bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations
Authors: Jenab Mazda , McKay James , Bueno-de-Mesquita Hendrik B. , van Duijnhoven Franzel J.B. , Ferrari Pietro , Slimani Nadia , Jansen Eugène H.J.M. , Pischon Tobias , Rinaldi Sabina , Tjønneland Anne , Olsen Anja , Overvad Kim , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise , Engel Pierre , Kaaks Rudolf , Linseisen Jakob , Boeing Heiner , Fisher Eva , Trichopoulou Antonia , Dilis Vardis , Oustoglou Erifili , Berrino Franco , Vineis Paolo , Mattiello Amalia , Masala Giovanna , Tumino Rosario , Vrieling Alina , van Gils Carla H. , Peeters Petra H. , Brustad Magritt , Lund Eiliv , Chirlaque María-Dolores , Barricarte Aurelio , Suárez Laudina Rodríguez , Molina Esther , Dorronsoro Miren , Sala Núria , Hallmans Göran , Palmqvist Richard , Roddam Andrew , Key Timothy J. , Khaw Kay-Tee , Bingham Sheila , Boffetta Paolo , Autier Philippe , Byrnes Graham , Norat Teresa , Riboli Elio
Published: September 2009

Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2485-91)
Human Papillomavirus Types 16 and 18 DNA Load in Relation to Coexistence of Other Types, Particularly Those in the Same Species
Authors: Xi Long Fu , Edelstein Zoe R. , Meyers Craig , Ho Jesse , Cherne Stephen L. , Schiffman Mark
Published: September 2009

Background: Infection with multiple human papillomavirus (HPV) types is common. However, it is unknown whether viral DNA load is related to the coexistence of other types.

Methods: Study subjects were 802 and 303 women who were positive for HPV16 and HPV18, respectively, at enrollment into the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study. HPV16 and HPV18 E7 copies per nanogram of cellular DNA in cervical swab samples were measured by real-time PCR in triplicate.

Results: Concurrent coinfection was common in this population of women with minor cervical lesions; multiple HPV types were detected in 573 (71.4%) of 802 HPV16-positive women and 227 (74.9%) of 303 HPV18-positive women. The adjusted odds ratio associating coinfection with per 1 log unit increase in HPV16 DNA load was 0.78 (95% confidence interval, 0.68-0.89); it was 0.64 (95% confidence interval, 0.52-0.79) for a similar analysis of HPV18 DNA load. Women with, compared with without, coinfection of A9 species types possessed a significantly lower HPV16 DNA load (P < 0.001), whereas women with, compared with without, coinfection of A7 species types possessed a significantly lower HPV18 DNA load (P = 0.001). A trend of decrease in HPV16 DNA load with increasing number of the coexisting non-HPV16 A9 species types was statistically significant (Ptrend = 0.001).

Conclusion: Coinfection with other types was associated with lower HPV16 and HPV18 DNA load. The extent of reduction was correlated to phylogenetic distance of the coexisting types to HPV16 and HPV18, respectively. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2507–12)
Polymorphic Variants in Hereditary Pancreatic Cancer Genes Are Not Associated with Pancreatic Cancer Risk
Authors: McWilliams Robert R. , Bamlet William R. , de Andrade Mariza , Rider David N. , Couch Fergus J. , Cunningham Julie M. , Matsumoto Martha E. , Rabe Kari G. , Hammer Traci J. , Petersen Gloria M.
Published: September 2009

Background: Inherited risk of pancreatic cancer has been associated with mutations in several genes, including BRCA2, CDKN2A (p16), PRSS1, and PALB2. We hypothesized that common variants in these genes, single nucleotide polymorphisms (SNP), may also influence risk for pancreatic cancer development.

Methods: A clinic-based case-control study in non-Hispanic white persons compared 1,143 patients with pancreatic adenocarcinoma with 1,097 healthy controls. Twenty-eight genes directly and indirectly involved in the Fanconi/BRCA pathway (includes BRCA1, BRCA2, and PALB2) were identified and 248 tag SNPs were selected. In addition, 11 SNPs in CDKN2A, PRSS1, and PRSS2 were selected. Association studies were done at the gene level by principal components analysis, whereas recursive partitioning analysis was used to investigate pathway effects. At the individual SNP level, adjusted additive, dominant, and recessive models were investigated, and gene-environment interactions were also assessed.

Results: Gene level analyses showed no significant association of any genes with altered pancreatic cancer risk. Multiple single SNP analyses showed associations, which will require replication. Exploratory pathway analyses by recursive partitioning showed no association between SNPs and risk for pancreatic cancer.

