bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in lung volume and upper airway using MRI during application of nasal expiratory positive airway pressure in patients with sleep-disordered breathing
Authors: Braga C. W. , Chen Q. , Burschtin O. E. , Rapoport D. M. , Ayappa I.
Published: July 2011

Nasal expiratory positive airway pressure (nEPAP) delivered with a disposable device (Provent, Ventus Medical) has been shown to improve sleep-disordered breathing (SDB) in some subjects. Possible mechanisms of action are 1) increased functional residual capacity (FRC), producing tracheal traction and reducing upper airway (UA) collapsibility, and 2) passive dilatation of the airway by the expiratory pressure, carrying over into inspiration. Using MRI, we estimated change in FRC and ventilation, as well as UA cross-sectional area (CSA), in awake patients breathing on and off the nEPAP device. Ten patients with SDB underwent nocturnal polysomnography and MRI with and without nEPAP. Simultaneous images of the lung and UA were obtained at 6 images/s. Image sequences were obtained during mouth and nose breathing with and without the nEPAP device. The nEPAP device produced an end-expiratory pressure of 4–17 cmH2O. End-tidal Pco2rose from 39.7 ± 5.3 to 47.1 ± 6.0 Torr ( P < 0.01). Lung volume changes were estimated from sagittal MRI of the right lung. Changes in UA CSA were calculated from transverse MRI at the level of the pharynx above the epiglottis. FRC determined by MRI was well correlated to FRC determined by N2washout ( r = 0.76, P = 0.03). nEPAP resulted in a consistent increase in FRC (46 ± 29%, P < 0.001) and decrease in ventilation (50 ± 15%, P < 0.001), with no change in respiratory frequency. UA CSA at end expiration showed a trend to increase. During wakefulness, nEPAP caused significant hyperinflation, consistent with an increase in tracheal traction and a decrease in UA collapsibility. Direct imaging effects on the UA were less consistent, but there was a trend to dilatation. Finally, we showed significant hypoventilation and rise in Pco2during use of the nEPAP device during wakefulness and sleep. Thus, at least three mechanisms of action have the potential to contribute to the therapeutic effect of nEPAP on SDB.
Effects of surfactant depletion on regional pulmonary metabolic activity during mechanical ventilation
Authors: de Prost Nicolas , Costa Eduardo L. , Wellman Tyler , Musch Guido , Winkler Tilo , Tucci Mauro R. , Harris R. Scott , Venegas Jose G. , Vidal Melo Marcos F.
Published: July 2011

Inflammation during mechanical ventilation is thought to depend on regional mechanical stress. This can be produced by concentration of stresses and cyclic recruitment in low-aeration dependent lung. Positron emission tomography (PET) with18F-fluorodeoxyglucose (18F-FDG) allows for noninvasive assessment of regional metabolic activity, an index of neutrophilic inflammation. We tested the hypothesis that, during mechanical ventilation, surfactant-depleted low-aeration lung regions present increased regional18F-FDG uptake suggestive of in vivo increased regional metabolic activity and inflammation. Sheep underwent unilateral saline lung lavage and were ventilated supine for 4 h (positive end-expiratory pressure = 10 cmH2O, tidal volume adjusted to plateau pressure = 30 cmH2O). We used PET scans of injected13N-nitrogen to compute regional perfusion and ventilation and injected18F-FDG to calculate18F-FDG uptake rate. Regional aeration was quantified with transmission scans. Whole lung18F-FDG uptake was approximately two times higher in lavaged than in nonlavaged lungs (2.9 ± 0.6 vs. 1.5 ± 0.3 10−3/min; P < 0.05). The increased18F-FDG uptake was topographically heterogeneous and highest in dependent low-aeration regions (gas fraction 10–50%, P < 0.001), even after correction for lung density and wet-to-dry lung ratios.18F-FDG uptake in low-aeration regions of lavaged lungs was higher than that in low-aeration regions of nonlavaged lungs ( P < 0.05). This occurred despite lower perfusion and ventilation to dependent regions in lavaged than nonlavaged lungs ( P < 0.001). In contrast,18F-FDG uptake in normally aerated regions was low and similar between lungs. Surfactant depletion produces increased and heterogeneously distributed pulmonary18F-FDG uptake after 4 h of supine mechanical ventilation. Metabolic activity is highest in poorly aerated dependent regions, suggesting local increased inflammation.
The relationship between muscle deoxygenation and activation in different muscles of the quadriceps during cycle ramp exercise
Authors: Chin Lisa M. K. , Kowalchuk John M. , Barstow Thomas J. , Kondo Narihiko , Amano Tatsuro , Shiojiri Tomoyuki , Koga Shunsaku
Published: July 2011

