bluuebunny/crossref_metadata_2025 huggingface dataset:
Does echocardiography accurately reflect CMR-determined changes in left ventricular parameters following exercise training? A prospective longitudinal study
Authors: Spence Angela L. , Naylor Louise H. , Carter Howard H. , Dembo Lawrence , Murray Connor P. , O'Driscoll Gerry , George Keith P. , Green Daniel J.
Published: February 2013

Cardiac adaptation in response to exercise has historically been described using echocardiography. Cardiac magnetic resonance (CMR), however, has evolved as a preferred imaging methodology for cardiac morphological assessment. While direct imaging modality comparisons in athletes suggest that large absolute differences in cardiac dimensions exist, it is currently unknown whether changes in cardiac morphology in response to exercise training are comparable when using echocardiography and CMR. Twenty-two young men were randomly assigned to undertake a supervised and intensive endurance or resistance exercise-training program for 24 wk. Echocardiography and CMR assessment of left ventricular (LV) mass, LV end-diastolic volume, internal cavity dimensions, and wall thicknesses were completed before and after training. At baseline, pooled data for all cardiac parameters were significantly different between imaging methods, while LV mass ( r = 0.756, P < 0.001) and volumes (LV end-diastolic volume, r = 0.792, P < 0.001) were highly correlated across modalities. Changes in cardiac morphology data with exercise training were not significantly related when echocardiographic and CMR measures were compared. For example, posterior wall thickness increased by 8.3% ( P < 0.05) when assessed using echocardiography, but decreased by 2% when using CMR. In summary, echocardiography and CMR imaging modalities produce findings that differ with respect to changes in cardiac size and volume following exercise training.
Hyperactivated JNK Is a Therapeutic Target in pVHL-Deficient Renal Cell Carcinoma
Authors: An Jiabin , Liu Huiren , Magyar Clara E. , Guo Yanchuan , Veena Mysore S. , Srivatsan Eri S. , Huang Jiaoti , Rettig Matthew B.
Published: February 2013

Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-α) is the most well-studied effect of VHL inactivation, direct inhibition of HIFα or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e., HIF-α) and gene replacement therapy of tumor suppressor genes (i.e., VHL). Here, we have established that phosphorylated c-Jun, a substrate of the c-Jun-NH2-kinase (JNK), is selectively activated in clear cell RCC patient specimens. Using multiple isogenic cell lines, we show that HIF-α–independent JNK hyperactivation is unique to the pVHL-deficient state. Importantly, pVHL-deficient RCCs are dependent upon JNK activity for in vitro and in vivo growth. A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a CARD9/BCL10/TRAF6 complex as a proximal signal to sequentially stimulate TAK1 (MAPKKK), MKK4 (MAPKK), and JNK (MAPK). JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos to form a transcriptionally competent AP1 complex that drives transcription of the Twist gene and induces epithelial–mesenchymal transition. Thus, JNK represents a novel molecular target that is selectively activated in and drives the growth of pVHL-deficient clear cell RCCs. These findings can serve as the preclinical foundation for directed efforts to characterize potent pharmacologic inhibitors of the JNK pathway for clinical translation. Cancer Res; 73(4); 1374–85. ©2012 AACR.
Amino Acid Substitutions in the Core Region Associate with Insulin Resistance in Chronic Hepatitis C
Authors: Hung Chao-Hung , Hu Tsung-Hui , Lee Chuan-Mo , Huang Chao-Min , Chen Chien-Hung , Wang Jing-Houng , Lu Sheng-Nan
Published: February 2013

Background/Aims: Hepatitis C virus (HCV) core protein can induce liver steatosis and glucose intolerance in transgenic mice. We aimed to clarify the association of HCV core region heterogeneity with the development of insulin resistance (IR) among patients with chronic hepatitis C (CHC). Methods: A total of 56 non-diabetic CHC genotype-1b patients were enrolled. IR was evaluated by the homeostasis model assessment (HOMA). The amino acid (aa) sequences in the core region were determined by polymerase chain reaction and direct sequencing. Results: Patients with a higher HOMA-IR (≥3.5) had a higher ratio of aa substitutions in core 70 (p = 0.025), a higher body mass index (p = 0.021) and serum total cholesterol level (p = 0.044) and presence of hepatic steatosis (≥5%) as compared with those with a lower HOMA-IR (<3.5). Multivariate analysis showed that independent factors of higher HOMA-IR were mutated aa70 (odds ratio 3.80, p = 0.033) and body mass index (odds ratio 1.20, p = 0.042). Patients with mutated aa70 had a higher serum tumor necrosis factor-α level than those with wild-type (p = 0.014). Conclusions: Substitution of the HCV-1b core region at position 70 was an independent factor associated with developing IR among patients with CHC.
Effectiveness of the ThinPrep Imaging System in the Detection of Abnormal Cervicovaginal Cytology: A Practical Experience in Korea
Authors: Ha Sang Yun , Lee Yun Kyung , Oh Young Lyun
Published: February 2013

