bluuebunny/crossref_metadata_2025 huggingface dataset:
Two‐Dimensional Dual‐Permeability Analyses of a Bromide Tracer Experiment on a Tile‐Drained Field
Authors: Gerke Horst H. , Dusek Jaromir , Vogel Tomas , Köhne J. Maximilian
Published: August 2007

Preferential flow has been hypothesized as an important factor for chemical leaching from tile‐drained agricultural fields with structured soils originating from glacial till sediments. Previous studies showed that one‐dimensional single‐porosity models (1D‐SPM) failed and that one‐dimensional dual‐permeability models (1D‐DPERM) were limited in explaining both Br leaching and residual Br distribution, although tile water outflow peaks could somehow be reproduced. The objective of this paper was to analyze the tile outflow and leaching patterns using a two‐dimensional (2D)‐DPERM and a standard 2D‐SPM for comparison. Flow and transport were simulated in a 2D vertical cross‐section of 5.9 m length and 2 m depth using previously tested parameters. Simulated drainage rates and Br‐effluent concentrations were made comparable with collector data from a field experiment by weighing results for irrigated and nonirrigated plots according to their area fractions. The 2D‐DPERM simulations for surface application of Br in dissolved form in both domains overestimated the observed initial outflow concentration peaks, in contrast to closer approximation of observations assuming Br application in the soil matrix domain only. The simulated 2D mass transfer rate distribution showed most intensive exchange between domains near the water table and in the topsoil. Results from the 2D‐DPERM analyses suggest that conditions at the soil surface, near the water table, and of the field‐scale mixing are significantly affecting leaching patterns, in addition to local nonequilibrium effects. Here, the description of preferential flow toward tile drain could be strongly improved with the 2D‐DPERM compared with the 2D‐SPM. Further improvements remain challenging with respect to DPERM numerical modeling and field experimentation, with special attention toward soil structure and soil surface conditions.
Incretin Receptors for Glucagon-Like Peptide 1 and Glucose-Dependent Insulinotropic Polypeptide Are Essential for the Sustained Metabolic Actions of Vildagliptin in Mice
Authors: Flock Grace , Baggio Laurie L. , Longuet Christine , Drucker Daniel J.
Published: August 2007

OBJECTIVE—Dipeptidyl peptidase-4 (DPP4) inhibitors lower blood glucose in diabetic subjects; however, the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions of DPP4 inhibitors remains uncertain.

RESEARCH DESIGN AND METHODS—We examined the efficacy of continuous vildagliptin administration in wild-type (WT) and dual incretin receptor knockout (DIRKO) mice after 8 weeks of a high-fat diet.

RESULTS—Vildagliptin had no significant effect on food intake, energy expenditure, body composition, body weight gain, or insulin sensitivity in WT or DIRKO mice. However, glycemic excursion after oral glucose challenge was significantly reduced in WT but not in DIRKO mice after vildagliptin treatment. Moreover, vildagliptin increased levels of glucose-stimulated plasma insulin and reduced levels of cholesterol and triglycerides in WT but not in DIRKO mice. Vildagliptin treatment reduced the hepatic expression of genes important for cholesterol synthesis and fatty acid oxidation, including phospho-mevalonate kinase (Mvk), acyl-coenzyme dehydrogenase medium chain (Acadm), mevalonate (diphospho)decarboxylase (Mvd), and Acyl-CoA synthetase (Acsl1), in WT but not in DIRKO mice. However, vildagliptin also reduced levels of hepatic mRNA transcripts for farnesyl di-phosphate transferase (Fdft1), acetyl coenzyme A acyltransferase 1 (Acaa1), and carnitine palmitoyl transferase 1 (Cpt 1) in DIRKO mice. No direct effect of GLP-1 receptor agonists was detected on cholesterol or triglyceride synthesis and secretion in WT hepatocytes.

CONCLUSIONS—These findings illustrate that although GLP-1 and GIP receptors represent the dominant molecular mechanisms for transducing the glucoregulatory actions of DPP4 inhibitors, prolonged DPP4 inhibition modulates the expression of genes important for lipid metabolism independent of incretin receptor action in vivo.
Perceptual and Physiologic Effects of Histamine Challenge on Nasal Breathing
Authors: Lane Andrew P. , Drake Amelia F. , Warren Donald W.
Published: August 2007

The purpose of this study is to determine the effect of histamine-induced nasal congestion on nasal airflow and the perception of externally applied resistance to nasal breathing. Nasal cross-sectional area and nasal airflow during free breathing were measured in 15 adult subjects before and after histamine challenge. The threshold for perception of resistance to nasal breathing was determined using a dynamic perturbator device, with both free breathing and controlled nasal airflow. The average threshold for perception of nasal resistance was 0.383 Pa/cm3/s at baseline. After histamine application, there was a significant decrease in nasal cross-sectional area (p = 0.0001), associated with a decrease in nasal airflow (r = 0.6). The average threshold of perception increased to 1.373 Pa/cm3/s (p < 0.0001). When nasal airflow was controlled at the baseline rate, the threshold of perception improved to 0.638 Pa/cm3/s (p = 0.024). These findings indicate that nasal congestion causes a reduction in both nasal airflow and the perception of resistance to nasal breathing. The ability to detect nasal airway impairment is improved with increased nasal airflow. An improved understanding of the physiology of the subjective perception of nasal patency may lead to innovative methods for the treatment of nasal obstruction.
Treatment of the Obstructive Nose by CO2-Laser Reduction of the Inferior Turbinates: Technique and Results
Authors: Katz S. , Schmelzer B. , Vidts G.
Published: August 2007

