bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-term magnesium deficiency results in decreased levels of serum sphingomyelin, lipid peroxidation, and apoptosis in cardiovascular tissues
Authors: Altura Burton M. , Shah Nilank C. , Jiang Xian-Cheng , Li Zhiqiang , Perez-Albela José Luis , Sica Anthony C. , Altura Bella T.
Published: May 2009

The present study tested the hypothesis that short-term dietary deficiency of magnesium (Mg) (21 days) in rats would 1) result in decreased serum(s) [the present study tested the levels of Mg, sphingomyelin (SM), and phosphatidylcholine (PC)]; 2) promote DNA fragmentation, lipid peroxidation (LP), and activation of caspase-3 in cardiac (ventricular and atrial) and vascular(aortic) muscle; and 3) low levels of Mg2+added to drinking water would either prevent or greatly ameliorate these manifestations. The data indicate that short-term Mg deficiency (10% normal dietary intake) resulted in profound reductions in serum-ionized Mg and total Mg with an elevation in serum-ionized calcium (Ca2+), significant lowering of serum SM and serum PC, with concomitant LP, DNA fragmentation, and activation of caspase-3 in ventricular (right and left chambers), atrial (right and left chambers) and abdominal aortic smooth muscle. The greater the reduction in serum-ionized Mg, the greater the effects on DNA fragmentation, LP, and caspase-3 activity. The intake of water-borne Mg2+at all levels greatly attenuated or inhibited the reductions in serum SM and serum PC, activation of LP, DNA fragmentation, and the activation of caspase-3; even very low levels of Mg2+in drinking water (i.e., 15 parts·million−1·day−1) were cardio- and vascular protective. In addition, we demonstrate that short-term dietary deficiency of Mg probably results in a downregulation of SM synthase and a decreased synthesis of PC.
Exercise training induces a cardioprotective phenotype and alterations in cardiac subsarcolemmal and intermyofibrillar mitochondrial proteins
Authors: Kavazis Andreas N. , Alvarez Sophie , Talbert Erin , Lee Youngil , Powers Scott K.
Published: May 2009

Endurance exercise is known to provide cardioprotection against ischemia-reperfusion-induced myocardial injury, and mitochondrial adaptations may play a critical role in this protection. To investigate exercise-induced changes in mitochondrial proteins, we compared the proteome of subsarcolemmal and intermyofibrillar mitochondria isolated from the myocardium of sedentary (control) and exercise-trained Sprague-Dawley rats. To achieve this goal, we utilized isobaric tags for relative and absolute quantitation, which allows simultaneous identification and quantification of proteins between multiple samples. This approach identified a total of 222 cardiac mitochondrial proteins. Importantly, repeated bouts of endurance exercise resulted in significant alterations in 11 proteins within intermyofibrillar mitochondria (seven increased; four decreased) compared with sedentary control animals. Furthermore, exercise training resulted in significant changes in two proteins within subsarcolemmal mitochondria (one increased; one decreased) compared with sedentary control animals. Differentially expressed proteins could be classified into seven functional groups, and several novel and potentially important cardioprotective mediators were identified. We conclude that endurance exercise induces alterations in mitochondrial proteome that may contribute to cardioprotective phenotype. Importantly, based on our findings, pharmacological or other interventions could be used to develop a strategy of protecting the myocardium during an ischemic attack.
Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts
Authors: Folmes Clifford D. L. , Wagg Cory S. , Shen Mei , Clanachan Alexander S. , Tian Rong , Lopaschuk Gary D.
Published: May 2009

Activation of 5′-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) α2-subunit of AMPK (AMPK-α2DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14C]glucose, 0.4 mM [9, 10-3H]palmitate, and 100 μU/ml insulin. AMPK-α2DN hearts had reduced AMPK activity at the end of reperfusion (82 ± 9 vs. 141 ± 7 pmol·mg−1·min−1) with no changes in high-energy phosphates. Despite this, AMPK-α2DN hearts had improved recovery of function during reperfusion (14.9 ± 0.8 vs. 9.4 ± 1.4 beats·min−1·mmHg·10−3). During reperfusion, fatty acid oxidation provided 44.0 ± 2.8% of total acetyl-CoA in AMPK-α2DN hearts compared with 55.0 ± 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 ± 9.4% vs. 85.3 ± 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.
Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells
Authors: Kim Suil , Nadel Jay A.
Published: May 2009

