bluuebunny/crossref_metadata_2025 huggingface dataset:
Markers of inflammation are inversely associated with V̇o2 max in asymptomatic men
Authors: Kullo Iftikhar J. , Khaleghi Mahyar , Hensrud Donald D.
Published: December 2006

We investigated whether markers of inflammation, including a cytokine (IL-6), acute-phase reactants [C-reactive protein (CRP) and fibrinogen], and white blood cell (WBC) count are associated with maximal O2 consumption (V̇o2 max) in men without coronary heart disease (CHD). In asymptomatic men ( n = 172, 51 ± 9.3 yr old), V̇o2 max was measured during a symptom-limited graded treadmill exercise test. Physical activity level was assessed by a standardized questionnaire. IL-6 and CRP were measured by immunoassays, fibrinogen by the Clauss method, and WBC count with a Coulter counter. IL-6 and CRP were logarithmically transformed to reduce skewness. Multivariable regression was used to assess whether markers of inflammation were associated with V̇o2 max after adjustment for age, body mass index, CHD risk factors, and lifestyle variables (physical activity level, percent body fat, and alcohol intake). V̇o2 max was 34.5 ml·kg−1·min−1 (SD 6.1). Log IL-6 ( r = −0.38, P < 0.001), log CRP ( r = −0.40, P < 0.001), fibrinogen ( r = −0.42, P < 0.001), and WBC count ( r = −0.22, P = 0.004) were each correlated with V̇o2 max. In separate multivariable linear regression models that adjusted for age, body mass index, CHD risk factors, and lifestyle variables, log IL-6 [β-coeff = −1.66 ± 0.63 (SE), P = 0.010], log CRP [β-coeff = −0.99 ± 0.33 (SE), P = 0.003], fibrinogen [β-coeff = −1.51 ± 0.44 (SE), P = 0.001], and WBC count [β-coeff = −0.52 ± 0.30 (SE), P = 0.088] were each inversely associated with V̇o2 max. In conclusion, higher circulating levels of IL-6, CRP, and fibrinogen are independently associated with lower V̇o2 max in asymptomatic men.
Leukemia-Specific T-Cell Reactivity Induced by Leukemic Dendritic Cells Is Augmented by 4-1BB Targeting
Authors: Houtenbos Ilse , Westers Theresia M. , Dijkhuis Annemiek , de Gruijl Tanja D. , Ossenkoppele Gert J. , van de Loosdrecht Arjan A.
Published: December 2006

Purpose: Acute myelogenous leukemia (AML) blasts are able to differentiate into leukemia-derived dendritic cells (AML-DC), thereby enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, additional measures are likely needed to potentiate vaccines and overcome the intrinsic tolerant state of the patients' immune system. Engagement of the costimulatory molecule 4-1BB can break immunologic tolerance and increase CTL responses. In this study, we examined the role of the 4-1BB ligand (4-1BBL) on T-cell responses induced by AML-DC.

Experimental Design: In allogeneic and autologous cocultures of T cells and AML-DC, the effect of the addition of 4-1BBL on T-cell proliferation, T-cell subpopulations, and T-cell function was determined.

Results: Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8+ T cells. Increased differentiation into effector and central memory populations was observed in both CD4+ and CD8+ T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-γ production, which is significantly increased by targeting 4-1BB. T cells primed in the presence of 4-1BBL show specificity for the leukemia-associated antigen Wilms' tumor 1, whereas cytotoxicity assays with leukemic blast targets showed the cytolytic potential of T cells primed in the presence of 4-1BBL.

Conclusion: We conclude that 4-1BBL is an effective adjuvant to enhance T-cell responses elicited by AML-DC.
Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway
Authors: Woodley-Cook Joel , Shin Lucy Y.Y. , Swystun Laura , Caruso Sonya , Beaudin Suzanne , Liaw Patricia C.
Published: December 2006

Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms for the thrombogenic effect of chemotherapeutic drugs are poorly understood. We hypothesize that exposure of vascular endothelial cells to chemotherapeutic agents results in the loss of a thromboresistant phenotype. In this study, we examined the effects of the chemotherapeutic agent doxorubicin on the endothelium-based protein C anticoagulant pathway. The endothelial cell protein C receptor (EPCR) and thrombomodulin are two endothelial cell surface receptors required for the conversion of zymogen protein C to the anticoagulant enzyme activated protein C. Exposure of human umbilical vein endothelial cells (HUVEC) to doxorubicin resulted in a dose- and time-dependent decrease in cell surface EPCR levels. This decrease occurred as a result of receptor shedding as well as from a down-regulation in EPCR mRNA levels. In contrast, doxorubicin treatment of HUVECs resulted in a dose- and time-dependent increase in cell surface thrombomodulin attributed to an up-regulation of thrombomodulin mRNA levels. The net effect of the doxorubicin-induced changes in EPCR and thrombomodulin levels was a decrease in the capacity of HUVECs to convert protein C to activated protein C. Preliminary studies suggest that doxorubicin free radical metabolites mediate the doxorubicin-induced changes in EPCR expression but not those of thrombomodulin expression. In summary, these results suggest that doxorubicin alters the hemostatic balance of endothelial cells by down-regulating the endothelium-based protein C anticoagulant pathway. [Mol Cancer Ther 2006;5(12):3303–11]
Blockade of transforming growth factor-β-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade
Authors: Choo Min-Kyung , Kawasaki Noritaka , Singhirunnusorn Pattama , Koizumi Keiichi , Sato Shintaro , Akira Shizuo , Saiki Ikuo , Sakurai Hiroaki
Published: December 2006

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF-α ligand family that selectively induces apoptosis in a variety of tumor cells. To clarify the molecular mechanism of TRAIL-induced apoptosis, we focused on transforming growth factor-β-activated kinase 1 (TAK1) mitogen-activated protein kinase (MAPK) kinase kinase, a key regulator of the TNF-α-induced activation of p65/RelA and c-Jun NH2-terminal kinase/p38 MAPKs. In human cervical carcinoma HeLa cells, TRAIL induced the delayed phosphorylation of endogenous TAK1 and its activator protein TAB1 and TAB2, which contrasted to the rapid response to TNF-α. Specific knockdown of TAK1 using small interfering RNA (siRNA) abrogated the TRAIL-induced activation of p65 and c-Jun NH2-terminal kinase/p38 MAPKs. TRAIL-induced apoptotic signals, including caspase-8, caspase-3, caspase-7, and poly(ADP-ribose) polymerase, were enhanced by TAK1 siRNA. Flow cytometry showed that the binding of Annexin V to cell surface was also synergistically increased by TRAIL in combination with TAK1 siRNA. In addition, pretreatment of cells with 5Z-7-oxozeaenol, a selective TAK1 kinase inhibitor, enhanced the TRAIL-induced cleavage of caspases and binding of Annexin V. The TAK1-mediated antiapoptotic effects were also observed in human lung adenocarcinoma A549 cells. In contrast, TAK1-deficient mouse embryonic fibroblasts are resistant to TRAIL-induced apoptosis, and treatment of control mouse embryonic fibroblasts with 5Z-7-oxozeaenol did not drastically promote the TRAIL-induced activation of a caspase cascade. These results suggest that TAK1 plays a critical role for TRAIL-induced apoptosis, and the blockade of TAK1 kinase will improve the chances of overcoming cancer. [Mol Cancer Ther 2006;5(12):2970–6]
Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells
Authors: Herynk Matthew H. , Beyer Amanda R. , Cui Yukun , Weiss Heidi , Anderson Elizabeth , Green Tim P. , Fuqua Suzanne A.W.
Published: December 2006

It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor α (ERα) that confers hypersensitivity to low levels of estrogen. Because ERα and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERα-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERα-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchorage-dependent growth IC50 of 0.47 μmol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERα had an elevated IC50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERα. These data clearly show an important role for ERα and estrogen signaling in c-Src–mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERα in estrogen-dependent breast cancer. [Mol Cancer Ther 2006;5(12):3023–31]
The endothelial cytoskeleton as a target of electroporation-based therapies
Authors: Kanthou Chryso , Kranjc Simona , Sersa Gregor , Tozer Gill , Zupanic Anze , Cemazar Maja
Published: December 2006

Electroporation-based therapies, such as electrochemotherapy and electrogene therapy, result in the disruption of blood vessel networks in vivo and cause changes in blood flow and vascular permeability. The effects of electroporation on the cytoskeleton of cultured primary endothelial cells and on endothelial monolayer permeability were investigated to elucidate possible mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were electroporated in situ and then immunofluorescence staining for filamentous actin, β-tubulin, vimentin, and VE-cadherin as well as Western blotting analysis of levels of phosphorylated myosin light chain and cytoskeletal proteins were performed. Endothelial permeability was determined by monitoring the passage of FITC-coupled dextran through endothelial monolayers. Exposure of endothelial cells to electric pulses resulted in a profound disruption of microfilament and microtubule cytoskeletal networks, loss of contractility, and loss of vascular endothelial cadherin from cell-to-cell junctions immediately after electroporation. These effects were voltage dependent and reversible because cytoskeletal structures recovered within 60 min of electroporation with up to 40 V, without any significant loss of cell viability. The cytoskeletal effects of electroporation were paralleled by a rapid increase in endothelial monolayer permeability. These results suggest that the remodeling of the endothelial cytoskeleton and changes in endothelial barrier function could contribute to the vascular disrupting actions of electroporation-based therapies and provide an insight into putative mechanisms responsible for the observed increase in permeability and cessation of blood flow in vivo. [Mol Cancer Ther 2006;5(12):3145–52]
Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells
Authors: Fiskus Warren , Pranpat Michael , Balasis Maria , Herger Bryan , Rao Rekha , Chinnaiyan Arul , Atadja Peter , Bhalla Kapil
Published: December 2006

Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes. [Mol Cancer Ther 2006;5(12):3096–104]
Terbinafine inhibits endothelial cell migration through suppression of the Rho-mediated pathway
Authors: Ho Pei-Yin , Zhong Wen-Bin , Ho Yuan-Soon , Lee Wen-Sen
Published: December 2006

We showed previously that terbinafine, an allylamine with fungicidal activity, could inhibit angiogenesis by suppressing the endothelial cell proliferation. In the present study, we further showed that terbinafine (0–120 μmol/L) dose dependently inhibited the adhesion and migration of human umbilical vascular endothelial cells (HUVEC). Western blot analysis showed that terbinafine decreased the levels of Ras protein and membrane-bound RhoA protein. Moreover, the terbinafine-induced migration inhibition in HUVEC was prevented by pretreatment with farnesol or geranylgeraniol. Pretreatment of HUVEC with Ras inhibitor peptide or a ROCK (a kinase associated with RhoA for transducing RhoA signaling) inhibitor, Y27632, abolished the farnesol- or geranylgeraniol-induced prevention effect on the terbinafine-induced migration inhibition, respectively. These data suggest that the consuming or depletion of geranylgeranyl pyrophosphate and consequent suppression of protein geranylgeranylation and farnesylation, which is essential for activation of Rho GTPases and Ras, respectively, might account for the terbinafine-induced inhibition of HUVEC migration. The levels of phosphorylated focal adhesion kinase and paxillin protein and the mRNA levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were also decreased by terbinafine treatment. Taken together, these results indicate that suppression of Rho-mediated pathway might be involved in the signal transduction leading to the inhibition of cell migration caused by terbinafine in HUVEC. [Mol Cancer Ther 2006;5(12):3130–8]
Plumbagin induces G2-M arrest and autophagy by inhibiting the AKT/mammalian target of rapamycin pathway in breast cancer cells
Authors: Kuo Po-Lin , Hsu Ya-Ling , Cho Chien-Yu
Published: December 2006

This study is the first to investigate the anticancer effect of plumbagin in human breast cancer cells. Plumbagin exhibited cell proliferation inhibition by inducing cells to undergo G2-M arrest and autophagic cell death. Blockade of the cell cycle was associated with increased p21/WAF1 expression and Chk2 activation, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C. Plumbagin also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the levels of inactivated phospho-Cdc2 and phospho-Cdc25C by Chk2 activation. Plumbagin triggered autophagic cell death but not predominantly apoptosis. Pretreatment of cells with autophagy inhibitor bafilomycin suppressed plumbagin-mediated cell death. We also found that plumbagin inhibited survival signaling through the phosphatidylinositol 3-kinase/AKT signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin, forkhead transcription factors, and glycogen synthase kinase 3β. Phosphorylation of both of mammalian target of rapamycin downstream targets, p70 ribosomal protein S6 kinase and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased plumbagin-mediated autophagic cell death, whereas reduction of AKT expression by small interfering RNA potentiated the effect of plumbagin, supporting the inhibition of AKT being beneficial to autophagy. Furthermore, suppression of AKT by plumbagin enhanced the activation of Chk2, resulting in increased inactive phosphorylation of Cdc25C and Cdc2. Further investigation revealed that plumbagin inhibition of cell growth was also evident in a nude mouse model. Taken together, these results imply a critical role for AKT inhibition in plumbagin-induced G2-M arrest and autophagy of human breast cancer cells. [Mol Cancer Ther 2006;5(12):3209–21]
Assessment of celecoxib pharmacodynamics in pancreatic cancer
Authors: Jimeno Antonio , Amador Maria Luz , Kulesza Peter , Wang Xiaofei , Rubio-Viqueira Belen , Zhang Xiangfeng , Chan Audrey , Wheelhouse Jenna , Kuramochi Hidekazu , Tanaka Koji , Danenberg Kathleen , Messersmith Wells A. , Almuete Virna , Hruban Ralph H. , Maitra Anirban , Yeo Charles J. , Hidalgo Manuel
Published: December 2006