Objective: The purpose of this study is to report our experience with the implementation of the ThinPrep Imaging System (TIS) in a tertiary hospital in Korea and to evaluate the effectiveness of the TIS compared to manual methods in the screening of cervical cytology. Study Design: Detection rates of cervical abnormalities in the pre- and post-TIS periods (January 2009 to February 2010 and March 2010 to December 2010, respectively) were compared. Follow-up cytological and histological results with concurrent or subsequent human papillomavirus (HPV) tests were retrieved. Results: ASC-US, ASC-H, LSIL, and HSIL were more frequently detected in the post-TIS period than in the pre-TIS period (p < 0.005). The proportions of correlated cases of ASC-US were 42.2 and 40.4% in the pre- and post-TIS periods, respectively. The detection rates of high-risk types of HPV in ASC-US were not significantly different between the two groups. The proportion of correlated biopsy for ASC-H, LSIL, and HSIL was similar in both periods. HPV positivity for ASC-H, LSIL, and HSIL showed no significant change between the two periods. Conclusion: The TIS is potentially useful for the detection of abnormal cervical cytology on the basis of the increased detection rate of squamous cell abnormalities, with a relatively similar proportion of correlated cases compared to the manual screening method.
Malignant Pleural Effusion Resulting from Metastasis of Thyroid Primaries: A Cytomorphological Analysis
Authors: Olson Matthew T. , Nuransoy Ayşe , Ali Syed Z.
Published: February 2013

Background: Malignant serous cavity effusion caused by primary thyroid cancer is extremely rare in routine clinical practice. Therefore, it is often not included in the differential diagnostic workup of patients presenting with positive effusion cytology. Methods: The clinical features were reviewed for 6 patients seen at our institution over the last 26 years for malignant effusion resulting from metastatic thyroid cancer. The cytomorphology from 4 of these cases was also reviewed. Results: All of the patients found in this study presented with malignant pleural effusion – other serous cavity effusions resulting from metastatic thyroid carcinoma were not seen. These comprised 0.25% of all patients with a known history of thyroid carcinoma and 0.67% of all malignant pleural effusions. One patient had a history of bone metastases, but all the others had no pathological evidence of distant metastatic disease prior to the pleural effusion. Conclusions: Malignant pleural effusion rarely results from a thyroid carcinoma after some latency. The diagnosis requires immunohistochemical staining as well as the pertinent clinical context.
Optimal Sampling Devices for Liquid-Based Procedure in Screening for Cervical Cancer: Comparison between Cotton Stick/Cytobrush and Cervex-Brush
Authors: Kuramoto Hiroyuki , Banno Midori , Hori Masuko , Miyagawa Jun , Iida Manichi , Kawaguchi Miwa
Published: February 2013

Objective: To find an appropriate sampling device for a liquid-based procedure in the population screening for cervical cancer, focusing on bleeding at sampling and the amount of cells smeared. Methods and Materials: 1,000 consecutive women who underwent primary screening were studied. The specimens were obtained with the cotton stick/Cytobrush® method in the first 500 cases or with the Cervex-Brush® in the following 500 subjects, and were processed using the Thinlayer Advanced Cytology Assay System (TACAS™) following the manufacturer’s instructions. Results: (1) Bleeding at cellular sampling using the cotton stick/Cytobrush and Cervex-Brush methods occurred in 1.2 and 8.8% of the cases, respectively (p < 0.0001). (2) The incidences of cells obtained with the two methods which covered the whole area, <1/2 and ≥1/4, and <1/4 of the observation fields were 55.4 versus 62.2% (p < 0.05), 14.6 versus 9.4% (p < 0.05), and 2.0 versus 4.0% (p < 0.05), respectively. (3) The incidences of endocervical or metaplastic cells obtained with ≥500 and <10 were 34.6 versus 20.0% (p < 0.01) and 9.4 versus 18.4% (p < 0.01), respectively. In cases of cells covering <1/4, incidences with <10 were 0 and 0.6% (n = 3), respectively. (4) Detection rates of abnormal cytology were 3.4 and 5.2% (n.s.), including atypical squamous cells of undetermined significance in 2.4 and 3.2%. Conclusions: The cotton stick/Cytobrush is superior to the Cervex-Brush as a cellular sampling device for the TACAS liquid-based procedure.
A Combination of α-Fetoprotein and Des-γ-Carboxy Prothrombin Is Superior in Detection of Hepatocellular Carcinoma
Authors: Ertle Judith M. , Heider Dominik , Wichert Marc , Keller Benedikt , Kueper Robert , Hilgard Philip , Gerken Guido , Schlaak Joerg F.
Published: February 2013

