bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexistence of IgE-Mediated Allergy and Type 1 Diabetes in Childhood
Authors: Caffarelli Carlo , Cavagni Giovanni , Pierdomenico Rossella , Chiari Giovanni , Spattini Andrea , Vanelli Maurizio
Published: June 2004

Background: Autoimmune disorders are considered to be associated with a Th1 immune response while allergic diseases with a Th2 response. We carried out a study to determine whether there is an inverse relationship between allergic diseases in IgE-sensitized children or positive skin-prick test reactions to allergens and type 1 diabetes mellitus (DM1) in children. Methods: Sixty-three children with DM1 and 108 controls were enrolled. Parents of all children compiled a questionnaire on allergic diseases. All children underwent skin-prick tests for common aero-allergens and food-allergens. Results: A history of allergic symptoms, especially wheezing, asthma and allergic rhinitis was significantly less common in the group with DM1. Allergic symptoms in children with IgE sensitization or parental atopy were no more likely in children with DM1 than in normal control subjects. There was no association between skin-prick test results to inhalants and food allergens and DM1. Conclusions: Consistently with the Th1/Th2 paradigm, we observed a reduction in the frequency of allergic symptoms in children with DM1. However, our study did not succeed in demonstrating an inverse relation between Th1- and Th2-mediated diseases in children with IgE sensitization or an atopic genetic predisposition.
Decrease of Interleukin-10-Producing T Cells in the Peripheral Blood of Severe Unstable Atopic Asthmatics
Authors: Matsumoto Koichiro , Inoue Hiromasa , Fukuyama Satoru , Tsuda Miyuki , Ikegami Tomomi , Kibe Atsuko , Yoshiura Yuki , Komori Masashi , Hamasaki Naotaka , Aizawa Hisamichi , Nakanishi Yoichi
Published: June 2004

Background: Although IL-10 is known as an immunoregulatory cytokine produced by various cells including T cells, its basic profile in atopic asthma remains uncertain. Objective: The profiles of IL-10 production in circulating CD4+ T cells of atopic asthmatics were investigated with respect to clinical severity. Methods: Forty atopic asthmatics were divided into three groups: mild, and severe but stable and severe unstable asthmatics. Eosinophils were counted in the peripheral blood and sputum, and exhaled nitric oxide was assessed. PBMCs were stimulated with or without anti-CD3 and anti-CD28 antibodies and then processed for detecting IL-10-producing CD4+ cells using flow cytometry. Results: There was no difference in the eosinophil count in blood or sputum and in nitric oxide level among the three groups. IL-10-producing CD4+ cells were mainly detected in a CD45RO+ memory population. The frequency of IL-10-producing cells after stimulation was significantly lower in the severe unstable group compared to the mild group. In addition, the frequency of IL-10-producing cells in the severe unstable group was significantly lower than that in the severe stable group despite the fact that both groups received similar treatments with high-dose inhaled corticosteroids. The IL-10 production of CD4+CD45RO+ cells in response to dexamethasone did not differ among the three groups. Conclusions: IL-10-producing CD4+CD45RO+ cells in the peripheral blood are decreased in severe unstable asthmatics, which is not explained by the effect of high-dose inhaled corticosteroid medication.
Association between Cathepsin D Polymorphism and Alzheimer’s Disease in a Chinese Han Population
Authors: Li Xiao-Qing , Chen Deng , Zhang Zhen-Xin , Qu Qiu-Ming , Zhang Jun-Wu
Published: June 2004

Cathepsin D (CTSD) is an intracellular aspartyl protease, which is active in the endosomal/lysosomal system. CTSD may play a role in Alzheimer’s disease (AD) through cleaving the amyloid precursor protein into β-amyloid peptide and degrading tau protein into fragments. A functional polymorphism in exon 2 of the cathepsin D gene (C→T, Ala224Val) has recently been reported to increase the risk for AD in some of the Caucasian populations, with a significant overrepresentation of the T allele, but these reports have not been universally duplicated. We performed an association study between CTSD polymorphism and AD in 156 sporadic AD patients and 183 controls of Chinese Han ethnicity. Our data revealed that the distribution of CTSD genotypes and alleles was similar in patients and controls. No direct association was found between CTSD polymorphism and AD risk. There might be a weak synergistic interaction between CTSD T and APOEΕ4 allele in increasing the risk for developing AD.
Category Verbal Fluency Test Performance in Chinese Elderly with Alzheimer’s Disease
Authors: Mok Edward Hei Lim , Lam Linda Chiu Wa , Chiu Helen Fung Kum
Published: June 2004

Introduction: The applicability of category verbal fluency test (VFT) as a screening test for Alzheimer’s disease (AD) in the Chinese population was studied. Methods: VFTs with categories of ‘animal’, ‘fruit’ and ‘vegetable’ were administrated to 72 subjects with AD and 81 aged-matched, community-dwelling, non-demented elderly (NC) in Hong Kong. Results: A significant difference in VFT scores between NC and AD groups was found (t-test, p < 0.05). CMMSE scores were significantly correlated with VFT performances in both subject groups. The correlation of combined VFT scores with age and educational level was significant only in the NC group (Pearson correlation, p < 0.05). At a cut-off score of 24/25, the sensitivity and specificity of the VFT in screening of dementia were 86.8 and 93.4% for subjects with no formal education. For literate subjects, an optimal cut-off score of 31/32 was identified across different educational levels. Conclusion: Although VFT performance was influenced by demographic factors like age and education, cognitive function was the most determining factor. With easy administration and satisfactory sensitivity and specificity, VFT is a useful and quick clinical screening test for AD in Chinese elderly.
Severe Cerebral Amyloid Angiopathy Characterizes an Underestimated Variant of Vascular Dementia
Authors: Haglund Mattias , Sjöbeck Martin , Englund Elisabet
Published: June 2004

