bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration in the ubiquitin structure and function in the human lens: a possible mechanism of senile cataractogenesis
Authors: Stiuso P , Libondi T , Facchiano A.M , Colicchio P , Ferranti P , Lilla S , Colonna G
Published: November 2002

High‐performance liquid chromatography purification followed by mass spectrometry analyses highlighted that human senile cataractous lens includes a 8182 Da species which is absent in the normal lens, whereas a 8566/8583 Da species is present in both lenses. Western blot analysis identified both species as ubiquitin. The species at lower molecular weight is a shorter form due to the cleavage of the C‐terminal residues 73–76. As it is the last amino acid of ubiquitin which is involved in the protein degradation mechanism, we suggest that this structure modification compromises the function of ubiquitin and consequently the physiologically occurring degradation of the lens proteins.
GluR2 ligand‐binding core complexes: importance of the isoxazolol moiety and 5‐substituent for the binding mode of AMPA‐type agonists
Authors: Kasper C , Lunn M.-L , Liljefors T , Gouaux E , Egebjerg J , Kastrup J.S
Published: November 2002

X‐ray structures of the GluR2 ligand‐binding core in complex with (S)‐Des‐Me‐AMPA and in the presence and absence of zinc ions have been determined. (S)‐Des‐Me‐AMPA, which is devoid of a substituent in the 5‐position of the isoxazolol ring, only has limited interactions with the partly hydrophobic pocket of the ligand‐binding site, and adopts an AMPA‐like binding mode. The structures, in comparison with other agonist complex structures, disclose the relative importance of the isoxazolol ring and of the substituent in the 5‐position for the mode of binding. A relationship appears to exist between the extent of interaction of the ligand with the hydrophobic pocket and the affinity of the ligand.
A heat‐activated MAP kinase in tomato: a possible regulator of the heat stress response
Authors: Link Vinzenz , Sinha Alok K , Vashista Pooja , Hofmann Markus G , Proels Reinhard K , Ehness Rainer , Roitsch Thomas
Published: November 2002

Adaptation to elevated temperatures is of major importance for the survival of plants. The role of kinases in heat stress response was studied in tomato by in gel and in solution kinase assays using myelin basic protein as substrate. The application of heat stress in a naturally occurring temperature range resulted in a fast and transient activation of a 50 kDa mitogen‐activated protein (MAP) kinase both in a photoautotrophic cell suspension culture and in leaves of mature plants. The heat activation of the MAP kinase was shown to be calcium‐dependent. The specific phosphorylation of tomato heat stress transcription factor HsfA3 by a partially purified preparation of the heat‐activated MAP kinase supports a physiological role of the identified kinase activity in transducing the heat stress signal.
Evidence of a trimolecular complex involving LPS, LPS binding protein and soluble CD14 as an effector of LPS response
Authors: Thomas Celestine J , Kapoor Mili , Sharma Shilpi , Bausinger Huguette , Zyilan Umit , Lipsker Dan , Hanau Daniel , Surolia Avadhesha
Published: November 2002

The kinetics of the interaction of lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP) and CD14 was studied using surface plasmon resonance. The association and dissociation rate constants for the binding of LPS and rsCD14 were 2.9×104 M−1 s−1 and 0.07 s−1 respectively, yielding a binding constant of 4.2×105 M−1. Significantly, the presence of LBP increased not only the association rate but also the association constant for the interaction between LPS and CD14 by three orders of magnitude. Our experimental results suggest that LBP interacts with LPS and CD14 to form a stable trimolecular complex that has significant functional implications as it allows monocytes to detect the presence of LPS at a concentration as low as 10 pg/ml or 2 pM, and to respond by secreting interleukin‐6. Thus, LBP is not merely transferring LPS to CD14 but it forms an integral part of the LPS–rLBP–rsCD14 complex.
Cleavage of a DNA–RNA–DNA/DNA chimeric substrate containing a single ribonucleotide at the DNA–RNA junction with prokaryotic RNases HII
Authors: Haruki Mitsuru , Tsunaka Yasuo , Morikawa Masaaki , Kanaya Shigenori
Published: November 2002

We have analyzed the cleavage specificities of various prokaryotic Type 2 ribonucleases H (RNases H) on chimeric DNA–RNA–DNA/DNA substrates containing one to four ribonucleotides. RNases HII from Bacillus subtilis and Thermococcus kodakaraensis cleaved all of these substrates to produce a DNA segment with a 5′‐monoribonucleotide. Consequently, these enzymes cleaved even the chimeric substrate containing a single ribonucleotide at the DNA–RNA junction (5′‐side of the single ribonucleotide). In contrast, Escherichia coli RNase HI and B. subtilis RNase HIII did not cleave the chimeric substrate containing a single ribonucleotide. These results suggest that bacterial and archaeal RNases HII are involved in excision of a single ribonucleotide misincorporated into DNA.
Abundance of the RSC nucleosome‐remodeling complex is important for the cells to tolerate DNA damage in Saccharomyces cerevisiae
Authors: Koyama Hirofumi , Itoh Masayuki , Miyahara Kohji , Tsuchiya Eiko
Published: November 2002

The essential Nps1p/Sth1p is a catalytic subunit of the nucleosome‐remodeling complex, RSC, of Saccharomyces cerevisiae that can alter nucleosome structure by using the energy of ATP hydrolysis. Besides the ATPase domain, Nps1p harbors the bromodomain, of which the function(s) have not yet been defined. We have isolated a temperature‐sensitive mutant allele of NPS1, nps1‐13, which has amino acid substitutions within the bromodomain. This mutation perturbed the interaction between the RSC components and enhanced the sensitivity of the cells to several DNA‐damaging treatments at the permissive temperature. Reduced expression of NPS1 also caused DNA damage sensitivity. These results suggest the importance of the Nps1p bromodomain in RSC integrity and a model in which high amounts of RSC would be required for the cells to overcome DNA damage.
If space is provided, bulky modification on the rim of Azurin's β‐barrel results in folded protein
Authors: Pozdnyakova Irina , Wittung-Stafshede Pernilla
Published: November 2002