Conclusion: In a candidate gene and pathway SNP association study analysis, common variations in the Fanconi/BRCA pathway and other candidate familial pancreatic cancer genes are not associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2009;18(9):2549–52)
Mix Gonadal Dysgenesis Associated with Ring Y Chromosome Mosaics in a Phenotypic Male
Authors: Lopez-Valdes J.A. , Nieto K. , Najera N. , Cervantes A. , Kofman-Alfaro S. , Queipo G.
Published: September 2009

Ring chromosomes are present in 1 in 25,000 human fetuses; 99% arise de novo while less than 1% of rings are inherited. This chromosomal rearrangement may arise through a cytogenetic mechanism involving breaks in chromosome arms and fusion of the proximal broken ends, leading to a loss of distal material. Most patient Y ring chromosomes are present in a 45,X/46,X,r(Y) mosaic karyotype; molecular analyses of infertile men have shown that it is not rare to find r(Y) in these patients. However, the clinical spectrum in those cases with a 45,X cell line is broad and depends on the percentage of the monosomic cell line in different tissues. Y chromosome abnormalities and 45,X mosaic karyotypes are often associated with disorders of sex determination. Here, we report a male patient with hypospadias, cryptorchidism and a mosaic karyotype containing a low proportion of 45,X monosomic cells and multiple ring Y chromosomes in peripheral blood. Clinical, surgical, and molecular evidence was sufficient for a diagnosis of mixed gonadal dysgenesis. We suggest that a detailed cytogenetic and molecular analysis should be done in all males with bilateral descended testes and infertility.
Identification of Suitable Normalizing Genes for Quantitative Real-Time RT-PCR Analysis of Gene Expression in Fetal Mouse Gonads
Authors: Svingen T. , Spiller C.M. , Kashimada K. , Harley V.R. , Koopman P.
Published: September 2009

In biological research, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assays are commonly employed to study mRNA abundance in cells and tissues. This type of assay usually relies on assessing transcript abundance relative to constitutively expressed endogenous reference genes. Therefore, it is important that the reference genes themselves are stably expressed in the cells or tissues analyzed, independent of factors such as age, sex, disease or experimental manipulations. Since no gene is expressed at the same level in all cells at all times, suitable reference genes must be identified for the specific cellular system or tissue being investigated. Here, we sought to identify stably expressed endogenous reference genes during embryonic gonad development in the mouse. We measured the transcript abundance of 10 frequently employed normalizing genes, of which 4 were stably expressed in fetal gonads from 11.5 to 14.5 dpc irrespective of sex. Based on our analysis, we suggest that Rn18s, Rps29, Tbp and Sdha are suitable reference genes for qRT-PCR expression studies during early gonad differentiation in the mouse.
Urethral Instability: Current Pathophysiological Concept
Authors: Groenendijk P.M. , Heesakkers J.P.F.A. , Ouwerkerk T.J. , Lycklama à Nijeholt A.A.B.
Published: September 2009

The role of urethral pressure variations during filling cystometry is seldom assessed as a potential cause of voiding dysfunction and/or storage disorders. In this article, we review current research in the field of urethral pressure variations and discuss the way of determining urethral pressure variations, its value for the clinical practice and hypothesize the origin of urethral pressure variations. The observation and recognition of urethral pressure variations (urethral instability) could be valuable in the diagnosis and evaluation of therapy in functional lower urinary tract disorders.
Cystoprostatectomy as a Treatment of Prostate Cancer Involving the Bladder Neck
Authors: Kumazawa Teruaki , Tsuchiya Norihiko , Saito Mitsuru , Inoue Takamitsu , Narita Shintaro , Horikawa Youhei , Yuasa Takeshi , Satoh Shigeru , Kato Tetsuro , Nanjyo Hiroshi , Habuchi Tomonori
Published: September 2009

Objective: We evaluated the clinicopathological findings and short- and long-term outcomes of prostate cancer (PCa) patients with bladder neck invasion who underwent cystoprostatectomy. Patients and Methods: Between 1989 and 2005, we performed 17 cystoprostatectomies for PCa patients having bladder neck invasion without distant visceral or distant lymph node metastasis. Of the 17 patients, 11 were treated with neoadjuvant hormone therapy and all patients were treated with adjuvant hormone therapy immediately after surgery. Results: All 7 patients in whom pelvic lymph node swelling was identified by preoperative imaging studies had pathological lymph node metastasis. Of the 10 patients judged as cN0 preoperatively, 7 (70.0%) had lymph node metastasis. Although local recurrence was found in 2 (11.8%) patients, no additional urinary diversion or inconvenient urinary symptoms due to PCa progression were observed in any patients. The 5-year prostate-specific antigen recurrence-free survival rate was 62.2%. Cause-specific survival at 5 years after surgery was 87.1%. The 5-year cause-specific survival rate of node-positive patients was 92.3%. Conclusion: Cystoprostatectomy followed by immediate hormone therapy may be a feasible treatment option to achieve excellent local control for patients with previously untreated PCa, even in the presence of pelvic lymph node metastasis.
De novo Urothelial Carcinoma in Kidney Transplantation Patients with End-Stage Aristolochic Acid Nephropathy in China
Authors: Yuan Ming , Shi Bing-Yi , Li Han-Zhong , Xia Ming , Han Yong , Xu Xiao-Guang , Zhang Yin-Sheng
Published: September 2009