Cerebral amyloid angiopathy (CAA) is a frequent finding on neuropathological examination of patients with Alzheimer’s disease (AD). A recent study from our laboratory showed that CAA also frequently occurred in vascular dementia with additional mild Alzheimer encephalopathy (VaD-ae, i.e. Alzheimer pathology that does not fulfill criteria for AD). Because CAA is associated with cerebral hemorrhages and infarctions, it is of significant interest to confirm or dismiss the hypothesis that CAA contributes clinically in the many patients that present with VaD-ae. Therefore, we examined entire temporal lobes of 11 VaD-ae cases and 11 age-matched AD cases with Aβ immunohistochemistry. Six of 11 VaD-ae cases had severe CAA, more extensive than in any AD case. There was a trend toward more cortical infarctions in this group, indicating that CAA in VaD may be of clinical importance and an underestimated cause of dementia.
Contribution of Apolipoprotein E and Cathepsin D Genotypes to the Familial Aggregation of Alzheimer’s Disease
Authors: Heun Reinhard , Ptok Ursula , Kölsch Heike , Maier Wolfgang , Jessen Frank
Published: June 2004

Objective: The familial aggregation of late-onset Alzheimer’s disease (AD) might be caused by the clustering of genetic risk factors in families. This study investigates the influence of variants of candidate genes on the familial aggregation of AD. Methods: The occurrence of AD was examined in 1,420 first-degree relatives of 70 AD patients and 144 nondemented controls classified by the presence of AD and relevant candidate genes in index subjects. Results: Relatives of nondemented controls with an apolipoprotein E4 or a cathepsin D T allele had a higher cumulative lifetime incidence of AD than relatives of subjects without the respective alleles. This effect was not detected in relatives of AD patients. Variants of the interleukin-6, bleomycin hydrolase and α2-macroglobulin genes did not significantly influence the (age-adjusted) risk of AD in relatives. Conclusions: Familial aggregation of late-onset AD is likely to be caused by several genetic risk factors. Variants of the apolipoprotein E and cathepsin D genes influenced the risk of AD in relatives of nondemented control subjects. The lack of an influence of these genotypes on the risk of AD in relatives of AD subjects may be the consequence of complementary reductions of other genetic risk factors such as various, yet unknown susceptibility genes in patients and, consequently, in their first-degree relatives.
Autoimmune Responses to Amyloid Structures of Aβ(25–35) Peptide and Human Lysozyme in the Serum of Patients with Progressive Alzheimer’s Disease
Authors: Gruden M.A. , Davudova T.B. , Mališauskas M. , Zamotin V.V. , Sewell R.D.E. , Voskresenskaya N.I. , Kostanyan I.A. , Sherstnev V.V. , Morozova-Roche L.A.
Published: June 2004

We have found an increased level of serum antibodies to the prefibrillar structures of both Aβ(25–35) peptide and human lysozyme in Alzheimer’s disease (AD) patients compared to age-matched controls, indicating that autoimmunity is implicated in AD. In the serum of AD patients with a long-term duration (>15 years) the titer of serum antibodies to aggregates of Aβ(25–35) peptide increased by approximately 5-fold, whilst the antibody titer to lysozyme protofilaments decreased by approximately 8-fold compared to patients with AD duration of <5 years. The content of immunoglobulins of the A, G and M types declined, particularly in AD duration of >15 years. An increase in the concentration of immune complexes and higher lysozyme activity was detected in the serum of all patients and this was suggestive of an inflammatory reaction. We propose that the autoimmune response to different amyloid structures in AD can be viewed as a clearance pathway targeting amyloid development. Autoimmune response can be exploited as a marker of ongoing protein aggregation and hence be used as a diagnostic feature of AD.
Five-Year Outcome of Cholinergic Treatment of Alzheimer’s Disease: Early Response Predicts Prolonged Time until Nursing Home Placement, but Does Not Alter Life Expectancy
Authors: Wallin Å.K. , Gustafson L. , Sjögren M. , Wattmo C. , Minthon L.
Published: June 2004

Fifty consecutive outpatients with Alzheimer’s disease (AD) received treatment with the cholinesterase inhibitor tacrine in an open longitudinal study. Assessments using Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale – cognitive subscale, and a global rating were made at baseline and at 6, 12, 24, 36, 48 and 60 months. Three outcome groups were characterized: responders, unchanged and deteriorated. Additional outcome measures were time until nursing home placement, and mortality rate. At 6 months –75%, at 12 months –42%, at 24 months –20%, and after that 10% of the patients still on medication had improved or remained stable. The mortality rate did not differ between the outcome groups. Response to tacrine treatment at 6 or 12 months was found to predict a prolonged time until nursing home placement. No predictors for a positive treatment response could be identified at baseline.
Preparation of Lithium Hexafluorophosphate from LiF and P in Fluorine Atmosphere
Authors: Kim Jae-Ho , Nagahara Kazushi , Yonezawa Susumu , Takashima Masayuki
Published: June 2004