Pseudomonas aeruginosa azurin is a blue‐copper protein with a β‐barrel fold. Here we report that, at conditions where thermal unfolding of apo‐azurin is reversible, the reaction occurs in a single step with a transition midpoint (T
m) of 69°C (pH 7). The active‐site mutation His117Gly creates a cavity in the β‐barrel near the surface but does not perturb the overall fold (T
m of 64°C, pH 7). Oxidation of the active‐site cysteine (Cysteine‐112) in wild‐type azurin, which occurs readily at higher temperatures, results in a modified protein that cannot adopt a native‐like structure. In sharp contrast, Cysteine‐112 oxidation in His117Gly azurin yields a modified apo‐azurin that appears folded and displays cooperative, reversible unfolding (T
m∼55°C, pH 7). We conclude that azurin's β‐barrel is a rigid structural element that constrains the structure of its surface; a bulky modification can only be accommodated if complementary space is provided.
Zonal distribution of glycogen synthesis in isolated rat hepatocytes
Authors: Fernández-Novell Josep M , López-Iglesias Carmen , Ferrer Juan C , Guinovart Joan J
Published: November 2002

Incubation of hepatocytes isolated from fasted rats with [14C]glucose for short periods of time showed that the initial stages of glycogen synthesis occur near the plasma membrane. Incubation with [14C]glucose followed by cold glucose demonstrated that glycogen synthesis is always active at the hepatocyte periphery and that previously synthesised glycogen moves towards the centre of the cell, while its place is filled by newly synthesised molecules. However, the reverse experiment, incubation with cold glucose before addition of [14C]glucose, showed that, as glycogen synthesis progresses, it also becomes gradually active in more internal sites of the hepatocyte. These results indicate a spatial order in the synthesis of hepatic glycogen.
Regulation of the frontocortical sodium pump by Na+ in Alzheimer's disease: difference from the age‐matched control but similarity to the rat model
Authors: Kairane Czeslava , Roots Kristiina , Uusma Tanel , Bogdanovic Nenad , Karelson Ello , Kõks Sulev , Zilmer Mihkel
Published: November 2002

The Na+ and K+ dependence of the frontocortical Na,K‐ATPase in Alzheimer's disease (AD) was compared with that in human control (Co) and rat AD model. In AD, the relationship between the Na/K ratio and the Na,K‐ATPase activity showed noticeable left‐shift with three‐fold increase in the enzyme affinity for Na+ (K
0.5=10 and 30 mM in AD and Co, respectively). The Na+ dependence of the enzyme in AD showed two different Hill coefficients (n
H), 1.1 and 0.3, whereas the Co value of n
H was higher (1.4). The rat AD model generated by ibotenic acid revealed a Na+ dependence similar to AD. The K+ dependence of the Na,K‐ATPase showed no significant difference in AD and Co. Compared with Co, AD produced a shift in the break of the Na,K‐ATPase Arrhenius plot, suggesting remarkable alterations in the enzyme lipid environment. Our findings support the hypothesis that dysfunction of the Na,K‐ATPase in AD is provoked by altered Na+ dependence of the enzyme. An impairment of the pump functionality might serve as an early mechanism of AD that should be interrupted by selective pharmacological agents.
Identification of human Kir2.2 (KCNJ12) gene encoding functional inward rectifier potassium channel in both mammalian cells and Xenopus oocytes
Authors: Kaibara Muneshige , Ishihara Keiko , Doi Yoshiyuki , Hayashi Hideki , Ehara Tsuguhisa , Taniyama Kohtaro
Published: November 2002

Arginine residue at position 285 (R285) in the intracellular C‐terminal domain of inward rectifier potassium channel Kir2.2 is conserved in many species, but missing in previously reported human Kir2.2 sequences. We here identified the human Kir2.2 gene in normal individuals, which contained R285 in the deduced amino‐acid sequence (hKir2.2/R285). All 30 individuals we examined were homozygous for Kir2.2/R285 gene. The hKir2.2/R285 was electrophysiologically functional in both mammalian cells and Xenopus oocytes. However, the hKir2.2 missing R285 was functional only in Xenopus oocytes, but not in mammalian cells. Thus, R285 in Kir2.2 is important for its functional expression in mammalian cells.
Identification of the amino terminal subunit of the glycoprotein of Borna disease virus
Authors: Kiermayer Simone , Kraus Ina , Richt Jürgen A , Garten Wolfgang , Eickmann Markus
Published: November 2002

The only surface membrane glycoprotein of Borna disease virus (BDV) is synthesized as a polypeptide with a molecular mass of 57 kDa and N‐glycosylated to a precursor glycoprotein (GP) of about 94 kDa. It is processed by the cellular protease furin into the C‐terminal membrane‐anchored subunit GP‐C, also known as gp43, and a presumptive N‐terminal subunit GP‐N, that is highly glycosylated and has a molecular mass of about 51 kDa. However, up to now the latter remained undetected in BDV‐infected material. We describe a novel approach to identify glycan masked linear antigenic epitopes. In the present study, GP‐N was identified in BDV‐infected cells by a combination of lectin precipitation, enzymatic deglycosylation on blot and immunochemistry using an N‐terminal specific antiserum. The GP‐N has an apparent molecular mass of 45–50 kDa in its glycosylated form and 27 kDa in its deglycosylated form. N‐glycan analysis revealed that the precursor GP contains only mannose‐rich N‐glycans, whereas GP‐N and GP‐C contain mannose‐rich and complex‐type N‐glycans.
Acidianus ambivalens type‐II NADH dehydrogenase: genetic characterisation and identification of the flavin moiety as FMN
Authors: Bandeiras Tiago M , Salgueiro Carlos , Kletzin Arnulf , Gomes Cláudio M , Teixeira Miguel
Published: November 2002

