bluuebunny/crossref_metadata_2025 huggingface dataset:
Anterior Urethral Strictures: A Brief Review of the Current Surgical Treatment
Authors: Singh Onkar , Gupta Shilpi Singh , Arvind Nand Kishore
Published: February 2011

A review of the recent literature on the surgical management of anterior urethral stricture was performed. The literature was searched via PubMed using the search terms ‘urethral stricture’ and ‘urethroplasty’ from 1996 to 2009. The management of anterior urethral strictures is changing rapidly in the sense that the reconstructive procedures have evolved greatly. Penile skin, because of its location and because it is hairless, has been popular and used for a long time. Since the early 1990s, buccal mucosa graft (BMG) was introduced in urethral reconstructive surgery and has become the first choice of most practicing urologists. Recently, there has been an increase in the use of lingual mucosa graft with various doctors reporting easy harvesting and lesser morbidity in comparison to BMG. Also, fibrin glue has recently been used to fix the graft with promising results. With the success of tissue-engineered materials that are still in the experimental phase, the urologist would no longer be limited by the quantity of the graft. These substitutes will also boost the appealing scarless endoscopic urethroplasty. This article provides a brief up-to-date review of the main surgical techniques in the management of anterior urethral stricture disease for the contemporary practicing urologists. Present controversies have been given special emphasis. The possible future techniques and the future of the anterior urethral stricture surgery are also discussed in brief.
The Diagnostic Accuracy and Lower Cutoff Value of Three Methods for Quantifying Urethral Resistance in Men
Authors: Zhao Jimao , Zhao Zhenhua , Song Jian , Ji Zhengguo , Tian Ye
Published: February 2011

Introduction: We estimated the diagnostic accuracy of Abrams-Griffiths number (AG), urethral resistance factor (URA) and detrusor-adjusted mean passive urethral resistance relation factor (DAMPF) for bladder outlet obstruction (BOO) in benign prostate hyperplasia (BPH) patients. Materials and Methods: AG, URA and DAMPF were obtained by pressure-flow studies from BPH patients. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic accuracy of the AG, URA and DAMPF in the diagnosis of BOO. Results: Among the 172 cases there were 154 classified as obstructed (89.5%) and 18 as unobstructed (10.5%). There were statistically significant differences in AG, URA and DAMPF between the obstructed and the unobstructed cases. The ROC curve demonstrated a similar diagnostic accuracy in the diagnosis of BOO for AG and URA values, and the least was seen for the DAMPF value. An AG cutoff of >33 provided a sensitivity of 89.61% and a specificity of 100%. A URA cutoff of >28 provided a sensitivity of 91.56% and a specificity of 100%. A sensitivity of 93.51% and the weakest specificity of 77.78% were recorded for DAMPF values of >52. AG and URA had a similar accuracy, while the efficacy of DAMPF is significantly lower in the diagnosis of BOO. Conclusions: AG or URA appeared to be the best discriminating parameters of BOO in BPH patients. The DAMPF could be used to aid the BOO diagnosis. Lower cutoff values were suggested for these BOO parameters.
Immunohistochemical Expression of Retinoblastoma Protein and p16 in Renal Cell Carcinoma
Authors: Maruschke M. , Thur S. , Kundt G. , Nizze H. , Hakenberg O.W.
Published: February 2011

Introduction: The regulation proteins retinoblastoma protein (pRb) and p16 play an important role in the cell cycle as tumor suppressors. pRb is the main substrate for the function of cyclin-dependent kinases during the cell cycle in the transition from G1 to S phase. In this study, the immunohistochemical expression of pRb and p16 in renal cell carcinoma (RCC) were examined. Methods: Paraffin-embedded specimens from 94 patients with RCC were examined immunohistologically, using primary antibodies for p16 and pRb (Novocastra) and a biotin-conjugated anti-mouse IgG secondary antibody. Microscopically, the expression of p16 and pRb was evaluated by examination of the staining intensity of 100 cells of each specimen, and compared with epidemiological parameters (tumor size, TNM, nuclear grade and follow-up). Statistical analyses were conducted by SPSS, version 15.0 (SPSS® Inc., Chicago, Ill., USA), the χ2 test (Fisher’s exact test), the Kaplan-Meier method and Mantel’s log rank test. Results: All 94 tumors showed a positive reaction for pRb (weakly positive in 67.0%; strongly positive in 33.0%). p16 was expressed in only 52.1% (weakly positive in 48.9%; intermediately positive in 3.2%; no strongly positive expression). The expression of p16-positive tumors was significantly associated with the expression of pRb (p = 0.040). Tumor size, grading, lymph node and distant metastases did not correlate with p16/pRb expression. Conclusion: pRb and p16 control the cell cycle as tumor suppressors. Therefore, in many tumors they are dysregulated. There are distinct differences in expression in various individual RCC. However, in a limited number of cases there was no significant correlation with clinical parameters.
A Special Terpene Combination (Rowatinex®) Improves Stone Clearance after Extracorporeal Shockwave Lithotripsy in Urolithiasis Patients: Results of a Placebo-Controlled Randomised Controlled Trial
Authors: Romics Imre , Siller György , Kohnen Ralf , Mavrogenis Stelios , Varga József , Holman Endre
Published: February 2011

