bluuebunny/crossref_metadata_2025 huggingface dataset:
Benzethonium Chloride: A Novel Anticancer Agent Identified by Using a Cell-Based Small-Molecule Screen
Authors: Yip Kenneth W. , Mao Xinliang , Au P.Y. Billie , Hedley David W. , Chow Sue , Dalili Shadi , Mocanu Joseph D. , Bastianutto Carlo , Schimmer Aaron , Liu Fei-Fei
Published: September 2006

Purpose: This study aims to identify a novel therapeutic agent for head and neck cancer and to evaluate its antitumor efficacy.

Experimental Design: A cell-based and phenotype-driven high-throughput screening of ∼2,400 biologically active or clinically used compounds was done using a tetrazolium-based assay on FaDu (hypopharyngeal squamous cancer) and NIH 3T3 (untransformed mouse embryonic fibroblast) cells, with secondary screening done on C666-1 (nasopharyngeal cancer) and GM05757 (primary normal human fibroblast) lines. The “hit” compound was assayed for efficacy in combination with standard therapeutics on a panel of human cancer cell lines. Furthermore, its mode of action (using transmission electron microscopy and flow cytometry) and its in vivo efficacy (using xenograft models) were evaluated.

Results: Benzethonium chloride was identified as a novel cancer-specific compound. For benzethonium (48-hour incubation), the dose required to reduce cell viability by 50% was 3.8 μmol/L in FaDu, 42.2 μmol/L in NIH 3T3, 5.3 μmol/L in C666-1, and 17.0 μmol/L in GM05757. In vitro, this compound did not interfere with the effects of cisplatin, 5-fluorouracil, or γ-irradiation. Benzethonium chloride induced apoptosis and activated caspases after 12 hours. Loss of mitochondrial membrane potential (ΔΨM) preceded cytosolic Ca2+ increase and cell death. In vivo, benzethonium chloride ablated the tumor-forming ability of FaDu cells, delayed the growth of xenograft tumors, and combined additively with local tumor radiation therapy. Evaluation of benzethonium chloride on the National Cancer Institute/NIH Developmental Therapeutics Program 60 human cancer cell lines revealed broad-range antitumor activity.

Conclusions: This high-throughput screening identified a novel antimicrobial compound with significant broad-spectrum anticancer activity.
HATH1 Expression in Mucinous Cancers of the Colorectum and Related Lesions
Authors: Park Eun Taek , Oh Hee Kyung , Gum James R. , Crawley Suzanne C. , Kakar Sanjay , Engel Juan , Leow Ching Ching , Gao Wei-Qiang , Kim Young S.
Published: September 2006

Purpose: Mucinous cancers and signet ring carcinomas are distinct classes of colon cancers characterized by their production of copious quantities of intestinal goblet cell mucin, MUC2. Deletion of transcription factor HATH1 ablates the biogenesis of goblet cells in developing mouse intestine, and forced expression of HATH1 results in elevated expression of MUC2 in colon cancer cells. The aim of this study was to assess the possible role of HATH1 in the development of mucinous cancers and signet ring carcinomas.

Experimental Design: Immunohistochemistry and confocal microscopy was used to examine HATH1 expression and subcellular distribution in normal colon and small intestine, mucinous cancers, signet ring carcinomas, and nonmucinous cancers and in precursor lesions, including hyperplastic polyps, serrated adenomas, tubular adenomas, and villous adenomas. We also analyzed the transactivation of MUC2 promoter/reporter constructs by a HATH1 expression vector.

Results: HATH1 expression transactivated MUC2 promoter/reporter constructs, an activity that was significantly inhibited by mutation of putative HATH1-binding sites. HATH1 was expressed in the nuclei of goblet cells and in the cytoplasm and nuclei of enteroendocrine cells of the colon. In the small intestine, only cytoplasmic expression of HATH1 in enteroendocrine cells was detected. HATH1 was found to be strongly expressed in the nuclei of hyperplastic polyps, serrated adenomas, villous adenomas, mucinous cancers, and signet ring carcinomas but repressed in nonmucinous cancers and tubular adenomas.

Conclusions: This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas. In addition, the expression of HATH1 in hyperplastic polyps, serrated adenomas, and villous adenomas lends support to the hypothesis that these neoplasms are frequent precursors in mucinous cancer and signet ring carcinoma development.
Approval Summary: Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma
Authors: Cohen Martin H. , Johnson John R. , Massie Tristan , Sridhara Rajeshwari , McGuinn W. David , Abraham Sophia , Booth Brian P. , Goheer M. Anwar , Morse David , Chen Xiao H. , Chidambaram Nallaperumal , Kenna Leslie , Gobburu Jogarao V. , Justice Robert , Pazdur Richard
Published: September 2006

Purpose: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma.