Pure lithium hexafluorophosphate (LiPF6) has been successfully prepared by the reaction between the elemental fluorine and the equi-molar mixture of LiF and P (F2 direct method). The product was pure enough to be used as an electrolyte salt of lithium secondary battery. Especially, the stepwise introducing of fluorine gas into a reaction system was effective to prepare LiPF6 in a high yield. The results of Rietveld refinement of XRD data revealed that the structure of LiPF6 was trigonal (, Z = 3, a0 = 0.4932(2), c0 = 1.2641(5) nm, cell volume; 2.663(2) × 10−28 m3). The cell constants of LiPF6 prepared by the F2 direct method were almost the same as those of LiPF6 prepared by the reaction between LiF and PF5 in a liquid anhydrous hydrogen fluoride (L-AHF method).
Solid Phase Synthesis of Hydroxy Benzothiazepinones through Cyclative Release under Thermolysis
Authors: Kumar H M Sampath , Chakravarthy P Pawan , Rao M Shesha , Joyasawal Sipak , Yadav J S
Published: June 2004

Hydroxy benzothiazepinones were synthesized by a simple procedure involving epoxidation of polymer bound cinnamic acids followed by nucleophilic opening of the resulting glycidic ester by o-aminothiophenol to afford the intermediate hydroxy anilino-esters which underwent cyclization cleavage on heating in DMF to release the product completely.
Synthesis of Novel Spiro-condensed Dithienosiloles and the Application to Organic FET
Authors: Ohshita Joji , Lee Kwang-Hoi , Hamamoto Daisuke , Kunugi Yoshihito , Ikadai Junnai , Kwak Young-Woo , Kunai Atsutaka
Published: June 2004

Spirobi(dithienosilole)s were prepared and their optical and FET properties were studied. They showed absorption maxima at 358–368 nm, a little red shifted from those of the corresponding non-spiro type dithienosiloles, indicating that spiro-conjugation operates in these molecules to an extent. The field-effect hole mobility of spirobi[bis(trimethylsilyl)dithienosilole] was determined to be 1.4 × 10−6 cm2 V−1 s−1.
Nanotube Formation in Solution between β-Cyclodextrin and Cinchonine
Authors: Wen Xianhong , Guo Ming , Liu Ziyang , Tan Fei
Published: June 2004

The nanotube could been formed between the drug cinchonine and β-cyclodextrin in solution when they were mixed together and sonicated for about 1 h. Fluorescence anisotropy methods characterized the number of cyclodextrin in nanotube. AM1 calculation implied that H bonds played an important role to stabilize the nanostructure.
Photochromism of Furylfulgide in a Single-crystalline Phase
Authors: Kobatake Seiya , Irie Masahiro
Published: June 2004

(E)-2,5-Dimethyl-3-furylethylidene(isopropylidene)succinic anhydride (1E) was found to undergo photochromism in the single-crystalline phase. Upon irradiation with 366-nm light, the single crystal turned red. When the photogenerated colored crystal was observed under polarized light, the red color intensity changed by rotating the crystal. The colored crystal was stable at room temperature.
Cu–Pd Bimetallic Cluster/AC as a Novel Catalyst for the Reduction of Nitrate to Nitrite
Authors: Sakamoto Yoshinori , Nakata Kou , Kamiya Yuichi , Okuhara Toshio
Published: June 2004

Cu–Pd/AC catalysts that are derived from Cu–Pd clusters were shown to possess high activity for the reduction of nitrate to nitrite, but were inactive for the reduction of nitrite. In contrast, the Pd/AC catalyst was inactive for the reduction of nitrate, whereas conventional Cu–Pd/AC afforded various products, including nitrite, nitrogen, and ammonia.
Contrast Medium‐Induced Nephrotoxicity: Pathophysiology and Prevention
Authors: Gerlach Anthony T. , Pickworth Kerry K.
Published: June 2004

Contrast medium‐induced nephrotoxicity (CMN) is a common form of iatrogenic acute renal failure. Typically, patients experience changes in serum creatinine or creatinine clearance between 1 and 5 days after exposure to a contrast medium, but they rarely require dialysis. The mechanism for CMN is not understood, but renal insufficiency, dehydration, and congestive heart failure are risk factors. The frequency of CMN with high‐osmolality versus low‐osmolality media is controversial. Prophylaxis can reduce CMN. Of many different strategies, hydration with normal saline before and after exposure offers the best protection with the fewest adverse effects.
The Effect of Ritonavir on the Pharmacokinetics of Meperidine and Normeperidine
Authors: Piscitelli Stephen C. , Kress Diane Rock , Bertz Richard J. , Pau Alice , Davey Richard
Published: June 2004

Study Objective. To determine the effects of ritonavir on the pharmacokinetics of meperidine and normeperidine.

Design. Open‐label, crossover, pharmacokinetic study.

Setting. United States government research hospital.

