bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent Direct or TNF-α-Promoted Anticancer Effects of 2,3-Dehydrosilybin: Comparison Study with Silybin
Authors: Thongphasuk Piyanut , Stremmel Wolfgang , Chamulitrat Walee
Published: December 2007

Background: Silybin (SIL) exhibits anticancer properties and has now entered clinical trials. In this study, anticancer effects of 2,3-dehydrosilybin (DHS) were compared with SIL either alone or in combination with TNF-α. Methods: Cell cytotoxicity identified as apoptosis and necrosis was measured based on DNA fragment sizes using flow cytometry and DNA laddering. Results: After 24 h treatment,DHS at 30–50 µM markedly induced mainly apoptosis in transformed HepG2 and FIB cells. DHS induced necrosis markedly in HT29 but marginally in less transformed EPI cells. We found that apoptosis was the major mode of cell death when DHS was used in combination with TNF-α after 6 h treatment. TNF-α could promote DHS-induced apoptosis in HepG2, HT29 and FIB cells, but not in EPI cells. SIL could not reproduce this TNF-α-enhanced apoptosis. Conclusion: Our data provide evidence for the therapeutic use of DHS as an anticancer agent which is more effective than SIL.
Chronic Stroke Longitudinal Motor Improvements: Cumulative Learning Evidence Found in the Upper Extremity
Authors: Cauraugh James H. , Kim Sang-Bum , Summers Jeffery J.
Published: December 2007

Background: The purpose was to determine the cumulative longitudinal effects of upper extremity distributed practice with variable treatment protocols involving EMG-triggered neuromuscular stimulation and coupled bilateral movements. Methods: Sixteen chronic stroke subjects were randomly selected to complete 5 effective upper extremity treatment protocols over 12 months. The subjects were randomly assigned to 1 of 2 treatment orders. Consistent across the orders and protocols, the participants completed 90 min of training per day for 4 days during separate 2-week rehabilitation periods. Results: Data for the 5 primary outcome measures were analyzed in separate mixed design ANOVAs (treatment order × test session: 2 × 6). The analyses revealed distinct cumulative treatment evidence later in training in comparison to the baseline motor capabilities: (1) higher number of blocks moved; (2) higher percentage of blocks moved by the impaired hand; (3) faster motor reaction time (peripheral component), and (4) faster total reaction time. Conclusions: These chronic stroke patients displayed robust cumulative motor improvement effects from the longitudinally distributed practice of active neuromuscular stimulation and coupled bilateral movements.
Association between Human Paraoxonase 1 Activity and Intima-Media Thickness in Subjects under 55 Years of Age with Carotid Artery Disease
Authors: Harangi Mariann , Seres Ildiko , Magyar Maria T. , Csipo Istvan , Sipka Sandor , Valikovics Attila , Csiba Laszlo , Bereczki Daniel , Paragh Gyorgy
Published: December 2007

Background: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis. Methods: Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA. Results: In the whole study population we found a negative correlation between PON1 activity and IMT (r = –0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = –0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = –0.28, p = 0.008; r = –0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly. Conclusion: The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.
Effect of Age and Glycaemic Control on the Association between Fibrinogen and Risk of Acute Coronary Events after Transient Ischaemic Attack or Stroke
Authors: Howard S.C. , Algra A. , Rothwell P.M.
Published: December 2007

Background: Fibrinogen is an independent risk factor for acute vascular events, but there is uncertainty as to whether it is causal. One potential causal mechanism is the formation of low permeability fibrin clot in association with raised fibrinogen. We hypothesised that if this effect of fibrinogen were causally related to risk of vascular events, the risk relationship would be affected by the two other factors that affect fibrin clot permeability – age and glycaemic control. Methods: We studied the relationship between fibrinogen and risk of incident coronary events by age and baseline glucose levels in pooled data from three cohorts of patients with known cerebrovascular disease (UK-TIA Aspirin trial; Dutch TIA trial; Oxford TIA Study) during 23,272 patient-years of follow-up. Results: Risk of coronary events increased linearly with fibrinogen, but there was a significant interaction with age (p = 0.01 across tertiles of age), with the association being strongest for individuals aged <60 years (upper fibrinogen quintile hazard ratio = 3.95, 95% CI = 2.67–5.85, p < 0.0001). The risk relation was diminished in individuals with impaired glucose tolerance or diabetes. The effects of age and glycaemic control were independent, such that there was an almost fivefold increase in risk across quintiles of fibrinogen in patients aged <60 years with below median normal glucose levels (upper quintile hazard ratio = 4.90, 95% CI = 2.79–8.58, p < 0.0001). Conclusions: The effect of age and glycaemic control on the relationship between fibrinogen and risk of acute coronary events supports the hypothesis of a causal effect of fibrinogen mediated via the permeability of fibrin clot.
Prospective Evaluation of Multidetector-Row CT Angiography for the Diagnosis of Vasospasm following Subarachnoid Hemorrhage: A Comparison with Digital Subtraction Angiography
Authors: Chaudhary Saadia R. , Ko Nerissa , Dillon William P. , Yu Melissa B. , Liu Songling , Criqui Geoffrey I. , Higashida Randall T. , Smith Wade S. , Wintermark Max
Published: December 2007