In our department we treat chronically enlarged inferior turbinates (not responding to adequate medical therapy) with the CO2-laser or by partial inferior turbinoplasty. In this work the technique is described and short- and long-term results are evaluated. We divided our study group into two populations: one group with a follow-up of 18 months for which we could obtain objective measurements of the nasal patency by means of a preoperative and postoperative active anterior rhinomanometry, and another group with a follow-up of more than 15 years, for which (because of the absence of a pre-operative rhinomanometry) we could only obtain a subjective evaluation of the results by means of a questionnaire. Relief of nasal obstruction was reported by 88.5% of the patients until 5 years after laser surgery on the inferior turbinates. There seems to be no functional impairment on the nasal mucosa after this kind of surgery. The advantages and drawbacks of this technique are discussed.
Olfactory Function Evaluated by SPECT
Authors: Di Nardo W. , Di Girolamo S. , Galli A. , Meduri G. , Paludetti G. , De Rossi G.
Published: August 2007

Few articles on neuroimaging techniques in the study of central and peripheral olfactory pathways are present in the literature. By Single Photon Emission Computed Tomography (SPECT), cortical perfusion increment after sensorial stimulation can be evaluated objectively. In the present research, 10 healthy adults underwent SPECT by CER.TO.96 cerebral tomograph, before and after olfactory stimulation with lavender-water. A variable degree of cortical activation was detected in all patients. Cyrus rectus (+24.5%), orbito-frontal cortex (right +26.6%, left +25.6%), and superior temporal (right +9.9%, left +5.5%) cortical areas were always activated. A slight perfusion increase was present in middle temporal (right +3.2%, left +2.1%) and parieto-occipital (right +0.4%, left +2%) regions. Five patients affected by posttraumatic anosmia were also investigated: they showed a perfusion increment markedly inferior to 0.5% in every olfactory area. SPECT is a rather diffused, easily performed technique which yields objective semi-quantitative information on brain perfusion. Hence, it can be regarded as a promising contribution in the fields of smell neurophysiology, clinical olfactometry, and medicolegal queries.
Isolated Sphenoid Sinus Lesions
Authors: Cakmak Ozcan , Shohet Michael R. , Kern Eugene B.
Published: August 2007

Pathologic conditions involving the sphenoid sinus alone are rare. A retrospective chart review was performed of 182 cases of isolated sphenoid sinus lesions seen at the Mayo Clinic between 1935 and 1998. There were 53 cases of sinusitis, 44 mucoceles, and 15 fungus-related cases (61.5%), and the rest of the cases were divided among numerous other pathologic entities. Symptoms, differential diagnosis, and various therapeutic modalities are discussed. We believe that these data will be useful to clinicians considering multiple pathologic possibilities when faced with a lesion involving the sphenoid sinus alone.
The Search for New Drugs from Higher Plants
Authors: Hostettmann Kurt , Marston Andrew
Published: August 2007

Plants have a rich history as medicines for human use. Recently introduced plant-derived drugs include paclitaxel from Taxus (Taxaceae) species for the treatment of cancers, artemisinin for malaria therapy and the alkaloid galanthamine for the management of Alzheimer's disease.
A judicious combination of chemical and biological screening techniques can provide a steady supply of lead compounds for the improved treatment of human ailments. By this means, candidate compounds can be rapidly selected for further development, as is the case for xanthones from gentians
and coumarins from Peucedanum ostruthium (Apiaceae), which may be of relevance in Alzheimer's disease. Encouraging results are also being obtained for hypericin from Hypericum perforatum (Hypericaceae) in the photodynamic therapy of cancer. An aspect that must not be forgotten
is that the usual biological screening procedures do not pick up prodrugs which have to be metabolized by the human body into active analogues. A good example is salicin from Salix species (Salicaceae) which is metabolized in the body to give the anti-inflammatory and analgesic compound
salicylic acid. Investigations which include simulation of metabolism are thus of primordial importance.
A Simple Method for High-Throughput Extract Prefractionation for Biological Screening
Authors: Appleton David R. , Buss Antony D. , Butler Mark S.
Published: August 2007

The screening of crude natural product extracts can be problematic, especially in enzyme/protein-based assays, due to promiscuous inhibitors and interference compounds, while high salt and lipid content can significantly dilute compounds of interest. Described herein is a simple method
for high-throughput fractionation of crude extracts that can help address some of these issues. Results obtained indicate a significant improvement in assay hit rates without a reduction of hit quality and show how prefractionation aids the discovery of compounds that would be undetected by
screening crude extracts alone.
Accelerated Dereplication of Natural Products, Supported by Reference Libraries
Authors: Bitzer Jens , Köpcke Bärbel , Stadler Marc , Hellwig Veronika , Ju Yu-Ming , Seip Stephan , Henkel Thomas
Published: August 2007