Introduction: Aristolochic acid contained in Chinese herbs has been proved to be nephrotoxic and carcinogenic. Immunosuppression is associated with an increased risk of developing malignancies. What will be the result if these two significant risk factors are concomitantly present in transplanted patients with aristolochic acid nephropathy (AAN)? Patients and Methods: A 2-center cohort of 1,612 renal transplant recipients was studied retrospectively from January 1998 to December 2006. We performed an evaluation of the database and review of the charts and pathology reports of these recipients. Results: Kidney transplantations were performed in 17 patients with AAN. Nine (52.9%) of these recipients developed urothelial carcinoma (UC), compared with a 0.46% prevalence of urinary tract tumors among kidney-transplanted patients in China. Eight cases (88.9%) involved the upper urinary tract (bilateral, 3 cases, 37.5%; unilateral, 5 cases, 62.5%). All patients underwent surgical treatment. Six patients (75%) had recurrence during the follow-up period. Three patients died within a mean of 20 months after tumor excision. Conclusions: The risk for UC is distinctly increased in patients with AAN after transplantation. Regular screening for early detection of malignancy is mandatory.
Pure Primary Prostatic Osteosarcoma Arising in a Non-Irradiated Prostate
Authors: Rabbani Farhang , Fine Ronnie G. , D’Adamo David , Edgar Mark , Akin Oguz , Paty Philip
Published: September 2009

A 68-year-old man who initially presented with hematuria was found on prostate biopsy to have sarcoma of the prostate with osteogenic features. Radiological examination revealed a locally advanced pelvic mass involving the prostate, seminal vesicles, and rectal wall without metastatic disease. The patient underwent total pelvic exenteration with intraoperative radiotherapy. The tumor was composed of two nodules measuring 7.5 and 4.5 cm involving the prostate, both seminal vesicles, the bladder, rectum, and perirectal fibroadipose tissue. The final diagnosis was osteogenic sarcoma of the prostate.
Simultaneous Occurrence of Renal Oncocytoma and B Small Cell Lymphoma in the Same Kidney: Report of Two Cases
Authors: Nigro Michele , Piscioli Irene , Franceschetti Ilaria , Barberini Francesco , Lupattelli Luciano , Scialpi Michele
Published: September 2009

Two cases of simultaneous occurrence of oncocytoma (OC) associated with small B-cell lymphoma in the same kidney were investigated. Computed tomography, performed for staging purposes, incidentally revealed a small hypo- and hyperattenuating renal mass. Diagnosis of OC was performed on the specimen by morphology, immunohistochemistry and electron microscopy. The patients are in complete remission after a vaccinotherapy with follicular dendritic cells. The occurrence of OC and non-Hodgkin lymphoma in the same kidney has never been reported. These case reports outline that computerized tomography is a sensitive method in the staging of lymphoma. However, when some solid, small hyper- or hypoattenuating masses occur in the kidney, the diagnosis by computed tomography alone is always a challenge and other malignant neoplasms may be considered. Immunohistochemistry and electron microscopy allow a definitive diagnosis of OC.
Pharmacokinetics of Propofol and Extrahepatic UGT1A6 Gene Expression in Anhepatic Rats
Authors: Gu Jianteng , Lu Kaizhi , Xia Peiyuan , Tang Min , Dai Qing , Ma Daqing , Tao Guocai
Published: September 2009

Objective: The metabolic enzyme of UDP-glucuronosyltransferase 1A6 (UGT1A6) has been considered to metabolize propofol intra- or extrahepatically. The aim of the present study was to investigate the pharmacokinetics of propofol and UGT1A6 mRNA expression in extrahepatic organs before and during the anhepatic status in rats. Methods: Male Sprague-Dawley rats were injected with propofol (10 mg/kg) intravenously and a blood sample was taken at 2–60 min after injection. The hepatic hilum was occluded under laparotomy and then the propofol injection and blood sampling were repeated as above 24 h later. The plasma concentrations of propofol were analyzed and UGT1A6 mRNA expression in the kidney, small intestine, lung and brain from other cohort rats at 30 and 60 min of anhepatic status were semiqualified by RT-PCR. Results: T1/2α,T1/2β and Vd of propofol were not changed significantly before and during the anhepatic status. The area under curve, derived from a time-dependent concentration response curve, was significantly increased whereas plasma clearance rate was decreased significantly in the anhepatic period when compared to that in the control period, respectively. UGT1A6 mRNA expression in extrahepatic organs was significantly increased at 30 or 60 min of the anhepatic status when compared to those in the control status. Conclusion: The pharmacokinetics of propofol during the prehepatic and anhepatic status are largely similar, which is associated with the upregulation of extrahepatic UGT1A6 gene. The marginal accumulation of propofol during anhepatic period is likely to be due to both the limited function of this metabolic pathway and physiological disturbance induced by hepatic hilum occlusion.
Computed Tomographic Angiography: Diagnostic Procedure of Choice in the Management of Subarachnoid Hemorrhage in the Elderly Patient?
Authors: Pechlivanis I. , Harders A. , Tüttenberg J. , Barth M. , Schulte-Altedorneburg G. , Schmieder K.
Published: September 2009