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E2 in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E2 both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens. [Mol Cancer Ther 2006;5(12):3240–7]
Barriers to Access: Results from Focus Groups to Identify Genetic Service Needs in the Community
Authors: Beene-Harris Rosalyn Y. , Wang Catharine , Bach Janice V.
Published: December 2006

Objective: In efforts to prepare for implications of genomic advances, a needs assessment was undertaken from 2000 to 2002 by the Michigan Department of Community Health to develop a comprehensive state plan for genetic services. This paper reports on the access barriers to genetic services identified from focus groups conducted with members of the community and genetic service providers. Methods: Included in this study were the following five target groups: a sickle cell anemia parent support group, a Native American student group, parents of children with birth defects or other special health care needs, adults with genetic conditions, and genetic service providers from the statewide genetic counselors’ association. Discussions of all groups were audio taped, transcribed and analyzed using content analysis. Results: Individual barriers to access identified included lack of awareness of personal risk, lack of knowledge of genetic services and resources, and lack of trust/fear of discrimination. Institutional barriers to access identified included provider lack of knowledge and awareness of genetic services, lack of workforce, coordination of care, cost and insurance, and location from services. Conclusions: Barriers to access cut across overlapping dimensions and overcoming these barriers will require solutions that target multiple dimensions in order to be effective.
Influence of Consanguinity on the Pattern of Familial Aggregation of Congenital Cardiovascular Anomalies in an Outpatient Population
Authors: Seliem Mohamed A. , Bou-Holaigah Issam H. , Al-Sannaa Nouriya
Published: December 2006

Background: Familial aggregation of congenital heart disease (CHD) has been well described in different populations, in particular those with a high consanguinity rate. Extensive genetic study of affected families has improved the understanding of basic genetics of different cardiac lesions. Objective: To identify the role of consanguinity as a risk factor among familial cases of CHD in a stable outpatient population of a tertiary care center in the Eastern Province of Saudi Arabia. Methods: All familial cases of CHD seen over 5 years (1996–2000) in the Division of Pediatric Cardiology were identified. The presence or absence of parental consanguinity (first cousin marriage) was defined in each of these families. Results: Ninety-three cases were identified in 37 families. Twenty-three (62%) families resulted from consanguineous marriages. In 4 families where there were 2 marriages, the affected children came from the consanguineous marriage in 3 of these families. Discordant lesions occur only among non-consanguineous cases, while all consanguineous cases were concordant. Five sets of twins of the same sex (one set are monozygotic by DNA analysis) occurred among consanguineous marriages, in 3 of these both twins were affected with the same disease. Affected parents were seen in 2 families with consanguineous marriage and none in the non-consanguineous marriages. The prevalence of dilated cardiomyopathy was much higher among consanguineous cases (26 vs. 2). Conclusions: Familial aggregation of congenital heart disease is common in our population. Consanguinity is common in these families, and the distribution of congenital heart disease differs in this subgroup compared to the rest of the familial cases. Further genetic studies of these families may help to shed more light on basic genetics and the specific pathogenetic mechanisms involved.
Integrating Genetics into Advanced Practice Nursing Curriculum: Strategies for Success
Authors: Seibert Diane , Edwards Quannetta T. , Maradiegue Ann
Published: December 2006

Keeping up with the volume of new genetic information emerging from the human genome project is a challenge for almost all healthcare providers, but nurses who received little or no formal genetic training often find it particularly intimidating. Nursing faculty may be reluctant to add genetic content to existing courses, much less tackle the work of teaching an entire course in genetics. This article provides nursing faculty with some strategies and straightforward curriculum modifications to assist them in integrating genetic content into graduate-level nursing curriculum. Advanced Practice Nurses in particular should understand genetics well enough to be aware of and appreciate the wide variety of genetic conditions that might be encountered in a clinical setting. The authors offer practical suggestions for incorporating genetics into Advanced Practice Nursing curricula.
Guidelines for Guidelines
Authors: Amerling Richard , Winchester James F. , Ronco Claudio
Published: December 2006

Practice guidelines are proliferating in medicine. In addition to methodological problems that cause guidelines to be outdated rapidly, they are plagued by conflicts of interest. They are largely consensus opinions of panels of experts, most of whom are supported by industry. Professional societies, health insurers, Centers for Medicare and Medicaide Services, and dialysis providers also benefit from guidelines. Little attention is paid to the potential for harm to patients, and to the profession of medicine, from the widespread use of guidelines.
Haemodialysis Fluid: Composition and Clinical Importance
Authors: Hoenich Nicholas A. , Ronco Claudio
Published: December 2006

