bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo
Authors: Kang Jin Seok , Wanibuchi Hideki , Morimura Keiichirou , Gonzalez Frank J. , Fukushima Shoji
Published: December 2007

CYP2E1 metabolizes many low–molecular weight toxins and carcinogens. Some in vitro experiments suggest that CYP2E1 may be involved in the metabolic activation of diethylnitrosamine. However, there has been no direct evidence demonstrating a role for CYP2E1 in diethylnitrosamine-mediated carcinogenesis in vivo. To clarify this, we carried out a diethylnitrosamine-induced hepatocarcinogenesis experiment using Cyp2e1-null mice. Male 14-day-old wild-type and Cyp2e1-null mice were treated with diethylnitrosamine (10 mg/kg of body weight) and killed at weeks 24 and 36 after diethylnitrosamine treatment for investigation of tumors and at 6, 24, and 48 h for examination of apoptosis and gene expression. Liver weights of Cyp2e1-null mice were significantly different at weeks 24 and 36 compared with wild-type mice (P < 0.01). Liver tumor incidences of Cyp2e1-null mice were significantly decreased at weeks 24 and 36 compared with wild-type mice (P < 0.01). Cyp2e1-null mice showed significant decrease in the multiplicities of hepatocellular adenoma at weeks 24 and 36 (P < 0.05 and P < 0.01, respectively), and of hepatocellular carcinoma at week 36 (P < 0.01) compared with wild-type mice. Apoptotic index and caspase-3 and/or Bax mRNA expression of Cyp2e1-null mice were significantly different at 6, 24, and 48 h after diethylnitrosamine treatment compared with wild-type mice (P < 0.05). We conclude that Cyp2e1-null mice show lower tumor incidence and multiplicity compared with wild-type mice in diethylnitrosamine-induced hepatocarcinogenesis. It is suggested that CYP2E1 completely participates in diethylnitrosamine-induced hepatocarcinogenesis, and high frequency of tumors in wild-type mice could be associated with the increased apoptosis. [Cancer Res 2007;67(23):11141–6]
Suppression of Proximal T Cell Receptor Signaling and Lytic Function in CD8+ Tumor-Infiltrating T Cells
Authors: Monu Ngozi , Frey Alan B.
Published: December 2007

CD8+ tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3ζ is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLCγ-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56lck is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting “switch”. Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56lck (∼10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56lck in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56lck in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56lck activation motif (Y394), thus inhibiting effector phase functions. [Cancer Res 2007;67(23):11447–54]
Identification and Characterization of a Membrane Receptor for Proteolysis-Inducing Factor on Skeletal Muscle
Authors: Todorov Penio T. , Wyke Stacey M. , Tisdale Michael J.
Published: December 2007

Proteolysis-inducing factor (PIF) is a sulfated glycoprotein produced by cachexia-inducing tumors, which induces atrophy of skeletal muscle. PIF has been shown to bind specifically with high affinity (Kd, in nanomolar) to sarcolemma membranes from skeletal muscle of both the mouse and the pig, as well as murine myoblasts and a human muscle cell line. Ligand binding was abolished after enzymatic deglycosylation, suggesting that binding was mediated through the oligosaccharide chains in PIF. Chondroitin sulfate, but not heparan or dermatan sulfate, showed competitive inhibition (Kd, 1.1 × 10−7 mol/L) of binding of PIF to the receptor, suggesting an interaction with the sulfated oligosaccharide chains. Ligand blotting of [35S]PIF to triton solublized membranes from C2C12 cells provided evidence for a binding protein of apparent Mr of ∼40,000. Amino acid sequence analysis showed the PIF receptor to be a DING protein. Antisera reactive to a 19mer from the N-terminal amino acid residues of the binding protein attenuated protein degradation and activation of the ubiquitin-proteasome pathway induced by PIF in murine myotubes. In addition, the antisera was highly effective in attenuating the decrease in body weight in mice bearing the MAC16 tumor, with a significant increase in muscle wet weight due to an increase in the rate of protein synthesis, together with a reduction in protein degradation through attenuation of the increased proteasome expression and activity. These results confirm that the PIF binding protein has a functional role in muscle protein atrophy in cachexia and that it represents a potential new therapeutic target. [Cancer Res 2007;67(23):11419–27]
MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy
Authors: Weidhaas Joanne B. , Babar Imran , Nallur Sunitha M. , Trang Phong , Roush Sarah , Boehm Michelle , Gillespie Erin , Slack Frank J.
Published: December 2007

Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the proto-oncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies. [Cancer Res 2007;67(23):11111–6]
Runx2 Disruption Promotes Immortalization and Confers Resistance to Oncogene-Induced Senescence in Primary Murine Fibroblasts
Authors: Kilbey Anna , Blyth Karen , Wotton Sandy , Terry Anne , Jenkins Alma , Bell Margaret , Hanlon Linda , Cameron Ewan R. , Neil James C.
Published: December 2007