Subjects. Eight healthy volunteers who tested negative for the human immunodeficiency virus.

Intervention. Subjects received oral meperidine 50 mg and had serial blood samples collected for 48 hours. They then received ritonavir 500 mg twice/day for 10 days, followed by administration of a second 50‐mg meperidine dose and collection of serial samples.

Measurements and Main Results. Plasma samples were assayed for meperidine, normeperidine, and ritonavir. Meperidine's area under the curve (AUC) decreased in all subjects by a mean of 67 ± 4% in the presence of ritonavir (p<0.005). Mean ± SD maximum concentration was decreased from 126 ± 47 to 51 ± 21 ng/ml. Normeperidine's mean AUC was increased 47%, suggesting induction of hepatic metabolism.

Conclusion. Meperidine's AUC is significantly reduced, not increased, by concomitant ritonavir. Based on these findings, the risk of narcotic‐related adverse effects from this combination appears to be minimal. However, increased concentrations of normeperidine suggest a potential for toxicity with increased dosages or long‐term therapy.
Pharmacokinetics and Pharmacodynamics of Ceftizoxime in Patients with Dosages Adjusted for Renal Function
Authors: Neuhauser Melinda M. , McKinnon Peggy S. , Hershberger Ellie , Rybak Michael J.
Published: June 2004

Study Objective. Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class‐specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cpmin) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function.

Design. Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages.

Setting. University‐affiliated hospital.

Patients. Forty‐three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Clcr; ml/min): group 1, above 100; group 2, 61–99; group 3, 31–60; and group 4, 15–30.

Interventions. Ceftizoxime serum concentrations were obtained at steady state.

Measurements and Main Results. Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half‐life tended to be greater in patients with renal impairment. The Cpmin and area under the concentration‐time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups.

Conclusion. Our dosing guidelines achieved similar Cpmin among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.
Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease
Authors: McNaught Kevin St. P. , Perl Daniel P. , Brownell Anna‐Liisa , Olanow C. Warren
Published: June 2004

Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin‐proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD‐inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z‐lle‐Glu(OtBu)‐Ala‐Leu‐al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon‐11‐labeled 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, α‐synuclein/ubiquitin–containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness. Ann Neurol 2004
Reaktionen zwischen und in Molekülkristallen
Authors: Braga Dario , Grepioni Fabrizia
Published: June 2004

Reaktionen in und zwischen Molekülkristallen, insbesondere mechanisch ausgelöste Umsetzungen, werden in diesem Kurzaufsatz diskutiert. Den Schwerpunkt bilden Prozesse innerhalb oder zwischen Festkörpern, die vor allem durch supramolekulare Wechselwirkungen gesteuert werden: Templatcycloadditionen, Bildung von Einschlussverbindungen, Reaktionen von Molekülkristallen mit Umorganisation nichtkovalenter Bindungen und Bildung von Komplexen und Koordinationsverbindungen. Lösungsmittelfreie mechanochemische Verfahren wie Mahlen und Kneten bieten sich als umweltschonende Methoden zur Synthese von molekularen und supramolekularen Feststoffen an.
Sulfotransferases: Structure, Mechanism, Biological Activity, Inhibition, and Synthetic Utility
Authors: Chapman Eli , Best Michael D. , Hanson Sarah R. , Wong Chi‐Huey
Published: June 2004

The sulfonation (also known as sulfurylation) of biomolecules has long been known to take place in a variety of organisms, from prokaryotes to multicellular species, and new biological functions continue to be uncovered in connection with this important transformation. Early studies of sulfotransferases (STs), the enzymes that catalyze sulfonation, focused primarily on the cytosolic STs, which are involved in detoxification, hormone regulation, and drug metabolism. Although known to exist, the membrane‐associated STs were not studied as extensively until more recently. Involved in the sulfonation of complex carbohydrates and proteins, they have emerged as central players in a number of molecular‐recognition events and biochemical signaling pathways. STs have also been implicated in many pathophysiological processes. As a result, much interest in the complex roles of STs and in their targeting for therapeutic intervention has been generated. Progress in the elucidation of the structures and mechanisms of sulfotransferases, as well as their biological activity, inhibition, and synthetic utility, are discussed in this Review.
Astrometry of the 1572 supernova (B Cassiopeiae)
Authors: Green D. W. E.
Published: June 2004

Contemporary European measurements of the Milky Way supernova of 1572 (B Cas) have been analyzed to compute a modern position for the star in 1572. This work adds to that done by previous 20th‐century authors by using a new procedure and previously unused astrometry by 16th‐century European observers. Comparison is made with earlier analyses and to modern positional data on the supernova remnant (3C 10). (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
New variable stars among or near to H‐alpha emission stars
Authors: Kohoutek L. , Wehmeyer R.
Published: June 2004

This paper is dealing with the discovery of 11 new or new suspected variables, found as a by‐product during the preparation of our Catalogue of Stars in the Northern Milky Way Having H‐alpha in Emission. We give: (1) The coordinates of the variables and of the respective comparison stars; (2) the maximum and the minimum brightnesses of the observed m(pg), which were determined by visual estimation using the brightnesses in Catalogue USNO A2.0; (3) finding charts of the variables together with their comparison stars used (in electronic form only). (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Possible connection between period change and magnetic activity of the very short‐period binary VZ Piscium
Authors: Qian S. B. , Soonthornthum B. , Xiang F. Y. , Zhu L. Y. , He J. J.
Published: June 2004