Purpose: To evaluate the accuracy of multidetector-row CT angiography (CTA) for the diagnosis of large-vessel vasospasm following subarachnoid hemorrhage by comparison to digital subtraction angiography (DSA). Methods: Thirty-three patients with acute subarachnoid hemorrhage were enrolled in a prospective study and underwent a total of 40 CTA and DSA examinations within 24 h of each other. Two neuroradiologists reviewed the CTA examinations independently. A third neuroradiologist blinded to the CTA results reviewed the DSA examinations. In each patient, for both techniques, 23 arterial segments were evaluated for their degree of narrowing; the reviewers were asked to attribute every narrowing to ‘vasospasm’ or ‘hypoplasia’. Agreement between CTA and DSA for the degree of narrowing, and agreement between the two CTA readers, were calculated using weighted ĸ-coefficients. Sensitivity, specificity, accuracy, positive and negative predictive value (NPV) of CTA to detect large-vessel vasospasm were calculated considering DSA as the gold standard. Results: Substantial correlation (ĸ = 0.638) was found between CTA and DSA for the detection of arterial narrowing. Interobserver agreement between the two CTA reviewers for the degree of luminal narrowing was substantial (ĸ = 0.712).CTA was 87% accurate for the diagnosis of large-vessel vasospasm; the NPV of CTA was 95%. CTA was more accurate, and interobserver agreement higher, for the proximal arterial segments (basilar and vertebral arteries) than for the distal ones (P2 segments). Using CTA as a screening modality, 83% of unnecessary DSA would have been avoided. Conclusion: Compared to the gold standard of DSA, CTA is accurate for the detection of large-vessel vasospasm, and has a very high NPV.
Universal False Discovery Rate Estimation Methodology for Genome-Wide Association Studies
Authors: Forner Karl , Lamarine Marc , Guedj Mickaël , Dauvillier Jérôme , Wojcik Jérôme
Published: December 2007

Genome-wide case-control association studies aim at identifying significant differential markers between sick and healthy populations. With the development of large-scale technologies allowing the genotyping of thousands of single nucleotide polymorphisms (SNPs) comes the multiple testing problem and the practical issue of selecting the most probable set of associated markers. Several False Discovery Rate (FDR) estimation methods have been developed and tuned mainly for differential gene expression studies. However they are based on hypotheses and designs that are not necessarily relevant in genetic association studies. In this article we present a universal methodology to estimate the FDR of genome-wide association results. It uses a single global probability value per SNP and is applicable in practice for any study design, using any statistic. We have benchmarked this algorithm on simulated data and shown that it outperforms previous methods in cases requiring non-parametric estimation. We exemplified the usefulness of the method by applying it to the analysis of experimental genotyping data of three Multiple Sclerosis case-control association studies.
Ignoring Intermarker Linkage Disequilibrium Induces False-Positive Evidence of Linkage for Consanguineous Pedigrees when Genotype Data Is Missing for Any Pedigree Member
Authors: Li Bingshan , Leal Suzanne M.
Published: December 2007

Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband’s sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband’s married-in-grandparents in the analysis.
Utah Family-Based Analysis: Past, Present and Future
Authors: Cannon Albright Lisa A.
Published: December 2007

A unique genealogical resource linked to phenotype data was created in Utah over 30 years ago. Here we review the history and content of this resource. In addition, we review three current methodologies used in conjunction with this resource to define the heritable contribution to phenotypes and to identify predisposition genes responsible for these phenotypes. Example analyses and high-risk pedigrees are presented. Finally we briefly review ways this resource, or others like it, may expand in future.
Adjusting for Founder Relatedness in a Linkage Analysis Using Prior Information
Authors: Sheehan N.A. , Egeland T.
Published: December 2007

In genetic linkage studies, while the pedigrees are generally known, background relatedness between the founding individuals, assumed by definition to be unrelated, can seriously affect the results of the analysis. Likelihood approaches to relationship estimation from genetic marker data can all be expressed in terms of finding the most likely pedigree connecting the individuals of interest. When the true relationship is the main focus, the set of all possible alternative pedigrees can be too large to consider. However, prior information is often available which, when incorporated in a formal and structured way, can restrict this set to a manageable size thus enabling the calculation of a posterior distribution from which inferences can be drawn. Here, the unknown relationships are more of a nuisance factor than of interest in their own right, so the focus is on adjusting the results of the analysis rather than on direct estimation. In this paper, we show how prior information on founder relationships can be exploited in some applications to generate a set of candidate extended pedigrees. We then weight the relevant pedigree-specific likelihoods by their posterior probabilities to adjust the lod score statistics.
Association of Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Promoter SNP with Peak Bone Mineral Density in Chinese Women
Authors: Cheung Ching-Lung , Huang Qing-Yang , Chan Vivian , Kung Annie W.C.
Published: December 2007

