bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated expression of membrane type 1 metalloproteinase (MT1‐MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system
Authors: Rathke-Hartlieb Silvia , Budde Petra , Ewert Stefan , Schlomann Uwe , Staege Martin Sebastian , Jockusch Harald , Bartsch Jörg W. , Frey Jürgen
Published: July 2002

Reactive astrocytes occurring in response to neurodegeneration are thought to play an important role in neuronal regeneration by upregulating the expression of extracellular matrix (ECM) components as well as the ECM degrading metalloproteinases (MMPs). We examined the mRNA levels and cellular distribution of membrane type matrix metalloproteinase 1 (MT1‐MMP) and tissue inhibitors 1–4 of MMPs (TIMPs) in brain stem and spinal cord of wobbler (WR) mutant mice affected by progressive neurodegeneration and astrogliosis. MT1‐MMP, TIMP‐1 and TIMP‐3 mRNA levels were elevated, whereas TIMP‐2 and TIMP‐4 expression was not affected. MT1‐MMP was expressed in reactive astrocytes of WR. In primary astrocyte cultures, MT1‐MMP mRNA was upregulated by exogeneous tumor necrosis factor α. Increased plasma membrane and secreted MMP activities were found in primary WR astrocytes.
HIF‐1‐dependent transcriptional activity is required for oxygen‐mediated HIF‐1α degradation
Authors: Berra Edurne , Richard Darren E , Gothié Emmanuel , Pouysségur Jacques
Published: July 2002

Hypoxia‐inducible factor‐1α (HIF‐1α) plays a central role in oxygen homeostasis. In normoxia, HIF‐1α is a short lived protein, whereas hypoxia rapidly increases HIF‐1α protein levels by relaxing its ubiquitin–proteasome‐dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF‐1α, does not modulate the degradation/stabilization profile of HIF‐1α. However, we present evidence that the rate of HIF‐1α degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF‐1α is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF‐1‐dependent transcriptional activity. In keeping with these findings, we postulate that HIF‐1α is targetted to the proteasome via a HIF‐1α proteasome targetting factor (HPTF) which expression is directly under the control of HIF‐1‐mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel–Lindau protein (pVHL).
Alzheimer‐associated presenilin‐2 confers increased sensitivity to poptosis in PC12 cells
Authors: Deng Gangmin , Pike Christian J. , Cotman Carl W.
Published: July 2002

Presenilin‐2 is a gene of unknown function recently identified based upon linkage with some forms of familial Alzheimer's disease. To investigate potential effects of PS‐2 on cell viability, rat pheochromocytoma (PC12) cells were stably transfected with cDNA constructs encoding either full‐length human PS‐2 or, for comparison, mouse Bcl‐xL. Overexpression of PS‐2 conferred increased sensitivity to the apoptotic stimuli staurosporine and hydrogen peroxide. In contrast, Bcl‐xL overexpression significantly reduced cell death induced by these stimuli. These results suggest that one function of PS‐2 may involve modulation of cell viability.
Rat prolactin synthesis by lactating mammary epithelial cells
Authors: Lkhider Mustapha , Delpal Serge , Le Provost Fabienne , Ollivier-Bousquet Michèle
Published: July 2002

It has previously been suggested that the mammary cell could produce prolactin (PRL). This hypothesis was investigated by incubation with [35S]methionine‐cysteine followed by SDS‐PAGE, immunoblotting and autoradiography of immunoprecipitated PRL, and by electron microscopic analysis after incubation without or with cycloheximide. Immunoreactive 14‐, 23‐, 25‐, 32‐ and 36‐kDa PRL forms were radioactive. By two‐dimensional electrophoresis analysis, immunoreactive and radioactive spots, of about 25 kDa and high molecular weight, were also detected. After incubation of mammary epithelial cells with cycloheximide, immunogold electron microscopy showed a drastic decrease of labelling in organelles involved in synthesis and secretion, compared to those incubated in control medium. These results make it possible to conclude that lactating mammary tissue is able to synthesize PRL.
The C‐terminal domain of the Gs‐coupled EP4 receptor confers agonist‐dependent coupling control to Gi but no coupling to Gs in a receptor hybrid with the Gi‐coupled EP3 receptor
Authors: Neuschäfer-Rube Frank , Hänecke Kristina , Blaschke Volker , Jungermann Kurt , Püschel Gerhard P
Published: July 2002

Prostaglandin E2 receptors (EPR) belong to the family of G‐protein‐coupled receptors with 7 transmembrane domains. They form a family of four subtypes, which are linked to different G‐proteins. EP1R are coupled to Gq, EP2 and EP4R to Gs and EP3R to Gi. Different C‐terminal splice variants of the bovine EP3R are coupled to different G‐proteins. A mouse EP3R whose C‐terminal domain had been partially truncated no longer showed agonist‐induced Gi‐protein activation and was constitutively active. In order to test the hypothesis that the C‐terminal domain confers coupling specificity of the receptors on the respective G‐proteins, a cDNA for a hybrid rEP3hEP4R, containing the N‐terminal main portion of the Gi‐coupled rat EP3βR including the 7th transmembrane domain and the intracellular C‐terminal domain of the Gs‐coupled human EP4R, was generated by PCR. HEK293 cells transiently transfected with the chimeric rEP3hEP4R cDNA expressed a plasma membrane PGE2 binding site with a slightly lower K
d value for PGE2 but an identical binding profile for receptor‐specific ligands as cells transfected with the native rat EP3βR. In HepG2 cells stably transfected with the chimeric rEP3hEP4R cDNA PGE2 did not increase cAMP formation characteristic of Gs coupling but attenuated the forskolin‐stimulated cAMP synthesis characteristic of Gi coupling. This effect was inhibited by pre‐treatment of the cells with pertussis toxin. Thus, the hybrid receptor behaved both in binding and in functional coupling characteristics as the native rat EP3βR. Apparently, the intracellular C‐terminal domain did not confer coupling specificity but coupling control, i.e. allowed a signalling state of the receptor only with agonist binding.
An increase in cytosolic calcium ion concentration precedes hypoosmotic shock‐induced activation of protein kinases in tobacco suspension culture cells
Authors: Takahashi Koji , Isobe Minoru , Muto Shoshi
Published: July 2002