Mucous hypersecretion is a serious feature of chronic airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Although mucins are produced via activation of an EGF receptor (EGFR) signaling cascade, the mechanisms leading to exaggerated mucin production in mucous hypersecretory diseases are unknown. Because expression of ICAM-1 and of the ICAM-1 ligand fibrinogen is increased in the airways of subjects with mucous hypersecretory diseases, we hypothesized that fibrinogen binding to ICAM-1 could increase EGFR-dependent mucin production in human airway (NCI-H292) epithelial cells. Consistent with this hypothesis, we found that an ICAM-1 neutralizing antibody and an ICAM-1(8–22) peptide that binds fibrinogen decreased mucin production induced by the EGFR ligand transforming growth factor (TGF)-α dose-dependently. Exogenous fibrinogen and a fibrinogen(117–133) peptide that binds ICAM-1 rescued mucin production in cells treated with the ICAM-1(8–22) peptide. Surprisingly, the ICAM-1(8–22) peptide increased EGFR phosphotyrosine and phospho-ERK1/2 in cells treated with TGF-α. The ICAM-1(8–22) peptide-induced increases in EGFR phosphotyrosine and phospho-ERK1/2 were prevented by exogenous fibrinogen, by the fibrinogen(117–133) peptide, and by selective inhibitors of phospholipase C (PLC), protein kinase C (PKC)-α/β, and metalloproteases. These results suggest that fibrinogen binding to ICAM-1 promotes mucin production by decreasing TGF-α-induced EGFR and ERK1/2 activation and that the fibrinogen-ICAM-1-dependent decrease in EGFR and ERK1/2 activation occurs via inhibition of an early positive feedback pathway involving PLC- and PKC-α/β-dependent metalloprotease activation and subsequent metalloprotease-dependent EGFR reactivation.
15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells
Authors: Liu Cheng , Xu Dawei , Liu Li , Schain Frida , Brunnström Åsa , Björkholm Magnus , Claesson Hans-Erik , Sjöberg Jan
Published: May 2009

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1α, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.
Hypoxia-induced mitogenic factor/FIZZ1 induces intracellular calcium release through the PLC-IP3 pathway
Authors: Fan Chunling , Su Qingning , Li Yun , Liang Lihua , Angelini Daniel J. , Guggino William B. , Johns Roger A.
Published: May 2009

Hypoxia-induced mitogenic factor (HIMF), also known as “found in inflammatory zone 1” (FIZZ1) or resistin-like molecule-α (RELMα), is a profound vasoconstrictor of the pulmonary circulation and a strong mitogenic factor in pulmonary vascular smooth muscle. To further understand the mechanism of these contractile and mitogenic responses, we examined the effect of HIMF on intracellular Ca2+ in human pulmonary artery smooth muscle cells (SMC). Ca2+ imaging in fluo 4-loaded human pulmonary artery SMC revealed that recombinant murine HIMF increased intracellular Ca2+ concentration ([Ca2+]i) in a sustained and oscillatory manner. This increase occurred independent of extracellular Ca2+ influx. Pretreatment of human pulmonary artery SMC with U-73122, a specific inhibitor of phosphatidylinositol-phospholipase C (PLC) completely prevented the HIMF-induced Ca2+ signal. The [Ca2+]i increase was also abolished by pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist. Ryanodine pretreatment did not affect initiation of [Ca2+]i activation or internal release but reduced [Ca2+]i at the plateau phase. Pretreatment with the Gαi-specific inhibitor pertussis toxin and the Gαs-specific inhibitor NF-449 did not block the Ca2+ signal. Knockdown of Gαq/11 expression did not prevent Ca2+ release, but the pattern of Ca2+ release changed from the sustained oscillatory transients with prolonged plateau to a series of short [Ca2+]i transients that return to baseline. However, pretreatment with the tyrosine kinase inhibitor genistein completely inhibited the internal Ca2+ release. These results demonstrate that HIMF can stimulate intracellular Ca2+ release in human pulmonary artery SMC through the PLC signaling pathway in an IP3- and tyrosine phosphorylation-dependent manner and that Gαq/11 protein-coupled receptor and ryanodine receptor contribute to the increase of [Ca2+]i.
Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension
Authors: Teng Ru-Jeng , Eis Annie , Bakhutashvili Ivane , Arul Nandini , Konduri Girija G.
Published: May 2009

Persistent pulmonary hypertension of newborn (PPHN) is associated with impaired pulmonary vasodilation at birth. Previous studies demonstrated that a decrease in angiogenesis contributes to this failure of postnatal adaptation. We investigated the hypothesis that oxidative stress from NADPH oxidase (Nox) contributes to impaired angiogenesis in PPHN. PPHN was induced in fetal lambs by ductus arteriosus ligation at 85% of term gestation. Pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN (HTFL-PAEC) or control lambs (NFL-PAEC) were compared for their angiogenic activities and superoxide production. HTFL-PAEC had decreased tube formation, cell proliferation, scratch recovery, and cell invasion and increased cell apoptosis. Superoxide (O2−) production, measured by dihydroethidium epifluorescence and HPLC, were increased in HTFL-PAEC compared with NFL-PAEC. The mRNA levels for Nox2, Rac1, p47phox, and Nox4, protein levels of p67phox and Rac1, and NADPH oxidase activity were increased in HTFL-PAEC. NADPH oxidase inhibitor, apocynin (Apo), and antioxidant, N-acetyl-cysteine (NAC), improved angiogenic measures in HTFL-PAEC. Apo and NAC also reduced apoptosis in HTFL-PAEC. Our data suggest that PPHN is associated with increased O2− production from NADPH oxidase in PAEC. Increased oxidative stress from NADPH oxidase contributes to the impaired angiogenesis of PAEC in PPHN.
Expression of the gas-transporting proteins, Rh B glycoprotein and Rh C glycoprotein, in the murine lung
Authors: Han Ki-Hwan , Mekala Kavya , Babida Venetia , Kim Hye-Young , Handlogten Mary E. , Verlander Jill W. , Weiner I. David
Published: May 2009