Dialysis fluid is produced by the blending of treated water with electrolytes at the patients bed side. Its preparation and composition are important elements of treatment optimisation since many of the constituents play a role in patient well-being. Ideally the composition of the dialysis fluid should match that of plasma, but due to differences between patients, as well as the increasing number of elderly patients receiving treatment, have resulted in a move towards individualisation of the electrolyte and buffer composition to patient needs. Such individualisation is facilitated by the availability of technology, however it is not yet possible to individualise minor electrolytes, such as K+, Ca2+ and Mg2+. Early dialysis treatments were frequently accompanied by pyrogen reactions arising from bacterial contamination of the dialysis fluid. Today the focus is on the stimulation of mononuclear cells by bacterial fragments contributing to chronic inflammation associated with long-term haemodialysis therapy, and which has led to suggestions regarding the desirability of using ultra-pure dialysis fluid to prevent or to delay complications associated with their presence.
A Kinetic Model of Calcium Mass Balance during Dialysis Therapy
Authors: Gotch F. , Kotanko P. , Handelman G. , Levin N.
Published: December 2006

A kinetic model of Ca mass balance during dialysis has been developed. It is a single-compartment, variable-volume model to compute Ca mass balance during dialysis in its volume of distribution, the extracellular fluid. The model was used to analyze literature data which were suitable for the assessment of Ca mass balance over the course of dialysis. The modeled analyses predicted the serial plasma Ca concentrations very well. The mass balance analyses revealed a pool of rapidly diffusible Ca beyond the extracellular fluid distribution volume where Ca could be mobilized (M+Ca) or sequestered (M–Ca) very rapidly at rate equal but opposite in sign to dialyzer flux and thus effectively maintain near constant plasma Ca in the face of dialyzer Ca concentration gradients. This pool is likely the large pool of diffusible (miscible) Ca in connective tissue and on bone surfaces. Analysis of net Ca flux during dialysis with CdiCa = 2.50 mEq/l suggests that 80% of patients are in positive Ca balance during dialysis. Further studies are required to verify the model and to develop a model of interdialytic Ca mass balance.
Combination of All-Trans-Retinoic Acid and Gemtuzumab Ozogamicin in an Elderly Patient with Acute Promyelocytic Leukemia and Severe Cardiac Failure
Authors: Finizio O. , Pezzullo L. , Rocco S. , Bene L. , De Rosa C. , Nunziata G.R. , Mettivier V.
Published: December 2006

All-trans-retinoic acid (ATRA) combined with anthracyclines is currently the standard treatment for acute promyelocytic leukemia (APL). In elderly patients the presence of comorbidities, such as cardiomyopathy or different organ failures, often represents an absolute contraindication to standard chemotherapy. In this particular setting of patients, alternative front-line approaches are needed. Here we report the use of gemtuzumab ozogamicin as consolidation therapy in a 68-year-old patient not eligible for standard dose anthracycline due to severe cardiac failure and chronic anticoagulant therapy, affected by low-risk APL. Induction therapy was started with ATRA alone, at a dose of 45 mg/m2 for 80 days. The patient obtained a complete hematological and molecular remission. At day +170 the patient was treated with 6 mg/m2 gemtuzumab ozogamicin monthly for two months (2 total doses) as a consolidation therapy and then started a maintenance program with ATRA 45 mg/m2 for 15 days every three months, for a total time of two years. No adverse events were observed in every phase of treatment and the patient is still in complete continuous hematological and molecular remission 29 months from diagnosis. This approach represents an intriguing therapeutic option to be investigated in randomized studies in low- and intermediate-risk elderly patients (older than 65 years), aiming to minimize or to eliminate standard chemotherapy in advantage of new non-conventional agents, including ATO.
Subsets of Finns with High HDL to Total Cholesterol Ratio Show Evidence for Linkage to Type 2 Diabetes on Chromosome 6q
Authors: Shtir Corina , Nagakawa I. Sharon , Duren William L. , Conneely Karen N. , Scott Laura J. , Silander Kaisa , Valle Timo T. , Tuomilehto Jaakko , Buchanan Thomas A. , Bergman Richard N. , Collins Francis S. , Boehnke Michael , Watanabe Richard M.
Published: December 2006

Objectives: The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families. Methods: Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement. Results: OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM. Conclusions: These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM.
Non-Steroidal Anti-Inflammatory Drugs, Lower Oesophageal Sphincter-Relaxing Drugs and Oesophageal Cancer
Authors: Ranka Satish , Gee Jenny M. , Johnson Ian T. , Skinner Jane , Hart Andrew R. , Rhodes Michael
Published: December 2006

