bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination Chemoprevention of HER2/neu-Induced Breast Cancer Using a Cyclooxygenase-2 Inhibitor and a Retinoid X Receptor–Selective Retinoid
Authors: Brown Powel H. , Subbaramaiah Kotha , Salmon Amoi P. , Baker Rebecca , Newman Robert A. , Yang Peiying , Zhou Xi Kathy , Bissonnette Reid P. , Dannenberg Andrew J. , Howe Louise R.
Published: July 2008

The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in ∼40% of human breast carcinomas and in precancerous breast lesions, particularly in association with overexpression of human epidermal growth factor receptor 2 (HER2/neu). Experimental breast cancer can be suppressed by pharmacologic inhibition or genetic ablation of Cox-2, suggesting potential clinical utility of COX-2 inhibitors with respect to breast cancer. Importantly, several clinical trials have found reduced colorectal adenoma formation in individuals administered selective COX-2 inhibitors. However, such trials also identified increased cardiovascular risk associated with COX-2 inhibitor use. The goal of this research was to test whether improved chemopreventive efficacy could be achieved by combining submaximal doses of a selective COX-2 inhibitor and a retinoid X receptor–selective retinoid (rexinoid). The rate of HER2/neu-induced mammary tumor formation was substantially delayed by coadministration of the COX-2 inhibitor celecoxib (500 ppm in diet) and the rexinoid LGD1069 (10 mg/kg body weight; oral gavage) to MMTV/neu mice. Median time to tumor formation was increased from 304 to >600 days (P < 0.0001). The combination was substantially more effective than either drug individually. Similarly, potent suppression of aromatase activity was observed in mammary tissues from the combination cohort (44% of control; P < 0.001). Regulation of aromatase expression and activity by COX-derived prostaglandins is well established. Interestingly however, single agent LGD1069 significantly reduced mammary aromatase activity (71% of control; P < 0.001) without modulating eicosanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor–dependent transcription confers potent anticancer efficacy, suggesting a novel avenue for clinical evaluation.
Epidermal Growth Factor Receptor Abnormalities in the Pathogenesis and Progression of Lung Adenocarcinomas
Authors: Tang Ximing , Varella-Garcia Marileila , Xavier Ana C. , Massarelli Erminia , Ozburn Natalie , Moran Cesar , Wistuba Ignacio I.
Published: July 2008

To identify the characteristics and sequence of epidermal growth factor receptor (EGFR) abnormalities relevant to the pathogenesis and progression of lung adenocarcinoma, we performed a precise mapping analysis of EGFR mutation, gene copy number, and total and phosphorylated EGFR protein expression for the same tissue sites. We examined normal bronchial and bronchiolar epithelium (NBE) and tumor tissues obtained from 50 formalin-fixed lung adenocarcinomas, including 24 EGFR-mutant primary tumors with nine corresponding lymph node metastases and 26 wild-type primary tumors. NBE in 12 of 24 (50%) mutant and 3 of 26 (12%) wild-type tumors harbored EGFR mutations; these NBE also showed a lack of EGFR copy number increase and frequent EGFR (69%) and phosphorylated EGFR (33%) overexpression. EGFR mutation and protein overexpression were more frequent in NBE sites within tumors than in NBE sites adjacent to and distant from tumors, suggesting a localized field effect. Sites with high and low EGFR copy numbers were heterogeneously distributed in six of nine primary tumors and in one of eight metastases. EGFR protein overexpression was significantly higher in metastasis sites than in primary tumors. We conclude from our findings that EGFR mutations and protein overexpression are early phenomena in the pathogenesis of lung adenocarcinoma and that EGFR mutation precedes an increase in gene copy number. In EGFR-mutant adenocarcinoma metastases, the higher levels of EGFR overexpression and more homogeneously distributed high gene copy numbers suggest tumor progression. Our findings have important implications for the development of new strategies for targeted chemoprevention and therapy in lung adenocarcinoma using EGFR inhibitors.
The Untapped Potential of Genetically Engineered Mouse Models in Chemoprevention Research: Opportunities and Challenges
Authors: Abate-Shen Cory , Brown Powel H. , Colburn Nancy H. , Gerner Eugene W. , Green Jeffery E. , Lipkin Martin , Nelson William G. , Threadgill David
Published: July 2008

The past decade has witnessed the unveiling of a powerful new generation of genetically engineered mouse (GEM) models of human cancer, which are proving to be highly effective for elucidating cancer mechanisms and interrogating novel experimental therapeutics. This new generation of GEM models are well suited for chemoprevention research, particularly for investigating progressive stages of carcinogenesis, identifying biomarkers for early detection and intervention, and preclinical assessment of novel agents or combinations of agents. Here we discuss opportunities and challenges for the application of GEM models in prevention research, as well as strategies to maximize their relevance for human cancer.
Graft Duodenal Perforation due to Internal Hernia after Simultaneous Pancreas-Kidney Transplantation: Report of a Case
Authors: Fumimoto Yuichi , Tanemura Masahiro , Hoshida Yoshihiko , Nishida Toshirou , Sawa Yoshiki , Ito Toshinori
Published: July 2008

