bluuebunny/crossref_metadata_2025 huggingface dataset:
National Cancer Data Base report on osteosarcoma of the head and neck
Authors: Smith Russell B. , Apostolakis Louis W. , Karnell Lucy H. , Koch Brenton B. , Robinson Robert A. , Zhen Weining , Menck Herman R. , Hoffman Henry T.
Published: October 2003

BACKGROUND

Osteosarcoma is the most common primary bone malignancy overall but is encountered infrequently in the head and neck. Limited data are available on the significance of prognostics factors and results of therapy for patients with head and neck osteosarcoma (HNOS). It is known that surgical therapy is critical to successful outcome. The impact of adjuvant chemotherapy has not been defined well.

METHODS

The National Cancer Data Base has collected data on cases of HNOS by voluntary accrual from participating hospitals. This database was used to assess patient demographics, tumor characteristics, treatment, and outcome for an 11‐year period extending from 1985 to 1996.

RESULTS

The data set contained 496 cases of HNOS. Overall, the 5‐year disease‐specific survival rate was 59.7%. Factors associated with a poor prognosis were age older than 60 years; nonmandibular tumor location; tumor size > 6 cm; histologic type of osteoblastic, not otherwise specified (NOS); advanced disease stage; nonsurgical initial therapy; and positive margins of resection. Increased use of multimodality therapy was noted during the later years of the study. No substantial difference in the 5‐year survival rate was noted between treatment with surgery alone (74.7%) and surgery with adjuvant chemotherapy (71.3%), despite the greater prevalence of tumors with poor prognostic factors in the surgery and adjuvant chemotherapy group.

CONCLUSIONS

Surgery with clear margins is an important factor in successful therapy for patients with HNOS. Improved survival has been noted within the last 2 decades compared with historic controls. Multiple negative prognostic factors have been identified and should be considered in treatment planning. The role of chemotherapy has not been defined well, but its incorporation into treatment of patients with high‐risk tumors may improve survival. Cancer 2003. © 2003 American Cancer Society.

DOI 10.1002/cncr.11716
Social networks and quality of life among female long‐term colorectal cancer survivors
Authors: Sapp Amy L. , Trentham‐Dietz Amy , Newcomb Polly A. , Hampton John M. , Moinpour Carol M. , Remington Patrick L.
Published: October 2003

BACKGROUND

The population of long‐term colorectal cancer survivors in the United States continues to increase, but little is known about how they fare—physically, mentally, or socially—in the years after diagnosis. The current study examines female long‐term colorectal cancer survivors' health‐related quality of life (HRQoL) in relation to social networks.

METHODS

A population‐based sample of female colorectal cancer survivors (n = 726) residing in Wisconsin was recontacted approximately 9 years after the initial diagnosis. Of 443 women who were alive in 1999, 307 women completed a follow‐up questionnaire. Analysis was conducted on 259 participants who completed the Medical Outcomes Study Short Form 36 Health Status Survey and a modified version of Berkman and Syme's Social Network Index. Using multivariate analyses, HRQoL summary scores were tested for associations with individual and composite measures of social networks, including marital/partner status; number of children, relatives, and friends; and the frequency of religious and community participation.

RESULTS

After adjusting for age, extent of disease at diagnosis, number of comorbidities, body mass, and education, HRQoL was similar to norms published for the general population. Individual social network measures (including the number of relatives and friends) and composite network measures (including network size, the number of ties seen at least once per month, and overall social connectedness) were associated positively with mental health.

CONCLUSIONS

Social networks may have an important relation with HRQoL—particularly mental health—among female long‐term colorectal cancer survivors. The results of this study should be of interest to those seeking to understand or improve HRQoL among this growing population. Cancer 2003. © 2003 American Cancer Society.

DOI 10.1002/cncr.11717
Reirradiation and hyperthermia in rectal carcinoma
Authors: Juffermans Jorine H. M. , Hanssens Patrick E. J. , van Putten Wim L. J. , van Rhoon Gerard C. , van der Zee Jacoba
Published: October 2003

BACKGROUND

The objective of this study was to evaluate the palliative effect of reirradiation and hyperthermia in patients with unresectable, recurrent colorectal carcinoma.

METHODS

The medical records of 54 patients with unresectable, recurrent colorectal carcinoma that caused pain and who were treated with reirradiation and hyperthermia, were evaluated retrospectively. Previous radiotherapy was given up to a total dose ranging from 25–70 grays (Gy). The median interval between prior radiotherapy and reirradiation was 22 months (range, 4–97 months). The total reirradiation dose varied from 24 Gy to 32 Gy given in fractions of 4 Gy twice weekly. Three or four hyperthermia treatments were given once weekly. Toxicity was registered. The influence of World Health Organization (WHO) performance status, maximum tumor dimension, and time between first radiotherapy and reirradiation on therapeutic outcome was evaluated. The results of this study were compared with published results on patients who received radiotherapy with or without hyperthermia.

RESULTS

Forty‐seven patients (87%) completed the planned treatment schedule. The maximum toxicity was Grade 2. All patients were evaluated for palliative effect. The median follow‐up was 10 months. A good or complete palliative effect was achieved in 72% of patients for a median duration of 6 months. Patients who had a better WHO performance status, smaller tumors, and a longer interval between first radiotherapy and reirradiation had slightly better outcomes, although none of those parameters reached statistical significance.

