness) motivates people to attend to and connect with others but to do so in a self-protective and paradoxically self-defeating fashion. Although recent research has shed light on the neural correlates of social perception, cooperation, empathy, rejection, and love, little is known about how individual differences in loneliness relate to neural responses to social and emotional stimuli. Using functional magnetic resonance imaging, we show that there are at least two neural mechanisms differentiating social perception in lonely and nonlonely young adults. For pleasant depictions, lonely individuals appear to be less rewarded by social stimuli, as evidenced by weaker activation of the ventral striatum to pictures of people than of objects, whereas nonlonely individuals showed stronger activation of the ventral striatum to pictures of people than of objects. For unpleasant depictions, lonely individuals were characterized by greater activation of the visual cortex to pictures of people than of objects, suggesting that their attention is drawn more to the distress of others, whereas nonlonely individuals showed greater activation of the right and left temporo-parietal junction to pictures of people than of objects, consistent with the notion that they are more likely to reflect spontaneously on the perspective of distressed others.
Two Types of Action Error: Electrophysiological Evidence for Separable Inhibitory and Sustained Attention Neural Mechanisms Producing Error on Go/No-go Tasks
Authors: O'Connell Redmond G. , Dockree Paul M. , Bellgrove Mark A. , Turin Alessandra , Ward Seamus , Foxe John J. , Robertson Ian H.
Published: May 2008

Disentangling the component processes that contribute to human executive control is a key challenge for cognitive neuroscience. Here, we employ event-related potentials to provide electrophysiological evidence that action errors during a go/no-go task can result either from sustained attention failures or from failures of response inhibition, and that these two processes are temporally and physiologically dissociable, although the behavioral error—a nonintended response—is the same. Thirteen right-handed participants performed a version of a go/no-go task in which stimuli were presented in a fixed and predictable order, thus encouraging attentional drift, and a second version in which an identical set of stimuli was presented in a random order, thus placing greater emphasis on response inhibition. Electrocortical markers associated with goal maintenance (late positivity, alpha synchronization) distinguished correct and incorrect performance in the fixed condition, whereas errors in the random condition were linked to a diminished N2–P3 inhibitory complex. In addition, the amplitude of the error-related negativity did not differ between correct and incorrect responses in the fixed condition, consistent with the view that errors in this condition do not arise from a failure to resolve response competition. Our data provide an electrophysiological dissociation of sustained attention and response inhibition.
Distinct Neurophysiological Mechanisms Mediate Mixing Costs and Switch Costs
Authors: Wylie Glenn R. , Murray Micah M. , Javitt Daniel C. , Foxe John J.
Published: May 2008

Using event-related potentials (ERPs), we investigated the neural response associated with preparing to switch from one task to another. We used a cued task-switching paradigm in which the interval between the cue and the imperative stimulus was varied. The difference between response time (RT) to trials on which the task switched and trials on which the task repeated (switch cost) decreased as the interval between cue and target (CTI) was increased, demonstrating that subjects used the CTI to prepare for the forthcoming task. However, the RT on repeated-task trials in blocks during which the task could switch (mixed-task blocks) were never as short as RTs during single-task blocks (mixing cost). This replicates previous research. The ERPs in response to the cue were compared across three conditions: single-task trials, switch trials, and repeat trials. ERP topographic differences were found between single-task trials and mixed-task (switch and repeat) trials at ∼160 and ∼310 msec after the cue, indicative of changes in the underlying neural generator configuration as a basis for the mixing cost. In contrast, there were no topographic differences evident between switch and repeat trials during the CTI. Rather, the response of statistically indistinguishable generator configurations was stronger at ∼310 msec on switch than on repeat trials. By separating differences in ERP topography from differences in response strength, these results suggest that a reappraisal of previous research is appropriate.
Brain Imaging and Brain Privacy: A Realistic Concern?
Authors: Farah Martha J. , Smith M. Elizabeth , Gawuga Cyrena , Lindsell Dennis , Foster Dean
Published: May 2008