Although complications including graft thrombosis, graft pancreatitis, and rejection have been well documented after pancreas transplantation, the occurrence of graft duodenal perforation is uncommon. In this article, we report a case of graft duodenal perforation due to internal hernia after simultaneous pancreas-kidney transplantation (SPK). A patient with type I diabetes mellitus and diabetic nephropathy had undergone SPK from a cadaveric donor. One year later, she was admitted to our hospital for severe lower abdominal pain with preshock status. She was immediately examined by abdominal computed tomography and both peripancreas graft fluid accumulation and severe dilatation of the ileum were detected. On emergency operation, two punched holes located at the graft duodenal side near the suture line and an obstruction of herniated bowel behind the graft pancreas were detected. These holes were repaired and the internal hernia was reduced. However, a control of the intraabdominal infection was very difficult despite intensive treatment with antibiotics and additional abdominal drainage. Finally, a graft pancreatectomy was unavoidably required. When complications, including symptomatic intraabdominal infection, require re-laparotomy after pancreas transplantation, the therapeutic focus should be switched from salvaging the graft to the preservation of life.
Acute Hepatitis A-Associated Acute Renal Failure in Adults
Authors: Kim Su Hyun , Yoon Hye Eun , Kim Yong Kyun , Kim Jin Young , Choi Bum Soon , Choi Young Jin , Kim Young Ok , Kim Yong Soo , Bang Byung Kee , Yang Chul Woo
Published: July 2008

Background/Aims: The development of acute renal failure (ARF) is a very rare complication in patients with acute hepatitis A (AHA). Methods: We retrospectively investigated the overall incidence, risk factors, and clinical outcomes of ARF associated with AHA. Diagnosis of AHA was made according to the typical hepatitis symptoms and positivity of immunoglobulin M anti-hepatitis A virus in 208 patients with AHA. Results: ARF was noted in 12 (5.7%) patients, and dialysis was required in 8 (66%) patients. The median duration of hospitalization for patients with ARF was 18 days (range, 6–50 days). The development of ARF was observed in older patients (p = 0.004) and in patients with diabetes (p = 0.001), excessive alcohol consumption (p = 0.01), prolonged international normalized ratio (p = 0.019), and elevated aspartate aminotransferase concentration (p = 0.034). Multivariate analysis revealed that old age (odds ratio, OR, 1.2), elevated aspartate aminotransferase concentration (OR, 1.05), and diabetes (OR, 18.5) were independent risk factors for ARF (each p < 0.001). The prognosis of patients with ARF was good, and renal function recovered completely. Conclusion: ARF associated with AHA is not rare, and the possibility of AHA should be considered in patients with ARF with hepatic dysfunction.
Improvement of Periodic Limb Movements following Kidney Transplantation
Authors: Beecroft Jaime M. , Zaltzman Jeffery , Prasad G.V. Ramesh , Meliton Galo , Hanly Patrick J.
Published: July 2008

Background/Aims: Periodic limb movements are common in patients with end-stage renal disease. Kidney transplantation significantly improves renal function and may therefore reduce periodic limb movements. We evaluated the effect of kidney transplantation on periodic limb movements in a group of patients with end-stage renal disease. Methods: Eighteen patients (aged 27–65) who were receiving dialysis and were candidates for living donor or deceased donor kidney transplantation (n = 12) or were predialysis with a suitable living donor arranged (n = 6) were recruited from the transplant clinic. Attended overnight polysomnography was performed before and after kidney transplantation. Patients were divided based on a periodic limb movement index >15 events/h during sleep. Results: Kidney transplantation was associated with a significant reduction in periodic limb movement index in all patients (8 (0–110) events/h vs. 2 (0–80) events/h) and this reduction was greatest in 7 patients with a periodic limb movement index >15 events/h (40 (24–110) events/h to 14 (1–80) events/h, p < 0.005). Conclusion: Successful kidney transplantation improves periodic limb movements in patients with end-stage renal disease. This may improve sleep quality and sleep-related quality of life in kidney transplant recipients, which should have a beneficial impact on clinical outcomes.
Validation of the Virga GFR Equation in a Renal Transplant Population
Authors: Zahran Ahmed , Hossain Mohammad Akhtar , Kora Mahmoud Abd Elaziz , Galal Ali Zaki , Shoker Ahmed
Published: July 2008

Background: Virga and colleagues derived a glomerular filtration rate (GFR) equation which demonstrated a superior performance over Cockcroft-Gault (C-G) and modified diet in renal disease-isotope dilution mass spectrometry (MDRD-IDMS) formulas in chronic kidney disease (CKD) patients. Aim: To validate the performance of the Virga equation on 103 renal transplant patients. Methods: We compared the performances of the MDRD-IDMS, C-G and Virga equations using inulin clearance as a reference test. Error, accuracy, relative accuracy, precision, scatter, and coefficient of variance of each equation were tested. Results: The mean absolute percentage error in estimated GFR by the new equation was 39.8 ± 36.34% (mean ± SD). Relative accuracy at 10, 30 and 50% range were 18.44, 48.54 and 73.78%, respectively. It has a bias of 0.09 ± 0.169 and a precision of 19.69. Inulin clearance (GFR) in stages 1–4 were 106.19 ± 14.11, 71.17 ± 7, 42.37 ± 8.40 and 22.92 ± 3.48 ml/min/1.73 m2, respectively. Comparative statistics in the overall population and in patients with transplant CKD stage 3T showed that the MDRD-IDMS equation had better accuracy. The performance of MDRD-IDMS over the Virga equation was clearly superior for males. In patients with CKD stage 2T, the Virga equation showed superiority over MDRD-IDMS. In the overall and subpopulations, the Virga equation performed better than the C-G equation. Conclusion: Among renal transplant patients, the results suggest that the best GFR estimate is probably obtained using the MDRD-IDMS equation in moderate kidney failure whilst the Virga formula was superior to MDRD-IDMS for patients with mild kidney failure. As in untransplanted patients, estimating GFR with the MDRD-IDMS equation is not advisable in the range of normal renal function because of its known underestimation of renal function.
Effect of Membrane Flux and Dialyzer Biocompatibility on Survival in End-Stage Diabetic Nephropathy
Authors: Götz Angela K. , Böger Carsten A. , Popal Massoud , Banas Bernhard , Krämer Bernhard K.
Published: July 2008