Natural products are an indispensable source for drug discovery. The major challenge for exploiting this evolutionary optimized pool of potential lead structures is the fast and reliable recognition of known compounds, i. e. dereplication. This task is essential for the discovery
process in high-throughput screening scenarios, since it allows the focus to be placed on novel chemical structures at an early stage. Furthermore, information on identified compounds will help to rationalize observed bioactivities. This article describes an effective, library-supported strategy
for the dereplication of crude extracts and pre-fractionated samples, using an HPLC-based multidetector platform and NMR techniques, respectively.
Efficient Structure Elucidation of Natural Products in the Pharmaceutical Industry
Authors: Moss Serge , Bovermann Günter , Denay Regis , France Julien , Guenat Christian , Oberer Lukas , Ponelle Monique , Schröder Harald
Published: August 2007

The procedure of structure elucidation of natural products at Novartis is discussed. Structure elucidation in an industrial environment has to be time efficient, which is achieved by an optimized workflow and a close integration of all analytical methods used in this process. After
a preliminary dereplication step based on LC/MS, compounds are delivered to the structure analysis unit. A second dereplication step is based on IR spectroscopic data. Subsequent MS analysis leads to the molecular weight or molecular composition. NMR spectroscopy is finally used for complete
structure elucidation, respectively for confirmation of structural suggestions made on the basis of IR and MS data. Challenges like a large number of structure elucidation requests, low amounts of material, variation of sample purity or complexity of structures are faced with modern analytical
equipment and high expertise in all disciplines.
New Tubulin Inhibitors from Plants – A Critical Assessment
Authors: Gertsch Jürg , Meier Sarah , Tschopp Natalie , Altmann Karl-Heinz
Published: August 2007

The search for improved cytotoxic agents continues to be an important line of modern anticancer drug discovery and a promising mechanistic approach towards this goal is the functional inhibition of cellular microtubules. Tubulin inhibitors are compounds which either stabilize or destabilize
microtubules in vitro, leading to G2/M cell cycle arrest and apoptosis in cancer cells. While destabilizing agents, such as vinca alkaloids inhibit the assembly of ??-tubulin heterodimers, stabilizing compounds like taxol induce the de novo formation
of stable microtubules in vitro. In this study we have investigated a number of plant-derived compounds that have recently been reported to interact with the tubulin/microtubule system and to induce taxol-like effects. This includes the sesquiterpene lactones parthenolide and costunolide,
the coumarin derivative ferulenol, and the jatrophane ester JTE1. In addition, we have screened a small natural product library (84 cytotoxic compounds) and 107 cytotoxic plant extracts in an assay sys- tem that allows the detection of both microtubule-stabilizing and -destabilizing
agents in a 96-well setup within the same experimental format. None of the plant extracts inhibited or induced tubulin polymerization in vitro. From the compound library only the known plant-derived tubulin inhibitors vinblastine, colchicine, podophyllotoxin, chelidonine, rotenone,
and taxol were identified as hits. Curcumin, which was recently reported to destabilize cellular microtubules, was inactive in our assay. Interestingly, rotenone, which is widely used as a mitochondrial respiration chain I inhibitor, potently inhibited microtubule assembly in vitro
and showed higher affinity to ??-tubulin than vinblastine, although it was significantly less cytotoxic. None of the plant-derived natural products that were recently reported to be microtubule-stabilizing agents were found to be active in our assay system. In conclusion, plant-derived
natural products clearly represent an interesting and productive source for microtubule-destabilizing agents. In contrast, apart from taxol and related structures, no plant-derived natural product with potent in vitro microtubule-stabilizing properties has yet been identified.
Cyanobacterial Natural Products for the Inhibition of Biofilm Formation and Biofouling
Authors: Gademann Karl
Published: August 2007

Biofouling is defined by the non-specific attachment of biological material (proteins, carbohydrates, prokaryotic cells and higher organisms) to surfaces upon their exposure to any biological fluid. Biofouling is a serious problem in many areas ranging from marine technology, nuclear
power plants, dentistry, food processing to biomedical implants. This process can be addressed either actively by chemical compounds inhibiting growth, settlement or biofilm formation, or passively by generating repellent or resistant surfaces. This highlight article gives an overview over
different secondary metabolites from cyanobacteria useful in this context. A candidate for active antifouling is nostocarboline, a carboline alkaloid from Nostoc. It has distinct and powerful activities against both prokaryotic and eukaryotic photosynthetic organisms. This compound
is a candidate for the replacement of toxic tributyltin (TBT) antifouling coatings. Another passive strategy is presented utilizing the strong binding of anachelin to metal oxide surfaces. This anchor binds polyethyleneglycol (PEG) efficiently to surfaces and renders TiO2 protein
resistant. This anchor displays superior properties when compared to dopamine or DOPA, a key constituent in mussel adhesive proteins (MAP). Implications for biomaterials design are discussed.
Bone Morphogenetic Proteins and Their Receptors in the Eye
Authors: Wordinger Robert J. , Clark Abbot F.
Published: August 2007

The human genome encodes at least 42 different members of the transforming growth factor-β superfamily of growth factors. Bone morphogenetic proteins (BMPs) are the largest subfamily of proteins within the transforming growth factor-β superfamily and are involved in numerous cellular functions including development, morphogenesis, cell proliferation, apoptosis, and extracellular matrix synthesis. This article first reviews BMPs and BMP receptors, BMP signaling pathways, and mechanisms controlling BMP signaling. Second, we review BMP and BMP receptor expression during embryonic ocular development/ differentiation and in adult ocular tissues. Lastly, future research directions with respect to BMP, BMP receptors, and ocular tissues are suggested.
Mammary Epithelial Cells Treated Concurrently with TGF-α and TGF-β Exhibit Enhanced Proliferation and Death
Authors: Casey T. M. , Mulvey T. M. , Patnode T. A. , Dean A. , Zakrzewska E. , Plaut K.
Published: August 2007

