bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting HER-2/neuin Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion
Authors: Czerniecki Brian J. , Koski Gary K. , Koldovsky Ursula , Xu Shuwen , Cohen Peter A. , Mick Rosemarie , Nisenbaum Harvey , Pasha Terry , Xu Min , Fox Kevin R. , Weinstein Susan , Orel Susan G. , Vonderheide Robert , Coukos George , DeMichele Angela , Araujo Louis , Spitz Francis R. , Rosen Mark , Levine Bruce L. , June Carl , Zhang Paul J.
Published: February 2007

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neupos DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-γ and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu–HLA-A2 tetramer-staining CD8pos T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-γ–secreting CD4pos (85%) and CD8pos (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of “immunoediting” for HER-2/neu–expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer. [Cancer Res 2007;67(4):1842–52]
APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer
Authors: Samowitz Wade S. , Slattery Martha L. , Sweeney Carol , Herrick Jennifer , Wolff Roger K. , Albertsen Hans
Published: February 2007

Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P = 0.0003) and CIMP (P = 0.02) and directly related to p53 and Ki-ras mutations (P = 0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P = 0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P = 0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%). In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer. (Mol Cancer Res 2007;5(2):165–70)
Correlating breakage-fusion-bridge events with the overall chromosomal instability and in vitro karyotype evolution in prostate cancer
Authors: Vukovic B. , Beheshti B. , Park P. , Lim G. , Bayani J. , Zielenska M. , Squire J.A.
Published: February 2007

Chromosomal instability (CIN) is thought to underlie the generation of chromosomal changes and genomic heterogeneity during prostatic tumorigenesis. The breakage-fusion-bridge (BFB) cycle is one of the CIN mechanisms responsible for characteristic mitotic abnormalities and the occurrence of specific classes of genomic rearrangements. However, there is little detailed information concerning the role of BFB and CIN in generating genomic diversity in prostate cancer. In this study we have used molecular cytogenetic methods and array comparative genomic hybridization analysis (aCGH) of DU145, PC3, LNCaP, 1532T and 1542T to investigate the in vitro role of BFB as a CIN mechanism in karyotype evolution. Analysis of mitotic structures in all five prostate cancer cell lines showed increased frequency of anaphase bridges and nuclear strings. Structurally rearranged dicentric chromosomes were observed in all of the investigated cell lines, and Spectral Karyotyping (SKY) analysis was used to identify the participating rearranged chromosomes. Multicolor banding (mBAND) and aCGH analysis of some of the more complex chromosomal rearrangements and associated amplicons identified inverted duplications, most frequently involving chromosome 8. Chromosomal breakpoint analysis showed there was a higher frequency of rearrangement at centromeric and pericentromeric genomic regions. The distribution of inverted duplications and ladder-like amplifications was mapped by mBAND and by aCGH. Adjacent spacing of focal amplifications and microdeletions were observed, and focal amplification of centromeric and end sequences was present, particularly in the most unstable line DU145. SKY analysis of this line identified chromosome segments fusing with multiple recipient chromosomes (jumping translocations) identifying potential dicentric sources. Telomere free end analysis indicated loss of DNA sequence. Moreover, the cell lines with the shortest telomeres had the most complex karyotypes, suggesting that despite the expression of telomerase, the reduced telomere length could be driving the observed BFB events and elevated levels of CIN in these lines.
Characterisation of supernumerary chromosomal markers: a study of 13 cases
Authors: Douet-Guilbert N. , Marical H. , Pinson L. , Herry A. , Le Bris M.J. , Morel F. , De Braekeleer M.
Published: February 2007

Marker chromosomes are defined as ‘structurally abnormal chromosomes in which no part can be identified’ (ISCN 1995). Supernumerary marker chromosomes (SMC) are ‘additional markers’ whose origin and composition cannot be determined by conventional cytogenetics. Molecular cytogenetic methods are necessary to identify these additional chromosomal markers. In one third, the SMCs are clinically well-defined in the literature, the remaining two thirds present a major problem for genetic counselling in prenatal diagnosis. At present, different molecular cytogenetic methods are used to determine the origin of SMCs. In this work, we studied 13 SMCs detected by RHG-banding, completed by C-banding and/or NOR-staining. 24-color FISH was used as the primary technique when the chromosomal origin was unknown. Targeted FISH procedures with specific probes (whole chromosome painting, centromeric probe, locus-specific identifier, BAC, etc.) were then performed to confirm and/or specify the chromosomal material present in the SMC. Seven SMCs were found to be associated with phenotypic abnormalities. Five derived from autosomes and two from gonosomes; these are: der(12)t(4;12), dic(15), i(18p), r(19), der(22)t(11;22), r(X), and der(Y). Two markers, r(8) and idic(15), were identified during investigations of infertile couples. Three cases seemed to be phenotypically normal. Four were discovered prenatally: r(2) and r(19) referred for elevated maternal serum markers, der(13/21) referred for advanced maternal age. The fourth SMC, der(14/22), was found during familial investigation following the identification of the same marker in an infertile son. The precise characterisation of the SMCs is of utmost importance for genetic counselling, especially in prenatal diagnosis.
Identification of a human chromosome-specific interstitial telomere-like sequence (ITS) at 22q11.2 using double-strand PRINS
Authors: Yan J. , Bouchard E.F. , Samassekou O. , Chen B.-Z.
Published: February 2007