New times of light minimum of the short‐period (P = 0d.26) close binary system, VZ Psc, are presented. A period investigation of the binary star, by combining the three new eclipse times with the others collected from the literatures, shows that the variation of the period might be in an alternate way. Under the hypothesis that the variation of the orbital period is cyclic, a period of 25 years and an amplitude of 0.d0030 for the cyclic change are determined. If this periodic variation is caused by the presence of a third body, the mass of the third body (m3) should be no less than 0.081M⊙. Since both components of VZ Psc are strong chromospherically active and the level of activity of the secondary component is higher than that of the primary one, the period may be more plausibly explained by cyclic magnetic activity of the less massive component. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Harnessing the potential of chemical defenses from antimicrobial activities
Authors: Lu Chunhua , Shen Yuemao
Published: June 2004

Resistance to the drugs used in the treatment of many infectious diseases is increasing, while microbial infections are being found to be responsible for more life‐threatening diseases than previously thought. Despite a large investment in the invention and application of high‐throughput screening techniques involving miniaturization and automation, and a diverse array of strategies for designing and constructing various chemical libraries, relatively few new drugs have resulted. Natural products, however, have been a major source of drugs for centuries. Since some of them are produced by organisms as a result of selection in favour of improved defense against competing deleterious microorganisms, in principle they would be less likely to incur resistance. Furthermore, the production of those defensive secondary metabolites is inducible because their original function is a response to environmental challenges. Moreover, symbioses, co‐habitation associations between two or more different species of organisms, are universal in nature, and the production of secondary metabolites by symbiotic microbes may be an important adaptation allowing microbes to affect their hosts. Therefore, co‐culture strategies, using combinations of plant cell–pathogenic microbes, plant cell–endophytes (or symbionts), and symbiont–pathogenic microbes, based on the principles of chemical defense and the known mechanisms of organism interactions, may be an efficient general approach in the search for new anti‐microbial drugs. BioEssays 26:808–813, 2004. © 2004 Wiley Periodicals, Inc.
Glutamine breakdown in rapidly dividing cells: waste or investment?
Authors: Aledo J. Carlos
Published: June 2004

Tumours, and in general rapidly dividing cells, behave as dissipative devices that apparently waste glutamine, since its consumption seems to exceed both energetic and nitrogen needs. Although not conclusive, there is compelling evidence suggesting that the consumption of such large amounts of glutamine is essential to sustain high rates of cellular proliferation. Herein, I first review the experimental evidence linking proliferation with high rates of glutamine breakdown. Then, the current knowledge on the proteins and activities involved in this high glutamine consumption will be summarized. Finally, the significance of the apparent waste of glutamine will be discussed on bioenergetic grounds. The discussion leads to the hypothesis that glutamine breakdown might energize some endergonic processes, as well as accelerating other exergonic processes related to cellular proliferation. BioEssays 26:778–785, 2004. © 2004 Wiley Periodicals, Inc.
Eye development: a view from the retina pigmented epithelium
Authors: Ramón Martínez‐Morales Juan , Rodrigo Isabel , Bovolenta Paola
Published: June 2004

The retina pigment epithelium (RPE) is a highly specialised epithelium that serves as a multifunctional and indispensable component of the vertebrate eye. Although a great deal of attention has been paid to its transdifferentiation capabilities and its ancillary functions in neural retina development, little is known about the molecular mechanisms that specify the RPE itself. Recent advances in our understanding of the genetic network that controls the progressive specification of the eye anlage in vertebrates have provided some of the initial cues to the mechanisms responsible for RPE patterning. Here, we have outlined many recent findings that suggest that a limited number of transcription factors, including Otx2, Mitf and Pax6 and a few signalling cascades, are the elements required for the onset of RPE specification in vertebrates. Furthermore, using this information and the data available on the specification of the pigmented cells of primitive chordates, we have ventured some hypotheses on the origin of RPE cells during evolution. BioEssays 26:766–777, 2004. © 2004 Wiley Periodicals, Inc.
Tumour necrosis factor α production by polymorphonuclear neutrophils treated with mouse anti‐human CD19 monoclonal antibody
Authors: Nishimura Motoko
Published: June 2004