Experimental Design: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*).

Results: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults.

Conclusions: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).
In vivo Efficacy of STX213, A Second-Generation Steroid Sulfatase Inhibitor, for Hormone-Dependent Breast Cancer Therapy
Authors: Foster Paul A. , Newman Simon P. , Chander Surinder K. , Stengel Chloe , Jhalli Roma , Woo Lawrence L.W. , Potter Barry V.L. , Reed Michael J. , Purohit Atul
Published: September 2006

Purpose: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model.

Experimental Design: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly.

Results: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P < 0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity.

Conclusions: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.
Increased Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in African-Americans Compared with Caucasians
Authors: Mattison Lori Kay , Fourie Jeanne , Desmond Renee A. , Modak Anil , Saif Muhammad Wasif , Diasio Robert B.
Published: September 2006

Purpose: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)–associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD deficiency in the African-American population are unknown.

Experimental Design: Healthy African-American (n = 149) and Caucasian (n = 109) volunteers were evaluated for DPD deficiency using both the [2-13C]uracil breath test and peripheral blood mononuclear cell DPD radioassay.

Results: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07). African-American women showed the highest prevalence of DPD deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively).

Conclusion: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.
The Ras Inhibitor Farnesylthiosalicylic Acid as a Potential Therapy for Neurofibromatosis Type 1
Authors: Barkan Batya , Starinsky Sigal , Friedman Eitan , Stein Reuven , Kloog Yoel
Published: September 2006

Purpose: Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that dislodges all active Ras isoforms from the membrane. We assessed the ability of FTS to reverse the transformed phenotype of neurofibromatosis type 1 (NF1)–associated tumor cell lines of malignant peripheral nerve sheath tumor (MPNST).

Experimental Design: nf1 mutations were genotyped, allelic losses were analyzed, and neurofibromin expression levels were determined in MPNST cell lines ST88-14, S265P21, and 90-8. The effects of FTS on GTP-bound Ras (Ras-GTP) and its prominent downstream targets, as well as on cell morphology, anchorage-dependent and anchorage-independent growth, and tumor growth in mice, were assessed.

Results: The MPNST cell lines were biallelic, NF1 inactive, and neurofibromin deficient. We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RalA in all NF1-deficient MPNST cell lines (NF1 cells) to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line. These effects of FTS led to lower steady-state levels of Ras-GTP and its activated targets. Both anchorage-dependent and anchorage-independent growth of NF1 cells were dose dependently inhibited by FTS, and the inhibition correlated positively with Ras-GTP levels. NF1 cells were found to possess strong actin stress fibers, and this phenotype was also corrected by FTS. NF1 tumor growth in a nude mouse model was inhibited by oral FTS.

Conclusions: FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1.
Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy
Authors: Hahn Stephen M. , Putt Mary E. , Metz James , Shin Daniel B. , Rickter Elizabeth , Menon Chandrakala , Smith Debbie , Glatstein Eli , Fraker Douglas L. , Busch Theresa M.
Published: September 2006

Purpose: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues.

Experimental Design: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models.

Results: Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P < 0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P = 0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (≤2.31).

Conclusions: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.
Curcumin Inhibits Neurotensin-Mediated Interleukin-8 Production and Migration of HCT116 Human Colon Cancer Cells
Authors: Wang Xiaofu , Wang Qingding , Ives Kirk L. , Evers B. Mark
Published: September 2006

Purpose: Neurotensin, a gut tridecapeptide, acts as a potent cellular mitogen for various colorectal and pancreatic cancers that possess high-affinity neurotensin receptors. Cytokine/chemokine proteins are increasingly recognized as important local factors that play a role in the metastasis and invasion of multiple cancers. The purpose of this study was to (a) determine the effect of neurotensin on cytokine/chemokine gene expression and cell migration in human cancer cells and (b) assess the effect of curcumin, a natural dietary product, on neurotensin-mediated processes.

Experimental Design: The human colorectal cancer, HCT116, was treated with neurotensin, with or without curcumin, and interleukin (IL)-8 expression and protein secretion was measured. Signaling pathways, which contribute to the effects of neurotensin, were assessed. Finally, the effect of curcumin on neurotensin-mediated HCT116 cell migration was analyzed.

