bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Synthesis, Characterization, and Biocompatibility Study of Hydroxyapatite/Chitosan Phosphate Nanocomposite for Bone Tissue Engineering Applications
Authors: Pramanik Nabakumar , Mishra Debasish , Banerjee Indranil , Maiti Tapas Kumar , Bhargava Parag , Pramanik Panchanan
Published: January 2009

A novel bioanalogue hydroxyapatite (HAp)/chitosan phosphate (CSP) nanocomposite has been synthesized by a solution‐based chemical methodology with varying HAp contents from 10 to 60% (w/w). The interfacial bonding interaction between HAp and CSP has been investigated through Fourier transform infrared absorption spectra (FTIR) and x‐ray diffraction (XRD). The surface morphology of the composite and the homogeneous dispersion of nanoparticles in the polymer matrix have been investigated through scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. The mechanical properties of the composite are found to be improved significantly with increase in nanoparticle contents. Cytotoxicity test using murine L929 fibroblast confirms that the nanocomposite is cytocompatible. Primary murine osteoblast cell culture study proves that the nanocomposite is osteocompatible and highly in vitro osteogenic. The use of CSP promotes the homogeneous distribution of particles in the polymer matrix through its pendant phosphate groups along with particle‐polymer interfacial interactions. The prepared HAp/CSP nanocomposite with uniform microstructure may be used in bone tissue engineering applications.
Distributed Source Localization Based on TOA Measurements in Wireless Sensor Networks
Authors: Qiu Wanzhi , Skafidas Efstratios
Published: January 2009

We study the problem of source localization in multihop wireless sensor networks. A fully distributed algorithm based on sensor measurements of time of arrivals (TOAs) is proposed. In contrast to centralized methods where all TOA measurements are transmitted via certain routes to a central location (the sink) for processing, the proposed method distributes the processing among the relay nodes on the routes to the sink. Fusion strategies are proposed so that the raw and intermediate data are progressively processed, and only the refined results are further relayed. As a result, the proposed scheme has improved flexibility and scalability since it does not impose any special requirements on the sink node. The proposed distributed strategy also has the potential to save energy and bandwidth due to reduced radio transmissions.
Influence of Surface Properties on the Adhesion of Staphylococcus epidermidis to Acrylic and Silicone
Authors: Sousa Cláudia , Teixeira Pilar , Oliveira Rosário
Published: January 2009

The aim of the present study was to compare the ability of eight Staphylococcus epidermidis strains to adhere to acrylic and silicone, two polymers normally used in medical devices manufacture. Furthermore, it was tried to correlate that with the surface properties of substrata and cells. Therefore, hydrophobicity and surface tension components were calculated through contact angle measurements. Surface roughness of substrata was also assessed by atomic force microscopy (AFM). No relationship was found between microbial surface hydrophobicity and adhesion capability. Nevertheless, Staphylococcus epidermidis IE214 showed very unique adhesion behaviour, with cells highly aggregated between them, which is a consequence of their specific surface features. All strains, determined as being hydrophilic, adhered at a higher extent to silicone than to acrylic, most likely due to its more hydrophobic character and higher roughness. This demonstrates the importance of biomaterial surface characteristics for bacterial adhesion.
Drug Release Profile from Calcium-Induced Alginate-Phosphate Composite Gel Beads
Authors: Murata Yoshifumi , Kodama Youko , Isobe Takashi , Kofuji Kyoko , Kawashima Susumu
Published: January 2009

Calcium-induced alginate-phosphate composite gel beads were prepared, and model drug release profiles were investigated in vitro. The formation of calcium phosphate in the alginate gel matrix was observed and did not affect the rheological properties of the hydrogel beads. X-ray diffraction patterns showed that the calcium phosphate does not exist in crystalline form in the matrix. The initial release amount and release rate of a water-soluble drug, diclofenac, from the alginate gel beads could be controlled by modifying the composition of the matrix with calcium phosphate. In contrast, the release profile was not affected by the modification for hydrocortisone, a drug only slightly soluble in water.
On the Toxicity of Therapeutically Used Nanoparticles: An Overview
Authors: El-Ansary A. , Al-Daihan S.
Published: January 2009

Human beings have been exposed to airborne nanosized particles throughout their evolutionary stages, and such exposures have increased dramatically over the last century. The rapidly developing field of nanotechnology will result in new sources of this exposure, through inhalation, ingestion, and injection. Although nanomaterials are currently being widely used in modern technology, there is a serious lack of information concerning the human health and environmental implications of manufactured nanomaterials. Since these are relatively new particles, it is necessary to investigate their toxicological behavior. The objective of this review was to trace the cellular response to nanosized particle exposure. Therapeutic application of selected nanoparticles together with their range of toxic doses was also reviewed. Effect of therapeutically used nanoparticles on cell membrane, mitochondrial function, prooxidant/antioxidant status, enzyme leakage, DNA, and other biochemical endpoints was elucidated. This paper highlights the need for caution during the use and disposal of such manufactured nanomaterials to prevent unintended environmental impacts.
Selective Spectrophotometric and Spectrofluorometric Methods for the Determination of Amantadine Hydrochloride in Capsules and Plasma via Derivatization with 1,2‐Naphthoquinone‐4‐sulphonate
Authors: Mahmoud Ashraf M. , Khalil Nasr Y. , Darwish Ibrahim A. , Aboul-Fadl Tarek
Published: January 2009

