bluuebunny/crossref_metadata_2025 huggingface dataset:
Linguistic diversity of the Americas can be reconciled with a recent colonization
Authors: Nettle Daniel
Published: July 2002

The Americas harbor a very great diversity of indigenous language stocks, many more than are found in any other continent. J. Nichols [(1990)Language66, 475–521] has argued that this diversity indicates a great time depth ofin situevolution. She thus infers that the colonization of the Americas must have begun around 35,000 years ago. This estimate is much earlier than the date for which there is strong archaeological support, which does not much exceed 12,000 years. Nichols’ assumption is that the diversity of linguistic stocks increases linearly with time. This paper compares the major continents of the world to show that this assumption is not correct. In fact, stock diversity is highest in the Americas, which are by consensus the youngest continents, intermediate in Australia and New Guinea, and lowest in Africa and Eurasia where the time depth is greatest. If anything, then, after an initial radiation, stock diversity decreases with time. A simple model is outlined that predicts these dynamics. It assumes that early in the peopling of continents, there are many unfilled niches for communities to live in, and so fissioning into new lineages is frequent. As the habitat is filled up, the rate of fissioning declines and lineage extinction becomes the dominant evolutionary force.
Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression
Authors: Wysk Mark , Yang Derek D. , Lu Hong-Tao , Flavell Richard A. , Davis Roger J.
Published: July 2002

The p38 mitogen-activated protein kinase is activated by treatment of cells with cytokines and by exposure to environmental stress. The effects of these stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6. We have examined the function of the p38 MAP kinase signaling pathway by investigating the effect of targeted disruption of the
Mkk3
gene. Here we report that
Mkk3
gene disruption caused a selective defect in the response of fibroblasts to the proinflammatory cytokine tumor necrosis factor, including reduced p38 MAP kinase activation and cytokine expression. These data demonstrate that the MKK3 protein kinase is a critical component of a tumor necrosis factor-stimulated signaling pathway that causes increased expression of inflammatory cytokines.
A first-generation packaging cell line for Epstein–Barr virus-derived vectors
Authors: Delecluse Henri-Jacques , Pich Dagmar , Hilsendegen Tanja , Baum Christopher , Hammerschmidt Wolfgang
Published: July 2002

On the basis of the B lymphotropic Epstein–Barr virus (EBV), we have constructed a virus-free packaging cell line that allows encapsidation of plasmids into herpesvirus particles. This cell line harbors an EBV mutant whose packaging signals have been deleted. The gene vectors, which can encompass very large, contiguous pieces of foreign DNA, carry all cis-acting elements involved in amplification and encapsidation into virus-like particles as well as those essential for extrachromosomal maintenance in the recipient cell. Although this first-generation packaging cell line suffers from unwanted recombination between the helper virus genome and gene vector DNAs, this approach opens the way to delivery and stable maintenance of any transgene in human B cells.
Mach bands as empirically derived associations
Authors: Lotto R. Beau , Williams S. Mark , Purves Dale
Published: July 2002

If Mach bands arise as an empirical consequence of real-world
luminance profiles, several predictions follow. First, the appearance
of Mach bands should accord with the appearance of naturally occurring
highlights and lowlights. Second, altering the slope of an ambiguous
luminance gradient so that it corresponds more closely to gradients
that are typically adorned with luminance maxima and minima in the
position of Mach bands should enhance the illusion. Third, altering a
luminance gradient so that it corresponds more closely to gradients
that normally lack luminance maxima and minima in the position of Mach
bands should diminish the salience of the illusion. Fourth, the
perception of Mach bands elicited by the same luminance gradient should
be changed by contextual cues that indicate whether the gradient is
more or less likely to signify a curved or a flat surface. Because each
of these predictions is met, we conclude that Mach bands arise because
the association elicited by the stimulus (the percept) incorporates
these features as a result of past experience.
Treatment of
Mycobacterium tuberculosis
with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-
l
-glutamate/glutamine cell wall structure, and bacterial replication
Authors: Harth Günter , Zamecnik Paul C. , Tang Jin-Yan , Tabatadze David , Horwitz Marcus A.
Published: July 2002

New antibiotics to combat the emerging pandemic of drug-resistant strains of
Mycobacterium tuberculosis
are urgently needed. We have investigated the effects on
M. tuberculosis
of phosphorothioate-modified antisense oligodeoxyribonucleotides (PS-ODNs) against the mRNA of glutamine synthetase, an enzyme whose export is associated with pathogenicity and with the formation of a poly-
l
-glutamate/glutamine cell wall structure. Treatment of virulent
M. tuberculosis
with 10 μM antisense PS-ODNs reduced glutamine synthetase activity and expression by 25–50% depending on whether one, two, or three different PS-ODNs were used and the PS-ODNs' specific target sites on the mRNA. Treatment with PS-ODNs of a recombinant strain of
Mycobacterium smegmatis
expressing
M. tuberculosis
glutamine synthetase selectively inhibited the recombinant enzyme but not the endogenous enzyme for which the mRNA transcript was mismatched by 2–4 nt. Treatment of
M. tuberculosis
with the antisense PS-ODNs also reduced the amount of poly-
l
-glutamate/glutamine in the cell wall by 24%. Finally, treatment with antisense PS-ODNs reduced
M. tuberculosis
growth by 0.7 logs (1 PS-ODN) to 1.25 logs (3 PS-ODNs) but had no effect on the growth of
M. smegmatis
, which does not export glutamine synthetase nor possess the poly-
l
-glutamate/glutamine (P-
l
-glx) cell wall structure. The experiments indicate that the antisense PS-ODNs enter the cytoplasm of
M. tuberculosis
and bind to their cognate targets. Although more potent ODN technology is needed, this study demonstrates the feasibility of using antisense ODNs in the antibiotic armamentarium against
M. tuberculosis.
Unfolding and internalization of proteins by the ATP-dependent proteases ClpXP and ClpAP
Authors: Singh Satyendra K. , Grimaud Regis , Hoskins Joel R. , Wickner Sue , Maurizi Michael R.
Published: July 2002