Background and Aim: The incidence of hepatocellular carcinoma (HCC) is increasing in western countries. Despite its low sensitivity, the diagnosis of HCC still depends on detection of α-fetoprotein (AFP). Therefore, the aim of this study was to evaluate the combined analysis of AFP and des-γ-carboxy prothrombin (DCP) in a European cohort. Methods: We performed a single-center study (164 HCC/422 controls), in which the serum concentrations of AFP and DCP were determined. Results: AFP and DCP were elevated in HCC patients compared to controls (p < 0.0001). By combination of AFP and DCP, the sensitivity was improved from 28.7% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 54.9%) to 78.0% using cutoffs of 10 ng/ml for AFP and 5 ng/ml for DCP (DCP alone, cutoff 5 ng/ml: 63.4%). Among early-stage patients, the sensitivity increased from 20% for AFP (cutoff 400 ng/ml; AFP at cutoff 10 ng/ml: 38%) to 55% in combination (DCP alone, cutoff 5 ng/ml: 47%). The area under the curve (AUC) for AFP and DCP was similar (AFP: 0.88; DCP: 0.87; combined: 0.91). Among non-cirrhotic patients, DCP (AUC: 0.93) showed a better performance than AFP (AUC: 0.84). Especially patients with non-alcoholic steatohepatitis had a high percentage of DCP-positive tumors. Conclusion: The data suggest that AFP alone is not sufficient for the serological diagnosis of HCC in European patients, while a combination of AFP and DCP can increase the sensitivity even in early-stage patients.
Diagnosis-Related Groups for Stroke in Europe: Patient Classification and Hospital Reimbursement in 11 Countries
Authors: Peltola Mikko , Quentin Wilm ,   on behalf of the EuroDRG Group
Published: February 2013

Background: Diagnosis-related groups (DRGs) are increasingly being used for various purposes in many countries. However, there are no studies comparing different DRG systems in the care of stroke. As part of the EuroDRG project, researchers from 11 countries (i.e. Austria, England, Estonia, Finland, France, Germany, Ireland, the Netherlands, Poland, Sweden and Spain) compared how their DRG systems deal with stroke patients. The study aims to assist clinicians and national authorities to optimize their DRG systems. Methods: National or regional databases were used to identify hospital cases with a diagnosis of stroke. DRG classification algorithms and indicators of resource consumption were compared for those DRGs that individually represent at least 1% of stroke cases. In addition, standardized case vignettes were defined, and quasi prices according to national DRG-based hospital payment systems were ascertained. Results: European DRG systems vary widely: they classify stroke patients according to different sets of variables (between 1 and 7 classification variables) into diverging numbers of DRGs (between 1 and 10 DRGs). In 6 of the countries more than half of the patients are concentrated within a single DRG. The countries’ systems also vary with respect to the evaluation of different kinds of stroke patients. The most complex DRG is considered 3.8 times more resource intensive than an index case in Finland. By contrast, in England, the DRG system does not account for complex cases. Comparisons of quasi prices for the case vignettes show that hypothetical payments for the index case amount to only EUR 907 in Poland but to EUR 7,881 in Ireland. Conclusions: Large variations in the classification of stroke patients raise concerns whether all systems rely on the most appropriate classification variables and whether the DRGs adequately reflect differences in the complexity of treating different groups of patients. Learning from other DRG systems may help in improving the national systems. Clinicians and national DRG authorities should consider how other countries’ DRG systems classify stroke patients in order to optimize their DRG system and to ensure fair and appropriate reimbursement. In future, quantitative research is needed to verify whether the most important determinants of cost are considered in different patient classification systems, and whether differences between systems reflect country-specific differences in treatment patterns and, most importantly, what influence they have on patient outcomes.
Dual Gliomas with Syringomyelia in a Child: Case Report and Literature Review
Authors: Patibandla Mohana Rao , Kumar Ashish , Bhattacharjee Suchanda , Sahu Barada Prasad , Uppin Megha , Challa Sundaram
Published: February 2013

Background and Importance: The occurrence of multiple tumors of different histopathologies in the central nervous -system is rare. Here, we report a case of a child with dual neuroepithelial tumors of different histological cell types and -review the available literature for analyzing the causal hypo-thesis. Case Report: A 7-year-old girl presented with history of headaches associated with multiple episodes of early morning projectile vomiting and visual blurring. Magnetic resonance imaging (MRI) showed a well-defined lesion in the hypothalamic region. The patient underwent resection of the tumor by the transcallosal transfornicial approach. Histopathology was suggestive of pilocytic astrocytoma. After 3 years, the patient presented with low back pain radiating to the right lower limb followed by sudden onset of weakness in both lower limbs. Recent MRI brain and spine scans showed a small residual lesion at the hypothalamus with D1 to D10 syrinx. A T1 hypointense and T2 hyperintense cystic lesion from D10 to S2 with intensely enhancing solid component at the S1, S2 region was also detected. The patient underwent L4 to S2 laminectomy and the histopathological examin-ation revealed myxopapillary ependymoma. Conclusion: The presence of multiple neuroepithelial tumors of different histopathology in the same patient is extremely rare, and we report one such case of dual gliomas with hypothalamic pilocytic astrocytoma and cauda equina myxopapillary ependymoma in a 10-year-old patient. During the course of development, displacement and dedifferentiation of primitive totipotent neuroepithelial germ cells may be a causal factor for the appearance of the different neuroepithelial tumors in neuraxis concomitantly or subsequently, which might be substantiated by common cytogenetic abnormalities in different neuroepithelial tumor histogenesis.
Idiopathic Intraventricular Aneurysm Presenting with Intraventricular Hemorrhage: Case Report and Review of the Literature
Authors: Madhugiri Venkatesh S. , Gundamaneni Sudheer Kumar , Yadav Awdhesh Kumar , Sasidharan Gopalakrishnan M. , Roopesh Kumar V.R.
Published: February 2013