Objective: To investigate the safety and efficacy of a special terpene combination in the treatment of patients with urolithiasis after extracorporeal shockwave lithotripsy (ESWL). Patients and Methods: 222 patients with clinically stable kidney or ureter stones of 0.3–2.0 cm undergoing complication-free ESWL were randomised to receive a special terpene combination (Rowatinex®; 3 × 2 capsules/day) or placebo. The study consisted of a 12-week active treatment phase and a 2-week follow-up phase. All patients had a physical examination, and diagnosis of kidney stones was made by X-ray, intravenous pyelogram or ultrasound at weeks 1, 4, 8 and 12 as well as after 2 weeks of follow-up. Stone-free status was defined as obviously successful expulsion of calculi/fragments, being without any stone. Results: In all, when compared to placebo, significantly more patients receiving the terpene combination treatment in the intent-to-treat (ITT) group [72 (67.9%) vs. 49 (50.0%); p = 0.0009] and the per-protocol (PP) group [69 (78.4%) vs. 48 (52.2%); p = 0.0004] were stone-free at the end of the study. Treatment with the terpene combination was also more effective when analysed with respect to the size of the treated stone. In addition, treatment with the terpene combination significantly reduced the median time to stone-free status from 85.0 to 56.0 days (p = 0.0061) and from 85.0 to 49.5 days (p = 0.0028) in the ITT and PP populations, respectively. Nine mild-to-moderate adverse events (AE; terpene combination group: 7 AE in 4 patients; placebo group: 2 AE in 2 patients) were assessed as drug-related. Conclusions: Treatment with the terpene combination is well tolerated and safe. The terpene combination was found to be an efficacious treatment in eliminating calculi fragments generated by ESWL as compared to placebo. The pharmacodynamic properties of the terpene combination (antilithogenic, antibacterial, antiinflammatory, spasmolytic and analgesic effects), which have been also confirmed in preclinical studies, represent a valuable alternative to the different drugs used in the treatment of urolithiasis.
Preoperative Hydronephrosis Predicts Advanced Bladder Cancer but Is Not an Independent Factor for Cancer-Specific Survival after Radical Cystectomy
Authors: Hofner Thomas , Haferkamp Axel , Knapp Lena , Pahernik Sascha , Hadaschik Boris , Djakovic Nenad , Wagener Nina , Hohenfellner Markus
Published: February 2011

Introduction: Hydronephrosis and BMI are analyzed together with established factors such as TNM stage and surgical margins in a multivariate modality to investigate their status as independent prognostic factors for bladder cancer-specific survival in patients undergoing radical cystectomy. Patients and Methods: We studied a prospective cohort of 328 patients who underwent radical cystectomy for bladder cancer at our institution. Statistical analyses were performed using the Kaplan-Meier method, Kendall-tau rank correlation and multivariate Cox proportional hazard model. Results: Hydronephrosis was positively correlated with advanced tumor stage, positive lymph node involvement and positive surgical margins. Adjusted for all other investigated parameters, BMI and hydronephrosis did not affect cancer-specific survival. In multivariate analysis only non-organ-confined disease (HR: 1.40, 95% CI: 1.04–1.87, p = 0.024), positive lymph node stage (HR 1.71: 95% CI: 1.12–2.61, p = 0.013) and positive surgical margins (HR 3.00, 95% CI: 1.74–5.15, p < 0.001) were prognostic factors. Conclusions: Hydronephrosis at the time of radical cystectomy is significantly correlated with the presence of more advanced bladder cancer and positive surgical margins. However, the long-established parameters pT stage, pN stage and surgical margins predominantly influence cancer-specific survival for patients undergoing radical cystectomy irrespective of hydronephrosis and BMI status.
Clusterin Immunoreactivity as a Predictive Factor for Progression of Non-Muscle-Invasive Bladder Carcinoma
Authors: Ekici Sinan , Eroğlu Alper , Doğan Ekici A. Işın , Türkeri Levent
Published: February 2011