Objective: Low-density lipoprotein receptor-related protein 5 (LRP5) is important for osteoblast differentiation and mutations of the gene are associated with both low and high bone mass syndromes. Our study aimed to evaluate the importance of LRP5 in the determination of peak bone mass acquisition in Chinese females in the general population. Methods: A total of 286 young southern Chinese females (aged 22–44 years) with low bone mineral density (BMD) (defined by a BMD Z score ≤–1.28 at either the hip or spine) or high BMD (Z score ≧+1) were studied. The LRP5 gene was sequenced for single nucleotide polymorphisms (SNPs) and 4 SNPs were tagged from 8 genotyped SNPs for this study. Results: Single locus allele association tests revealed significant associations of rs682429 and rs686921 with BMD variation (p < 0.05). Omnibus test (likelihood ratio test) revealed overall significant association between LRP5 gene locus and total hip BMD, with rs682429 being most predictive. rs682429 is located in 5′UTR, 2 bases adjacent to a consensus recognition site for the Elk-1 binding element. Conclusion: Common variations of the LRP5 promoter are associated with BMD in young women. These significant associations appear to be driven by rs682429. Functional studies are necessary to elucidate the role of this SNP on the effect of Elk-1 binding element transcriptional activity of LRP5 gene.
Prognostic Value of Natriuretic Peptides in Chagas’ Disease: A 3-Year Follow-Up Investigation
Authors: Moreira Maria da Consolação V. , Heringer-Walther Silvia , Wessel Niels , Moreira Ventura Tiago , Wang Yong , Schultheiss Heinz-Peter , Walther Thomas
Published: December 2007

Background: Chagas’ disease (CD) affects around 18 million people in Latin America. To determine the diagnostic and prognostic value of natriuretic peptides in patients with CD, we measured atrial (ANP) and brain natriuretic peptide (BNP), and compared the findings with other dilated cardiomyopathies (DCM). Methods: Blood samples were obtained from 111 CD patients, 62 patients with DCM due to other causes, and 43 gender- and age-matched healthy subjects. The CD and DCM patients were subdivided according to their NYHA classification. Natriuretic peptide concentrations were determined by immunoradiometric assays. Results: ANP and more pronounced BNP levels were increased in CD and DCM patients in relation to the NYHA class. Circulating BNP concentrations were higher in CD patients in NYHA classes I–II than in the corresponding DCM patients (p = 0.020). Importantly, ANP and BNP were already significantly elevated in CD patients without systolic ventricular dysfunction (p ≤ 0.001). In CD patients, both peptides were highly correlated with echocardiographic parameters (p < 10–14). Both ANP and BNP had comparable ability to predict death or the necessity for heart transplant (p < 0.0001). Conclusion: Natriuretic peptide levels can be used as a marker of asymptomatic CD without ventricular dysfunction and thus could be an ideal tool to identify these patients for early therapy.
Extremely Late Pacemaker-Infective Endocarditis due to Stenotrophomonas maltophilia
Authors: Takigawa Masateru , Noda Takashi , Kurita Takashi , Okamura Hideo , Suyama Kazuhiro , Shimizu Wataru , Aihara Naohiko , Nakajima Hiroyuki , Kobayashi Junjiro , Kamakura Shiro
Published: December 2007

This case report describes a patient with an intravascular infection of a pacemaker system with Stenotrophomonas maltophilia, which occurred 17 years after the implantation. The patient was treated with appropriate antibiotics and debridement of the infectious tissue in the pocket, and the entire pacemaker system was removed by open heart surgery. She was discharged from our center after a 6-week course of antibiotics and implantation of a new pacemaker.
Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure
Authors: Rastogi Sharad , Mishra Sudhish , Zacà Valerio , Mika Yuval , Rousso Benny , Sabbah Hani N.
Published: December 2007

Objectives: Therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV systolic and diastolic function in dogs with heart failure (HF). This study examined the effects of CCM therapy on mRNA and protein expression of cytoskeletal proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the LV myocardium of dogs with HF. Methods: HF was produced in 14 dogs by coronary microembolizations. Dogs were randomized to 3 months of CCM therapy (n = 7) or to sham-operated controls (n = 7). LV tissue from 6 normal (NL) dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction and protein expression using Western blots. Results: Compared with NL dogs, controls showed upregulation of mRNA and protein expression of the cytoskeletal proteins tubulin and fibronectin and MMP-1, MMP-2 and MMP-9, and downregulation of the cytoskeletal protein titin. Normalized expression of all these genes and proteins was seen after CCM therapy. No differences in expression of TIMP-1 and TIMP-2 were observed among groups. Conclusions: CCM therapy normalizes expression of key cytoskeletal proteins and MMPs and may partly explain the improvement in LV function seen in HF following CCM therapy.
Progressive Mitral Valve Thickening and Progressive Muscle Cramps as Manifestations of Glycogenosis VII (Tarui’s Disease)
Authors: Finsterer Josef , Stöllberger Claudia
Published: December 2007