The Runx genes play paradoxical roles in cancer where they can function either as dominant oncogenes or tumor suppressors according to context. We now show that the ability to induce premature senescence in primary murine embryonic fibroblasts (MEF) is a common feature of all three Runx genes. However, ectopic Runx–induced senescence contrasts with Ras oncogene–induced senescence, as it occurs directly and lacks the hallmarks of proliferative stress. Moreover, a fundamental role for Runx function in the senescence program is indicated by the effects of Runx2 disruption, which renders MEFs prone to spontaneous immortalization and confers an early growth advantage that is resistant to stress-induced growth arrest. Runx2−/− cells are refractory to H-RasV12–induced premature senescence, despite the activation of a cascade of growth inhibitors and senescence markers, and are permissive for oncogenic transformation. The aberrant behavior of Runx2−/− cells is associated with signaling defects and elevated expression of S-G2-M cyclins and their associated cyclin dependent kinase activities that may override the effects of growth inhibitory signals. Coupling of stress responses to the cell cycle represents a novel facet of Runx tumor suppressor function and provides a rationale for the lineage-specific effects of loss of Runx function in cancer. [Cancer Res 2007;67(23):11263–71]
Combined 1p/19q Loss in Oligodendroglial Tumors: Predictive or Prognostic Biomarker?
Authors:   The German Glioma Network, Weller Michael , Berger Hilmar , Hartmann Christian , Schramm Johannes , Westphal Manfred , Simon Matthias , Goldbrunner Roland , Krex Dietmar , Steinbach Joachim P. , Ostertag Christoph B. , Loeffler Markus , Pietsch Torsten , von Deimling Andreas
Published: December 2007

Purpose: The combined loss of genetic material on chromosomes 1p and 19q is strongly associated with favorable outcome in patients with WHO grade 3 anaplastic oligodendroglial tumors. The prognostic value of 1p/19q loss in WHO grade 2 oligodendroglial tumors is less well defined. Importantly, the possible effect of combined 1p/19q loss has not been studied in patients who were not treated with radiotherapy or chemotherapy.

Experimental Design: Seventy-six patients with oligodendroglioma (n = 33), oligoastrocytoma (n = 30), anaplastic oligodendroglioma (n = 6), or anaplastic oligoastrocytoma (n = 7) were identified who had not received radiotherapy or chemotherapy after their first operation until the end of follow-up or until the first progression and had tissue for 1p/19q status available. 1p/19q status was assessed by multiplex ligation–dependent probe amplification.

Results: After a median follow-up of 3.8 years, progressive disease was documented in 34 patients. The estimated median progression-free survival was 4.6 years. Fifty-eight of the 76 patients had a combined loss of 1p and 19q. The absence or presence of combined 1p/19q loss was not prognostic for progression-free survival using multivariate adjustment for histology, extent of resection, and gender.

Conclusions: Combined 1p/19q loss is not a sensitive prognostic biomarker in patients with oligodendroglial tumors who do not receive radiotherapy or chemotherapy. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress.
Plasma, Tumor, and Tissue Disposition of STEALTH Liposomal CKD-602 (S-CKD602) and Nonliposomal CKD-602 in Mice Bearing A375 Human Melanoma Xenografts
Authors: Zamboni William C. , Strychor Sandra , Joseph Erin , Walsh Dustin R. , Zamboni Beth A. , Parise Robert A. , Tonda Margaret E. , Yu Ning Y. , Engbers Charles , Eiseman Julie L.
Published: December 2007

Purpose: S-CKD602 is a STEALTH liposomal formulation of CKD-602, a camptothecin analogue. The cytotoxicity of camptothecin analogues is related to the duration of exposure in the tumor. STEALTH liposomal formulations contain lipid conjugated to methoxypolyethylene glycol and have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. For STEALTH liposomal formulations of anticancer agents to achieve antitumor effects, the active drug must be released into the tumor extracellular fluid (ECF).

Experimental Design: S-CKD602 at 1 mg/kg or nonliposomal CKD-602 at 30 mg/kg was administered once via tail vein to mice bearing A375 human melanoma xenografts. Mice (n = 3 per time point) were euthanized at 0.083 to 24 h, 48 h, and 72 h after S-CKD02 and from 0.083 to 24 h after nonliposomal CKD-602. Plasma samples were processed to measure encapsulated, released, and sum total (encapsulated plus released) CKD-602, and tumor and tissue samples were processed to measure sum total CKD-602. Microdialysis samples of tumor ECF were obtained from 0 to 2 h, 4 to 7 h, and 20 to 24 h after nonliposomal CKD-602 and from 0 to 2 h, 24 to 27 h, 48 to 51 h, and 72 to 75 h after S-CKD602. A liquid chromatography-mass spectrometry assay was used to measure the total (sum of lactone and hydroxyl acid) CKD-602. The area under the concentration-versus-time curves (AUC) from 0 to infinity and time >1 ng/mL in tumor were estimated.