Transforming growth factor-α (TGF-α) stimulates while TGF-β inhibits mammary epithelial cell growth, suggesting that when cells are treated concurrently with the growth factors their combined effects would result in no net growth. However, combined treatments stimulate proliferation and cellular transformation in several cell lines. The objective of this paper was to describe the effect of long-term (6 days) concurrent TGF-α and TGF-β treatment on normal mammary epithelial cell growth pattern, morphology, and gene expression. Growth curve analysis showed that TGF-α enhanced while TGF-β suppressed growth rate until Day 4, when cells entered lag phase. However, cells treated concurrently with both growth factors exhibited a dichotomous pattern of growth marked by growth and death phases (with no intermittent lag phase). These changes in growth patterns were due to a marked induction of cell death from Day 2 (16.5%) to Day 4 (89.5%), resulting in the transition from growth to death phases, even though the combined treated cultures had significantly more ( P < 0.05) cells in S phase on Day 4. TGF-β stimulated epithelial to mesenchyme transdifferentiation (EMT) in the presence of TGF-α, as characterized by increased expression of fibronectin and changes in TGF-β receptor binding. Expression patterns of genes that regulate the cell cycle showed significant interaction between treatment and days, with TGF-β overriding TGF-α–stimulated effects on gene expression. Overall, the combined treatments were marked by enhanced rates of cellular proliferation, death, and trans-differentiation, behaviors reminiscent of breast tumors, and thus this system may serve as a good model to study breast tumorigenesis.
Subcutaneous Fat Accumulation Shows a Beneficial Correlation with Serum Cholesterol in Postmenopausal Japanese Women
Authors: Tanaka Misuzu , Koga Ririko , Tsuda Hiroko , Imai Katsumi , Abe Shimako , Masuda Takashi , Iwamoto Masako , Nakazono Eri , Kamohara Tomoko , Kinukawa Naoko , Sakata Toshiie
Published: August 2007

This study aimed to investigate whether accumulation of subcutaneous abdominal fat has a beneficial correlation with lipid metabolism in premenopausal and/or postmenopausal Japanese women. The study enrolled 146 premenopausal women, ranging in age from 19 to 54 years, and 82 postmeno-pausal women, ranging in age from 47 to 66 years. Fat distribution, including abdominal visceral fat area (VFA) and abdominal subcutaneous fat area (SFA), were measured in an outpatient clinic by magnetic resonance imaging. Homogeneity of the regression slopes for SFA to total cholesterol ( P = 0.030), low-density lipoprotein cholesterol ( P = 0.020), apolipoprotein B (apoB) ( P = 0.001), and the ratio of apoB to apolipoprotein A-I (apoA-I) ( P = 0.003) were not found between premenopausal and postmenopausal women, even after adjustment for both VFA and age. However, the regression slopes for VFA to all measured lipid parameters, as well as apolipoproteins, were homogeneous between the premenopausal and postmeno-pausal groups. Abdominal SFA in postmenopausal women correlated negatively with total cholesterol ( P = 0.007), low-density lipoprotein cholesterol ( P = 0.002), apoB ( P < 0.001), and the ratio of apoB to apoA-I ( P = 0.001), after adjustment for age and VFA, but this was not the case in premenopausal women. The mechanisms involved in the beneficial effects of subcutaneous fat accumulation in postmenopausal women remain obscure, but upregulated aromatase expression, derived from adipose tissue, may possibly improve lipid and apolipoprotein metabolism.
Physiology of Alpha-Fetoprotein as a Biomarker for Perinatal Distress: Relevance to Adverse Pregnancy Outcome
Authors: Mizejewski Gerald J.
Published: August 2007

The many physiologic roles of human alpha-fetoprotein (HAFP) and its correlation with perinatal distress/pregnancy outcome are rarely addressed together in the biomedical literature, even though HAFP has long been used as a biomarker for fetal birth defects. Although the well being of the fetus can be monitored by the measurement of gestational age–dependent HAFP in biologic fluid levels (serum, amniotic fluid, urine, and vaginal fluids) throughout pregnancy, the majority of clinical reports reflect largely second trimester and (less likely) first trimester testing due to regulatory clinical restrictions. However, reports of third-trimester and pregnancy term measurement of HAFP levels performed in clinical research and/or investigational settings have gradually increased over the years and have expanded our base knowledge of AFP-associated pregnancy disorders during these stages. The different structural forms of HAFP (isoforms, epitopes, molecular variants, etc.) detected in the various biologic fluid compartments have been limited by antibody recognition of specific epitopic sites developed by the kit manufacturers based on antibody specificity, sensitivity, and precision. Concomitantly, the advances in elucidating the various biologic actions of AFP are opening new vistas toward understanding the physiologic roles of AFP during pregnancy. The present review surveys HAFP as a biomarker for fetal distress during the perinatal period in view of its structural and functional properties. An attempt is then made to relate the AFP fluid levels to adverse pregnancy complications and outcomes. Hence, the present review was divided into two major sections: (I) AFP structure and function considerations and (II) the relationship of AFP levels to the distressed fetus during the third trimester and at term.
Evaluation of Poly (Glycerol-Adipate) Nanoparticle Uptake in an In Vitro 3-D Brain Tumor Co-Culture Model
Authors: Meng W. , Kallinteri P. , Walker D. A. , Parker T. L. , Garnett M. C.
Published: August 2007

