bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroimaging With Calibrated fMRI
Authors: Hyder Fahmeed
Published: September 2004

The conventional functional MRI (fMRI) map offers information indirectly about localized changes in neuronal activity because it reflects changes in blood oxygenation, not actual neuronal activity. To provide a neurophysiological basis of fMRI, researchers have used electrophysiology to show correlations of fMRI and electric signals. However, quantitative interpretation of the degree to which neuronal activity has changed still cannot be made from conventional fMRI data. The fMRI signal has 2 parts: one describes the correlation between oxidative metabolism (cerebral metabolic rate of oxygen [CMRO
2
]) and cerebral blood flow (CBF), which supports the bioelectric work to sustain neuronal excitability; the other is the requisite dilation of blood vessels (cerebral blood volume [CBV]), which is the mechanical response involved in removal of waste while providing nutrients. Since changes in energy metabolism are related to bioelectric work, we tested whether spiking frequency of a neuronal ensemble (ν) is reflected by local energy metabolism (CMRO
2
) in rat brain. We used extracellular recordings to measure Δν/ν and calibrated fMRI (ie, using fMRI signal, CBF, and CBV maps) to measure ΔCMRO
2
/CMRO
2
during sensory stimulation. We found that ΔCMRO
2
/CMRO
2
is ≈Δν/ν, which suggests efficient energy use during brain work. Thus, calibrated fMRI provides data on where and by how much the neuronal activity has changed. Possibilities of utilizing calibrated fMRI as a neuroimaging method are discussed.
Future Targets and Cascades for Neuroprotective Strategies
Authors: Chan Pak H.
Published: September 2004

Cumulative evidence suggests that apoptosis plays a pivotal role in neuronal death after cerebral ischemia in various experimental animal models. The time-dependent molecular and biochemical sequelae that lead to apoptotic cell death after the interruption of cerebral blood flow have been established. Many neuroprotective agents that target cell death pathways have been failures, and alternative strategies need to be considered. One such strategy is to target the neuronal survival signaling pathway, which involves the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway. It has been demonstrated that PI3-K/Akt and downstream phosphorylated Bad and proline-rich Akt substrate survival signaling cascades are upregulated in surviving neurons in the ischemic brain that overexpresses copper-zinc superoxide dismutase activity. These studies provide an impetus for novel therapeutic targets in neuroprotective strategies in stroke.
Functional Imaging in Stroke Recovery
Authors: Cramer Steven C.
Published: September 2004

Assessing neurobiology of brain systems can provide information not available from anatomic or behavioral assessment. Such information may be of value in understanding, defining, and prescribing potential therapeutic interventions that target restorative brain events after stroke. A number of methods have been used to study stroke recovery, each with its relative merits and limitations. Several studies suggest that greater injury is associated with reduced laterality of brain activity. This might be in relation to changes in interhemispheric inhibition and is a phenomenon that is likely useful for functional gains in some patients. Many other features of brain activity change in the months after a stroke, including the site and size of activation in relevant brain network nodes. While there is incomplete agreement regarding which features of altered brain activity predict and parallel better behavioral outcome, studies converge on the conclusion that best outcome is achieved by activating the brain in a pattern that most resembles the normal state.
Evaluation and Investigation of Surface Treatment of Industrial Coatings by Impedance Spectroscopy
Authors: Neshati J. , Fardi M.R.
Published: September 2004

Three organic coatings of commercial grade (zinc rich epoxy–polyamide) were applied to steel substrates and immersed for up to 2160 h in 0.5M NaCl at 25°C. These coated plates were assessed by ac impedance in the frequency range 100 kHz to 1 mHz. The coatings were evaluated in salt spray and humidity tests according to ASTM B117 and D-2247. X-ray diffraction and X-ray fluorescence techniques were applied to analyse the coated surface. Electrolytic penetration through the coating changes the dynamic characteristics of the conduction and resistance of the coating film of the protected system over time. Equivalent circuits were used to interpret the physical and electrochemical properties of the changes so, for each coating system, equivalent circuits were appointed using analysis of impedance curves. The numerical quantities of elements were estimated by the Boukamp method. The mechanism and kinetics of the electrochemical systems were assessed by studying the changes in electrochemical parameters v. time. The qualities of the coatings can be compared by measuring the fluctuations in capacitance, dielectric constant and percentage of water uptake. The results obtained from impedance and salt spray tests were compared. Results showed that the best quality coatings can be introduced by measuring the capacitance, water uptake and dielectric constant.
Investigation of Cr(III) Based Conversion Coatings on Electrogalvanised Steel
Authors: Zhang X. , van den Bos C. , Sloof W.G. , Terryn H. , Hovestad A. , de Wit J.H.W.
Published: September 2004

The corrosion behaviour of Cr(III) based conversion coatings on electrogalvanised steel was studied using polarisation and electrochemical impedance spectroscopy measurements in 0.01M NaCl solution (pH 6). The Cr(III) based conversion treatments were carried out in two different commercial trivalent chromium baths (pH 1.8–2.0). With an immersion time of 1 min, the thickness of the first type of Cr(III) based coating (blue) was about 94 nm and the thickness of the second type of coating (iridescent yellow) was about 250 nm; these thicknesses were determined by spectroscopic ellipsometry. As a comparison, a Cr(VI) based coating on electrogalvanised steel was also studied. The morphologies and compositions of the coatings were investigated by means of scanning electron microscopy, Fourier transform infrared spectroscopy and Auger electron spectroscopy. The Cr(III) coatings contained mainly a mixture of zinc oxides and chromium oxides/ hydroxides, and no Cr(VI) was detected in these coatings. The polarisation measurements in NaCl solution showed a retarded cathodic reaction for both the Cr(III) and the Cr(VI) based coatings. The corrosion resistance of the thicker Cr(III) coating was greater than that of the thinner Cr(III) coating. However, in the cases studied, the Cr(III) coatings still did not inhibit the corrosion of the electrogalvanised steel as effectively as did the Cr(VI) based coatings. The reason may be that the Cr(III) coatings do not possess the ‘self-healing’ properties that the Cr(VI) based coatings do.
Diffusion Coatings for Heat Exchanger Materials
Authors: Rohr V. , Schütze M.
Published: September 2004