Hypoosmotic shock induced a transient increase in cytosolic free calcium concentration ([Ca2+]cyt) and subsequent activation of 50‐, 75‐ and 80‐kDa protein kinases in tobacco (Nicotiana tabacum L.) suspension culture cells. Depletion of external calcium suppressed both the elevation of [Ca2+]cyt and the activation of protein kinases in response to hypoosmotic shock, indicating that the elevation of [Ca2+]cyt is prerequisite for the activation of protein kinases. Pharmacological analysis indicated that the hypoosmotic shock‐activated protein kinases were activated by phosphorylation, suggesting that the activities of these protein kinases are regulated by putative protein kinases. These results suggest that the hypoosmotic signal is transduced to protein kinase cascades which are triggered by [Ca2+]cyt elevation.
Sensing by intrahepatic muscarinic nerves of a portal‐arterial glucose concentration gradient as a signal for insulin‐dependent glucose uptake in the perfused rat liver
Authors: Stümpel Frank , Jungermann Kurt
Published: July 2002

In vivo, insulin increases net hepatic glucose uptake efficiently only in the presence of a portal‐arterial glucose gradient. In isolated perfused rat livers supplied with a glucose gradient (portal 10 mM/arterial 5 mM) insulin‐induced glucose uptake was blocked by atropine; in livers not supplied with the gradient (portal=arterial 5 mM) insulin‐dependent glucose uptake was elicited by acetylcholine. Apparently, the gradient was sensed and transformed into a metabolic signal by intrahepatic nerves, releasing acetylcholine to muscarinic receptors.
The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand‐receptor interactions
Authors: Alroy Iris , Yarden Yosef
Published: July 2002

Ligand‐induced activation of receptor tyrosine kinases (RTK) results in the initiation of diverse cellular pathways, including proliferation, differentiation and cell migration. The ErbB family of RTKs represents a model for signal diversification through the formation of homo‐ and heterodimeric receptor complexes. Each dimeric receptor complex will initiate a distinct signaling pathway by recruiting a different set of Src homology 2‐ (SH2‐) containing effector proteins. Further complexity is added due to the existence of an oncogenic receptor that enhances and stabilizes dimerization but has no ligand (ErbB‐2), and a receptor that can recruit novel SH‐2‐containing proteins, but is itself devoid of kinase activity (ErbB‐3). The resulting signaling network has important implications for embryonic development and malignant transformation.
Lithium inhibits Alzheimer's disease‐like tau protein phosphorylation in neurons
Authors: Muñoz-Montaño Juan Ramón , Moreno Francisco J. , Avila Jesús , Dı́az-Nido Javier
Published: July 2002

In Alzheimer's disease, tau protein becomes hyperphosporylated, which can contribute to neuronal degeneration. However, the implicated protein kinases are still unknown. Now we report that lithium (an inhibitor of glycogen synthase kinase‐3) causes tau dephosphorylation at the sites recognized by antibodies Tau‐1 and PHF‐1 both in cultured neurons and in vivo in rat brain. This is consistent with a major role for glycogen synthase kinase‐3 in modifying proline‐directed sites on tau protein within living neurons under physiological conditions. Lithium also blocks the Alzheimer's disease‐like proline‐directed hyperphosphorylation of tau protein which is observed in neurons treated with a phosphatase inhibitor. These data raise the possibility of using lithium to prevent tau hyperphosphorylation in Alzheimer's disease.
Nociceptin/orphanin FQ stimulates extracellular acidification and desensitization of the response involves protein kinase C
Authors: Pei Gang , Ling Kun , Pu Lu , Cunningham Martin D , Ma Lan
Published: July 2002

A Chinese hamster ovary (CHO) cell line, CHO‐ORL1, stably expressing human opioid receptor‐like receptor 1 (ORL1) has been used to determine ORL1‐mediated signaling events using microphysiometry. Nociceptin/orphanin FQ (N/OFQ), a specific endogenous agonist of ORL1, induced an increase in extracellular acidification rate (ECAR) in CHO‐ORL1 cells. The ECAR response stimulated by N/OFQ was concentration‐dependent and pertussis toxin‐sensitive. Repeated exposures of the cells to N/OFQ caused desensitization of ORL1. The ECAR response was recovered at the half‐life of approximately 12 min after the initial challenge. Pretreatment with inhibitor of cAMP‐dependent kinase did not affect desensitization of ORL1. However, specific inhibitors for protein kinase C almost abolished N/OFQ‐induced desensitization of extracellular acidification responsiveness, indicating the involvement of protein kinase C in the process.
Identification of potential activators of proteinase‐activated receptor‐21
Authors: Fox Mark T. , Harriott Patrick , Walker Brian , Stone Stuart R.
Published: July 2002