Background: The objective of this study was to establish whether 3D computed tomographic angiography (CTA) can be used to determine further management in patients older than 70 years admitted with acute subarachnoid hemorrhage (SAH). Patients and Methods: CTA evaluation included analysis of the source images, image-slice-based multiplanar reconstruction, multi-intensity projection (MIP) and finally 3-dimensional rendering. The location and size of the aneurysm, its precise anatomical morphology and the configuration of the circle of Willis were evaluated. Based on these findings, surgery, endovascular coiling or conservative management was selected. Results: Between October 2001 and June 2005, 44 patients over 70 years of age (38 females, 6 males) were admitted to our neurosurgical department with acute SAH. All patients underwent CTA, and additional 2D digital subtraction angiography (2D-DSA) was performed in 14 patients. Forty-five aneurysms (38 ruptured and 7 unruptured) were diagnosed. Six patients were found to have SAH of unknown origin (no aneurysm on CTA nor 2D-DSA). In 20 patients surgery was performed, in 10 patients endovascular coiling of the aneurysm was carried out, and 12 patients were treated conservatively. The findings on CTA and 2D-DSA could be compared for 26 patients (59%). Correlation between CTA and 2D-DSA was good in 25 of these cases (96%). Glasgow Outcome Scale scores of 4 or 5 were calculated for 37% of the operated patients, 27% of those treated with coils, and 36% of the patients treated conservatively. Conclusion: In older patients with degenerative vascular diseases, CTA can replace 2D-DSA in most cases if the image quality is excellent and analysis is performed carefully.
Validity and Reliability of the SF-36 Administered to Caregivers of Patients with Alzheimer’s Disease: Evidence from a South American Sample
Authors: Machnicki Gerardo , Allegri Ricardo F. , Ranalli Cristina G. , Serrano Cecilia M. , Dillon Carol , Wyrwich Kathleen W. , Taragano Fernando E.
Published: September 2009

Background: Being a caregiver of a patient with Alzheimer’s disease is associated with impaired health status and declines in health-related quality of life (HRQoL). This paper evaluates the reliability and validity of the Argentinean version of the Medical Outcomes Study Short-Form Health Survey (SF-36) among caregivers of patients with Alzheimer’s disease. Methods: Forty-eight caregivers of Alzheimer’s disease patients completed the SF-36, the Zarit Burden Interview (ZBI) and the Neuropsychiatric Inventory (NPI). Patients were evaluated for dementia severity using the Clinical Dementia Rating (CDR) and for cognitive status using the Mini Mental State Examination (MMSE). Results: The SF-36 scales demonstrated adequate-to-strong internal consistency (Cronbach’s alpha range: 0.72 to 0.92). Correlations between the SF-36 scales and the ZBI were moderate to strong (range: –0.19 to –0.79, all p < 0.01 expect for physical function). Significant correlations between the SF-36 scales and the CDR, MMSE and NPI were lower (range: –0.30 to –0.40, p < 0.001) and strongest in mental health-related scales of the SF-36. The SF-36 demonstrated good factorial validity. Conclusions: The Argentinean translation of the SF-36 is reliable and valid for use to measure the HRQoL of caregivers of patients with Alzheimer’s disease.
Effect of Intermittent Hypercapnia on Respiratory Control in Rat Pups
Authors: Steggerda Justin A. , Mayer Catherine A. , Martin Richard J. , Wilson Christopher G.
Published: September 2009

Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventilatory response to subsequent hypercapnic and hypoxic exposure in neonatal rat pups. Exposure cycles consisted of 5 min of intermittent hypercapnia (5% CO2, 21% O2, balance N2) followed by 10 min of normoxia. Rat pups were exposed to 18 exposure cycles each day for 1 week, from postnatal day 7 to 14. We analyzed diaphragm electromyograms (EMGs) from pups exposed to subsequent acute hypercapnic (5% CO2) and hypoxic (12% O2) challenges. In response to a subsequent hypercapnia challenge, there was no significant difference in the ventilatory response between control and intermittent hypercapnia-exposed groups. In contrast, intermittent hypercapnia-exposed rat pups showed an enhanced ventilatory response to hypoxic challenge with an increase in minute EMG to 118 ± 14% of baseline versus 107 ± 13% for control pups (p < 0.05). We speculate that prior hypercapnic exposure may increase peripheral chemoreceptor response to subsequent hypoxic exposures and result in perturbed neonatal respiratory control.
Cardiac Output Measurement in Ventilated Lambs with a Significant Left-to-Right Shunt Using the Modified Carbon Dioxide Fick Method
Authors: de Boode Willem P. , Hopman Jeroen C.W. , Wijnen Marc H.W.A. , Tanke Ronald B. , van der Hoeven Hans G. , Liem K. Djien
Published: September 2009

Background: It remains a great challenge to measure systemic blood flow in critically ill newborns. In a former study we validated the modified carbon dioxide Fick (mCO2F) method for measurement of cardiac output in a newborn lamb model. In this new study we studied the influence of a left-to-right shunt on the accuracy of the mCO2F method. Objective: To analyze the influence of a left-to-right shunt on the agreement between cardiac output measurement with the mCO2F method and ultrasonic transit time pulmonary blood flow in a lamb model. Methods: The study was approved by the Ethical Committee on Animal Research of the Radboud University Nijmegen and performed in 8 random-bred lambs. A Gore-Tex® shunt was placed between the left pulmonary artery and the descending aorta. This aortopulmonary shunt was intermittently opened and closed, while cardiac output was manipulated by creating hemorrhagic hypotension. Cardiac output measurement with the mCO2F method (QmCO2F) was compared with pulmonary blood flow obtained by a transit time ultrasonic flow probe positioned around the common pulmonary artery (QAPC). Results: Bias, defined as QmCO2F – QAPC, was calculated for each measurement. With an open shunt there was a significant left-to-right shunt (mean Qp/Qs ratio 2.26; range 1.56–3.69). Mean bias (SD) was –12.3 (50.4) ml·kg–1·min–1 and –12.3 (42.7) ml·kg–1·min–1 for measurements with a closed and open shunt, respectively (no statistical significant difference). Conclusions: Cardiac output measurement with the mCO2F method is reliable and easily applicable in ventilated newborn lambs, also in the presence of a significant left-to-right shunt.
NFKB1 –94 Insertion/Deletion ATTG Polymorphism in Gastroenteropancreatic Neuroendocrine Tumors
Authors: Burnik Ferda Sevimli , Yalçın Şuayib
Published: September 2009