Polymorphonuclear neutrophils (PMNs) play pivotal roles as phagocytic cells in immune defence against bacteria and parasites, exerting their effects by production of reactive oxygen species, several cytokines, chemokines and by phagocytotic reaction. In our investigation of properties of activated PMNs, we discovered that one of the two kinds of mouse anti‐human CD19 monoclonal antibodies (mAbs) clone SJ25‐C1, weakly binds to freshly prepared PMNs. Moreover, the treatment of freshly prepared PMNs with anti‐CD19 mAb (clone SJ25‐C1) at 37°C for 6 h induces the production and the secretion of tumour necrosis factor α (TNF α) by PMNs in vitro which was detectable in culture supernatants by bioassay using mouse cell line L929 cells. The concentration of TNF α secreted into the culture supernatant of PMNs cultured in the presence of anti‐CD19 mAb (clone SJ25‐C1) was higher than those of PMNs treated at 37°C for 6 h with various PMN activators, such as anti‐CD24 mAb, granulocytes‐macrophage colony stimulation factor (GM‐CSF) or interferon γ (IFN γ). In contrast, another clone of anti‐CD19 mAb, HD37, did not bind to freshly prepared PMNs and failed to produce TNF α. To confirm that anti‐CD19 mAb (clone SJ25‐C1)‐treated PMNs definitely produce TNF α, we measured the levels of intracellular expression of TNF α in PMNs permeabilized by saponin. These cells were treated with fluorescence‐conjugated mouse anti‐human TNF α mAb for detection of intracellular TNF α expression. Consequently, large amounts of intracellular TNF α were detected in PMNs treated with anti‐CD19 mAb (clone SJ25‐C1) but not in those treated with anti‐CD19 mAb (clone HD37). Copyright © 2004 John Wiley & Sons, Ltd.
Effect of new and known 1,4‐dihydropyridine derivatives on blood glucose levels in normal and streptozotocin‐induced diabetic rats
Authors: Briede Janīna , Stivriņa Māra , Stoldere Dzintra , Bisenieks Egīls , Uldriķis Jānis , Poikāns Jānis , Makarova Natālija , Duburs Gunārs
Published: June 2004

Analysis of the effect of several 1,4‐DHP Ca2+ channel antagonists on experimental and clinical diabetes shows that structurally similar Ca2+ channel antagonists can exert opposite effects on Ca2+ influx, glucose homeostasis and insulin secretion. The influence of the Ca2+ channel antagonists on pancreatic β cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ‐induced diabetic rats. The compounds tested were: 1,4‐DHP derivatives cerebrocrast (1), etaftoron (2), OSI‐1190 (3), OSI‐3802 (4), OSI‐2954 (5) and known 1,4‐DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure–function relationships of the effect of 1,4‐DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF2 group in position 2 of the 4‐phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg kg−1, p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ‐induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long‐lasting influence on glucose metabolism, especially in STZ‐induced diabetic rats. Copyright © 2004 John Wiley & Sons, Ltd.
Antioxidant‐associated chemoprevention by sodium selenite in N‐nitrosodiethylamine‐induced and phenobarbital‐promoted hepatocarcinogenesis in rats
Authors: Thirunavukkarasu C. , Babu E. , Ebrahim A. S. , Chandramohan N. , Sakthisekaran D.
Published: June 2004

The anticarcinogenic/antioxidant potential of sodium selenite (Se), a micronutrient, was evaluated on liver tumourigenesis induced by N‐nitrosodiethylamine (DEN) and promoted by phenobarbital (PB; 0.05% in diet). Male, albino rats of the Wistar strain were exposed intravenously to a single dose of DEN (200 mg kg−1 body weight). Se (4 ppm in drinking water) was supplemented before initiation, or during initiation and/or during the promotion period of carcinogenesis. At the end of 16 weeks (after DEN administration) nodular incidence, the total number of nodules and non‐enzymic antioxidants such as vitamin E, vitamin C, total thiol, protein thiol and non‐protein thiol contents were measured in hepatoma, surrounding tissue and kidney tissue of control and experimental groups. In hepatoma‐bearing animals the above biochemical changes were decreased when compared with normal control animals. On Se treatment throughout the study, (20 weeks) the above biochemical changes reverted to normal levels. Pre‐ and post‐treatment with Se also shows a tendency to reverse the above changes. The results indicate that prior application of Se significantly reverses the adverse changes produced during the tumourigenesis. Furthermore, prior applications of Se significantly reduced the cumulative number of tumours per tumour‐bearing animals. The present study reveals the antitumour potential of Se against DEN‐induced liver carcinogenesis. Copyright © 2004 John Wiley & Sons, Ltd.
Protein kinase A activity is associated with metacyclogenesis in Leishmania amazonensis
Authors: Genestra Marcelo , Cysne‐Finkelstein Léa , Leon Leonor
Published: June 2004

Because of the importance of cell signalling processes in proliferation and differentiation, the adenylate cyclase pathway was studied, specifically the protein kinase A (PKA) in Leishmania amazonensis. The PKAs of soluble (SF) and enriched membrane fractions (MF) from infective/non‐infective promastigotes and axenic amastigotes were assayed. In order to purify the PKA molecule, fractions were chromatographed on DEAE‐cellulose columns and the phosphorylative activity was evaluated using [γ32P]‐ATP as the phosphate source. These experiments were performed in the presence of cyclic adenosine monophosphate (cAMP) and an inhibitor of PKA. Our data demonstrated that the PKA activity was significantly higher (about two times) in SF from promastigotes with a high concentration of metacyclic forms, when compared with the non‐infective promastigotes, suggesting an association of this activity and the metacyclogenesis process. A discrete phosphorylative activity in axenic amastigotes was observed. As the adenylate cyclase/cAMP pathway would be involved in the parasite–host interiorization, the PKA activity may constitute a good intracellular target for studies of leishmanicidal drugs. Copyright © 2004 John Wiley & Sons, Ltd.
Influence of diadenosine tetraphosphate (Ap4A) on lipid metabolism
Authors: Rüsing D. , Verspohl E. J.
Published: June 2004