Functional neuroimaging has been used to study a wide array of psychological traits, including aspects of personality and intelligence. Progress in identifying the neural correlates of individual differences in such traits, for the sake of basic science, has moved us closer to the applied science goal of measuring them and thereby raised ethical concerns about privacy. How realistic are such concerns given the current state of the art? In this article, we describe the statistical basis of the measurement of psychological traits using functional neuroimaging and examine the degree to which current functional neuroimaging protocols could be used for this purpose. By analyzing the published data from 16 studies, we demonstrate that the use of imaging to gather information about an individual's psychological traits is already possible, but to an extremely limited extent.
Reward and Social Valuation Deficits following Ventromedial Prefrontal Damage
Authors: Moretti Laura , Dragone Davide , di Pellegrino Giuseppe
Published: May 2008

Lesion and imaging studies have implicated the ventromedial prefrontal cortex (vmPFC) in economic decisions and social interactions, yet its exact functions remain unclear. Here, we investigated the hypothesis that the vmPFC represents the subjective value or desirability of future outcomes during social decision-making. Both vmPFC-damaged patients and control participants acted as the responder in a single-round ultimatum game. To test outcome valuation, we contrasted concrete, immediately available gains with abstract, future ones. To test social valuation, we contrasted interactions with a human partner and those involving a computer. We found that, compared to controls, vmPFC patients substantially reduced their acceptance rate of unfair offers from a human partner, but only when financial gains were presented as abstract amounts to be received later. When the gains were visible and readily available, the vmPFC patients' acceptance of unfair offers was normal. Furthermore, unlike controls, vmPFC patients did not distinguish between unfair offers from a human agent and those from a computerized opponent. We conclude that the vmPFC encodes the expected value of abstract, future goals in a common neural currency that takes into account both reward and social signals in order to optimize economic decision-making.
The Lateral and Ventromedial Prefrontal Cortex Work as a Dynamic Integrated System: Evidence from fMRI Connectivity Analysis
Authors: Longe Olivia , Senior Carl , Rippon Gina
Published: May 2008

Recent functional magnetic resonance imaging (fMRI) investigations of the interaction between cognition and reward processing have found that the lateral prefrontal cortex (PFC) areas are preferentially activated to both increasing cognitive demand and reward level. Conversely, ventromedial PFC (VMPFC) areas show decreased activation to the same conditions, indicating a possible reciprocal relationship between cognitive and emotional processing regions. We report an fMRI study of a rewarded working memory task, in which we further explore how the relationship between reward and cognitive processing is mediated. We not only assess the integrity of reciprocal neural connections between the lateral PFC and VMPFC brain regions in different experimental contexts but also test whether additional cortical and subcortical regions influence this relationship. Psychophysiological interaction analyses were used as a measure of functional connectivity in order to characterize the influence of both cognitive and motivational variables on connectivity between the lateral PFC and the VMPFC. Psychophysiological interactions revealed negative functional connectivity between the lateral PFC and the VMPFC in the context of high memory load, and high memory load in tandem with a highly motivating context, but not in the context of reward alone. Physiophysiological interactions further indicated that the dorsal anterior cingulate and the caudate nucleus modulate this pathway. These findings provide evidence for a dynamic interplay between lateral PFC and VMPFC regions and are consistent with an emotional gating role for the VMPFC during cognitively demanding tasks. Our findings also support neuropsychological theories of mood disorders, which have long emphasized a dysfunctional relationship between emotion/motivational and cognitive processes in depression.
Violation of Expectation: Neural Correlates Reflect Bases of Prediction
Authors: Bubic Andreja , von Cramon D. Yves , Jacobsen Thomas , Schröger Erich , Schubotz Ricarda I.
Published: May 2008

Setting perceptual expectations can be based on different sources of information that determine which functional networks will be involved in implementing preparatory top–down influences and dealing with situations in which expectations are violated. The goal of the present study was to investigate and directly compare brain activations triggered by violating expectations within two different task contexts. In the serial prediction task, participants monitored ordered perceptual sequences for predefined sequential deviants. In contrast, the target detection task entailed a presentation of stimuli which had to be monitored for predefined nonsequential deviants. Detection of sequential deviants triggered an increase of activity in premotor and cerebellar components of the “standard” sequencing network and activations in additional frontal areas initially not involved in sequencing. This pattern of activity reflects the detection of a mismatch between the expected and presented stimuli, updating of the underlying sequence representation (i.e., forward model), and elaboration of the violation. In contrast, target detection elicited activations in posterior temporal and parietal areas, reflecting an increase in perceptual processing evoked by the nonsequential deviant. The obtained results suggest that distinct functional networks involved in detecting deviants in different contexts reflect the origin and the nature of expectations being violated.