Interstitial telomeric sequences (ITSs), telomere-like repeats at intrachromosomal sites, are common in mammals and consist of tandem repeats of the canonical telomeric repeat, TTAGGG, or a repeat similar to this. We report that the ITS in human chromosome region 22q11.2 is, in the sequenced genome database, 101 tandem repeats of the sequence TTAGGGAGG. Using the primed in situ labeling (PRINS) technique and primers against the canonical telomeric repeat (TTAGGG), we illuminated telomeric sites for all chromosomes and an ITS locus at 22q11.2. Using the TTAGGGAGG sequence, we designed PRINS primers that efficiently and specifically illuminate the 22q11.2 ITS locus without illuminating telomeric and other ITS loci. The 22q11.2 locus has more repeat units than other ITSs loci enabling an unprecedented high detection frequency for this interstitial telomere locus. The 22q11.2 is associated with hot spots for disease-related chromosome breaks for multiple disorders, such as DiGeorge syndrome and chronic myeloid leukemia. We describe our findings that the ITS at 22q11.2 is in the same area of, and proximal to the common rearrangement region of multiple disorders. We suggest that the ITS might be involved in DNA repair processes in this area to protect the chromosome from more serious damage.
Genomic structure and transcript variants of the bovine DAZL gene
Authors: Liu W.-S. , Wang A. , Uno Y. , Galitz D. , Beattie C.W. , Ponce de León F.A.
Published: February 2007

The Deleted in AZoospermia Like (DAZL) gene is a member of the DAZ family and encodes an RNA-binding protein that is expressed in prenatal and postnatal germ cells of males and females. In the human, there are five highly-related members in the DAZ family, four (DAZ1–4) on the Y chromosome and one (DAZL) on an autosome (HSA3). Mutations in these genes have been linked to severe spermatogenic failure and infertility in men. In the present study, we have cloned and characterized the bovine DAZL (bDAZL) gene. The full-length bDAZL cDNA is predicted to encode a protein of 295 amino acids with an RNA recognition motif. The deduced protein sequence of bDAZL is 96 and 97% similar to human and mouse DAZL, respectively. Fluorescence in situ hybridization (FISH) maps bDAZL to the distal region on BTA1q. The bDAZL gene consists of 11 exons and 10 introns. A bDAZL pseudogene was identified on BTA16. Expression analysis of bDAZL in 13 different tissues by RT-PCR shows that two transcripts, variant 1 (2,996 bp) and variant 2 (1,373 bp), of the bDAZL gene are detected only in testis mRNA. The variants probably result from alternative RNA splicing as variant 1 contains an additional 1,623-bp insertion in the 3′ UTR. Our results lay the groundwork for possible single nucleotide polymorphism (SNP) and functional studies of the DAZL gene in cattle.
Sexual Function after Tension-Free Vaginal Tape Procedure
Authors: Marszalek Martin , Roehlich Michaela , Racz Ursula , Metzenbauer Martin , Ponholzer Anton , Rauchenwald Michael , Madersbacher Stephan
Published: February 2007

Introduction: Aim of this cross-sectional study was to analyze the sexual function of women after tension-free vaginal tape (TVT) procedure. Patients and Methods: To evaluate the female sexual function after the TVT procedure, we designed a 36-item questionnaire including 21 questions on incontinence, 15 questions on sexuality and 3 questions on the personal impression of the procedure. Diagnostic workup consisted of a detailed medical history, urinalysis, postvoid residual urine volume assessment, ultrasound of the kidney and a urodynamic study. Results: Fifty-two women completed the entire questionnaire. Overall, 82.7% of the women were satisfied with the TVT procedure. A proportion of 74.0% indicated that they became totally continent after the operation. One third of the sexually active women reported an improvement of their sexual life after TVT, 14.3% a worsening, and 52.4% reported no change. Deterioration of sexual function was significantly associated with de novo urge, dyspareunia and sensation of postvoid residual urine volume. Conclusion: In summary, our investigations showed that the influence of the TVT procedure on female sexual function is evident, but of low impact, and in general will not be of relevance.
Impact of the Level of Muscle Invasion in Organ-Confined Bladder Cancer
Authors: Girgin Cengiz , Sezer Akif , Delibaş Mustafa , Şahin Oğuz , Öder Mehmet , Dinçel Çetin
Published: February 2007