The relationship between muscle deoxygenation and activation was examined in three different muscles of the quadriceps during cycling ramp exercise. Seven young male adults (24 ± 3 yr; mean ± SD) pedaled at 60 rpm to exhaustion, with a work rate (WR) increase of 20 W/min. Pulmonary oxygen uptake was measured breath-by-breath, while muscle deoxygenation (HHb) and activity were measured by time-resolved near-infrared spectroscopy (NIRS) and surface electromyography (EMG), respectively, at the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM). Muscle deoxygenation was corrected for adipose tissue thickness and normalized to the amplitude of the HHb response, while EMG signals were integrated (iEMG) and normalized to the maximum iEMG determined from maximal voluntary contractions. Muscle deoxygenation and activation were then plotted as a percentage of maximal work rate (%WRmax). The HHb response for all three muscle groups was fitted by a sigmoid function, which was determined as the best fitting model. The c/d parameter for the sigmoid fit (representing the %WRmax at 50% of the total amplitude of the HHb response) was similar between VL (47 ± 12% WRmax) and VM (43 ± 11% WRmax), yet greater ( P < 0.05) for RF (65 ± 13% WRmax), demonstrating a “right shift” of the HHb response compared with VL and VM. The iEMG also showed that muscle activation of the RF muscle was lower ( P < 0.05) compared with VL and VM throughout the majority of the ramp exercise, which may explain the different HHb response in RF. Therefore, these data suggest that the sigmoid function can be used to model the HHb response in different muscles of the quadriceps; however, simultaneous measures of muscle activation are also needed for the HHb response to be properly interpreted during cycle ramp exercise.
Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes
Authors: Rebbeck Timothy R. , Mitra Nandita , Domchek Susan M. , Wan Fei , Friebel Tara M. , Tran Teo V. , Singer Christian F. , Tea Muy-Kheng Maria , Blum Joanne L. , Tung Nadine , Olopade Olufunmilayo I. , Weitzel Jeffrey N. , Lynch Henry T. , Snyder Carrie L. , Garber Judy E. , Antoniou Antonis C. , Peock Susan , Evans D. Gareth , Paterson Joan , Kennedy M. John , Donaldson Alan , Dorkins Huw , Easton Douglas F. , Rubinstein Wendy S. , Daly Mary B. , Isaacs Claudine , Nevanlinna Heli , Couch Fergus J. , Andrulis Irene L. , Freidman Eitan , Laitman Yael , Ganz Patricia A. , Tomlinson Gail E. , Neuhausen Susan L. , Narod Steven A. , Phelan Catherine M. , Greenberg Roger , Nathanson Katherine L.
Published: July 2011

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (PFDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations. Cancer Res; 71(17); 5792–805. ©2011 AACR.
Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer
Authors: Darshan Medha S. , Loftus Matthew S. , Thadani-Mulero Maria , Levy Benjamin P. , Escuin Daniel , Zhou Xi Kathy , Gjyrezi Ada , Chanel-Vos Chantal , Shen Ruoqian , Tagawa Scott T. , Bander Neil H. , Nanus David M. , Giannakakou Paraskevi
Published: July 2011

Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy. Cancer Res; 71(18); 6019–29. ©2011 AACR.
Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
Authors: Herman Ariel G. , Hayano Miki , Poyurovsky Masha V. , Shimada Kenichi , Skouta Rachid , Prives Carol , Stockwell Brent R.
Published: July 2011

E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53-independent oncogenic effects. We developed a high-throughput cellular Mdm2 auto-ubiquitination assay, which we used to discover a class of small-molecule Mdm2 ligase activity inhibitors. These compounds inhibit Mdm2 and p53 ubiquitination in cells, reduce viability of cells with wild-type p53, and synergize with DNA-damaging agents to cause cell death. We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents.

Significance: We identified a class of small-molecule inhibitors of the Mdm2-MdmX hetero-complex E3 ligase activity through a high-throughput cell-based Mdm2 ubiquitination screen. This is a new target for small-molecule therapeutics and may be developed to treat specific cancers. Cancer Discovery; 1(4); 312–25. ©2011 AACR.