A family of gas-transporting proteins, the Mep/Amt/Rh glycoprotein family, has been identified recently. These are integral membrane proteins, are widely expressed in sites of gas transport, and are known to transport the gaseous molecule, NH3, and recent evidence indicates they can transport CO2. Because the mammalian lung is a critical site for gas transport, the current studies examine the expression of the nonerythroid members of this extended family, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg), in the normal mouse lung. Real-time RT-PCR and immunoblot analysis demonstrated both Rhbg and Rhcg mRNA and protein expression, respectively. Immunohistochemistry demonstrated both Rhbg and Rhcg were expressed in bronchial and bronchiolar epithelial cells. Rhbg was expressed by Clara cells, specifically, whereas all bronchial/bronchiolar epithelial cells, with the exception of goblet cells, expressed Rhcg. Rhbg expression was basolateral, whereas Rhcg exhibited apical and intracellular immunolabel, polarized expression similar to that observed in Rhbg- and Rhcg-expressing epithelial cells in other organs. There was no detectable expression of either Rhbg or Rhcg in alveolar endothelial or epithelial cells, in pneumocytes or in vascular tissue. In vitro studies using cultured bronchial epithelial cells confirm Rhbg and Rhcg expression, demonstrate that saturable, not diffusive, transport is the primary mechanism of ammonia/methylammonia transport, and show that the saturable transport mechanism has kinetics similar to those demonstrated previously for Rhbg and Rhcg. These findings suggest Rhbg and Rhcg may contribute to bronchial epithelial cell ammonia metabolism and suggest that they do not contribute to pulmonary CO2transport.
Metallothionein as an Anti-Inflammatory Mediator
Authors: Inoue Ken-ichiro , Takano Hirohisa , Shimada Akinori , Satoh Masahiko
Published: May 2009

The integration of knowledge concerning the regulation of MT, a highly conserved, low molecular weight, cystein-rich metalloprotein, on its proposed functions is necessary to clarify how MT affects cellular processes. MT expression is induced/enhanced in various tissues by a number of physiological mediators. The cellular accumulation of MT depends on the availability of cellular zinc derived from the diet. MT modulates the binding and exchange/transport of heavy metals such as zinc, cadmium, or copper under physiological conditions and cytoprotection from their toxicities, and the release of gaseous mediators such as hydroxyl radicals or nitric oxide. In addition, MT reportedly affects a number of cellular processes, such as gene expression, apoptosis, proliferation, and differentiation. Given the genetic approach, the apparently healthy status of MT-deficient mice argues against an essential biological role for MT; however, this molecule may be critical in cells/tissues/organs in times of stress, since MT expression is also evoked/enhanced by various stresses. In particular, because metallothionein (MT) is induced by inflammatory stress, its roles in inflammation are implied. Also, MT expression in various organs/tissues can be enhanced by inflammatory stimuli, implicating in inflammatory diseases. In this paper, we review the role of MT of various inflammatory conditions.
Comparison of 6- and 12-Core Prostate Biopsy in Taiwanese Men: Impact of Total Prostate-Specific Antigen, Prostate-Specific Antigen Density and Prostate Volume on Prostate Cancer Detection
Authors: Chiang I-Ni , Chang Shang-Jen , Pu Yeong-Shiau , Huang Kuo-How , Yu Hong-Jen , Huang Chao-Yaun
Published: May 2009

Introduction: We retrospectively compared 6- and 12-core prostate biopsies in Taiwanese men and evaluated the impact of prostate volume (PV), prostate-specific antigen (PSA), and PSA density (PSAD) on the prostate cancer detection rate (PCDR). Patients and Methods: 1,086 consecutive patients with a total PSA of 4.1–20.0 ng/ml and/or abnormal digital rectal examination undergoing first-time transrectal ultrasound-guided biopsy were included. Group I patients (n = 562) underwent sextant biopsy and group II patients (n = 524) underwent sextant biopsy with an extra three lateral cores on both sides. The patients were further stratified into subgroups according to PV (cut-off: 35 ml), PSA (cut-off: 10.0 ng/ml), and PSAD (cut-off: 0.2). Results: Prostate cancer was diagnosed in 228/1,086 (21.0%) patients. The PCDR was higher in group II (23.7%) than group I (18.5%). 12-Core biopsy yielded a significantly higher PCDR than 6-core biopsies in patients with PV >35 ml, PSA 4.1–10.0 ng/ml, PSAD ≤0.20, but not in patients with PV ≤35 ml, PSA 10.1–20.0 ng/ml, PSAD >0.20. Conclusions: 12-Core biopsy yielded a significantly higher PCDR in Taiwanese men with a total PSA of 4.1–20.0 ng/ml, especially in patients with PSA 4.1–10.0 ng/ml, PSAD ≤0.20, and PV >35 ml.
Free PSA/Total PSA Ratio Increases the Detection Rate of Prostate Cancer in Twelve-Core Biopsy
Authors: Yokomizo Yumiko , Miyoshi Yasuhide , Nakaigawa Noboru , Makiyama Kazuhide , Ogawa Takehiko , Yao Masahiro , Kubota Yoshinobu , Uemura Hiroji
Published: May 2009