Nuclear factor-κB (NF-κB) is a transcription factor responsible for modulating the expression of many genes involved in immune response, inflammatory process, cell growth and survival. A functional and common promoter polymorphism of the NF-κB1 (NFKB1) gene leads to alteration in the activation pattern and expression of NF-κB, and thus, is probably associated with carcinogenesis. The aim of this study was to detect the importance and the frequency of NFKB1 –94 insertion/deletion ATTG promoter polymorphism in patients with gastroenteropancreatic neuroendocrine tumor. A case-control cohort including 50 patients with gastroenteropancreatic neuroendocrine tumor and 100 healthy controls was genotyped with the polymerase chain reaction method. Polymerase chain reaction products were analyzed in agarose gel electrophoresis and processed with the Van91I restriction enzyme. There are 2 cleavage points on the amplified region. When ATTG insertion or deletion is present, the function of restriction enzyme changes. Thirty patients (60%) had ID (insertion/deletion), 18 (36%) had II (insertion/insertion) and 2 (4%) had DD (deletion/deletion) genotypes. Fifty-eight of the control group (58%) had ID, 30 (30%) had II and 12 (12%) had DD genotypes. The frequencies of D and I alleles were 34 and 66 in the study group, and 82 and 118 in the control group, respectively. Although the frequencies of I and D alleles and genotype distribution did not differ between the study and control groups, there seem to be important differences concerning the DD genotype analyses of the NFKB1 –94ins/delATTG promoter polymorphism between patients with pancreatic neuroendocrine tumor and those with carcinoid tumor. This may support the view that the genetics of carcinoid tumors and pancreatic neuroendocrine tumors are different and should be further studied.
Uric Acid: A Novel Risk Factor for Acute Kidney Injury in High-Risk Cardiac Surgery Patients?
Authors: Ejaz A. Ahsan , Beaver Thomas M. , Shimada Michiko , Sood Puneet , Lingegowda Vijaykumar , Schold Jesse D. , Kim Tad , Johnson Richard J.
Published: September 2009

Background: Uric acid has been reported to be a risk factor for the development of chronic kidney disease; however, no study has examined whether uric acid may confer a risk for acute kidney injury. Methods: We investigated the relation between serum uric acid and the incidence of postoperative acute kidney injury in patients undergoing high-risk cardiovascular surgery (cardiac valve and aneurysm surgery). Results: Following cardiovascular surgery, 18 of 58 patients (31%) developed acute kidney injury, with 11 of 24 (45.8%) in the elevated uric acid group (defined as >6 mg/dl) and 7 of 34 (20.5%) in the normal uric acid group (p = 0.05). After controlling for baseline renal function, left ventricular ejection fraction, use of nesiritide, type of surgery, and history of previous surgery, an elevated preoperative uric acid conferred a 4-fold risk for acute kidney injury (OR: 3.98, CI: 1.10–14.33, p = 0.035) and longer hospital stay (36.35 vs. 24.66 days, p = 0.009). Conclusion: This preliminary study suggests that uric acid may be a novel risk factor for acute kidney injury in patients undergoing high-risk cardiovascular surgery.
Remote Magnetic Catheter Navigation for Cavotricuspid Isthmus Ablation in Patients With Common-Type Atrial Flutter
Authors: Vollmann Dirk , Lüthje Lars , Seegers Joachim , Hasenfuss Gerd , Zabel Markus
Published: September 2009

Background—

Conventional catheter ablation of cavotricuspid isthmus (CTI)-dependent atrial flutter is a widely applied standard therapy. Remote magnetic catheter navigation (RMN) may provide benefits for different ablation procedures, but its efficacy for CTI ablation has not been evaluated in a randomized, controlled trial.

Methods and Results—

Ninety patients undergoing de novo ablation of atrial flutter were randomly assigned to conventional manual (n=45) or RMN-guided (n=45) CTI ablation with an 8-mm-tip catheter. Complete bidirectional isthmus block was achieved in 84% (RMN) and 91% (conventional catheter ablation) of the cases (
P
=0.52). RMN was associated with shorter fluoroscopy time (median, 10.6 minutes; interquartile range [IQR], 7.6 to 19.9, versus 15.0 minutes; IQR, 11.5 to 23.1;
P
=0.043) but longer total radiofrequency application (17.1 minutes; IQR, 8.6 to 25, versus 7.5 minutes; IQR, 3.6 to 10.9;
P
<0.0001), ablation time (55 minutes; IQR, 28 to 76, versus 17 minutes; IQR, 7 to 31;
P
<0.0001), and procedure duration (114�35 versus 77�24 minutes,
P
<0.0001). Procedure duration in the RMN group did not decrease significantly with case experience. Long-term procedure success, defined as achievement of complete CTI block and freedom from atrial flutter recurrence during 6 months of follow-up, was lower in the RMN group (73% versus 89%,
P
=0.063). Right atrial angiography after ablation revealed no significant differences between groups in terms of right atrial diameter or CTI length, morphology, and angulation. Furthermore, none of these parameters was predictive for difficult (ablation time >20 minutes) or unsuccessful ablation.