This article is highlighted in the In This Issue feature, p. 275
An Insulin-Like Growth Factor-I Receptor Defect Associated with Short Stature and Impaired Carbohydrate Homeostasis in an Italian Pedigree
Authors: Mohn A. , Marcovecchio M.L. , de Giorgis T. , Pfaeffle R. , Chiarelli F. , Kiess W.
Published: July 2011

Background: Mutations in the insulin-like growth factor-I (IGF-I) receptor (IGF1R) have been associated with prenatal and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate homeostasis. Methods: We investigated clinical, endocrine and metabolic parameters in four family members carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old male (index case), his sister and two paternal aunts. Results: All family members showed a variable degree of impairment in prenatal growth, with birth weight standard deviation scores (SDS) between –1.65 and –2.37 and birth length SDS between –1.78 and –3.08. Their postnatal growth was also impaired, with height SDS between –1.75 and –4.86. The index case presented high IGF-I levels during childhood and adolescence and delayed bone age. The index case and his two paternal aunts had impaired glucose tolerance (IGT) associated with a variable degree of alterations in insulin sensitivity and secretion. In contrast, the index case’s sister, who had had IGT during pregnancy, showed normal glucose metabolism but reduced insulin sensitivity. Conclusion: This is the first study showing an association between a novel IGF1R mutation and a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism.
The Application of Vagus Nerve Stimulation and Deep Brain Stimulation in Depression
Authors: Mohr Pavel , Rodriguez Mabel , Slavíčková Anna , Hanka Jan
Published: July 2011

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6–12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS.
Clopidogrel Effectively Suppresses Endothelial Microparticle Generation Induced by Indoxyl Sulfate via Inhibition of the p38 Mitogen-Activated Protein Kinase Pathway
Authors: Ryu Jung-Hwa , Kim Seung-Jung
Published: July 2011

Background/Aims: Endothelial microparticles (EMPs) are closely associated with vascular dysfunction. We investigated the effects of several drugs on EMP generation in human umbilical vein endothelial cells (HUVECs), and the involvement of the mitogen-activated protein kinase (MAPK) in EMP generation. Methods: CD31+CD42-EMP counts were measured by flow cytometry in supernatants of HUVECs incubated with indoxyl sulfate. The EMP responses to losartan, lovastatin, clopidogrel, and mesoglycan were examined. We then measured the effects of MAPK inhibitors on EMPs. Results: (1) Indoxyl sulfate induced EMP release in HUVECs in a dose-dependent fashion; (2) all drugs (10–50 µM) inhibited EMP generation induced by indoxyl sulfate, with clopidogrel being the most effective; (3) the p38 MAPK inhibitor suppressed EMP generation induced by indoxyl sulfate, and (4) clopidogrel significantly suppressed MAPK signaling activated by indoxyl sulfate, with the most potency on p38. Conclusion: The p38 signaling involves EMP generation induced by indoxyl sulfate and is effectively suppressed by clopidogrel.
Measurement of Vascular Access Flow by Online Clearance Monitor in Online Hemodiafiltration
Authors: Tiranathanagul Khajohn , Susantitaphong Paweena , Towannang Piyaporn , Injan Patcharin , Praditpornsilpa Kearkiat , Eiam-Ong Somchai
Published: July 2011

Background: Measurement of ionic dialysance has been shown to accurately determine urea dialyzer clearance and vascular access flow rate (Qa) in diffusive hemodialysis. Recently, online clearance monitoring (OCM) in an online hemodiafiltration (OL-HDF) machine could accurately measure urea dialyzer clearance. In the present study, OCM was utilized to assess the Qa in OL-HDF. Methods: In 32 stable end-stage renal disease patients undergoing predilution OL-HDF, the values of Qa measured by the OCM technique (QaOCMT) in a Fresenius 4008H HDF machine were compared with those determined by the standard ultrasound dilution technique (QaUDT). Results: The values of QaUDT and QaOCMT measured at the beginning of the HDF session were 800.5 ± 910.3 and 794.6 ± 895.4 ml/min (nonsignificant). There was a significant correlation between the two techniques (r = 0.95, p < 0.01). A Bland-Altman plot demonstrated a good agreement. Conclusion: The vascular access flow determined by OCM, which is integrated mostly in the current HDF machine, is highly accurate, easy to perform, and economical and can be used for vascular access surveillance in OL-HDF.
Is There a Necessity for Individual Blood Water Corrections when Conductivity-Based Access Blood Flow Measurements Are Made?
Authors: Huang Shih-Han S. , Heidenheim Paul A. , Gallo Kerri , Jayakumar Saumya , Lindsay Robert M.
Published: July 2011