CONCLUSIONS

The described combined treatment was feasible and well tolerated. Comparison of results from radiotherapy plus hyperthermia with results after radiotherapy alone suggested that additional hyperthermia prolonged the duration of palliation. Firm proof of the contribution of hyperthermia will require performing a Phase III study. Cancer 2003. © 2003 American Cancer Society.

DOI 10.1002/cncr.11719
Internalization of interphotoreceptor retinoid‐binding protein by the Xenopus retinal pigment epithelium
Authors: Cunningham Lisa L. , Gonzalez‐Fernandez Federico
Published: October 2003

Xenopus rods and cones secrete into the interphotoreceptor matrix (IPM) a 124‐kDa glycoprotein termed interphotoreceptor retinoid‐binding protein (IRBP; Hessler et al. [1996] J. Comp. Neurol. 367:329–341). IRBP is confined to the IPM, being too large to diffuse through the zonulae adherentes between adjacent photoreceptor and Müller cells. Despite this physical entrapment within the subretinal space, IRBP is rapidly cleared from the IPM by an unknown mechanism. Immunohistochemistry and immunoelectron microscopy were used to localize IRBP in intact and detached retina‐retinal pigment epithelium (RPE) eyecups. The effects of light, dark, and time of day on the compartmentalization of IRBP were characterized by quantitative Western blot analysis and by immunoprecipitation of IRBP labeled in vivo by intraocular injection of [35S]methionine. Immunohistochemistry showed that the apparent intercellular IRBP in both the RPE and the photoreceptors is resistant to saline extraction, in contrast to that in the IPM. In the RPE, IRBP was associated with matrix material within phagosomes and endosomes. The IPM, RPE, and retina contained 75%, 18%, and 7% of the total IRBP in the eye, respectively. The IPM and RPE contain 130 ± 14 pmoles and 34 ± 4 pmoles of IRBP, respectively. The amounts of IRBP in the RPE at middark and midlight were the same. Furthermore, the in vivo uptake of [35S]methionine‐labeled IRBP was light independent. Our studies suggest that IRBP is not strictly confined to the subretinal space but rather that significant amounts are present intracellularly, particularly within the RPE, which does not synthesize IRBP. Furthermore, IRBP secreted by the photoreceptors is taken up from the IPM mainly through a light‐independent endocytic pathway separate from outer segment phagocytosis. The role of RPE endocytosis should be explored in relation to the function of IRBP. J. Comp. Neurol. 466:331–342, 2003. © 2003 Wiley‐Liss, Inc.
Synaptic connections of cholinergic antennal lobe relay neurons innervating the lateral horn neuropile in the brain of Drosophila melanogaster
Authors: Yasuyama Kouji , Meinertzhagen Ian A. , Schürmann Friedrich‐Wilhelm
Published: October 2003

Presumed cholinergic projection neurons (PNs) in the brain of the fruit fly Drosophila melanogaster, immunoreactive to choline acetyltransferase (ChAT), convey olfactory information between the primary sensory antennal lobe neuropile and the mushroom body calyces, and finally terminate in the lateral horn (LH) neuropile. The texture and synaptic connections of ChAT PNs in the LH and, comparatively, in the smaller mushroom body calyces were investigated by immuno light and electron microscopy. The ChAT PN fibers of the massive inner antennocerebral tract (iACT) extend into all portions of the LH, distributing in a nonrandom fashion. Immunoreactive boutons accumulate in the lateral margins of the LH, whereas the more proximal LH exhibits less intense immunolabeling. Boutons with divergent presynaptic sites, unlabeled as well as ChAT‐immunoreactive, appear to be the preponderant mode of synaptic input throughout the LH. Synapses of ChAT‐labeled fibers appear predominantly as divergent synaptic boutons (diameters 1–3 μm), connected to unlabeled postsynaptic profiles, or alternatively as a minority of tiny postsynaptic spines (diameters 0.05–0.5 μm) among unlabeled profiles. Together these spines encircle unidentified presynaptic boutons of interneurons which occupy large areas of the LH. Thus, synaptic circuits in the LH differ profoundly from those of the PNs in the mushroom body calyx, where ChAT spines have not been encountered. Synaptic contacts between LH ChAT elements were not observed. The synaptic LH neuropile may serve as an output area for terminals of the ChAT PNs, their presynaptic boutons providing input to noncholinergic relay neurons. The significance of the postsynaptic neurites of the ChAT PNs is discussed; either local or other interneurons might connect the ChAT PNs within the LH, or PNs might receive inputs arising from outside the LH. J. Comp. Neurol. 466:299–315, 2003. © 2003 Wiley‐Liss, Inc.
Hodological characterization of the medial amygdala in anuran amphibians
Authors: Moreno Nerea , González Agustín
Published: October 2003