Aims: We examined the effects of dialyzer membrane flux and biocompatibility on mortality in diabetic dialysis patients. Methods: We enrolled 402 prevalent chronic hemodialysis patients from 30 centers in Germany in 1999 for a prospective observational study until 2003. We compared 2 groups in post hoc analysis: high-flux (HF, n = 166) versus low-flux (LF, n = 236) membrane, and high biocompatibility (HB, n = 300) versus low biocompatibility (LB, n = 102). All-cause mortality (ACM) was the primary endpoint. Death causes were the secondary endpoints. Results: Multivariate Cox regression analysis showed no significant difference in risk for ACM with respect to flux (hazard ratio, HR, 0.79; p = 0.08; ACM 63% in HF vs. 70% in LF dialysis) and biocompatibility level (HR 1.00; p = 0.98; ACM 67% for HB vs. 66% for LB). The multivariate analysis of different causes of death did not reveal any outcome differences dependent on flux and biocompatibility level apart from a slightly better cumulative survival regarding the death cause ‘infectious’ in our HF dialysis group (HR 0.48; p = 0.07, Kaplan-Meier analysis p = 0.03). Conclusion: Our data indicate that mortality of hemodialysis patients with type-2 diabetic nephropathy is influenced neither by dialyzer flux level nor by biocompatibility.
Should Adolescents with Glomerulopathies Be Treated as Children or Adults?
Authors: Requião-Moura Lúcio R. , Veras de S. Freitas Tainá , Franco Marcello F. , Pereira Aparecido B. , Mastroianni-Kirsztajn Gianna
Published: July 2008

Background: Glomerular diseases are an important cause of end-stage renal disease, especially among young adults. However, clinical and epidemiological surveys involving adolescent populations are scarce. Aim: To determine the pattern of glomerulopathies (GP) in adolescents submitted to renal biopsy. Methods: A retrospective study of patients’ records of the Glomerulopathy Section, UNIFESP (Brazil), was performed Results: Among 72 adolescents (12–18 years) with GP, 15.6 ± 1.5 years, 58.3% females, the most frequent clinical manifestation was nephrotic syndrome (NS, 71%) and focal segmental glomerulosclerosis (FSGS) was the main histological pattern (24%), followed by minimal change disease (MCD, 19.5%). After comparing the main causes of NS in adolescents with those of adults, we found no statistically significant differences in clinical presentation or outcome. Renal failure-free survival of 1 and 5 years for all GP corresponded to 87.9 and 73.6%, respectively (88.5 and 76.3% for NS). Conclusions: NS was the main manifestation; FSGS and MCD were the most common histological diagnoses. Our data suggest the GP and particularly the NS pattern in adolescents is similar to that of adults, pointing to the need for an adaptation in diagnostic and treatment protocols for this age group, a pattern which corresponds more closely to that of adults.
More Dietetic Time, Better Outcome?
Authors: Morey Belinda , Walker Rebecca , Davenport Andrew
Published: July 2008

Background/Aim: A randomized controlled trial was conducted involving 67 stable adult haemodialysis patients with hyperphosphataemia. The objective was to determine the effect of monthly dietetic consultations on patients’ serum phosphate concentrations and calcium × phosphate product. Methods: The intervention group received monthly dietetic consultations for 6 months using advanced counselling skills aimed at limiting phosphate intake in the diet and improving compliance with phosphate binders, whereas standard care with dietetic consultations every 6 months was provided to the control group. Results: Serum phosphate concentrations decreased in the intervention group from 2.05 ± 0.48 to 1.80 ± 0.48 mmol/l by month 3 (p < 0.05). However, this subsequently increased and by month 6 there was no significant difference from baseline. After controlling for confounding variables, the difference between the groups was approaching significance at month 3, but there was no difference by month 6, or following conclusion of the study. The calcium × phosphate product similarly decreased in both groups, achieving K/DOQI standards, but was not sustained either during the remainder of the study but decreased further by the 12-month follow-up and, although it was not significantly different, it did improve significantly from baseline in both the intervention and control groups. Conclusion: Increased frequency of dietetic consultations can result in improved phosphate control in the short term, and therefore more innovative strategies appear necessary to sustain longer-term control.
Role of Macrophage Migration Inhibition Factor in Kidney Disease
Authors: Lan Hui Y.
Published: July 2008

Macrophage migration inhibitory factor (MIF) has been shown to play a pathogenic role in kidney disease. This article will review the current understanding of the expression of MIF and its functional role in immune-mediated renal injury in both human and animal models of kidney disease. Upregulation of MIF is found in both human and experimental kidney disease including renal allograft rejection and contributes significantly to macrophage and T-cell accumulation and progressive renal injury. It is now clear that MIF is a stress factor, a pro-inflammatory cytokine, a growth factor and a hormone. MIF acts through many mechanisms to mediate renal injury including the innate and adaptive immune systems, the induction of cytokines, chemokines, adhesion molecules as well as interactions with glucocorticoids and the hypothalamic-pituitary-adrenal axis. MIF exerts its biological activities via signaling through its CD74/CD44 receptor complex to activate the downstream ERK1/2 MAP kinase. The functional importance of MIF in kidney disease is demonstrated by the findings that treatment with a neutralizing anti-MIF antibody is able to prevent or reverse renal injury in crescentic anti-GBM glomerulonephritis. In addition, mice null for MIF are protected against immune-mediated lupus nephritis. MIF plays a critical role in kidney diseases and further studies of the functional role and signaling mechanisms of MIF in human kidney diseases are needed.
Paricalcitol Treatment and Arterial Tone in Experimental Renal Insufficiency
Authors: Karavalakis Emmanouil , Eräranta Arttu , Vehmas Tuija I. , Koskela Jenni K. , Kööbi Peeter , Mustonen Jukka , Niemelä Onni , Rysä Jaana , Ruskoaho Heikki , Pörsti Ilkka
Published: July 2008