Background: In the present study, we compared 12- with 8-core biopsy in patients with prostate-specific antigen (PSA) levels of 4.0–20.0 ng/ml. We also examined whether the free/total (F/T) PSA ratio is useful for cancer detection in 12-core biopsy. Methods: A total of 419 men with PSA level between 4.0 and 20.0 ng/ml underwent transrectal ultrasound-guided transperineal needle biopsies of the prostate. Of these men, 235 underwent 8-core biopsy and 184 underwent 12-core biopsy. We compared the cancer detection rate between the 8- and 12-core biopsy groups by analyzing the PSA value, and especially the F/T PSA ratio. Results: The cancer detection rate in the 12-core group (35.9%) was significantly higher than in the 8-core group (23.8%). In cases of PSA level of 4.0–20.0 ng/ml with F/T PSA ratio less than 0.11, the cancer detection rate was 53.1% in the 12-core biopsy group. Performing 12-core biopsy resulted in a marked difference of cancer detection rate between men with F/T PSA ratio less than 0.11 and those with more than 0.12 in gray zone PSA (48.2% and 17.5%, respectively). Conclusions: Twelve-core biopsy can achieve a higher detection rate of prostate cancer than 8-core biopsy using F/T PSA ratio.
Role of AgNOR Count and Its Correlation with Serum PSA Levels in Prostatic Lesions
Authors: Goel Tanmaya , Garg Shveta
Published: May 2009

Objective: Prostatic diseases are a major cause of morbidity and mortality. The need is to detect the disease early in its natural history and manage it aggressively. Prostate-specific antigen (PSA) is not very sensitive, thus other indices are being employed. Argyrophillic nucleolar organizer region (AgNOR) count is the proliferative index marker used in our study. Our main objective was to evaluate the role of AgNOR in prostatic lesions and to find a correlation between serum PSA and AgNOR counts. Patients and Methods: We evaluated 60 patients of prostate diseases over a year. The patients were classified as benign prostatic hyperplasia (BPH), prostatitis, or prostatic adenocarcinoma (Ca). Patients with suspicious areas or foci of prostatic intraepithelial neoplasia (PIN) on histology were subjected to a slide review. All slides were H&E and AgNOR stained. Results: The difference between the mean AgNOR counts of BPH and prostatitis was significant, as between BPH and PIN (p < 0.001). The difference between low- and high-grade PIN was also significant.Ca prostate showed a significant increase in AgNOR counts from benign diseases; and also between localized and metastatic carcinoma (p < 0.001). On finding a correlation between serum PSA values and AgNOR counts, they were significant for benign and carcinoma cases (p < 0.001), though not for PIN. Conclusions: Our study depicts the usefulness of AgNOR counts in the diagnosis of various prostatic diseases including the pre malignant PIN. The relation between serum PSA and AgNOR was highly significant for BPH and Ca prostate. Hence, AgNOR is an efficient adjunct to our diagnostic armamentarium leading to improved prognostication and management.
A Lower Risk of Dying from Urological Cancer in Down Syndrome: Clue for Cancer Protecting Genes on Chromosome 21
Authors: Satgé Daniel , Sasco Annie J. , Day Steven , Culine Stéphane
Published: May 2009

Objective: It was the aim of this study to evaluate the risk of dying from bladder and kidney cancer in persons with Down syndrome (DS), as compared with the general population. Methods: Using data of the French national mortality statistics (INSERM) during a 21-year period, 1979–1999, we compared the observed number of deaths from renal and bladder cancer in DS subjects with the expected number of deaths from these cancers. The expected number of deaths was calculated taking into account the prevalence of DS at birth and the life expectancy of persons with DS, assuming the risk was identical to the one of the general population. Results: A significant 6-fold decreased risk of dying from urological cancer was found in persons with DS, with 5 cases observed, while 30 were expected. The relative risk of dying was 0.27 for bladder cancer (p = 0.0017) and 0.06 for kidney cancer (p < 0.0001). Other mortality studies provided similar values. Conclusions: Children and adults with DS have a decreased risk of dying from urological neoplasms. Genes on chromosome 21 could play a protective role against urological cancer.
Aurora-A/STK-15 Is Differentially Expressed in the Micropapillary Variant of Bladder Cancer
Authors: Compérat Eva , Roupret Morgan , Conort Pierre , Chartier-Kastler Emmanuel , Bitker Marc-Olivier , Richard François , Capron Fréderique , Haertig Alain , Cussenot Olivier , Camparo Philippe
Published: May 2009

Introduction: Micropapillary carcinoma (MPC) of the bladder is a rare and aggressive histologic variant of urothelial carcinoma (UC). At the time of presentation, most MPC are muscle invasive with frequent vascular invasion (VI). Our series explores protein expression of markers known to be indicators of poor clinical outcome and progression, trying to explain aggressiveness of MPC. Patients and Methods: 18 patients with MPC were reviewed. We explored protein expression of p53, MIB-1, Aurora-A and survivin in MPC and compared their expression to conventional urothelial carcinoma (CUC) of the same grade and stage. Results: Patients, aged 46–85 years, underwent transurethral resection or cystoprostatectomy for UC. MPC was either pure (39%) or only partially present (61%). 55% of the patients died. VI was seen in 95%. MPC displayed overexpression of p53 and MIB-1, Aurora-A and survivin. No statistically significant difference could be made with CUC except for Aurora-A (p = 0.03). Conclusions: This is the first study to explore different markers of bad clinical outcome in MPC. We suggest that Aurora-A via mechanisms implied into early steps of mitosis might play a role in aggressive clinical behavior of MPC.
Cigarette Smoking and Drinking Water Source: Correlation with Clinical Features and Pathology of Superficial Bladder Carcinoma
Authors: Serretta Vincenzo , Altieri Vincenzo , Morgia Giuseppe , Allegro Rosalinda , Ruggirello Antonina , Di Lallo Alessandra , Carrieri Giuseppe , Melloni Darvinio
Published: May 2009