Background and Aims: The incidence of oesophageal cancer has doubled in the last three decades. Non-steroidal anti-inflammatory drugs (NSAIDs) may be protective, whilst bronchodilators and calcium channel blockers that relax the lower oesophageal sphincter (LOS) may increase gastro-oesophageal reflux and the risk of oesophageal adenocarcinoma. We conducted a case-control study to examine the association between the use of NSAIDs and drugs which relax the LOS and the risk of oesophageal cancer. Methods: In Norfolk, 411 patients with a primary neoplasm of the oesophagus or cardia were matched with 1,644 controls with non-melanotic skin lesions. Data on the use of NSAIDs, bronchodilators and calcium channel blockers was collected. Results: Intake of NSAIDs was less in cases of oesophageal cancer as compared to the control group. The odds ratios (OR) and 95% confidence intervals (CI) for different NSAIDs were as follows: aspirin 0.35 (0.24–0.51); other NSAIDs 0.25 (0.16–0.40), and Cox-2 inhibitors 0.46 (0.20–0.94). LOS-relaxing drugs were consumed more frequently in cases of oesophageal cancer as compared to the controls. The OR for LOS-relaxing drugs was: inhaled bronchodilators 3.2 (95% CI 2.2–4.7); theophylline 1.9 (95% CI 1.3–5.1), and calcium channel blockers 2.4 (95% CI 1.2–5.0). Conclusion: Within the limitations of a case-control study using patients with non-melanotic skin lesions as controls, our results are consistent with the hypothesis that oesophageal cancer has a negative association with NSAID use, and a positive association with drugs that relax the LOS.
Children Diagnosed with Diabetes during Infancy Have Unique Clinical Characteristics
Authors: Nimri Revital , Phillip Moshe , Shalitin Shlomit
Published: December 2006

Objective: Characterizing clinical and biochemical features of children diagnosed with diabetes mellitus between the ages of 6–24 months. Design and Methods: Medical records of 42 children diagnosed with diabetes mellitus at age of 6–24 months were reviewed for gender, ethnic origin, family medical history, clinical and biochemical features at onset of diabetes compared with 60 diabetic patients diagnosed at age 5–16 years. Results: Children diagnosed at 6–24 months had at onset more symptoms of apathy, restlessness, hyperglycemia during acute illness and a lower rate of remission than those diagnosed at older age (p < 0.001), significantly more episodes of diabetic ketoacidosis (83% vs. 40%, p < 0.001), lower HbA1c levels (mean 11.6 ± 3.4 vs. 13.75 ± 3.4%, p < 0.05) and a higher rate of celiac disease (12% vs. 3%, p = 0.046). There were no significant differences as to other autoimmune diseases. Conclusions: Patients with diabetes presenting at 6–24 months might be associated with a different clinical pattern and higher rate of celiac disease than diabetes presenting later in life. Understanding the nature and course of diabetes in this age group is crucial for planning interventional and preventive programs.
Clinical Outcomes Associated with Conversion from Epoetin alfa to Darbepoetin alfa in Hospitalized Hemodialysis Patients
Authors: Sarac Erdal , Chikyarappa Anand , Sabol Brian , Gemmel David , Globe Denise , Barlev Arie , Audhya Paul
Published: December 2006

Background/Aims: Hemodialysis patients are often hospitalized, during which time they require continuity of care in the inpatient setting. The goal of the present study was to evaluate the clinical outcomes associated with a conversion algorithm from outpatient epoetin alfa to inpatient darbepoetin alfa in hospitalized hemodialysis patients at the St. Elizabeth Health Center. Methods: We conducted a retrospective chart review of hemodialysis patient hospital admissions after a therapeutic interchange from epoetin alfa to darbepoetin alfa was implemented at St. Elizabeth Health Center. Chronic hemodialysis patients admitted from December 2002 to October 2003 were identified as part of a therapeutic interchange cohort receiving inpatient darbepoetin alfa after conversion from outpatient epoetin alfa according to the Aranesp® package insert during their hospitalization. After discharge, these patients were returned to their preadmission outpatient epoetin alfa dosages and frequencies. Patients admitted prior to implementation of the therapeutic interchange (January 2002 to April 2002) received epoetin alfa during hospitalization and served as a historical control. Hemoglobin values were recorded prior to hospital admission, at the time of discharge, and 30 days after discharge. Results: Mean hemoglobin levels declined from preadmission to discharge, in both the interchange and historical cohorts (6.6 and 2.5%, respectively) and rebounded at 30 days after discharge. Using a linear regression model, the only variables significantly associated with the hemoglobin level at discharge were the hemoglobin level before admission and receipt of a blood transfusion. Conclusion: An algorithm-based conversion from outpatient epoetin alfa to inpatient darbepoetin alfa for hospitalized chronic hemodialysis patients utilizing the dose conversion table specified in the Aranesp® package insert is associated with hemoglobin outcomes similar to inpatient epoetin alfa.
Bidirectional Role of Tumor Necrosis Factor-α in Coronary Microembolization
Authors: Skyschally Andreas , Gres Petra , Hoffmann Simone , Haude Michael , Erbel Raimund , Schulz Rainer , Heusch Gerd
Published: December 2006