Early studies in anuran amphibians defined the amygdala as a single unit that only later could be subdivided into medial and lateral parts with the achievement of sensitive immunohistochemical and tracing techniques. However, the terminology used was often misleading when comparing with “homologous” amygdaloid nuclei in amniotes. Recently, the basal telencephalon of anurans has been demonstrated to be more complex than previously thought, and distinct amygdaloid nuclei were proposed on the basis of immunohistochemistry. Moreover, developmental data are increasing that support this notion. In the present study, we analyzed the patterns of afferent and efferent connections of the medial amygdala (MeA; formerly amygdala pars lateralis), considered as the main target of the vomeronasal information from the accessory olfactory bulb, as in other vertebrates. By means of axonal transport of dextran amines, the afferent and efferent connections of the MeA were traced in Rana perezi and Xenopus laevis under in vivo and in vitro conditions. Largely similar results were found in both species. The results showed abundant intratelencephalic and extratelencephalic connections that were readily comparable to those of other tetrapods. Most of these connections were reciprocal and, in particular, the strong relation of the MeA with the hypothalamus, via the stria terminalis, was demonstrated. Immunohistochemical techniques showed staining patterns that revealed abundant peptidergic afferents to the MeA, as well as minor inputs containing other neurotransmitters such as catecholamines. Double‐labeling experiments demonstrated that the peptidergic fibers that reach the MeA originate in the ventral hypothalamus, whereas the catecholaminergic innervation of the MeA arises in the caudal extent of the posterior tubercle. Taken together, the results about connectivity in our study support the comparison of the MeA in anurans with its counterparts (and similarly named) amygdaloid nuclei in amniotes. Most of the hodological features of the medial amygdala seem to be shared by those tetrapods with well‐developed vomeronasal systems. J. Comp. Neurol. 466:389–408, 2003. © 2003 Wiley‐Liss, Inc.
Dopaminergic amacrine cells in the inner nuclear layer and ganglion cell layer comprise a single functional retinal mosaic
Authors: Eglen Stephen J. , Raven Mary A. , Tamrazian Eric , Reese Benjamin E.
Published: October 2003

Many types of retinal neuron are distributed in an orderly manner across the surface of the retina. Indeed, the existence of such regularity amongst a population of neurons, termed a retinal mosaic, may be a defining feature of functionally independent types of retinal neuron. We have examined the spatial distribution of dopaminergic amacrine cells in the ferret retina both in the inner nuclear layer (INL) and in the ganglion cell layer (GCL) to determine whether the cells in each layer form an independent retinal mosaic as evidence of whether they should be considered as two separate types. Ferret retinas contain approximately 1,900 dopaminergic amacrine cells, of which 27% are located in the GCL, and the rest in the INL. Based on analysis of their Voronoi domains as well as autocorrelation analysis and tests for complete spatial randomness, we found that the distribution of INL cells was statistically regular, while that of the GCL cells was not. However, by using cross‐correlation analysis, these two groups of cells were found to be spatially dependent: an exclusion zone was detected in the cross‐correlogram of roughly the same size as that found in the autocorrelograms of both INL and GCL cells. Such a pattern would be expected if dopaminergic amacrine cells in the INL and GCL were members of a single regular population differing only in their somatic depth. By using computer simulations, we tested this hypothesis directly, confirming that a random assignment of 27% from the total population produces cross‐correlograms that are indistinguishable from those of the biological mosaics. We conclude, therefore, that the cells in the two layers form a single functional population; those in the GCL appear to be misplaced. Somatic positioning with respect to depth within the retina is not, by itself, a reliable guide for functional classification. J. Comp. Neurol. 466:343–355, 2003. © 2003 Wiley‐Liss, Inc.
Regeneration of supraspinal axons after complete transection of the thoracic spinal cord in neonatal opossums (Monodelphis domestica)
Authors: Fry Elizabeth Jane , Stolp Helen Bronwyn , Lane Michael Aron , Dziegielewska Katarzyna Magdalena , Saunders Norman Ruthven
Published: October 2003

These studies define the time table and origin of supraspinal axons regenerating across a complete spinal transection in postnatal Monodelphis domestica. After lumbar (L1) spinal cord injection of fluorophore–dextran amine conjugate on postnatal (P) day 4, a consistent number of neurons could be labeled. The numbers of labeled neurons remained stable for several weeks, but subsequently declined by P60 in control animals and by P35 in animals with complete spinal transection (T4–T6) performed at P7. In control animals, 25–40% of neurons labeled with a fluorophore injected (L1) at P4 could also be double‐labeled by a second fluorophore injected (T8–T10) at different older ages. In spinally transected animals, total numbers of neurons labeled with the second marker were initially lower compared with age‐matched controls, but were not significantly different by 3 weeks after injury. The proportion of double‐labeled neurons in spinally transected animals increased from approximately 2% 1 week after injury (P14) to approximately 50% by P60, indicating that a substantial proportion of neurons with axons transected at P7 is able to regenerate and persist into adulthood. However, the proportion of axons originating from regenerating neurons made only a small contribution at older ages to total numbers of fibers growing through the injury site, because much of development of the spinal cord occurs after P7. Evidence was obtained that degenerating neurons with both apoptotic and necrotic morphologies were present in brainstem nuclei; the number of neurons with necrotic morphology was much greater in the brainstem of animals with spinal cords transected at P7. J. Comp. Neurol. 466:422–444, 2003. © 2003 Wiley‐Liss, Inc.
A parallel data assimilation model for oceanographic observations
Authors: van Hees Fons , van der Steen Aad J. , van Leeuwen Peter Jan
Published: October 2003

In this paper we describe the development of a program that aims at achieving the optimal integration of observed data in an oceanographic model describing the water transport phenomena in the Agulhas area at the tip of South Africa. Two parallel implementations, MPI and OpenMP, are described and experiments with respect to speed and scalability on a Compaq AlphaServer SC and an SGI Origin3000 are reported. Copyright © 2003 John Wiley & Sons, Ltd.
Coordinating components in middleware systems
Authors: Radestock Matthias , Eisenbach Susan
Published: October 2003