Objective: Water source and cigarette smoking are related to clinical characteristics and pathology of superficial transitional cell carcinoma of the bladder. Methods: Tumor number, dimension, G-grade, T-stage, recurrences, cigarette smoking and water supply were recorded in patients harboring Ta–T1 G1–3 transitional cell carcinoma of the bladder. Results: Of 577 patients, 61% had multiple and 36% recurrent tumors. Two hundred and forty-one patients (42%) were current smokers and 188 (33%) were former smokers. Bottled water was the only drinkable source for 249 (45%) patients, municipal water supply for 177 (32%), artesian wells for 38 (7%), spring water for 7 (1%) and mixed source for 89 (16%). By adopting a cut-off of 30 years of smoking, patients affected by recurrent tumors varied from 22 to 43% (p = 0.0001). T1 tumors were more frequent in patients drinking nonbottled water (p = 0.03). Nonbottled supply was more frequent in never smokers (p = 0.015) and could represent a weak risk factor not detectable in smokers. Conclusions: Cigarette smoking correlates with the number of recurrences. T1 tumors were statistically more frequent in patients taking nonbottled drinking water. Chlorinated water supply was more frequent among patients who did not present cigarette smoking as a risk factor.
Early-Stage Adenocarcinoma in Barrett’s Esophagus: Aspects of Surgical Therapies
Authors: Horváth Örs Péter , Kalmár Katalin
Published: May 2009

Adenocarcinomas in Barrett’s esophagus are increasingly diagnosed at early stages thanks to effective surveillance programs. Subtotal esophagectomy with extended lymphadenectomy is considered the best curative treatment for patients with early adenocarcinoma of the esophagus. However, such treatment is associated with substantial morbidity and compromised quality of life. Limited resection, minimal invasive surgical procedures or endoscopic mucosal ablation have been proposed as less invasive alternatives. A comparison of treatment-associated morbidity, recurrence rate, long-term survival and functional outcome suggests that none of these alternative methods can be universally recommended. An individualized strategy should be employed based on staging (tumor penetration into the mucosa/submucosa, presence of lymph node metastasis), multicentricity of tumor, length of the underlying Barrett’s mucosa and risk factors of the affected patient. Surgical resection (radical or limited) remains the treatment of choice for tumors invading the submucosa, multicentric tumor growth and recurrence after endoscopic mucosectomy.
Weakly Acidic Reflux
Authors: Tack Jan , Blondeau Kathleen
Published: May 2009

The advent of pH impedance monitoring has allowed assessment of the role of weakly acidic reflux, in addition to the traditionally considered acid reflux, in the pathophysiology of gastroesophageal reflux disease. Typical reflux symptoms studied off proton pump inhibitor (PPI) therapy are mainly associated with acid reflux events, while weakly acidic reflux is only significantly associated with symptom occurrence when assessed on PPI therapy. A major role in weakly acidic reflux in the absence of acid suppressive therapy has only been established for reflux-related cough. Further studies are needed to address the impact of weakly acidic reflux on the management and therapeutic choices in gastroesophageal reflux disease patients with symptoms that persist on PPI therapy. There is a lack of outcomes studies addressing the issue of reflux inhibitors and surgery for weakly acidic reflux that persists in patients on PPIs.
DTNBP1, NRG1, DAOA, DAO and GRM3 Polymorphisms and Schizophrenia: An Association Study
Authors: Jönsson Erik G. , Saetre Peter , Vares Maria , Andreou Dimitrios , Larsson Kristina , Timm Sally , Rasmussen Henrik B. , Djurovic Srdjan , Melle Ingrid , Andreassen Ole A. , Agartz Ingrid , Werge Thomas , Hall Håkan , Terenius Lars
Published: May 2009

Background: Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. Methods: In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. Results: One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. Conclusions: The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships.
Association between the Serotonin Transporter Gene (5-HTTLPR) and Anger-Related Traits in Korean Schizophrenic Patients
Authors: Kim Youl-Ri , Jahng Jeong Won , Min Sung Kil
Published: May 2009