Introduction: There is a need for prognostic markers which can predict the subset of patients who will not respond sufficiently to conservative management in non-muscle-invasive bladder carcinoma. We analyzed the association of clusterin (CLU) with clinicopathological factors. Materials and Methods: Immunohistochemical CLU expression was investigated in paraffin-embedded archival tissues of initial transurethral resection specimens of 46 patients with non-muscle-invasive bladder carcinoma. The result was expressed as the proportion of the number of CLU-containing tumor cells to the total number of tumor cells detected in each slide and ‘percent CLU expression’ was calculated for each patient. Results: Of the 46 cases (35 male, 11 female), 18 were ≧65 years of age. CLU expression was significantly higher in male and elderly patients. Following the initial transurethral resection, 39 patients showed tumor recurrence, and progression was seen in 25 patients, of whom 17 progressed to muscle invasion during follow-up. Although there was no significant correlation between CLU expression and recurrence, significant correlation with overall progression and progression to muscle-invasive disease was observed in this cohort of patients (p = 0.001 and p = 0.014, respectively). Among the patients with progression to muscle invasion, 13 underwent radical cystectomy with pT2 tumor in 5 patients in the final pathology of surgical specimens and pT3 and higher in the remainder. Conclusions: CLU immunoreactivity showed correlation with age, gender and progression, mainly progression to muscle invasion. Thus, CLU can be used as a molecular marker to predict the potential of progression to muscle-invasive disease in a particular tumor which in turn may prove useful in the decision-making process for early cystectomy without losing time with conservative management.
Are Referral Centers for Non-Muscle-Invasive Bladder Cancer Compliant to EAU Guidelines? A Report from the Vesical Antiblastic Therapy Italian Study
Authors: Gontero Paolo , Oderda Marco , Altieri Vincenzo , Bartoletti Riccardo , Cai Tommaso , Colombo Renzo , Curotto Antonio , Di Stasi Savino , Maffezzini Massimo , Tamagno Stefania , Serretta Vincenzo , Sogni Filippo , Terrone Carlo , Tizzani Alessandro , Morgia Giuseppe , Mirone Vincenzo , Carmignani Giorgio
Published: February 2011

Introduction: Adherence to international guidelines is viewed as a prerequisite for optimal medical care delivery. Previously reported surveys for non-muscle-invasive bladder cancer (NMIBC) employed mailed questionnaires to urologists or patients resulting in conflicting degrees of agreement with existing guidelines. In the current study, contemporary information on the management of NMIBC was generated from a sample of Italian centers. Patients and Methods: Eight Italian referral centers for the treatment of NMIBC were asked to collect information relative to all consecutive patients with a histology-proven NMIBC undergoing a transurethral resection from January 1 to March 31, 2009. The primary study objective was to verify the level of adherence of disease management with European guidelines. Results: 344 patients resulted in being evaluable. 49.2% of high-risk patients underwent a repeat transurethral resection. Bacillus Calmette-Guérin was employed in 35% of cases, while chemotherapy was in 22%. An early single regimen was adopted in 136 patients and only in 1 out of 3 low-risk patients. High-risk NMIBC received bacillus Calmette-Guérin and chemotherapy as first-line therapy in 66 and 12.5% respectively. After 3 months, cystoscopy had been reported for 82.5% of patients with a recurrence rate of 13%. Conclusion: Adherence of Italian Institutions to EAU guidelines was optimal when reporting baseline variables. Significant degrees of discrepancy emerged in treatment choices.
Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation
Authors: Tisdale Paul B. , Bennett Andrew J. , Seevaratnam Nandini , Macdonald Ian A. , Tsintzas Kostas
Published: February 2011

Aim: This study investigated whether changing fuel use, by increasing pyruvate dehydrogenase complex (PDC) flux, independently of plasma substrate availability and insulin signalling, would alter metabolic gene expression. Methods: The PDC activator, dichloroacetate (DCA), was administered as an intravenous infusion in healthy male subjects at a rate of 50 mg kg–1 min–1, for 90 min. Saline was infused as a control (CON) on a separate occasion in a randomised sequence. Muscle biopsies were taken from the vastus lateralis at 0 and 30 min into the infusion and 90 min after infusion. Gene expression was quantified using RT-qPCR, and immunoblotting was used to confirm that there were no changes in insulin signalling via the PI3K/Akt pathway. Results: Blood glucose concentrations fell during both trials but 3 h after the start of the infusion they were lower in DCA (p < 0.05) than CON. Blood lactate concentrations also declined in both trials (p < 0.01), however, this decrease was also more pronounced in DCA than CON (p < 0.001). Carbohydrate oxidation was increased by DCA, 0.037 ± 0.017 g min–1 (p < 0.05) at 3 h with no change observed in CON. UCP3 and PGC1α mRNA expression were induced in CON (as a response to continued fasting) but this was attenuated by DCA. Akt phosphorylation and the expression of other metabolic genes and transcription factors were unchanged throughout the intervention. Conclusion: It is concluded that PDC flux can be increased independently of plasma substrate availability, without causing downstream alterations to metabolic gene expression in the short term.
Microvascular Endothelial Dysfunction in Obstructive Sleep Apnea Is Caused by Oxidative Stress and Improved by Continuous Positive Airway Pressure Therapy
Authors: Büchner Nikolaus J. , Quack Ivo , Woznowski Magdalena , Stähle Constanze , Wenzel Ulrich , Rump Lars C.
Published: February 2011