Objective: We evaluated whether there is a survival difference between patients having pT2a and pT2b invasive bladder carcinomas without nodal involvement and distant metastases. Patients and Methods: Three hundred and thirty-six patients with invasive carcinomas of the bladder underwent radical cystectomy. Seventy-five patients with organ-confined disease were evaluated. The pathological stage was used as predictor of survival. Kaplan-Meier method and log-rank test were used to evaluate survival rates. Cox proportional-hazard models were used to identify whether pathological stage, grade, diversion type, age, and gender affect the outcome. Results: Thirty-five patients were in the pT2aN0 group with a mean age of 57.8 ± 1.4 (range 37–76) years, and 40 patients were in the pT2bN0 group with a mean age of 59.5 ± 1.1 (range 37–76) years. There were 2 female patients. The mean follow-up period was 27.41 ± 20.5 (range 3–80) months. The disease-specific 5-year survival rate of the pT2N0 cases was 80.3%. The disease-specific 5-year survival rates for the pT2aN0 and pT2bN0 patients were 84.3 and 66.0%, respectively. The disease-specific mean survival times of pT2aN0 and pT2bN0 cases were 76.2 ± 4.7 and 56.3 ± 7.7 months, respectively. There was no statistically significant survival difference between pT2aN0 and pT2bN0 patients by log-rank test (p = 0.1767). According to the Cox multivariate regression analysis, stage, grade, diversion type, age, and gender were not predictive of the survival in patients with organ-confined bladder cancer (p > 0.05). Conclusions: The level of muscle invasion in organ-confined bladder cancer does not have an influence on the patient survival. Also stage, grade, diversion type, age, and gender are not predictive of survival in patients with organ-confined muscle-invasive bladder cancer.
Captopril Reduces Interstitial Renal Fibrosis and Preserves More Normal Renal Tubules in Neonatal Dogs with Partial Urethral Obstruction: A Preliminary Study
Authors: Shirazi Mehdi , Noorafshan Ali , Bahri Mohammad Arabzadeh , Tanideh Nader
Published: February 2007

Purpose: Chronic renal damage due to tubulointerstitial fibrosis is one of several complications of posterior urethral valves in a significant number of children. As activation of the renin-angiotensin system plays an important role in this injury, we conducted this study to investigate whether administration of captopril reduced renal fibrosis in an experimental model using partial urethral obstruction (PUO) in neonatal dogs. Material and Methods: Experimental PUO was induced in all pups. These animals were then divided into two groups: in the first group (experimental), captopril 35 mg/kg/day, dissolved in drinking water, was administered for 6 weeks. The second group (positive control) did not receive any treatment. After 6 weeks all dogs underwent left nephrectomy. Volume fraction and absolute volume of the histological kidney parameters, i.e., normal glomerulus, normal tubule, vessels, degenerated glomerulus, degenerated tubule, fibrous tissue, were estimated using modern unbiased stereological methods. Results: The absolute volume of interstitial fibrosis was lower in the experimental group (PUO with captopril treatment) (∼73%; p < 0.008) in comparison with positive control animals (PUO with no treatment). The mean absolute volume of normal tubules in the experimental group was more than the positive control group (∼33%, p < 0.008). The mean absolute volume of normal and degenerated glomerulus, vessels and degenerated tubule did not show a significant difference between the two groups. Conclusion: Administration of captopril decreases interstitial renal fibrosis and preserves renal tubules in neonatal dogs with PUO.
Primäres malignes Melanom der Vagina – Fallbericht und Literaturübersicht
Authors: Betschart C. , von Orelli S. , Mihic D. , Fink D.
Published: February 2007

Das primäre maligne Melanom der Vagina ist ein sehr seltenes Malignom mit weltweit weniger als 300 publizierten Fällen. Noch viel seltener sind Melanommetastasen in der Vagina mit bis anhin 5 beschriebenen Fällen. Bei der von uns beschriebenen Patientin zeigte sich ein von der linken Vaginalwand ausgehendes, 6 cm im Durchmesser messendes und 2,5 cm tiefes Melanom der Vagina ohne lokoregionäre Lymphknoten- oder Fernmetastasen in der Bildgebung. In der Literatur werden als Erfolg versprechendste Therapiemodalitäten die «wide local excision» mit adjuvanter Radiotherapie und die Radikaloperation mit adjuvanter Radiotherapie diskutiert, die ähnliche 5-Jahres-Überlebensraten zeigen. Zur Reduktion des doch erheblichen Risikos der Fernmetastasierung war als weiterführende systemische Therapie eine Immunmodulation mit Interferon-α2b vorgesehen, welche bei fortgeschrittenen Melanomen der Haut etabliert ist. Leider lag bei der Planung der Interferontherapie 6 Monate nach Diagnosestellung im PET-CT eine ausgedehnte Metastasierung vor, so dass anstelle der Interferontherapie eine palliative Chemotherapie mit Dacarbazine und Thalidomid durchgeführt wurde.
C-Reactive Protein Distribution and Correlates among Men and Women with Chronic Coronary Heart Disease
Authors: Benderly M. , Haim M. , Boyko V. , Tanne D. , Behar S. , Matas Z. , Zimlichman R. , Goldbourt U.
Published: February 2007