Background/Aims:Access blood water flow rate (Qaw) can be measured during hemodialysis using an online effective ionic dialysance (EID) methodology. Fresenius employ this methodology in their 2008K dialysis machine. The machine computer converts Qaw to an access blood flow rate (Fresenius Qa) using a generic blood water constant (BWC). We wished to validate this BWC. Methods: 18 patients had Fresenius Qa measurements using the EID and these were compared with a ‘gold standard’ ultrasound dilution methodology (Transonic Qa). Qa values were also obtained by removing the BWC from Fresenius Qa values to obtain the Qaw and recorrecting it with individualized patient factors using hematocrit and total protein values (HctTp Qa). The measurements were repeated after 1 h. Results:There were no significant differences between Fresenius and Transonic, nor between HctTp and Transonic Qa values (p > 0.17). There were strong correlations between both sets of values (r > 0.856; p < 0.001). There was a significant correlation between the pairs of Transonic Qa values (r = 0.823; p < 0.007), but not for Fresenius Qa pairs (r = 0.573; p > 0.07). It was surmised that the BWC was not valid post-dialysis. Conclusion:The generic BWC is comparable to individualized blood water correction factors when Qa measures are made early in dialysis and prior to ultrafiltration treatment.
Sleep Deprivation in Mood Disorders
Authors: Benedetti Francesco , Colombo Cristina
Published: July 2011

Growing clinical evidence in support of the efficacy and safety of sleep deprivation (SD), and its biological mechanisms of action suggest that this technique can now be included among the first-line antidepressant treatment strategies for mood disorders. SD targets the broadly defined depressive syndrome, and can be administered according to several different treatment schedules: total versus partial, single versus repeated, alone or combined with antidepressant drugs, mood stabilizers, or other chronotherapeutic techniques, such as light therapy and sleep phase advance. The present review focuses on clinical evidence about the place of SD in therapy, its indications, dosage and timing of the therapeutic wake, interactions with other treatments, precautions and contraindications, adverse reactions, mechanism of action, and comparative efficacy, with the aim of providing the clinical psychiatrist with an updated, concise guide to its application.
Transcranial Magnetic Stimulation in the Management of Mood Disorders
Authors: Allan Charlotte L. , Herrmann Lucie L. , Ebmeier Klaus P.
Published: July 2011

Background: Many trials of transcranial magnetic stimulation (TMS) have used small samples and, therefore, lack power. Here we present an up-to-date meta-analysis of TMS in the treatment of depression. Methods: We searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). We identified 1,789 studies. Thirty-one were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. Results: We found a moderately sized effect in favour of TMS [Random Effects Model Hedges’ g = 0.64, 95% confidence interval (95% CI) = 0.50–0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (≤50% reduction in depression scores) was 4.1 (95% CI = 2.9–5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. Nine studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges’ g = –0.02, 95% CI = –0.22 to +0.18) and no heterogeneity in outcome. Discussion: TMS appears to be an effective treatment; however, at 4 weeks’ follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind randomized controlled designs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.
Asymmetric Cerebral Blood Flow in Patients with Mild Cognitive Impairment: Possible Relationship to Further Cognitive Deterioration
Authors: Edman Åke , Edenbrandt Lars , Fredén-Lindqvist Johan , Nilsson Magnus , Wallin Anders
Published: July 2011

Aim: To explore patterns of cerebral blood flow in patients with mild cognitive impairment (MCI), who (1) eventually deteriorate into overt dementia, with no particular focus on the type of dementia, or (2) do not appear to further deteriorate in their cognitive functions. Methods: Thirty-seven MCI patients, with or without vascular pathology, were studied prospectively. The patients underwent 99mTc-HMPAO SPECT analysis at baseline. Possible clinical conversion into dementia within a 2-year period was assessed. Results: Nineteen patients had progressive MCI (PMCI), while 18 patients were considered clinically stable (SMCI). PMCI patients had more often abnormally low cerebral blood flow in at least one of the frontal, temporal, parietal or occipital lobes compared to SMCI patients (12/19 vs. 5/18; p = 0.049). At least one of the temporal regions was found to be abnormal in 9 PMCI patients in contrast to only 1 SMCI patient (p = 0.008). More specifically, blood flow in the medial portion of the left temporal region was abnormal in 8 PMCI patients, a pattern seen in 1 SMCI patient only (p = 0.019). Conclusion: The results suggest that blood flow reductions particularly in the left medial temporal region indicate an elevated risk of further cognitive decline in MCI patients.
Impact of Hemodialysis Therapy on Anemia of Chronic Kidney Disease: The Potential Mechanisms
Authors: Bowry Sudhir K. , Gatti Emanuele
Published: July 2011