Background: Endothelial dysfunction has recently been demonstrated in obstructive sleep apnea (OSA), but the underlying mechanisms are not entirely understood. Oxidative stress is a typical feature of OSA. Objectives: We investigated the influence of oxidative stress and continuous positive airway pressure (CPAP) on microvascular endothelial function in OSA. Methods: Endothelial function of forearm resistance vessels was assessed by strain gauge venous occlusion plethysmography after intra-arterial infusion of the endothelium-independent vasodilator sodium nitroprusside (1.6, 3.2, and 4.0 µg/min) and the endothelium-dependent vasodilator acetylcholine (Ach, 15, 30 and 40 µg/min) in patients with (n = 11) and without (n = 8) OSA (apnea-hypopnea index ≧15/h). These measurements have been repeated after local intra-arterial infusion of the antioxidant vitamin C (25 µg/min). Furthermore, 6 patients have been reevaluated after 6 months of OSA treatment. Results: Patients with OSA demonstrated impaired endothelial function compared to those without OSA. Thus, related to baseline flow, the increase in forearm blood flow induced by Ach was blunted in patients with OSA (148.7 ± 29.7% in OSA vs. 233.6 ± 45.7% in controls, p = 0.001). This difference, however, was abolished by co-infusion of vitamin C. Endothelial function markedly improved following treatment in 5 of 6 OSA patients. Conclusions: This study strongly suggests that microvascular endothelial function is affected by OSA predominantly through increased oxidative stress, and treatment of OSA may improve endothelial function mainly by reducing oxidative stress. The role of oxidative stress-induced endothelial dysfunction as a potential promoter of atherosclerosis and an increased cardiovascular risk in patients with OSA should be investigated in further controlled studies.
Psychological Stress and Psychosomatic Treatment: Major Impact on Serious Blood Disorders?
Authors: Gramotnev Dmitri K. , Gramotnev Galina
Published: February 2011

Objective: To demonstrate evidence of possible major impacts of psychological stress and psychosomatic interventions on myeloproliferative blood disorders and develop new approaches for the unification and quantified analysis of stress and psychosomatic treatments. Methods: This 3.5- year longitudinal study was based upon the regular blood tests of a person with myelofibrosis who experienced severe and repeated work-related psychological stress and was subjected to psychosomatic treatment in the form of regular (∼4 h per day) self-hypnosis sessions. Statistical data analysis was conducted on the basis of an introduced concept of generalized stress that mathematically unifies psychological stress and psychosomatic treatment. Results: Severe stress and psychosomatic treatment were statistically shown to have a major (dominant) impact on blood platelet counts well described by an exponential dependence on cumulative levels of generalized stress. The typical relaxation time for the impacts of both stress and treatment was shown to be ∼2 months. Only ∼12% of the total variation in platelet counts could be attributed to factors other than psychological stress and psychosomatic treatment. The psychosomatic intervention resulted in a consistent reduction of high platelet counts from ∼1,400 × 109 l–1 to approximately the middle of the normal range, with other blood parameters being either approximately stable or showing indications of a strengthening immune system. Conclusions: Our findings give hope for a possible development of psychosomatic treatments of at least some blood disorders. They also indicate a highly instrumental role of platelets in the quantified analysis of stress, psychosomatic interventions, and their neuroimmunological pathways.
Long-Term Resistance Training Is Associated with Reduced Circulating Levels of IL-6, IFN-Gamma and TNF-Alpha in Elderly Women
Authors: Córdova Claudio , Lopes-e-Silva, Jr. Fernando , Pires Alause S. , Souza Vinícius C. , Brito Ciro J. , Moraes Clayton F. , Sposito Andrei C. , Nóbrega Otávio T.
Published: February 2011

Objective: The increase in inflammatory activity associated with aging is a characteristic of chronic disease processes that accounts for most of the mortality in the elderly. Resistance training (RT) has been shown to promote metabolic and functional benefits in this population. The objective of this study was to investigate the association between long-term RT and circulating levels of the proinflammatory mediators IL-6, TNF-α and IFN-γ in elderly women. Methods: This cross-sectional study included 54 older outpatients divided into a group that underwent RT (n = 28) for an average of 8.6 ± 0.3 months and a sedentary group (n = 26). Measurements were taken only at the end of the intervention, and cytokine values were log-transformed. Dietary intake was controlled as a confounding factor. Results: The RT group presented reduced levels of log10IFN-γ (approx. 45%; p = 0.003), log10IL-6 (approx. 30%; p = 0.002) and log10TNF-α (approx. 22%; p = 0.036). Total caloric intake and systolic arterial blood pressure were significantly lower in the RT group (p = 0.001 and p = 0.022, respectively). Pearson’s product moment correlation test revealed a negative association between the fat-free mass (FFM) index and log-transformed IL-6 levels (p = 0.03; n = 54) and a trend towards significance for the correlation between the FFM index and log10IFN-γ (p = 0.05; n = 54). Conclusion: Long-term, moderate-intensity RT in elderly women is associated with lower circulating levels of cytokines that are potentially implicated in disorders associated with physical inactivity and aging.
Lung Sequestration: A Rare Cause for Pulmonary Symptoms in Adulthood
Authors: Gompelmann Daniela , Eberhardt Ralf , Heuβel Claus-Peter , Hoffmann Hans , Dienemann Hendrik , Schuhmann Maren , Böckler Dittmar , Schnabel Philipp A. , Warth Arne , Lopez-Benitez Ruben , Herth Felix J.F.
Published: February 2011