New selective and sensitive spectrophotometric and spectrofluorometric methods have been developed and validated for the determination of amantadine hydrochloride (AMD) in capsules and plasma. The methods were based on the condensation of AMD with 1,2‐naphthoquinone‐4‐sulphonate (NQS) in an alkaline medium to form an orange‐colored product. The spectrophotometric method involved the measurement of the colored product at 460  nm. The spectrofluorometric method involved the reduction of the product with potassium borohydride, and the subsequent measurement of the formed fluorescent reduced AMD‐NQS product at 382  nm after excitation at 293  nm. The variables that affected the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9972–0.9974) and low LOD (1.39 and 0.013 μg mL−1) were obtained in the ranges of 5–80 and 0.05–10 
μg mL−1 for the spectrophotometric and spectrofluorometric methods, respectively. The precisions of the methods were satisfactory; RSD
≤2.04%. Both methods were successfully applied to the determination of AMD in capsules. As its higher sensitivity, the spectrofluorometric method was applied to the determination of AMD in plasma; the recovery was 96.3–101.2 ± 0.57–4.2%. The results obtained by the proposed methods were comparable with those obtained by the official method
Signal Transducers and Activators of Transcription Mediate Fibroblast Growth Factor–Induced Vascular Endothelial Morphogenesis
Authors: Yang Xinhai , Qiao Dianhua , Meyer Kristy , Friedl Andreas
Published: January 2009

The fibroblast growth factors (FGF) play diverse roles in development, wound healing, and angiogenesis. The intracellular signal transduction pathways, which mediate these pleiotropic activities, remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STAT) in mouse microvascular endothelial cells (EC). Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the Matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type wherein FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel EC nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain ECs, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion, and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain EC mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both seem to be involved in the activation of STAT5, as their inhibition reduces FGF2- and FGF8b-induced STAT5 phosphorylation and EC tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations show that FGFs use distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway. [Cancer Res 2009;69(4):1668–77]
p34SEI-1 Inhibits Apoptosis through the Stabilization of the X-Linked Inhibitor of Apoptosis Protein: p34SEI-1 as a Novel Target for Anti–Breast Cancer Strategies
Authors: Hong Seung-Woo , Kim Chang-Jae , Park Won-Sang , Shin Jae-Sik , Lee Soon-Duck , Ko Seong-Gyu , Jung Sam-Il , Park In-Chul , An Sung-Kwan , Lee Won-Keun , Lee Wang-Jae , Jin Dong-Hoon , Lee Myeong-Sok
Published: January 2009

The p34SEI-1 protein exerts oncogenic effects via regulation of the cell cycle, which occurs through a direct interaction with cyclin-dependent kinase 4. Such regulation can increase the survival of various types of tumor cells. Here, we show that the antiapoptotic function of p34SEI-1 increases tumor cell survival by protecting the X-linked inhibitor of apoptosis protein (XIAP) from degradation. Our findings show that p34SEI-1 inhibits apoptosis. This antiapoptotic effect was eliminated by the suppression of p34SEI-1 expression. We also determined that direct binding of p34SEI-1 to the BIR2 domain prevents ubiquitination of XIAP. Interestingly, p34SEI-1 expression is absent or weak in normal tissues but is strongly expressed in tissues obtained from patients with breast cancer. Furthermore, the expression levels of p34SEI-1 and XIAP seem to be coordinated in human breast cancer cell lines and tumor tissues. Thus, our findings reveal that p34SEI-1 uses a novel apoptosis-inhibiting mechanism to stabilize XIAP. [Cancer Res 2009;69(3):741–6]
The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells
Authors: Rao V. Ashutosh , Klein Sarah R. , Agama Keli K. , Toyoda Eriko , Adachi Noritaka , Pommier Yves , Shacter Emily B.
Published: January 2009

Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is being developed as an iron chelator with selective anticancer activity. We investigated the mechanism whereby Dp44mT kills breast cancer cells, both as a single agent and in combination with doxorubicin. Dp44mT alone induced selective cell killing in the breast cancer cell line MDA-MB-231 when compared with healthy mammary epithelial cells (MCF-12A). It induces G1 cell cycle arrest and reduces cancer cell clonogenic growth at nanomolar concentrations. Dp44mT, but not the iron chelator desferal, induces DNA double-strand breaks quantified as S139 phosphorylated histone foci (γ-H2AX) and Comet tails induced in MDA-MB-231 cells. Doxorubicin-induced cytotoxicity and DNA damage were both enhanced significantly in the presence of low concentrations of Dp44mT. The chelator caused selective poisoning of DNA topoisomerase IIα (top2α) as measured by an in vitro DNA cleavage assay and cellular topoisomerase-DNA complex formation. Heterozygous Nalm-6 top2α knockout cells (top2α+/−) were partially resistant to Dp44mT-induced cytotoxicity compared with isogenic top2α+/+ or top2β−/− cells. Specificity for top2α was confirmed using top2α and top2β small interfering RNA knockdown in HeLa cells. The results show that Dp44mT is cytotoxic to breast cancer cells, at least in part, due to selective inhibition of top2α. Thus, Dp44mT may serve as a mechanistically unique treatment for cancer due to its dual ability to chelate iron and inhibit top2α activity. [Cancer Res 2009;69(3):948–57]
Translymphatic Chemotherapy by Intrapleural Placement of Gelatin Sponge Containing Biodegradable Paclitaxel Colloids Controls Lymphatic Metastasis in Lung Cancer
Authors: Liu Jiang , Meisner Dale , Kwong Elizabeth , Wu Xiao Y. , Johnston Michael R.
Published: January 2009

As a means of treating lymphatic metastasis from lung cancer, the pharmacokinetics and therapeutic effects of an intrapleural (ipl) implantable drug delivery system consisting of a gelatin sponge impregnated with polylactide-co-glycolide paclitaxel (PLGA-PTX) microspheres were studied. PLGA-PTX with 7% (w/w) drug loading were incorporated into gelatin matrix. The pharmacokinetics were studied in rats with one of the following regimens: (a) Taxol 8 mg/kg by i.v. injection; (b) Taxol 8 mg/kg ipl; (c) PLGA-PTX (100 mg/kg) ipl; (d) sponge containing PLGA-PTX (100 mg/kg) ipl. PTX concentrations in lymph node and plasma were determined by liquid chromatography mass spectrometry, and the area under the curve (AUC) was calculated. Therapeutic efficacy was assessed in an orthotopic lung cancer model with tumor resection 14 days following tumor implantation. Animals were randomized to ipl placement of PLGA-PTX sponge, placebo sponge, or no treatment. Lymph node metastases were examined at 32 d. The results show that the mediastinal lymph node AUC was significantly higher with ipl. placement of PLGA-PTX sponge compared with i.v. and ipl administration of Taxol. This represents 100- to 400-fold increase of lymphatic drug exposure compared with i.v. dosing. Peak plasma concentration was significantly reduced in the PLGA-PTX sponge group compared with i.v. dosing. PLGA-PTX particles were microscopically identified in lymphatic tissue and resulted in an 80% reduction of lymphatic metastasis compared with controls. Translymphatic-targeted drug delivery significantly decreases lymphatic metastasis in an orthotopic lung cancer model. This effect may be attributable to the improved distribution of PTX to the lymphatic system. [Cancer Res 2009;69(3):1174–81]
In vivo Molecular Imaging of Cancer with a Quenching Near-Infrared Fluorescent Probe Using Conjugates of Monoclonal Antibodies and Indocyanine Green
Authors: Ogawa Mikako , Kosaka Nobuyuki , Choyke Peter L. , Kobayashi Hisataka
Published: January 2009

Near-infrared (NIR) fluorophores have several advantages over visible fluorophores, including improved tissue penetration and lower autofluorescence; however, only indocyanine green (ICG) is clinically approved. Its use in molecular imaging probes is limited because it loses its fluorescence after protein binding. This property can be harnessed to create an activatable NIR probe. After cell binding and internalization, ICG dissociates from the targeting antibody, thus activating fluorescence. ICG was conjugated to the antibodies daclizumab (Dac), trastuzumab (Tra), or panitumumab (Pan). The conjugates had almost no fluorescence in PBS but became fluorescent after SDS and 2-mercaptoethanol, with a quenching capacity of 10-fold for 1:1 conjugates and 40- to 50-fold for 1:5 conjugates. In vitro microscopy showed activation within the endolysosomes in target cells. In vivo imaging in mice showed that CD25-expressing tumors were specifically visualized with Dac-ICG. Furthermore, tumors overexpressing HER1 and HER2 were successfully characterized in vivo by using Pan-ICG(1:5) and Tra-ICG(1:5), respectively. Thus, we have developed an activatable NIR optical probe that “switches on” only in target cells. Because both the antibody and the fluorophore are Food and Drug Administration approved, the likelihood of clinical translation is improved. [Cancer Res 2009;69(4):1268–72]
Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
Authors: Song Heesang , Li Yonghe , Lee Jiyeon , Schwartz Alan L. , Bu Guojun
Published: January 2009