Background: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. Methods: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. Results: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. Conclusions: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.
Very Late In-Stent Restenosis in a Bare Metal Stent
Authors: Koutouzis Michael , Nikolidakis Savvas , Arealis George , Kyriakides Zenon S.
Published: February 2007

Restenosis after coronary artery stenting is a common phenomenon and represents a topic of great interest. Although a great volume of research is referring to restenosis, still many issues are not fully understood by the cardiological community. Here we present a case of very late restenosis, after a bare metal stent implantation.
‘Syringe-in-the-Pocket’ – A New Approach to the Outpatient Thromboembolic Prophylaxis of Recurrent Atrial Fibrillation
Authors: Kosior Dariusz A. , Torbicki Adam , Opolski Grzegorz
Published: February 2007

Chronic anti-coagulation is not an attractive prospect to patients with atrial fibrillation (AF) after successful restoration of sinus rhythm. We researched the feasibility of self-screening for AF performed by instructed patients and, where necessary, prompt self-administration of an initial dose of low-molecular weight heparin (LMWH) prior to seeking medical attention. Materials and Methods: Persistent AF qualified to elective cardioversion was our focus. Two hundred and sixty-three consecutive patients (M/F: 179/84, mean age: 59.8 ± 8.6) were followed for a mean of 2.6 ± 1.7 years. All patients were trained to identify AF by palpation of the radial pulse and to self-inject LMWH in the case of arrhythmia recurrence. Two hundred and thirty-two patients who correctly recognized AF recurrence and those without episodes of AF during 4 weeks after cardioversion were equipped with nadroparine after acenocoumarol discontinuation. In 191 patients AF recurred during further observation, 172 of them correctly identified AF episodes, including 162 who performed LMWH injections at home. Seven patients who had performed LMWH injections presented with sinus rhythm on arrival to hospital, six patients had AF. Two out of 21 patients who failed to identify their AF episodes and one patient of those who correctly detected the AF recurrence, but failed to perform LMWH self-injection suffered from ischemic stroke (sensitivity 96.1%, specificity 60.4%). No side effects of domiciliary LMWH self-injection were identified. Conclusion: When properly trained, the majority of patients can accurately diagnose AF recurrence and self-inject an initial dose of LMWH, which makes it a feasible and potentially attractive anti-thromboembolic strategy.
Assessment of Atrial Conduction in Patients with Scleroderma by Tissue Doppler Echocardiography and P Wave Dispersion
Authors: Can Ilknur , Onat Ahmet Mesut , Aytemir Kudret , Akdogan Ali , Ureten Kemal , Kiraz Sedat , Ertenli Ihsan , Ozer Necla , Tokgozoglu Lale , Oto Ali
Published: February 2007

Background: Atrial conduction abnormalities in patients with scleroderma have not been evaluated in terms of P wave duration, P wave dispersion (Pd) and electromechanical coupling measured by tissue Doppler echocardiography. Methods: Twenty-four patients with scleroderma and 24 control subjects underwent resting electrocardiogram (ECG), M mode and tissue Doppler echocardiography. The P wave duration was calculated in all leads of the surface ECG. The difference between the maximum (Pmax) and minimum P wave duration was calculated and defined as Pd. Interatrial and intraatrial electromechanical delays were measured with tissue Doppler tissue echocardiography. Results: The left ventricular dimensions, fractional shortening, and left atrial diameter did not differ between the patients and the controls. Pd and Pmax were significantly higher in patients with scleroderma compared with controls: 51 ± 17 versus 28 ± 7 ms (p < 0.01) and 109 ± 10 versus 93 ± 6 ms (p < 0.01), respectively. There was a delay between the onset of the P wave on surface ECG and the onset of the late diastolic wave (A wave; PA) obtained by tissue Doppler echocardiography in patients with scleroderma compared with controls measured at lateral septal annulus (lateral PA; 122 ± 8 vs. 105 ± 7 ms, p = 0.001), septal mitral annulus (104 ± 11 vs. 93 ± 10 ms, p = 0.01) and tricuspid annulus (right ventricular PA; 71 ± 9 vs. 64 ± 7 ms, p = 0.05). Interatrial conduction time (lateral PA – right ventricular PA) was delayed in patients with scleroderma compared with controls (88 ± 13 vs. 76 ± 11 ms, p = 0.01). A positive correlation was detected between interatrial electromechanical delay (lateral PA – right ventricular PA) and Pd (r = 0.5, p = 0.03). Conclusion: Atrial conduction abnormalities as estimated with Pd and Pmax are significantly higher in patients with scleroderma compared with controls. There is a delay in both intraatrial and interatrial electromechanical coupling intervals in patients with scleroderma.
A High Association of Aortic Valve Sclerosis Detected by Transthoracic Echocardiography with Coronary Arteriosclerosis
Authors: Sui Shu-Jian , Ren Man-Yi , Xu Fu-Yu , Zhang Yun
Published: February 2007