Configuration and coordination are central issues in the design and implementation of middleware systems and are one of the reasons why building such systems is more complex than constructing stand‐alone sequential programs. Through configuration, the structure of the system is established—which elements it contains, where they are located and how they are interconnected. Coordination is concerned with the interaction of the various components—when an interaction takes place, which parties are involved, what protocols are followed. Its purpose is to coordinate the behaviour of the various components to meet the overall system specification. The open and adaptive nature of middleware systems makes the task of configuration and coordination particularly challenging. We propose a model that can operate in such an environment and enables the dynamic integration and coordination of components by observing and coercing their behaviour through the interception of the messages exchanged between them. Copyright © 2003 John Wiley & Sons, Ltd.
Resource management in open Linda systems
Authors: Menezes Ronaldo
Published: October 2003

Coordination systems, in particular Linda, have established themselves as important tools for the development of applications to open systems such as the Internet.

This paper shows how to tackle a forgotten, but crucial problem in open coordination systems: memory management. As with any system which intends to be of wide use and because memory is a finite resource, coordination systems must address the problems of memory exhaustion. This paper first explores the orthogonality between coordination and computation in order to make it clear that the problem of memory exhaustion in coordination systems cannot be solved using garbage collection schemes implemented at the computation language—a garbage collection scheme must exist in the coordination environment as well.

Following the explanation on orthogonality, the paper will focus on describing a garbage collection scheme for the Linda family of coordination systems. It is expected that the solution in Linda can be adapted to other coordination systems as long as they are based on tuple space communication. Copyright © 2003 John Wiley & Sons, Ltd.
BaMoO4 thin films prepared by electrochemical method at room temperature
Authors: Bi J. , Xiao D. Q. , Gao D. J. , Yu P. , Yu G. L. , Zhang W. , Zhu J. G.
Published: October 2003

Highly crystallized BaMoO4 films were prepared on molybdenum substrates in Ba(OH)2 solutions by electrochemical method at room temperature. The deposition conditions (reaction temperature and current density) during electrochemical formation were researched. The films were characterized by using the X‐ray Diffraction (XRD), Scanning Electronic Microscopy (SEM) and X‐ray Photoelectron Spectroscopy (XPS) analyses. The XRD analyses show that the films are good crystalline with single scheelite‐type tetragonal structure; the SEM photographs show that the films are densely deposited with double tetragonal tapers in shape; and the XPS analyses reveal that the composition of the BaMoO4 films (embodied Ba2+, Mo6+ and O2‐) is in agreement with stoichiometry. The optimum electrochemical conditions for BaMoO4 films formation are the lower reacting temperature (near room temperature) and the feasible current density (about 1mA/cm2)
Effect of crystal disorder on linewidth of the Raman modes in GaS1‐xSex layered mixed crystals
Authors: Gasanly N. M.
Published: October 2003

The linewidths of Raman‐active intralayer compressional modes in GaS1‐xSex layered mixed crystals (0 ≤ x ≤ 1) have been measured in the 10‐300 K temperature range to study the anharmonic effect as a function of compositional variation and temperature. It was found that the anharmonicity increases with an increase in substitutional disorder. The cubic (three‐phonon) processes with energy conservation is responsible for the anharmonic contribution to the broadening of the intralayer phonon lines with temperature. (© 2003 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Studies on the growth and defects of La3Ga5SiO14 (LGS) crystals
Authors: Wang Z. M. , Yuan D. R. , Xu D. , Lv M. K. , Pan L. H.
Published: October 2003

New and high quality piezoelectric crystals La3Ga5SiO14 (LGS) grown by the Czochralski method in a Platinum or Iridium crucible are reported in this paper. The growth defects in the LGS crystals were investigated by Transmission electron microscopy (TEM). It was found that cracks, inclusions, grain boundary and thermal stress in the LGS crystals. Their formation mechanisms and the method of eliminating these defects are discussed. (© 2003 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Inhibition of NF‐kB/DNA Interactions and HIV‐1 LTR Directed Transcription by Hybrid Molecules Containing Pyrrolo [2,1‐c] [1,4] Benzodiazepine (PBD) and Oligopyrrole Carriers
Authors: Borgatti Monica , Rutigliano Cristina , Bianchi Nicoletta , Mischiati Carlo , Baraldi Pier Giovanni , Romagnoli Romeo , Gambari Roberto
Published: October 2003