The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands, including proteinases, that play critical roles in tumor invasion. Although several studies have shown an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by the forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist, receptor-associated protein, also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1 knockdown cells. More importantly, decreased cell migration and invasion of LRP1 knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway. [Cancer Res 2009;69(3):879–86]
Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells
Authors: Baumann Philipp , Mandl-Weber Sonja , Völkl Andreas , Adam Christian , Bumeder Irmgard , Oduncu Fuat , Schmidmaier Ralf
Published: January 2009

Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2′-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G1 cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366–75
Mendelian Randomization: How It Can—and Cannot—Help Confirm Causal Relations between Nutrition and Cancer
Authors: Schatzkin Arthur , Abnet Christian C. , Cross Amanda J. , Gunter Marc , Pfeiffer Ruth , Gail Mitchell , Lim Unhee , Davey-Smith George
Published: January 2009

Observational epidemiologic studies of nutrition and cancer have faced formidable methodologic obstacles, including dietary measurement error and confounding. We consider whether Mendelian randomization can help surmount these obstacles. The Mendelian randomization strategy, building on both the accuracy of genotyping and the random assortment of alleles at meiosis, involves searching for an association between a nutritional exposure–mimicking gene variant (a type of “instrumental variable”) and cancer outcome. Necessary assumptions are that the gene is independent of cancer, given the exposure, and also independent of potential confounders. An allelic variant can serve as a proxy for diet and other nutritional factors through its effects on either metabolic processes or consumption behavior. Such a genetic proxy is measured with little error and usually is not confounded by nongenetic characteristics. Examples of potentially informative genes include LCT (lactase), ALDH2 (aldehyde dehydrogenase), and HFE (hemochromatosis), proxies, respectively, for dairy product intake, alcoholic beverage drinking, and serum iron levels. We show that use of these and other genes in Mendelian randomization studies of nutrition and cancer may be more complicated than previously recognized and discuss factors that can invalidate the instrumental variable assumptions or cloud the interpretation of these studies. Sample size requirements for Mendelian randomization studies of nutrition and cancer are shown to be potentially daunting; strong genetic proxies for exposure are necessary to make such studies feasible. We conclude that Mendelian randomization is not universally applicable, but, under the right conditions, can complement evidence for causal associations from conventional epidemiologic studies.
Temporal Evolution of Clinical Parameters before Death in Dialysis Patients: A New Concept
Authors: Kotanko Peter , Thijssen Stephan , Usvyat Len , Tashman Adam , Kruse Anja , Huber Christoph , Levin Nathan W.
Published: January 2009

Background: Chronic hemodialysis (HD) patients experience an appallingly high mortality in the range of 20% per year. Little is known on the dynamics of key clinical and laboratory variables in the weeks and months preceding death. In order to gain more insight into events preceding death, we embarked on a novel methodological approach which encompasses data analysis from the date of death backwards in time. Methods: The current study investigates the dynamics of postdialytic weight and serum albumin levels in the 24 months preceding death. We performed a retrospective analysis of 2,462 maintenance HD patients who died between July 1, 2005 and April 30, 2008. Patients’ monthly serum albumin levels were extracted for the 24 months preceding the date of death. Similarly, the median weekly postdialysis weight was extracted for the 104 weeks prior to death. Data were analyzed with linear mixed models. Results: Both albumin levels and postdialytic body weight showed a significant decrease irrespective of gender and race in the 3 final months of life. The most pronounced decreases in postdialytic weight and albumin levels were observed in patients with infection as cause of death, the smallest changes occurred in subjects with cerebrovascular events. Conclusions: In their final 3 months of life, HD patients experience a marked decrease in body weight and serum albumin levels. A better understanding of dynamic patterns of key variables before death may be useful in developing processes which alert medical caregivers to patients at increased risk, in order to institute timely diagnostic and therapeutic interventions.
Prenatal Causes of Kidney Disease
Authors: Koleganova N. , Piecha G. , Ritz E.
Published: January 2009

It has recently been increasingly recognised that disturbed intra-uterine development may impact on renal and cardiovascular risk in adult life, e.g. albuminuria and chronic kidney disease, hypertension, type 2 diabetes or cardiovascular events. According to Barker’s hypothesis, when resources in utero are restricted, their allocation to the development of the kidney and pancreatic islets is restricted to guarantee appropriate development of the brain and heart. The underlying epigenetic mechanisms involve modification of gene expression by altered DNA methylation and histone acetylation as well as by allocation of stem cells. The result of this trade-off between the brain and kidney during organogenesis is a diminished number of nephrons (‘nephron underdosing’) which predisposes to albuminuria and risk of chronic kidney disease, as well as hypertension. In parallel, changed appetite centres, insulin resistance and β-cell development predispose to obesity, metabolic syndrome and type 2 diabetes and the resulting renal sequelae. Numerous factors may trigger intra-uterine restriction of fetal growth, such as uterine underperfusion, maternal malnutrition, hyperglycaemia and hyperinsulinaemia of the mother, smoking or medications.
New Insights into Lipid Metabolism in Chronic Kidney Disease: What Are the Practical Implications?
Authors: Kaysen George A.
Published: January 2009