Despite the inherent problems associated with in vivo animal models of tumor growth and metastases, many of the current in vitro brain tumor models also do not accurately mimic tumor-host brain interactions. Therefore, there is a need to develop such co-culture models to study tumor biology and, importantly, the efficacy of drug delivery systems targeting the brain. So far, few investigations of this nature have been published. In this paper we describe the development of a new model system and its application to drug delivery assessment. For our new model, a co-culture of DAOY cell brain tumor aggregates and organo-typic brain slices was developed. Initially, the DAOY aggregates attached to cerebellum slices and invaded as a unit. Single cells in the periphery of the aggregate detached from the DAOY aggregates and gradually replaced normal brain cells. This invasive behavior of DAOY cells toward organotypic cerebellum slices shows a similar pattern to that seen in vivo. After validation of the co-culture model using transmission electron microscopy, nanoparticle (NP) uptake was then evaluated. Confocal micrographs illustrated that DAOY cells in this co-culture model took up most of the NPs, but few NPs were distributed into brain cells. This finding corresponded with results of NP uptake in DAOY and brain aggregates reported elsewhere.
Gene Expression Analysis of Murine Lungs Following Pulmonary Exposure to Asian Sand Dust Particles
Authors: Yanagisawa Rie , Takano Hirohisa , Ichinose Takamichi , Mizushima Katsura , Nishikawa Masataka , Mori Ikuko , Inoue Ken-ichiro , Sadakane Kaori , Yoshikawa Toshikazu
Published: August 2007

The respiratory health impact of Asian sand dust events originating in the deserts of China has become a concern within China and in its neighboring countries. We examined the effects of Asian sand dust particles (ASDPs) on gene expression in the murine lung using microarray analysis and elucidated the components responsible for lung inflammation. Male ICR mice were intratracheally administrated ASDPs, heat-treated ASDPs (ASDP-F, lipopolysaccaride [LPS], or β-glucan free), or kaolin particles. We performed microarray analysis for murine lungs, the results of which were confirmed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). We also assessed the protein expression and histologic changes. Exposure to ASDP, ASDP-F, or kaolin upregulated (>2-fold) 112, 36, or 9 genes, respectively, compared with vehicle exposure. In particular, ASDP exposure markedly enhanced inflammatory response–related genes, including chemokine (C-X-C motif) ligand 1/keratinocyte-derived chemokine, chemokine (C-X-C motif) ligand 2/macrophage inflammatory protein-2, chemokine (C-C motif) ligand 3/macrophage inflammatory protein-1α, and chemokine (C-X-C motif) ligand 10/interferon-gamma–inducible protein-10 (>6-fold). The results were correlated with those of the quantitative RT-PCR and the protein expression analyses in overall trend. In contrast, exposure to ASDP-F attenuated the enhanced expression of these proinflammatory molecules. Kaolin exposure increased the expression of genes and proteins for the chemokines. In histopathologic changes, exposure to ASDP prominently enhanced pulmonary neutrophilic inflammation, followed by kaolin and ASDP-F exposure in the order. Taken together, exposure to ASDP causes pulmonary inflammation via the expression of proinflammatory molecules, which can be attributed to LPS and β-glucan absorbed in ASDPs. Furthermore, microarray analysis should be effective for identifying potentially novel genes, sensitive biomarkers, and pathways involved in the health effects of the exposure to environmental particles (e.g., ASDPs).
In Vivo Evaluation of a PAMAM-Cystamine-(Gd-DO3A) Conjugate as a Biodegradable Macromolecular MRI Contrast Agent
Authors: Xu Rongzuo , Wang Yanli , Wang Xuli , Jeong Eun-Kee , Parker Dennis L. , Lu Zheng-Rong
Published: August 2007

Macromolecular Gd(III) chelates are superior magnetic resonance imaging (MRI) contrast agents for blood pool and tumor imaging. However, their clinical development is limited by the safety concerns related to the slow excretion and long-term gadolinium tissue accumulation. A generation 6 PAMAM Gd(III) chelate conjugate with a cleavable disulfide spacer, PAMAM-G6-cystamine-(Gd-DO3A), was prepared as a biodegradable macromolecular MRI contrast agent with rapid excretion from the body. T1 and T2 relaxivities of the contrast agent were 11.6 and 13.3 m M−1sec−1 at 3T, respectively. Blood pool and tumor contrast enhancement of the agent were evaluated in female nude mice bearing MDA-MB-231 human breast carcinoma xenografts with a nondegradable conjugate PAMAM-G6-(Gd-DO3A) as a control. PAMAM-G6-cystamine-(Gd-DO3A) resulted in significant contrast enhancement in the blood for about 5 mins, and Gd-DO3A was released from the conjugate and rapidly excreted via renal filtration after the disulfide spacer was cleaved. The nondegradable control had much longer blood circulation and excreted more slowly from the body. PAMAM-G6-cystamine-(Gd-DO3A) also resulted in more prominent tumor contrast enhancement than the control. However, PAMAM-G6-cystamine-(Gd-DO3A) demonstrated high toxicity due to the intrinsic toxicity of PAMAM dendrimers. In conclusion, although PAMAM-G6-cystamine-(Gd-DO3A) showed some advantages compared with the nondegradable control, PAMAM dendrimers are not suitable carriers for biodegradable macromolecular MRI contrast agents, due to their high toxicity.
Flaxseed Alone or in Combination with Tamoxifen Inhibits MCF-7 Breast Tumor Growth in Ovariectomized Athymic Mice with High Circulating Levels of Estrogen
Authors: Chen Jianmin , Power Krista A. , Mann Jaskaren , Cheng Astor , Thompson Lilian U.
Published: August 2007