Diadenosine polyphosphates (ApxA) are physiologically released and may be partly involved in the pathogenesis of diabetes mellitus. Ap4A (diadenosine tetraphosphate) leads to an increase in blood glucose while it decreases insulin levels in plasma. A possible link between ApxA and diabetes mellitus‐associated diseases such as insulin resistance and hyperlipidemia (plasma free fatty acids, cholesterol and its biosynthesis, triacylglycerols) has not been investigated yet. Parameters such as free fatty acid and cholesterol content in blood were determined enzymically. The biosynthesis of cholesterol and triacylglycerols was determined in HepG2 cells using the radioactive precursor [14C]‐acetate and by using gas chromatography. Plasma free fatty acids were significantly decreased 5 and 10 min after an Ap4A bolus (0.75 mg kg−1 b.w.) given to rats. Plasma cholesterol was reduced 5 and 60 min after Ap4A administration. LPDS (lipoprotein‐deficient serum)‐stimulated cholesterol biosynthesis in HepG2 cells was significantly reduced after 1 h incubation with Ap4A. Triacylglycerol (TAG) biosynthesis in HepG2 cells was not significantly influenced by Ap4A; there was just a tendency for a concentration‐dependent decrease in TAG levels. In conclusion Ap4A as a diabetogenetic compound is not likely to be responsible for the development of insulin resistance or of hyperlipidemia. Parameters such as free fatty acids, cholesterol and triacylglycerols are not elevated by Ap4A, but are even decreased. Ap4A seems to be involved in the development of diabetes mellitus by increasing blood glucose and decreasing plasma insulin as shown earlier, but not in diabetes mellitus‐associated diseases such as insulin resistance or hyperlipidemia. Copyright © 2004 John Wiley & Sons, Ltd.
HCV infective virions can be carried by human platelets
Authors: Pugliese A. , Gennero L. , Cutufia M. , Enrietto M. , Morra E. , Pescarmona P. , Ponzetto A.
Published: June 2004

It has been previously demonstrated that platelets (PLTs) can bind and transport HIV‐1 infectious virions. Hepatitis C virus (HCV)–HIV‐1 co‐infection occurs frequently among users of illicit intravenous drugs, thereby increasing the severity of HIV disease and the evolution towards chronic active hepatitis and hepatocellular carcinoma of HCV‐related hepatitis. In the present study we investigated whether or not PLTs can carry HCV, and studied the binding mechanisms. Purified PLTs, obtained from healthy donors, HCV negative and HIV negative, were adsorbed with HCV‐containing serum and then employed to infect a THP‐1 monocytoid cell line. Replication of HCV was observed as shown by positivity for the E2 antigen within THP‐1 cells, by indirect immunofluorescence; moreover, HCV‐RNA was detected in supernatants of THP‐1 cells at day 7 post‐incubation with HCV‐adsorbed PLTs. The binding of HCV to PLTs seems to involve fibronectin (FN), as already shown in the case of HIV‐1. Indeed, treatment with RGD (Gly‐Arg‐Gly‐Asp‐Ser), the key oligopeptide of FN binding, inhibits the ability of HCV to be carried by PLTs in infective forms; the same phenomenon occurs with Mabs to FN. Moreover the infection of THP‐1 cells seems to increase FN surface expression, as demonstrated by immunofluorescence tests. Copyright © 2004 John Wiley & Sons, Ltd.
Tartrate‐resistant acid phosphatase: a potential target for therapeutic gold
Authors: Hayman Alison R. , Cox Timothy M.
Published: June 2004

Gold compounds are disease‐modifying agents for the treatment of rheumatoid arthritis. They act on the immune system but the mechanism is not fully understood. Gold has been shown to affect antigen processing by T‐cells and also reduces expression of cytokines in macrophages. Tartrate‐resistant acid phosphatase (TRAP), expressed by osteoclasts, macrophages and dendritic cells is an enzyme with roles in skeletal metabolism and the immune response. TRAP is able to degrade skeletal phosphoproteins including osteopontin, identical to the T‐cell cytokine, Eta‐1; we thus propose that TRAP regulates the Eta‐1 pathway common to the immune system and skeleton. We compared the distribution of osteopontin and TRAP in sections of 18‐day‐old embryonic mice by immunohistochemistry. Both proteins occurred in the same locations. To determine whether gold compounds exert their effects by modification of TRAP activity, we examined the action of gold chloride and the prodrugs, aurothioglucose and aurothiomalate on the dephosphorylation of osteopontin by TRAP. Aurothioglucose and aurothiomalate had little effect on phosphatase activity; gold chloride was a potent non‐competitive inhibitor (Ki < 47 × 10−9 M). These findings indicate a possible molecular mechanism for the action of therapeutic gold and further implicate TRAP in the control of immunity. Copyright © 2004 John Wiley & Sons, Ltd.
Vibrational and Quantum‐Chemical Study of Nonlinear Optical Chromophores Containing Dithienothiophene as the Electron Relay
Authors: Casado Juan , Hernández Víctor , Kim Oh‐Kil , Lehn Jean‐Marie , López Navarrete Juan T. , Delgado Ledesma Salvador , Ponce Ortiz Rocío , Ruiz Delgado Mari Carmen , Vida Yolanda , Pérez‐Inestrosa E.
Published: June 2004