Background: The serotonin transporter-linked polymorphic region (5-HTTLPR) short allele confers a general sensitivity to environmental stimuli, and anger is suspected to have a direct influence on aggressive behavior in schizophrenia. In the present study, we investigated whether the 5-HTTLPR gene was associated with aggression and/or anger-related traits in schizophrenia. Methods: A total of 103 schizophrenic patients, including 46 aggressive and 57 nonaggressive patients, were recruited from psychiatric hospitals in Korea. All of the aggressive patients had committed at least 2 significant violent acts requiring repeated confinement in each of the 2 weeks preceding study inclusion, as well as 2 or more serious assaults on others. Blood samples were collected from all patients for 5-HTTLPR genotyping, and all patients underwent clinical assessments for symptoms of schizophrenia, aggressive behavior and anger-related traits. Results: There was no significant difference in the distribution of the 5-HTTLPR genotype/alleles between the aggressive and nonaggressive patients. Aggressive patients carrying the s allele exhibited more anger-related traits than those with the l/l homozygotes, but this difference was not significant after correction for multiple testing. Furthermore, there was a dose-dependent relationship between the s allele and high angry temperament subscale scores in the aggressive patients. Conclusion: These findings seem to support the idea that 5-HTTLPR predisposes aggressive patients to exhibit more anger-related traits, though they do not support the existence of a direct association between 5-HTTLPR and aggressive behavior in schizophrenia in the Korean population; however, larger studies are needed.
Evaluation of Laser Fluorescence in the Monitoring of the Initial Stage of the De-/Remineralization Process: An in vitro and in situ Study
Authors: Spiguel M.H. , Tovo M.F. , Kramer P.F. , Franco K.S. , Alves K.M.R.P. , Delbem A.C.B.
Published: May 2009

This study aimed to evaluate laser fluorescence (LF) for monitoring the initial stage of subsurface de- and remineralization (<150 μm depth). Ninety-six sound blocks of bovine enamel, selected according to surface hardness (SH) and LF were used in two experimental studies, in vitro and in situ. In vitro, blocks were exposed to a demineralizing solution, then remineralized by pH cycling for 6 days. In situ, 10 volunteers wore acrylic palatal appliances, each containing 4 dental enamel blocks that were demineralized for 14 days by exposure to 20% sucrose solution. Following this treatment, blocks were submitted to remineralization for 1 week with fluoride dentifrice (1,100 μg F/g). In both experiments, SH and LH were measured after demineralization and after remineralization. Further, enamel blocks were selected after the demineralization/remineralization steps for measurement of cross-sectional hardness and integrated loss of subsurface hardness (ΔKHN). SH and ΔKHN showed significant differences among the phases in each study. LF values for sound, demineralized and remineralized enamel were: 5.2 ± 1.1, 8.1 ± 1.2 and 5.6 ± 0.8, respectively, in the in vitro study, and 5.3 ± 0.3, 16.5 ± 4.7 and 6.5 ± 2.5, respectively, in the in situ study, values for demineralized enamel being significantly higher than for sound and remineralized enamel in both studies. However, LF was correlated with ΔKHN only in situ. LF was capable of monitoring de- and remineralization in early lesions in situ, when bacteria are presumably present in the caries lesion body, but is not correlated with mineral changes in bacteria-free systems.
Combined Pulmonary and Aortic Valve Stenosis – Prenatal Diagnosis and Postnatal Interventional Therapy
Authors: Herberg Ulrike , Goltz Diane , Weiss Henning , Gembruch Ulrich , Breuer Johannes
Published: May 2009

Combined pulmonary and aortic valvar stenosis is an extremely rare congenital anomaly. Fetuses and neonates with critical pulmonary valve stenosis or atresia and intact ventricular septum may present with varying degrees of abnormalities of the right ventricle, tricuspid valve, and coronary arteries, but combination of right and left ventricular outflow tract obstruction is hardly ever seen. Until bilateral balloon valvuloplasty had been established in the neonate, the only therapeutic option was the surgical relief of right and left ventricular obstruction. We highlight the essentials of perinatal management in cases with severe bilateral valvar obstruction and provide a guideline for sequential interventional therapy of this rare lesion.
NF-κB-Dependent Induction of Cathelicidin-Related Antimicrobial Peptide in Murine Mast Cells by Lipopolysaccharide
Authors: Li Guiming , Domenico Joanne , Jia Yi , Lucas Joseph J. , Gelfand Erwin W.
Published: May 2009

Background: An important aspect of the innate immune response to pathogens is the production of anti-microbial peptides such as cathelicidin-related antimicrobial peptide (CRAMP), the murine homologue of human cathelicidin LL-37. In this study, mechanisms regulating LPS-induction of CRAMP gene expression in mast cells were investigated. NF-κB and MAPK pathways were the focus of investigation. Methods: Mouse bone marrow-derived mast cells were grown in culture and stimulated with LPS. MAPKs and NF-κB were monitored by immunoblot analysis. ERK, JNK and p38 MAPK were inhibited using siRNAs or a pharmacological inhibitor. Accumulation of the p65 component of NF-κB was inhibited by siRNA and NF-κB activation was inhibited by overexpression of IκBα. MEKK2 or MEKK3 were overexpressed by transfection. The effects of all of these treatments on CRAMP gene expression were monitored by RT-PCR. Results: Inhibition of ERK, JNK or p38 MAPK had little discernible effect on LPS-inducible CRAMP gene expression. Overexpression of MEKK2 or MEKK3 likewise had little impact. However, inhibition of the accumulation of p65 NF-κB prevented LPS-induced CRAMP mRNA. An important role for NF-κB in CRAMP gene expression was confirmed by overexpression of IκBα, which reduced both basal and induced levels of CRAMP mRNA. Conclusions: NF-κB, but not MAPKs, plays an important role in LPS-mediated induction of CRAMP gene in mast cells. Defects which inhibit NF-κB activity may increase susceptibility to bacterial and viral pathogens which are sensitive to cathelicidins.
Inhibition of Secretory Phospholipase A2-Induced Cytokine Production in Human Lung Macrophages by Budesonide
Authors: Triggiani Massimo , Granata Francescopaolo , Petraroli Angelica , Loffredo Stefania , Frattini Annunziata , Staiano Rosaria Ilaria , Monaco Guglielmo , Marone Gianni
Published: May 2009