Background: Lung sequestration is a rare congenital pulmonary disorder and is usually diagnosed in children with recurrent pulmonary infections. Lung sequestrations are not commonly found to be a cause of respiratory symptoms in adults. Objectives: It was the aim of this study to show that pulmonary sequestration is rare in advanced age and can be accompanied by severe pulmonary symptoms. Methods: We conducted a case series analysis of patient characteristics, symptoms, diagnosis and treatment of 11 adults with a lung sequestration at the Thoraxklinik Heidelberg between 2001 and 2009. Results: From 2001 to 2009, intralobar lung sequestration was diagnosed and treated in 11 adults aged 19 to 58 years with an average age of 39.9 ± 11.3 years and a male:female distribution of 5:6. In 3 patients (27.3%), the predominant symptom was hemoptysis. Recurrent pulmonary infections occurred in 1 patient (9.1%); pneumonia and lung abscess were detected in 2 patients (18.2%). In 3 cases (27.3%), dry cough was the predominant symptom, and in only 2 cases (18.2%), lung sequestration was asymptomatic. Eight patients (72.7%) were diagnosed by imaging techniques prior to surgery. In 3 cases (27.3%), diagnosis was made intraoperatively and by pathological examination. Surgical intervention included 7 lobectomies (63.6%), 3 wedge resections (27.3%) and 1 (9.1%) segmentectomy. Conclusion: Lung sequestration in adults is rare, but it can cause severe pulmonary symptoms. In cases of recurrent pulmonary infections of identical localization or recurrent hemoptysis, lung sequestration should be considered in order for the diagnosis to be made rapidly. Surgical resection is the treatment of choice.
Nuclear Receptor Coactivators Are Coexpressed with Steroid Receptors and Regulated by Estradiol in Mouse Brain
Authors: Tognoni Christina M. , Chadwick, Jr. Joseph G. , Ackeifi Courtney A. , Tetel Marc J.
Published: February 2011

Background/Aims: The steroid hormones, including estradiol (E) and progesterone, act in the brain to regulate female reproductive behavior and physiology. These hormones mediate many of their biological effects by binding to their respective intracellular receptors. The receptors for estrogens (ER) and progestins (PR) interact with nuclear receptor coactivators to initiate transcription of steroid-responsive genes. Work from our laboratory and others reveals that nuclear receptor coactivators, including steroid receptor coactivator-1 (SRC-1) and SRC-2, function in brain to modulate ER-mediated induction of the PR gene and hormone-dependent behaviors. In order for steroid receptors and coactivators to function together, both must be expressed in the same cells. Methods: Triple-label immunofluorescence was used to determine if E-induced PR cells also express SRC-1 or SRC-2 in reproductively relevant brain regions of the female mouse. Results: The majority of E-induced PR cells in the medial preoptic area (61%), ventromedial nucleus of the hypothalamus (63%) and arcuate nucleus (76%) coexpressed both SRC-1 and SRC-2. A smaller proportion of PR cells expressed either SRC-1 or SRC-2, while a few PR cells expressed neither coactivator. In addition, compared to control animals, 17β-estradiol benzoate (EB) treatment increased SRC-1 levels in the arcuate nucleus, but not the medial preoptic area or the ventromedial nucleus of the hypothalamus. EB did not alter SRC-2 expression in any of the three brain regions analyzed. Conclusions: Taken together, the present findings identify a population of cells in which steroid receptors and nuclear receptor coactivators may interact to modulate steroid sensitivity in brain and regulate hormone-dependent behaviors in female mice. Given that cell culture studies reveal that SRC-1 and SRC-2 can mediate distinct steroid-signaling pathways, the present findings suggest that steroids can produce a variety of complex responses in these specialized brain cells.
Roles of Prostaglandin E
2
–EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation
Authors: Hosono Kanako , Suzuki Tatsunori , Tamaki Hideaki , Sakagami Hiroyuki , Hayashi Izumi , Narumiya Shuh , Alitalo Kari , Majima Masataka
Published: February 2011

Objective—

One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE
2
receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation.

Methods and Results—

Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE
2
enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate–dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE
2
. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts.

Conclusion—

Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.
Abdominal Aortic Aneurysm Growth Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide
Authors: Richards Jennifer M.J. , Semple Scott I. , MacGillivray Thomas J. , Gray Calum , Langrish Jeremy P. , Williams Michelle , Dweck Marc , Wallace William , McKillop Graham , Chalmers Roderick T.A. , Garden O. James , Newby David E.
Published: February 2011

Background—

Abdominal aortic aneurysms are a major cause of death. Prediction of aneurysm expansion and rupture is challenging and currently relies on the simple measure of aneurysm diameter. Using MRI, we aimed to assess whether areas of cellular inflammation correlated with the rate of abdominal aortic aneurysm expansion.