The DNA binding properties and the effects on protein/DNA interactions of a series of four hybrids prepared combining oligopyrrole minor groove binders and pyrrolo [2,1‐c][1,4] benzodiazepine (PBD) were studied. In addition, the effects on in vitro and ex vivo transcription directed by the long terminal repeat (LTR) of the human immunodeficiency type 1 virus (HIV‐1) were analysed and structure‐activity relationships developed. These hybrids (compounds 2–5) contain from one to four pyrrole units, respectively. To investigate sequence‐selectivity and stability of drugs/DNA complexes, DNase I foothyphen‐printing, filter binding, and arrested polymerase‐chain reaction (PCR) were performed on HIV‐1 LTR gene sequences. The antiproliferative activity of the hybrids was tested in vitro on T‐lymphoid Jurkat cell lines and compared to antiproliferative effects of the natural product distamycin A 1 and pyrrolo [2,1‐c][1,4] benzodiazepine (PBD 6). The results obtained demonstrate that hybrids 2–5 exhibit different DNA‐binding activity with respect to both distamycin A 1 and PBD 6. A direct relationship was found between number of pyrrole rings present in the hybrids 2–5 and stability of drugs/DNA complexes. With respect to antiproliferative effects, it was found that the increase in the length of the polypyrrole backbone leads to an increase of in vitro antiproliferative effects, i.e., the hybrid 5, containing the four pyrroles distamycin analogs, is more active than 2, 3 and 4 against the Jurkat cell lines. With respect to inhibition of HIV‐1 LTR driven transcription, it was found that the hybrid 5 containing the four pyrroles distamycin analogs, is more active than 2, 3 and 4. Interestingly, the present results suggest that the hybrid 3 exhibits low antiproliferative activity on Jurkat cell lines, being still active in inhibiting HIV‐1 LTR driven transcription both in vitro and ex vivo. Drug Dev. Res. 60:173–185, 2003. © 2003 Wiley‐Liss, Inc.
Hypolipidemic Activity of New Phenoxyacetic Derivatives Related to α‐Asarone with Minimal Pharmacophore Features
Authors: Cruz María del Carmen , Salazar María , Garciafigueroa Yésica , Hernández Dolores , Díaz Francisco , Chamorro Germán , Tamariz Joaquín
Published: October 2003

Five new series of potential hypolipidemic agents 3–7 were synthesized, in order to establish the minimal pharmacophore features associated to the potent hypocholesterolemic activity of natural α‐asarone (1) and synthetic clofibrate mimetic derivatives 2. The compounds were examined in hyperlipidemic male mice after oral administration of 25, 50, and 100 mg/Kg for 6 days. The isomeric series of acids and esters 3a–3c and 4a–4c were unexpectedly less active than the most simple structural isomeric compounds 5–7. This reveals that the phenoxyacetic acid scaffold carrying a hydrocarbon side chain, also found in derivatives 2, seems to be the most favorable lead for further development of potent hypolipidemic drugs. Drug Dev. Res. 60:186–195, 2003. © 2003 Wiley‐Liss, Inc.
Synthesis and anti‐Helicobacter pylori properties of NO‐donor/metronidazole hybrids and related compounds
Authors: Bertinaria Massimo , Galli Ubaldina , Sorba Giovanni , Fruttero Roberta , Gasco Alberto , Brenciaglia Maria Immacolata , Scaltrito Maria Maddalena , Dubini Francesco
Published: October 2003

Two series (A, B) of 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)ethyl derivatives (6–9, 18–23) conjugated through an oxygen or an aminomethyl bridge with either a furoxan NO‐donor moiety or a furazan substructure, devoid of NO‐donor properties, were synthesised. A third group (C) of 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)ethyl derivatives conjugated with nitrooxy and dinitrooxy NO‐donor functions (35, 38) as well as the corresponding analogue without these functions (40) were prepared. All the compounds were evaluated in vitro for their activity against a number of Helicobacter pylori strains. Metronidazole (1) and its amino analogue (11) were taken as reference compounds. All the synthesised hybrids and their analogues exhibited good anti‐H. pylori activity with MIC50 in the range less than 0.0039–1, resulting in compounds more active than metronidazole. Derivatives 6–9 displayed good potency also against metronidazole‐resistant strains. Compounds lacking the 5‐nitroimidazole moiety (24–29, 30–33) proved to be inactive against H. pylori with the exception of 33. The lack of significant differences in the antibacterial potency between furoxan and furazan hybrids in both series (A, B) suggest that the role of the N‐oxide moiety of the furoxan system either as an inductor of oxidative stress or as a promoter of NO‐donor properties is marginal. The substitution of the furoxan substructures with nitrooxy moieties (35, 38) afforded active compounds. In view of their NO‐donor properties, NO‐metronidazole hybrids could represent potential therapeutic tools both in the treatment of gastric ulcer and in a number of extragastrointestinal disorders such as ischaemic heart diseases and atherosclerosis‐related to some H. pylori strains. Drug Dev. Res. 60:225–239, 2003. © 2003 Wiley‐Liss, Inc.
Syntheses, calcium channel modulation effects, and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates
Authors: Velazquez Carlos , Vo Dean , Knaus Edward E.
Published: October 2003

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH2)n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl (16), 2‐pyridyl (17), or benzofurazan‐4‐yl (20) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC50 values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl (18), or 4‐pyridyl (19) substituent with IC50 values > 29.91 μM, relative to the reference drug nifedipine (IC50=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d, 17a–d, and 20a–d having alkyl spacer groups of variable chain length [–CO2(CH2)nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O2‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate (16b, EC50=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC50=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 (3, EC50=9.40 μM). The O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable •NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.
Growth inhibition of lung cancer cells by adenosine 5′‐triphosphate
Authors: Agteresch Hendrik J. , van Rooijen M. Helena C. , van den Berg J. Willem O. , Minderman‐Voortman Gardi J. , Wilson J. H. Paul , Dagnelie Pieter C.
Published: October 2003