Aim: To examine whether treatment of secondary hyperparathyroidism with paricalcitol provides benefits to arteries in uremic rats. Methods: 5/6-nephrectomized rats were treated (NX+Pari) or not treated (NX) with paricalcitol (200 ng/kg, thrice weekly) for 12 weeks. Aortic histology and isolated segments of the main and 2nd-order mesenteric arterial branches were studied. Results: Creatinine clearance was reduced by 54–61%, plasma phosphate increased 2.1- to 2.5-fold, and blood pressure by 40 mm Hg in both NX groups. PTH increased 13-fold in NX and 5-fold in NX+Pari rats. Calcification in aortic cross-sections increased from 2.1 to 7.1% after paricalcitol. In the large mesenteric artery, vasoconstriction to noradrenaline was reduced in NX+Pari rats. In the large and small arteries, vasorelaxation to acetylcholine was impaired in NX rats and unaffected by paricalcitol. In the small artery, paricalcitol increased nitric oxide synthase inhibition-resistant relaxation to acetylcholine, and maximal relaxation to levcromakalim. The small arteries of NX rats featured increased wall cross-sectional area, while paricalcitol further increased wall thickness and the wall:lumen ratio. Conclusion: Paricalcitol treatment showed both benefits and harmful effects in uremic rats: in the large artery vasoconstriction was reduced but calcification increased, while in the small artery vasorelaxation via potassium channels was moderately improved but hypertrophic remodeling was aggravated.
Increased Acid Load and Deletion of AE1 Increase Slc26a7 Expression
Authors: Sun Xuming , Petrovic Snezana
Published: July 2008

Background/Aims: Slc26a7 is a member of a family of anion transport proteins, Solute-Linked Carrier 26 (Slc26). Slc26a7, which can mediate Cl–/HCO3– exchange, is expressed in the acid-secreting, A-intercalated cells of the kidney collecting duct. On the basolateral side of the A-intercalated cells, Slc26a7 co-localizes with the anion exchanger 1 (AE1), a Cl–/HCO3– exchanger that mediates bicarbonate reabsorption in the collecting duct. Methods: To test if Slc26a7 is involved in acid-base regulation, as its localization and function suggest, we examined the effect of acid loading and deletion of AE1 on Slc26a7 expression with quantitative real-time RT-PCR and Western blotting. Results: Four days of acid loading increased Slc26a7 mRNA expression in the kidney inner medulla by 57% (n = 6 acid loaded vs. n = 6 control rats; p < 0.001), whereas mRNA expression in the outer medulla and the cortex did not change. Western blotting analysis demonstrated increased Slc26a7 protein expression in both outer (140%) and inner medulla (50%) in acid-loaded animals (n = 3) compared to controls (n = 3; p < 0.05). The expression of Slc26a7 mRNA was increased by 66% in the kidneys of AE1 knockout mice (n = 5) compared to the wild types (n = 5, p < 0.001). The increase in Slc26a7 mRNA correlated with a twofold increase in protein expression (p < 0.05). Conclusion:We suggest that the increase in Slc26a7 expression caused by acid challenge and deletion of AE1 represents an adaptive response, indicating that Slc26a7 contributes to the regulation of acid-base balance by the kidney.
Altered Verbal Working Memory Process in Patients with Alzheimer’s Disease
Authors: Lim Hyun-Kook , Juh Rahyeong , Pae Chi-Un , Lee Byeong-Taek , Yoo Seung-Schik , Ryu Seung-Ho , Kwak Kyeong-Rin , Lee Chul , Lee Chang-Uk
Published: July 2008

Impaired working memory processing is one of the broad range of cognitive deficits in patients with Alzheimer’s disease (AD). We aimed to elucidate the differences in brain activities involved in the process of working memory between AD patients and healthy comparison subjects. Twelve patients with AD were recruited along with 12 healthy volunteers as a comparison group. Functional magnetic resonance imaging was employed to assess cortical activities during the performance of a 1-back working memory paradigm using the Korean alphabet as mnemonic content. Subsequently, the difference in neural activities between the 2 groups was analyzed. The AD group performed the tasks with reduced accuracy. Group comparison analysis revealed that the AD group showed decreased brain activity in the left frontal pole (Brodmann area, BA, 10), the left ventrolateral prefrontal cortex (BA47), the left insula (BA13) and the right premotor cortex (BA6) compared to the control group. The AD group showed increased activation in the left precuneus (BA7) compared to the control group. A decreased level of activation in the prefrontal cortex and an increased level of activation in the parietal neural networks from the patient group may document an altered verbal working memory process in the patients with AD.
Sugar Chains of Cerebrospinal Fluid Transferrin as a New Biological Marker of Alzheimer’s Disease
Authors: Taniguchi Miyako , Okayama Yuka , Hashimoto Yuki , Kitaura Miki , Jimbo Daiki , Wakutani Yosuke , Wada-Isoe Kenji , Nakashima Kenji , Akatsu Hiroyasu , Furukawa Katsutoshi , Arai Hiroyuki , Urakami Katsuya
Published: July 2008