Progressive heart valve thickening and shrinkage, and progressive muscle cramps have not been reported as manifestations of glycogenosis type VII (Tarui’s disease). In a 72-year-old female, Tarui’s disease was diagnosed in 1997, initially manifesting as simple partial seizures since 1977, anginal chest pain since 1982 and muscle cramps since 1983. During the following years, low voltage ECG, ectopic supraventricular tachycardia, thickening of the mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy and diastolic dysfunction also developed. Neurological manifestations progressed to complex partial seizures, double vision, reduced tendon reflexes, central facial palsy, bradydiadochokinesia, distal weakness of the upper extremities and worsening muscle cramps. Thickening and shrinkage of the heart valves had further increased at 72 years of age. Progression of Tarui’s disease may manifest as progressive thickening of the heart valves due to glycogen storage. Valve thickening may consecutively lead to valve insufficiency, enlargement of the atrium and atrial fibrillation. Progression of neurological manifestations may manifest as worsening muscle cramps.
Is There a Relation between Non-Calcifying Coronary Plaques and Acute Coronary Syndromes? A Retrospective Study Using Multislice Computed Tomography
Authors: Feuchtner Gudrun , Postel Thomas , Weidinger Franz , Frick Matthias , Alber Hannes , Dichtl Wolfgang , Jodocy Daniel , Mallouhi Ammar , Pachinger Otmar , zur Nedden Dieter , Friedrich Guy J.
Published: December 2007

Objectives: The purpose of this study was to assess whether different coronary plaque types as classified by multislice computed tomography (CT) are retrospectively correlated with acute coronary syndromes (ACS) in an unselected study population. Methods: Sixty-three consecutive patients were examined with 16-slice CT coronary angiography. Coronary plaque types were classified as calcifying type 1, mixed (calcifying > non-calcifying) type 2, mixed (non-calcifying > calcifying) type 3, and non-calcifying type 4. Patients who had an ACS within 17 days were included. All patients underwent invasive coronary angiography. Results: Fifty-eight patients (92%) had coronary plaques evaluated by CT: 18 type 1 (31%), 10 type 2 (17%), 16 type 3 (28%) and 14 type 4 (24%). The presence of a non-calcifying plaque component (types 2–4; 40 of 63 patients, 63%) was correlated with ACS (n = 15; 24%) (p < 0.001). Only type 3 was significantly correlated with ACS (p = 0.01), but plaque types 2 and 4 were not. The diagnostic accuracy of CT for detection of stenosis >50% in proximal segments was: sensitivity 98%, specificity 90%, negative predictive value 97%, positive predictive value 97% per patient. Conclusions: Mixed calcifying/non-calcifying plaques with a predominantly non-calcifying component (type 3) as classified by multislice CT are retrospectively correlated with ACS.
Pulmonary Artery Aneurysm as a Cause for Chest Pain in a Patient with Noonan’s Syndrome: A Case Report
Authors: Brown Jennifer R. , Plotnick Gary
Published: December 2007

A pulmonary artery aneurysm is defined as pulmonary artery dilatation >4 cm. Pulmonary artery aneurysms are rare findings and are usually not associated with chest pain. This is the first report of a case of pulmonary artery aneurysm causing chest pain in a patient with Noonan’s syndrome. Chest X-ray showed cardiomegaly and a prominent main pulmonary artery segment and CT confirmed a pulmonary artery aneurysm with a pulmonary artery root measuring 5.6 cm. The patient underwent pulmonary valvuloplasty as well as pulmonary arterioplasty to repair the pulmonary artery aneurysm, and experienced subsequent relief of chest pain. In conclusion, pulmonary artery aneurysm is a rare complication in patients with Noonan’s syndrome and can be the cause of chest pain in such patients.
Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese
Authors: Han Yaling , Xi Suya , Zhang Xiaolin , Yan Chenghui , Yang Yong , Kang Jian
Published: December 2007