In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-α (TNF-α) expression, resulting in progressive contractile dysfunction. However, TNF-α is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-α expression is increased. ME (group1; n=7) was induced by intracoronary infusion of microspheres (42 μm; 3000 per mL/min inflow). Controls (group 2; n=8) received saline. Groups 3 and 4 (n=4 each) were pretreated with ovine TNF-α antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF-α was increased (66±21 pg/g wet weight; mean±SEM) or after placebo (TNF-α, 21±10 pg/g;
P
<0.05). Infarct size (percentage area at risk) was determined after 2 hours of reperfusion (triphenyl tetrazolium chloride staining). ME decreased systolic wall thickening progressively over 6 hours (group 1 versus group 2, 65±4% versus 90±1%; percentage of baseline;
P
<0.05). TNF-α antibodies attenuated the progressive decrease in systolic wall thickening following ME (group 3, 77±5% of baseline;
P
<0.05 versus group 1) with no effect in controls (group 4; 90±8% of baseline). With ME, infarct size was decreased to 18±4% versus 33±4% in group 2 (
P
<0.05). The infarct size reduction was abolished by TNF-α antibodies (group 3 versus group 4, 29±3% versus 35±5%). In ME, TNF-α is responsible for both progressive contractile dysfunction and delayed protection against infarction.
Ethnicity, sight loss and invisibility
Authors: Johnson Mark R.D. , Morjaria-Keval Asesha
Published: December 2006

Research and development in the field of sight loss and provision for visual impairment among black and minority ethnic groups in Britain is poorly developed. There are real and inexcusable inequalities in access to services for people from minority ethnic communities, and a distinct lack of knowledge about the issues involved among both sight-loss service-providing bodies who are relatively uninformed about ethnic and cultural diversity, and among black and minority ethnic communities in respect of sight loss and provision to meet the needs of visually impaired people. The article, based on systematic review of published and ‘grey’ literature and action research, describes some key issues which might be taken into account to ensure that the gulf between these two silos of information and experience may be bridged, and insists that so-called ‘colour-blind practice’ is not acceptable.
Modern Women, Traditional Abrahamic Religions and Interpreting Sacred Texts
Authors: Harrison Victoria S.
Published: December 2006

This article surveys some of the ways in which certain representative feminists from each of the Abrahamic religions have argued that patriarchal religious traditions have systematically excluded women from contributing to traditionally accepted interpretations of their sacred texts. It shows how, in response to this exclusion, feminist theologians from each of these religions have observed a need to interpret the scriptures of their traditions from the standpoint provided by their own experience as women–thus offering new interpretations which they perceive to constitute a powerful tool with which to mount a critique of the theological traditions that had excluded them. The article concludes that, as women achieve greater opportunities for assessing their sacred texts themselves, this will have a growing effect on how the texts are read, on the religious institutions that claim to be justified by them and on the core religious concepts, such as ‘God’, that lie at the heart of those texts, whether their tradition be Jewish, Christian or Islamic.
The Prodigal Daughter: Orthodoxy Revisited
Authors: Daggers Jenny
Published: December 2006

The article argues on behalf of a neglected tradition of feminist engagement with orthodox Christian theological themes, which deserves recognition as an aspect of feminist theology. As a preface to this argument, the heritage and current vibrancy of feminist liberation theology as a struggle for justice is first affirmed, then Christian theological currents are mapped by means of crosscutting coordinates. Evidence of feminist engagement across this theological map, and of the map operating within feminist theology, is presented to show that feminist theology exceeds its mainstream identity as a liberation theology, and to reject the notion of liberation theology as a successor theology. The core of the article begins with Woodhead's neo-orthodox critique of feminist theology and responds in two ways: by identifying an existing feminist engagement with orthodoxy which is ignored by Woodhead; and by reading the texts she criticizes as imaginative revisitings of core Christian themes. The creative potential of imaginative revisiting of orthodox themes is further explored, concluding with a parable of the prodigal daughter.
The Possibility of a Gender-Transcendent God: Taking Macmurray Forward
Authors: Mclntosh Esther
Published: December 2006