Objective: To examine whether aortic valve sclerosis (AVS) detected by transthoracic echocardiography (TTE) has a high association with coronary arteriosclerosis. Methods: Clinical and angiographic features and TTE findings were retrospectively analyzed in a blinded fashion for 138 consecutive patients, of whom 58 had AVS and 80 had non-AVS diseases. Both histological and immunohistochemical studies were performed on frozen aortic valve sections obtained at autopsy from 7 AVS and 3 non-AVS patients. Results: AVS and coronary artery disease (CAD) had similar clinical risk factors. The AVS group had a higher positive rate of coronary angiography and a higher incidence rate of multivessel CAD than the non-AVS group. The sensitivity, specificity, positive predictive value and negative predictive value of AVS in diagnosing CAD were 63.8, 71.3, 61.7 and 73.1%, respectively. Early lesions of AVS were characterized by accumulation of lipid and infiltration of macrophages and T lymphocytes as indicated by immunohistochemical staining. Late lesions were characterized by formation of calcific plaques, proliferation of fibrous connective tissue and immunohistochemical staining identifying a few macrophages or T lymphocytes and little lipid accumulation on the surface of aortic valve leaflets. Late lesions in the basement of aortic valve leaflets were characterized by hyperplastic granulation tissues. Three aortic valve leaflets from the non-AVS group were characterized by nonspecific thickened tips, increased collagen, no calcification, no lipid accumulation and no inflammatory cells. Conclusions: There were significant similarities in clinical risk factors, histopathological alterations of AVS and coronary atherosclerosis. AVS detected by TTE had a high association with coronary arteriosclerosis.
Gender Differences in the Renin-Angiotensin and Nitric Oxide Systems: Relevance in the Normal and Diseased Kidney
Authors: McGuire Barry B. , Watson R. William G. , Pérez-Barriocanal Fernando , Fitzpatrick John M. , Docherty Neil G.
Published: February 2007

Female gender is associated with better renal function and resistance to renal injury, suggesting that an oestrogen-based effect or increased androgenic effects are responsible. Studies in rodents have confirmed a biological basis for this, based on the differential effects of androgens and oestrogens on the normal and diseased kidney. Many researchers in the field believe that the pre-menopausal levels of oestrogen are key to the protection observed in females. The key pressor effects of the renin-angiotensin (RA) system are due to both direct vasoconstrictory properties and alterations in renal control of extracellular fluid volume. Additionally, the RA has been shown to promote diverse aspects of renal injury. RA activity is positively modulated by androgens and antagonized by oestrogens. Nitric oxide (NO) is a potent vasorelaxant with a key role in renal control of extracellular fluid homeostasis. NO can variously have both protective and deleterious effects on renal injury. Endogenous oestrogen has an anti-hypertensive effect as well as protective effects against cell and organ damage, many of which are mediated via increases in NO generation. We examine how the RA- and NO-generating systems may underpin key aspects of gender differences in normal renal function and renal disease.
Primary Lumbar Hernia Repair: The Open Approach
Authors: Cavallaro G. , Sadighi A. , Miceli M. , Burza A. , Carbone G. , Cavallaro A.
Published: February 2007

Background: Lumbar hernias arise through posterolateral abdominal wall defects, named inferior triangle (Petit) and superior triangle (Grynfelt). Most of the lumbar hernias are secondary to trauma or previous surgery, while primary lumbar hernias are rare. There are two possible surgical approaches: the anterior approach with lumbar incision and the laparoscopic (transabdominal or totally extraperitoneal) approach. Methods: We present a series of nine surgical procedures for primary lumbar hernia in 7 adult patients (2 affected by bilateral hernias). Seven were Grynfelt hernias, and two were Petit hernias. All surgical repairs were performed using synthetic mesh placed in the extraperitoneal space, below the muscular layers, using a tension-free technique. Results: There was no surgical complication, except for 1 case with a subcutaneous haematoma. The mean hospital stay was 2.3 days. All patients returned to normal daily activities within 15 days after surgery. After a median follow-up period of 25 months, there was no case of recurrence or postsurgical sequelae, such as pain or muscular weakness. Conclusions: Primary lumbar hernias are rare congenital defects of the abdominal wall. Repair of these rare hernias can be successfully performed via the anterior approach with the use of synthetic mesh – this method of repair is easy, safe, and effective.
Anterior Cerebral Artery A1 Segment Hypoplasia May Contribute to A1 Hypoplasia Syndrome
Authors: Chuang Yu-Ming , Liu Chih-Yang , Pan Po-Jung , Lin Ching-Po
Published: February 2007