Background: Recently, the C1019T polymorphism in the human gene encoding connexin 37 (CX37, encoded by GJA4) has been reported to be associated with coronary artery disease (CAD)/myocardial infarction in different racial groups, but no data are currently available in northern Han Chinese. The aim of our study is to investigate the association between 3 GJA4 gene polymorphisms (–1930C/T, C1019T and I1297D) and the susceptibility to CAD in northern Han Chinese. Methods: 502 CAD patients and 410 controls confirmed by coronary angiography were genotyped by polymerase chain reaction restriction fragment length polymorphism analysis in an independent case-control study. Results: The overall distribution of GJA4 C1019T genotypes among CAD patients and healthy controls was significantly different (p < 0.01). Frequencies of C1019T CC homozygote and C allele were significantly higher in the patient group than those in the control group. Stratification analysis showed that the C1019T C allele significantly increased the risk of CAD only among male subjects (p = 0.006; OR 1.38; 95% CI 1.09–1.74). After adjustment for conventional risk factors, binary logistic regression analysis showed that the C allele carrier (CC + CT) of C1019T was an independent risk factor for CAD (p < 0.05). Further linkage disequilibrium tests and haplotype analysis revealed that the C-C-D haplotype conferred an increased risk of CAD. Conclusions: Our study suggests that GJA4 gene C1019T polymorphism and/or its related C-C-D haplotype might contribute to an increased risk of CAD and potentially play an important role in the development of coronary atherosclerosis in northern Han Chinese.
Brain Natriuretic Peptide Levels Predict Perioperative Events in Cardiac Patients Undergoing Noncardiac Surgery: A Prospective Study
Authors: Leibowitz David , Planer David , Rott David , Elitzur Yair , Chajek-Shaul Tova , Weiss A. Teddy
Published: December 2007

Objectives: Brain natriuretic peptide (BNP) levels correlate with prognosis in patients with cardiac disease and may be useful in the risk stratification of cardiac patients undergoing noncardiac surgery (NCS). The objective of this study was to examine whether BNP levels predict perioperative events in cardiac patients undergoing NCS. Methods: Patients undergoing NCS with at least 1 of the following criteria were included: a clinical history of congestive heart failure (CHF), ejection fraction <40%, or severe aortic stenosis. All patients underwent echocardiography and measurement of BNP performed using the ADVIA-Centaur BNP assay (Bayer HealthCare). Clinical endpoints were death, myocardial infarction or pulmonary congestion requiring intravenous diuretics at 30 days of follow-up. Results: Forty-four patients were entered into the study; 15 patients (34%) developed cardiac postoperative complications. The mean BNP level was 1,366 ± 1,420 pg/ml in patients with events and 167 ± 194 pg/ml in patients without events, indicating a highly significant difference (p < 0.001). The ROC area under the curve was 0.91 (95% CI 0.83–0.99) with an optimal cutoff of >165 pg/ml (100% sensitivity, 70% specificity). Conclusions: BNP levels may predict perioperative complications in cardiac patients undergoing NCS, and the measurement of BNP should be considered to assess the preoperative cardiac risk.
Activity of Caspofungin and Voriconazole against Clinical Isolates of Candida and Other Medically Important Yeasts by the CLSI M-44A Disk Diffusion Method with Neo-Sensitabs Tablets
Authors: Carrillo-Muñoz A.J. , Quindós G. , del Valle O. , Santos P. , Giusiano G. , Ezkurra P.A. , Estivill M.D. , Casals J.B.
Published: December 2007

In vitro activity of caspofungin and vori conazole against 184 clinical isolates of Candida and other medically important yeasts in comparison with that of fluconazole, ketoconazole, itraconazole and amphotericin B was determined by using a disk diffusion method (Neo-Sensitabs) standardized according to the recommendations of the CLSI documents M44-A and M44–S1 (same medium: Mueller-Hinton plus methylene blue; inoculum and minimal inhibitory concentration/zone breakpoints). Seventy-two percent of clinical isolates were susceptible to caspofungin, 23.6% showed an intermediate susceptibility (most of them were Candida parapsilosis) and 4.3% were resistant (values for Candida spp. were 71.2, 23.8 and 5%, respectively). For voriconazole, 96.7% of clinical isolates were susceptible and 3.3% were resistant (Candida spp.: 96 and 3.8%, respectively). Both caspofungin and voriconazole showed high activity against a wide variety of clinically important yeasts.
Fixed Dose Rate Infusion of Gemcitabine with Oral Doxifluridine and Leucovorin for Advanced Unresectable Pancreatic Cancer: A Phase II Study
Authors: Kim Hawk , Park Jae-Hoo , Shin Su Jin , Kim Mee-Ja , Bang Sung-Jo , Park Neung Hwa , Nah Yang Won , Nam Chang Woo , Joo Kwang Ro , Min Young Joo
Published: December 2007

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m2 was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m2 t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1–21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.
Cervical Actinomycosis with Spinal Cord Compression
Authors: Xu Guo-Ping , Xu Zu-De , Gao Bu-Lang , Chen Qi , Li Qing-Quan , Xu Jing-Da , Li Hai-Xia , Cao Xi-Xi , Jing Juan
Published: December 2007

Cervical actinomycosis with spinal cord compression is extremely rare. The clinical presentation of spinal actinomycosis may be nonspecific and back pain is the most consistent early symptom. Here, we present such a case with fever, pain in the neck and upper back, progressive weakness and numbness in all 4 limbs with difficulty ambulating, constipation and uroschesis. Correct diagnosis is difficult because the clinical and radiological findings of actinomycosis closely resemble metastatic tumors and other infectious processes. Timely surgical debridement and decompression contributed to the prompt improvement of the patient’s conditions, and histopathological demonstration of the inflammatory granulation tissue and Gram-positive sulfur-containing filamentous bacteria led to the correct diagnosis of actinomycosis. The diagnosis must be made promptly because delayed treatment can result in irreversible neurologic damage or death. Timely and long-term antibacterial therapy is essential for the complete recovery of the patient with actinomycosis.
Role of Triptolide as an Adjunct Chemotherapy for Ovarian Cancer
Authors: Westfall Suzanne D. , Nilsson Eric E. , Skinner Michael K.
Published: December 2007