Background: Secretory phospholipases A2 (sPLA2) are an emerging class of mediators of inflammation. These enzymes are released in vivo in patients with systemic inflammatory diseases and allergic disorders. sPLA2s may activate inflammatory cells by both enzymatic and nonenzymatic mechanisms. The aim of this study was to evaluate the effect of the inhaled glucocorticoid budesonide on sPLA2-induced activation of primary human macrophages. Methods: Macrophages isolated from human lung tissue were preincubated (3–18 h) with budesonide (1–1,000 nM) before stimulation with 2 distinct sPLA2s (group IA and group X). At the end of incubation the release of TNF-α, IL-6 and IL-8 was assessed by ELISA. Specific mRNA for these products was determined by quantitative RT-PCR. Activation of mitogen-activated kinases ERK 1/2 and p38 was assessed by Western blot. Results: Budesonide inhibited the release of TNF-α, IL-6 and IL-8 from sPLA2-stimulated macrophages in a concentration-dependent manner. The inhibitory effect of budesonide was due to a reduction of gene expression and was complete after 18 h of preincubation. Budesonide had no effect on sPLA2-induced arachidonic acid mobilization and exocytosis, assessed as β-glucuronidase release. Suppression of cytokine/chemokine production by budesonide was associated with inhibition of sPLA2-induced ERK 1/2 and p38 activation. Conclusions: Budesonide inhibits the production of proinflammatory cytokines/chemokines from human lung macrophages activated by sPLA2. Budesonide represents the first example of a drug able to block the nonenzymatic effects of sPLA2 on human inflammatory cells and, therefore, may provide a useful therapeutic options for diseases associated with enhanced release of sPLA2s in vivo.
Decreased Expression of MicroRNA-143 and -145 in Human Gastric Cancers
Authors: Takagi Takeshi , Iio Akio , Nakagawa Yoshihito , Naoe Tomoki , Tanigawa Nobuhiko , Akao Yukihiro
Published: May 2009

Objective: Downregulation of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. We investigated the role of the miRNAs miR-143 and miR-145 in gastric cancers. Methods: The expression levels of miR-143 and miR-145 in the samples from 43 patients with gastric cancer were determined by real-time PCR using TaqMan assay. The growth inhibitory effect was estimated by the transfection of human gastric cancer cells with the miRNA. Results: The expression levels of miR-143 and -145 were decreased in most human gastric cancers examined, as previously reported to occur in colon tumors. The transfection of human gastric MKN-1 cells with miR-145 resulted in a greater growth inhibitory effect than that with miR-143, results which were contrary to those in colon cancers. In MKN-1 cells, an additive effect on growth inhibition was shown by the combined transfection with miR-143 and miR-145; further, higher sensitivity to 5-fluorouracil was also observed following the transfection with miR-143 or miR-145. The possible candidate target messenger RNAs of miR-145 were identified to be insulin receptor substrate-1 and β-actin. Conclusion: Taken together, these findings suggest that miR-143 and miR-145 act as anti-oncomirs common to gastrointestinal tumors.
Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure
Authors: Garnier Anne , Zoll Joffrey , Fortin Dominique , N'Guessan Benoît , Lefebvre Florence , Geny Bernard , Mettauer Bertrand , Veksler Vladimir , Ventura-Clapier Renée
Published: May 2009

Background—

Evidence is emerging to support the concept that the failing heart is “energy depleted” and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-γ coactivator-1α, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown.

Methods and Results—

In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-γ coactivator-1α protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-γ coactivator-1α and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (−30%) and, to a lesser degree, angiotensin II (−20%) decreased proliferator-activated receptor-γ coactivator-1α mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline).

Conclusions—

Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.
Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice
Authors: Spinale Francis G. , Escobar G. Patricia , Mukherjee Rupak , Zavadzkas Juozas A. , Saunders Stuart M. , Jeffords Laura B. , Leone Allyson M. , Beck Christy , Bouges Shenikqua , Stroud Robert E.
Published: May 2009

Background—

The direct consequences of a persistently increased myocardial expression of the unique matrix metalloproteinase (MMP) membrane type-1 (MT1-MMP) on myocardial remodeling remained unexplored.

Methods and Results—

Cardiac-restricted MT1-MMPexp was constructed in mice using the full-length human MT1-MMP gene ligated to the myosin heavy chain promoter, which yielded approximately a 200% increase in MT1-MMP when compared with age/strain-matched wild-type (WT) mice. Left ventricular (LV) function and geometry was assessed by echocardiography in 3-month (“young”) WT (n=32) and MT1-MMPexp (n=20) mice and compared with 14-month (“middle-aged”) WT (n=58) and MT1-MMPexp (n=35) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups, as was LV ejection fraction. In the middle-aged WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle-aged mice, LV end-diastolic volume was ≈43% higher and LV ejection fraction 40% lower (both
P
<0.05). Moreover, in the middle-aged MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with ≈3-fold increase in the processing of the profibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14-day survival after myocardial infarction was significantly lower in middle-aged MT1-MMPexp mice.