The thermoacidophilic archaeon Acidianus ambivalens contains a monomeric 47 kDa type‐II NADH dehydrogenase (NDH), which contains a covalently bound flavin. In this work, by a combination of several methods, namely 31P‐nuclear magnetic resonance and fluorescence spectroscopies, it is proven that this enzyme contains covalent FMN, a novelty among this family of enzymes, which were so far thought to mainly have the flavin dinucleotide form. Discrimination between several possible covalent flavin linkages was achieved by spectral and fluorescence experiments, which identified an 8α‐N(1)‐histidylflavin‐type of linkage. Analysis of the gene‐deduced amino acid sequence of type‐II NDH showed no transmembranar helices and allowed the definition of putative dinucleotide and quinone binding motifs. Further, it is suggested that membrane anchoring can be achieved via amphipatic helices.
A split‐ubiquitin‐based assay detects the influence of mutations on the conformational stability of the p53 DNA binding domain in vivo
Authors: Johnsson Nils
Published: November 2002

Many mutations in the human tumor suppressor p53 affect the function of the protein by destabilizing the structure of its DNA binding domain. To monitor the effects of those mutations in vivo the stability of the DNA binding domain of p53 and some of its mutants was investigated with the split‐ubiquitin (split‐Ub) method. The split‐Ub‐derived in vivo data on the relative stability of the mutants roughly correlate with the quantitative data from in vitro denaturation experiments as reported in the literature. A variation of this assay allows visualizing the difference in stability between the wild‐type p53 core and the mutant p53V143A by a simple growth assay.
Selective cyclooxygenase‐2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells
Authors: Yamazaki Ryuta , Kusunoki Natsuko , Matsuzaki Takeshi , Hashimoto Shusuke , Kawai Shinichi
Published: November 2002

Although the influence of selective cyclooxygenase (COX)‐2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the effects of different COX‐2 inhibitors. Celecoxib strongly suppressed the proliferation of COX‐2 expressing HT‐29 cells at 10–40 μM. NS‐398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT‐29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase‐3/7 activation. DNA fragmentation was also increasd in COX‐2 non‐expressing cell lines (SW‐480 and HCT‐116) by exposure to celecoxib for 6–24 h. All six COX‐2 inhibitors suppressed the production of prostaglandin E2 by HT‐29 cells, suggesting that the pro‐apoptotic effect of celecoxib was unrelated to inhibition of COX‐2. Inactivation of Akt might explain the differential pro‐apoptotic effect of these selective COX‐2 inhibitors on colon adenocarcinoma cells.
Regulation of the phosphorylation of elongation factor 2 by MEK‐dependent signalling in adult rat cardiomyocytes
Authors: Wang Lijun , Proud Christopher G
Published: November 2002

The Gq‐coupled agonists phenylephrine and endothelin‐1 each activate protein synthesis in cardiomyocytes as part of the programme that leads to cardiac hypertrophy. Here we show that they each induce the dephosphorylation of elongation factor (eEF) 2, a protein that in its dephosphorylated state mediates the translocation step of elongation. The ability of both agonists to induce dephosphorylation of eEF2 requires signalling via the mTOR and MEK/Erk signalling pathways, but is independent of phosphoinositide 3‐kinase. Expression of an activated form of MEK leads to dephosphorylation of eEF2, in an mTOR independent manner, indicating that signalling via MEK/Erk suffices to cause dephosphorylation of eEF2.
Absence of a conserved proline and presence of a conserved tyrosine in the CB2 cannabinoid receptor are crucial for its function
Authors: Song Z.H , Feng Wenke
Published: November 2002

A majority (84%) of G protein‐coupled receptors have a proline (P5.50) in the middle of the fifth transmembrane domain. However, one of the unique structural features of cannabinoid receptors is the replacement of the conserved P5.50 by a leucine (L5.50). It has been shown that a conserved tyrosine (Y5.58), located at the cytoplasmic side of P5.50, is crucial for the signal transduction of several G protein‐coupled receptors. We proposed that the replacement of P5.50 by L5.50 and the presence of the conserved Y5.58 in this context are important for the function of CB2. Mutating L5.50 to a proline abolished ligand binding, whereas mutating Y5.58 to an alanine resulted in a rightward shift of the competition binding curves. Both of these mutations led to a complete loss of the ability of cannabinoid agonists to inhibit forskolin‐stimulated cAMP accumulation.
Anti‐HIV‐1 property of trichosanthin correlates with its ribosome inactivating activity
Authors: Wang Jian-Hua , Nie Hui-Ling , Tam Siu-Cheung , Huang Hai , Zheng Yong-Tang
Published: November 2002

Trichosanthin (TCS) is a type I ribosome inactivating (RI) protein possessing anti‐tumor and antiviral activity, including human immunodeficiency virus (HIV). The mechanism of these actions is not entirely clear, but is generally attributed to its RI property. In order to study the relationship between the anti‐HIV‐1 activity of TCS and its RI activity, three TCS mutants with different RI activities were constructed by using site‐directed mutagenesis. The anti‐HIV‐1 activities of the three mutants were tested in vitro. Results showed that two TCS mutants, namely TCSM(120–123), TCSE160A/E189A, with the greatest decrease in RI activity, lost almost all of the anti‐HIV activity and cytopathic effect. Another mutant TCSR122G, which exhibited a 160‐fold decrease in RI activity, retained some anti‐HIV activity. The results from this study suggested that RI activity of TCS may have significant contribution to its anti‐HIV‐1 property.
Hetero‐oligomerization of adenosine A1 receptors with P2Y1 receptors in rat brains
Authors: Yoshioka Kazuaki , Hosoda Ritsuko , Kuroda Yoichiro , Nakata Hiroyasu
Published: November 2002