A significant and increasing number of chronic kidney disease (CKD) patients are treated with online hemodiafiltration (OL-HDF), even in the absence of more conclusive survival data. OL-HDF affords several clinical benefits including control of anemia of CKD, a common affliction in dialysis patients. In efforts to understand the underlying mechanisms that contribute to the purported benefits of OL-HDF, we examined the potential role and impact of OL-HDF on key stages of anemia and its correction: erythropoiesis of bone marrow, circulating erythrocytes and on anemia therapy. We review evidence that indicates OL-HDF may modulate key processes of anemia and its therapy, including underlying conditions and responses of uremic toxicity and inflammation that aggravate anemia. Our assessment indicates that OL-HDF favorably impacts anemia by not only eliminating putative uremic inhibitors that suppress erythropoiesis, reducing red cell destruction and increasing iron availability, but also by mechanisms restricting underlying inflammation and endothelial dysfunction that are crucial to both CKD and anemia.
Blumgart’s Technique of Pancreaticojejunostomy: An Appraisal
Authors: Mishra Pramod Kumar , Saluja Sundeep Singh , Gupta Monica , Rajalingam Rajesh , Pattnaik Premanand
Published: July 2011

Background: Although mortality of Whipple’s pancreaticoduodenectomy (WPD) is reduced to <5%, morbidity still remains between 30 and 50%. Pancreaticojejunal anastomosis remains the main cause of morbidity. Blumgart anastomosis using transpancreatic U sutures has been proposed to decrease the leak rate and its associated morbidity. We analyzed the results of Blumgart anastomosis applied in consecutive cases of WPD. Methods: Of 189 patients with periampullary or pancreatic cancer admitted, 100 patients underwent WPD. Except for 2 patients (no duct identified preoperatively), all patients underwent pancreaticojejunostomy by the Blumgart anastomotic technique. The records of 98 patients were analyzed for pancreatic leak and its related complications using the definitions given by the International Study Group for Pancreatic Surgery. Results: Of 98 patients, 63 were men. The mean operative time was 390 min (270–690 min) and blood loss was 275 ml (100–1,000 ml). Overall mortality was 3.06%. The clinically significant pancreatic anastomotic failure leak was seen in only 7 (7.14%) cases (grade B, n = 4; grade C, n = 3) with one patient requiring relaparotomy due to leak. Only one patient died due to a leak-related complication. Conclusion: Blumgart pancreaticojejunal anastomosis can be routinely used for reconstruction in WPD. It is a technically simple procedure and is associated with low rates of fistula and its related complications.
An Alternative Approach for Mitral Paravalvular Leak with Dacron Patch Curtaining under the Guidance of Real-Time 3-Dimensional Transesophageal Echocardiography
Authors: Ozkan Mehmet , Aykan Ahmet Cagri , Gursoy Ozan , Tuncer Mehmet Altug , Cakal Beytullah , Yildiz Mustafa , Kahveci Gokhan
Published: July 2011

Objectives: The aim of this study was to evaluate real-time 3-dimensional transesophageal echocardiography (RT-3D TEE) in the assessment of mitral paravalvular leakage curtaining surgery with a Dacron patch. Methods: RT-3D TEE was used before and after the operation. Results: Repairing a mitral paravalvular leak with Dacron patch curtaining was a useful, simple and new technique with promising feasibility and durability. Conclusions: In selected patients in whom the mitral paravalvular defect is relatively large, and may thus not be suitable for closing with primary suture, Dacron patch curtaining may be feasible for repair guided with RT-3D TEE; both are described for the first time.
Validation of the CHADS2 clinical prediction rule to predict ischaemic stroke
Authors: Wallace Emma , Dillon Ciara , Dimitrov Borislav , Fahey Tom , Keogh Claire
Published: July 2011

The CHADS2 predicts annual risk of ischaemic stroke in non-valvular atrial fibrillation. This systematic review and meta-analysis aims to determine the predictive value of CHADS2. The literature was systematically searched from 2001 to October 2010. Data was pooled and analysed using discrimination and calibration statistical measures, using a random effects model. Eight data sets (n=2815) were included. The diagnostic accuracy suggested a cut-point of ≥1 has higher sensitivity (92%) than specificity (12%) and a cut-point of ≥4 has higher specificity (96%) than sensitivity (33%). Lower summary estimates were observed for cut-points ≥2 (sensitivity 79%, specificity 42%) and ≥3 (specificity 77%, sensitivity 50%). There was insufficient data to analyse cut-points ≥5 or ≥6. Moderate pooled c statistic values were identified for the classic (0.63, 95% CI 0.52–0.75) and revised (0.60, 95% CI 0.43–0.72) view of stratification of the CHADS2 . Calibration analysis in-dicated no significant difference between the predicted and observed strokes across the three risk strata for the classic or revised view. All results were associated with high heterogeneity, and conclusions should be made cautiously. In conclusion, the pooled c statistic and calibration analysis suggests minimal clinical utility of both the classic and revised view of the CHADS2 in predicting ischaemic stroke across all risk strata. Due to high heterogeneity across studies and low event rates across all risk strata, the results should be interpreted cautiously. Further validation of CHADS2 should perhaps be undertaken, given the methodological differences between many of the available validation studies and the original CHADS2 derivation study.
Binding characteristics of thrombin-activatable fibrinolysis inhibitor to streptococcal surface collagen-like proteins A and B
Authors: Serón Mercedes , Plug Tom , Arnoud Marquart J. , Marx Pauline , Herwald Heiko , de Groot Philip , Meijers Joost
Published: July 2011