The risk of cardiovascular disease increases with declining glomerular filtration rate. Hyperlipidemia and dyslipidemia, characterized by increased triglycerides and low levels of high-density lipoprotein, are both associated with cardiovascular outcome as well as the risk of progression of loss of renal function. Both hyperlipidemia and dyslipidemia respond to pharmacologic therapy, including hydroxymethylglutaryl-CoA reductase inhibitors and fibric acid derivatives, to alteration in diet as well as to extreme measures such as bariatric surgery. However, the effects of these modalities on cardiovascular or renal outcomes are dependent upon the level of renal function. There is strong evidence that patients with stages 1–3 chronic kidney disease attain benefit from lipid-lowering therapy both with reduction in cardiovascular risk and possibly reduction in the rate of decline in renal function. Among dialysis patients little risk reduction appears to be achieved by treatment of low-density lipoprotein cholesterol level. Bariatric surgery reduces hyperlipidemia in patients with chronic kidney disease, but has also been associated with subsequent rapid decline in renal function secondary to oxalate deposition.
Local Factors Compared with Systemic Factors in the Formation of Bladder Uric Acid Stones
Authors: Li Wei-Ming , Chou Yii-Her , Li Ching-Chia , Liu Chia-Chu , Huang Shu-Pin , Wu Wen-Jeng , Huang Chun-Hsiung
Published: January 2009

Aim: The aim of this study was to evaluate the clinical characteristics of uric acid urolithiasis and how the presentation differs between urolithiasis of the upper urinary tract (UUT) compared with urolithiasis of the bladder. We attempted to evaluate the importance of local vs. systemic factors in the formation of bladder uric acid stones. Patients and Methods: The medical records of 77 consecutive patients with uric acid urolithiasis from January 2004 to December 2006 were reviewed retrospectively. In all patients, histories were recorded, and physical examinations, renal function tests and urine analysis were done. The features of the treated stones were recorded, and the chemical composition was analyzed by computed Fourier transform infrared spectrophotometry. Results: Among 77 patients with uric acid stones, 66 were male and 11 were female (ratio of 7.6:1). Mean age was 59.50 ± 10.46 years. Of the stones, 55 (71.4%) were located in the UUT (UUT group) and 22 (28.6%) in the bladder (bladder group). Multiple presentations of urolithiasis at diagnosis were found in 56 (72.7%) patients. The mean values of serum creatinine and uric acid were 148.28 ± 70.69 and 443.33 ± 95.91 μmol/l, respectively. Mean body mass index (BMI) was 26.78 ± 2.90, and 72.7% of patients were overweight or obese. Mean urinary pH was 5.39. No significant differences existed between the 2 groups in regard to gender, BMI, urinary pH, stone nature, or presence of hypertension, gout, and/or urinary tract infections. In the bladder group, the incidence of benign prostate hyperplasia was significantly increased, and the incidence of diabetes mellitus was significantly lower, as were levels of serum uric acid and creatinine. Conclusions: Uric acid urolithiasis was predominant in men in this study. These patients tended to be obese or overweight, with multiple stone presentations and low urinary pH. Furthermore, the bladder uric acid stone group had significantly lower levels of serum creatinine and uric acid, and lower percentages of diabetes mellitus but higher incidences of benign prostate hyperplasia in comparison with the UUT group. The local factor seems more important than the systemic factor in the formation of bladder uric acid stone.
Statistical Evaluation of Hemodynamic Effects of Regular Use of Sildenafil on the Human Corpora Cavernosa
Authors: Natali Alessandro , Bartolini Marco , Lucarini Silvia , Vignolini Graziano , Nelli Federico , Menchi Ilario
Published: January 2009

Introduction: Sildenafil citrate is currently used on demand in the treatment of erectile failure, regardless of etiology. Nevertheless, recent data suggest a significant improvement in nocturnal penile erections in potent and impotent men taking a single dose at bedtime. The present study analyzes whether continuous use of sildenafil positively correlates with improvement of penile blood flow and treatment satisfaction referred by patients with erectile dysfunction (ED) of vascular origin. Patients and Methods: A total of 32 patients, mean age 54, with ED of vascular etiology, were evaluated at the beginning and at the end of our study using the International Index of Erectile Function (IIEF-5) and pharmaco-penile duplex ultrasonography during basic and dynamic phases. These patients were treated with sildenafil (50 mg) twice a week for 4 months. During pharmaco-penile duplex ultrasonography, we measured basal peak flow velocity, basal acceleration of peak flow in both cavernous arteries before intracavernous (i.c.) pharmaco-stimulation, maximum peak flow velocities and end-diastolic flow velocities after i.c. stimulation. The data observed were compared with those of 10 patients with ED who voluntarily decided not to take any treatment. Results and Conclusions: In this study, basal peak flow velocity, basal acceleration, maximum peak flow velocity and IIEF-5 scores were found to significantly increase after treatment. All differences were statistically significant (p < 0.05). Only few mild adverse effects were observed. Our data suggest that the regular use of sildenafil (50 mg) improves the blood flow in cavernous arteries increasing sexual performance in patients with ED of vascular origin.
Elevated Plasma Chromogranin A Is the First Indication of Recurrence in Radically Operated Midgut Carcinoid Tumors
Authors: Welin Staffan , Stridsberg Mats , Cunningham Janet , Granberg Dan , Skogseid Britt , Eriksson Barbro , Janson Eva T.
Published: January 2009