Adenosine and ATP modulate cellular and tissue functions via specific P1 and P2 receptors, respectively. Although, in general, adenosine inhibits excitability and ATP functions as an excitatory transmitter in the central nervous system, little is known about the direct interaction between P1 and P2 receptors. We recently demonstrated that the Gi/o‐coupled adenosine A1 receptor (A1R) and Gq/11‐coupled P2Y1 receptor (P2Y1R) form a heteromeric complex with a unique pharmacology in cotransfected HEK293T cells using the coimmunoprecipitation of differentially epitope‐tagged forms of the receptor [Yoshioka et al. (2001) Proc. Natl. Acad. Sci. USA 98, 7617–7622], although it remained to be determined whether this hetero‐oligomerization occurs in vivo. In the present study, we first demonstrated a high degree of colocalization of A1R and P2Y1R by double immunofluorescence experiments with confocal laser microscopy in rat cortex, hippocampus and cerebellum in addition to primary cultures of cortical neurons. Then, a direct association of A1R with P2Y1R was shown in coimmunoprecipitation studies using membrane extracts from these regions of rat brain. Together, these results suggest the widespread colocalization of A1R and P2Y1R in rat brain, and both receptors can exist in the same neuron, and therefore associate as hetero‐oligomeric complexes in the rat brain.
Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords – screening by molecular indexing and subsequent cDNA microarray analysis
Authors: Ishigaki Shinsuke , Niwa Jun-ichi , Ando Yoshio , Yoshihara Tsuyoshi , Sawada Ko-ichi , Doyu Manabu , Yamamoto Masahiko , Kato Kikuya , Yotsumoto Yoshihisa , Sobue Gen
Published: November 2002

To analyze the genes related to the pathophysiology of sporadic amyotrophic lateral sclerosis (SALS) we performed gene profiling of SALS spinal cords using molecular indexing combined with cDNA microarray. Eighty‐four fragments were cloned in the first screening procedure with molecular indexing. Subsequent quantitative microarray screening revealed 11 genes which were differentially expressed in SALS. Real‐time RT‐PCR verified that the expression level of the following six genes was altered in SALS: dorfin, metallothionein‐3, 30 kDa TATA‐binding protein‐associated factor, neugrin, ubiquitin‐like protein 5 and macrophage‐inhibiting factor‐related protein‐8. These results indicated that genes associated with the ubiquitin–proteasome system, oxidative toxicity, transcription, neuronal differentiation and inflammation might be involved in the pathogenesis of SALS.
Irreversible inactivation of magnesium‐dependent neutral sphingomyelinase 1 (NSM1) by peroxynitrite, a nitric oxide‐derived oxidant
Authors: Josephs Michelle , Katan Matilda , Rodrigues-Lima Fernando
Published: November 2002

Previous results have indicated that the generation of ceramide by hydrolysis of sphingomyelin by magnesium‐dependent neutral sphingomyelinase 1 (NSM1) is reversibly inhibited by hydrogen peroxide (H2O2) and oxidized glutathione (GSSG). This redox‐dependent reversible regulation of NSM1 activity has been shown to involve the reversible formation and breakage of disulfide bonds. In this paper, we show that peroxynitrite, a nitric oxide‐derived oxidant generated by SIN1, inactivates dose‐dependently the NSM1 activity in an irreversible manner. In addition, we show that, in contrast to the reversible inhibition of NSM1 by H2O2 or GSSG which involves the formation of disulfide bonds, irreversible inactivation of this enzyme by peroxynitrite generated from SIN1 is likely due to definitive oxidative thiol modification. These results suggest that depending on the nature of the oxidative stress, the enzymatic activity of NSM1 could be reversibly or irreversibly inactivated.
The stimulation of heart glycolysis by increased workload does not require AMP‐activated protein kinase but a wortmannin‐sensitive mechanism
Authors: Beauloye Christophe , Marsin Anne-Sophie , Bertrand Luc , Vanoverschelde Jean-Louis , Rider Mark H , Hue Louis
Published: November 2002

Increasing heart workload stimulates glycolysis by enhancing glucose transport and fructose‐2,6‐bisphosphate (Fru‐2,6‐P2), the latter resulting from 6‐phosphofructo‐2‐kinase (PFK‐2) activation. Here, we investigated whether adenosine monophosphate (AMP)‐activated protein kinase (AMPK) mediates PFK‐2 activation in hearts submitted to increased workload. When heart work was increased, PFK‐2 activity, Fru‐2,6‐P2 content and glycolysis increased, whereas the AMP:adenosine triphosphate (ATP) and phosphocreatine/creatine (PCr:Cr) ratios, and AMPK activity remained unchanged. Wortmannin, the well‐known phosphatidylinositol‐3‐kinase inhibitor, blocked the activation of protein kinase B and the increase in glycolysis and Fru‐2,6‐P2 content induced by increased work. Therefore, the control of heart glycolysis by contraction differs from that in skeletal muscle where AMPK is involved.
Pyrococcus furiosus ferredoxin is a functional dimer
Authors: Hasan M.N , Hagedoorn P.L , Hagen W.R
Published: November 2002

Pyrococcus furiosus ferredoxin is subject to a monomer/dimer equilibrium as a function of ionic strength. At physiological ionic strength, approximately 0.35 M NaCl, the protein is very predominantly homodimer. The monomeric form exhibits impaired electron transfer on glassy carbon; it also has a decreased S=3/2 over S=1/2 ratio as shown by electron paramagnetic resonance spectroscopy. Even following sterilization at 121°C the dimer is stable in denaturing gel electrophoresis.
Role of the carboxyl terminus on the catalytic activity of protein kinase CK2α subunit
Authors: Tapia Julio , Jacob Germaine , Allende Catherine C , Allende Jorge E
Published: November 2002