Results: We show that neurotensin, acting through the native high-affinity neurotensin receptor, induced IL-8 expression in human colorectal cancer cells in a time- and dose-dependent fashion. This stimulation involves Ca2+-dependent protein kinase C, extracellular signal-regulated kinase–dependent activator protein-1, and extracellular signal-regulated kinase–independent nuclear factor-κB pathways. Curcumin inhibited neurotensin-mediated activator protein-1 and nuclear factor-κB activation and Ca2+ mobilization. Moreover, curcumin blocked neurotensin-stimulated IL-8 gene induction and protein secretion and, at a low concentration (i.e., 10 μmol/L), blocked neurotensin-stimulated colon cancer cell migration.

Conclusions: Neurotensin-mediated induction of tumor cell IL-8 expression and secretion may contribute to the procarcinogenic effects of neurotensin on gastrointestinal cancers. Furthermore, a potential mechanism for the chemopreventive and chemotherapeutic effects of curcumin on colon cancers may be through the inhibition of gastrointestinal hormone (e.g., neurotensin)–induced chemokine expression and cell migration.
Adjuvanticity of Plasmid DNA Encoding Cytokines Fused to Immunoglobulin Fc Domains
Authors: Ferrone Cristina R. , Perales Miguel-Angel , Goldberg Stacie M. , Somberg C. Joy , Hirschhorn-Cymerman Daniel , Gregor Polly D. , Turk Mary Jo , Ramirez-Montagut Teresa , Gold Jason S. , Houghton Alan N. , Wolchok Jedd D.
Published: September 2006

Purpose: Plasmid DNAs encoding cytokines enhance immune responses to vaccination in models of infectious diseases and cancer. We compared DNA adjuvants for their ability to enhance immunity against a poorly immunogenic self-antigen expressed by cancer.

Experimental Design: DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8+ T-cell responses and tumor immunity. A DNA vaccine against a self-antigen, gp100, expressed by melanoma was used in combination with DNA encoding cytokines and cytokines fused to the Fc domain of mouse IgG1 (Ig).

Results: We found that (a) cytokine DNAs generally increased CD8+ T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses; (c) adjuvant effects were sensitive to timing of DNA injection; (d) the most efficacious individual adjuvants for improving tumor-free survival were IL-12/Ig, IL-15/Ig, IL-21/Ig, GM-CSF/Ig, and CCL21; and (e) combinations of IL-2/Ig + IL-12/Ig, IL-2/Ig + IL-15/Ig, IL-12/Ig + IL-15/Ig, and IL-12/Ig + IL-21/Ig were most active; and (f) increased adjuvanticity of cytokine/Ig fusion DNAs was not related to higher tissue levels or greater stability.

Conclusions: These observations support the potential of cytokine DNA adjuvants for immunization against self-antigens expressed by cancer, the importance of timing, and the enhancement of immune responses by Fc domains through mechanisms unrelated to increased half-life.
Genetic Education for Non-Geneticist Health Professionals
Authors: Harris Rodney , Challen Kirsty , Benjamin Caroline , Harris Hilary
Published: September 2006

Objectives: It was the aim of this study to assess educational needs and priorities in genetics amongst non-genetic health professionals. Methods: The methods used included website reviews and direct contact with individuals and organisations involved in health professional education. Results and Conclusions: Health professional education and training differed in structure with wide variation in the content and duration of genetics education provided. Evidence from the UK, France and Germany indicates that genetics professionals are influencing the genetics content of medical curricula. In post-graduate training, some specialist regulators have adopted specific genetics education requirements, but many programmes lack any explicit genetics. We show that within each country, a sometimes confusing plethora of organisations has responsibility for setting, assessing and delivering medical and midwifery education.
France: Genetics Education for Non-Genetics Health Care Providers
Authors: Julian-Reynier Claire , Arnaud Sandrine
Published: September 2006

Objective: This paper explores the treatment of medical genetics in undergraduate medical education, specialists’ training and continuing medical education (CME) for general practitioners, specialists, nurses and midwives. Methods: We conducted a qualitative survey of websites, published or unpublished documents, telephone interviews and mailed questionnaires. Results: Genetics is a medical speciality in France, and the small number of university professors in genetics are in charge of the genetic component of medical training of all future practitioners. The study was complicated by the ongoing waves of reforms in the French health and educational systems and by the autonomy of the faculties. Specialist training and CME in genetics is heterogeneous and not organised as a priority. Conclusions: Specialist education and CME in genetics of non-geneticist health care providers needs to be adapted to the fast ongoing developments of this field of knowledge.
Education in Medical Genetics for Physicians: Germany
Authors: Schmidtke Jörg , Paul Yasmin , Nippert Irmgard
Published: September 2006