Background/Aims: Alzheimer’s disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. Methods: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by lectin blotting using wheat germ agglutinin (WGA), and sugar chain analysis was performed by isoelectric focusing. Results: In Alzheimer’s CSF, several glycoproteins had lower WGA-binding activities, one of which was sufficiently sensitive and specific to distinguish AD from nondemented controls and other dementias. Further analysis identified this glycosylated protein as transferrin, and altered sugar chain composition of transferrin isoforms was observed despite normal protein levels in CSF. Conclusion: The decreased WGA-binding activity of transferrin in AD is probably due to altered glycosylation of transferrin molecules. Transferrin glycosylation is thus a potential biological marker for AD diagnosis, and changes in this glycosylation may play an important role in the pathophysiology of AD.
Establishing a Benchmark for Complications Using Frame-Based Stereotactic Surgery
Authors: Lunsford L. Dade , Niranjan Ajay , Khan Aftab A. , Kondziolka Douglas
Published: July 2008

We sought to establish a benchmark for complications using frame-based stereotactic surgery for both deep and lobar brain surgery. During a 28-year interval, we performed frame-based stereotactic surgery in 2,651 patients. Our database was retrospectively used to assess the risks of complications after frame-based stereotactic surgery.Routine immediate intraoperative imaging detected new blood products after diagnostic biopsy in 43 cases (2.6%); only 6 patients (0.36%) required craniotomy for hematoma evacuation. Perioperative seizures occurred in 6 patients (0.36%), and 2 patients developed burr hole site infections. One patient (1%) developed an intra-abscess hemorrhage after biopsy and catheter drainage. Two deaths (0.08%) related to surgery occurred. Some centers are currently migrating to frameless, even pinless, neuronavigation-guided needle procedures for both lobar and deep brain targets. Although experimental accuracy under optimal conditions is reported to be similar to that of frame-based systems, the complication rates from a significant number of cases have yet to be reported. This report establishes the safety profile of frame-based stereotactic surgery based on a 28-year period. These results may serve as a benchmark against which free-hand or guided neuronavigation approaches may be measured, as both the advantages and risks of such procedures are assessed.
Isolated Left Ventricular Noncompaction as a Cause for Heart Failure and Heart Transplantation: A Single Center Experience
Authors: Kovacevic-Preradovic T. , Jenni R. , Oechslin E.N. , Noll G. , Seifert B. , Attenhofer Jost C.H.
Published: July 2008

Objectives: To determine the prevalence of isolated left ventricular noncompaction (IVNC) as a cause of heart failure and heart transplantation. Methods: There were 960 patients seen in the heart failure clinic from 1987 to 2005, with a complete evaluation including echocardiography at our center (study population, 82% men, mean age 52 years). The following data were collected: type of heart disease, age at echocardiography and at heart transplantation, and frequency of heart transplantation. Echocardiographic diagnosis of IVNC was based on our published criteria. Results: The etiologies of heart failure were coronary artery disease (CAD; 37%), idiopathic dilated cardiomyopathy (33%), valvular heart disease (11%), congenital heart disease (5%), IVNC (3%), hypertensive heart disease (3%), hypertrophic cardiomyopathy (2%), myocarditis (1%), and <1% other diagnoses. Heart transplantation was performed in 253 patients (26%) due to idiopathic dilated cardiomyopathy (42%), CAD (39%), valvular heart disease (5%), congenital heart disease (5%), IVNC (2%), or other etiologies (≤1% each). Conclusions: The most common causes for heart failure remain idiopathic dilated cardiomyopathy, CAD and valvular heart disease. Strictly using the criteria for the definition of IVNC, IVNC is a rare underlying cardiomyopathy for both, heart failure (2.7%) and heart transplantation (2%) in our center.
The Comparative Effects of Long-Term Carvedilol versus Bisoprolol Therapy on QT Dispersion in Patients with Chronic Heart Failure
Authors: Aygul Nazif , Ozdemir Kurtulus , Duzenli Mehmet Akif , Aygul Meryem Ulku
Published: July 2008

Objectives: Carvedilol and bisoprolol reduce QT dispersion (QTD) in chronic heart failure (CHF). However, it is unclear whether there is a difference between the effects of the two drugs. The aim of the present study was to compare the long-term effects of carvedilol and bisoprolol on QTD in patients with CHF. Methods: Eighty-one patients with CHF with no previous β-blocker therapy were included in this prospective study. The patients were randomly allocated to carvedilol or bisoprolol therapy. Left ventricular ejection fraction (LVEF), heart rate (HR), QTD, and corrected QTD (QTcD) were calculated at baseline and at the 6th month of therapy. Results: In comparison to baseline values in both therapy groups, LVEF was significantly improved, and a statistically significant decrease was found in HR (carvedilol from 76 ± 12 to 65 ± 10 beats/min, p < 0.001; bisoprolol from 78 ± 13 to 65 ± 8 beats/min, p < 0.001) and QTcD (carvedilol from 85 ± 28 to 65 ± 22 ms, p < 0.001; bisoprolol from 83 ± 22 to 61 ± 20 ms, p < 0.001). In our study, carvedilol and bisoprolol were found to have similar effects on LVEF, HR, and QTcD. Conclusions: Carvedilol and bisoprolol decrease HR and QTcD in patients with CHF, and there is no meaningful difference between the two β-blockers as regards their effects on these parameters.
Erectile Dysfunction after Therapy with Metoprolol: The Hawthorne Effect
Authors: Cocco G.
Published: July 2008