Streptococcus pyogenes is the causative agent in a wide range of diseases in humans. Thrombin-activatable fibrinolysis inhibitor (TAFI) binds to collagen-like proteins SclA and SclB at the surface of S. pyogenes. Activation of TAFI at this surface redirects inflammation from a transient to chronic state by modulation of the kallikrein/kinin system. We investigated TAFI binding characteristics to SclA/SclB. Thirty-four overlapping TAFI peptides of ∼20 amino acids were generated. Two of these peptides (P18: residues G205-S221, and P19: R214-D232) specifically bound to SclA/SclB with high affinity, and competed in a dose-dependent manner with TAFI binding to SclA/SclB. In another series of experiments, the binding properties of activated TAFI (TAFIa) to SclA/SclB were studied with a quadruple TAFI mutant (TAFI-IIYQ) that after activation is a 70-fold more stable enzyme than wild-type TAFIa. TAFI and TAFI-IIYQ bound to the bacterial proteins with similar affinities. The rate of dissociation was different between the proenzyme (both TAFI and TAFI-IIYQ) and the stable enzyme TAFIa-IIYQ. TAFIa-IIYQ bound to SclA/ SclB, but dissociated faster than TAFI-IIYQ. In conclusion, the bacterial proteins SclA and SclB bind to a TAFI fragment encompassing residues G205-D232. Binding of TAFI to the bacteria may allow activation of TAFI, whereafter the enzyme easily dissociates.
Differentiation of cGMP-dependent and -independent nitric oxide effects on platelet apoptosis and reactive oxygen species production using platelets lacking soluble guanylyl cyclase
Authors: Rukoyatkina Natalia , Walter Ulrich , Friebe Andreas , Gambaryan Stepan
Published: July 2011

Platelet activation is an irreversible process resulting in platelet apoptosis and necrosis, and circulating platelets contain many components of the apoptotic machinery. Cyclic guanosine monophosphate (cGMP) generated by nitric oxide (NO) activated soluble guanylyl cyclase (sGC) plays a crucial role in preventing platelet activation. However, in addition to activation of sGC, cGMP-independent NO effects in platelets have been described. To differentiate between cGMP-dependent and -independent NO effects on platelet apoptosis and reactive oxygen species (ROS) production, we generated platelet-specific sGC-deficient mice (PS-GCKO). Platelet apoptosis was induced by a combination of thrombin/convulxin (Thr/Cvx) and assessed by phosphatidylserine (PS) surface exposure, and loss of the mitochondrial membrane potential. NO-induced inhibition of PS externalisation was mediated only by cGMP-dependent mechanisms. Inhibition of the mitochondrial membrane potential decrease at low NO concentration was also cGMP-dependent but became cGMP-independent at high NO concentrations. In contrast, inhibition of ROS formation at any NO concentration was mediated by cGMP-independent mechanisms, very likely due to direct radical scavenging. NO inhibits platelet apoptosis by cGMP-dependent mechanisms and ROS production by cGMP-independent mechanisms. The PS-GCKO mouse model is an important tool for the differentiation of cGMP-dependent and -independent NO effects on platelets.
Cilostazol Suppresses Angiotensin II–Induced Vasoconstriction via Protein Kinase A–Mediated Phosphorylation of the Transient Receptor Potential Canonical 6 Channel
Authors: Nishioka Kinue , Nishida Motohiro , Ariyoshi Marina , Jian Zhong , Saiki Shota , Hirano Mayumi , Nakaya Michio , Sato Yoji , Kita Satomi , Iwamoto Takahiro , Hirano Katsuya , Inoue Ryuji , Kurose Hitoshi
Published: July 2011

Objective—

The goal of this study was to determine whether inhibition of transient receptor potential canonical (TRPC) channels underlies attenuation of angiotensin II (Ang II)–induced vasoconstriction by phosphodiesterase (PDE) 3 inhibition.