Methods and Results—

Stable patients (n=29; 27 male; age, 70±5 years) with asymptomatic abdominal aortic aneurysms (4.0 to 6.6 cm) were recruited from a surveillance program and imaged using a 3-T MRI scanner before and 24 to 36 hours after administration of ultrasmall superparamagnetic particles of iron oxide (USPIO). The change in T2* value on T2*-weighted imaging was used to detect accumulation of USPIO within the abdominal aortic aneurysm. Histological examination of aneurysm tissue confirmed colocalization and uptake of USPIO in areas with macrophage infiltration. Patients with distinct mural uptake of USPIO had a 3-fold higher growth rate (n=11, 0.66 cm/y;
P
=0.020) than those with no (n=6, 0.22 cm/y) or nonspecific USPIO uptake (n=8, 0.24 cm/y) despite having similar aneurysm diameters (5.4±0.6, 5.1±0.5, and 5.0±0.5 cm, respectively;
P
>0.05). In 1 patient with an inflammatory aneurysm, there was a strong and widespread uptake of USPIO extending beyond the aortic wall.

Conclusions—

Uptake of USPIO in abdominal aortic aneurysms identifies cellular inflammation and appears to distinguish those patients with more rapidly progressive abdominal aortic aneurysm expansion. This technique holds major promise as a new method of risk-stratifying patients with abdominal aortic aneurysms that extends beyond the simple anatomic measure of aneurysm diameter.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00794092.
Mortality Implications of Primary Percutaneous Coronary Intervention Treatment Delays: Insights From the Assessment of Pexelizumab in Acute Myocardial Infarction Trial
Authors: Hudson Michael P. , Armstrong Paul W. , O'Neil William W. , Stebbins Amanda L. , Weaver W. Douglas , Widimsky Petr , Aylward Philip E. , Ruzyllo Witold , Holmes David , Mahaffey Kenneth W. , Granger Christopher B.
Published: February 2011

Background—

Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI.

Methods and Results—

We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively,
P
<0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively,
P
<0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (χ
2
6.0,
P
<0.014), and symptom onset-to-hospital arrival (χ
2
9.8,
P
<0.007) remained independent determinants.

Conclusions—

Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00091637.
Use of a Screening Tool Improves Appropriate Referral to an Electrophysiologist for Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death
Authors: Gravelin Laura M. , Yuhas Jennifer , Remetz Michael , Radford Martha , Foley John , Lampert Rachel
Published: February 2011

Background—

Despite data showing the benefits of implantable cardioverter-defibrillator (ICD) insertion for primary prevention in populations at risk for sudden death, professional society guidelines recommending primary prevention, and recognition by payers of the clinical value of ICDs in these populations, ICDs for primary prevention remain underused. We sought to determine whether implementing a screening tool would increase appropriate identification of patients showing clinical evidence of ICD benefit and prompt referral to an electrophysiologist for ICD implantation.

Methods and Results—

Screening tools were affixed to medical records for patients seen in 2 outpatient cardiology offices that queried ejection fraction and whether referral to an electrophysiologist was made (N=6632). The number of appropriate referrals in the screening period were compared with analogous data collected before implementation of the screening tool (control period) through retrospective record review (n=3606). Significantly more eligible patients were offered referral during the screening period than during the control period at both sites, 80% (8/10 eligible) versus 33% (5/15) at site 1 (
P
<0.02) and 100% (44/44) versus 60% (21/35) at site 2 (
P
<0.001). Of all patients offered referral, 41% (32/78) accepted.

Conclusions—

The use of a screening tool increases referral to electrophysiology for patients in whom placement of an ICD confers the benefit of sudden cardiac death primary prevention. Barriers to referral include both physician and patient factors. Verification of these findings on a larger scale as well as studies defining the foundation of these barriers may further improve use of ICDs in patients for whom their mortality benefit is well described.
Extent of and Reasons for Nonuse of Implantable Cardioverter Defibrillator Devices in Clinical Practice Among Eligible Patients With Left Ventricular Systolic Dysfunction
Authors: Allen LaPointe Nancy M. , Al-Khatib Sana M. , Piccini Jonathan P. , Atwater Brett D. , Honeycutt Emily , Thomas Kevin , Shah Bimal R. , Zimmer Louise O. , Sanders Gillian , Peterson Eric D.
Published: February 2011

Background—

Several studies that used claims and registry data have reported that 40% to 80% of patients eligible for an implantable cardioverter defibrillator (ICD) fail to receive one in clinical practice, and the rates are especially high among women and blacks. The extent and documented reasons for nonuse of ICDs among patients with left ventricular systolic dysfunction are unknown.

Methods and Results—

Using hospital claims and clinical data, we identified patients hospitalized with a heart failure diagnosis and left ventricular ejection fraction ≤30% between January 1, 2007, and August 30, 2007, at a tertiary-care center. Using claims data, we determined placement of an ICD or cardiac resynchronization therapy with defibrillation device at any time up to 1 year after hospitalization. Medical records for patients without an ICD were abstracted to determine reasons for nonuse. Patients with an ICD were compared with patients without an ICD and also with patients without an ICD who did not have any contraindication for an ICD as identified through chart abstraction. Of the 542 potentially eligible patients identified, 224 (41%) did not have an ICD. In the initial adjusted analysis, female sex (odds ratio=1.90; 95% CI, 1.28 to 2.81) and increasing age (odds ratio=1.07; 95% CI, 1.04 to 1.11) were associated with a higher likelihood of not having an ICD. After detailed chart review, of the 224 patients without an ICD, 117 (52%) were ineligible for the device and 38 (17%) patients refused the device, resulting in only 69 (13%) patients eligible for an ICD who failed to receive one. In this subsequent adjusted analysis, remaining factors associated with a higher likelihood of not having an ICD were absence of ventricular arrhythmias (odds ratio=4.93; 95% CI, 2.56 to 9.50), noncardiology hospital service (odds ratio=3.73; 95% CI, 1.98 to 7.04), and lack of health insurance (odds ratio=3.10; 95% CI, 1.48 to 6.46).