Conclusions—

RMN-guided CTI ablation is associated with reduced radiation exposure but prolonged ablation and procedure times as compared with conventional catheter navigation. Our findings suggest that ablation lesions produced with an RMN-guided 8-mm catheter are less effective irrespective of CTI anatomy.

Trial Registration—

clinicaltrials.gov Identifier: NCT00560872
Cardiac Na
+
Current Regulation by Pyridine Nucleotides
Authors: Liu Man , Sanyal Shamarendra , Gao Ge , Gurung Iman S. , Zhu Xiaodong , Gaconnet Georgia , Kerchner Laurie J. , Shang Lijuan L. , Huang Christopher L.-H. , Grace Andrew , London Barry , Dudley Samuel C.
Published: September 2009

Rationale
:

Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na
+
current (
I
Na
) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism.

Objective
:

Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na
v
1.5).

Methods and Results
:

HEK293 cells stably expressing Na
v
1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD
+
on arrhythmic risk was evaluated in wild-type or SCN5A
+/−
mouse heart. A280V GPD1-L caused a 2.48±0.17-fold increase in intracellular NADH level (
P
<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased
I
Na
(0.48±0.09 or 0.19±0.04 of control group, respectively;
P
<0.01), which was reversed by NAD
+
, chelerythrine, or superoxide dismutase. NAD
+
antagonism of the Na
+
channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI
6–22
. The effects of NADH and NAD
+
were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD
+
to SCN5A
+/−
mouse hearts ameliorated the risk of ventricular tachycardia.

Conclusions
:

Our results show that Na
v
1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and
I
Na
. This effect required protein kinase C activation and was mediated by oxidative stress. NAD
+
could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na
v
1.5 by altering the oxidized to reduced NAD(H) balance.
Decreased Expression and Activity of cAMP Phosphodiesterases in Cardiac Hypertrophy and Its Impact on β-Adrenergic cAMP Signals
Authors: Abi-Gerges Aniella , Richter Wito , Lefebvre Florence , Mateo Philippe , Varin Audrey , Heymes Christophe , Samuel Jane-Lise , Lugnier Claire , Conti Marco , Fischmeister Rodolphe , Vandecasteele Grégoire
Published: September 2009

Rationale
:

Multiple cyclic nucleotide phosphodiesterases (PDEs) degrade cAMP in cardiomyocytes but the role of PDEs in controlling cAMP signaling during pathological cardiac hypertrophy is poorly defined.

Objective
:

Evaluate the β-adrenergic regulation of cardiac contractility and characterize the changes in cardiomyocyte cAMP signals and cAMP-PDE expression and activity following cardiac hypertrophy.

Methods and Results
:

Cardiac hypertrophy was induced in rats by thoracic aortic banding over a time period of 5 weeks and was confirmed by anatomic measurements and echocardiography. Ex vivo myocardial function was evaluated in Langendorff-perfused hearts. Engineered cyclic nucleotide-gated (CNG) channels were expressed in single cardiomyocytes to monitor subsarcolemmal cAMP using whole-cell patch-clamp recordings of the associated CNG current (
I
CNG
). PDE variant activity and protein level were determined in purified cardiomyocytes. Aortic stenosis rats exhibited a 67% increase in heart weight compared to sham-operated animals. The inotropic response to maximal β-adrenergic stimulation was reduced by ≈54% in isolated hypertrophied hearts, along with a ≈32% decrease in subsarcolemmal cAMP levels in hypertrophied myocytes. Total cAMP hydrolytic activity as well as PDE3 and PDE4 activities were reduced in hypertrophied myocytes, because of a reduction of PDE3A, PDE4A, and PDE4B, whereas PDE4D was unchanged. Regulation of β-adrenergic cAMP signals by PDEs was blunted in hypertrophied myocytes, as demonstrated by the diminished effects of IBMX (100 μmol/L) and of both the PDE3 inhibitor cilostamide (1 μmol/L) and the PDE4 inhibitor Ro 201724 (10 μmol/L).

Conclusions
:

β-Adrenergic desensitization is accompanied by a reduction in cAMP-PDE and an altered modulation of β-adrenergic cAMP signals in cardiac hypertrophy.
Tbx1
Regulates Proliferation and Differentiation of Multipotent Heart Progenitors
Authors: Chen Li , Fulcoli Filomena Gabriella , Tang Susan , Baldini Antonio
Published: September 2009

Rationale
:

TBX1
encodes a T-box transcription factor implicated in DiGeorge syndrome, which affects the development of many organs, including the heart. Loss of
Tbx1
results into hypoplasia of heart regions derived from the second heart field, a population of cardiac progenitors cells (CPCs). Thus, we hypothesized that
Tbx1
is an important player in the biology of CPCs.

Objective
:

We asked whether
Tbx1
is expressed in multipotent CPCs and, if so, what role it may play in them.