Conclusions—

Persistently increased myocardial MT1-MMP expression, in and of itself, caused LV remodeling, myocardial fibrosis, dysfunction, and reduced survival after myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium.
Randomized Comparison of the Nobori Biolimus A9-Eluting Coronary Stent With the Taxus Liberté Paclitaxel-Eluting Coronary Stent in Patients With Stenosis in Native Coronary Arteries
Authors: Chevalier Bernard , Silber Sigmund , Park Seung-Jung , Garcia Eulogio , Schuler Gerhard , Suryapranata Harry , Koolen Jacques , Hauptmann Karl E. , Wijns William , Morice Marie-Claude , Carrie Didier , van Es Gerrit-Anne , Nagai Hirofumi , Detiege Danny , Paunovic Dragica , Serruys Patrick W.
Published: May 2009

Background—

The newly developed Nobori coronary stent coated with a bioresorbable polymer, polylactic acid, and the antiproliferative agent Biolimus A9 has the potential to reduce restenosis by suppressing neointima formation.

Methods and Results—

We conducted a randomized (2:1), controlled trial comparing the Biolimus A9-eluting stent Nobori and the paclitaxel-eluting stent Taxus Liberté, in 243 patients (153 Nobori and 90 Taxus) at 29 centers in Europe, Asia, and Australia. Patients with previously untreated lesions in up to 2 native coronary arteries were considered for enrollment. The primary end point was in-stent late loss at 9 months, whereas secondary end points included other quantitative coronary angiography parameters, such as in-segment late loss and the rate of restenosis as well as key intravascular ultrasound parameters. Clinical secondary end points were stent thrombosis and composite of major adverse cardiac events comprising death, myocardial infarction, and target vessel revascularization. At 9 months, the in-stent late loss was significantly lower in the Nobori group compared with the Taxus group (0.11�0.30 mm versus 0.32�0.50 mm) reaching both the primary hypothesis of noninferiority of Nobori stent versus Taxus Liberté stent (
P
<0.001) and the secondary hypothesis of superiority (
P
=0.001). This finding was confirmed by a significant reduction in binary restenosis from 6.2% in Taxus to 0.7% in Nobori (
P
=0.02) and neointimal volume obstruction, detected by intravascular ultrasound, from 5.5�7.2% in Taxus to 1.8�5.2% in Nobori (
P
=0.01). The major adverse cardiac events rate was 4.6% in the Nobori and 5.6% in the Taxus cohort of patients. The stent thrombosis rate was 0% in the Nobori arm and 4.4% in the Taxus arm.

Conclusions—

The NOBORI 1 clinical trial confirmed its primary hypothesis—noninferiority of the Nobori Biolimus A9-eluting stent versus the Taxus Liberté stent in reducing neointimal proliferation. Both stents showed a low major adverse cardiac events rate in the studied population.
Bleeding in Patients Undergoing Percutaneous Coronary Intervention
Authors: Mehta Sameer K. , Frutkin Andrew D. , Lindsey Jason B. , House John A. , Spertus John A. , Rao Sunil V. , Ou Fang-Shu , Roe Matthew T. , Peterson Eric D. , Marso Steven P.
Published: May 2009

Background—

Bleeding in patients undergoing percutaneous coronary intervention (PCI) is associated with increased morbidity, mortality, length of hospitalization, and cost. We identified baseline clinical characteristics associated with bleeding complications after PCI and developed a simplified, clinically useful algorithm to predict patient risk.

Methods and Results—

Data were analyzed from 302 152 PCI procedures performed at 440 US centers participating in the National Cardiovascular Data Registry. As defined by the National Cardiovascular Data Registry, bleeding required transfusion, prolonged hospital stay, and/or a drop in hemoglobin >3.0 g/dL from any location, including percutaneous entry site, retroperitoneal, gastrointestinal, genitourinary, and other/unknown location. Bleeding complications occurred in 2.4% of patients. From the best-fitting model consisting of 15 clinical elements associated with post-PCI bleeding in a random 80% training cohort, we developed a parsimonious risk algorithm. Predictors of bleeding included age, gender, previous heart failure, glomerular filtration rate, peripheral vascular disease, no previous PCI, New York Heart Association/Canadian Cardiovascular Society Functional Classification class IV heart failure, ST-elevation myocardial infarction, non–ST-elevation myocardial infarction, and cardiogenic shock. The parsimonious model was validated in the remaining 20% of the population (c-statistic, 0.72) and in clinically relevant subgroups of patients. This simplified model was used to derive a clinical risk algorithm, with larger numbers corresponding with greater risk. In 3 categories, bleeding rates were greater in patients with higher estimates (≤7, 0.7%; 8 to 17, 1.8%; ≥18, 5.1%).

Conclusions—

This report identifies baseline clinical factors associated with bleeding and proposes a clinically useful algorithm to estimate bleeding risk. This model is potentially actionable in altering therapeutic decision making and improving outcomes in patients undergoing PCI.