We have assessed the relative amount of genetics education at each of the 3 levels of medical training in Germany, namely the undergraduate, postgraduate and continuous medical education stages. Our data show that genetics is ill represented at all levels. Written examinations at the end of the relevant section at the undergraduate level include very few questions related to medical genetics, and particularly few in subjects such as pathology, internal medicine and gynaecology and obstetrics. At the postgraduate level, only 4 specialties require knowledge in medical genetics that may be subject to examination. At the continuous medical education level, medical genetics plays a very minor role. All 3 levels have been subject to reform in recent years, but effects that might ensue from these reforms cannot be expected before 2008.
Education in Medical Genetics for Non-Genetic Health Care Providers in Sweden
Authors: Henriksson Karin , Kristoffersson Ulf
Published: September 2006

We investigated the content and extent of education in medical/clinical genetics among Swedish universities, university colleges and colleges of health providing undergraduate education for medical doctors and nurses. In addition, selected medical specialist training programmes and programmes for midwifes and district nurses were analysed to detect elements of education or training in medical/clinical genetics. The main results are that, although basic cell biology is taught during the first semesters in all educations, there is little or no genetics taught during the clinical parts of the educational programmes. Moreover, with regard to post-graduate education, it is almost absent. There is a need to improve education and training in genetics for all health care professionals to meet the expected increase in genetic issues in clinical medicine.
Genetics Education for Non-Genetic Health Care Professionals in the Netherlands (2002)
Authors: Plass Anne Marie C. , Baars Marieke J.H. , Beemer Frits A. , ten Kate Leo P.
Published: September 2006

Objective: The aim of the present study was to investigate whether medical care providers in the Netherlands are adequately educated in genetics by collecting information about the current state of genetics education of non-genetics health care professionals. Method: The curricula of the 8 universities providing medical education and of all varieties of specialised medical training were examined for the year 2002. Results: In most universities, the number of hours spent on genetics education is small, and genetics is relatively invisible, being integrated within several courses, comprising only a small proportion of the total course (a mean of 8%). Only 3 of the programmes for medical specialist training and the training of medical doctors for mentally handicapped people indicated a formal genetics education programme. Continued education courses on genetics are offered irregularly. Training in midwifery involves at least 3 weeks of genetics education. Courses on genetics are offered frequently to practicing midwifes. Conclusion: There appear to be no general, nationally defined final goals for education in genetics for non-genetics health care professionals in the Netherlands. Furthermore, the lack of visibility of genetics in medical education in the Netherlands was striking.
Genetics Teaching for Non-Geneticist Health Care Professionals in the UK
Authors: Challen Kirsty , Harris Hilary , Benjamin Caroline M. , Harris Rodney
Published: September 2006

Objectives: It was the aim of this study to describe the structure and content of training in genetics for non-genetics specialist health care professionals in the UK. Methods: Data were collected by assessment of published syllabi and curricula and through contact with educational leads at responsible organisations. Results: Twenty-six universities, 7 Royal Colleges and various intercollegiate boards and committees are involved in the provision of medical education at various levels, in addition to institutions offering nursing and/or midwifery training. Genetics is taught in variable formats, quantities and contents, and although some institutions are moving to adopt minimum competencies in genetics, this is by no means widespread. Conclusions: Given the wide number of stakeholders in the field, consensus competencies seem most likely to advance practice, and thus, phase II of the GenEd project will survey professionals to ascertain their priorities for genetic education.
‘Genetics Home Reference’: Helping Patients Understand the Role of Genetics in Health and Disease
Authors: Fomous Cathy , Mitchell Joyce A. , McCray Alexa
Published: September 2006

The surge of information generated by the Human Genome Project has left many health professionals and their patients struggling to understand the role of genetics in health and disease. To aid the lay public and health professionals, the US National Library of Medicine developed an online resource called ‘Genetics Home Reference’ (GHR), located at http://ghr.nlm.nih.gov/. Launched in April 2003, GHR’s goal is to help the public interpret the health implications of the Human Genome Project. It bridges the clinical questions of consumers and the rich technical data emerging from the sequenced human genome. The GHR web site is designed for easy navigation among summaries for genetic conditions and the related gene(s) and chromosome(s). This design strategy enhances the user’s appreciation of how genes, chromosomes, and conditions are interrelated.
Estimation of the Ratio of Renal Artery Stenosis with Magnetic Resonance Angiography Using Parallel Imaging Technique in Suspected Renovascular Hypertension
Authors: Bicakci Kenan , Soker Gokhan , Binokay Figen , Akgul Erol , Aksungur Erol , Sertdemir Yasar
Published: September 2006