Results: For S-CKD602, the CKD-602 sum total AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 201,929, 13,194, and 187 ng/mL h, respectively. For S-CKD602, 82% of CKD-602 remains encapsulated in plasma. For nonliposomal CKD-602, the CKD-602 AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 9,117, 11,661, and 639 ng/mL·h, respectively. The duration of time the CKD-602 concentration was >1 ng/mL in tumor ECF after S-CKD602 and nonliposomal CKD-602 was >72 and ∼20 h, respectively. For S-CKD602, the CKD-602 sum total exposure was 1.3-fold higher in fat as compared with muscle. The ratio of CKD-602 sum total exposure in fat to muscle was 3.8-fold higher after administration of S-CKD602 compared with nonliposomal CKD-602.

Conclusion: S-CKD602 provides pharmacokinetic advantages in plasma, tumor, and tumor ECF compared with nonliposomal CKD-602 at 1/30th of the dose, which is consistent with the improved antitumor efficacy of S-CKD602 in preclinical studies. The distribution of S-CKD602 is greater in fat compared with muscle whereas the distribution of nonliposomal CKD-602 is greater in muscle compared with fat. These results suggest that the body composition of a patient may affect the disposition of S-CKD602 and released CKD-602.
A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer
Authors: Gravdal Karsten , Halvorsen Ole J. , Haukaas Svein A. , Akslen Lars A.
Published: December 2007

Purpose: Cell adhesion molecules are of crucial importance in cancer invasion and metastasis. Epithelial to mesenchymal transition, characterized by reduced E-cadherin and increased N-cadherin expression, has been recognized as a feature of aggressive tumors, but the importance of this phenotype has not been settled in human prostate cancer. We here present novel data, with special focus on the independent relationship between an E-cadherin to N-cadherin switch (EN-switch) and patient prognosis.

Experimental Design: Tissue microarray sections from a consecutive series of 104 radical prostatectomies during 1988 to 1994 with detailed clinicopathologic data and long follow-up were studied immunohistochemically for the expression of E-cadherin, N-cadherin, P-cadherin, β-catenin, and p120CTN.

Results: Low E-cadherin expression was significantly associated with adverse clinicopathologic features, whereas other biomarkers were mostly related to Gleason score. In univariate survival analyses, cadherin switching (high N-cadherin and low E-cadherin) showed strong and significant associations with multiple end points of progression and cancer-specific death. Expression of the “basal cell marker” P-cadherin was associated with shorter time to skeletal metastasis (P = 0.036). In multivariate analysis of time to clinical recurrence, the “EN-switch” (hazard ratio, 4.3; P < 0.0005) had strong and independent prognostic effect, together with Gleason score.

Conclusion: These novel data unravel the importance of epithelial to mesenchymal transition for prostate cancer progression, and demonstration of a switch from E-cadherin to N-cadherin expression could have significant effect on the care of prostate cancer patients.
Lack of Association of Single-Nucleotide Polymorphisms in Pregnane X Receptor, Hepatic Nuclear Factor 4α, and Constitutive Androstane Receptor with Docetaxel Pharmacokinetics
Authors: Tham Lai-San , Holford Nicholas H.G. , Hor Sok-Ying , Tan Theresa , Wang Lingzhi , Lim Rui-Chen , Lee How-Sung , Lee Soo-Chin , Goh Boon-Cher
Published: December 2007

Purpose: This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4α (HNF4α), on the pharmacokinetics of docetaxel.

Experimental Design: Docetaxel was given as an i.v. infusion of 75 mg/m2 over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4α were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model.

Results: Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, α1 acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4α and 5′ untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance.

Conclusions: SNPs identified in CYP3A gene expression regulators CAR, HNF4α, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.
First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer
Authors: Dudek Arkadiusz Z. , Yunis Carla , Harrison Lester I. , Kumar Sandeep , Hawkinson Ronald , Cooley Sarah , Vasilakos John P. , Gorski Kevin S. , Miller Jeffrey S.
Published: December 2007

Purpose: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans.

Experimental Design: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles.

Results: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m2. Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m2; higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels ≥0.6 mg/m2. Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen.