ClpX and ClpA are molecular chaperones that interact with specific proteins and, together with ClpP, activate their ATP-dependent degradation. The chaperone activity is thought to convert proteins into an extended conformation that can access the sequestered active sites of ClpP. We now show that ClpX can catalyze unfolding of a green fluorescent protein fused to a ClpX recognition motif (GFP-SsrA). Unfolding of GFP-SsrA depends on ATP hydrolysis. GFP-SsrA unfolded either by ClpX or by treatment with denaturants binds to ClpX in the presence of adenosine 5′-
O
-(3-thiotriphosphate) and is released slowly (
t
1/2
≈ 15 min). Unlike ClpA, ClpX cannot trap unfolded proteins in stable complexes unless they also have a high-affinity binding motif. Addition of ATP or ADP accelerates release (
t
1/2
≈ 1 min), consistent with a model in which ATP hydrolysis induces a conformation of ClpX with low affinity for unfolded substrates. Proteolytically inactive complexes of ClpXP and ClpAP unfold GFP-SsrA and translocate the protein to ClpP, where it remains unfolded. Complexes of ClpXP with translocated substrate within the ClpP chamber retain the ability to unfold GFP-SsrA. Our results suggest a bipartite mode of interaction between ClpX and substrates. ClpX preferentially targets motifs exposed in specific proteins. As the protein is unfolded by ClpX, additional motifs are exposed that facilitate its retention and favor its translocation to ClpP for degradation.
Requirement of phosphatidylglycerol for photosynthetic function in thylakoid membranes
Authors: Sato Norihiro , Hagio Miki , Wada Hajime , Tsuzuki Mikio
Published: July 2002

To investigate the role of phosphatidylglycerol (PG) in photosynthesis, we constructed a mutant defective in the CDP-diacylglycerol synthase gene from a cyanobacterium,
Synechocystis
sp. PCC6803. The mutant, designated as SNC1, required PG supplementation for growth. Growth was repressed in PG-free medium concomitantly with the decrease in cellular content of PG. These results indicate that PG is essential, and that SNC1 is defective in PG synthesis. Decrease in PG content was accompanied by a reduction in the cellular content of chlorophyll, but with little effect on the contents of phycobilisome pigments, which showed that levels of chlorophyll–protein complexes decreased without alteration of those of phycobilisomes. Regardless of the decrease in the PG content, CO
2
-dependent photosynthesis by SNC1 was similar to that by the wild type on a chlorophyll basis, but consequently became lower on a cell basis. Simultaneously, the ratio of oxygen evolution of photosystem II (PSII) measured with
p
-benzoquinone to that of CO
2
-dependent photosynthesis, which ranged between 1.3 and 1.7 in the wild type. However, it was decreased in SNC1 from 1.3 to 0.4 during the early growth phase where chlorophyll content and CO
2
-dependent photosynthesis were little affected, and then finally to 0.1, suggesting that PSII first lost its ability to reduce
p
-benzoquinone and then decreased in its level and actual activity. These results indicate that PG contributes to the accumulation of chlorophyll–protein complexes in thylakoid membranes, and also to normal functioning of PSII.
Zinc transfer potentials of the α- and β-clusters of metallothionein are affected by domain interactions in the whole molecule
Authors: Jiang Li-Juan , Vašák Milan , Vallee Bert L. , Maret Wolfgang
Published: July 2002

The α- and β-polypeptides of human metallothionein (isoform 2), obtained by chemical synthesis, were converted into their respective zinc/thiolate clusters, and each domain was investigated separately. Proton titration data for the N-terminal β-domain fit a simple model with three ionizations of the same apparent pK
a
value of 4.9 and a collective binding constant for zinc of 5 × 10
−12
M at pH 7.0. The zinc cluster in the C-terminal α-domain is more stable than that in the β-domain. Its pH titration is also more complex, indicating at least two classes of zinc sites with different affinities. The whole molecule is stabilized with regard to the individual domains. Chemical modification implicates lysine side chains in both the stabilization of the β-domain cluster and the mutual stabilization of the domains in the whole molecule. The two zinc clusters also differ in the reactivity of their cysteine sulfurs and their potential to donate zinc to an acceptor molecule dependent on its type and characteristics. The isolated β-domain cluster reacts faster with Ellman's reagent and is a better zinc donor toward zinc-depleted sorbitol dehydrogenase than is the isolated α-domain cluster, whereas the reverse is observed when a chelating agent is the zinc acceptor. Thus, although each cluster assembles independently of the other, the cumulative properties of the individual domains do not suffice to describe metallothionein either structurally or functionally. The two-domain structure of the whole molecule is important for its interaction with ligands and for control of its reactivity and overall conformation.
The
retro
-GCN4 leucine zipper sequence forms a stable three-dimensional structure
Authors: Mittl Peer R. E. , Deillon Christine , Sargent David , Liu Niankun , Klauser Stephan , Thomas Richard M. , Gutte Bernd , Grütter Markus G.
Published: July 2002