Flaxseed (FS) is rich in mammalian lignan precursors and α-linolenic acid, which have been suggested as having anticancer effects. Previous studies have shown that 10% FS inhibits the growth of human estrogen–dependent breast cancer (MCF-7) in athymic mice, and it enhances the inhibitory effect of tamoxifen (TAM). This study determined whether the effect of FS, alone or in combination with TAM, is dose dependent, and it explored the potential mechanism of action. Ovariectomized athymic mice with estradiol (E2) supplementation (1.7 mg/pellet, 60-day release) and established MCF-7 tumors were treated with basal diet control (0FS), 5% FS (5FS), 10% FS (10FS), and TAM (TAM/ 0FS; 5 mg/pellet, 60-day release), alone or in combination (TAM/ 5FS and TAM/10FS) for 8 weeks. Compared with control, 5FS and 10FS significantly inhibited tumor growth by 26% and 38%, respectively. TAM/0FS had an effect similar to the 10FS. TAM/ 5FS and TAM/10FS, respectively, induced significant 48% and 43% reductions in tumor size compared with 0FS, and 18% and 10% reductions compared with TAM/0FS. The relative uterine weight was significantly lower in all TAM groups compared with the control. The reduction of tumor growth resulted from decreased cell proliferation and increased cell apoptosis. TAM/ 5FS caused a significantly higher expression of estrogen receptor-α (ERα) compared with 5FS and TAM/0FS, whereas TAM/10FS had a higher ERα than 10FS and TAM/0FS. Compared with the control, progesterone receptor (PgR) expression was significantly reduced in all treatment groups, but insulin-like growth factor-1 (IGF-1) expression was reduced only by 10FS, TAM/5FS and TAM/10FS. Tumor cell proliferation was significantly positively associated with expression of PgR and IGF-1 and negatively associated with apoptosis and ERα. Apoptosis was only associated with ERα. In conclusion, FS inhibited MCF-7 tumor growth in a dose-dependent manner and enhanced the inhibitory effect of TAM due to the modulation of ER and growth factor signal transduction pathways.
Hematologic and Urinary Excretion Anomalies in Patients with Chronic Fatigue Syndrome
Authors: Niblett Suzanne H. , King Katrina E. , Dunstan R. Hugh , Clifton-Bligh Phillip , Hoskin Leigh A. , Roberts Timothy K. , Fulcher Greg R. , McGregor Neil R. , Dunsmore Julie C. , Butt Henry L. , Klineberg Iven , Rothkirch T. B.
Published: August 2007

Patients with chronic fatigue syndrome (CFS) have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients and 82 nonfatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles. Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges. However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio. Evaluation of the urine excretion parameters also revealed a number of anomalies. The overnight urine output and rate of amino acid excretion were both reduced in the CFS group ( P < 0.01). Significant decreases in the urinary excretion of asparagine ( P < 0.0001), phenylalanine ( P < 0.003), the branch chain amino acids ( P < 0.005), and succinic acid ( P < 0.0001), as well as increases in 3-methylhistidine ( P < 0.05) and tyrosine ( P < 0.05) were observed. It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.
Biogenic Amine Actions on Cholangiocyte Function
Authors: DeMorrow Sharon , Francis Heather , Alpini Gianfranco
Published: August 2007

Biogenic amines, such as serotonin, histamine, dopamine, and the catecholamines epinephrine and norepinephrine, regulate a multitude of cellular responses. A great deal of effort has been invested into understanding the effects of these molecules and their corresponding receptor systems on cholangiocyte secretion, apoptosis, and growth. This review summarizes the results of these efforts and highlights the importance of these regulatory molecules on the physiology and pathophysiology of cholangiocytes.
Macrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability
Authors: Sullivan Jerome l.
Published: August 2007

Hepcidin has emerged as the key hormone in the regulation of iron balance and recycling. Elevated levels increase iron in macrophages and inhibit gastrointestinal iron uptake. The physiology of hepcidin suggests an additional mechanism by which iron depletion could protect against atherosclerotic lesion progression. Without hepcidin, macrophages retain less iron. Very low hepcidin levels occur in iron deficiency anemia and also in homozygous hemochromatosis. There is defective retention of iron in macrophages in hemochromatosis and also evidently no increase in atherosclerosis in this disorder. In normal subjects with intact hepcidin responses, atherosclerotic plaque has been reported to have roughly an order of magnitude higher iron concentration than that in healthy arterial wall. Hepcidin may promote plaque destabilization by preventing iron mobilization from macrophages within atherosclerotic lesions; the absence of this mobilization may result in increased cellular iron loads, lipid peroxidation, and progression to foam cells. Marked downregulation of hepcidin (e.g., by induction of iron deficiency anemia) could accelerate iron loss from intralesional macrophages. It is proposed that the minimally proatherogenic level of hepcidin is near the low levels associated with iron deficiency anemia or homozygous hemochromatosis. Induced iron deficiency anemia intensely mobilizes macrophage iron throughout the body to support erythropoiesis. Macrophage iron in the interior of atherosclerotic plaques is not exempt from this process. Decreases in both intralesional iron and lesion size by systemic iron reduction have been shown in animal studies. It remains to be confirmed in humans that a period of systemic iron depletion can decrease lesion size and increase lesion stability as demonstrated in animal studies. The proposed effects of hepcidin and iron in plaque progression offer an explanation of the paradox of no increase in atherosclerosis in patients with hemochromatosis despite a key role of iron in atherogenesis in normal subjects.
Mild Calorie Restriction Does Not Affect Testosterone Levels and Testicular Gene Expression in Mutant Mice
Authors: Rocha Juliana S. , Bonkowski Michael S. , França Luiz R. , Bartke Andrzej
Published: August 2007