Intraventricular hemorrhage (IVH) is a relatively commonly encountered problem in neurosurgical practice. The underlying causes could include hypertension, arteriovenous malformations (AVM), angiomas, trauma, tumors, aneurysms and moyamoya disease. Truly idiopathic intraventricular aneurysms (IVA) are rare. A high index of suspicion needs to be maintained since, with the appropriate treatment, the outcome is generally good. We report the case of a 14-year-old boy who presented with sudden onset headache and vomiting. CT angiogram pointed to the possibility of an IVA. This was confirmed by MRI with three-dimensional constructive interference in steady state (CISS-3D) sequences and digital subtraction angiography. The patient underwent microsurgical excision of the aneurysm and is doing well on follow-up. Idiopathic IVA can present with IVH at any age. MRI with CISS-3D and MR angiography would be the imaging modality of choice since it can also rule out other causes of intraventricular bleeding such as tumors and AVM. These lesions could be managed effectively by microsurgical excision/clipping. The necessity of investigating every patient who presents with IVH is debatable.
Clinical Studies on the Treatment of Cancer Cachexia with Megestrol Acetate plus Thalidomide
Authors: Wen Hong-Sheng , Li Xu , Cao Yu-Zhu , Zhang Cui-Cui , Yang Fang , Shi Yu-Ming , Peng Li-Ming
Published: February 2013

Background: The management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge in clinical practice. To date, practice guidelines for the prevention and treatment of CACS are lacking. The authors conducted a randomized study to confirm the effectiveness and safety of treatment of CACS utilizing megestrol acetate (MA) plus thalidomide. Methods: One hundred and two candidates with CACS were randomly assigned to two treatment groups (trial group and control group): the trial group received MA (160 mg po, bid) plus thalidomide (50 mg po, bid), while the control group received MA (160 mg po, bid) alone. Treatment duration was 8 weeks. Results: Analysis of the trial group demonstrated a significant increase from baseline in body weight (<0.01), quality of life (p = 0.02), appetite (p = 0.01), and grip strength (p = 0.01), and a significant decrease in fatigue, Glasgow Prognostic Score (p = 0.05), Eastern Cooperative Oncology Group performance status (p = 0.03), IL-6 (p < 0.01), and tumor necrosis factor-α (p = 0.02). In contrast, in the control group, endpoints with a significant improvement from baseline included body weight (p < 0.02) and appetite (p = 0.02). The mean changes in the endpoints from baseline in the trial group were significantly greater compared with the control group: in the primary endpoints, body weight (p = 0.05), fatigue (p < 0.01) and quality of life (p = 0.01), and in the secondary endpoints, grip strength (p = 0.05), Glasgow Prognostic Score (p = 0.02), Eastern Cooperative Oncology Group performance status (p = 0.02), IL-6 (p < 0.01) and tumor necrosis factor-α (p = 0.01). Toxicity was found to be relatively negligible in both groups. Conclusion: A combination regimen of MA and thalidomide is more effective than MA alone in the treatment of CACS.
Visual Reproduction on the Wechsler Memory Scale-Revised as a Predictor of Alzheimer’s Disease in Japanese Patients with Mild Cognitive Impairments
Authors: Hori Takumi , Sanjo Nobuo , Tomita Makoto , Mizusawa Hidehiro
Published: February 2013

Background: The Visual Reproduction (VR) test is used to assess mild cognitive impairment (MCI), but the characteristics of visual memory in Japanese MCI patients remain unclear. Methods: VR scores of 27 MCI patients were evaluated using the Wechsler Memory Scale-Revised. Scores of MCI, no-dementia, and Alzheimer’s disease (AD) groups were then compared. Results: The annual conversion rate of MCI to AD was 18.8%. Mean VR-I and VR-II baseline scores for MCI patients were 33.3 ± 5.6 and 20.5 ± 14.0, respectively. Mean VR-II scores for converted and nonconverted MCI patients were 7.2 ± 8.7 and 29.8 ± 9.3, respectively. Conclusions: It is likely that VR-II and VR-II/I scores are more sensitive for predicting conversion to AD in Japanese than in American MCI patients. Our results indicate that VR is a sensitive and useful measure for predicting the conversion of Japanese MCI patients to AD within 2 years.
Evaluation of Open and Laparoscopic Radical Cystoprostatectomy Combined with Orthotopic Neobladder: A Single-Surgeon Experience
Authors: Akin Yigit , Celik Orcun , Ates Mutlu , Nuhoglu Baris , Erdogru Tibet
Published: February 2013

Aim: To compare the outcomes of laparoscopic (LRCP) and open radical cystoprostatectomy (ORCP) with orthotopic urinary diversion for muscle-invasive organ-confined bladder cancer by a single surgeon. Patients and Methods: Prospectively documented 15 LRCP and 15 ORCP patients, followed for at least 3 years, were included in our study. The demographic parameters of patients, preoperative radiologic staging, previous operations, surgical outcomes, complications, oncologic results and intermediate-term follow-up, postoperative chemotherapy and follow-up periods were recorded and evaluated. Results: The mean oncologic follow-up was 3 years. Transfusion rate, estimated blood loss, oral intake and narcotic analgesic requirement were statistically less in the LRCP group (p < 0.05). However, operation time and hospital stay were similar in both groups. The complication rates were not significantly different between the two groups. The mean number of dissected lymph nodes was 20.0 ± 1.7 in the ORCP and 22.6 ± 2.0 in the LRCP group. One patient in each group had a margin positive for bladder cancer. Conclusions: The laparoscopic approach may be feasible for muscle-invasive organ-confined bladder cancer. Furthermore, LRCP provides less blood loss, early oral intake and postoperative pain management. Additionally, continence and sexual function may be provided by LRCP as with ORCP.
Long-Term Use of Lipid-Lowering Drugs Slows Progression of Carotid Atherosclerosis
Authors: Herder Marit , Arntzen Kjell Arne , Johnsen Stein Harald , Eggen Anne Elise , Mathiesen Ellisiv B.
Published: February 2013