The question of whether a protein whose natural sequence is inverted adopts a stable fold is still under debate. We have determined the 2.1-Å crystal structure of the
retro
-GCN4 leucine zipper. In contrast to the two-stranded helical coiled-coil GCN4 leucine zipper, the
retro
-leucine zipper formed a very stable, parallel four-helix bundle, which now lends itself to further structural and functional studies.
Cohérence et vérité. Le rôle des modalisateurs épistémiques dans l'établissement de la vérité propositionnelle
Authors: Legros Denis , Baudet Serge
Published: July 2002

Nous présentons, tout d'abord, les caractéristiques essentielles de notre modèle de vérité‐cohérence (Baudet, Jhean‐Larose, Legros, 1994) qui permet de définir la valeur de vérité associée à une assertion non pas simplement comme une connaissance sur le vrai de cette assertion, mais comme l'état final d'une activité cognitive qui participe au processus de référenciation.

Nous présentons ensuite des résultats qui apportent des arguments à la thèse de la pertinence psychologique du concept de vérité. Ces résultats valident la première phase de notre modèle: la sélection d'un ensemble cohérent de candidat‐vrais à la vérité. Cette sélection est opérée grâce à l'attribution d'une valeur de plausibilité déterminée par des indices explicites de l'engagement de l'émetteur quant à la vérité des propositions contenues dans les phrases du texte.

Selon ces résultats, les modalisateurs épistémiques du type “Je sais” et du type “Je crois”, engagent l'émetteur de façon différente quant à la vérité des propositions, ils déterminent des degrés de plausibilité et donc des rapports de cohérence différents entre les assertions et le modèle mental qui y réfère.

Ces résultats valident donc l'hypothèse selon laquelle la fonction principale de l'opérateur d'énonciation du type “Je sais”, employé dans un texte, est d'informer le lecteur de l'engagement ferme du locuteur envers la valeur de vérité de la proposition, et donc de l'inviter à introduire la proposition p dans son domaine de connaissance, alors que la fonction de l'opérateur “Je crois” est d'indiquer les réserves du locuteur envers cette valeur de vérité.
Prototypical Behaviour Patterns of Social Intelligence: An Intercultural Comparison between Chinese and German Subjects
Authors: Willmann Elke , Feldt Kimberly , Amelang Manfred
Published: July 2002

By using the Act Frequency Approach (Buss & Craik, 1980), Chinese subjects (N = 31) generated a list of acts (specific behaviours) considered to represent social intelligence. These acts were rated by Chinese subjects (N = 39) and German subjects (N = 29) for prototypicality. A comparison of results showed that the construct of social intelligence is culture dependent. For the Chinese, social intelligent behaviours seem to reflect the classical traditions and ideals of Confucianism. Acts that received the highest scores were those that described conforming to and fulfilling expected roles, and acts in which the wellbeing of the entire society was described as being more important that the desires of an individual. This was especially true for older subjects and for women. Items controlling for socially desirable behaviour and social engagement showed clear differences between the two cultures; as expected, the German subjects rated these items lower, whereas the Chinese subjects found both items to be high prototypical of social intelligence.
Working Memory and Spoken Language Comprehension in Young Children
Authors: Adams Anne‐Marie , Bourke Lorna , Willis Catherine
Published: July 2002

This study has two theoretical dimensions: (a) to explore which components of Baddeley's (1986) working memory model are associated with children's spoken language comprehension, and (b) to compare the extent to which measures of the components of this fractionated model and an index of a unitary model (listening span) are able to predict individual differences in spoken language comprehension. Correlational analyses revealed that within a group of 66 4– and 5‐year‐old children both listening span and phonological memory, but not visuospatial memory, were associated with vocabulary knowledge and spoken language comprehension. However, of the proposed measures of central executive function—dual task coordination, sustained attention, verbal fluency—only the latter was related to children's ability to understand spoken language. Hierarchical regression analyses indicated that variance in vocabulary knowledge was best explained by phonological memory skills, whereas individual differences in spoken language comprehension exhibited unique and independent associations with verbal fluency.
The Relative Importance of Ethnicity: Ethnic Categorization among Older Children
Authors: Verkuyten Maykel , Kinket Barbara
Published: July 2002