Background: Renovascular hypertension, which may lead to end-stage renal failure, necessitates prompt diagnosis and medication. Although various diagnostic tools exist for evaluation of renal arteries, magnetic resonance angiography (MRA), with the improvement of hardware and software systems, has become a very promising technique in screening patients with suspected renal hypertension. In this study, we aimed to assess renal artery stenosis on MRA in patients with suspected renovascular disease using a parallel imaging technique which allows faster scanning with higher resolution. Methods: Eighty-four patients with hypertension underwent MRA and digital angiography. Results: MRA detected renal artery stenosis with a sensitivity rate ranging from 69.3 to 100% and specificity rate ranging from 85.7 to 96%. Conclusion: Contrast-enhanced MRA of renal arteries is very effective in the demonstration of renal artery stenoses and assessment of stenosis ratio. Furthermore, parallel imaging technology has improved this procedure by reducing the scan time. Renal MRA, as a diagnostic tool, can accurately direct patients with renovascular disease to intravascular treatment.
Blockade of Renin-Angiotensin System Reduces QT Dispersion and Improves Intracellular Ca/Mg Status in Hemodialysis Patients
Authors: Averbukh Zhan , Berman Sylvia , Efrati Shai , Manevits Elena , Rosenberg Rosa , Malcev Ela , Galperin Elena , Weissgarten Joshua
Published: September 2006

Background: Electrolyte impairments are common in hemodialysis (HD) patients. Consequently, QT dispersion (QTd) is prolonged, correlating with high intracellular magnesium. In patients with cardiac disorders, renin-angiotensin system (RAS) inhibition reduces QTd. Aim: To compare the effects of ACE inhibition or AT-1 blockade on QTd duration and intracellular magnesium (Mg)/calcium (Ca) in peripheral blood mononuclear cells (PBMC) from chronic HD patients. Methods: 24 HD patients received cilazapril for 8 weeks and, following a 2-week withdrawal, were switched to valsartan for additional 8 weeks. QTd measurements and PBMC isolation were performed at the beginning and the end of each period. Total intracellular Ca and Mg were assessed by atomic spectrometer, and cytosolic free Ca2+ by fluorocytometer. Results: Both treatments significantly decreased QTd, demonstrating similar reduction magnitudes. In both groups, PBMC exhibited basally low cytosolic Ca2+ and undisturbed high transmembrane Ca2+ influx following phytohemagglutinin stimulation. Total intracellular Ca was increased, while Mg was reduced, following either treatment. The total intracellular Ca/Mg ratio inversely correlated with QTd duration. Conclusions: (1) RAS inhibition reduces prolonged QTd in HD patients. (2) In PBMC from ordinarily Ca-depleted HD patients, RAS suppression brings about elevation of total intracellular Ca. (3) RAS blockade decreases high intracellular Mg in PBMC from HD patients. Consequently, the Ca/Mg ratio increases, inversely correlating with QTd reduction.
Prevalence and Risk Factors of Atherosclerotic Renal Artery Stenosis in 1,200 Chinese Patients Undergoing Coronary Angiography
Authors: Zhang Yue , Ge Jun-bo , Qian Ju-ying , Ye Zhi-Bin
Published: September 2006

Aims: Atherosclerotic renal artery stenosis (ARAS) is a common and potentially reversible cause of end-stage renal failure. Our study aimed to determine the prevalence and predictors of ARAS in Chinese patients undergoing coronary angiography for suspected coronary heart disease (CAD), or for acute or chronic myocardial infarction. Methods: Selective renal arteriography was performed immediately after coronary angiography in 1,200 consecutive patients. Medical history and laboratory data were obtained before the procedure. Significant renal artery stenosis was defined as ≧50% narrowing of the luminal diameter. Uni- and multivariate logistic regression analyses were made to explore the association of the clinical and laboratory variables, including some items which had never or rarely been studied, with ARAS or CAD. Results: Of the 1,200 patients, 840 were male and 360 female. Their mean age was 62 ± 10 years. Low-grade (<50%) and significant coronary artery stenosis was found in 108 (9%) and 610 (51%) patients respectively. By multivariate logistic regression analysis, risk factors associated with the presence of coronary artery stenosis included male, older age, smoking, high serum concentration of low density lipoprotein, lipoprotein (a), and fast blood glucose ≧7.0 mmol/l. Significant ARAS was present in 116 (9.7%) patients, of which 20 (1.7%) were bilateral. The incidence of ARAS was similar in patients with suspected CAD or myocardial infarction. Multivariate logistic regression analysis showed the association of the clinical variables with ARAS included: older age, hypercholesterolemia, a more than 10-year history of hypertension, proteinuria and SCr ≧133 µmol/l. The severity of ARAS is significantly related to the severity of coronary artery disease. Conclusion: ARAS is a frequent finding in Chinese patients undergoing coronary angiography, especially in patients with significant coronary artery stenosis and risk factors for ARAS. Renal arteriography can be a helpful examination in these patients.
Weekly Variation of the QT Dispersion in Healthy Subjects and in Patients with Coronary Heart Disease
Authors: Oren Hüseyin , Cosgun Ayhan
Published: September 2006