Methods and Results—

Pretreatment of rat thoracic aorta with cilostazol, a selective PDE3 inhibitor, suppressed vasoconstriction induced by Ang II but not that induced by KCl. The Ang II–induced contraction was largely dependent on Ca
2+
influx via receptor-operated cation channels. Cilostazol specifically suppressed diacylglycerol-activated TRPC channels (TRPC3/TRPC6/TRPC7) through protein kinase A (PKA)–dependent phosphorylation of TRPC channels in HEK293 cells. In contrast, we found that phosphorylation of TRPC6 at Thr69 was essential for the suppression of Ang II–induced Ca
2+
influx by PDE3 inhibition in rat aortic smooth muscle cells (RAoSMCs). Cilostazol specifically induced phosphorylation of endogenous TRPC6 at Thr69. The endogenous TRPC6, but not TRPC3, formed a ternary complex with PDE3 and PKA in RAoSMCs, suggesting the specificity of TRPC6 phosphorylation by PDE3 inhibition. Furthermore, inhibition of PDE3 suppressed the Ang II–induced contraction of reconstituted ring with RAoSMCs, which were abolished by the expression of a phosphorylation-deficient mutant of TRPC6.

Conclusion—

PKA-mediated phosphorylation of TRPC6 at Thr69 is essential for the vasorelaxant effects of PDE3 inhibition against the vasoconstrictive actions of Ang II.
Overexpression of Catalase in Myeloid Cells Causes Impaired Postischemic Neovascularization
Authors: Hodara Roberto , Weiss Daiana , Joseph Giji , Velasquez-Castano Juan C. , Landázuri Natalia , Han Ji Woong , Yoon Young-sup , Taylor W. Robert
Published: July 2011

Objective—

Myeloid lineage cells (MLCs) such as macrophages are known to play a key role in postischemic neovascularization. However, the role of MLC-derived reactive oxygen species in this process and their specific chemical identity remain unknown.

Methods and Results—

Transgenic mice with MLC-specific overexpression of catalase (Tg
Cat-MLC
mice) were created on a C57BL/6 background. Macrophage catalase activity was increased 3.4-fold compared with wild-type mice. After femoral artery ligation, laser Doppler perfusion imaging revealed impaired perfusion recovery in Tg
Cat-MLC
mice. This was associated with fewer collateral vessels, as assessed by microcomputed tomography angiography, and decreased capillary density. Impaired functional recovery of the ischemic limb was also evidenced by a 50% reduction in spontaneous running activity. The deficient neovascularization was associated with a blunted inflammatory response, characterized by decreased macrophage infiltration of ischemic tissues, and lower mRNA levels of inflammatory markers, such as tumor necrosis factor-α, osteopontin, and matrix mettaloproteinase-9. In vitro macrophage migration was impaired in Tg
Cat-MLC
mice, suggesting a role for H
2
O
2
in regulating the ability of macrophages to infiltrate ischemic tissues.

Conclusion—

MLC-derived H
2
O
2
plays a key role in promoting neovascularization in response to ischemia and is a necessary factor for the development of ischemia-induced inflammation.
Cardiomyocytes Obtained From Induced Pluripotent Stem Cells With Long-QT Syndrome 3 Recapitulate Typical Disease-Specific Features In Vitro
Authors: Malan Daniela , Friedrichs Stephanie , Fleischmann Bernd K. , Sasse Philipp
Published: July 2011

Rationale:

Current approaches for the investigation of long-QT syndromes (LQTS) are mainly focused on identification of the mutation and its characterization in heterologous expression systems. However, it would be extremely helpful to be able to characterize the pathophysiological effects of mutations and to screen drugs in cardiomyocytes.

Objective:

The aim of this study was to establish as a proof of principle the disease-specific cardiomyocytes from a mouse model with LQTS 3 by use of induced pluripotent stem (iPS) cells and to demonstrate that the mutant cardiomyocytes display the characteristic pathophysiological features in vitro.

Methods and Results:

We generated disease-specific iPS cells from a mouse model with a human mutation of the cardiac Na
+
channel that causes LQTS 3. The control and LQTS 3–specific iPS cell lines were pluripotent and could be differentiated into spontaneously beating cardiomyocytes. Patch-clamp measurements of LQTS 3–specific cardiomyocytes showed the biophysical effects of the mutation on the Na
+
current, with faster recovery from inactivation and larger late currents than observed in controls. Moreover, LQTS 3–specific cardiomyocytes had prolonged action potential durations and early afterdepolarizations at low pacing rates, both of which are classic features of the LQTS 3 mutation.