Background: Patients with malignant midgut carcinoids are occasionally diagnosed with limited tumor spread, and surgery with radical intention is performed. Despite curative intent, recurrences occur frequently, motivating long-term biochemical and radiological follow-up. This study aimed to compare the usefulness of various methods in detecting such recurrences. Methods: This retrospective study included 56 patients with radically operated midgut carcinoids referred to our University Hospital for evaluation and follow-up between 1985 and 2004. Patients were monitored 1–3 times per year using plasma-chromogranin A (P-CgA), urinary 5-hydroxyindoleacetic acid (U-5HIAA) concentrations as well as radiological examinations, including ultrasonography, computerized tomography or magnetic resonance investigation. In a subset of cases, somatostatin receptor scintigraphy and/or positron emission tomography with 5-hydroxytryptophan was performed. Time from operation until established recurrence was recorded. Results: Tumor recurrence was established in 33 of 56 patients after a median of 32 months (range 6–217). Elevated P-CgA was the first marker to become pathologically elevated in 28 of these 33 patients (85%). In 3 of these 28 patients, radiology was simultaneously positive for a recurrence. Conclusion: P-CgA was the first marker to indicate tumor recurrence in the majority of radically operated midgut carcinoid patients. To avoid unnecessary and costly examinations in asymptomatic patients, we suggest that follow-up should comprise measurements of P-CgA twice a year and annual ultrasonography until P-CgA is elevated or clinical symptoms occur, at which time all efforts should be made to identify recurrent tumor lesions in order to give the patient the best possible treatment which, if possible, should be surgical removal of the recurrence.
Left Ventricular Hypertrophy Induced by Reduced Aortic Compliance
Authors: Ioannou Christos V. , Morel Denis R. , Katsamouris Asterios N. , Katranitsa Sofia , Startchik Irena , Kalangos Afksentios , Westerhof Nico , Stergiopulos Nikos
Published: January 2009

Aim: It was the aim of this study to investigate the long- term effects of reduced aortic compliance on cardiovascular hemodynamics and cardiac remodeling. Method: Sixteen swine, divided into 2 groups, a control and a banding group, were instrumented for pressure and flow measurement in the ascending aorta. Teflon prosthesis was wrapped around the aortic arch in order to limit wall compliance in the banding group. Hemodynamic parameters were recorded throughout a 60-day period. After sacrifice, the mean cell surface of the left ventricle was documented. Results: Banding decreased aortic compliance by 49 ± 9, 44 ± 16 and 42 ± 7% on the 2nd, 30th and 60th postoperative day, respectively (p < 0.05), while systolic pressure increased by 41 ± 11, 30 ± 11 and 35 ± 12% (p < 0.05), and pulse pressure by 86 ± 27, 76 ± 21 and 88 ± 23%, respectively (p < 0.01). Aortic characteristic impedance increased significantly in the banding group. Diastolic pressure, cardiac output and peripheral resistance remained unaltered. The mean left ventricular cell surface area increased significantly in the banding group. Conclusions: Acute reduction in aortic compliance results in a significant increase in characteristic and input impedance, a significant decrease in systemic arterial compliance and a subsequent increase in systolic and pulse pressures leading to left ventricular hypertrophy.
Assessment of Viable Tumour Tissue Attached to Needle Applicators after Local Ablation of Liver Tumours
Authors: Snoeren Nikol , Jansen Maarten C. , Rijken Arjen M. , van Hillegersberg Richard , Slooter Gerrit , Klaase Joost , van den Tol Petrousjka M. , van der Linden Edwin , Ten Kate Fibo J.W. , van Gulik Thomas M.
Published: January 2009