Aims: It is often assumed that β-blockers, e.g. metoprolol (METO), induce erectile dysfunction (ED) in men. However, cardiovascular diseases can also induce ED and there is also the possibility that psychological factors, such as fear of the disease and side effects of the prescribed drug, may also induce ED. Thus, it is often assumed that β-blockers induce ED in a large percentage of men, but this statement is not well validated and the role of the pharmacologic effect of METO per se on the occurrence of ED is largely unknown. To get an answer we selected 114 men (age 57 ± 4.7 years) without ED but with newly diagnosed arterial hypertension, and who could be treated with METO. Methods: METO (100 mg/day) was given as a retard formulation. The hypertensive men were randomized into 3 groups. In group 1 patients were fully informed (they knew that the drug was METO and that it might induce ED). In group 2 patients were partially informed (they knew that the drug was METO, but were not informed that it might induce ED). In group 3 patients were not informed either about the drug used or about the possible occurrence of ED. The first phase of the study lasted 60 days. After 60 days the incidence of ED was 32% in group 1, 13% in group 2, and 8% in group 3 (p < 0.01). All patients with ED entered the second, cross-over, double-blind phase of the study. METO was continued at unchanged dosage, and tadalafil (20 mg) and a placebo were given to treat ED. Results: Both treatments were equally effective. Conclusion: Prejudice about the possible occurrence, i.e. the Hawthorne effect, of ED with METO facilitates the occurrence of this side effect in hypertensive men. Since the etiology of this ED is largely psychological, it is not surprising that placebo is as effective as tadalafil in reversing this side effect.
Reproducibility of Dermoscopic Features of Congenital Melanocytic Nevi
Authors: Ingordo Vito , Iannazzone Silvia S. , Cusano Francesco , Naldi Luigi
Published: July 2008

Background: The dermoscopic features of congenital melanocytic nevi (CMN) have recently been described, and some structures have been proposed as distinctive of these moles. Objective: The aim of our study was to evaluate the agreement between observers, i.e. the reproducibility, in the identification of these features. Method: Fifty-two CMN, randomly selected from 127 male subjects carrying at least 1 CMN, were examined by a 1st medium-experienced observer. The image recording was performed according to the dermoscopic patterns of the Consensus Net Meeting on Dermoscopy and to the features proposed for CMN by Seidenari et al. The presence/absence of these features was recorded in a specifically developed patient’s card, and the most typical dermoscopic features of the lesions were also photographed and observed again in this form by the same investigator and by a 2nd basic-experienced observer. The reproducibility of the dermoscopic features assessed directly and on photographs by the 1st observer (intraobserver agreement) and the agreement between the 1st and the 2nd observers judging nevi on photographs (interobserver agreement) were estimated by Cohen’s kappa statistics. Results: Intraobserver agreement was highly satisfactory for all the dermoscopic features, with the exception of focal thickening of network lines and follicles (satisfactory), and hyperpigmented areas and target vessels (fairly satisfactory), which were more frequently identified on Dermaphot pictures. Interobserver agreementwas highly satisfactory for network, globules/dots, blotches, focal hypopigmentation, skin furrow hypopigmentation and follicles; it was satisfactoryfor perifollicular hypopigmentation, vessels and target vessels, and barely satisfactory for focal thickening of network lines, target globules and hyperpigmented areas; finally, it was fairly satisfactory for target network. Conclusion: The identification of dermoscopic features of CMN seems to show a good reproducibility, with a satisfactory intra- and interobserver agreement. Other studies involving a higher number of experienced and less experienced observers are requested to confirm these results.
Salivary Epidermal Growth Factor Levels in Behçet’s Disease and Recurrent Aphthous Stomatitis
Authors: Adışen Esra , Aral Arzu , Aybay Cemalettin , Gürer Mehmet Ali
Published: July 2008

Background: Epidermal growth factor (EGF) in saliva is cytoprotective against injuries and contributes to the maintenance of the integrity of the gastrointestinal mucosa. Low salivary EGF levels have been observed in patients with various forms of oral mucosal disease. Objective: Our aim wasto determine whether salivary EGF is low in patients with recurrent aphthous stomatitis (RAS) or those with Behçet’s disease (BD) when compared with healthy controls. Methods: The study population consisted of 33 BD and 16 RAS patients and 60 healthy controls. Measurement of EGF concentration in human saliva was performed with an enzyme-linked immunosorbent assay using an antibody-coated solid phase. Results: The mean salivary EGF levels (±SD) of active (with oral ulceration) and inactive stages (absence of oral ulceration) of BD (1,939.7 ± 1,561.5 and 2,305.7 ± 1,481.6 pg/ml, respectively) and RAS patients (1,650.5 ± 704.7 and 1,069.9 ± 539.2 pg/ml, respectively) were both lower than those of the healthy controls (2,758.7 ± 1,657.9 pg/ml) (p < 0.05 for each). Conclusions: BD and RAS patients have reduced salivary EGF levels even in the absence of oral ulcerations. EGF could be involved in the pathogenesis of BD and RAS by disturbing the mucosal integrity that may result in a susceptibility to the development of oral ulcers in these diseases.
Maggots Do Not Survive in Pyoderma Gangrenosum
Authors: Renner Regina , Treudler Regina , Simon Jan C.
Published: July 2008