Methods and Results
:

We used clonal analysis of
Tbx1
-expressing cells and loss and gain of function models, in vivo and in vitro, to define the role of Tbx1 in CPCs. We found that
Tbx1
is expressed in multipotent heart progenitors that, in clonal assays, can give rise to 3 heart lineages expressing endothelial, smooth muscle and cardiomyocyte markers. In multipotent cells, Tbx1 stimulates proliferation, explaining why
Tbx1
−/−
embryos have reduced proliferation in the second heart field. In this population, Tbx1 is expressed while cells are undifferentiated and it disappears with the onset of muscle markers. Loss of
Tbx1
results in premature differentiation, whereas gain results in reduced differentiation in vivo. We found that Tbx1 binds serum response factor, a master regulator of muscle differentiation, and negatively regulates its level.

Conclusions
:

The Tbx1 protein marks CPCs, supports their proliferation, and inhibits their differentiation. We propose that
Tbx1
is a key regulator of CPC homeostasis as it modulates positively their proliferation and negatively their differentiation.
Spontaneous Calcium Oscillations Regulate Human Cardiac Progenitor Cell Growth
Authors: Ferreira-Martins João , Rondon-Clavo Carlos , Tugal Derin , Korn Justin A. , Rizzi Roberto , Padin-Iruegas Maria Elena , Ottolenghi Sergio , De Angelis Antonella , Urbanek Konrad , Ide-Iwata Noriko , D'Amario Domenico , Hosoda Toru , Leri Annarosa , Kajstura Jan , Anversa Piero , Rota Marcello
Published: September 2009

Rationale
:

The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown.

Objective
:

Ca
2+
promotes cell growth raising the possibility that changes in intracellular Ca
2+
initiate division of c-kit–positive human cardiac progenitor cells (hCPCs) and determine their fate.

Methods and Results
:

Ca
2+
oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca
2+
. These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca
2+
oscillations in hCPCs were regulated by the release of Ca
2+
from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca
2+
by the sarco-/endoplasmic reticulum Ca
2+
pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na
+
-Ca
2+
exchanger, store-operated Ca
2+
channels and plasma membrane Ca
2+
pump were present and functional in hCPCs, they had no direct effects on Ca
2+
oscillations. Conversely, Ca
2+
oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca
2+
oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca
2+
oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny.

Conclusion
:

IP3R-mediated Ca
2+
mobilization control hCPC growth and their regenerative potential.
Twenty-Four–Hour Holter Monitor Follow-Up Does Not Provide Accurate Heart Rhythm Status After Surgical Atrial Fibrillation Ablation Therapy
Authors: Hanke Thorsten , Charitos Efstratios I. , Stierle Ulrich , Karluss Antje , Kraatz Ernst , Graf Bernhard , Hagemann Axel , Misfeld Martin , Sievers Hans H.
Published: September 2009

Background—

Twenty-four–hour Holter monitoring (24HM) is commonly used to assess cardiac rhythm after surgical therapy of atrial fibrillation (AF). However, this “snapshot” documentation leaves a considerable diagnostic window and only stores short-time cardiac rhythm episodes. To improve accuracy of rhythm surveillance after surgical ablation therapy and to compare continuous heart rhythm surveillance versus 24HM follow-up intraindividually, we evaluated a novel implantable continuous cardiac rhythm monitoring (IMD) device (Reveal XT 9525).

Methods and Results—

Forty-five cardiac surgical patients (male 37, mean age 69.7±9.2 years) with a mean preoperative AF duration of 38±45 m were treated with either left atrial epicardial high-intensity focus ultrasound ablation (n=33) or endocardial cryothermy (n=12) in case of concomitant mitral valve surgery. Rhythm control readings were derived simultaneously from 24HM and IMD at 3-month intervals with a total recording of 2021 hours for 24HM and 220 766 hours for IMD. Mean follow-up was 8.30±3.97 m (range 0 to 12 m). Mean postoperative AF burden (time period spent in AF) as indicated by IMD was 37±43%. Sinus rhythm was documented in 53 readings of 24HM, but in only 34 of these instances by the IMD in the time period before 24HM readings (64%,
P
<0.0001), reflecting a 24HM sensitivity of 0.60 and a negative predictive value of 0.64 for detecting AF recurrence.

Conclusion—

For “real-life” cardiac rhythm documentation, continuous heart rhythm surveillance instead of any conventional 24HM follow-up strategy is necessary. This is particularly important for further judgment of ablation techniques, devices as well as anticoagulation and antiarrhythmic therapy.
Does Reasonable Incomplete Surgical Revascularization Affect Early or Long-Term Survival in Patients With Multivessel Coronary Artery Disease Receiving Left Internal Mammary Artery Bypass to Left Anterior Descending Artery?
Authors: Rastan Ardawan Julian , Walther Thomas , Falk Volkmar , Kempfert Joerg , Merk Denis , Lehmann Sven , Holzhey David , Mohr Friedrich Wilhelm
Published: September 2009

Background—

The objective was to evaluate the impact of complete revascularization (CR) versus reasonable incomplete surgical revascularization (IR) in others than left anterior descending artery territory on early and late survival in patients with multivessel coronary artery disease (CAD).