Objective—

Data on the effect of lipid-lowering drugs (LLD) on carotid atherosclerosis outside clinical trials are limited. The aim of this study was to determine the effect of LLD on change in carotid intima media thickness and total plaque area in a general population.

Approach and Results—

Subjects were 1532 women and 1442 men who participated in a longitudinal population-based study with ultrasound examination of intima media thickness and total plaque area in the right carotid artery at baseline and after 13 years follow-up. Long-term use of LLD was defined as use for >5 years, any-time use of LLD was defined as use at baseline or at 6 years or at 13 years of follow-up. In multivariable models adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent cardiovascular disease, and daily smoking, long-term use of LLD had a protective effect on progression of both intima media thickness (β=–0.0387 mm;
P
=0.002) and total plaque area (β=–0.400 mm
2
;
P
=0.006). There was a weaker protective effect of any-time use of LLD on progression of intima media thickness (β=–0.024 mm;
P
=0.046) and total plaque area (β=–0.318 mm
2
;
P
=0.06).

Conclusions—

LLD protected against progression of carotid atherosclerosis. The protective effect was strongest in long-term users.
A 28-kDa Splice Variant of NADPH Oxidase-4 Is Nuclear-Localized and Involved in Redox Signaling in Vascular Cells
Authors: Anilkumar Narayana , Jose Gorka San , Sawyer Iain , Santos Celio X.C. , Sand Claire , Brewer Alison C. , Warren Derek , Shah Ajay M.
Published: February 2013

Objective—

Reactive oxygen species–generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase proteins (Noxs) are involved in cell differentiation, migration, and apoptosis. Nox4 is unique among Noxs in being constitutively active, and its subcellular localization may therefore be particularly important. In this study, we identified and characterized a novel nuclear-localized 28-kDa splice variant of Nox4 in vascular cells.

Approach and Results—

Nox4 immunoreactivity was noted in the nucleus and nucleolus of vascular smooth muscle cells and multiple other cell types by confocal microscopy. Cell fractionation, sequence analyses, and siRNA studies indicated that the nuclear-localized Nox4 is a 28-kDa splice variant, Nox4D, which lacks putative transmembrane domains. Nox4D overexpression resulted in significant NADPH-dependent reactive oxygen species production as detected by several different methods and caused increased phosphorylation of extracellular-signal-regulated kinase1/2 and the nuclear transcription factor Elk-1. Overexpression of Nox4D could also induce DNA damage as assessed by γ-H2AX phosphorylation. These effects were inhibited by a single amino acid substitution in the Nox4D NADPH-binding region.

Conclusions—

Nox4D is a nuclear-localized and functionally active splice variant of Nox4 that may have important pathophysiologic effects through modulation of nuclear signaling and DNA damage.
Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes
Authors: Moran Corey S. , Jose Roby J. , Moxon Joseph V. , Roomberg Alicia , Norman Paul E. , Rush Catherine , Körner Heinrich , Golledge Jonathan
Published: February 2013

Objective—

We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E–deficient mouse model.

Approach and Results—

Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of interferon (IFN)-γ and IFNγ-induced CCR2 expression in apolipoprotein E–deficient mouse bone marrow monocytes. Further, everolimus diminished IFNγ/lipopolysaccharide-stimulated M1 polarization in apolipoprotein E–deficient mouse bone marrow monocyte–differentiated macrophages.

Conclusions—

Systemic administration of everolimus limits aortic aneurysm in the A2-infused apolipoprotein E–deficient mouse model via suppressed development of bone marrow CCR2 monocytes and reduced egress of these cells into the circulation.
Panoramic Electrophysiological Mapping but not Electrogram Morphology Identifies Stable Sources for Human Atrial Fibrillation
Authors: Narayan Sanjiv M. , Shivkumar Kalyanam , Krummen David E. , Miller John M. , Rappel Wouter-Jan
Published: February 2013

Background—

The foundation for successful arrhythmia ablation is the mapping of electric propagation to identify underlying mechanisms. In atrial fibrillation (AF), however, mapping is difficult so that ablation has often targeted electrogram features, with mixed results. We hypothesized that wide field-of-view (panoramic) mapping of both atria would identify causal mechanisms for AF and allow interpretation of local electrogram features, including complex fractionated atrial electrograms (CFAE).