In order to identify physiological activators of proteinase‐activated receptor‐2 (PAR‐2), a peptide chloromethane inhibitor (biotinyl‐Ser‐Lys‐Gly‐Arg‐CH2Cl) based on the cleavage site for activation of PAR‐2 was synthesised and tested with 12 trypsin‐like serine proteinases. The second‐order rate constant (k
i/K
i) for the formation of the covalent proteinase‐inhibitor complex varied by 2×105‐fold between the proteinases. Biotinyl‐Ser‐Lys‐Gly‐Arg‐CH2Cl reacted very rapidly with trypsin, acrosin from sperm and tryptase from mast cells: the k
i/K
i values with these proteinases were greater than 105 M−1 s−1. Thus, the specificity of these proteinases matched the sequence of the activation site of PAR‐2 and it can be concluded that these proteinases are potential physiological activators of PAR‐2.
Substrate and sequential site specificity of cytoplasmic histone acetyltransferases of maize and rat liver
Authors: Kölle Doris , Sarg Bettina , Lindner Herbert , Loidl Peter
Published: July 2002

The cytoplasmic B‐type histone acetyltransferase was purified to apparent homogeneity from maize embryos. We established a novel protocol for easy large‐scale preparation of acetylated core histone species, using preparative acetic acid‐urea‐Triton PAGE. The pure maize histone acetyltransferase B was highly specific for histone H4 under various assay conditions, modifying H4 up to the di‐acetylated isoform. Only non‐acetylated H4 isoform was accepted as substrate, whereas mono‐acetylated H4 could not be further acetylated. The enzyme selectively acetylated lysines 12 and 5 in a sequential manner. The same results were obtained with a partially purified cytoplasmic histone acetyltransferase of rat liver. Protein sequencing results were supported by immunological characterization of acetylated H4 subspecies with site‐specific H4‐acetyllysine antibodies.
Cleavage and activation of proteinase‐activated receptor‐2 on human neutrophils by gingipain‐R from Porphyromonas gingivalis
Authors: Lourbakos Afrodite , Chinni Carla , Thompson Philip , Potempa Jan , Travis James , Mackie Eleanor J , Pike Robert N
Published: July 2002

Gingipain‐R, the major arginine‐specific proteinase from Porphyromonas gingivalis, a causative agent of adult periodontal disease, was found to cleave a model peptide representing the cleavage site of proteinase‐activated receptor‐2 (PAR‐2), a G‐protein‐coupled receptor found on the surface of neutrophils. The bacterial proteinase was also shown to induce an increase in the intracellular calcium concentration of enzyme‐treated neutrophils, most probably due to PAR‐2 activation. This response by neutrophils to gingipain‐R may be a mechanism for the development of inflammation associated with periodontal disease.
Effect of CRF and related peptides on calcium signaling in human and rodent melanoma cells
Authors: Fazal Nadeem , Slominski Andrzej , Choudhry Mashkoor A , Wei Edward T , Sayeed Mohammed M
Published: July 2002

Corticotropin releasing factor (CRF) induces a rapid, within seconds, and dose‐dependent increase in the intracellular Ca2+ in both human and hamster melanoma cells. This effect is inhibited by depletion of extracellular calcium using 3 mM EGTA and is attenuated by the CRF receptor antagonist, α‐helical‐CRF(9‐41). Other peptides of the CRF superfamily, sauvagine and urocortin, also induce increases in cytoplasmic calcium concentration but at higher concentrations than CRF. We conclude that malignant melanocytes express CRF receptors, which are coupled to activation of plasma membrane calcium channels.
Evidence that the AMP‐activated protein kinase stimulates rat liver carnitine palmitoyltransferase I by phosphorylating cytoskeletal components
Authors: Velasco Guillermo , Gómez del Pulgar Teresa , Carling David , Guzmán Manuel
Published: July 2002

The activity of hepatic carnitine palmitoyltransferase I (CPT‐I) may be modulated by interactions with cytoskeletal components [Velasco et al. (1998) J. Biol. Chem. 273, 21497–21504]. We have studied whether the AMP‐activated protein kinase (AMPK) is involved in this process. AMPK stimulated CPT‐I in permeabilized hepatocytes but not in isolated liver mitochondria. In addition, AMPK abrogated the inhibition of CPT‐I of isolated mitochondria induced by a cytoskeletal fraction. These two effects of AMPK were not evident when the kinase was inactivated by pretreatment with protein phosphatase 2C. Cytokeratins 8 and 18 were phosphorylated by AMPK in vitro and by incubation of intact hepatocytes with 5‐aminoimidazole‐4‐carboxamide ribonucleoside, a cell‐permeable activator of AMPK. These results provide the first evidence that AMPK stimulates CPT‐I by direct phosphorylation of cytoskeletal components.
Isolation and expression analysis of a novel human homologue of the Drosophila glial cells missing (gcm) gene
Authors: Kanemura Yonehiro , Hiraga Shoju , Arita Norio , Ohnishi Takanori , Izumoto Shuichi , Mori Kanji , Matsumura Hirotaka , Yamasaki Mami , Fushiki Shinji , Yoshimine Toshiki
Published: July 2002