Conclusions—

On the basis of a detailed chart review, the true rate of ICD underuse may be substantially lower than previous estimates. In addition, after accounting for ICD eligibility criteria, patient sex and age disparities in ICD therapy were no longer present.
Low Serum Homoarginine Is a Novel Risk Factor for Fatal Strokes in Patients Undergoing Coronary Angiography
Authors: Pilz Stefan , Tomaschitz Andreas , Meinitzer Andreas , Drechsler Christiane , Ritz Eberhard , Krane Vera , Wanner Christoph , Böhm Bernhard O. , März Winfried
Published: February 2011

Background and Purpose—

Low serum concentrations of the amino acid homoarginine have been associated with endothelial dysfunction and an increased risk of all-cause and cardiovascular mortality. We aimed to investigate whether homoarginine levels are also associated with fatal strokes and a history of nonfatal cerebrovascular disease.

Methods—

Serum homoarginine was measured in 3305 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline (1997 to 2000) and were followed up with respect to mortality.

Results—

During a median follow-up time of 9.9 years, 991 patients died including 61 fatal (ischemic and hemorrhagic) strokes. In a binary logistic regression analysis, the odds ratio (with 95% CI) for fatal stroke per SD of homoarginine was 0.52 (0.37 to 0.73;
P
<0.001) and remained significant after multivariable adjustments (0.62 [0.42 to 0.91];
P
=0.014). For previous cerebrovascular disease events, the multivariable adjusted OR per SD of homoarginine was 0.82 (0.70 to 0.96;
P
=0.014).

Conclusions—

Low homoarginine levels are a novel risk factor for fatal strokes and are reduced in patients with a history of cerebrovascular disease. Further studies are needed to explore the significance of homoarginine to risk stratification and therapeutic approaches in the prevention of strokes.
Eulerian and Lagrangian Statistics from Surface Drifters and a High-Resolution POP Simulation in the North Atlantic
Authors: McClean Julie L. , Poulain Pierre-Marie , Pelton Jimmy W. , Maltrud Mathew E.
Published: February 2011

Eulerian and Lagrangian statistics were calculated from the North Atlantic surface drifter dataset for the years 1993–97 and a high-resolution eddy-resolving configuration of the Los Alamos National Laboratory (LANL) Parallel Ocean Program (POP) model. The main purpose of the study was to statistically quantify the state of the surface circulation in the North Atlantic Ocean for this period and compare it with the equivalent modeled state. Diffusivities and time and length scales are anisotropic over most of the ocean basin, except in most of the subpolar regions. Typical time and length scales are 2–4 days and 20–50 km. Longest timescales are found in the energetically quiescent regions in the south and southeast sectors of the basin. The longest length scales are found in the energetic western boundary current system, the most dispersive region of the domain. In many respects the eddy-resolving model reproduced a surface circulation in good statistical agreement with that depicted by the drifters. Model time and length scales were also anisotropic, with typical timescales of 2–4 days and length scales of 20–50 km in the zonal direction, and 30–50 km in the meridional direction. An eddy-permitting POP simulation produced unrealistic time and length scales that were too long and too short relative to the drifter scales; these were attributed to the model being too stable hydrodynamically.
“Teddies” and the Origin of the Leeuwin Current
Authors: Nof Doron , Pichevin Thierry , Sprintall Janet
Published: February 2011

The outflow from the Indonesian seas empties approximately 5–7 Sv of surface warm (and low salinity) Indonesian Throughflow water into the southern Indian Ocean (at roughly 12°S). Using a nonlinear 1½-layer model with a simple geometry consisting of a point source (of anomalous water) situated along a meridional wall on a β plane, the spreading of these waters is examined. An analytical solution is constructed with the aid of the “slowly varying” approach, and process-oriented numerical simulations are performed.

It is found that, immediately after emptying into the ocean, the outflow splits into two branches. One branch carries approximately 13% of the source mass flux and forms a chain of high amplitude anticyclonic eddies (lenses) immediately to the west of the source. These eddies drift westward and penetrate into the interior of the Indian Ocean. The second branch carries the remaining 87% of the mass flux via a coastal southward flowing current. Ultimately, this second branch separates from the coast and turns westward. (A detailed examination of this second branch separation is, nevertheless, beyond the scope of this study.)