Methods and Results—

Contact mapping was performed using biatrial multipolar catheters in 36 AF subjects (29 persistent). Stable AF rotors (spiral waves) or focal sources were seen in 35 of 36 cases and targeted for ablation (focal impulse and rotor modulation) before pulmonary vein isolation. In 31 of 36 subjects (86.1%), AF acutely terminated (n=20; 16 to sinus rhythm) or organized (n=11; 19±8% slowing) with 2.5 minutes focal impulse and rotor modulation (interquartile range, 1.0–3.1) at one source, defined as the primary source. Subjects exhibited 2.1±1.0 concurrent AF sources of which the primary, by phase mapping, precessed in limited areas (persistent 2.5±1.7 versus paroxysmal 1.7±0.5 cm
2
;
P
=0.30). Notably, source regions showed mixed electrogram amplitudes and CFAE grades that did not differ from surrounding atrium (
P
=NS). AF sources were not consistently surrounded by CFAE (
P
=0.67).

Conclusions—

Stable rotors and focal sources for human AF were revealed by contact panoramic mapping (focal impulse and rotor modulation mapping), but not by electrogram footprints. AF sources precessed within areas of ≈2 cm
2
, with diverse voltage characteristics poorly correlated with CFAE. Most CFAE sites lie remote from AF sources and are not suitable targets for catheter ablation of AF.
Validation of a Cardiopulmonary Exercise Test Score in Heart Failure
Authors: Myers Jonathan , Oliveira Ricardo , Dewey Frederick , Arena Ross , Guazzi Marco , Chase Paul , Bensimhon Daniel , Peberdy Mary Ann , Ashley Euan , West Erin , Cahalin Lawrence P. , Forman Daniel E.
Published: February 2013

Background—

Cardiopulmonary exercise test (CPX) responses are strong predictors of outcomes in patients with heart failure. We recently developed a CPX score that integrated the additive prognostic information from CPX. The purpose of this study was to validate the score in a larger, independent sample of patients.

Methods and Results—

A total of 2625 patients with heart failure underwent CPX and were followed for cardiovascular (CV) mortality and major CV events (death, transplantation, left ventricular assist device implantation). Net reclassification improvement (NRI) for the score and each of its components were determined at 3 years. The VE/VCO
2
slope was the strongest predictor of risk and was attributed a relative weight of 7, with weighted scores for abnormal heart rate recovery, oxygen uptake efficiency slope, end-tidal CO
2
pressure, and peak VO
2
having scores of 5, 3, 3, and 2, respectively. A summed score of >15 was associated with an annual mortality rate of 12.2% and a relative risk >9 for total events, whereas a score of <5 was associated with an annual mortality rate of 1.2%. The composite score was the most accurate predictor of CV events among all CPX responses considered (C indexes, 0.70 for CV mortality and 0.72 for the composite outcome). Each component of the score provided significant NRI compared with peak VO
2
(category-free NRI, 0.61–0.77), and the score provided significant NRI above clinical risk factors for both CV events and mortality (NRI, 0.63 and 0.65 for CPX score compared with clinical variables alone).

Conclusions—

These results validate the application of a simple, integrated multivariable score based on readily available CPX responses.
Donor Predictors of Allograft Use and Recipient Outcomes After Heart Transplantation
Authors: Khush Kiran K. , Menza Rebecca , Nguyen John , Zaroff Jonathan G. , Goldstein Benjamin A.
Published: February 2013

Background—

Despite a national organ-donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft nonuse, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.

Methods and Results—

We studied a cohort of 1872 potential organ donors managed by the California Transplant Donor Network from 2001 to 2008. Forty-five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft nonuse included age>50 years, female sex, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay, left-ventricular dysfunction and regional wall motion abnormalities, and left-ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes mellitus was predictive of increased recipient mortality.

Conclusions—

Whereas there are many donor predictors of allograft discard in the current era, these characteristics seem to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.
Relationship of Right- to Left-Sided Ventricular Filling Pressures in Advanced Heart Failure
Authors: Drazner Mark H. , Velez-Martinez Mariella , Ayers Colby R. , Reimold Sharon C. , Thibodeau Jennifer T. , Mishkin Joseph D. , Mammen Pradeep P.A. , Markham David W. , Patel Chetan B.
Published: February 2013

Background—

Although right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) are correlated in heart failure, in a sizeable minority of patients, the RAP and PCWP are not tightly coupled. The basis of this variability in the RAP/PCWP ratio, and whether it conveys prognostic value, is not known.

Methods and Results—

We analyzed the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial database. Baseline characteristics, including echocardiographic assessment of right ventricular (RV) structure and function, and invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP ratio. Multivariable Cox proportional hazard models assessed the association of RAP/PCWP ratio with the primary ESCAPE outcome (6-month death or hospitalization [days]) adjusting for systolic blood pressure, blood urea nitrogen, 6-minute walk distance, and PCWP. The RAP/PCWP tertiles were 0.27 to 0.4 (tertile 1); 0.41 to 0.615 (tertile 2), and 0.62 to 1.21 (tertile 3). Increasing RAP/PCWP was associated with increasing median right atrial area (23, 26, 29 cm
2
, respectively;
P
<0.005), RV area in diastole (21, 27, 27 cm
2
, respectively;
P
<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units, respectively;
P
=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g·m/m
2
per beat, respectively;
P
<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months (hazard ratio, 1.16 [1, 1.4];
P
<0.05).