A novel human homologue (GCMB) of the Drosophila glial cells missing gene (dGCM) was isolated using RACE. GCMB contained a gcm motif sequence and a nuclear targeting sequence similar to that of dGCM and mouse GCMb. Homology searches indicated that GCMB was located within chromosome 6p24.2. Transcripts of GCMB were detected by means of RT‐PCR in fetal brain, normal adult kidney, 3/3 medulloblastomas, 1/3 gliomas and 4/8 non‐neuroepithelial tumor cell lines. Our data suggest that humans have two homologues of gcm like mice and that human gcm genes form a novel family which may function not only during fetal development but also in the postnatal or pathological stage.
Characterization of the calcyclin (S100A6) binding site of annexin XI‐A by site‐directed mutagenesis
Authors: Sudo Toshiki , Hidaka Hiroyoshi
Published: July 2002

Residues in annexin XI‐A essential for binding of calcyclin (S100A6) were examined by site‐directed mutagenesis. GST fusion proteins with the calcyclin binding site of annexin XI‐A, GST‐AXI 34–62 and GST‐AXI 49–77 bound to calcyclin‐Sepharose Ca2+‐dependently. The mutants GST‐AXI L52E, M55E, A56E and M59E lost the binding ability, whereas GST‐AXI A57E retained the ability. These results demonstrate that the hydrophobic residues L52, M55, A56 and M59 on one side surface of the α‐helix are critical for the binding. Assays with GST fusion proteins and synthesized peptides corresponding to the calcyclin binding site indicated that other regions around the calcyclin binding site are important to stabilize the conformation.
Crystal structure of the β‐glycosidase from the hyperthermophileThermosphaera aggregans: insights into its activity and thermostability
Authors: Chi Young-In , Martinez-Cruz Luis A , Jancarik Jarmalia , Swanson Ronald V , Robertson Dan E , Kim Sung-Hou
Published: July 2002

The glycosyl hydrolases are an important group of enzymes that are responsible for cleaving a range of biologically significant carbohydrate compounds. Structural information on these enzymes has provided useful information on their molecular basis for the functional variations, while the characterization of the structural features that account for the high thermostability of proteins is of great scientific and biotechnological interest. To these ends we have determined the crystal structure of the β‐glycosidase from a hyperthermophilic archeonThermosphaera aggregans. The structure is a (β/α)8barrel (TIM‐barrel), as seen in other glycosyl hydrolase family 1 members, and forms a tetramer. Inspection of the active site and the surrounding area reveals two catalytic glutamate residues consistent with the retaining mechanism and the surrounding polar and aromatic residues consistent with a monosaccharide binding site. Comparison of this structure with its mesophilic counterparts implicates a variety of structural features that could contribute to the thermostability. These include an increased number of surface ion pairs, an increased number of internal water molecules and a decreased surface area upon forming an oligomeric quaternary structure.
Accumulation of protein‐bound epidermal glucosylceramides in β‐glucocerebrosidase deficient type 2 Gaucher mice
Authors: Doering Thomas , Proia Richard L , Sandhoff Konrad
Published: July 2002

The epidermal permeability barrier for water is essentially maintained by extracellular lipid membranes within the interstices of the stratum corneum. Ceramides, the main components of these membranes, derive in large part from hydrolysis of glucosylceramides mediated by the lysosomal enzyme β‐glucocerebrosidase. As analyzed in this work, the β‐glucocerebrosidase deficiency in type 2 Gaucher mice (RecNci I) resulted in an accumulation of all epidermal glucosylceramide species accompanied with a decrease of the related ceramides. However, the levels of one ceramide subtype, which possesses an α‐hydroxypalmitic acid, was not altered in RecNci I mice suggesting that the β‐glucocerebrosidase pathway is not required for targeting of this lipid to interstices of the stratum corneum. Most importantly, ω‐hydroxylated glucosylceramides which are protein‐bound to the epidermal cornified cell envelope of the transgenic mice accumulated up to 35‐fold whereas levels of related protein‐bound ceramides and fatty acids were decreased to 10% of normal control. These data support the hypothesis that in wild‐type epidermis ω‐hydroxylated glucosylceramides are first transferred enzymatically from their linoleic esters to proteins of the epidermal cornified cell envelope and then catabolized to protein‐bound ceramides and fatty acids, thus contributing at least in part to the formation of the lipid‐bound envelope.
Monoclonal antibody to the δ opioid receptor acts as an agonist in dual regulation of adenylate cyclase in NG108‐15 cells
Authors: Gomes Ivone , Gupta Achla , Singh S.P , Sharma Shail K
Published: July 2002

Monoclonal antibodies generated against multiple antigenic peptides of the N‐terminal sequence (3LVPSARAELQSSPLV17) of the cloned δ opioid receptor immunoprecipitated a 58 kDa protein from CHAPS‐solubilized NG108‐15 membranes. The immunoprecipitates bound [3H]DPDPE – but not [3H]DAMGO – with a K
d of 6.4 nM and a B
max of 75 pM. Western blot analysis revealed a distinct band of 58 kDa. The antibodies inhibited basal and PGE1‐stimulated cAMP levels, and mimicked the effect of agonists manifest in a compensatory increase in cAMP formation. The antibody will be potentially useful in the analysis of functional epitopes on the δ opioid receptor.
Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases
Authors: Kostoulas Georgios , Lang Angela , Nagase Hideaki , Baici Antonio
Published: July 2002