In this study the relative importance of ethnic categories is investigated among Dutch and Turkish children (10 to 12 years of age). Children were asked to categorize and indicate preferences with respect to eight hypothetical contemporaries in different situations that were described by a combination of ethnicity, gender, and a psychological characteristic (“expressed affect or smartness”). The results show, first, that children preferred to use psychological characteristics for categorization. Second, the use of ethnic categories was domain‐dependent: Ethnicity was used less often in indicating preferences for playing than preferences for working on an educational task and for explaining quarrels. Third, the use of ethnic categories was affected by stereotypes. It is concluded that the widely accepted idea that ethnicity plays a central role in the judgements of children in multi‐ethnic situations seems overstated.
Conclusion:Millets, States, and National Identities
Authors: Mentzel Peter
Published: July 2002

The previous essays have presented a (frequently tragic) history of the Muslims of Southeastern Europe. The development of national identities among the Muslim populations has been an important chapter in this story. A recurring theme in the different case studies presented in this special issue is that the ways in which the Balkan Muslim population perceived itself did not always match the perception of the Christian population, especially the nationalists. Likewise, while the non-Muslim population often considered all Muslims to be an undifferentiated mass (usually referred to as “Turks”), the Muslims themselves often had highly nuanced and complex self-perception. While this self-identification included Islam as an important component, Islam was by no means the only, or even most important, aspect of identity.
Gender‐related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders
Authors: SANNIBALE CLAUDIA , HALL WAYNE
Published: July 2002

This study explored gender‐related symptoms and correlates of alcohol dependence in a cross‐sectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol‐related problems approximating same‐gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.
Soluble form of ICAM‐1, VCAM‐1, E‐ and L‐selectin in human milk
Authors: Xyni Kyriaki , Rizos Dimitrios , Giannaki Galini , Sarandakou Angeliki , Phocas Iphigenia , Creatsas George
Published: July 2002

In breast milk and paired serum from 70 lactating women and 40 of their term, infection‐free neonates, on the 2nd and 5th day postpartum slCAM‐1, sVCAM‐1, sE‐ and sL‐selectin were measured by ELISA and compared with those in 26 healthy adults (controls). Seven infant formulas and fresh milk from five cows were also analyzed. Human colostrum values of slCAM‐1, sVCAM‐1 (similar to those in maternal and control serum), sE‐selectin and sL‐selectin (˜10 and ˜100 times lower than in maternal and control serum) were significantly higher than those in milk, while they varied widely. None of the adhesion molecules was detected in fresh cow’s milk or infant formulas. Exclusively breast‐fed infants showed significantly higher values of slCAM‐1 and sL‐selectin on the 2nd day of life than those supplemented also with formula. Only slCAM‐1 values correlated positively between colostrum and time‐matched maternal serum. These findings show in human milk important amounts of slCAM‐1 and sVCAM‐1 but minimal amounts of sE‐ and sL‐selectin, which could affect the immune system of the neonate.
Suppressive effects of co‐stimulatory molecule expressions on mouse splenocytes by anti‐allergic agents in vitro
Authors: Ito Jun-ichi , Asano Kazuhito , Tryka Elzbieta , Kanai Ken-ichi , Yamamoto Sumiko , Hisamitsu Tadashi , Suzaki Harumi
Published: July 2002

The influence of anti‐allergic drugs, epinastine hydrochloride (EP) and disodium cromoglycate (DSCG), on the co‐stimulatory molecule expression was examined using in vitro cell culture technique. Spleen cells obtained from BALB/c mice 10 days after immunization with haemocyanin absorbed to aluminium hydroxide were cultured in the presence of 100.0 μg/ml haemocyanin and various concentrations of the agents. Low concentrations (< 1.5 2 10-4 M) of EP and DSCG did not influence spleen cell blastic activity induced by antigenic stimulation, whereas these agents caused significant inhibition of spleen cell activation when 2 × 10-4 M of the agents were added to cell cultures. EP and DSCG also did not affect blastic activity of sensitized splenic T cells by anti‐CD3 monoclonal antibody stimulation even when these cells were cultured in the presence of 2 × 10-4 M of the agents. We next examined the influence of EP and DSCG on the expression of co‐stimulatory molecules on spleen cells in response to antigenic stimulation. Sensitized spleen cells were cultured in the presence of 2 × 10-4 M of the agents and the expression of molecules were examined by flow cytometer 24 h later. EP and DSCG suppressed the expression of costimulatory molecules, CD40 and CD80, but not CD86, on splenic B cells which were enhanced by antigenic stimulation in vitro.
Effect of heparin and related glycosaminoglycan on PDGF‐induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity
Authors: Sasaki Masahiro , Kashima Masayuki , Ito Takefumi , Watanabe Akiko , Sano Masaaki , Kagaya Manabu , Shioya Takanobu , Miura Mamoru
Published: July 2002

Fibroblast migration, proliferation, extacellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with plumomary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamin and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF‐induced lung fibroblast proliferation and chemotactic response
in vitro. In addition, we examined the effect of heparin on both the induction of matorix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro.

Heparin, de‐N‐sulphated heparin but not heparan sulphate inhibited PDGF‐induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF‐stimulated human lung fibroblast chemotaxis. Negatively
charged poly‐L‐gultamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant‐proliferative and anti‐chemotactic effects of heparin.

Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPs, including MMP‐1 (interstitial collagenase), MMP‐2 (gelatinase A) and MMP‐9 (gelatinase B). Only heparin inhibited both MMP‐1 and MMP‐2/MMP‐9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP‐1) and type 2 (TIMP‐2) inhibited PDGF‐stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity.

The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF‐induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.
Rapid and simple determination of histamine‐N‐methyl transferase activity by high‐performance liquid chromatography with UV detection
Authors: Inoue Hajime , Hisamatsu Ken-Ichi , Yamauchi Miki , Kumagai Norio
Published: July 2002

A rabid, simple and low‐cost assay method of histamine‐N‐methyltransferase activity was developed. Methylhistamine, which was separated from the enzymatic reaction system on reversed‐phase high‐performance liquid chromatography using an ion‐paired chromatographic technique, was detected spectrophotometrically at 226 nm. The mobile phase used for the separation of methylhistamine was 0.05 M NH4H2 PO4
(pH 3.0) containing 2 mM of sodium octanesulfonate. The new assay technique could detect methylhistamine as an enzyme activity product of histamine‐N‐methyltransferase in the brain and kidney of rats. Chloropheniramine maleate, an antihistamine, activated the histamine N‐ methyltransferase. Whether neurotransmitter or neuromodulator, the role of histamine in the brain has not yet been made clear. Therefore, the present method could be applicable for the enzymatic investigation of histamine metabolism in central nervous system or inflammatory reactions.
Tumour necrosis factor‐alpha (TNFα) stimulates the growth of human bone marrow stromal cells
Authors: Rougier F. , Cornu E. , Gachard N. , Praloran V. , Denizot Y.
Published: July 2002

This study reports that TNF‐α is a potent mitogen for human bone marrow sternal cells in vitro (assessed by [3H]‐thymidine incorporation into DNA and cell counts). In contrast, cytokines such as IL‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐6, LIF, SCF, M‐CSF, G‐CSF and GM‐CSF had no effect. The effect of TNF‐α on the growth of human bone marrow stromal cells could be of importance during inflammatory processes which take place in the marrow, for example marrow fibrosis.
Smoking and nicotine in inflammatory bowel disease: good or bad for cytokines?
Authors: Zijlstra F. J.
Published: July 2002

Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis and Crohn′s disease respectively. Transdermal application of nicotine had similar effects in ulcerative colitis and therefore was considered to be an effective basic drug which could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid resistant ulcerative colitis. In this communication the short‐term use of nicotine in ulcerative colitis is reviewed.
Rooperol tetraacetate decreases cytokine mRNA levels and binding capacity of transcription factors in U937 cells
Authors: Guzdek A. , Rokita H. , Cichy J. , Allison A. C. , Koj A.
Published: July 2002

We have previously described inhibition of the synthesis of three acute‐phase inflammatory cytokines in human and rat macrophages by acetate esters of rooperol, a dicatechol of plant origin. Analysing the mechanism of anticytokine activity of rooperol, we compared levels of TNF α , IL‐1 β and IL‐6 mRNAs in the human promonocytic U937 cell line pretreated with phorbol myristate acetate (PMA) and incubated with rooperol tetraacetate (RTA) alone or in combination with LPS (500 ng/ml). It was found that 10 μM RTA decreased the levels of cytokine mRNAs both in the presence and absence of LPS, suggesting pretranslational inhibition of cytokine synthesis. Electrophoretic mobility shift analysis (EMSA) showed that RTA may influence cytokine mRNA expression by decreasing the binding activity of transcription factors NF‐ κB and AP‐1.
Interleukin‐5 modulates interleukin‐8 secretion in eosinophilic inflammation
Authors: Faccioli L. H. , Medeiros A. I. , Malheiro A. , Pietro R. C. L. R. , Januário A. , Vargaftig B. B.
Published: July 2002

Serum and BALF (bronchoalveolar lavage fluid) IL‐8 levels and serum levels were investigated in Tox ocara canis infected guinea‐pigs and the role of IL‐5 as a modulator of cytokine secretion was studied. Serum levels increased early in infected animals, exceeding control levels 4 h after infection, peaked between days 6 and 18, and continued to exceed control levels after 48 days of infection. Serum and BALF IL‐8 levels showed the same profile as blood eosinophilia, increasing 6 days post‐infection and peaking between days 18 and 24. Treatment of infected animals with anti‐IL‐5 Ab suppressed eosinophilia with a parallel increase in blood IL‐8 levels, whereas no change was found in levels. To support our in vivo observation we carried out experiments in vitro using guinea‐pig LPS‐stimulated adherent peritoneal cells which release large amounts of IL‐8 into the supernatants. When rIL‐5 was added to LPS‐stimulated cells, 65% inhibition of IL‐8 release into the supernatants was observed. Pre‐incubation of cells with anti‐IL‐5 Ab prevented the inhibition of IL‐8 release into the supernatants induced by rIL‐5. Our results demonstrate for the first time that TNF‐ α and IL‐8 are released concomitant with or after IL‐5 in the eosinophilic inflammation induced by T. canis . Moreover, in addition to showing that IL‐5 is fundamental for the induction of blood eosinophilia, the present results suggest that this cytokine may play a new biological role by acting as modulator of IL‐8 secretion.
in vitro activation of complement and contact system by lactic acidosis
Authors: Sonntag J. , Emeis M. , Strauss E. , Obladen M.
Published: July 2002