Preliminary clinical data suggest that adenosine 5′‐triphosphate (ATP) may inhibit lung tumor growth. Because studies of ATP on lung cancer cells are lacking, the aim of the present study was to explore effects of extracellular ATP on the growth and morphology of human lung tumor cells. Five human lung tumor cell lines derived from tumors with different cellular characteristics, i.e., a small cell carcinoma (GLC4), a large cell carcinoma (H460), a squamous cell carcinoma (H520), a mesothelioma (MERO82), and a papillary adenocarcinoma (H441), were exposed to 0, 0.5, 1, 2, and 3 mM ATP. Total cell numbers and dead or damaged cells were measured on days 1, 2, and 3. ATP induced a significant, dose‐dependent growth inhibition in GLC4, H460, H520, and MERO82 cells. In contrast, H441 cells showed already maximal inhibition at 0.5 mM. Compared to untreated control cell lines, a significant growth inhibition (mean ± SEM) of 65 ± 5% (GLC4), 59 ± 5% (H460), 45 ± 5% (H520), 38±2% (MERO82), and 55 ± 8% (H441) was shown after 3 days incubation with 3 mM ATP. ATP also induced changes in morphology and attachment to the substratum. Although not demonstrated by the Trypan Blue exclusion test, on photographs it seems that ATP induces death of GLC4 and H460 cells at higher concentrations. In conclusion, in four out of five explored lung tumor cell lines, ATP induces a dose‐dependent growth inhibition. Lung adenocarcinoma cells show already maximal inhibition at the lowest tested ATP dose. There is a relationship between growth inhibition and morphology changes. Drug Dev. Res. 60:196–203, 2003. © 2003 Wiley‐Liss, Inc.
Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat
Authors: Pokorski Mieczysław , Matysiak Zdzisław , Marczak Magdalena , Ostrowski Robert P. , Kapuściński Andrzej , Matuszewska Iwona , Kańska Marianna , Czarnocki Zbigniew
Published: October 2003

N‐acyl‐dopamines are a novel class of biologically active lipids that have recently been identified in the brain and have the potential to interact with neural signaling pathways. This study seeks to determine the ability of N‐oleoyl‐dopamine, a synthetic amide of oleic acid and dopamine, to cross the blood brain barrier. We determined the tissue content of radioactivity in selected brain regions, in a short‐run study design, following injections of [3H]N‐oleoyl‐dopamine (0.4 µCi) into the internal carotid artery in the rat. These results were compared with intracarotid injections of [3H]dopamine and with intravenous injections of both radiolabeled compounds. The level of radioactivity was determined using liquid scintillation and was expressed as the percentage of its total dose injected per gram of tissue. We found that the 15‐min brain uptake of radioactivity, with no distinct regional variations, amounted to about 6% following the intracarotid [3H]N‐oleoyl‐dopamine, which was a significant 3–4‐fold increase over that following similar administration of [3H]dopamine. Intravenous injections of [3H]N‐oleoyl‐dopamine gave a much smaller yield of radioactivity in brain tissue samples which was still severalfold greater than that for intravenous [3H]dopamine. Qualitative thin‐layered chromatography screening showed the presence of unchanged N‐oleoyl‐dopamine in the brain following injections. We conclude that N‐oleoyl‐dopamine has an appreciable ability to cross the blood‐brain barrier, which contrasts the limited transfer of dopamine alone. N‐oleoyl‐dopamine might exert physiological effects due to its known affinity for the central vanilloid receptors or to better satisfying the brain tissue demand for dopamine. The study suggests a potential pharmacological role for N‐oleoyl‐dopamine delivered exogenously in helping regulate the brain function. Drug Dev. Res. 60:217–224, 2003. © 2003 Wiley‐Liss, Inc.
Investigating the safety of plants used in South African traditional medicine: Testing for genotoxicity in the micronucleus and alkaline comet assays
Authors: Taylor Joslyn L.S. , Elgorashi Esameldin E. , Maes Annemie , Van Gorp Urbain , De Kimpe Norbert , van Staden Johannes , Verschaeve Luc
Published: October 2003

Previous studies indicate that traditional botanical remedies can be valuable for treating human disease. The potential risk from long‐term use of such remedies has not, however, been fully investigated, especially in terms of their potential carcinogenic activity. In the present study, 51 South African plant species were selected on the basis of their use in traditional medicine and crude extracts were sequentially prepared from different dried plant parts using dichloromethane followed by 90% methanol. These extracts were tested for genotoxic activity in human peripheral blood lymphocytes using the micronucleus test, with further testing of select extracts using the alkaline comet assay. Screening results indicated the induction of significant numbers of micronuclei by many of the plant extracts. Several samples also induced DNA damage in human white blood cells using the alkaline comet assay. Although a number of these plants are recognised as toxic by traditional healers, several plants that are used in common remedies were found to be genotoxic and potentially dangerous. Environ. Mol. Mutagen. 42:144–154, 2003. © 2003 Wiley‐Liss, Inc.
Development and characterization of a stable epithelial cell line from Muta™Mouse lung
Authors: White Paul A. , Douglas George R. , Gingerich John , Parfett Craig , Shwed Phil , Seligy Vern , Soper Lynda , Berndt Lynn , Bayley Janet , Wagner Shelley , Pound Kathleen , Blakey David
Published: October 2003