Application of maggots is well established in wound therapy. We report upon 2 patients with leg ulcers due to pyoderma gangrenosum who received immunosuppressive therapy and in whom a reduced survival of maggots (Lucilia sericata sp.) led to ineffectiveness of this therapy.
Hyaluronic Acid New Formulation: Experience in HIV-Associated Facial Lipoatrophy
Authors: Bechara Falk G. , Gambichler Thilo , Brockmeyer Norbert H. , Sand Michael , Altmeyer Peter , Hoffmann Klaus
Published: July 2008

Background: Facial lipoatrophy (FLA) is a stigmatizing complication of antiretroviral therapy in patients with human immunodeficiency virus (HIV) infection. Objectives: To evaluate the efficacy and safety of facial volume restoration in patients with HIV-associated FLA, using a novel long-lasting, hyaluronic acid high-density formulation. Methods: Twenty-one males with FLA were enrolled in this prospective, open-label, monocenter pilot study. Each patient received subcutaneous implantation of high-density hyaluronic acid. The aesthetic outcome was evaluated using the Global Aesthetic Improvement Scale every 3 months until 12 months after implantation. Additionally, patient satisfaction was analyzed, changes in patient quality of life were recorded using the Dermatology Life Quality Index (DLQI), and side effects were documented. Results: Nineteen patients (n = 19; 90.5%) were much improved or better 3 months after implantation, while 2 patients (n = 2; 9.5%) were improved and received a touch-up. Twelve months after implantation, still 16 patients (n = 16; 76.2%) were much improved or better, and 4 patients (n = 4; 19%) were improved. Patient satisfaction was high at every evaluation point over 12 months. The median DLQI before treatment was 16 (range: 13–19). Twelve months after augmentation, a significant decrease in the DLQI was observed (median: 9; range: 6–14) resulting in a relative reduction and significant improvement of the DLQI of 43.75% (p < 0.05), respectively. Side effects were mild and temporary (ecchymosis, edema and erythema). Conclusion: We propose the use of this new formulated hyaluronic acid for HIV-associated FLA as an efficacious and safe therapeutic option causing immediate augmentation of the soft tissues. The implant showed sustained longevity of 12 months and resulted in significant aesthetic improvement. It is notable for its simple and safe method of implantation and results in high patient satisfaction.
A Novel Sartan Derivative With Very Low Angiotensin II Type 1 Receptor Affinity Protects the Kidney in Type 2 Diabetic Rats
Authors: Izuhara Yuko , Sada Toshio , Yanagisawa Hiroaki , Koike Hiroyuki , Ohtomo Shuichi , Dan Takashi , Ito Sadayoshi , Nangaku Masaomi , van Ypersele de Strihou Charles , Miyata Toshio
Published: July 2008

Background—

Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear.

Methods and Results—

139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs). The 9 most powerful compounds were then tested for transition metal chelation, angiotensin II type 1 receptor (AT1R) affinity, and pharmacokinetic parameters. R-147176 was eventually selected as it strongly inhibits advanced glycation but is 6700 times less effective than olmesartan in AT1R binding. It is orally bioavailable and toxicologically safe. Despite a minimal blood pressure lowering effect, it provides significant renoprotection in 3 experimental rat models with renal injury, ie, obese, hypertensive, type 2 diabetic rats (SHR/NDmcr-cp), normotensive type 2 diabetic rats (Zucker diabetic fatty), and remnant kidney rats.

Conclusion—

R-147176 retains renal protective properties despite a minimal blood pressure–lowering effect. Clearly, the renal benefits of ARBs do not necessarily depend on blood pressure lowering and AT1R affinity, but rather on the inhibition of AGEs and oxidative stress inherent to their chemical structure. R-147176 opens new avenues in the treatment of cardiovascular and kidney diseases.
Leptin Enhances the Recruitment of Endothelial Progenitor Cells Into Neointimal Lesions After Vascular Injury by Promoting Integrin-Mediated Adhesion
Authors: Schroeter Marco R. , Leifheit Maren , Sudholt Philipp , Heida Nana-Maria , Dellas Claudia , Rohm Ilonka , Alves Frauke , Zientkowska Marta , Rafail Stavros , Puls Miriam , Hasenfuss Gerd , Konstantinides Stavros , Schäfer Katrin
Published: July 2008

The adipocytokine leptin modulates vascular remodeling and neointima formation. Because endothelial progenitor cells (EPCs) participate in vascular repair, we analyzed the effects of leptin on human EPC function in vitro and in vivo. After 7 days in culture, EPCs expressed the leptin receptor and responded to leptin stimulation with increased STAT3 phosphorylation. Incubation of EPCs with leptin (at concentrations between 1 and 100 ng/mL) increased the number of EPCs adhering to vitronectin and fibronectin in a receptor-specific manner. It also enhanced the capacity of EPCs to incorporate into a monolayer of human endothelial cells and the adherence of these cells to activated platelets. Leptin upregulated αvβ5 and α4 integrin expression in EPCs, and the effects of leptin on EPC function could be prevented, at least in part, by RGD peptides and function-blocking antibodies. Intravenous injection of fluorescently labeled human EPCs into athymic nude mice shortly after vascular injury revealed that preincubation of EPCs with leptin augmented their accumulation within intimal lesions, accelerating reendothelialization and decreasing neointima formation in an αvβ5 and α4 integrin-dependent manner. Our findings suggest that leptin specifically modulates the adhesive properties and the homing potential of EPCs and may thus enhance their capacity to promote vascular regeneration in vivo.
Hypoxic Vasodilation by Red Blood Cells
Authors: Diesen Diana L. , Hess Douglas T. , Stamler Jonathan S.
Published: July 2008