Protein kinase CK2 (also known as casein kinase 2) has catalytic (α, α′) and regulatory (β) subunits. The role of carboxyl amino acids in positions from 324 to 328 was studied for Xenopus laevis CK2α. Deletions and mutations of these residues were produced in recombinant CK2α, which was assayed for kinase activity. Activity dropped 7000‐fold upon deletion of amino acids 324–328. The key residues are isoleucine 327 and phenylalanine 324. A three dimensional model of CK2α indicates that these hydrophobic residues of helix αN may interact with hydrophobic residues in helix αE which is linked to the catalytic center.
IRF‐8/ICSBP and IRF‐1 cooperatively stimulate mouse IL‐12 promoter activity in macrophages
Authors: Masumi Atsuko , Tamaoki Satoshi , Wang I-Ming , Ozato Keiko , Komuro Katsutoshi
Published: November 2002

IRF‐8/ICSBP and IRF‐1 are IRF family members whose expression is induced in response to IFN‐γ in macrophages. IL‐12 is a cytokine produced in macrophages that plays a critical role in host defense. IFN‐γ and bacterial lipopolysaccharide (LPS) induce IL‐12p40 transcription, which is necessary for the production of IL‐12. We have previously shown that IL‐12p40 expression is impaired in ICSBP‐deficient mice and that transfection of ICSBP together with IRF‐1 can activate IL‐12p40 expression in mouse macrophage cells. To further study the role of ICSBP and IRF‐1, we investigated murine IL‐12p40 promoter activity in the macrophage cell line RAW 264.7. We show here that co‐transfection of ICSBP and IRF‐1 synergistically stimulates IL‐12 promoter activity to a level comparable to that induced by IFN‐γ/LPS. Mutation of the Ets or NFκB site previously shown to be important for IL‐12p40 transcription did not abolish the activation by ICSBP and IRF‐1. However, mutation of the ISRE‐like site found downstream from the NFκB and C/EBP sites abrogated the activation by ICSBP and IRF‐1. Together, these results indicate that ICSBP and IRF‐1 cooperatively stimulate murine IL‐12 transcription through a novel regulatory element in the murine promoter.
On the continuation of solutions for elliptic equations in two variables
Authors: Müller Frank
Published: November 2002

We consider nonlinear elliptic differential equations of second order in two variables

F(x,y,z(x,y),z_x(x,y),\dots,z_{yy}(x,y))=0

,

(x,y)\in \Omega \subset \mathbb{R}^{2}

. Supposing analyticity of

F

, we prove analyticity of the real solution

z=z(x,y)

in the open set

\Omega

. Furthermore, we show that

z

may be continued as a real analytic solution for

F=0

across the real analytic boundary arc

\Gamma \subset \partial \Omega

, if

z

satisfies one of the boundary conditions

z=\varphi

or

z_{\bm{n}} = \psi (x,y,z,z_{\bm t})

on

\Gamma

with real analytic functions

\varphi

and

\psi

, respectively (

z_{\bm n}

denotes the derivative of

z

w.r.t. the outer normal

\bm n

on

\Gamma

and

z_{\bm t}

its derivative w.r.t. the tangent). The proof is based on ideas of H. Lewy combined with a uniformization method. Studying quasilinear equations, we get somewhat better results concerning the initial regularity of the given solution and a little more insight.

Nous considérons les équations différentielles non-linéaires elliptiques d’ordre deuxième dépendant de deux variables

F(x,y,z(x,y),z_x(x,y),\dots,z_{yy}(x,y))=0

,

(x,y)\in \Omega \subset \mathbb{R}^{2}

. Supposent l’analyticité de

F

, nous démontrons l’analyticité de la solution réelle

z=z(x,y)

dans l’ensemble ouvert

\Omega

. En outre, nous démontrons qu’on peut prolonger

z

comme solution analytique réelle de

F=0

à travers la courbe

\Gamma \subset \partial \Omega

, si

z

vérifie une des conditions aux limites

z=\varphi

or

z_{\bm{n}} = \psi (x,y,z,z_{\bm t})

sur

\Gamma

avec des fonctions analytiques réelles

\varphi

et

\psi

(

z_{\bm n}

designe la dérivée de

z

par rapport à la normale extérieure

\bm n

sur

\Gamma

et

z_{\bm t}

la dérivée de

z

par rapport à la tangente). La démonstration est fondée sur des idées de H. Lewy, combinées avec une méthode d’uniformisation. En regardant des équations quasi-linéaires, nous réalisons des résultats améliorés en ce qui concerne la regularité initiale de la solution donnée et un peu plus de compréhension.
On the linearization of some singular, nonlinear elliptic problems and applications
Authors: Hernández Jesús , Mancebo Francisco J , Vega José M
Published: November 2002

This paper deals with the spectrum of a linear, weighted eigenvalue problem associated with a singular, second order, elliptic operator in a bounded domain, with Dirichlet boundary data. In particular, we analyze the existence and uniqueness of principal eigenvalues. As an application, we extend the usual concepts of linearization and Frechet derivability, and the method of sub and supersolutions to some semilinear, singular elliptic problems.

On étudie le spectre d’un problème à valeurs propres avec poids associé avec un opérateur elliptique singulier d’ordre deux sur un domaine borné avec condition au bord de Dirichlet. En particulier, on considère l’existence et l’unicité des valeurs propres principales. On donne comme application des extensions des notions de linéarisation et différentielle de Fréchet et de la méthode de sous et sursolutions à quelques problèmes elliptiques semilinéaires singuliers.
Convexity estimates for nonlinear elliptic equations and application to free boundary problems
Authors: Dolbeault Jean , Monneau Régis
Published: November 2002

We prove the convexity of the set which is delimited by the free boundary corresponding to a quasi-linear elliptic equation in a 2-dimensional convex domain. The method relies on the study of the curvature of the level lines at the points which realize the maximum of the normal derivative at a given level, for analytic solutions of fully nonlinear elliptic equations. The method also provides an estimate of the gradient in terms of the minimum of the (signed) curvature of the boundary of the domain, which is not necessarily assumed to be convex.