We have isolated and characterized a stable epithelial cell line from Muta™Mouse lung that is a suitable complement to the in vivo assay system. The cells are contact inhibited, forming a flat monolayer, and retain several epithelial/pulmonary characteristics. The genome is stable across more than 50 generations, with a modal chromosome number of 78. Spontaneous rates of micronuclei (19.2 ± 1.4 per 1,000), sister chromatid exchanges (0.25 ± 0.004 per chromosome), and chromosome aberrations (∼ 4%) are lower than, or comparable to, other transgenic cell lines currently used in mutagenicity research. Fluorescence in situ hybridization analyses showed that 80% of cells contain three λgt10lacZ loci. Slot‐blot analyses indicated that the average cell contains ∼17 transgene monomers. Spontaneous mutant frequency at the lacZ transgene is stable (39.8 ± 1.1 × 10−5), and the direct‐acting mutagens N‐ethyl‐N‐nitrosourea and ICR‐191 yielded increases in mutant frequency of 6.3‐ and 3.2‐fold above control, respectively. Benzo[a]pyrene (BaP) exposure increased mutant frequency more than 25‐fold above control and did not require an exogenous metabolic activation mixture. Inhibition of Cyp1A1 by 5 μM α‐naphthoflavone eliminated BaP mutagenesis. Activation and mutation induction by the heterocyclic amine 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine required a low concentration (0.05% v/v) of exogenous rat liver S9. High activity of α, μ, and π glutathione‐S‐transferase isozymes appears to confer resistance to the cytotoxic effects of xenobiotics. The cell line is a suitable complement to the in vivo Muta™Mouse assay, and provides an opportunity for routine in vitro mutagenicity testing using an endpoint that is identical to that employed in vivo. Environ. Mol. Mutagen. 42:166–184, 2003. © 2003 Wiley‐Liss, Inc.
Metabolic polymorphisms and the micronucleus frequency in buccal epithelium of adolescents living in an urban environment
Authors: Montero Regina , Serrano Luis , Dávila Víctor , Segura Yayoi , Arrieta Andrea , Fuentes Raquel , Abad Iris , Valencia Lucía , Sierra Patricia , Camacho Rafael
Published: October 2003

Micronuclei and other biomarkers were evaluated in oral cells from 11‐ to 16‐year‐old girls living in a foster home in the central area of México City. Variables analyzed for possible association with these biomarkers include smoking habits, body mass index, metabolic polymorphisms for NAT1 and GSTM1 and whether the cells were obtained from the cheek or pharynx. The results indicated that individuals having the NAT1*10 homozygous genotype showed a significant increase in chromatin buds and binucleated cells. When the damage in the cheek was compared with damage in the pharynx, a significant increase in micronuclei and binucleated cells was found for the latter tissue in all the individuals analyzed. Environ. Mol. Mutagen. 42:216–222, 2003. © 2003 Wiley‐Liss, Inc.
Association between atmospheric ozone levels and damage to human nasal mucosa in Florence, Italy
Authors: Pacini Stefania , Giovannelli Lisa , Gulisano Massimo , Peruzzi Benedetta , Polli Gianni , Boddi Vieri , Ruggiero Marco , Bozzo Corrado , Stomeo Francesco , Fenu Grazia , Pezzatini Silvia , Pitozzi Vanessa , Dolara Piero
Published: October 2003

We evaluated the effects of urban air pollutants on human nasal mucosa over an 8‐month period on 102 subjects living in Florence, Tuscany, Italy. A group of subjects living in a city with a lower level of pollution (Sassari, Sardinia, Italy) was also analyzed. Nasal mucosa cells were harvested by brushing, a noninvasive procedure. Half of the cells were used for genotoxicity studies using the alkaline comet assay, and half for morphological studies. The levels of DNA damage in the nasal mucosa were considerably higher (+73%) in the subjects living in Florence than in Sassari. High levels of atmospheric ozone in Florence air correlated with DNA damage, and to the prevalence of inflammatory pathologies of the upper respiratory tract, although the ozone concentrations were below the Italian recommended attention level. Furthermore, higher levels of DNA damage were correlated with a dysfunction in the ability to maintain a normal epithelial cell structure. These data suggest an association between ozone air levels and damage in the upper respiratory tract. It remains unclear whether ozone itself or other associated pollutants are responsible for the observed alterations. Environ. Mol. Mutagen. 42:127–135, 2003. © 2003 Wiley‐Liss, Inc.
Use of the comet assay for studying environmental genotoxicity: Comparisons between visual and image analyses
Authors: Avishai Nanthawan , Rabinowitz Claudette , Rinkevich Baruch
Published: October 2003

In order to evaluate the applicability of different measurement parameters employed in the comet assay for analyzing environmental samples, fish hepatoma (RTH‐149) cells were exposed to concentrations of the model genotoxic agent hydrogen peroxide (H2O2; 1, 5, and 10 μM) and to five water samples from sites along the Kishon River, the most polluted river in Israel. DNA damage was scored in parallel by visual and computer‐image (Viscomet) analyses using 12 different parameters. Each parameter exhibited a different profile of responses. The four visual parameters were highly sensitive to the lowest (1 μM) H2O2 concentration (1.8–7.0‐fold of the control). At 10 μM H2O2 exposure, the visual parameter, percentage severe damage, showed the highest (40.3‐fold) response while four other parameters, tail area, tail extent moment (Viscomet), mean actual tail length and cumulative tail length (visual analysis), also had substantially elevated responses (8–11‐fold). We found that the DNA damage induced by field samples was similar in magnitude to the damage induced by 1 μM H2O2, with only some of the parameters being highly sensitive to the damage. Only about one‐half of the parameters could distinguish four significant levels of genotoxicity among the five sampling sites, while the remaining parameters detected only three levels. It is concluded that the choice of parameters for analyzing genotoxicity in ecotoxicological studies should be made in accordance with the characteristics of each parameter. Environ. Mol. Mutagen. 42:155–165, 2003. © 2003 Wiley‐Liss, Inc.
Single‐cell immunohistochemical mutation load assay (SCIMLA) using human paraffin‐embedded tissues
Authors: Schlake Gudrun , Liu Qiang , Heinmöller Ernst , Hill Kathleen A. , Weiss Lawrence , Sommer Steve S.
Published: October 2003