Red blood cells (RBCs) have been ascribed an essential role in matching blood flow to local metabolic demand during hypoxic vasodilation. The vasodilatory function of RBCs evidently relies on the allosteric properties of hemoglobin (Hb), which couple the conformation of Hb to tissue oxygen tension (P
o
2
) and thereby provide a basis for the graded vasodilatory activity that is inversely proportional to Hb oxygen saturation. Although a large body of evidence indicates that the P
o
2
-coupled allosteric transition from R (oxy)-state to T (deoxy)-state subserves the release from Hb of vasodilatory nitric oxide (NO) bioactivity, it has not yet been determined whether the NO-based signal is a necessary and sufficient source of RBC-mediated vasoactivity and it has been suggested that ATP or nitrite may also contribute. We demonstrate here by bioassay that untreated human RBCs rapidly and substantially relax thoracic aorta from both rabbit and mouse at low P
o
2
(≈1% O
2
) but not at high P
o
2
(≈21% O
2
). RBC-mediated vasorelaxation is inhibited by prior depletion of
S
-nitroso-Hb, potentiated by low-molecular-weight thiols, and dependent on cGMP. Furthermore, these relaxations are largely endothelium-independent and unaffected by NO synthase inhibition or nitrite. Robust relaxations by RBCs are also elicited in the absence of endothelial, neuronal or inducible NO synthase. Finally, contractions that appear following resolution of RBC-mediated relaxations are dependent on NO derived from RBCs as well as the endothelium. Our results suggest that an
S
-nitrosothiol–based signal originating from RBCs mediates hypoxic vasodilation by RBCs, and that vasorelaxation by RBCs dominates NO-based vasoconstriction under hypoxic conditions.
Interferon-γ, a Th1 Cytokine, Regulates Fat Inflammation
Authors: Rocha Viviane Zorzanelli , Folco Eduardo J. , Sukhova Galina , Shimizu Koichi , Gotsman Israel , Vernon Ashley H. , Libby Peter
Published: July 2008

Adipose tissue (AT) can accumulate macrophages and secrete several inflammatory mediators. Despite its pivotal role in the progression of chronic inflammatory processes such as atherosclerosis, the adaptive role of immunity in obesity remains poorly explored. Visceral AT of diet-induced obese C57BL/6 mice had higher numbers of both CD4
+
and CD8
+
T cells than lean controls, monitored by flow cytometry. When stimulated in vitro, T cells from obese AT produced more interferon (IFN)γ than those from controls. AT from obese animals also had more cells expressing I-A
b
, a mouse class II histocompatibility marker implicated in antigen presentation, as determined by immunostaining. Differentiated 3T3-L1 cells stimulated with recombinant IFNγ or T-helper 1–derived supernatant produced several chemokines and their mRNAs. Obese IFNγ-deficient animals had significantly reduced AT expression of mRNA-encoding inflammatory genes such as tumor necrosis factor-α and monocyte chemoattractant protein-1, decreased AT inflammatory cell accumulation, and better glucose tolerance than control animals consuming the same diet. Obese mice doubly deficient for IFNγ receptor and apolipoprotein (Apo)E on a mixed 129SvEv/C57BL/6 (129/B6) genetic background, despite exhibiting similar AT mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1 as 129/B6-ApoE
−/−
controls, had decreased expression of important T cell–related genes, such as IFNγ-inducible protein-10 and I-A
b
, and lower plasma triglycerides and glucose. These results indicate a role for T cells and IFNγ, a prototypical T-helper 1 cytokine, in regulation of the inflammatory response that accompanies obesity.
Atheroprotective Effect of Human Apolipoprotein A5 in a Mouse Model of Mixed Dyslipidemia
Authors: Mansouri Roxane M. , Baugé Eric , Gervois Philippe , Fruchart-Najib Jamila , Fiévet Catherine , Staels Bart , Fruchart Jean-Charles
Published: July 2008

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)ApoA5 on atherogenesis. The influence of hApoA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia. Our results demonstrate that hApoA5 lowers plasma triglyceride levels in Western diet–fed ApoE2 knock-in mice. Moreover, atherosclerotic lesion development was significantly decreased in the hApoA5 transgenic mice. Finally, pharmacologic activation of hApoA5 expression by the peroxisome proliferator-activated receptor-α agonist fenofibrate resulted in an enhanced atheroprotection. These results identify an atheroprotective role of hApoA5 in a mouse model of mixed dyslipidemia.
RGS4 Regulates Parasympathetic Signaling and Heart Rate Control in the Sinoatrial Node
Authors: Cifelli Carlo , Rose Robert A. , Zhang Hangjun , Voigtlaender-Bolz Julia , Bolz Steffen-Sebastian , Backx Peter H. , Heximer Scott P.
Published: July 2008

Heart rate is controlled by the opposing activities of sympathetic and parasympathetic inputs to pacemaker myocytes in the sinoatrial node (SAN). Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M
2
muscarinic receptors and activation of Gα
i/o
signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of Gα
i/o
signaling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SAN are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SAN compared to right atrium. Conscious freely moving RGS4-null mice showed increased bradycardic responses to parasympathetic agonists compared to wild-type animals. Moreover, anesthetized RGS4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from RGS4-null mice showed enhanced negative chronotropic responses to carbachol, whereas SAN myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, RGS4-null SAN cells showed decreased levels of G protein–coupled inward rectifying potassium (GIRK) channel desensitization and altered modulation of acetylcholine-sensitive potassium current (
I
KACh
) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signaling and
I
KACh
activity.