Conclusions: 852A was safely administered i.v. at doses up to 1.2 mg/m2 thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.
Overlapping Repair in Patients with Anal Sphincter Injury
Authors: Demirbas Sezai , Atay Vedat , Sucullu Ilker , Filiz A. Ilker
Published: December 2007

Objective: The aim of this study was to demonstrate the improvement of anal canal function after overlap sphincter repair and confirm that this treatment option is superior in patients with nonobstetric sphincter damage. Subjects and Methods: From 1998 to 2003, 44 women who underwent overlapping sphincter repair were enrolled in this study. The women were allocated to one of two groups, obstetric trauma (n = 31) and nonobstetric (perineal) trauma (n = 13). Both groups were compared in terms of age, operation time, number of deliveries, hospital stay, need for analgesics, complication rate, pre- and postoperative outcomes of anal manometry and quality of life, using the fecal incontinence severity index and a questionnaire for fecal disorders. Results: Anal canal length was significantly extended postoperatively in both groups compared to preoperative length. Eight-week postoperative resting and squeeze pressures were significantly higher than preoperative pressures in both patients with nonobstetric and obstetric sphincter injury. Although significant increase was seen in both groups, the mean postoperative resting and squeeze pressures at 1 year were rather high in patients with nonobstetric sphincter injury. At the end of a year of follow-up, overall satisfaction of the repair was about 82%. Conclusion: Overlap sphincter repair was feasible, although patient satisfaction was slightly less in the obstetric than in the nonobstetric trauma group. The improvement of anal function at 20- to 24-month follow-up is attributed to both high squeeze pressure and broad anal canal.
A Model of Premature Aging in Mice Based on Altered Stress-Related Behavioral Response and Immunosenescence
Authors: Viveros María-Paz , Arranz Lorena , Hernanz Angel , Miquel Jaime , De la Fuente Mónica
Published: December 2007

The intensity of behavioral and neuroendocrine responses to stressful stimuli in rodent strains seems to be inversely related to their life span. We have previously shown that interindividual differences in members of outbred Swiss and inbred BALB/c mouse populations, both male and female, may be related to their behavior in a simple T-maze test. The animals that explore the maze slowly show impaired neuromuscular vigor and coordination, decreased locomotor activity, increased level of emotionality/anxiety, decreased levels of brain biogenic amines as well as immunosenescence and decreased life span, when compared to their control counterparts, which quickly explore the maze. These traits are similar to some of the alterations previously observed in aging animals and therefore we proposed that those ‘slow mice’ are biologically older than the fast animals and may be a model of prematurely aging mice (PAM). Although most of our work on this model has been performed on chronologically adult-mature animals, we have also shown that certain characteristics of PAM, such as increased anxiety and deficient immune response, are already present in chronologically young animals. Thus, it is tempting to hypothesize that chronic hyperreactivity to stress (trait anxiety) leading to immune dysfunction may have a causal relationship with impaired health and premature aging. In view of the link between oxidative stress and the aging process, the redox state of peritoneal leukocytes from PAM has been studied, showing an oxidative stress situation. In the present work we have determined the levels of a key antioxidant, reduced glutathione (GSH), and the oxidant malondialdehyde (MDA), a marker of lipid peroxidation, both in the spleen and brain of male and female PAM and non-PAM (NPAM). We found that GSH and MDA are decreased and increased, respectively, in PAM with respect to NPAM. Moreover, diet supplementation with antioxidants showed to be an effective strategy for protection against early immune and behavioral decline, altered redox state of leukocytes and premature mortality in PAM, which supports the validity of this model of premature aging as well as its link with oxidative stress.
Is There a Role for Cellular Prion Protein in Intrathymic T Cell Differentiation and Migration?
Authors: Terra-Granado Eugênia , Berbert Luiz Ricardo , de Meis Juliana , Nomizo Regina , Martins Vilma Regina , Savino Wilson , Silva-Barbosa Suse Dayse
Published: December 2007

The cellular prion protein (PrPC) is expressed in the nervous and immune systems. Functionally, PrPC has been suggested to participate in neuron survival, neuritogenesis and T lymphocyte activation. Moreover, PrPC interaction with laminin influences neuronal adhesion and neurite extension. Nevertheless, so far the physiological role of PrPC has not been completely elucidated, particularly in the immune system. The aim of the study was to evaluate the possible participation of PrPC in intrathymic T cell development. We evaluated T cell differentiation markers in thymocytes and peripheral lymphocytes, as well as thymocyte death in PrPC-null or PrPC-overexpressing (Tga20) mice, compared to wild-type controls. In these same animals, we ascertained laminin-driven thymocyte migration. Compared to controls, only marginal differences were found in PrPC-null animals. However, Tga20 mice exhibited a severe thymic hypoplasia, with 10–20% lymphocytes compared to wild-type counterparts. In particular, the frequency of CD4+CD8+ cells was largely reduced, and this was accompanied by a dramatic increase in the frequency of CD4–CD8– thymocytes, which could be as high as 60–65% of the whole-cell suspensions. Moreover, Tga20 mice exhibited an increase in thymocyte death, comprising the CD4+CD8+, as well as CD4+ and CD8+ single-positive cells. Additionally, laminin-driven migration was largely impaired in Tga20 mice, in which we also found a significant decrease in total T lymphocytes in the spleen and lymph nodes. Our results show that PrPC overexpression alters intrathymic T cell development, a defect that likely has a negative impact in the formation of the T cell peripheral pool.
The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition
Authors: Lin Congrong , Ke Xiaogang , Ranade Vasant , Somberg John
Published: December 2007

Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and IKr-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with IKr-inhibiting antiarrhythmic drugs on cardiac IKr. Methods and Results:IKr current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC50 of 173.3 ± 3.1 µM. Naringenin 100 µM alone inhibited HERG current by 31 ± 6%, and this inhibitory effect was increased with coadministration of 1 or 10 µM antiarrhythmic drugs. When 100 µM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with IKr-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.
Myocardial Contractile Response to Increasing Doses of Dobutamine in Patients with Reperfused Acute Myocardial Infarction by Cardiac Magnetic Resonance Imaging
Authors: Barmeyer Achim A. , Stork Alexander , Bansmann Martin , Muellerleile Kai , Bavastro Marcus , Heuer Mirko , Adam Gerhard , Meinertz Thomas , Lund Gunnar K.
Published: December 2007

Background: Cardiac magnetic resonance imaging uses contractile response to dobutamine (DCMR) and delayed contrast enhancement (DE) to assess myocardial viability. However, early after acute myocardial infarction (AMI) the optimal dose of dobutamine is unclear. Methods: In patients early after reperfused AMI, DCMR at 5, 10 and 20 µg*kg–1*min–1 and measurement of DE was performed. On three short-axis slices 18 segments were graded as no DE, DE <50% and DE ≧50%. Thickening (systolic-diastolic wall thickness) and contractile reserve (max. thickening – rest) were determined. Segments were classified dysfunctional if thickening was >2 SD below normal or <2 mm. Results: Forty-nine patients participated. In segments with no DE, thickening increased continuously but contractile reserve was low (0.9 ± 3.2 mm) and dysfunctional segments were unchanged (rest: 13.1% vs. 20 µg: 14.8%). In segments with DE, contractile reserve was high (1.4 ± 3.0 mm and 1.5 ± 3.0 mm) and dysfunctional segments decreased from rest to 20 µg (50 vs. 24.8% and 79.9 vs. 43.2%). Between 5 and 10 µg no change of thickening and of dysfunctional segments occurred. Conclusion: Early after AMI, DCMR demonstrated no diagnostic benefit in segments with no DE. In segments with DE, higher dose of dobutamine can provide additional information on contractile reserve and dysfunctional segments.
The Effects of External Counter Pulsation Therapy on Circulating Endothelial Progenitor Cells in Patients with Angina Pectoris
Authors: Barsheshet Alon , Hod Hanoch , Shechter Michael , Sharabani-Yosef Orna , Rosenthal Eti , Barbash Israel M. , Matetzky Shlomi , Tal Reshef , Bentancur Ariel G. , Sela Ben-Ami , Nagler Arnon , Leor Jonathan
Published: December 2007

Objectives: External counter pulsation therapy (ECPT) offers symptomatic relief and improves ischemia in patients with refractory angina pectoris. We aimed to determine the effects of ECPT on circulating endothelial progenitor cells (EPCs). Methods: We prospectively studied 25 patients with angina pectoris treated with ECPT (n = 15) or receiving standard care (n = 10). The number of EPCs positive for CD34 and kinase insert domain receptor (KDR) was determined by flow cytometry and the number of colony-forming units (CFUs) was assessed in a 7-day culture, before ECPT and after 9 weeks. Results: ECPT improved anginal score from a median of 3.0 to 2.0 (p < 0.001). Concomitantly, ECPT increased EPC number from a median of 10.2 to 17.8/105 mononuclear cells (p < 0.05), and CFUs from 3.5 to 11.0 (p = 0.01). Flow-mediated dilatation was improved by ECPT from 7.4 to 12.2% (p < 0.001) and correlated with EPC-CFUs (r = 0.461, p = 0.027). The levels of asymmetric dimethylarginine were reduced by ECPT from 0.70 to 0.60 µmol/l (p < 0.01). In contrast, the same parameters did not change in the control group, before and after follow-up. Conclusions: The present pilot study shows, for the first time, that ECPT is associated with increased number and colony-forming capacity of circulating EPCs.
Interventricular Mechanical Dyssynchrony Determines Abnormal Heightening of Plasma N-Terminal Probrain Natriuretic Peptide Level in Symptomatic Bradyarrhythmia Patients with Chronic Dual-Chamber vs. Single-Chamber Atrial Pacing
Authors: Lin Jih-Min , Lai Ling-Ping , Tsai Chia-Ti , Lin Lung-Chun , Tseng Chuen-Den , Lin Jiunn-Lee
Published: December 2007