Background: Triptolide (TPL) has been identified as the active component of the Tripterygium wilfordii hook F plant and demonstrated to possess antitumor properties and induce apoptosis in a variety of tumor cell lines. Since TPL actions are associated with changes in the activities of both p53 and NFĸB, which are implicated in the chemoresistance of ovarian cancer, the ability of TPL to be a potential chemotherapeutic for ovarian cancer was considered. Methods: TPL actions on human ovarian cancer cells were investigated in vitro and in vivo with a nude mouse model to monitor tumor burden both in the absence or presence of other chemotherapy agents. Results: TPL was effective as a single agent in inducing apoptosis of ovarian cancer cells in vitro, but not in vivo. TPL enhanced the cytotoxicity of carboplatin in culture and enhanced carboplatin-mediated reduction of tumor burden in nude mice inoculated with human ovarian cancer cells. Previously, a phosphatidylinositol 3-kinase (PI3 kinase) inhibitor was found to enhance carboplatin actions on ovarian cancer. Interestingly, the combined treatment of TPL, PI3 kinase inhibitor LY294002 and carboplatin was found to dramatically reduce ovarian tumor progression and burden in nude mice. Conclusion: In 44% of the animals tested the combined treatment caused complete regression of ovarian cancer. Combined observations indicate TPL may be an effective adjunct chemotherapy for ovarian cancer.
Interplay between Dose and Frequency of GnRH Administration in Determining Pituitary Gonadotropin Responsiveness
Authors: Hughes Virginia A. , Boepple Paul A. , Crowley, Jr. William F. , Seminara Stephanie B.
Published: December 2007

Background/Aims: The dose, frequency and contour of GnRH stimulation of the pituitary gonadotrope have been shown to be independent variables influencing pituitary LH secretion. The dynamic interaction between these variables during physiological and pathophysiological states has yet to be examined. Methods: Twelve men with GnRH deficiency and idiopathic hypogonadotropic hypogonadism undergoing GnRH therapy participated in a series of studies in which 2 log orders of GnRH doses (2.5–250 ng/kg) were administered at frequencies varying from 0.5 to 8 hourly. Pituitary responses were characterized by pulse amplitudes and nadirs. The relative sensitivity of the gonadotrope to GnRH was defined as that dose of GnRH capable of eliciting an LH pulse amplitude equal to the mean LH amplitude in normal men. Results: As GnRH stimulation of the gonadotrope slowed from 0.5 to 8 hourly, pulse amplitudes of LH increased whereas mean nadirs decreased (p < 0.05). Unique, curvilinear dose-response curves were found for each frequency that demonstrated an increasing slope (p < 0.03) as the frequency of GnRH stimulation slowed. Thus, the relative sensitivity of the gonadotrope increased as the frequency of GnRH stimulation decreased over the range of physiological frequencies tested. Conclusions: We conclude that a delicate interplay exists between the dose and frequency of GnRH stimulation of the gonadotrope that determines pituitary LH gonadotropin responsiveness in the human. Slower frequencies favor increased LH release largely due to decreasing LH nadirs and improved sensitivity of the gonadotropes to GnRH stimulation.
Development of Vestibular Evoked Myogenic Potentials in Preterm Neonates
Authors: Wang Shou-Jen , Chen Chun-Nan , Hsieh Wu-Shiun , Young Yi-Ho
Published: December 2007

Our recent study successfully recorded vestibular evoked myogenic potential (VEMP) responses in full-term newborns. However, when VEMP responses are elicited in preterm neonates remains unclear. This study employed the VEMP test in 27 low-risk preterm and 25 healthy full-term neonates without sedation to investigate the development of VEMP response after birth. Fourteen (26%) of 54 ears in preterm neonates exhibited VEMP responses, a response rate significantly lower than that of full-term neonates (72%). The mean latencies of peaks p13 and n23 in the preterm group were significantly longer than those in the full-term group. Analysis of variable parameters for present VEMPs in pre- and full-term neonates revealed that the cutoff values of body weight were 2.26 and 2.82 kg, and that those of postmenstrual age were 37.1 and 38.4 weeks, respectively. Both body weight and postmenstrual age were significantly negatively correlated with p13 and n23 latencies but not with p13-n23 amplitude. In conclusion, present VEMPs can be anticipated when the body weight of pre- and full-term neonates reaches >2.26 and 2.82 kg, respectively. It indicates that the sacculocollic reflex develops in the same manner, but the difference in response rate between full- and pre-term neonates may, at least in part, correlate with muscle bulk and strength, relative to the body weight adequate for the VEMP response.
Myofascial Trigger Point:A Possible Way of Modulating Tinnitus
Authors: Bezerra Rocha Carina A.C. , Sanchez Tanit Ganz , Tesseroli de Siqueira José T.
Published: December 2007