Nous démontrons la convexité de l’ensemble délimité par la frontière libre correspondant à une équation quasi-linéaire elliptique définie sur un domaine convexe en dimension 2. La méthode repose sur l’étude de la courbure des lignes de niveau aux points qui réalisent le maximum de la dérivée normale pour un niveau donné, pour des solutions analytiques d’équations elliptiques complètement non linéaires. La méthode donne aussi une estimation du gradient en fonction du minimum de la courbure (signée) du bord du domaine, qui n’est pas nécessairement supposé convexe.
Uniqueness and stability of regional blow-up in a porous-medium equation
Authors: Cortázar Carmen , del Pino Manuel , Elgueta Manuel
Published: November 2002

We study the blow-up phenomenon for the porous-medium equation in

\mathbf R^N

,

N⩾1

,

u_{t} = \Delta u^{m} + u^{m},

m>1

, for nonnegative, compactly supported initial data. A solution

u(x,t)

to this problem blows-up at a finite time

\bar T > 0

. Our main result asserts that there is a finite number of points

x_1,…,x_k∈\mathbf R^N

, with

\left|x_{i} - x_{j}\right| \geq 2R^*

for

i≠j

, such that

\lim \limits_{t\rightarrow \bar T}\left(\bar T - t\right)^{\frac{1}{m - 1}}u\left(t,x\right) = \sum \limits_{j = 1}^{k}w_{*}\left(\left|x - x_{j}\right|\right).

Here

w_{*}\left(\left|x\right|\right)

is the unique nontrivial, nonnegative compactly supported, radially symmetric solution of the equation

\Delta w^{m} + w^{m} - \frac{1}{m - 1}w = 0

in

\mathbf R^N

and

R^∗

is the radius of its support. Moreover

u(x,t)

remains uniformly bounded up to its blow-up time on compact subsets of

\mathbf {R}^{N}\backslash \bigcup _{j = 1}^{k}\bar B(x_{j},R^*)

. The question becomes reduced to that of proving that the

ω

-limit set in the problem

v_{t} = \Delta v^{m} + v^{m} - \frac{1}{m - 1}v

consists of a single point when its initial condition is nonnegative and compactly supported.

Nous étudions le phénomène d’explosion pour l’équation des milieux poreux dans

\mathbf R^N

,

N⩾1

,

u_{t} = \Delta u^{m} + u^{m},

m>1

, pour une donnée initiale positive ou nulle, à support compact. Une solution

u(x,t)

de ce problème explose en temps fini

\bar T > 0

. Notre principal résultat établit qu’il existe un nombre fini de points

x_1,…,x_k∈\mathbf R^N

, with

\left|x_{i} - x_{j}\right| \geq 2R^*

avec

i≠j

, tels que

\lim \limits_{t\rightarrow \bar T}\left(\bar T - t\right)^{\frac{1}{m - 1}}u\left(t,x\right) = \sum \limits_{j = 1}^{k}w_{*}\left(\left|x - x_{j}\right|\right).

Ici

w_∗(|x|)

est l’unique solution non triviale, positive ou nulle, à support compact et à symétrie radiale de l’équation

\Delta w^{m} + w^{m} - \frac{1}{m - 1}w = 0

dans

\mathbf R^N

et

R^∗

est le rayon de son support. De plus,

u(x,t)

reste uniformément bornée jusqu’à son temps d’explosion sur des sous-ensembles compacts

\mathbf {R}^{N}\backslash \bigcup _{j = 1}^{k}\bar B\left(x_{j},R^*\right)

. La question est ramenée à la démonstration que l’ensemble

ω

-limite du problème

v_{t} = \Delta v^{m} + v^{m} - \frac{1}{m - 1}v

est constitué d’un seul point quand sa donnée initiale est positive ou nulle et à support compact.
Attractors of the reaction-diffusion systems with rapidly oscillating coefficients and their homogenization
Authors: Efendiev M. , Zelik S.
Published: November 2002

The following reaction-diffusion system in spatially non-homogeneous almost-periodic media is considered in a bounded domain

\Omega \subset \mathbb{R}^{3}

:

\partial _{t}u = A_{ɛ}u - f\left(u\right) + g, \qquad u\mid_{\partial \Omega } = 0. \tag{1}

Here

u=(u^1,…,u^k)

is an unknown vector-valued function,

f

is a given nonlinear interaction function and the second order elliptic operator

A_ε

has the following structure:

(A_{ɛ}u)^l = \sum \limits_{i,j = 1}^{3}\partial_{x_i}(a_{ij}^{l}(ɛ^{ - 1}x)\partial _{x_j}u^{l}(x)), \qquad ɛ \ll 1,\ l = 1,2,3,

where

a_{ij}^l(y)

are given almost-periodic functions. We prove that, under natural assumptions on the nonlinear term

f(u)

, the longtime behavior of solutions of (1) can be described in terms of the global attractor

\mathcal{A}^{ɛ}

of the associated dynamical system and that the attractors

\mathcal{A}^{ɛ}

,

0<ε<ε_0⪡1

, converge to the attractor

\mathcal{A}^{0}

of the homogenized problem (1) as

ε→0

. Moreover, in the particular case of periodic media, we give explicit estimates for the distance between the non-homogenized

\mathcal{A}^{ɛ}

and the homogenized

\mathcal{A}^{0}

attractors in terms of the parameter 

ε

.