Objective: Debates about adverse effects of ventricular- vs. atrial-based pacing have never ended, especially regarding cardiovascular outcomes in common pacemaker populations. Methods: To investigate the contribution of right ventricular apical pacing to the left ventricular negative remodeling, we measured the inter- and intraventricular mechanical dyssynchrony by echocardiography as well as plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 116 consecutive patients of symptomatic bradyarrhythmias including sinus node dysfunction (SND) in 80 and atrioventricular block in 36. Dual-chamber rate-modulated pacing (DDDR) pacemakers were implanted in 76 patients (SND, 40), and single-chamber ventricular rate-modulated pacing (AAIR) pacemakers in 40 (all SND). Clinical manifestations were retrospectively correlated. Results: After 3.5 years of pacing, DDDR pacemaker patients demonstrated higher plasma NT-proBNP concentration (503 ± 111 pg/ml) than AAIR patients (194 ± 42 pg/ml, p = 0.002) despite similar cardiovascular function at baseline. Multivariate regression analysis revealed that the only predictor of the highest quartile of plasma NT-proBNP, i.e. ≧386 pg/ml, was the interventricular contraction time difference (p = 0.01). Reprograming to minimize ventricular pacing percentage in 8 patients of SND caused parallel reduction of plasma NT-proBNP. Conclusion: Interventricular mechanical dyssynchrony, imposed mostly by right ventricular apical pacing, could lead to abnormal heightening of plasma NT-proBNP concentration after chronic DDDR pacing in common pacemaker patients with normal baseline left ventricular function.
Functional Recovery of Chronic Ischemic Myocardium after Surgical Revascularization Correlates with Magnitude of Oxidative Metabolism
Authors: Pöling Jochen , Rees Wolfgang , Klaus Stephan , Bahlmann Ludger , Hübner Norbert , Heringlake Matthias , Mantovani Vittorio , Warnecke Henning
Published: December 2007

Background: The purpose of this study was to validate myocardial microdialysis measurements in patients after myocardial infarction with or without associated postoperative functional recovery in order to develop a highly sensitive tool for real-time in vivo detection of microcellular disorder during cardiac operations. Methods: In 20 patients undergoing coronary artery bypass grafting, microdialysis catheters were implanted into scar or hibernating segments detected by means of magnetic resonance imaging, and into a vital area of the right ventricle (control). Myocardial glucose, lactate and pyruvate were analyzed perioperatively. Myocardial ethanol washout was measured as a sign of recovered local blood flow. Results: After surgical revascularization, improvement of wall motion was found in all hibernating segments compared to the scar segments paralleling an increased glucose delivery to the tissue and increased myocardial tissue flow. The myocardial glucose/lactate ratio and pyruvate also showed significantly higher values. Microdialytic measurements of the viable segments were comparable with those of the right ventricle. Conclusions: Our results indicate that microdialysis measurements parallel magnetic resonance imaging findings in patients with revascularization of chronic ischemic myocardium with dyskinetic segments. The metabolism of those segments is characterized by a significantly increased tissue flow, an increased utilization of glucose and a better oxidative nutrition.
Simvastatin Inhibits C-Reactive Protein-Induced Pro-Inflammatory Changes in Endothelial Cells by Decreasing Mevalonate Pathway Products
Authors: Liang Yao-Jen , Shyu Kou-Gi , Wang Bao-Wie , Lai Ling-Ping
Published: December 2007

Objectives: The effects of HMG-CoA reductase inhibitors on C-reactive protein (CRP)-induced pro-inflammatory changes in endothelial cells remain unclear. We tested the hypothesis that simvastatin inhibited CRP-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products. Methods: Human umbilical vein endothelial cells were incubated with CRP and measurement of CD32, nuclear factor ĸB (NF-ĸB) activation, vascular cell adhesion molecule-1 expression and monocyte adhesion assay were performed. The effects of simvastatin, siRNA against CD32 (siCD32) and mevalonate pathway products were also examined. Results: Pre-treatment with simvastatin significantly attenuated the CRP-induced CD32 expression and NF-ĸB activation in human umbilical vein endothelial cells. Simvastatin also decreased CRP-induced vascular cell adhesion molecule-1 expression and reduced monocyte adhesion on endothelial cells. The inhibitory effects of simvastatin were significantly reversed by adding mevalonate and geranylgeranyl pyrophosphate (GGPP), but not by adding farnesyl pyrophosphate. Pre-treatment with siCD32 also decreased CRP-induced CD32 expression and inhibitor of ĸB degradation. However, neither mevalonate nor GGPP reversed the effects of siCD32. Conclusions: CRP-induced CD32 expression and NF-ĸB activation were attenuated by simvastatin. A decrease in mevalonate and subsequent GGPP contributes to the inhibitory effects of simvastatin. These findings may provide an explanation of using statins on patients with high serum CRP levels.
Ivabradine as an Alternative Therapeutic Trial in the Therapy of Inappropriate Sinus Tachycardia
Authors: Schulze Volker , Steiner Stefan , Hennersdorf Marcus , Strauer Bodo-Eckehard
Published: December 2007