It is suggested that the eddies recently observed to the west of the Island of Timor are a result of the above eddy generation process, which is not related to the classical eddy generation process associated with instabilities (i.e., the breakdown of a known steady solution). It is also suggested that this new nonlinear process explains why some of the Indonesian Throughflow water forms the source of the southward flowing coastal Leeuwin Current.
The Simulation of the Southern Great Plains Nocturnal Boundary Layer and the Low-Level Jet with a High-Resolution Mesoscale Atmospheric Model
Authors: Werth David , Kurzeja Robert , Dias Nelson Luís , Zhang Gengsheng , Duarte Henrique , Fischer Marc , Parker Matthew , Leclerc Monique
Published: February 2011

A field project over the Atmospheric Radiation Measurement–Cloud and Radiation Test Bed (ARM–CART) site during a period of several nights in September 2007 was conducted to explore the evolution of the low-level jet (LLJ). Data were collected from in situ (a multilevel tower) and remote (sodar) sensors, and the observed LLJ activity during the project was found to agree well with data from earlier studies regarding jet speed, height, and direction. To study nocturnal boundary layer (NBL) behavior, the Regional Atmospheric Modeling System was used to simulate the ARM–CART NBL field experiment and was validated against the data collected from the site. This model was run at high resolution for calculating the interactions among the various motions within the boundary layer and their influence on the surface. The model faithfully simulated the formation and dissolution of the low-level nocturnal jet during a synoptic situation in which low pressure with warm southerly advection replaced high pressure. An additional simulation at 32.5-m resolution was performed for the most stable 5.5-h period, using a turbulence scheme adjusted to allow for greater resolved turbulent kinetic energy, and the model reproduced the turbulence statistics as determined by a power spectrum. The benefit of the high-resolution simulation is evident in the much more realistically resolved model turbulent kinetic energy and the fluxes of momentum, heat, and water vapor.
Dominant Mode of Climate Variability, Intermodel Diversity, and Projected Future Changes over the Summertime Western North Pacific Simulated in the CMIP3 Models
Authors: Kosaka Yu , Nakamura Hisashi
Published: February 2011

A set of multimodel twentieth-century climate simulations for phase 3 of the Coupled Model Intercomparison Project (CMIP3) is analyzed to assess the model reproducibility of the Pacific–Japan (PJ) teleconnection pattern. It is the dominant low-frequency anomaly pattern over the summertime western North Pacific (WNP), characterized by a meridional dipole of zonally elongated vorticity anomalies in the lower troposphere and by anomalous precipitation over the tropical WNP. Most of the models can reproduce the PJ pattern reasonably well as one of the leading anomaly patterns or their combination. The model reproducibility of the pattern tends to be higher for those models in which the climatological-mean state over the WNP is better reproduced. Furthermore, intermodel diversity in the summertime climatological-mean fields over the WNP, especially in the lower troposphere, is found to be large and projected most strongly onto the observed PJ pattern. Nevertheless, the multimodel ensemble (MME) mean of these climatological-mean states is close to the observations.

Projected future changes in the summertime climatological-mean state under the Intergovernmental Panel on Climate Change’s (IPCC) Special Report on Emission Scenarios (SRES) A1B also bear certain similarities with the PJ pattern, in a manner consistent with the aforementioned sensitivity of the model climate to that pattern. The MME projection indicates an overall increase in precipitation over the entire tropics, but it is overwhelmed locally by the effects of the enhanced tropospheric stratification over the tropical WNP. A resultant local reduction of the mean ascent is dynamically consistent with the anticyclonic projection around the Philippines and the cyclonic projection around Japan in MME, as in the observed anomalous dipole associated with the PJ pattern. However, the polarity and magnitude of the PJ-like projected change vary substantially from one model to another.
Simulated Response to Recent Freshwater Flux Change over the Gulf Stream and Its Extension: Coupled Ocean–Atmosphere Adjustment and Atlantic–Pacific Teleconnection
Authors: Zhang Liping , Wu Lixin , Zhang Jiaxu
Published: February 2011

Recent observation has shown that the dominant mode of the net freshwater flux variations over the North Atlantic Ocean is the significant trend of freshwater loss over the Gulf Stream region and its extension. In this paper, the coupled ocean–atmosphere response to this freshwater flux change is investigated based on a series of the Fast Ocean–Atmosphere Model coupled-model experiments. The model demonstrates that the freshwater loss over the Gulf Stream and its extension region directly forces an anomalous cyclonic gyre and triggers a SST dipole with cooling in the western subtropical and warming in the eastern subpolar North Atlantic. The freshwater loss also forces a significant response in the atmosphere with a negative NAO-like response in early winter and a basin-scale ridge resembling the eastern Atlantic mode (EAM) in late winter. The salinification also strengthens the Atlantic meridional overturning circulation and thus the poleward heat transport, leading to tropical cooling.

The freshwater loss over the Gulf Stream and its extension also leads to an El Niño–like warming in the tropical Pacific and cooling in the North Pacific, similar to the responses in previous water-hosing experiments with an input of freshwater in the subpolar North Atlantic. The tropical Pacific responses subsequently strengthen the Northern Hemispheric atmospheric anomalies in early winter, but reverse them in late winter through an emanation of Rossby wave trains. Overall, the tropical Pacific air–sea coupling plays a damping role, while local air–sea coupling tends to enhance the ocean and atmospheric responses over the North Atlantic.