Nous considérons le systéme de réaction-diffusion suivant dans un milieu non homogéne presque périodique en espace dans un domaine borné

\Omega \subset \mathbb{R}^{3}

:

\partial _{t}u = A_{ɛ}u - f\left(u\right) + g, \qquad u\mid_{\partial \Omega } = 0. \tag{1}

Ici,

u=(u^1,…,u^k)

est une fonction vectorielle inconnue,

f

est une fonction d’interaction nonlinéaire donnée et l’opérateur elliptique du second ordre

A_ε

a la structure suivante :

(A_{ɛ}u)^l = \sum \limits_{i,j = 1}^{3}\partial_{x_i}(a_{ij}^{l}(ɛ^{ - 1}x)\partial _{x_j}u^{l}(x)), \qquad ɛ \ll 1,\ l = 1,2,3,

oú les

a_{ij}^l(y)

sont des fonctions presque périodiques données. Nous prouvons que, sous des hypothéses naturelles sur le term nonlinéaire

f(u)

, le comportement asymptotique des solutions de (1) peut etre décrit par l’attracteur global

\mathcal{A}^{ɛ}

du systéme dynamique associé et que les attracteurs

\mathcal{A}^{ɛ}

,

0<ε<ε_0⪡1

, convergent vers l’attracteur

\mathcal{A}^{0}

du probléme homogénéisé de (1) lorsque

ε→0

. De pluis, dans le cas particulier d’un milieu périodique, nous donnons des estimations explicites de la distance entre les attracteur non homogénéisés

\mathcal{A}^{ɛ}

et l’attracteur homogénéisé

\mathcal{A}^{0}

en fonction du paramétre 

ε

.
Short-term safety profile of zolpidem: objective measures of cognitive effects
Authors: DeClerk AC , Bisserbe JC
Published: November 2002

The potential effects of zolpidem, a non-benzodiazepine hypnotic, on cognitive and psychomotor functions have been explored in more than 30 placebo controlled studies, and in many cases in comparison with benzodiazepine reference hypnotics (ie flunitrazepam, nitrazepam, triazolam). Daytime impact of drug administration on alertness has been studied with the Multiple Sleep Latency Test, and no significant clinical impairment has been found after zolpidem 5 to 10 mg, unlike benzodiazepines. Evaluation of the effects of zolpidem on attention and psychomotor skills (critical flicker fusion threshold, substitution or copying tests, choice reaction times or driving tests, etc) indicate that zolpidem at recommended doses (5 mg in elderly and 10 mg in adults) is unlikely to produce significant detrimental residual effects on daytime vigilance, concentration and coordination performances on the morning after intake. In accordance with its pharmacokinetic and pharmacodynamic properties, the effects on zolpidem on memory functions were limited to the first hours after administration and no significant difference was observed between zolpidem (5–10 mg) and placebo 6 hours after administration; longer memory impairment was observed with flunitrazepam or triazolam. Various groups of subjects were included in these studies, both young adults and elderly subjects, healthy volunteers and insomniac patients, and duration of treatment varied between one single dose and 28 days of repeated intake. In conclusion, experimental evidence demonstrates a satisfactory safety profile of zolpidem (5–10 mg) on daytime cognitive functions as compared to other hypnotics.
Public health impact and treatment of insomnia
Authors: Dement WC , Pelayo R
Published: November 2002

A growing number of people are concerned about their sleep in the United States. There are an estimated 40 million US citizens with chronic sleep disorders. The cost to society of sleep disorders has been estimated at greater than $90 billion US dollars. Despite this enormous cost to society, there remains a pervasive lack of attention provided to medical management of this problem. This is compounded by inadequate funding of sleep disorders research. There are treatments available to improve insomnia. These include different behavioral and pharmacologic regimes that can be used separately or in combination. Successful treatment requires thorough knowledge of the differential diagnosis of insomnia. The greatest public health challenge in the management of insomnia is how to develop effective educational programs that will allow the general public to improve their sleep. This will require greater cooperation from primary care providers and the government. Sleep disorders are the most important public health problem not being addressed in the United States.
The socio-economics of insomnia: the materials and the methods
Authors: Stoller MK
Published: November 2002

Insomnia affects about one-third of the population, and is associated with increased morbidity and mortality, reduced production and higher rates of accidents. This suggests that insomnia may burden society with significant cost. However, a precise economic analysis of insomnia is a challenge. Insomnia is part of a very complex interplay of physical and psychological illness, functioning both as a cause and as a consequence. In this paper, some of the methodological issues related to an economic analysis of insomnia are discussed. Data is presented using an economic analysis as an organizer, thus illustrating what conclusions can be drawn, and where further research is needed.
Self-mutilating behaviour of psychiatric inpatients
Authors: Nijman H.L.I. , Dautzenberg M. , Merckelbach H.L.G.J. , Jung P. , Wessel I. , à Campo J.
Published: November 2002

In the present study two broad hypotheses about the origins of self-mutilation in psychiatric patients were evaluated. The first hypothesis states that self-mutilation originates from child abuse and experiences of neglect and is connected to dissociation in later life. The second hypothesis views self-mutilation as the consequence of impulse control problems. To test these two hypotheses, data concerning traumatic childhood experiences and dissociative symptoms (hypothesis 1), as well as data concerning aggressiveness, obsessive-compulsiveness and sensation seeking (hypothesis 2) were collected in a sample of 54 psychiatric inpatients. Twenty-four out of 54 patients (44%) reported having engaged in self-mutilation. Mean age of onset of this behaviour was 23 years. Self-report measures of self-mutilators were more in line with the first than with the second hypothesis. That is, patients who engaged in self-mutilation reported more traumatic childhood experiences and dissociative symptoms than did control patients. The two groups did not differ in terms of aggressiveness, obsessive-compulsiveness, and sensation seeking. In line with earlier studies, the current results indicate that self-mutilating behaviour is linked to a history of abuse and neglect.
Decreased frontal activation in schizophrenics during stimulation with the Continuous Performance Test - a functional magnetic resonance imaging study
Authors: Volz H.-P. , Gaser C. , Häger F. , Rzanny R. , Pönisch J. , Mentzel H.-J. , Kaiser W.A. , Sauer H.
Published: November 2002