Inappropriate sinus tachycardia is a disease which is relatively rarely found and sometimes difficult to treat. Up to now it has been mostly treated with a β-blocker or verapamil. If this did not work sinus node modulation was considered. Since the relatively new selective IF-stream blocker ivabradine has been approved for the therapy of chronic stable angina pectoris, a new therapeutic option is available. As ivabradine is well tolerated and only few side effects are known, it may become a new therapeutic step between medication and the invasive sinus node modulation. We report the case of a young female patient with inappropriate sinus tachycardia where a sustained therapeutic success was achieved with ivabradine medication as an alternative therapeutic trial after various ineffective medications.
The Effect of Anticonvulsant Drugs on the Fibrinolytic Activity of Tissue Plasminogen Activator
Authors: Zemke Daniel , Farooq Muhammad U. , Gupta Rishi , Kassab Mounzer , Reeves Mathew , Majid Arshad
Published: December 2007

Background and Purpose: Several anticonvulsant drugs have been found to be neuroprotective in preclinical models of stroke, and such drugs may possibly be given in combination with other stroke treatments such as recombinant tissue plasminogen activator (rt-PA). The goal of this study was to test for potential interactions between rt-PA and selected anticonvulsants. Methods: A spectrophotomeric assay was used to monitor the lysis of fibrin clots in the presence of rt-PA and the drugs levetiracetam, valproic acid, phenytoin and phenobarbital. Results: The drugs tested were found to have no effect on either the rate or total amount of lysis induced by rt-PA. Conclusions: Although further studies are required in order to explore the effects of these drugs in stroke patients, the results suggest that co-administration of rt-PA and anticonvulsant drugs may be safe and viable.
Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder
Authors: Grabe Hans Joergen , Ruhrmann Stephan , Spitzer Carsten , Josepeit Jana , Ettelt Susan , Buhtz Friederike , Hochrein Andrea , Schulze-Rauschenbach Svenja , Meyer Klaus , Kraft Susanne , Reck Claudia , Pukrop Ralf , Klosterkötter Joachim , Falkai Peter , Maier Wolfgang , Wagner Michael , John Ulrich , Freyberger Harald J.
Published: December 2007

Background: Previous studies suggested an association between exposure to trauma or stressful life events and obsessive-compulsive disorder (OCD). This study investigates the hypothesis that traumatic events and posttraumatic stress disorders (PTSD) precede the onset of OCD. Sampling and Methods: 210 cases with OCD from university treatment facilities were compared with 133 sex- and age-matched controls from the adult general population. The data were derived from a German family study on OCD (GENOS). Direct interviews were carried out with the German version of the Schedule for Affective Disorders and Schizophrenia – Lifetime Version for Anxiety Disorders (DSM-IV). Results: Severe traumatization occurred in 6.2% of the OCD cases and in 8.3% of the controls. The lifetime prevalence rates of traumatization, PTSD and acute stress disorder were not different between the subjects with OCD and controls (p > 0.05). In 6 cases, acute stress disorder, subclinical or full PTSD preceded the onset of OCD, in 3 cases the trauma-related disorders and OCD occurred within the same year, in 5 other cases, the trauma-related disorders started after the onset of OCD. Conclusion: There is no significant association of traumatization or PTSD with OCD compared with controls. Given the low rate of trauma-related disorders occurring before (2.9%) or within (1.5%) the same year as the onset of OCD other factors than severe traumatic events determine the onset of OCD in most of the cases.
Shortened Hemofilter Survival Time due to Lipid Infusion in Continuous Renal Replacement Therapy
Authors: Kazory Amir , Clapp William L. , Ejaz A. Ahsan , Ross Edward A.
Published: December 2007

Background: Continuous renal replacement therapy is widely used for the treatment of critically ill patients with acute renal failure in critical care units. The survival time of the extracorporeal circuit is an important factor in providing renal replacement therapy. Despite rigorous efforts to maintain hemofilter patency, clinicians are occasionally faced with an unexplained short circuit survival time. Methods: We present a critically ill patient undergoing continuous venovenous hemofiltration with regional citrate anticoagulation for management of acute renal failure in the context of sepsis. Once the patient was started on lipid infusion as part of total parenteral nutrition, we observed a shortened circuit survival due to premature hemofilter failure necessitating frequent changes of the hemofilter. The known potential causes for this phenomenon were ruled out. Results: Evaluation revealed grossly lipemic serum associated with severe hypertriglyceridemia. Discontinuation of the lipid infusion was followed by a rapid return of circuit survival time to its baseline. Evaluation of the hemofilter by electron microscopy revealed that the rapid blockage of the hollow fibers was caused by lipid microparticles and fibrin deposits. Conclusion: Since total parenteral nutrition is commonly administered to malnourished and hypercatabolic critically ill patients on continuous renal replacement therapy, we suggest that intravenous lipid therapy might be a previously unreported and unappreciated remediable cause of premature hemofilter failure.
Word Play
Authors: Karttunen Lauri
Published: December 2007