The tissue inhibitors of matrix metalloproteinases (MMPs), TIMP‐1 and TIMP‐2, are also angiogenesis inhibitors. Cathepsin B and MMPs are found at sites of neovascularization in pathologies such as cancer and osteoarthritis. Treatment of TIMP‐1, TIMP‐2, and of a mixture of both inhibitors from human articular chondrocytes with cathepsin B resulted in their fragmentation, whereby they lost their MMP‐inhibitory and anti‐angiogenic activities. Our data suggest that, besides directly participating in tissue destruction, cathepsin B can be harmful for two further reasons: it raises the activity of the MMPs also in the absence of mechanisms up‐regulating these enzymes, and it stimulates angiogenesis. This is a prerequisite for blood vessel invasion in a variety of pathological situations of which cancer and osteoarthritis are prominent examples.
The antiproliferative activity of the murine interferon‐inducible Ifi 200 proteins depends on the presence of two 200 amino acid domains
Authors: Gribaudo Giorgio , Riera Ludovica , De Andrea Marco , Landolfo Santo
Published: July 2002

Interferon‐inducible proteins, p200, have a modular organization consisting of one (p203) or two (p202 and p204) 200 amino acid motifs, designated as type a or b domains. The relationship between this domain organization and the antiproliferative activity was investigated by generating a hybrid protein with the 204 a domain upstream from the 203 b domain. This 204a/203b protein inhibits the proliferation of transfected cells, delays G0/G1 progression into S phase following serum restimulation, and inhibits the E2F‐mediated transcriptional activity. These results demonstrate for the first time that both a and b domains are needed for inhibition of proliferation by the Ifi 200 proteins.
A zinc‐finger transcription factor induced by TGF‐β promotes apoptotic cell death in epithelial Mv1Lu cells
Authors: Chalaux Elisabet , López-Rovira Teresa , Rosa Jose Luis , Pons Gabriel , Boxer Linda M. , Bartrons Ramon , Ventura Francesc
Published: July 2002

Transforming growth factor‐β (TGF‐β) superfamily members constitute a group of multifunctional factors that are able to stimulate apoptotic cell death in a variety of cells. In this report, we show that a zinc‐finger transcription factor (TIEG) is an immediate early gene transcriptionally induced by TGF‐β in the epithelial Mv1Lu cell line. We also demonstrate that, mimicking TGF‐β effects, ectopic overexpression of TIEG is sufficient to trigger the apoptotic cell program in these cells, which is preceded by a decrease of Bcl‐2 protein levels. Finally, apoptotic events elicited by TIEG overexpression can be effectively prevented by ectopic co‐expression of Bcl‐2. On the basis of these results we suggest that induction of TIEG expression has a role in the pro‐apoptotic properties of TGF‐β.
Delivery of patients with early onset, severe pre‐eclampsia
Authors: Hall D.R , Odendaal H.J , Steyn D.W
Published: July 2002

Objectives: To compare the effects of induction/labor to delivery before labor in early onset, severe pre‐eclampsia. Methods: Five‐year prospective case series. Delivery course and neonatal outcome were examined for 335 women with viable singletons. Results: Induction was successful in 45% of attempts. Women exposed to labor had longer (5.5 days, P<0.0001) admissions to delivery periods and were more often delivered for maternal indications (RR=2.87, 95% CI=1.98–4.16). Their babies were born 1.6 weeks older (P<0.0001) and 352 g heavier (P<0.0001) than those delivered before labor. Babies exposed to labor needed intensive care less often (RR=0.4, 95% CI=0.27–0.58), had lower rates of severe hyaline membrane disease (RR=0.26, 95% CI=0.11–0.59) and sepsis (RR=0.56, 95% CI=0.33–0.93), and were discharged earlier (P<0.0001). Conclusions: Exposure to induction/labor in selected patients is not detrimental to neonatal outcome in early, severe pre‐eclampsia.
Pre‐embryo donation: ethical and legal aspects
Authors: Eisenberg V.H. , Schenker J.G.
Published: July 2002

Genetic material donation has become an integral part of the management of infertility. Sperm, oocyte and pre‐embryo donation are successful both medically and technically. The practice of genetic material donation raises ethical, legal, religious and social issues. The practice of pre‐embryo donation raises several unique issues, such as the status of the pre‐embryo and its well‐being. Medical problems which need to be considered include selection of the donors, evaluation of the recipients and quality control of the genetic material. The relationship between the biological and social parents, and the safeguarding of the interests of the offspring, may be resolved by specific legislation pertaining to each country. Potential pre‐embryo banks should be subjected to licensing and should not be run by a commercial system. By practicing pre‐embryo donation, the medical profession and society should consider not only the interests of the infertile couple, but also the interests of the offspring.
Management of septate uterus by flexible hysteroscopy and Nd:YAG laser
Authors: Jourdain O , Dabysing F , Harle T , Lajus C , Roux D , Dallay D
Published: July 2002