Conclusions—

Increased RAP/PCWP ratio was associated with higher pulmonary vascular resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke work index), and an increased risk of adverse outcomes in patients with advanced heart failure.
Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke
Authors: Lees Kennedy R. , Bornstein Natan , Diener Hans-Christoph , Gorelick Philip B. , Rosenberg Gilad , Shuaib Ashfaq
Published: February 2013

Background and Purpose—

DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke.

Methods—

The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intent-to-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was an exploratory end point.

Results—

Enrollment terminated at n=446 after the planned interim analysis determined futility; follow-up continued. Final modified Rankin score distributions were equal between DP-b99 and placebo-treated groups (
P
=0.10;
P
adj
adjusted for baseline age and National Institutes of Health Stroke Scale=0.21). Fewer patients recovered to modified Rankin score ≤1 in the DP-b99–treated group (45/218; 20.6%) than after placebo (63/219; 28.8%) (
P
=0.05;
P
adj
=0.10). Similarly, fewer patients attained National Institutes of Health Stroke Scale ≤1 after DP-b99 (42/218; 19.3%) than placebo (56/219; 25.6%;
P
=0.10;
P
adj
=0.26). Mortality was similar between DP-b99 and placebo intent-to-treat groups (36/218; 16.5% vs 33/219; 15.1%;
P
=0.68). Home time was unchanged by treatment (median 36 vs 36.5 days;
P
=0.25).

Conclusions—

Despite encouraging preclinical and phase II trial data, DP-b99 shows no evidence of efficacy in treating human ischemic stroke.
Simvastatin Attenuates Stroke-induced Splenic Atrophy and Lung Susceptibility to Spontaneous Bacterial Infection in Mice
Authors: Jin Rong , Zhu Xiaolei , Liu Lin , Nanda Anil , Granger D. Neil , Li Guohong
Published: February 2013

Background and Purpose—

Statins are widely used in the primary and secondary prevention of ischemic stroke, but their effects on stroke-induced immunodepression and poststroke infections are elusive. We investigated the effects of simvastatin treatment on stroke-induced splenic atrophy and lung susceptibility to bacterial infection in acute experimental stroke in mice.

Methods—

Ischemic stroke was induced by transient middle cerebral artery occlusion, followed by reperfusion. In some experiments, splenectomies were performed 2 weeks before middle cerebral artery occlusion. Animals were randomly assigned to sham and middle cerebral artery occlusion groups treated subcutaneously with vehicle or simvastatin (20 mg/kg per day). Brain infarction, neurological function, brain interferon-γ expression, splenic atrophy and apoptosis, and lung infection were examined.

Results—

Simvastatin reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial antiapoptotic Bcl-2 expression and decreased proapoptotic Bax translocation from cytosol into mitochondria. Splenectomy reduced brain interferon-γ (3 days) and infarct size (5 days) after stroke, and these effects were reversed by adoptive transfer of splenocytes. Simvastatin inhibited brain interferon-γ (3 days) and reduced infarct volume and neurological deficits (5 days) after stroke, and these protective effects were observed not only in naive stroke mice but also in splenectomied stroke mice adoptively transferred with splenocytes. Simvastatin also decreased the stroke-associated lung susceptibility to spontaneous bacterial infection.

Conclusions—

Results provide the first direct experimental evidence that simvastatin ameliorates stroke-induced peripheral immunodepression by attenuating spleen atrophy and lung bacterial infection. These findings contribute to a better understanding of the beneficial effects of statins in the treatment of stroke.
Acute Effect of Ambient Air Pollution on Stroke Mortality in the China Air Pollution and Health Effects Study
Authors: Chen Renjie , Zhang Yuhao , Yang Chunxue , Zhao Zhuohui , Xu Xiaohui , Kan Haidong
Published: February 2013

Background and Purpose—

There have been no multicity studies on the acute effects of air pollution on stroke mortality in China. This study was undertaken to examine the associations between daily stroke mortality and outdoor air pollution (particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide) in 8 Chinese cities.

Methods—

We used Poisson regression models with natural spline-smoothing functions to adjust for long-term and seasonal trends, as well as other time-varying covariates. We applied 2-stage Bayesian hierarchical statistical models to estimate city-specific and national average associations of air pollution with daily stroke mortality.

Results—

Air pollution was associated with daily stroke mortality in 8 Chinese cities. In the combined analysis, an increase of 10 μg/m
3
of 2-day moving average concentrations of particulate matter <10 μm in aerodynamic diameter, sulfur dioxide, and nitrogen dioxide corresponded to 0.54% (95% posterior intervals, 0.28–0.81), 0.88% (95% posterior intervals, 0.54–1.22), and 1.47% (95% posterior intervals, 0.88–2.06) increase of stroke mortality, respectively. The concentration–response curves indicated linear nonthreshold associations between air pollution and risk of stroke mortality.