This article is a perspective on some important developments in semantics and in computational linguistics over the past forty years. It reviews two lines of research that lie at opposite ends of the field: semantics and morphology. The semantic part deals with issues from the 1970s such as discourse referents, implicative verbs, presuppositions, and questions. The second part presents a brief history of the application of finite-state transducers to linguistic analysis starting with the advent of two-level morphology in the early 1980s and culminating in successful commercial applications in the 1990s. It offers some commentary on the relationship, or the lack thereof, between computational and paper-and-pencil linguistics. The final section returns to the semantic issues and their application to currently popular tasks such as textual inference and question answering.
Weighted and Probabilistic Context-Free Grammars Are Equally Expressive
Authors: Smith Noah A. , Johnson Mark
Published: December 2007

This article studies the relationship between weighted context-free grammars (WCFGs), where each production is associated with a positive real-valued weight, and probabilistic context-free grammars (PCFGs), where the weights of the productions associated with a nonterminal are constrained to sum to one. Because the class of WCFGs properly includes the PCFGs, one might expect that WCFGs can describe distributions that PCFGs cannot. However, Z. Chi (1999, Computational Linguistics, 25(1):131–160) and S. P. Abney, D. A. McAllester, and P. Pereira (1999, In Proceedings of the 37th Annual Meeting of the Association for Computational Linguistics, pages 542–549, College Park, MD) proved that every WCFG distribution is equivalent to some PCFG distribution. We extend their results to conditional distributions, and show that every WCFG conditional distribution of parses given strings is also the conditional distribution defined by some PCFG, even when the WCFG's partition function diverges. This shows that any parsing or labeling accuracy improvement from conditional estimation of WCFGs or conditional random fields (CRFs) over joint estimation of PCFGs or hidden Markov models (HMMs) is due to the estimation procedure rather than the change in model class, because PCFGs and HMMs are exactly as expressive as WCFGs and chain-structured CRFs, respectively.
The Muslim Surgeon and Contemporary Ethical Dilemmas Surrounding the Restoration of Virginity
Authors: Rispler-Chaim Vardit
Published: December 2007

In the last few decades surgeons have been able to perform an operation that repairs a torn hymen, and thus allows young women and girls whose hymen is not intact to reappear as virgins. Most of the ethical issues related to hymen repair surgery concern the conduct of the surgeon and the question of whether restoration of virginity is a way to deceive husbands. The status of hymen restoration surgery has been the subject of several fatwas issued by leading religious authorities and articles written by Muslim lawyers, physicians and ethicists. Virginity restoration, based on the above sources, appears to have its supporters and opponents. The study of hymen restoration is also related to the status of women in society and their rights, to ancient social taboos, and to the impact of modern scientific technology on society at large.
Neo-Traditional Salafi Qur'an-Sunnah Hermeneutic and the Construction of a Normative Muslimah Image
Authors: Duderija Adis
Published: December 2007

The aim of this article is to outline and analyse the delineating features of the Neo-Traditional Salafi model of interpreting Qur'an and Sunnah indicants and the interpretational implications of this model in relation to constructing a "normative" concept of a Muslimah (model for a Muslim woman). The author argues that the NTS interpretational model is based on a range of epistemological and methodological assumptions pertaining to the conceptualisation and interpretation of the nature and the scope of the Qur'an and Sunnah.
Een negentiende-eeuws Gents collegedictaat over het ius publicum Belgicum
Authors: van Kappen O. Moorman
Published: December 2007

This contribution deals with a manuscript, containing lecture notes made in 1827–1828 by a Ghent student named Callenfels and relating to the lectures on ius publicum universale et Belgicum, given by Jacob Joseph Haus (1796–1881), professor of jurisprudence at Ghent University and native of Würzburg. As the course programme of the law faculties in the southern provinces required courses in natural law as well as in ius publicum and ius gentium, the assumption has been put forward these lectures would be restricted to the ius publicum universale such as lectured in many German law faculties in the 18th century. On further examination of the manuscript under consideration this presumption proves to be wrong. After the first 13 sections, which refer in fact to the ius publicum naturale in an enlightened sense, the remaining 253 sections outline the then positive constitutional law of the Netherlands, mainly on the basis of the Dutch written constitution of 1815.