Objective: To evaluate the efficiency of flexible Nd‐YAG laser hysteroscopic metroplasty. Methods: We present a retrospective study of 17 patients treated for septate uteri between 1990 and 1995. The indication of hysteroscopy was recurrent abortion in nine cases and eight with primary infertility with indication of IVF in another five cases. We did not prescribe any pretreatment. A flexible hysteroscope with a 100‐W Nd:YAG laser was used with glycine‐controlled flow. The septum was divided by the laser after exploration of the cavity. We proposed a control office hysteroscopy 2 months after surgery to prevent uterine adhesions. Results: There was no complication. Twelve patients conceived with 10 live births at term and two spontaneous abortions. Four are still infertile, two were lost from the study and two no longer desired pregnancy. Resectoscopic studies showed the same results. Conclusion: The advantages of this method are the excellent ergonomic properties of the fibroscope and the safety of the laser. We suggest that metroplasty does not improve the pregnancy rate but only the pregnancy outcome of these patients. However, for those with the indication of IVF the procedure seems useful in avoiding abortion.
The impact of total productive maintenance practices on manufacturing performance
Authors: McKone Kathleen E , Schroeder Roger G , Cua Kristy O
Published: July 2002

In this paper we investigate the relationship between Total Productive Maintenance (TPM) and manufacturing performance (MP) through Structural Equation Modeling (SEM). We find that TPM has a positive and significant relationship with low cost (as measured by higher inventory turns), high levels of quality (as measured by higher levels of conformance to specifications), and strong delivery performance (as measured by higher percentage of on‐time deliveries and by faster speeds of delivery). We also find that the relationship between TPM and MP can be explained by both direct and indirect relationships. In particular, there is a significant and positive indirect relationship between TPM and MP through Just‐In‐Time (JIT) practices.
The mediating role of operations knowledge in the relationship of context with performance
Authors: Germain Richard , Dröge Cornelia , Christensen William
Published: July 2002

Design knowledge intensity and throughput variance are both aspects of knowledge, the former relating to organizational management knowledge and the latter characteristic of operational process knowledge. We model and test their relationships to each other and to financial performance. We also examine two context variables as antecedent to knowledge: they are demand unpredictability (a dimension of environmental uncertainty) and mass output orientation (a measure of production technology type). The results show that knowledge completely mediates the effects of context on financial performance; i.e. the context variables impact knowledge and knowledge impacts financial performance, but the context variables have no direct effect on financial performance. Thus, knowledge appears to shield the firm from demand unpredictability, while mass output orientation type affects financial performance only through its impact on knowledge.
Organizational culture and advanced manufacturing technology implementation
Authors: McDermott Christopher M , Stock Gregory N
Published: July 2002

Using data collected from a sample of 97 manufacturing plants, we examine how organizational culture is related to outcomes associated with advanced manufacturing technology (AMT) implementation. Multiple item scales are developed and adapted from a wide range of sources in the literature to measure managers' perceptions of organizational culture, AMT benefits, and implementation outcomes such as operational benefits, organizational benefits, satisfaction, and competitive success. Regression analysis is used to analyze the relationships between these variables. The results suggest that cultural characteristics, as defined by the competing values model, are significantly related to AMT implementation outcomes. We conclude by discussing the managerial implications of these results.
The effects of static and intermittent compression on nitric oxide production in articular cartilage explants
Authors: Fermor Beverley , Weinberg J. Brice , Pisetsky David S. , Misukonis Mary A. , Banes Albert J. , Guilak Farshid
Published: July 2002

Nitric oxide (NO) production and NO synthase (NOS) expression are increased in osteoarthritis and rheumatoid arthritis, suggesting that NO may play a role in the destruction of articular cartilage. To test the hypothesis that mechanical stress may increase NO production by chondrocytes, we measured the effects of physiological levels of static and intermittent compression on NOS activity, NO production, and NOS antigen expression by porcine articular cartilage explants. Static compression significantly increased NO production at 0.1 MPa stress for 24 h (P < 0.05). Intermittent compression at 0.5 Hz for 6 h followed by 18 h recovery also increased NO production and NOS activity at 1.0 MPa stress (P < 0.05). Intermittent compression at 0.5 Hz for 24 h at a magnitude of 0.1 or 0.5 MPa caused an increase in NO production and NOS activity (P < 0.05). Immunoblot analysis showed stress‐induced upregulation of NOS2, but not NOSI or NOS3. There was no loss in cell viability following any of the loading regimens. Addition of 2 mM 1400 W (a specific NOS2 inhibitor) reduced NO production by 51% with no loss of cell viability. These findings indicate that NO production by chondrocytes is influenced by mechanical compression in vitro and suggest that biome‐chanical factors may in part regulate NO production in vivo. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Postnatal development of cholinergic system in mouse basal forebrain: acetylcholinesterase histochemistry and choline‐acetyltransferase immunoreactivity
Authors: Villalobos Julio , Rios Oscar , Barbosa Milton
Published: July 2002

The distribution of acetylcholinesterase histochemistry and choline‐O‐acetyltransferase immunohistochemistry in the basal forebrain was studied in newborn mice (P0) and until 60 days of postnatal life (P60). A weak acetylcholinesterase activity was found at P0 and P2 in the anterior and intermediate parts of the basal forebrain, and higher in the posterior region. The intensity of labeling, neuronal size and dendritic growth seems to increase progressively in all regions of basal forebrain from P4 to P10. The AChE+ cell count shows that in the anterior portion of the magnocellular basal nucleus the number of cells does not vary significantly from birth to the second month of postnatal life. However, in the intermediate and posterior portions of the nucleus the mean number of labeled cells increases significantly from birth to the end of the second week of postnatal life (P13). The choline‐acetyltransferase immunoreactivity appears only detectable at the end of the first week (P6) as a slight immunoreaction, which increases progressively in intensity at P8, and at P10 seems to attain the same intensity of labeling found at P60. These results seem to indicate that the acetylcholinesterase could have a non‐classic cholinergic role in the first stages of postnatal development, acting as a growth and cellular differentiation factor.
DNA polymerases δ and e in developing and aging rat brain
Authors: Prapurna Danam Rebecca , Rao Kalluri Subba
Published: July 2002