The hypothalamic-pituitary-gonadal (HPG) axis and the somatotropic axis are influenced by nutritional factors. Calorie restriction (CR) extends lifespan but suppresses both the HPG and the somatotropic axes. Since most CR studies use a fairly severe (40%–60%) reduction of calorie intake, we hypothesized that a milder CR (20%) might not be deleterious to reproduction in male mice. To test this hypothesis, we evaluated the effects of 20% CR on testicular testosterone content and on testicular expression of genes that are relevant to testicular function and reproductive competence, including insulin-like growth factor-I, cytochrome P450 aromatase (Cyp19a1), androgen receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, cytochrome P450c17 and 3-β-hydroxysteroid dehydrogenase/isomerase. To relate CR effects to the activity of the somatotropic axis, we have used growth hormone–resistant GHR knockout mice as well as transgenic mice overexpressing GH. Mild CR did not affect testosterone levels in testis homogenates and had little effect on expression of the examined genes in the reproductive organs. Altered activity of the GH/insulin-like growth factor–1 axis had a major impact on the parameters analyzed. The results also suggest that expression of several key genes involved in the control of testicular function is preserved under conditions of mild CR and encourage speculation that mild regimens of CR can produce longevity benefits without impairing reproduction.
Experimental Hypothyroidism Inhibits δ-Aminolevulinate Dehydratase Activity in Neonatal Rat Blood and Liver
Authors: Gravina Fernanda S. , da Silveira Clarice K. B. , de Assis Adriano M. , Rieger Débora K. , Guerini Carolina , Müller Alexandre P. , Farina Marcelo , Rotta Liane N. , Perry Marcos L. S.
Published: August 2007

The aim of this study was to investigate the potential relationship between hypothyroidism and δ-aminolevulinate dehydratase (δ-ALA-D) activity in rat blood and liver. Experimental hypothyroidism was induced in weanling rats by exposing their mothers to propylthiouracil (PTU) diluted in tap water (0.05% w/ v), ad libitum, during the lactational period (PTU group). Control (euthyroid) group included weanling rats whose mothers received just tap water, ad libitum, during the lactational period. Reverted-hypothyroid group (PTU + 3,3′,5-triiodo-L-thyronine [T3]) included weanling rats whose mothers were exposed to PTU similarly to those in the hypothyroid group, but pups received daily subcutaneous injections of T3(20 μg/kg, from Postnatal Days 2–20). After the treatment, serum T3levels were drastically decreased (around 70%) in the PTU group, and this phenomenon was almost reverted by exogenous T3. PTU decreased blood δ-ALA-D activity by 75%, and T3treatment prevented such phenomena. Erythrocytes and hemoglobin levels were increased by 10% in PTU-treated animals and higher increments (around 25%) were observed in these parameters when exogenous T3was coadministered. Dithiothreitol did not change blood δ-ALA-D activity of PTU-exposed animals when present in the reaction medium, suggesting no involvement of the enzyme’s essential thiol groups in PTU-induced δ-ALA-D inhibition. PTU did not affect blood δ-ALA-D activity in vitro. These results are the first to show a correlation between hypothyroidism and decreased δ-ALA-D activity and point to this enzyme as a potential molecule involved with hypothyroidism-related hematological changes.
A Thermoplastic Gel Electrolyte for Stable Quasi‐Solid‐State Dye‐Sensitized Solar Cells
Authors: Wu J. H. , Hao S. C. , Lan Z. , Lin J. M. , Huang M. L. , Huang Y. F. , Fang L. Q. , Yin S. , Sato T.
Published: August 2007

Dye‐sensitized solar cells (DSSCs) are receiving considerable attention as low‐cost alternatives to conventional solar cells. In DSSCs based on liquid electrolytes, a photoelectric efficiency of 11 % has been achieved, but potential problems in sealing the cells and the low long‐term stability of these systems have impeded their practical use. Here, we present a thermoplastic gel electrolyte (TPGE) as an alternative to the liquid electrolytes used in DSSCs. The TPGE exhibits a thermoplastic character, high conductivity, long‐term stability, and can be prepared by a simple and convenient protocol. The viscosity, conductivity, and phase state of the TPGE can be controlled by tuning the composition. Using 40 wt % poly(ethylene glycol) (PEG) as the polymeric host, 60 wt % propylene carbonate (PC) as the solvent, and 0.65 M KI and 0.065 M I2 as the ionic conductors, a TPGE with a conductivity of 2.61 mS cm–2 is prepared. Based on this TPGE, a DSSC is fabricated with an overall light‐to‐electrical‐energy conversion efficiency of 7.22 % under 100 mW cm–2 irradiation. The present findings should accelerate the widespread use of DSSCs.
Insight into Doping Effects in Apatite Silicate Ionic Conductors
Authors: Tolchard J. R. , Slater P. R. , Islam M. S.
Published: August 2007