Conclusions—

To our knowledge, this is the first multicity study in China, or even in other developing countries, to report the acute effect of air pollution on stroke mortality. Our results contribute to very limited data on the effect of air pollution on stroke for high-exposure settings typical in developing countries.
Periprocedural Arterial Spin Labeling and Dynamic Susceptibility Contrast Perfusion in Detection of Cerebral Blood Flow in Patients With Acute Ischemic Syndrome
Authors: Nael Kambiz , Meshksar Arash , Liebeskind David S. , Wang Danny J.J. , Ellingson Benjamin M. , Salamon Noriko , Villablanca Juan Pablo
Published: February 2013

Background and Purpose—

To compare the diagnostic performance of arterial spin-labeling (ASL) and dynamic susceptibility contrast (DSC) perfusion in detecting cerebral blood flow (CBF) changes before and after endovascular recanalization in acute ischemic syndrome.

Methods—

The inclusion criteria for this retrospective study were patients with acute ischemic syndrome who underwent endovascular recanalization and acquisition of both ASL and DSC before and after revascularization. ASL-CBF and multiparametric DSC maps were evaluated for image quality, location, and type of perfusion abnormality. Relative CBF (rCBF) was calculated in the infarction core and hypoperfused areas using coregistered ASL and DSC. Core and hypoperfused rCBF were used for paired pretreatment and posttreatment comparisons. Interobserver and intermodality agreement were evaluated by κ test, and
t
test was calculated for ASL and DSC rCBF values.

Results—

Twenty-five patients met our inclusion criteria. Five studies were rated nondiagnostic, resulting in 45 pairs of DSC–ASL available for comparison. ASL and DSC agreed on type and location of the perfusion abnormality in 71% and 80% of cases, respectively. The image quality of ASL was lower than DSC, resulting in interobserver variability for the type (κ=0.45) and location (κ=0.56) of perfusion abnormality. ASL was unable to show any type of perfusion abnormality in 11% of patients. In successfully recanalized patients, hyperperfusion (rCBF >1) was detected in 100% on DSC and 47% on ASL.

Conclusions—

ASL is less sensitive than DSC for detecting rCBF changes in patients with acute ischemic syndrome, particularly with respect to hyperperfusion after successful recanalization.
Effects of catechins and low temperature on embryonic development and hatching in Heterodera glycines and Meloidogyne incognita
Authors: Masler Edward P. , Masler Edward P. , Rogers Stephen T. , Masler Edward P. , Rogers Stephen T. , Chitwood David J.
Published: February 2013

Mimics of two natural influences, a chemical similar to one present in cyst nematodes and low temperature exposure of nematode eggs, were evaluated for their effects on quantitative and qualitative features of embryonic development and hatching. The polyphenol epigallocatechin gallate (EGCG), an analogue of a compound found in nematode cysts, reduced hatch from both Heterodera glycines and Meloidogyne incognita eggs. Reduction was by 22.7% in H. glycines and 68.5% in M. incognita at 14 days after exposure to 1.0 mM EGCG. Significant reductions in hatch were observed at 7 days after exposure in H. glycines eggs, and as early as 5 days in M. incognita. Half-maximal percentage hatch was delayed by 0.6 days in H. glycines and 1.1 days in M. incognita (16.2 and 18.3%, respectively). Decreased hatch was associated primarily with an increase in unhatched, but viable, second-stage juveniles (J2). Hatch levels could be completely restored by day 14 in both species if EGCG was replaced with water on day 3. Replacement on day 7 partially restored hatch in M. incognita but was not effective in H. glycines. Inhibition of chitinase activity by EGCG suggests one factor in J2 retention in the egg. Exposure to low temperature decreased hatch by ca 50% in both species but without accumulation of unhatched J2. This stage peaked on day 3 in H. glycines-treated eggs, and on day 7 in M. incognita. However, response to low temperature in each species was characterised by developmental arrest at the first-stage juvenile.
A rapid in vitro bioassay system for testing resistance factors of pine trees to Bursaphelenchus xylophilus
Authors: Fujia Zhang , Fujia Zhang , Mori Yasuhiro , Fujia Zhang , Mori Yasuhiro , Tsutsumi Yuji , Fujia Zhang , Mori Yasuhiro , Tsutsumi Yuji , Kondo Ryuichiro
Published: February 2013

Understanding resistance mechanisms to pine wilt disease is essential to a successful breeding programme because plant selection cannot always guarantee absolute resistance against every isolate of the pine wood nematode, Bursaphelenchus xylophilus. To examine resistance factors in Japanese black pine, Pinus thunbergii, we devised a novel in vitro bioassay system in which we tested proliferation of pine wood nematodes co-cultured with wood slices or methanol extracts from pines. Proliferation of pine wood nematodes was inhibited in assays with fresh wood slices from resistant Japanese black pines but not with susceptible pine or without wood slices (control). When resistant wood slices were extracted by methanol, the inhibition effect of proliferation of pine wood nematodes was diminished, whereas methanol extraction from susceptible wood slices did not affect the proliferation. To verify whether nematode proliferation was inhibited by pine extracts, methanol extracts were loaded on paper disks and used in the assay. Populations of pine wood nematodes were significantly suppressed when methanol extracts originated from a resistant pine, but not from a susceptible pine. These results strongly suggest that methanol extracts from resistant pine trees contain the inhibitors of pine wood nematode proliferation. This bioassay system is available not only for identifying inhibitors of pine wood nematode proliferation but also for rapid screening of resistant pines.