In order to investigate whether myofascial trigger points can modulate tinnitus, as well as the association between tinnitus and myofascial trigger points, 94 individuals with and 94 without tinnitus, matched by age and gender, were analyzed by means of bilateral digital pressure of 9 muscles. Temporary modulation of tinnitus was frequently observed (55.9%) during digital pressure, mainly in the masseter. The rate of tinnitus modulation was significantly higher on the same side of the myofascial trigger point subject to examination in 6 out of 9 muscles. An association between tinnitus and the presence of myofascial trigger points was observed (p < 0.001), as well as a laterality association between the ear with the worst tinnitus and the side of the body with more myofascial trigger points (p < 0.001). Thus, this relationship could be explained not only by somatosensory-auditory system interactions but also by the influence of the sympathetic system.
Electrically Evoked Auditory Steady-State Responses in a Guinea Pig Model: Latency Estimates and Effects of Stimulus Parameters
Authors: Jeng Fuh-Cherng , Abbas Paul J. , Brown Carolyn J. , Miller Charles A. , Nourski Kirill V. , Robinson Barbara K.
Published: December 2007

Cochlear implant speech processors typically extract envelope information of speech signals for presentation to the auditory nerve as modulated trains of electric pulses. Recent studies showed the feasibility of recording, at the scalp, the electrically evoked auditory steady-state response using amplitude-modulated electric stimuli. Sinusoidally amplitude-modulated electric stimuli were used to elicit such responses from guinea pigs in order to characterize this response. Response latencies were derived to provide insight regarding neural generator sites. Two distinct sites, one cortical and another more peripheral, were indicated by latency estimates of 22 and 2 ms, respectively, with the former evoked by lower (13–49 Hz) and the latter by higher (55–320 Hz) modulation frequencies. Furthermore, response amplitudes declined with increasing carrier frequency, exhibited a compressive growth with increasing modulation depths, and were sensitive to modulation depths to as low as 5%.
Prospective Mutation Screening of Three Common Deafness Genes in a Large Taiwanese Cohort with Idiopathic Bilateral Sensorineural Hearing Impairment Reveals a Difference in the Results between Families from Hospitals and Those from Rehabilitation Facilities
Authors: Wu Chen-Chi , Chen Pei-Jer , Chiu Yu-Hsun , Lu Ying-Chang , Wu Ming-Chueh , Hsu Chuan-Jen
Published: December 2007

Accurate epidemiological data on common deafness genes are essential to improve the efficiency and to reduce the cost of molecular diagnosis. They may depend on several factors, including a clear delineation of the source of patients being studied. In the present study, we hypothesize that patients with idiopathic sensorineural hearing loss recruited from different sources might reveal discrepancies in the epidemiological results of genetic screening, because patients from different sources might demonstrate distinct clinical or audiologic features and thus result in biased selection of subjects. To elucidate the relative importance of common deafness genes in Taiwanese and to verify our hypothesis, we conducted a prospective project screening mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA gene in a total of 420 Taiwanese families with idiopathic bilateral sensorineural hearing loss, of which 325 families were recruited from hospitals and 95 from hearing rehabilitation facilities. Allele frequencies of common mutations in these three genes and distributions of the corresponding genotypes were then compared between the two groups. The allele frequencies of mutations in SLC26A4, GJB2 and mitochondrial 12S rRNA in the probands of the 420 families were 14.4, 21.7 and 3.8%, respectively. The allele frequency of SLC26A4 mutations in the hospital group was significantly higher than that in the rehabilitation facility group (16.2 vs. 8.4%, χ2-test, p < 0.05), whereas no difference in the frequencies of GJB2 mutations and mitochondrial 12S rRNA mutations was found between the two groups. Distributions of probands classified by SLC26A4 genotypes were also different between the two groups (χ2-test, p < 0.05). Accordingly, a discrepancy in the genetic screening results might exist between different sources of idiopathic hearing-impaired patients. Further analysis of audiological results and construction of a logistic regression model showed that different audiological features, namely hearing levels and hearing loss patterns, might be responsible for the unequal distributions of mutations and probands between the hospital and rehabilitation facility groups.
Targeted Spinal Cord Therapeutics Delivery: Stabilized Platform and Microelectrode Recording Guidance Validation
Authors: Riley Jonathan , Butler John , Baker Kenneth B. , McClelland III Shearwood , Teng Qingshan , Yang Jun , Garrity-Moses Mary , Federici Thais , Boulis Nicholas M.
Published: December 2007