Novel apatite‐type silicates are attracting considerable interest as a new family of oxide‐ion conductors with potential use in fuel cells and ceramic membranes. Combined computer modeling and X‐ray absorption (EXAFS) techniques have been used to gain fresh insight, at the atomic level, into the site selectivity and local structures of a wide range of dopants in these apatite materials. The results indicate that an unusually broad range of dopant ions (in terms of size and charge state) can substitute for La in the La9.33Si6O26 apatite, in accord with current experimental data. The range is much wider than that observed for doping on a single cation site in most other oxide‐ion conductors, such as the perovskite LaGaO3. In addition, our local structural investigation demonstrates that this dopant behavior is related to the flexibility of the silicate substructure, which allows relatively large local distortion and alteration of the site volumes. This could be a key factor in the high oxide‐ion conductivity exhibited by these apatite silicates. Indeed, the breadth of possible doping regimes in these novel materials provides new opportunities to design and optimize the conduction properties for fuel cell electrolytes.
Photoelectrical Characteristics of a C/CNx Multiwalled Nanotube
Authors: Xiao K. , Fu Y. , Liu Y. Q. , Yu G. , Zhai J. , Jiang L. , Hu W. P. , Shuai Z. G. , Luo Y. , Zhu D. B.
Published: August 2007

A nanotube diode fabricated from a single C/CNx multiwalled nanotube exhibits a large photocurrent and a large photovoltage under illumination. The current–voltage (I–V) characteristics of the diode indicate a clear rectification effect. By comparing the I–V characteristics of C, CNx, and C/CNx nanotube diodes, we show that the rectifying characteristics of the C/CNx diode arises from the molecular junction formed at the C/CNx interface where the C and CNx segments are chemically bonded. External radiation photochemically generates electrons and holes in the C/CNx nanotube, producing a large photocurrent because of the influence of the strong electric field in the vicinity of the C/CNx junction. These unique photoresponsive characteristics of C/CNx nanotube junction diodes points to potential applications such as photovoltaic devices and photodiodes.
Ortho‐Nitrostilbenes in Polycarbonate for Holographic Data Storage
Authors: Erben C. , Boden E. P. , Longley K. L. , Shi X. , Lawrence B. L.
Published: August 2007

Holographic data storage materials based on dye‐doped polycarbonate that could find application in professional archival and consumer applications are described. The dyes are selected from the class of o‐nitrostilbenes, which irreversibly bleach under exposure to light and show high thermal stability before and after exposure. The reduction in concentration of the dye in the host after exposure induces refractive index variations over a wide range of wavelengths and extends well away from the dye absorption peak conforming to the Kramers–Kronig relationship. The materials are injection moldable into the standard disc format and have negligible shrinkage during data storage. Samples were produced using different dyes and various concentrations in a polycarbonate host and processed on professional CD/DVD equipment. The refractive index change is as high as 0.04, with a measured instantaneous sensitivity of 0.5 cm J–1 and M/# = 0.3.
Sulfur‐Functionalized Mesoporous Carbon
Authors: Shin Y. , Fryxell G. E. , Um W. , Parker K. , Mattigod S. V. , Skaggs R.
Published: August 2007

A simple synthesis route to mesoporous carbons that contain heteroaromatic functionality is described. The sulfur‐functionalized mesoporous carbon (S‐FMC) materials that have been prepared show excellent thermal stability, as well as excellent hydrothermal stability, and stability over a wide range of pH values. These materials also show excellent mercury sorption performance over a broad range of pH, much broader than is possible with thiol‐based functionality or most silica‐based sorbents. The superior performance of these mesoporous heterocarbons as heavy‐metal sorbent material is demonstrated. These materials are shown to be stable at elevated temperatures and extreme pHs, making them ideally suited as a new class of absorbent material.
Selective Crystallization of Organic Semiconductors on Patterned Templates of Carbon Nanotubes
Authors: Liu S. , Briseno A. L. , Mannsfeld S. C. B. , You W. , Locklin J. , Lee H. W. , Xia Y. , Bao Z.
Published: August 2007

A method of patterning large arrays of organic single crystals is reported. Using single‐walled carbon nanotube (SWNT) bundles as patterned templates, several organic semiconductor materials were successfully patterned, including p‐type pentacene, tetracene, sexiphenylene, and sexithiophene, as well as n‐type tetracyanoquinodimethane (TCNQ). This study suggests that the selective growth of crystals onto patterned carbon nanotubes is most likely due to the coarse topography of the SWNT bundles. Moreover, we observed that the crystals nucleated from SWNT bundles and grew onto SWNT bundles in a conformal fashion. The dependence of the number of crystals on the quantity of SWNT bundles is also discussed. The crystal growth can be directly applied onto transistor source‐drain electrodes and arrays of organic single‐crystal field effect transistors are demonstrated. The results demonstrate the potential of utilizing carbon nanotubes as nucleation templates for patterning a broad range of organic materials for applications in optoelectronics.