This paper borrows from philosopher John Macmurray's insightsin order to advance work in feminist theology relating to perceptions of God. Mac-murray argues that we cannot have an adequate concept of a personalGod, if our concept of the human person is inadequate.He asserts that we are persons by virtue of our agency and our personal relationships; hence, the growth and development of persons requires communities of equals. Beliefin God, then, is an attitude expressed through behaviour that creates and sustains such communities. As feminist theologians indicate, a‘male’ God is a stumbling block to equality; yet, thealogy remains on the periphery of mainstream academic and Christian circles. Hence, this paper sets the groundwork for a truly gender-transcendent concept of God, examining some contemporary language liturgies and employing Macmurray's portrayal of a supreme agent, in an attempt to resolve the main problems encountered by inclusive God-language.
The Effects of Exercise on Perceived Stress and IL-6 Levels Among Older Adults
Authors: Starkweather Angela R.
Published: December 2006

Biochemical markers of inflammation have been used in recent physical activity intervention studies. However, these same biochemical markers, mainly proinflammatory cytokines, may also be influenced by the individual’s level of stress and mood. Accordingly, this pilot study was implemented to determine the effect of a physical activity intervention on perceived stress, mood, quality of life, serum interleukin-6 (IL-6), and cortisol among 10 older adults, age 60 to 90. The results were compared to those of 10 older adults who were not engaging in regular physical activity. The 10-week intervention was applied using student nurses who taught the older adults how to calculate 60% of their maximum heart rate while ambulating for 30-min intervals. After the 10-week period, the participants in the exercise group reported significant improvements in stress, mood, and several quality of life indices. They also demonstrated a significant decrease in serum IL-6. Stress, mood, and quality of life scores in the exercise group were also significantly improved compared to the control group. This study adds information on the specific intensity, duration, and frequency of exercise necessary to achieve improvements in psychological variables and IL-6 levels. It also supports the need to measure psychological stress in physical activity intervention studies. Although the psychological variables were highly correlated, there were only weak correlations found with IL-6, suggesting that other factors are likely involved in reducing IL-6 when engaging in low-impact physical activity.
A placebo double-blind pilot study of dextromethorphan for problematic behaviors in children with autism
Authors: Woodard Cooper , Groden June , Goodwin Matthew , Bodfish James
Published: December 2006

We used a mixed group/single-case, double-blind, placebo-controlled, ABAB design to examine the safety and efficacy of the glutamate antagonist dextromethorphan for the treatment of problematic behaviors and core symptoms in eight children diagnosed with autism. All participants had increased levels of irritability at baseline as measured by the Aberrant Behavior Checklist, and demonstrated a wide variety of problematic behaviors. Group analyses revealed that dextromethorphan was equivalent to placebo in the treatment of problem behaviors and core symptoms. Analyses at the single-subject level demonstrated that three of the eight participants who had a behavioral profile consistent with attention-deficit hyperactivity disorder responded positively to dextromethorphan. Future research that employs a larger, more homogeneous sample is necessary to replicate the findings from this study.
Tics and Tourette syndrome in autism spectrum disorders
Authors: Canitano Roberto , Vivanti Giacomo
Published: December 2006

Autism spectrum disorders (ASDs) are more frequently associated with tic disorders than expected by chance. Variable rates of comorbidity have been reported and common genetic and neurobiological factors are probably involved. The aim of this study was to determine the rate of tic disorders in a clinical sample ( n = 105) of children and adolescents with ASDs and to describe the clinical characteristics of a group with comorbid ASDs and tics ( n = 24). The overlap between tics and other repetitive movements and behaviors in ASDs was carefully assessed. Among individuals with ASDs, 22 percent presented tic disorders: 11 percent with Tourette disorder (TD), and 11 percent with chronic motor tics. All had various degrees of cognitive impairment. An association between the level of mental retardation and tic severity was found. It is concluded that the occurrence of tics in ASDs should not be overlooked and should be carefully evaluated.
The Influence of Treadmill Inclination on the Gait of Ambulatory Hemiparetic Subjects
Authors: Werner C. , Lindquist A. R. , Bardeleben A. , Hesse S.
Published: December 2006

Introduction. This study evaluated the influence of the degree of treadmill belt inclination for training of ambulatory patients with hemiparetic stroke.

Methods. Twelve patients were instructed to walk at 5 different levels of inclination (0%-8%) while harness-secured on the treadmill. The gait velocity was kept constant during all conditions. Dependent variables were heart rate, gait cycle-dependent parameters, and electromyographic activation patterns of the weight-bearing muscles.

Results. Heart rate increased across all inclination levels, stride length increased and cadence decreased, whereas swing symmetry improved due to shortening of the relative swing phase of the affected side at the 6% and 8% inclination levels. No change in the activation pattern of the leg muscles was found.

Conclusion. An inclination up to at least 8% can be accommodated for treadmill training by ambulatory stroke patients. For a given belt speed, heart rate increased without exceeding critical levels and patients walked with a more symmetric pattern. This protocol appeared to be safe in this selected group of subjects.