Our study reveals the presence of DNA polymerases δ and e, participating in DNA replication and repair, along with already known polymerases α and β, in the developing and aging rat brain. This was achieved through a protocol that takes advantage of the reported differential sensitivities of different DNA polymerases towards certain inhibitors such as butylphenyl and butylanilino nucleotide analogs, 2′, 3′‐dideoxythymidine triphosphate, the monoclonal antibody of human polymerase α and the use of preferred template primers and proliferating cell nuclear antigen. The results indicate that while polymerase β seems to be the predominant one, significant levels of polymerases α, δ and e are also present at all the postnatal ages studied and that the relative proportion of polymerase e increases with age. The data suggest that the rat brain is equipped with a sustained DNA repair capacity throughout the life span.
Developmental expression of nitric oxide synthase in the rat diencephalon with special reference to the thalamic paratenial nucleus
Authors: Gorbatyuk Oleg , Landry Marc , Emson Piers , Akmayev Ildar , Hökfelt Tomas
Published: July 2002

Using immunohistochemistry and in situ hybridization the distribution of nitric oxide synthase (NOS) was investigated in the rat brain during pre‐ and postnatal development. At E15 weak NOS‐like immunoreactivity (NOS‐LI) could be seen in the differentiation field of the anterior hypothalamus. At E17 strong NOS‐LI was observed in the developing neurons of the hypothalamic paraventricular nucleus, supraoptic nucleus, anterodorsal nucleus and lateral hypothalamic areas. In the thalamic paratenial nucleus a strong NOS‐LI was observed in these neurons at E17, E18 and P1 with a weaker intensity at P3, P7, P9 and P15, whereas at P30 and in adult rats no NOS‐positive neurons could be detected. NOS expression at E17 and P3 was verified by in situ hybridization. These results suggest that NO may have a developmental role at least in one of the regions studied, the thalamic paratenial nucleus.
Increased basal activity of the HPA axis and renin‐angiotensin system in congenital learned helpless rats exposed to stress early in development
Authors: Edwards E. , King J.A. , Fray J.C.S.
Published: July 2002

Learned helpless behavior has been successfully bred in rats and designated as a genetic animal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the effects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic–pituitary–adrenal axis and the renin‐angiotensin system. The functioning of the hypothalamic–pituitary–adrenal axis was monitored through changes in corticosterone plasma levels in the adult animals after acute exposure to cold stress and maternal deprivation early in development. Renin‐angiotensin system functioning was assessed by plasma renin activity. Unstressed congenital learned helpless rats had corticosterone levels that were similar to control animals (congenital non‐learned helpless rats not stressed during development), but unstressed plasma renin activity levels of congenital learned helpless rats were lower than congenital non‐learned helpless rats. There was a step‐wise increase in corticosterone plasma levels in the congenital learned helpless rats with age of acute presentation of either cold stress or maternal deprivation stress (day 7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline corticosterone levels were significantly lower in congenital learned helpless rats compared to congenital non‐learned helpless controls. Similarly, in response to early exposure to cold stress and maternal deprivation, there was an increase in plasma renin activity levels of congenital learned helpless rats with age of presentation to either stressors. However, this increase in plasma renin activity levels was not evident in congenital non‐learned helpless controls. Taken together, these results suggest that exposure to stress early in development has long‐term effects on both the hypothalamic–pituitary–adrenal axis and the renin‐angiotensin system, two neuroendocrine indicators of stress responsivity.
Nonresponder anorectic patients after 6 months of multimodal treatment: predictors of outcome
Authors: Fassino S. , Abbate Daga G. , Amianto F. , Leombruni P. , Garzaro L. , Rovera G.G.
Published: July 2002

Currently the therapy of anorexia nervosa is a relevant clinical problem. The percentage of patients who respond to short-term pharmacotherapy and psychotherapy is still low and the condition often leads to chronic pathology or death. The present study aims to determine outcome predictors beyond personality traits, eating psychopathology, or particular clinical features.

Forty patients with restricter type anorexia nervosa were tested, at T0 and after 180 days, with psychometric tests and clinical evaluation instruments. Patients were then divided into two groups. One group included patients who showed relevant clinical improvement; the other included not-yet-improved patients.

A lower Novelty Seeking, higher levels of Ascetism and Maturity Fears characterised the not-yet-improved group. Correlation showed evidence of diverse bonds between personality and psychopathology in the improved and not-yet-improved groups. The psychopathology of non-yet-improved patients seemed to be more linked to their temperamental features, whereas improved patients seemed to be more influenced by their character. Different levels of psychological functioning can be expressed.

The present data suggest focusing pharmacotherapy and psychotherapy, even family counseling, with a progression more strictly related to the current personality functioning level and psychopathology of each patient.
New treatments for panic
Authors: Ballenger JC
Published: July 2002

Panic disorder is a chronic condition for many patients and can be socially, emotionally and occupationally disabling. Until recently, clomipramine and alprazolam were the only drugs approved for its treatment. While widely used in the US and Europe, both belong to drug classes (tricyclics and benzodiazepines) with well-recognised side effects that can be problematic and thus limit their use. Recently, paroxetine became the first selective serotonin reuptake inhibitor to receive approval and licensing for panic disorder.