Anterior cerebral artery A1 segment hypoplasia is an uncommon fetal variant of the circle of Willis. The frequency of this congenital variation is 1–13% as derived from angiograms and autopsy reports. Impaired collateral blood flow through the circle of Willis is a recognized risk factor for ischemic stroke. The A1 segment of the anterior cerebral artery is a principal supplier of anterior collateral blood flow. The aim of our study was to determine whether A1 segment hypoplasia may be responsible for acute ischemic stroke. We consecutively examined 280 acute ischemic stroke patients (aged 66.9 ± 14.2 years). Cerebral magnetic resonance angiography was performed within 72 h of ischemic stroke onset. The overall incidence of A1 variation in our experimental group was 15.0% (n = 42, agenesis/hypoplasia = 18/24), which was statistically higher than in the control group (n = 12). The majority (n = 30, 71.42%) had ipsilateral striatal lacunar infarctions. Based on our results, A1 agenesis/hypoplasia appears to be a risk factor contributing to ischemic stroke, especially to strokes in arteries penetrating the striatal area.
Detection of Gene × Gene Interactions in Genome-Wide Association Studies of Human Population Data
Authors: Musani Solomon K. , Shriner Daniel , Liu Nianjun , Feng Rui , Coffey Christopher S. , Yi Nengjun , Tiwari Hemant K. , Allison David B.
Published: February 2007

Empirical evidence supporting the commonality of gene × gene interactions, coupled with frequent failure to replicate results from previous association studies, has prompted statisticians to develop methods to handle this important subject. Nonparametric methods have generated intense interest because of their capacity to handle high-dimensional data. Genome-wide association analysis of large-scale SNP data is challenging mathematically and computationally. In this paper, we describe major issues and questions arising from this challenge, along with methodological implications. Data reduction and pattern recognition methods seem to be the new frontiers in efforts to detect gene × gene interactions comprehensively. Currently, there is no single method that is recognized as the ‘best’ for detecting, characterizing, and interpreting gene × gene interactions. Instead, a combination of approaches with the aim of balancing their specific strengths may be the optimal approach to investigate gene × gene interactions in human data.
Symbolic Modeling of Epistasis
Authors: Moore Jason H. , Barney Nate , Tsai Chia-Ti , Chiang Fu-Tien , Gui Jiang , White Bill C.
Published: February 2007

The workhorse of modern genetic analysis is the parametric linear model. The advantages of the linear modeling framework are many and include a mathematical understanding of the model fitting process and ease of interpretation. However, an important limitation is that linear models make assumptions about the nature of the data being modeled. This assumption may not be realistic for complex biological systems such as disease susceptibility where nonlinearities in the genotype to phenotype mapping relationship that result from epistasis, plastic reaction norms, locus heterogeneity, and phenocopy, for example, are the norm rather than the exception. We have previously developed a flexible modeling approach called symbolic discriminant analysis (SDA) that makes no assumptions about the patterns in the data. Rather, SDA lets the data dictate the size, shape, and complexity of a symbolic discriminant function that could include any set of mathematical functions from a list of candidates supplied by the user. Here, we outline a new five step process for symbolic model discovery that uses genetic programming (GP) for coarse-grained stochastic searching, experimental design for parameter optimization, graphical modeling for generating expert knowledge, and estimation of distribution algorithms for fine-grained stochastic searching. Finally, we introduce function mapping as a new method for interpreting symbolic discriminant functions. We show that function mapping when combined with measures of interaction information facilitates statistical interpretation by providing a graphical approach to decomposing complex models to highlight synergistic, redundant, and independent effects of polymorphisms and their composite functions. We illustrate this five step SDA modeling process with a real case-control dataset.
Pharmacokinetics of Terbinafine in the Rabbit Ocular Tissues after Topical Administration
Authors: Sun X.G. , Wang Z.X. , Wang Z.Q. , Deng S.J. , Li R. , Luo S.Y. , Wu Y.Y.
Published: February 2007

Objective: To determine the distribution of terbinafine in the cornea and aqueous humor after topical administration. Methods: A corn oil ointment of terbinafine 0.2% (resolved in sterile corn oil) was applied to the conjunctival sac of albino rabbits twice (with a 5-min interval). The concentration of terbinafine was determined with high-performance liquid chromatography (HPLC) 5, 15, 30, 60, 120 and 240 min after administration of terbinafine. Results: After topical administration, the concentration of terbinafine increased gradually, reached a peak (1.39 µg/ml at 30 min in the cornea and 82.9 ng/ml at 30 min in aqueous humor, respectively) and then decreased. The concentration was 0.18 µg/g at 240 min in the cornea, but terbinafine could not be tested at 120 min in aqueous humor. Conclusions: Topical ophthalmic terbinafine 0.2% could penetrate into the cornea and aqueous humor at concentrations adequate for inhibition of fungus.
Management of Multiple Myeloma with Bortezomib: Experts Review the Data and Debate the Issues
Authors: Dicato Mario , Boccadoro Mario , Cavenagh Jamie , Harousseau Jean-Luc , Ludwig Heinz , San Miguel Jesús , Sonneveld Pieter
Published: February 2007