Conclusions:

We demonstrate that disease-specific iPS cell–derived cardiomyocytes from an LQTS 3 mouse model with a human mutation recapitulate the typical pathophysiological phenotype in vitro. Thus, this method is a powerful tool to investigate disease mechanisms in vitro and to perform patient-specific drug screening.
PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy
Authors: Riehle Christian , Wende Adam R. , Zaha Vlad G. , Pires Karla Maria , Wayment Benjamin , Olsen Curtis , Bugger Heiko , Buchanan Jonathan , Wang Xiaohui , Moreira Annie Bello , Doenst Torsten , Medina-Gomez Gema , Litwin Sheldon E. , Lelliott Christopher J. , Vidal-Puig Antonio , Abel E. Dale
Published: July 2011

Rationale:

Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression.

Objective:

To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy.

Methods and Results:

PGC-1β deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine-supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein.

Conclusions:

PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.
Association Between Mycoplasma Pneumonia and Increased Risk of Ischemic Stroke
Authors: Chiang Chia-Hung , Huang Chin-Chou , Chan Wan-Leong , Chen Yu-Chun , Chen Tzeng-Ji , Lin Shing-Jong , Chen Jaw-Wen , Leu Hsin-Bang
Published: July 2011

Background and Purpose—

Infections have been hypothesized to play a role in vascular disease. The association between Mycoplasma pneumoniae (MP) infection and ischemic stroke remained undetermined.

Methods—

A total of 1094 patients with MP infection were enrolled as the study group and compared with 5168 sex-, age-, and comorbidity-matched subjects without MP, to be followed up prospectively from January 2003 to December 2007 for development of ischemic stroke.

Results—

During a maximum 5-year follow-up period, 49 patients with ischemic stroke were identified. Subjects with MP infection were significantly associated with increased risk of ischemic stroke compared with controls (1.10% versus 0.72%, respectively;
P
=0.01). The logrank test showed that patients with MP had significantly higher incidence of stroke development than did those without MP (
P
=0.046). After Cox model adjustment for risk factors and comorbidities, MP infection was still independently associated with increased risk of stroke (hazard ratio [HR], 2.07; 95% CI, 1.05–4.03).

Conclusions—

We conclude that MP infection is independently associated with risk of subsequent ischemic stroke development.
Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis
Authors: Kwon Sun U. , Hong Keun-Sik , Kang Dong-Wha , Park Jong-Moo , Lee Ju-Hun , Cho Yong-Jin , Yu Kyung-Ho , Koo Ja-Seong , Wong K.S. Lawrence , Lee Seung-Hoon , Lee Kyung Bok , Kim Dong-Eog , Jeong Sang-Wook , Bae Hee-Joon , Lee Byung-Chul , Han Moon-Ku , Rha Joung-Ho , Kim Hahn Young , Mok Vincent C. , Lee Yong-Seok , Kim Gyeong-Moon , Suwanwela Nijasri Charnnarong , Yun Sung-Cheol , Nah Hyun-Wook , Kim Jong S.
Published: July 2011

Background and Purpose—

An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence.

Methods—

In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications.

Results—

Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (
P
=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61;
P
=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%;
P
=0.078) and major hemorrhagic complications (0.9% versus 2.6%;
P
=0.163).

Conclusions—

This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00130039.
Effect of Increased Warfarin Use on Warfarin-Related Cerebral Hemorrhage
Authors: Huhtakangas Juha , Tetri Sami , Juvela Seppo , Saloheimo Pertti , Bode Michaela K. , Hillbom Matti
Published: July 2011

Background and Purpose—

Warfarin use has rapidly increased with the aging of the population. We investigated the temporal trends in the incidence and outcome of warfarin-related intracerebral hemorrhages (ICHs) in a defined population.

Methods—

We identified all subjects with first-ever primary ICH during 1993 to 2008 among the population of Northern Ostrobothnia, Finland. The number of warfarin users was obtained from the national register of prescribed medicines kept by the Social Insurance Institution of Finland. We calculated the annual incidence of warfarin-related ICHs, 28-day case fatality, and deaths from the primary bleed.

Results—

The proportion of warfarin users among the population increased 3.6-fold from 0.68% in 1993 to 2.28% in 2008. Of a total of 982 patients with ICH, 182 (18.5%) had warfarin-related ICH. One-year survival rate after onset of stroke was 35.2% among warfarin users and 67.9% among nonusers. The annual incidence (
P
=0.062) and 28-day case fatality of warfarin-related ICHs (
P
=0.002) decreased during the observation period. Warfarin users were older (mean difference 6.6; 95% CI, 5.0 to 8.1;
P
<0.001) than nonusers. Admission international normalized ratio values above the therapeutic range (2.0 to 3.0) decreased through the observation period, suggesting improved control of anticoagulant therapy over time.

Conclusions—

The annual incidence and case fatality of warfarin-related ICHs decreased, although the proportion of warfarin users almost quadrupled in our population.