Background/Aims: No validated delivery technique exists for accurate, reproducible delivery of biological therapies to discrete spinal cord targets. To address this unmet need, we have constructed a stabilized platform capable of supporting physiologic mapping, through microelectrode recording, and cellular or viral payload delivery to the ventral horn. Methods: A porcine animal model (n = 7) has been chosen based upon the inherent morphologic similarities between the human and porcine spine. Animals underwent physiologic mapping and subsequent microinjection of a green-fluorescent-protein-labeled cell suspension. Sacrifice (t = 3 h) was performed immediately following behavioral assessment. Results: Histologic analysis has supported our ability to achieve localization to the ipsilateral ventral horn in the spinal cord. Complications included death due to malignant hyperthermia (n = 1), hindlimb dysfunction attributable to epidural hematoma (n = 1), and hindlimb dysfunction attributable to cord penetration (n = 2). Conclusions: These results indicate an ability to achieve accurate targeting, but the elevated incidence of neurologic morbidity will require further studies with longer follow-ups that incorporate procedural and equipment modifications that will allow for a reduced number of cord penetrations and will account for observed cardiorespiratory-associated cord movement. These initial results reinforce the challenges of translating biological restorative therapies from small to large animal models and ultimately to humans.
Microelectrode-Guided Deep Brain Stimulation for Tourette Syndrome: Within-Subject Comparison of Different Stimulation Sites
Authors: Shields Donald C. , Cheng Ming L. , Flaherty Alice W. , Gale John T. , Eskandar Emad N.
Published: December 2007

Background: As medical therapy for Tourette syndrome (TS) is ineffective in a small subset of patients, surgical interventions, including deep brain stimulation at various sites, have been developed in recent years. Case Description: We present the case of a 40-year-old woman with TS whose severe tics had caused unilateral blindness. Despite trials of more than 40 medications, her symptoms improved significantly only after placement of bilateral deep brain stimulators in the anterior inferior internal capsule. However, symptomatic improvement was not complete, and her electrode connections eventually became permanently damaged by the remaining retrocollic jerks. She underwent removal of the internal capsule electrodes and placement of centromedian nucleus thalamic stimulators with significantly improved tic control. Conclusion: Whereas the anterior internal capsule site had also produced psychiatric side effects such as altered mood and impulse control, the thalamic site has not done so to date. Thus, distinct surgical targets for TS may be appropriate for patients with specific comorbidities.
Catheter Placement for Ommaya Reservoirs with Frameless Surgical Navigation: Technical Note
Authors: Greenfield Jeffrey P. , Schwartz Theodore H.
Published: December 2007

Objective: Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in oncology patients to avoid intraparenchymal infusion. We assessed the safety and precision of using frameless surgical navigation for the placement of Ommaya reservoir catheters. Methods: In 20 consecutive patients who required Ommaya reservoirs for the administration of intrathecal chemotherapy, the catheters were positioned with the guidance of frameless stereotaxy. Precision of catheter placement, operative time, operative complications, and postoperative complications were assessed. Results: All catheters were completely within cerebrospinal fluid and 90% were within 5 mm of the intended target, the ipsilateral foramen of Monro. The average operative time was 47 min, and there were no intraoperative complications. There were no reports of leukoencephalopathy, and 3 patients had minor delayed complications. Conclusion: Frameless surgical navigation is a useful and efficient method for ensuring accurate catheter placement during Ommaya reservoir implantation, and it reduces the risk of potential parenchymal toxicity.
Downregulation of Angiopoietin-1 and Tie2 in Chronic Hypoxic Pulmonary Hypertension
Authors: Yamamoto Akihito , Takahashi Hideki , Kojima Yuko , Tsuda Yasunari , Morio Yoshiteru , Muramatsu Masashi , Fukuchi Yoshinosuke
Published: December 2007

Background: Angiopoietins, newly discovered vascular-specific growth factors, and vascular endothelial growth factors (VEGF) play distinct and complementary roles in angiogenesis and vascular maturation. However, the exact roles of angiogenic factors in the adult pulmonary vasculature remain unclear. Objective: To elucidate possible roles of angiopoietins and VEGF in the development of hypoxic pulmonary hypertension (PH), changes in the expression of angiogenic factors were examined. Methods: The cellular distribution and expression of angiopoietins and their receptor Tie2 and VEGF were investigated by RT-PCR, immunoblot, and immunohistochemical methods in rat lung under normal and hypoxic conditions. Results: During the development of PH with vascular remodeling characterized by a decrease in vessel density of intrapulmonary arteries, protein expression of angiopoietin-1 (Ang-1), Tie2, and VEGF significantly decreased in the pulmonary arteries, and Tie2 receptor was inactivated in the lung. The expression of angiopoietin-3 (Ang-3), an endogenous antagonist of Ang-1, significantly increased in the intima under hypoxic conditions. Conclusions: Since both Ang-1/Tie2 and VEGF promote angiogenesis and vascular survival, and play protective roles in the adaptation of microvascular changes during the onset of PH, the downregulation of both Ang-1/Tie2 and VEGF and upregulation of Ang-3 appear to be associated with vascular rarefaction and the development of hypoxic PH.