Cure for multiple myeloma is rare; the success of treatment is measured by response, and length of remissions and survival. Initial treatment for patients young and fit enough is high-dose chemotherapy with autologous stem cell transplantation. Various chemotherapy regimens are employed as initial therapy in patients who cannot withstand the autologous stem cell transplantation regimen, and for treatment of refractory or relapsed disease. Commonly used agents either alone or in combination have included dexamethasone, vincristine, doxorubicin, melphalan, cyclophosphamide, etoposide, cisplatin and, more recently, thalidomide. Within the past few years, the first-in-class proteasome inhibitor bortezomib has been introduced for the treatment of relapsed multiple myeloma with data demonstrating efficacy and safety. Throughout Europe, a faculty of experts conducted a series of debates with over 450 clinicians to discuss the efficacy of bortezomib vis-à-vis other available therapies. Of primary concern was the place of bortezomib in maximizing efficacy throughout the course of the disease and treatment by increasing response rates and improving duration of response, while maintaining an acceptable level of toxicity. The experts concluded that bortezomib, with its unique mechanism of action and demonstrated clinical efficacy and safety, should be considered as standard, early treatment in patients with relapsed multiple myeloma, especially after first relapse.
Selective Fluid Cushion in the Submucosal Layer by Water Jet: Advantage for Endoscopic Mucosal Resection
Authors: Kaehler G.F.B.A. , Sold M.G. , Fischer K. , Post S. , Enderle M.
Published: February 2007

Background/Aim: Numerous new techniques have recently been reported and described for the endoscopic mucosal resection of large superficial lesions of the gastrointestinal tract. We present here for the first time the application of a water jet dissector for mucosa elevation. Materials and Methods: In an ex vivo study, the effectiveness of a water jet dissector (Helix Hydro-Jet®) placed directly on the stomach walls of 8 pigs was examined to create a mucosal elevation. After having determined optimal pressures, angle of application, and application times, 13 submucosal fluid cushions were produced in different areas of the stomach walls of 8 pigs in vivo, and the sizes of the resulting submucosal cushions were measured. Results: Using pressures between 30 and 70 bar, it was routinely possible to create submucosal fluid cushions in the stomach wall ex vivo as well as in vivo. Histological examination showed a selective edema in the submucosa without damage to the deeper mucosal layers of the gastric wall. Conclusions: The capacity of a targeted high-pressure water jet to penetrate the mucosa and selectively create a fluid cushion in the submucosa facilitates endoscopic resection of the mucosa. This new method could contribute to ameliorate the endoscopic treatment of mucosal tumors which previously could not be resected endoscopically due to their size, extent, or location.
Histopathological Effects of Bipolar Vessel Sealing Devices on Liver Parenchyma and Comparison with Suture Method: An Experimental Study
Authors: Sahin D.A. , Kusaslan R. , Sahin O. , Akbulut G. , Bas O. , Dilek O.N.
Published: February 2007

Background: LigaSureand SurgRx are bipolar vessel sealing devices providing hemostasis by denaturating collagen and elastin from the vessel wall and surrounding connective tissue. We aimed to histopathologically evaluate the lateral injury during rat liver resection with LigaSure and SurgRx. Methods: Suture technique was used in group A, LigaSure was used in group B and SurgRx was used in group C to resect one lobe of liver from midline. One of the resected pieces was histopathologically examined the same day and the other piece was left in the animal to be examined at the 7th day. Relaparotomy was performed at the 7th day. Results: Necrosis, exudate formation, chronic inflammation, histiocytes and fibroblasts scores were significantly lower in SurgRx group compared to the other groups. Conclusion: Our findings suggest that LigaSure and SurgRx can be safely used in liver resection as compared to suture technique while SurgRx was superior than LigaSure in inflammatory response as it causes lower lateral thermal injury and inflammatory scores probably due to its different technical properties.
An Unusual Cause of T Tube Obstruction: ‘Tricho-Tracheobezoar’
Authors: Suttithawil Wudthichai , Karnak Demet , Machuzak Michael , Gildea Thomas R. , Mehta Atul C.
Published: February 2007

A T tube is an upper airway device well described in the literature which is used to maintain tracheal lumen patency. Although tube occlusion is a known complication, it can be minimized by certain precautions. Otherwise, total occlusion can result in dramatic clinical deterioration or death. Herein, we describe a new clinical entity, ‘tricho-tracheobezoar’, using a new term defining a hairball in the trachea, which illustrates many of the potential pitfalls in the management of T tubes.
Increasing Survival of Ischemic Tissue by Targeting CD47
Authors: Isenberg Jeff S. , Romeo Martin J. , Abu-Asab Mones , Tsokos Maria , Oldenborg Anna , Pappan Loretta , Wink David A. , Frazier William A. , Roberts David D.
Published: February 2007