The short- and long-term efficacy and tolerability of paroxetine in panic disorder has been established in clinical trials of almost 1,000 patients meeting Diagnostic and Statistical Manual (DSM)-IIIR criteria for panic disorder, with or without agoraphobia. In a 12-week double-blind study of 120 panic patients receiving standardised cognitive therapy, paroxetine was significantly more effective than placebo in reducing panic attack frequency. In a 12-week placebo-controlled comparison in 367 panic patients, paroxetine was at least as effective as clomipramine and better tolerated. There was also some evidence that paroxetine had an earlier onset of action than clomipramine.

A 9-month extension of the placebo-controlled comparison with clomipramine showed that the efficacy of paroxetine and clomipramine is maintained when treatment is continued into the longer term. In a relapse prevention study, 105 responders to 3 months' treatment with paroxetine or placebo were re-randomised, either to continue existing treatment or to receive placebo for 3 months. Only 5% of patients who continued to take paroxetine experienced a relapse compared with 30% of those who switched to placebo (P = 0.002). Paroxetine was generally well tolerated. In the short-term trials, the frequency of withdrawals due to adverse events (7.3%) was lower than that for placebo (11.4%) or clomipramine (14.9%). In the longer term, the dropout rate due to adverse events increased in the clomipramine group (19.0%) but was unchanged in the paroxetine group (7.4%). Since most patients with panic disorder will require prolonged treatment, the long-term tolerability of paroxetine and its lack of potential for dependence are important advantages that will encourage good compliance with treatment and improve the quality of life of patients.
RETRACTED: MeCP2 drives hepatocellular carcinoma progression via enforcing HOXD3 promoter methylation and expression through the HB‐EGF/EGFR pathway
Authors: Wang Lumin , Gao Yi , Tong Dongdong , Wang Xiaofei , Guo Chen , Guo Bo , Yang Yang , Zhao Lingyu , Zhang Jing , Yang Juan , Qin Yannan , Liu Liying , Huang Chen
Published: May 2021

Homeobox D3 (HOXD3), a member of the homeobox family, was described to regulate tumorigenesis, invasion, metastasis, and angiogenesis in various tumor types. However, the molecular mechanisms regulating HOXD3 during hepatocellular carcinoma (HCC) migration, invasion, and angiogenesis remain elusive. In this study, we demonstrated that HOXD3 expression is enhanced by the binding of methyl‐CpG‐binding protein 2 (MeCP2), a methyl‐CpG binding protein, together with CREB1to the hypermethylated promoter of HOXD3. Inhibition of HOXD3 eliminated the tumorigenic effects of MeCP2 on HCC cells. Furthermore, HOXD3 directly targeted the promoter region of heparin‐binding epidermal growth factor (HB‐EGF) via the EGFR‐ERK1/2 cell signaling pathway and promoted invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. Additionally, elevated expression of MeCP2, CREB1, and HB‐EGF in HCC correlated with a poor survival rate. Our findings reveal the function of the MeCP2/HOXD3/HB‐EGF regulatory axis in HCC, rendering it an attractive candidate for the development of targeted therapeutics and as a potential biomarker in patients with HCC.
Microneedle‐Based Local Delivery of CCL22 and IL‐2 Enriches Treg Homing to the Skin Allograft and Enables Temporal Monitoring of Immunotherapy Efficacy
Authors: Puigmal Núria , Dosta Pere , Solhjou Zhabiz , Yatim Karim , Ramírez Cynthia , Choi John Y. , Alhaddad Juliano B. , Cosme Ana Paula , Azzi Jamil , Artzi Natalie
Published: May 2021

Skin allografts only serve as temporary dressing for patients suffering major burns due to their high immunogenicity and rejection by the immune system, requiring systemic immunosuppressive therapies that lead to deleterious side effects. Microneedle arrays composed of hyaluronic acid (HA) and placed on skin allografts can locally deliver immunomodulators and simultaneously sample immune cells in interstitial fluid to monitor the response to the therapy. The cells can be retrieved from the microneedles for downstream analysis by degrading the HA using a reducing agent. Using an allogeneic skin transplantation model, it is shown that the microneedle‐mediated local delivery of the chemokine CCL22 (to attract Tregs) and the cytokine IL‐2 (to promote their expansion) increases the local immune suppression in the allograft. Moreover, immune cell population in the allograft correlates with that seen in the microneedles. The delivery and sampling functions of the microneedle arrays can help regulate the immune system locally, without inducing systemic immune suppression, and facilitate the monitoring of the response to the therapy following skin transplantation.
Silver‐Catalyzed Direct Regioselective C3 Phosphonation of 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones With H‐phosphites
Authors: Guo Lina , Su Meiyun , Zhan Haiying , Liu Wenjie , Wang Shaohua
Published: May 2021

An efficient and simple protocol for silver‐catalyzed direct C3 phosphonation of 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones with dialkyl phosphites has been developed. The reaction shows high regioselectivity, broad scope of substrates, and good functional group compatibility. Importantly, the phosphorylated 4H‐pyrido[1,2‐a]pyrimidin‐4‐one product 3 u can be employed as efficient probes for Fe3+.