Background: A circadian and seasonal variation of QT dispersion (QTd) has been shown in healthy individuals. Nevertheless, no data exist regarding the weekly influences on the QTd in healthy individuals and in patients with coronary heart disease (CHD). Design: This study was designed to determine whether there is a weekly variability of QTd in healthy individuals and in patients with CHD. Methods: In this prospective registry study, 53 patients with documented CHD and 57 healthy control subjects were involved. Resting electrocardiograms (ECGs) with double amplitude were recorded at a speed of 50 mm/s on Monday and Friday mornings. QT intervals were measured and QTd were determined by calculating the difference between maximum and minimum QT intervals. Then, rate-corrected QTd (QTcd) were calculated using Bazett’s formula. Results: There was a significant weekly variation of QTd in control subjects (39.3 ± 6.3 vs. 36.2 ±6.1 ms) (p < 0.05) and in patients (56 ± 7.3 vs. 47.4 ± 5.4 ms) (p < 0.0001). There was also a significant weekly variation of QTcd both in control subjects (33 ± 5.3 vs. 30.7 ± 5.6 ms) (p < 0.05) and in patients (47.4 ± 6.4 vs. 41.9 ± 5.4 ms) (p < 0.0001). Conclusions: There is a weekly variation of QTd and QTcd in healthy individuals and in patients with CHD, both with a Monday preference. This fact should be taken into consideration during the chronopharmacological treatment or advisal of primary or secondary preventive measures to these subjects or patients.
Predictors of In-Hospital Mortality Present at Admission among Patients Hospitalised because of Decompensated Heart Failure
Authors: Formiga Francesc , Chivite David , Manito Nicolas , Casas Susana , Riera Antoni , Pujol Ramon
Published: September 2006

Chronic heart failure (HF) is associated with a poor prognosis and causes considerable mortality. The aim of this study was to identify the admission characteristics useful to predict in-hospital mortality in patients admitted because of decompensation of HF. We evaluated 414 patients (age 76.2 years, 57% women). The hospital mortality rate was 11.1%. We identified 4 independent predictors of mortality: low Barthel index (odds ratio 1.03; 95% confidence interval 1.01–1.04), creatinine level >200 µmol/l (odds ratio 3.40; 95% confidence interval 1.51–7.66), peripheral oedema (odds ratio 3.12; 95% confidence interval 1.28–7.58) and the protective effect of the new onset of the disease (odds ratio 0.2; 95% confidence interval 0.08–0.77). In conclusion, the mortality of patients admitted to the hospital with an exacerbation of HF can be predicted if either poor functional capacity, renal insufficiency, peripheral oedema or previous diagnoses of HF are present. This clinical finding may help clinicians in their decision making in HF in the emergency room.
Recent Clinical Advances in the Management of Critically Ill Patients with Acute Renal Failure
Authors: Clark William R. , Letteri Jeffrey J. , Uchino Shigehiko , Bellomo Rinaldo , Ronco Claudio
Published: September 2006

Background: Significant progress has been made in the field of renal replacement therapy for critically ill patients with acute renal failure (ARF) over the past few years. This review highlights these developments. Methods: Recent studies assessing the clinical utility of the RIFLE classification system for the diagnosis of ARF were reviewed. Clinical outcome studies evaluating the effect of continuous renal replacement therapy (CRRT) dose and timing of initiation were assessed. The final review topic was the effect of dialysis modality on the recovery of renal function in ARF patients. Conclusions: Based on recent clinical studies, the increasing use of the RIFLE criteria is justified, as this approach appears to be a robust method for both the diagnosis of and prognostication in ARF. A large randomized trial involving convective CRRT supports the commonly used prescription of 35 ml/ kg/h in clinical practice. Moreover, numerous recent outcome studies, also largely involving convective CRRT, provide a clinical rationale for the increasingly common clinical practice of earlier initiation. Finally, several recent studies suggest CRRT, relative to conventional hemodialysis, results in a greater rate of renal recovery in ARF patients.
High-Level Functional Capacity and 4-Year Mortality in an 80-Year-Old Population
Authors: Takata Yutaka , Ansai Toshihiro , Akifusa Sumio , Soh Inho , Sonoki Kazuo , Takehara Tadamichi
Published: September 2006