It would be advantageous to measure mutation load in situ in order to determine the relationship between a high mutation load and increased risk for cancer or other diseases and to evaluate sources of possible mutagen exposure. Previously, in situ mutation detection assays have been plagued with multiple rounds of amplification and high rates of false‐positives and false‐negatives. The single cell immunohistochemical mutation load assay (SCIMLA) was developed to measure somatic mutation frequency, pattern, and spectrum in normal tissues with a single round of amplification. The P53 gene was utilized as a mutation reporter because of the unusual property that missense mutations often cause P53 protein to accumulate in the cell, allowing the mutant proteins to be detected by immunohistochemical staining. Alternative reporter genes with stabilized mutant proteins may be envisioned. Single cells that stain positively for P53 protein overabundance (red cells) were microdissected from ethanol‐fixed and paraffin‐embedded tissues. A novel stimulated‐PCR (S‐PCR) protocol permitted successful amplification of a 1.8‐kb segment of the P53 gene (i.e., exons 5–9) in 87% of single mammary cells. Subsequent sequence analysis demonstrated that 35% of the amplified red‐stained epithelial cells from normal breast tissue have missense mutations at evolutionarily conserved amino acids. Jackpot mutations, presumably due to clonal expansion, were common. False‐positive missense mutations at conserved residues were observed in 3% of the clear cells (i.e., without red stain), presumably due to DNA polymerase error in early PCR cycles. The allele dropout rate was measured at 40% of the amplified cells. SCIMLA is applicable to a variety of tissues, utilizes a single amplification of an endogenous gene, displays mutant cells in situ, and may be adapted to other species. Environ. Mol. Mutagen. 42:206–215, 2003. © 2003 Wiley‐Liss, Inc.
Mainstreaming Evaluation
Authors: Sanders James R.
Published: October 2003

The concept of mainstreaming evaluation is defined, and the question of why mainstreaming is not more prevalent is addressed. A case of mainstreaming evaluation in a community hospice is presented, along with recommendations for moving organizations toward mainstreaming evaluation. This chapter and Sander's AEA presidential address (2002) provide a foundation for the discussions of mainstreaming evaluation.
Mainstreaming Evaluation or Building Evaluation Capability? Three Key Elements
Authors: Duignan Paul
Published: October 2003

Approaches to mainstreaming evaluation that appear to be successful in New Zealand, particularly in human services programs that serve both European and Maori populations, are presented. Three key elements are (1) to use an appropriate evaluation model, (2) to develop evaluation skills appropriate for each level of an organization, and (3) to use organization‐ or sector‐level strategizing to identify priority evaluation questions.
The Rigidity and Comfort of Habits: A Cultural and Philosophical Analysis of the Ups and Downs of Mainstreaming Evaluation
Authors: Grudens‐Schuck Nancy
Published: October 2003

Mainstreaming evaluation requires establishing aesthetic and ethical frameworks, as well as developing knowledge and skills that make “doing evaluation” seem like the right thing. Mainstreaming, however, can pose challenges to good evaluation practice; a view from cultural anthropology suggests that evaluation can have distinct meanings in different settings. Stories from program evaluation research in Indonesia illustrate the ways comforts and rigidities associated with mainstreamed evaluation processes may hinder high‐quality evaluation.
PIE à la Mode: Mainstreaming Evaluation and Accountability in Each Program in Every County of a Statewide School Readiness Initiative
Authors: Wandersman Abraham , Flaspohler Paul , Ace April , Ford Laurie , Imm Pamela S. , Chinman Matthew J. , Sheldon Jeffrey , Bowers Andrews Arlene , Crusto Cindy A. , Kaufman Joy S.
Published: October 2003

This chapter describes the framework and implementation of a program accountability system in a statewide initiative (South Carolina First Steps to School Readiness), which was developed (1) to enable practitioners to provide evaluation information required by legislative mandate and (2) to develop the capacity of practitioners to systematically plan their program, implement with quality, and self‐evaluate. The components of this program are reflected in its name: Planning, Implementation, and Evaluation (PIE). The chapter describes PIE in relation to program theory, usage, and efforts to mainstream.
Helping Evaluators Swim with the Current: Training Evaluators to Support Mainstreaming
Authors: Barnette J. Jackson , Barber Wallis Anne
Published: October 2003

Approaches to training in evaluation, with the aim of seeding the field of education with evaluators who can work with organizations in a more participatory and relevant way, are proposed. The methods suggested are intended to incline evaluators toward participatory approaches. Trained evaluators will be equipped to forge powerful learning partnerships with programs and participants, thus improving the prospects for mainstreaming evaluation.