Aim: Local recurrence and needle track seeding are serious complications after local ablation for liver malignancies and potentially affect long-term survival. The aim of this study was to assess the incidence of viable tissue adherent to the needle applicators after ablation to gain insight into the possible mechanisms of local recurrence and needle track seeding. Methods: A total of 40 consecutive patients underwent 59 local liver ablations. Cells and tissue attached to the needle applicators were analysed for morphology (HE, PAP and Giemsa staining) and viability (G6PD staining). Results: Macroscopic tissue adherence was visible following 31 of the ablative procedures, all with radiofrequency ablation. Four applications were performed percutaneously and 27 during an open procedure. Morphologically intact tumour cells could be identified in 8 patients (20%), and viable tumour cells in 5 patients (12.5%). Morphologically intact tumour cells or viable tumour cells could only be demonstrated when track ablation was not performed. Conclusion: Viable tumour cells adherent to the needle applicators were found in an alarming 12.5% of patients after local ablation. We recommend track ablation not only after the procedure but also during any shifting and (re-)positioning to prevent shedding of viable tumour cells during or after ablation.
A Comparison of Association Statistics between Pooled and Individual Genotypes
Authors: Knight Jo , Saccone Scott F. , Zhang Zhehao , Ballinger Dennis G. , Rice John P.
Published: January 2009

Background: Markers for individual genotyping can be selected using quantitative genotyping of pooled DNA. This strategy saves time and money. Methods: To determine the efficacy of this approach, we investigated the bivariate distribution of association test statistics from pooled and individual genotypes. We used a sample of approximately 1,000 samples with individual and pooled genotyping on 40,000 SNPs. Results and Conclusions: We found that the distribution of the joint test statistics can be modelled as a mixture of two bivariate normal distributions. One distribution has a correlation of zero, and is probably due to SNPs whose pooled genotyping was unsuccessful. The other distribution has a correlation of approximately 0.65 in our data. This latter distribution is probably accounted for by SNPs whose pooled genotyping accurately predicts the underlying allele frequency. Approximately 87% of the data belongs to this distribution. We also derived a method to investigate the effect of both the correlation and selection cut-off on the relative power of pooling studies. We demonstrate that pooled genotyping has good power to detect SNPs that are truly associated with disease-causing variants for SNPs showing good correlation between pooled and individual genotyping. Therefore, this approach is a cost effective tool for association studies.
Case-Deletion Diagnostics for Maximum Likelihood Multipoint Quantitative Trait Locus Linkage Analysis
Authors: Mendoza Maria C.B. , Burns Trudy L. , Jones Michael P.
Published: January 2009

Objectives: Case-deletion diagnostic methods are tools that allow identification of influential observations that may affect parameter estimates and model fitting conclusions. The goal of this paper was to develop two case-deletion diagnostics, the exact case deletion (ECD) and the empirical influence function (EIF), for detecting outliers that can affect results of sib-pair maximum likelihood quantitative trait locus (QTL) linkage analysis. Methods:Subroutines to compute the ECD and EIF were incorporated into the maximum likelihood QTL variance estimation components of the linkage analysis program MAPMAKER/SIBS. Performance of the diagnostics was compared in simulation studies that evaluated the proportion of outliers correctly identified (sensitivity), and the proportion of non-outliers correctly identified (specificity). Results: Simulations involving nuclear family data sets with one outlier showed EIF sensitivities approximated ECD sensitivities well for outlier-affected parameters. Sensitivities were high, indicating the outlier was identified a high proportion of the time. Simulations also showed the enormous computational time advantage of the EIF. Diagnostics applied to body mass index in nuclear families detected observations influential on the lod score and model parameter estimates. Conclusions: The EIF is a practical diagnostic tool that has the advantages of high sensitivity and quick computation.
POSSUM Predicts Survival in Patients with Unresectable Pancreatic Cancer
Authors: de Castro S.M.M. , Houwert J.T. , Lagard S.M. , Busch O.R.C. , van Gulik T.M. , Gouma D.J.
Published: January 2009

Background: The aim of this study was to evaluate the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) for patients with unresectable pancreatic cancer and to analyze whether POSSUM can predict the long-term outcome in these patients. Such a scoring system could be useful to aid in the decision between surgical and endoscopic palliation. Methods: Between January 1993 and December 2004, 241 patients were found to have unresectable pancreatic cancer during exploratory laparotomy and underwent a double bypass procedure consisting of a gastrojejunostomy and a hepaticojejunostomy. Results: Overall, 64 of 240 patients (27%) had one or more complications after bypass surgery and 4 patients (2%) died. POSSUM predicted morbidity in 114 patients (47%). The observed:predicted (O:P) ratio for morbidity was 0.56 and the model had a significant lack of fit (p < 0.001) using a goodness-of-fit analysis. The overall median survival was 7 months. The POSSUM scoring system was, however, an independent predictor of survival in multivariate analysis. Conclusions: Overall, POSSUM overpredicted morbidity but was an independent predictor of survival.
Cytogenetic Analysis of False-Positive Mucosa by Photodynamic Diagnosis Using 5-Aminolevulinic Acid – Possible Existence of Premalignant Genomic Alterations Examined by in vitro Experiment
Authors: Matsuyama Hideyasu , Yamamoto Yoshiaki , Nagao Kazuhiro , Ohmi Chietaka , Sakano Shigeru , Sasaki Kohsuke
Published: January 2009