The activation of complement and contact systems occurs in reperfusion injuries with initial tissue hypoxia, and lactic acidosis such as mycardial infarction and birth asphyxia. The aim of our experiment was the formal proof of activation by sole lactic acidosis. Lactic acid was added to blood and plasma samples from 10 healthy volunteers. C5a and factor XIIa were measured by EIA after incubation at 37°C for 1 h. Both concentrations increased (P < 0.0001 by Friedman analysis) in blood and plasma samples with increasing amount of added lactic acid. Lactic acidosis can activate C5 from the complement system and factor XII from the contact system directly, even in the absence of cellular components.
Wealth and Power: Quesnay's Political Economy of the “Agricultural Kingdom”
Authors: Steiner Philippe
Published: July 2002

The Physiocrats “New Science” of Political Economy is often represented as unrelated to the pursuit of national power. A recent study (Fourquet 1989), which rests on the approaches of Fernand Braudel (1979) and Immanuel Wallerstein (1980), has radicalized the thesis already propounded by Edmond Silberner (1939) who claimed that Quesnay was profoundly ignorant of military matters and failed to understand the power struggles being played out on the seas and in the colonies. Did not Quesnay propose turning back to an agricultural economy, banishing industry, trade, and the navy—in short, all the active forces thanks to which Great Britain had snatched domination of the world economy from Holland and thanks to which she would prevent France from obtaining it?

Yet this thesis is weak. It must be remembered that Quesnay's first economic writings date from 1756–57, that is to say a period when confrontation between France and England was at a peak, with the start of the Seven Years' War. How could an author who claims to de ne the economic government ofan agricultural nation ignore the military problems which were so crucial in this period? Even if he wanted to, how could he succeed in doing so once he came to deal with taxes and the highly sensitive question of finance? How could he make himself understood by his contemporaries with a political theory that set aside all the burning issues of the day? How could he find an audience among those developing the science of commerce who always accorded great importance to the pursuit of power?

Under scrutiny the traditional thesis appears inaccurate. After recalling the writings of some of his contemporaries, whom Quesnay knew and read (section 1), I shall show that articles drafted between 1756 and 1757, like published or unpublished works which Mirabeau and Quesnay elaborated between 1757 and 1760, give significant room to the nation's military power, particularly when the economic government is in question (section 2). From the years 1763–64 the idea of a natural order does not lead Quesnay to neglect the pursuit of power (section 3). These links between power and wealth in the work of the founder of Physiocracy will lead finally to some remarks on political economy as a form of rationalization of politics.
Routine Hospital Alcohol Detoxification Practice Compared to Symptom Triggered Management with an Objective Withdrawal Scale (CIWA‐Ar)
Authors: Reoux Joseph P. , Miller Kristin
Published: July 2002

Charts of patients hospitalized for uncomplicated alcohol withdrawal were examined and detoxification practices compared. Patients detoxified using a Clinical Institute Withdrawal Assessment for Alcohol‐revised (CIWA‐Ar) based PRN protocol on the addiction unit received significantly fewer chlordiazepoxide milligram equivalents over shorter duration than patients managed by other detoxification methods on other hospital units. Significantly fewer patients received benzodiazepines in the CIWA‐Ar protocol managed group, but inter‐group differences (p < 0.01) remained when only medicated patients were compared. Differences between the protocol and non‐protocol groups did not reach statistical significance when PRN only strategies were examined, suggesting that the use of a symptom‐triggered strategy may account for the noted effects.
A Family Study of the High‐Risk Children of Opioid‐ and Alcohol‐Dependent Parents
Authors: Wilens Timothy E. , Biederman Joseph , Bredin Elizabeth , Hahesy Amy L. , Abrantes Ana , Neft Deborah , Millstein Rachael , Spencer Thomas J.
Published: July 2002

In this article, the author sought to use a high‐risk study design focused on the children of parents with opioid or alcohol use disorders and children of parents with no substance use disorder (SUD) to evaluate the specificity of the risk conferred by the type of parental SUD. Using structured psychiatric interviews, cognitive assessments, and measures of social, academic, and family functioning, the authors studied 96 families (187 parents and 183 children, mean age of 11.6 years). Sixteen families had parental opioid dependence (22 children; 64% male), 14 families had parental alcohol dependence (22 children; 59% male), and 66 families had no SUD (controls; 139 children; 58% male). Fifty‐nine percent of children of opioid‐dependent parents had at least one major psychopathological condition, compared to 41% of the alcohol group and 28% of the control group (p < 0.01). The children of opioid‐ and alcohol‐dependent parents were of lower socioeconomic status and had significantly more difficulties in academic, social, and family functioning than did controls. Children of opioid‐ and alcohol‐dependent parents have significantly higher rates of psychopathology as well as more difficulties in academic, social, and family functioning compared to the children of non‐SUD parents. In addition, notable trends emerged for the opioid group to have more psychopathology and functional impairment than the alcohol group. With a growing consensus that certain risk factors for later SUD start in childhood with potentially treatable childhood‐onset disorders, new preventive approaches for individuals at risk may be developed targeting childhood precursors of SUD.
Molecular Alterations in Pediatric Sarcomas: Potential Targets for Immunotherapy
Authors: Goletz Theresa J. , Mackall Crystal L. , Berzofsky Jay A. , Helman Lee J.
Published: July 2002