The Continuous Performance Test (CPT) has become an essential constituent of the neuropsychological investigation of schizophrenia. Also, a vast number of brain imaging studies, mostly PET investigations, have employed the CPT as a cognitive challenge and established a relative hypofrontality in schizophrenics compared to controls. The aim of the present investigation was to clarify whether this predescribed hypofrontality could also be verified using functional magnetic resonance imaging (fMRI). 20 healthy volunteers and 14 schizophrenics on stable neuroleptic medication were included. Imaging was performed using the CPT-double-T-version and a clinical 1.5 T MRI-scanner with a single slice technique and a T2*-weighted gradient-echo-sequence. The schizophrenics exhibited a decreased activation in the right mesial prefrontal cortex, the right cingulate and the left thalamus compared to controls. These results obtained by fMRI are discussed in relation to published findings using PET.
Anxiolytic and hypnotic use in 376 psychiatric inpatients
Authors: Hardy P. , Payan C. , Bisserbe J.C. , Lepine J.P. ,   GERMED Neuropsychotropics Group
Published: November 2002

This objectives of this study were three-fold: retrospectively evaluate anxiolytic/hypnotic consumption by psychiatric inpatients, identify the risk factors of prolonged intakes, and prospectively measure the impact of hospitalisation on the use of those drugs. Three hundred and seventy-six patients hospitalised in 11 psychiatric departments in the Paris region were studied using a structured interview for the anxiolytic/hypnotic treatments, DSM-III-R criteria, GHQ-12, HAD, Spiegel's questionnaire, COVI's anxiety scale and the CGI. Eighty-five per cent of the patients had taken one anxiolytic/hypnotic or more in the 3 months preceding hospitalisation. Hospitalisation induced little change in anxiolytic/hypnotic use: dosage frequency increased from 77% to 84% between the week preceding hospitalisation and that preceding discharge; 26% of consumers were taking at least two anxiolytics or two hypnotics in the first period vs. 23% in the second. The absence of withdrawal during hospitalisation was related to the high age and a diagnosis of depression rather than schizophrenia, to the existence of continuous intake over the 3 months preceding hospitalisation and to higher drug doses during the 7 days preceding hospitalisation. Prescription of treatment at the end of hospitalisation in previously non-user subjects was related to a higher HAD anxiety score at discharge.
Polypharmacy in psychiatric treatment. Patterns of psychotropic drug use in Austrian psychiatric clinics
Authors: Rittmannsberger H. , Meise U. , Schauflinger K. , Horvath E. , Donat H. , Hinterhuber H.
Published: November 2002

There are great variations in the way psychotropic drugs are prescribed. Most experts are in favour of psychopharmacological monotherapy, but little is known about the extent to which it is actually practised. A survey of the psychopharmacological medication of all patients under treatment was carried out in three Austrian psychiatric clinics of various types on two separate days. A psychiatric university clinic, the psychiatric department of a general hospital and a regional mental hospital were selected for the survey.

It was established that only 8% to 22% of the patients underwent psycho-pharmacological monotherapy and that the patients received 2.2 to 3.3 psychotropics on average. Five to 22% of the patients received five or more psychotropic agents. The results are presented in more detail in relation to the diagnoses of schizophrenia and depression.

The rare occurence of monotherapy might be due to unsound treatment regimens in some instances, but much more to a general trend in psychiatry fostering polydrug use.
A double-blind comparison of sertraline and fluoxetine in the treatment of major depressive episode in outpatients
Authors: Sechter D. , Troy S. , Paternetti S. , Boyer P.
Published: November 2002

Depression is associated with considerable morbidity and mortality. As depressive disorders carry a high risk of relapse, treatment strategies include the use of a 6-month continuation period after resolution of the acute episode. Tolerability is of major importance when determining compliance and outcome during long-term therapy. Due to the superior tolerability profile of the selective serotonin reuptake inhibitors (SSRIs) over the older tricyclic antidepressants (TCAs), the former may be more suitable for extended therapy. Comparative studies have not shown differences between the SSRIs in terms of efficacy, but side-effect profiles may vary. A multicenter, double-blind, comparative study of sertraline and fluoxetine was carried out in outpatients fulfilling DSM-III-R criteria for major depressive disorder. Patients were randomised to receive sertraline (50—150 mg, n = 118) or fluoxetine (20—60 mg, n = 120) for 24 weeks. Assessments for depression (HAM-D, HAD, CGI-I, CGI-S), anxiety (Covi), sleep (Leeds Sleep Evaluation scale) and quality of life (SIP) were made at study entry and at weeks 2, 4, 8, 12, 18 and 24. All adverse events were recorded to allow evaluation of tolerability. In total, 88 patients in the sertraline group completed the study compared with 79 in the fluoxetine group. Side effects were responsible for the premature treatment withdrawal of seven (6%) sertraline patients and 12 (10%) fluoxetine patients. Two-hundred and thirty-four patients were included in an ITT analysis up to last visit (116 sertraline, 118 fluoxetine). At study endpoint, both treatments produced a significant improvement over baseline on all efficacy variables (P < 0.001). Although the magnitude of global changes in depression, anxiety, and quality of life was larger with sertraline than fluoxetine, none of the between-group differences reached statistical significance. However, significant differences in favour of sertraline were observed for individual HAM-D items including item 4 (insomnia onset) (P = 0.04), item 9 (agitation) (P = 0.02), and item 13 (general somatic symptoms) (P = 0.008). In addition, sertraline was associated with significantly superior performance on the Leeds Sleep Evaluation scale and on SIP items relating to sleep and rest, emotional behaviour and ambulation. Both sertraline and fluoxetine were well tolerated with no significant differences between treatments.
Stages of adjustment to a medical diagnosis of a serious somatic condition
Authors: Mekarski J.E.
Published: November 2002

Diagnosis of a serious somatic condition may precipitate a seven stage coping process: shock, denial, procrastination, bargaining, depression, anger and adaptation. Psychometric/statistical methods for operationalizing the stages are suggested.