Objective: Although photodynamic diagnosis is a powerful tool for the detection of flat urothelial tumors, false-positive fluorescent mucosa still requires further elucidation. Thus, we aimed to study the significance of nonmalignant fluorescent mucosa by a cytogenetic approach. Methods: Sixty specimens of bladder mucosa were collected from 20 patients who were suspected of having carcinoma in situ by fluorescence cystoscopy with 5-aminolevulinic acid. To detect the copy number aberrations, the multi-color fluorescence in situ hybridization technique was performed, and the variant fractions (total fractions other than those of the modal copy number) of chromosomes 7, 9 and 17 and the chromosomal instability were determined. To delineate the relevant gene to the fluorescent mucosa, a comparative genomic hybridization technique was applied for 8 established bladder cancer cell lines, and these results were compared with the in vitro fluorescent expression experiment. Results: Fluorescent mucosa was detected in 33 of the 34 malignant tissue specimens (16 carcinoma in situ, 18 other transitional cell carcinomas) and in 11 of the 26 nonmalignant tissue specimens (6 dysplasia, 20 normal mucosa), with a false-positive rate of 42.3%. The variant fraction of chromosome 9 was significantly higher in fluorescent than in non-fluorescent mucosa, not only for all tissues (33 vs. 17%; p = 0.0069), but also for nonmalignant tissues (28 vs. 15%; p = 0.0225). There was no alteration in chromosome 9 in 1 cell line without fluorescent mucosa, while 5 of the 7 cell lines with fluorescent mucosa had a common deleted region on 9q24.1. Conclusion: These data suggest that a substantial portion of nonmalignant fluorescent mucosa harbors alterations in chromosome 9.
Breast Cancer Patients on Endocrine Therapy Reveal More Symptoms when Self-Reporting than in Pivotal Trials: An Outcome Research Study
Authors: Ruhstaller Thomas , von Moos Roger , Rufibach Kaspar , Ribi Karin , Glaus Agnes , Spaeti Bruno , Koeberle Dieter , Mueller Urs , Hoefliger Markus , Hess Dagmar , Boehme Christel , Thuerlimann Beat
Published: January 2009

Objectives: The purpose of this investigation was firstly to assess the overall frequency of subjectively experienced symptoms self-reported by patients receiving endocrine therapy and secondly to compare these symptoms with side effects assessed by clinicians in pivotal trials. Methods: Unselected patients with early and advanced breast cancer receiving endocrine therapy were approached consecutively during a routine outpatient visit. They received a questionnaire called Checklist for Patients with Endocrine Therapy (C-PET), a validated self-assessment tool to determine prespecified symptoms associated with endocrine therapy. Data on toxicity were also obtained from previously published trials. Results: 405 patients were approached and 373 agreed to participate in this study. Some symptoms were significantly more often recorded by the women in the adjuvant setting completing the C-PET than by physicians’ reports in pivotal trials: hot flushes/sweats (C-PET 70%, ATAC 40% and BIG1-98 38%), low energy (C-PET 45%, ATAC 15% and BIG1-98 9%), fluid retention (C-PET 22% and BIG1-98 7%) and vaginal dryness (C-PET 30% and BIG1-98 3%). Similar differences were observed in the metastatic and adjuvant setting. Conclusions: A simple tool like the C-PET questionnaire is able to reflect the treatment burden of endocrine therapies and may be helpful to improve communication between patients and care providers. Some symptoms were significantly more often reported by the women in the C-PET than by physicians in pivotal trials.
Microstructural Changes in Uterine Leiomyomas and Myometrium: A Diffusion-Weighted Magnetic Resonance Imaging Study
Authors: Erdem Gulnur , Celik Onder , Karakas Hakki Muammer , Hascalik Seyma , Firat Ahmet Kemal
Published: January 2009

Although morphological and histopathological changes in uterine leiomyomas have been investigated in detail, the microstructural disruptions could not be studied in the living organism. Diffusion-weighted magnetic resonance imaging (DWI) is a novel tool to assess microstructural changes in vivo. The aim of this study was to investigate and characterize the diffusional property of leiomyomatous tissues with DWI. Sixteen females with a total of 21 leiomyomas were imaged with a 1.5-tesla clinical MR scanner. DWI images of leiomyomas, adjacent myometrial and myometrial tissues of healthy controls were obtained and quantified using apparent diffusion coefficient (ADC) maps. Mean ADC values of these groups were 1,201, 1,684, 1,661 mm2/s × 10–6, respectively. ADC values in leiomyomas were significantly lower than those observed in the myometrium (p < 0.001). Cut-off values produced 91% sensitivity and 100% specificity. As ADC values implied the presence of cytotoxic edema in leiomyomas, the technique was found to be promising in observing temporal variations in leiomyomas and to monitor even the most subtle effects of therapeutic interventions.