Purpose/results/discussion. Recurrent chromosomal translocations are common features of many human malignancies. While such translocations often serve as diagnostic markers, molecular analysis of these breakpoint regions and the characterization of the affected genes is leading to a greater understanding of the causal role such translocations play in
malignant transformation. A common theme that is emerging from the study of tumor‐associated translocations is the generation of chimeric genes that, when expressed, frequently retain many of the functional properties of the wild‐type genes from which they originated. Sarcomas, in particular, harbor chimeric genes that are often derived from transcription factors, suggesting that the resulting chimeric transcription factors contribute to tumorigenesis. The tumor‐specific expression of the fusion proteins make them likely candidates for tumor‐associated antigens (TAA) and are thus of interest in the development of new therapies. The focus of this review will be on the translocation events associated with Ewing′s sarcomas/PNETs (ES), alveolar rhabdomyosarcoma (ARMS), malignant melanoma of soft parts (MMSP) (clear cell sarcoma), desmoplastic small round cell tumor (DSRCT), synovial sarcoma (SS), and liposarcoma (LS), and the potential for targeting the resulting chimeric proteins in novel immunotherapies.
Functional Outcome in Sarcomas Treated With Limb‐Salvage Surgery or Amputation
Authors: Johansen Rikke , Nielsen Ole S. , Keller Johnny
Published: July 2002

Purpose. In all patients treated at the Centre for Bone and Soft Tissue Sarcomas of Aarhus the functional outcome is prospectively evaluated by use of the Enneking system for the functional evaluation after surgical treatment of tumours of the musculoskeletal system. This system has been accepted by the Musculoskeletal Tumour Society and the International
Symposium on Limb Salvage.

Patients/methods. In the present study the functional outcome after limb‐salvage surgery (89 patients) and amputation (58 patients) was compared. In the limb‐salvage group the treatment was surgery alone in 50% and surgery combined with either radiotherapy in 39% or chemotherapy in 11%. Inclusion criteria were: Deep seated extremity sarcomas, age >14 years, more than 1 year post‐treatment follow‐up time and alive at the end of the study. Median age was 49 years (range 14–88 years). Median tumour diameter was 8 cm (range 1–20 cm), median follow‐up time was 4.8 years (range 1–11 years). Wilcoxon and χ2‐tests were used for statistical analyses.

Results. The two groups were comparable according to age, sex, size of tumour, type of tumour, location of tumour, as well as post‐treatment follow‐up time. The functional scores were significantly higher after limb‐salvage surgery as compared to amputation, the median scores being 85 and 47, respectively (p<0.001). A similar difference was observed
if the Enneking scores were subdivided into general health‐related scores and extremity‐related scores. No association was found between functional scores and the following factors by use of univariate analysis: size of tumour, radiation therapy, localization of tumour and surgical margin.

Discussion. We conclude that this study indicates that limb‐salvage surgery is associated with a better functional outcome than that observed after amputation. However, whether this also indicates a difference in quality of life needs further studies.
Susceptibility of Fibromatosis Cells in Short‐Term Culture to Ifosfamide: A Possible Experimental Treatment in Clinically Aggressive Cases
Authors: Verrill Mark W. , Coley Helen M. , Judson Ian R. , Fisher Cyril
Published: July 2002

Purpose. Deep fibromatoses are large, often rapidly growing
but benign soft tissue tumours. Although surgery is the mainstay of treatment, in
unremitting and aggressive cases the use of cytotoxic chemotherapy may produce
objective tumour responses. Fresh tumour samples from four patients with fibromatosis
were investigated as part of a study of drug resistance in soft tissue tumours.

Methods. Following short‐term culture of fibromatosis cells in vitro ,
chemosensitivity to 4‐hydroperoxy‐ifosfamide, the active form of ifosfamide and
doxorubicin was tested. Following 72‐h continuous exposure to each drug,
surviving cell fraction was assessed using the lactate dehydrogenase assay.

Results. Mean IC50
values for ifosfamide and doxorubicin were
6.2 and 0.35 µmol/l, respectively. In samples of soft tissue sarcoma (STS) from the
same study the mean IC50
values for ifosfamide and doxorubicin were 14.8 and
1.69 µmol. The difference in mean ifosfamide IC50
values for fibromatosis and
STS samples was statistically significant.