Background: Little is known about the relationship between high-level functional capacity and mortality in elderly people. Objective: To evaluate the relationship between high-level functional capacity, such as intellectual activity and social role, and 4-year mortality in a population of 80-year-old community residents. Methods: Participating in the study were 697 individuals (277 males and 420 females) out of 1,282 80-year-old individuals residing in Fukuoka Prefecture, Japan. To measure high-level functional capacity, the daily activities of 656 of the 697 participants were examined through questionnaires, accompanied by physical and laboratory blood examinations. The 697 participants were followed up for 4 years after the baseline examination. For subjects who died during that period, the date and cause of death were recorded from resident registration cards and official death certificates. Results: The relative risk for all-cause mortality decreased with an increase in intellectual activity or total functional capacity, whereas no association was found between total mortality and either the ability to perform instrumental self-maintenance or the ability to maintain a social role. Similarly, the relative mortality risk due to cardiovascular diseases decreased with an increase in intellectual activity or total functional capacity. Mortality due to pneumonia also decreased with an increase in intellectual activity. Conclusion: In a population of 80-year-old community residents, levels of intellectual activity and total functional capacity may be associated with all-cause, cardiovascular, and pneumonia mortality, and may be strong predictors of survival.
Diffuse Cystic Disease of the Lung Associated with Simultaneous Bilateral Spontaneous Pneumothorax: An Unknown Component of Caroli Disease?
Authors: Türüt Hasan , Gulhan Erkmen , Gezer Suat , Tastepe İrfan
Published: September 2006

Simultaneous bilateral spontaneous pneumothorax is an uncommon and serious medical problem frequently related to an underlying lung disease such as parenchymal lung disease, inflammatory events or neoplasms. Recurrent pneumothorax associated with persistent air leakage may pose a therapeutic dilemma in patients with underlying lung diseases. Caroli disease (CD) is a very rare congenital disorder characterised by intrahepatic biliary cystic dilatations and frequently associated with polycystic kidney and hepatic fibrosis. To date, no relation between CD and the bilateral diffuse cystic structure of pulmonary parenchyma has been described. In this paper we present a patient with the diagnosis of CD in whom simultaneous bilateral spontaneous pneumothorax was the initial finding due to severe underlying pulmonary disease. Our patient’s demographic and clinical characteristics, laboratory findings and course made us exclude the other aetiologies leading to such diffuse multi-bullous pulmonary involvement. The coincidence of recurrent pneumothorax and severe pulmonary disease has led to a big therapeutic dilemma. Open or minimally invasive surgery could be morbid or even mortal because of the nature of the parenchyma and the operative risk due to CD. Therefore, we suggest a unique conservative management including tube thoracostomy by locating the correct air spaces with the aid of high-resolution computed tomography followed by talc pleurodesis in patients with severe multi-bullous lung disease associated with potential risks due to co-morbidities.
Spike Count Correlation Increases with Length of Time Interval in the Presence of Trial-to-Trial Variation
Authors: Kass Robert E. , Ventura Valérie
Published: September 2006

It has been observed that spike count correlation between two simultaneously recorded neurons often increases with the length of time interval examined. Under simple assumptions that are roughly consistent with much experimental data, we show that this phenomenon may be explained as being due to excess trial-to-trial variation. The resulting formula for the correlation is able to predict the observed correlation of two neurons recorded from primary visual cortex as a function of interval length.
Low-Dimensional Maps Encoding Dynamics in Entorhinal Cortex and Hippocampus
Authors: Pervouchine Dmitri D. , Netoff Theoden I. , Rotstein Horacio G. , White John A. , Cunningham Mark O. , Whittington Miles A. , Kopell Nancy J.
Published: September 2006

Cells that produce intrinsic theta oscillations often contain the hyperpolarization-activated current Ih. In this article, we use models and dynamic clamp experiments to investigate the synchronization properties of two such cells (stellate cells of the entorhinal cortex and O-LM cells of the hippocampus) in networks with fast-spiking (FS) interneurons. The model we use for stellate cells and O-LM cells is the same, but the stellate cells are excitatory and the O-LM cells are inhibitory, with inhibitory postsynaptic potential considerably longer than those from FS interneurons. We use spike time response curve methods (STRC), expanding that technique to three-cell networks and giving two different ways in which the analysis of the three-cell network reduces to that of a two-cell network. We show that adding FS cells to a network of stellate cells can desynchronize the stellate cells, while adding them to a network of O-LM cells can synchronize the O-LM cells. These synchronization and desynchronization properties critically depend on Ih. The analysis of the deterministic system allows us to understand some effects of noise on the phase relationships in the stellate networks. The dynamic clamp experiments use biophysical stellate cells and in silico FS cells, with connections that mimic excitation or inhibition, the latter with decay times associated with FS cells or O-LM cells. The results obtained in the dynamic clamp experiments are in a good agreement with the analytical framework.
Programmable Logic Construction Kits for Hyper-Real-Time Neuronal Modeling
Authors: Guerrero-Rivera Ruben , Morrison Abigail , Diesmann Markus , Pearce Tim C.
Published: September 2006