A series of nonlinear optical (NLO) donor–acceptor (D–A) chromophores containing a fused terthiophene, namely dithienothiophene (DTT), as the electron relay, the same donor group, and acceptors of various strengths, has been investigated by means of infrared and Raman spectroscopies, both in the solid state as well as in a variety of solvents, to evaluate the effectiveness of the intramolecular charge transfer from the electron‐donor to the electron‐acceptor end groups. The Raman spectral profiles of these NLO‐phores measured from their dilute solutions have been found to be rather similar to those of the corresponding solids, and thus their intramolecular charge transfer (ICT) shows very little dependence on the solvent polarity. The experimental results obtained for the DTT‐containing NLO‐phore with a 4‐(N,N‐dibutylamino)styryl end group as the donor and a 2,2‐dicyanoethen‐1‐yl end group as the acceptor differ from those previously obtained for two parent “push–pull” chromophores with the same D–A pair but built‐up around either a bis(3,4‐ethylenedioxythienyl) (BEDOT) or a bithienyl (BT) electron relay. Vibrational spectroscopy shows that DTT is significantly more efficient as an electron relay than BT (which has the same number of conjugated CC bonds) or BEDOT (which can be viewed as a rigidified version of BT on account of noncovalent intramolecular interactions between heteroatoms of adjacent rings). Density functional theory (DFT) calculations have also been performed on these NLO‐phores to assign their main electronic and vibrational features and to obtain information about their structures. An additional merit of these molecular materials was revealed by the infrared spectra of the DTT‐based NLO‐phores recorded at different temperatures. Thus, spectra recorded between −170 and 150 °C did not show any substantial change, indicating that the materials have a high thermal stability, which is of significance for their use as active components in optoelectronic devices.
Toward a 6π+6π Zwitterion or a Bioinhibitors‐Related OH‐Substituted Aminoquinone: Identification of a Key Intermediate in Their pH Controlled Synthesis
Authors: Braunstein Pierre , Siri Olivier , Taquet Jean‐philippe , Yang Qing‐Zheng
Published: June 2004

Their pH‐controlled reactivity places the N,N′‐dialkyl‐2‐amino‐5‐lithium alcoholate‐1,4‐benzoquinonemonoimines [C6H2(NHCH2R′) (NCH2R′)(O)(OLi)] 7 (R′=tBu) and 8 (R′=p‐C6H4‐tBu) at the crossroads of a new versatile strategy for the preparation of two very different classes of substituted quinones. We describe new 2‐(N‐alkyl)amino‐5‐hydroxy‐1,4‐benzoquinones, which are parent molecules to biologically active substituted aminobenzoquinones, for which changes of the N‐substituent will become readily possible. The results of the first X‐ray structural determination of such compounds ([C6H2(NHCH2tBu)(OH)(O)2] 13) are also reported and we compare the influence of the number of N‐substituents of the C6 ring on the supramolecular networks resulting from self‐assembling of 13, zwitterionic N,N′‐dineopentyl‐2‐amino‐5‐alcoholate‐1,4‐benzoquinonemonoiminium [C6H2(${^{\underline{.....}}}$NHCH2tBu)2(${^{\underline{.....}}}$O)2] 9 and N,N′,N′′,N′′′‐tetraneopentyl‐2,5‐diamino‐1,4‐benzoquinone diimine [C6H2(NHCH2tBu)2(NCH2tBu)2] 15.
Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy
Authors: Krupski Tracey L. , Smith Matthew R. , Chan Lee Won , Pashos Chris L. , Brandman Jane , Wang Qin , Botteman Marc , Litwin Mark S.
Published: June 2004

BACKGROUND

As evidence accumulates in favor of androgen deprivation therapy (ADT) in patients with recurrent or metastatic prostate carcinoma, concern has increased regarding bone loss associated with therapeutic hypogonadism. The current study described the natural history of bone complications in men with prostate carcinoma who have initiated ADT.

METHODS

Using 1992–2001 claims data from a 5% national random sample of Medicare beneficiaries, the authors identified men with prostate carcinoma who initiated ADT between 1992 and 1994. They analyzed inpatient, outpatient, and physician claims for bone complications over 7 subsequent years. They stratified the quartile of patients who survived longest into 2 cohorts: those who had received ADT for longer than and those who had received ADT for shorter than the median of 697 days. They evaluated the cumulative proportions of patients in each cohort with claims for pathologic fractures, osteoporosis/osteopenia, and nonpathologic fractures.

RESULTS

In the 1992–1994 sample, 4494 men with prostate carcinoma initiated ADT. Of these, 1126 survived > 2028 days (5.5 years). During the first 3 years of evaluation, the proportion of bone events was similar for men with shorter durations of ADT and men with longer durations of ADT. However, by 7 years, more men in the longer ADT cohort (45%) had sustained at least 1 pathologic or nonpathologic fracture compared with men in the shorter ADT cohort (40%).

CONCLUSIONS

In the current study, men with prostate carcinoma were found to be at risk for adverse bone effects from both the disease and the treatment. These longitudinal data revealed that fractures are common in this patient population and appear to be linked to the duration of ADT. Cancer 2004. © 2004 American Cancer Society.