Discussion. We are not aware of any other report suggesting
the use of ifosfamide in this condition. These observations suggest that, for patients
with inoperable or progressive lesions of fibromatosis causing significant morbidity,
it may be valuable to include ifosfamide in experimental treatment regimens.
Hyperthermic Isolated Limb Perfusion with TNF α and Cisplatin in theTreatment of Osteosarcoma of the Extremities: A Feasibility Study inHealthy Dogs
Authors: Van Ginkel Robert J. , Van Berlo Charles L. H. , Baas Peter C. , Koops Heimen Schraffordt , Stuling Ries Van Groningen B. , Elstrodt Jan , Hoekstra Harald J.
Published: July 2002

Purpose. The feasibility of hyperthermic isolated limb perfusion
(HILP) with tumor necrosis factor‐α (TNFα ) and cisplatin for the management of
osteosarcoma was studied in the canine model.

Methods. During seven perfusions in six healthy mongrel dogs
(weight 32±2 kg) technical aspects of HILP under mild hyperthermia (39– 40℃) were
studied. In five experiments HILP was performed with TNFα alone (0.5 mg/l extremity volume),
and in two experiments TNFα was combined with cisplatin (25 mg/l extremity volume).
During the perfusions physiological parameters were monitored and TNFα and total
cisplatin concentrations were determined.

Results. Perfusion conditions (pH, PCO2
, PO2, flow and pressure)
remained within physiological ranges.Three dogs died within 24 h despite a sublethal
systemic concentration of TNFα that leaked from the perfusion circuit. Three dogs were
terminated; one dog after the second experiment in accordance with Dutch ethical rules;
one dog showed an invagination of the small bowel resulting in an ileus; one dog because
of necrosis of the perfused limb.

Conclusions. This feasibility study in healthy dogs demonstrated that
HILP with TNFα and cisplatin was associated with a high mortality rate and does not allow
us to treat dogs with spontaneous osteosarcoma with TNFα and cisplatin HILP. Therefore,
an alternative model should be used in the search for the ideal combination of perfusion
agents for limb sparing treatment in human osteosarcoma.
Evaluation of Dose‐Intense Ifosfamide, with and Without Edatrexate, in Adults with Sarcoma
Authors: Casper Ephraim S. , Schwartz Gary M. , Leung Denis , Sugarman Alison , Bertino Joseph R.
Published: July 2002

Purpose. To define the maximally tolerated dose (MTD) of ifosfamide
when given with G‐CSF on an every other week schedule, and to define the MTD of
edatrexate that can be given every two weeks with an intense schedule of ifosfamide.

Patients and Methods. Forty‐one patients with metastatic or unresectable,
locally advanced sarcoma participated in this 2‐step phase I trial.The starting dose of
ifosfamide was 10 gm/m2
given by continuous intravenous infusion over 4 days every
2 weeks.When the MTD was defined, edatrexate, beginning at a dose of 40 mg/m2
intravenously every 2 weeks was added in subsequent cohorts of patients.

Results. Myelosuppression was the most prominent toxicity.
Fatigue, nausea, and vomiting were observed in the majority of patients. Ifosfamide
12 gm/m2 given every 2 weeks approached or exceeded the MTD. Edatrexate 100 mg/m2
could be given safety as an intravenous bolus with ifosfamide 10 gm/m2 every 2 weeks.
Therapeutic responses were observed in patients with measurable disease.

Conclusions. This study demonstrates the feasibility of administering
a dose‐intense schedule of ifosfamide alone or ifosfamide with edatrexate that might be
applied in the adjuvant or neo‐adjuvant setting.
Ii Chain Controls the Transport of Major Histocompatibility Complex Class II Molecules to and from Lysosomes
Authors: Brachet Valérie , Raposo Graça , Amigorena Sebastian , Mellman Ira
Published: July 2002

Major histocompatibility complex class II molecules are synthesized as a nonameric complex consisting of three αβ dimers associated with a trimer of invariant (Ii) chains. After exiting the TGN, a targeting signal in the Ii chain cytoplasmic domain directs the complex to endosomes where Ii chain is proteolytically processed and removed, allowing class II molecules to bind antigenic peptides before reaching the cell surface. Ii chain dissociation and peptide binding are thought to occur in one or more postendosomal sites related either to endosomes (designated CIIV) or to lysosomes (designated MIIC). We now find that in addition to initially targeting αβ dimers to endosomes, Ii chain regulates the subsequent transport of class II molecules. Under normal conditions, murine A20 B cells transport all of their newly synthesized class II I-Ab αβ dimers to the plasma membrane with little if any reaching lysosomal compartments. Inhibition of Ii processing by the cysteine/serine protease inhibitor leupeptin, however, blocked transport to the cell surface and caused a dramatic but selective accumulation of I-Ab class II molecules in lysosomes. In leupeptin, I-Ab dimers formed stable complexes with a 10-kD NH2-terminal Ii chain fragment (Ii-p10), normally a transient intermediate in Ii chain processing. Upon removal of leupeptin, Ii-p10 was degraded and released, I-Ab dimers bound antigenic peptides, and the peptide-loaded dimers were transported slowly from lysosomes to the plasma membrane. Our results suggest that alterations in the rate or efficiency of Ii chain processing can alter the postendosomal sorting of class II molecules, resulting in the increased accumulation of αβ dimers in lysosome-like MIIC. Thus, simple differences in Ii chain processing may account for the highly variable amounts of class II found in lysosomal compartments of different cell types or at different developmental stages.