Programmable logic designs are presented that achieve exact integration of leaky integrate-and-fire soma and dynamical synapse neuronal models and incorporate spike-time dependent plasticity and axonal delays. Highly accurate numerical performance has been achieved by modifying simpler forward-Euler-based circuitry requiring minimal circuit allocation, which, as we show, behaves equivalently to exact integration. These designs have been implemented and simulated at the behavioral and physical device levels, demonstrating close agreement with both numerical and analytical results. By exploiting finely grained parallelism and single clock cycle numerical iteration, these designs achieve simulation speeds at least five orders of magnitude faster than the nervous system, termed here hyper-real-time operation, when deployed on commercially available field-programmable gate array (FPGA) devices. Taken together, our designs form a programmable logic construction kit of commonly used neuronal model elements that supports the building of large and complex architectures of spiking neuron networks for real-time neuromorphic implementation, neurophysiological interfacing, or efficient parameter space investigations.
Soft Mixer Assignment in a Hierarchical Generative Model of Natural Scene Statistics
Authors: Schwartz Odelia , Sejnowski Terrence J. , Dayan Peter
Published: September 2006

Gaussian scale mixture models offer a top-down description of signal generation that captures key bottom-up statistical characteristics of filter responses to images. However, the pattern of dependence among the filters for this class of models is prespecified. We propose a novel extension to the gaussian scale mixturemodel that learns the pattern of dependence from observed inputs and thereby induces a hierarchical representation of these inputs. Specifically, we propose that inputs are generated by gaussian variables (modeling local filter structure), multiplied by a mixer variable that is assigned probabilistically to each input from a set of possible mixers. We demonstrate inference of both components of the generative model, for synthesized data and for different classes of natural images, such as a generic ensemble and faces. For natural images, the mixer variable assignments show invariances resembling those of complex cells in visual cortex; the statistics of the gaussian components of the model are in accord with the outputs of divisive normalization models. We also show how our model helps interrelate a wide range of models of image statistics and cortical processing.
The Scaling of Winner-Takes-All Accuracy with Population Size
Authors: Shamir Maoz
Published: September 2006

Empirical studies seem to support conflicting hypotheses with regard to the nature of the neural code. While some studies highlight the role of a distributed population code, others emphasize the possibility of a “single-best-cell” readout. One particularly interesting example of single-best-cell readout is provided by the winner-takes-all (WTA) approach. According to the WTA, every cell is characterized by one particular preferred stimulus, to which it responds maximally. The WTA estimate for the stimulus is defined as the preferred stimulus of the cell with the strongest response.

From a theoretical point of view, not much is known about the efficiency of single-best-cell readout mechanisms, in contrast to the considerable existing theoretical knowledge on the efficiency of distributed population codes. In this work, we provide a basic theoretical framework for investigating single-best-cell readout mechanisms. We study the accuracy of the WTA readout. In particular, we are interested in how the WTA accuracy scales with the number of cells in the population. Using this framework, we show that for large neuronal populations, the WTA accuracy is dominated by the tail of the single-cell-response distribution. Furthermore, we find that although the WTA accuracy does improve when larger populations are considered, this improvement is extremely weak compared to other types of population codes. More precisely, we show that while the accuracy of a linear readout scales linearly with the population size, the accuracy of the WTA readout scales logarithmically with the number of cells in the population.
On the Consistency of Bayesian Variable Selection for High Dimensional Binary Regression and Classification
Authors: Jiang Wenxin
Published: September 2006

Modern data mining and bioinformatics have presented an important playground for statistical learning techniques, where the number of input variables is possibly much larger than the sample size of the training data. In supervised learning, logistic regression or probit regression can be used to model a binary output and form perceptron classification rules based on Bayesian inference. We use a prior to select a limited number of candidate variables to enter the model, applying a popular method with selection indicators. We show that this approach can induce posterior estimates of the regression functions that are consistently estimating the truth, if the true regression model is sparse in the sense that the aggregated size of the regression coefficients are bounded. The estimated regression functions therefore can also produce consistent classifiers that are asymptotically optimal for predicting future binary outputs. These provide theoretical justifications for some recent empirical successes in microarray data analysis.