Methods and Results—

During a 7-year period, 8.806 consecutive patients with multivessel CAD affecting the proximal left anterior descending artery or left main stem underwent sternotomy for isolated coronary artery bypass grafting including left internal mammary artery-left anterior descending artery bypass. A total of 936 patients (10.6%) had IR of the circumflex or right coronary artery territory. IR was based on the traditional classification. Follow-up was 3.5±2.2 years. Patient groups were comparable regarding age (CR 67.1 versus IR 67.6 years), ejection fraction (57.2% versus 57.5%), and logEuroscore (4.5% versus 4.5%). Patients receiving IR presented with more complex CAD. Mean number of distal anastomoses was 3.0±0.8 CR versus 2.4±0.6 IR. Operation time (176 versus 187 minutes) and cross-clamp time (52 versus 56 minutes) were longer in the IR group (
P
<0.001). Hospital mortality was 3.3% CR versus 3.2% IR (
P
=0.520). Independent risk factors for hospital mortality were age, pulmonary hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and emergency indication, but not IR (
P
=0.922). Arterial revascularization was protective. Cumulative survival at 1-year was 93.1% CR versus 93.6% IR and at 5 years 82.2 CR versus 80.9% IR (
P
=0.457).

Conclusions—

In presence of left internal mammary artery-to-left anterior descending artery bypass, reasonable IR of the circumflex or right coronary artery territory did not adversely affect early or long-term survival in patients with multivessel CAD. In patients presenting with 1 poor target vessel; however, IR is a good therapeutic option and the benefit of CR should be balanced against the risks.
Mesenchymal Cell Transplantation and Myocardial Remodeling After Myocardial Infarction
Authors: Dixon Jennifer A. , Gorman Robert C. , Stroud Robert E. , Bouges Shenikqua , Hirotsugu Hamamoto , Gorman Joseph H. , Martens Timothy P. , Itescu Silviu , Schuster Michael D. , Plappert Theodore , St John-Sutton Martin G. , Spinale Francis G.
Published: September 2009

Background—

Targeted delivery of mesenchymal precursor cells (MPCs) can modify left ventricular (LV) cellular and extracellular remodeling after myocardial infarction (MI). However, whether and to what degree LV remodeling may be affected by MPC injection post-MI, and whether these effects are concentration-dependent, remain unknown.

Methods and Results—

Allogeneic MPCs were expanded from sheep bone marrow, and direct intramyocardial injection was performed within the borderzone region 1 hour after MI induction (coronary ligation) in sheep at the following concentrations: 25×10
6
(25 M, n=7), 75×10
6
(75 M, n=7), 225×10
6
(225 M, n=10), 450×10
6
(450 M, n=8), and MPC free media only (MI Only, n=14). LV end diastolic volume increased in all groups but was attenuated in the 25 and 75 M groups. Collagen content within the borderzone region was increased in the MI Only, 225, and 450 M groups, whereas plasma ICTP, an index of collagen degradation, was highest in the 25 M group. Within the borderzone region matrix metalloproteinases (MMPs) and MMP tissue inhibitors (TIMPs) also changed in a MPC concentration–dependent manner. For example, borderzone levels of MMP-9 were highest in the 25 M group when compared to the MI Only and other MPC treatment group values.

Conclusions—

MPC injection altered collagen dynamics, MMP, and TIMP levels in a concentration-dependent manner, and thereby influenced indices of post-MI LV remodeling. However, the greatest effects with respect to post-MI remodeling were identified at lower MPC concentrations, thus suggesting a therapeutic threshold exists for this particular cell therapy.
Preoperative sCD40L Levels Predict Risk of Atrial Fibrillation After Off-Pump Coronary Artery Bypass Graft Surgery
Authors: Antoniades Charalambos , Van-Assche Tim , Shirodaria Cheerag , Diesch Jonathan , Antonopoulos Alexios S. , Lee Justin , Cunnington Colin , Tousoulis Dimitris , Stefanadis Christodoulos , Casadei Barbara , Taggart David , Channon Keith M. , Leeson Paul
Published: September 2009

Background—

The risk of atrial fibrillation (AF) after coronary bypass surgery has been related to redox state, inflammation, and ischemia. Platelet activation is common to all of these pathways. We investigated the relation between AF and preoperative soluble CD40 ligand (sCD40L), a proinflammatory marker released by activated platelets. Furthermore, we studied the role of inflammation, endothelial function, and redox state in this relation.

Methods and Results—

sCD40L levels were measured in 144 patients in sinus rhythm the day before off-pump coronary artery surgery. Systemic inflammation was assessed from levels of C-reactive protein and soluble intercellular adhesion molecule-1, and endothelial function was assessed from the brachial artery flow–mediated dilatation response. Graft samples were collected during surgery to assess vascular redox state. AF occurred in 33% of patients after surgery, with 3% still in AF after 6 weeks. Preoperative sCD40L levels were significantly higher in those who developed in-hospital AF (odds ratio for a 1-SD increase in log[sCD40L]=1.97; 95% CI, 1.21 to 3.22;
P
=0.007; after adjustment for age, sex, Euroscore, and total duration of operation). sCD40L and vascular superoxide levels were higher in patients still in AF at 6 weeks, and endothelial function was lower, although the small number of events precluded statistical analysis in this group. Systemic endothelial function, redox state, and preoperative markers of systemic inflammation were not associated with in-hospital postoperative AF.

Conclusions—

Preoperative platelet activation, as assessed by sCD40L levels, is a novel predictor of postoperative AF, independent of systemic endothelial function, vascular redox state, and systemic inflammation.