Thrombospondin-1 (TSP1) limits the angiogenic and vasodilator activities of NO. This activity of TSP1 can be beneficial in some disease states, but endogenous TSP1 limits recovery of tissue perfusion following fixed ischemic injury in dorsal skin flaps in mice. Using mice lacking the TSP1 receptors CD36 or CD47, we now show that CD47 is the necessary receptor for limiting NO-mediated vascular smooth muscle relaxation and tissue survival following ischemic injury in skin flaps and hindlimbs. We further show that blocking CD47 or TSP1 using monoclonal antibodies and decreasing CD47 expression using an antisense morpholino oligonucleotide are effective therapeutic approaches to dramatically increase survival of soft tissue subjected to fixed ischemia. These treatments facilitate rapid vascular remodeling to restore tissue perfusion and increase skin and muscle viability. Thus, limiting CD47-dependent antagonism of NO-mediated vasodilation and vascular remodeling is a promising therapeutic modality to preserve tissues subject to ischemic stress.
Deoxymyoglobin Is a Nitrite Reductase That Generates Nitric Oxide and Regulates Mitochondrial Respiration
Authors: Shiva Sruti , Huang Zhi , Grubina Rozalina , Sun Junhui , Ringwood Lorna A. , MacArthur Peter H. , Xu Xiuli , Murphy Elizabeth , Darley-Usmar Victor M. , Gladwin Mark T.
Published: February 2007

Previous studies have revealed a novel interaction between deoxyhemoglobin and nitrite to generate nitric oxide (NO) in blood. It has been proposed that nitrite acts as an endocrine reservoir of NO and contributes to hypoxic vasodilation and signaling. Here, we characterize the nitrite reductase activity of deoxymyoglobin, which reduces nitrite approximately 36 times faster than deoxyhemoglobin because of its lower heme redox potential. We hypothesize that physiologically this reaction releases NO in proximity to mitochondria and regulates respiration through cytochrome
c
oxidase. Spectrophotometric and chemiluminescent measurements show that the deoxymyoglobin-nitrite reaction produces NO in a second order reaction that is dependent on deoxymyoglobin, nitrite and proton concentration, with a bimolecular rate constant of 12.4 mol/L
−1
s
−1
(pH 7.4, 37°C). Because the IC
50
for NO-dependent inhibition of mitochondrial respiration is approximately 100 nmol/L at physiological oxygen tensions (5 to 10 μmol/L); we tested whether the myoglobin-dependent reduction of nitrite could inhibit respiration. Indeed, the addition of deoxymyoglobin and nitrite to isolated rat heart and liver mitochondria resulted in the inhibition of respiration, while myoglobin or nitrite alone had no effect. The addition of nitrite to rat heart homogenate containing both myoglobin and mitochondria resulted in NO generation and inhibition of respiration; these effects were blocked by myoglobin oxidation with ferricyanide but not by the xanthine oxidoreductase inhibitor allopurinol. These data expand on the paradigm that heme-globins conserve and generate NO via nitrite reduction along physiological oxygen gradients, and further demonstrate that NO generation from nitrite reduction can escape heme autocapture to regulate NO-dependent signaling.
Important Role of Erythropoietin Receptor to Promote VEGF Expression and Angiogenesis in Peripheral Ischemia in Mice
Authors: Nakano Makoto , Satoh Kimio , Fukumoto Yoshihiro , Ito Yoshitaka , Kagaya Yutaka , Ishii Naoto , Sugamura Kazuo , Shimokawa Hiroaki
Published: February 2007

We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR
−/−
-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR
−/−
-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR
−/−
-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR
−/−
-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR
−/−
-rescued mice that had been transplanted with WT-BM or EpoR
−/−
-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR
−/−
-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
Caveolin-1 Deficiency Increases Cerebral Ischemic Injury
Authors: Jasmin Jean-François , Malhotra Samit , Singh Dhallu Manjeet , Mercier Isabelle , Rosenbaum Daniel M. , Lisanti Michael P.
Published: February 2007

Caveolins (Cav), the principal structural proteins of the caveolar domains, have been implicated in the pathogenesis of ischemic injury. Indeed, changes in caveolin expression and localization have been reported in renal and myocardial ischemia. Genetic ablation of the Cav-1 gene in mice was further shown to increase the extent of ischemic injury in a model of hindlimb ischemia. However, the role of Cav-1 in the pathogenesis of cerebral ischemia remains unknown. Immunoblot and immunofluorescence analyses of rat brains subjected to middle cerebral artery occlusion revealed marked increases in endothelial Cav-1 and Cav-2 protein levels. To directly assess the functional role of caveolins in the pathogenesis of cerebral ischemic injury, we next investigated the effects of cerebral ischemia in caveolin knockout (KO) mice. Interestingly, Cav-1 KO mice showed a marked increase of cerebral volume of infarction, as compared with wild-type and Cav-2 KO mice. Immunofluorescence analyses showed an increased number of proliferating endothelial cells in wild-type ischemic brains, as compared with Cav-1 KO ischemic brains. Immunoblot analyses of wild-type ischemic brains showed an increase in endothelial nitric oxide synthase protein levels. Conversely, the protein levels of endothelial nitric oxide synthase remained unchanged in Cav-1 KO ischemic brains. TUNEL analysis also showed increased apoptotic cell death in Cav-1 KO ischemic brains, as compared with wild-type ischemic brains. Our findings indicate cerebral ischemia induces a marked increase in endothelial Cav-1 and Cav-2 protein levels. Importantly, genetic ablation of the Cav-1 gene in mice results in increased cerebral volume of infarction. Mechanistically, Cav-1 KO ischemic brains showed impaired angiogenesis and increased apoptotic cell death.