There is a need to develop cleaner electric power systems, with reduced emission of pollutants. This implies an increase in the maximum temperature of heat exchanger tubes, which is now, 600°C in modern power plants. For conventionally used ferritic steels, this increase is limited by the steels’ mechanical properties and their corrosion resistance in coal, waste or biomass fired environments. Austenitic steels and nickel based alloys are potential candidates for increasing performance at higher temperature (700°C. Nonetheless, the corrosion resistance of these materials could be improved even further by applying a coating. Pack cementation is one of the easiest and cheapest coating processes. However, it requires a heating step which is presently performed at a minimum temperature of 750–800°C. The microstructure of the material may be significantly changed at these temperatures during the coating process, especially for ferritic–martensitic steels. Since the microstructure dictates the mechanical properties, these may also suffer from the coating process. As a consequence, there is a need to develop the pack cementation process at lower temperatures. In the present paper, ferritic steels P91 and HCM12A, and austenitic steels alloy 800H and a 347 type steel with 17Cr/13Ni, and the nickel based alloy IN617 were aluminised at temperatures below the above mentioned range. In order to facilitate the penetration of the protective elements during the coating process, different surface treatments were applied before the process to investigate the influence of an increase in the number of diffusion paths in the metal subsurface zone. The influence of surface treatments such as grinding or glass bead blasting on the efficiency of the process is discussed in detail.
Phosphate Coatings Porosity: Review of New Approaches
Authors: Kwiatkowski L.
Published: September 2004

The value of a phosphate coating's porosity varies between 0.1 and 25%, depending on process details and the method of determination. In the case of electrochemical methods, low amplitude or other low invasive techniques are recommended. The assumption that the mechanism of electrochemical/chemical reaction in pores of the phosphate coating and bare metal is the same is often not verified. The free surface at the bottom of the pores was found to be modified in pretreatment and post-treatment operations and in some cases was found to be more active than the clean bare metal surface. The reference sample should be at least treated in diluted phosphoric acid that has the same free and total acidity as the phosphating bath.
Aluminide Coatings for Nickel Based Superalloys
Authors: Khajavi M.R. , Shariat M.H. , Pasha A.
Published: September 2004

A number of aluminide coatings have been developed which are modified by additional elements (noble metals, Cr and reactive elements such as Y and Hf). This results in a marked improvement in their corrosion resistance. In the present paper, aluminide coatings are reviewed. The hot corrosion and oxidation resistance of these coatings in laboratory and field tests under different conditions are studied.
Impact of bone marrow hematopoiesis failure on T-cell generation during pathogenic simian immunodeficiency virus infection in macaques
Authors: Thiebot Hugues , Vaslin Bruno , Derdouch Sonia , Bertho Jean-Marc , Mouthon Franck , Prost Stéphane , Gras Gabriel , Ducouret Pierre , Dormont Dominique , Le Grand Roger
Published: September 2004

Experimental infection of macaques with pathogenic strains of simian immunodeficiency virus (SIV) represents one of the most relevant animal models for studying HIV pathogenesis. In this study, we demonstrated a significant decrease in the generation of CD4+ T cells from bone marrow (BM) CD34+ progenitors in macaques infected with SIVmac251. This decrease appears to result from changes in the clonogenic potential of BM progenitors of both the myeloid and lymphoid lineages. We also demonstrated a significant decrease in the numbers of the most immature long-term culture-initiating cells (LTC-ICs). Hematopoietic failure occurred as early as primary infection, in the absence of CD34+ BM cell infection and was not related to plasma viral load. No major change was observed in the phenotype of BM CD34+ cells from infected macaques, including apoptosis markers such as annexin V staining and BcL-2 expression, but a significantly higher that normal proportion of cells were in the G0/G1 phase. This is the first demonstration that failure of BM hematopoiesis results in impaired T-cell production, which may contribute to the disruption of T-lymphocyte homeostasis characteristic of pathogenic lentiviral infections in primates.
Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells
Authors: Evens Andrew M. , Lecane Philip , Magda Darren , Prachand Sheila , Singhal Seema , Nelson Jeff , Miller Richard A. , Gartenhaus Ronald B. , Gordon Leo I.
Published: September 2004

Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 μM MGd and 50 to 100 μM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
Proteolytic inactivation of ADAMTS13 by thrombin and plasmin
Authors: Crawley James T. B. , Lam Jonathan K. , Rance James B. , Mollica Luigina R. , O'Donnell James S. , Lane David A.
Published: September 2004

The multimeric size and the function of circulating von Willebrand factor are modulated via its proteolytic cleavage by the plasma metalloproteinase, ADAMTS13. It is unclear how ADAMTS13 activity is regulated within the vascular system. In the absence of a regulatory mechanism, ADAMTS13 activity might compromise platelet adhesion at sites of vascular injury. We hypothesized that at sites of vascular injury, ADAMTS13 activity could be regulated locally by coagulation proteinases. Initiation of coagulation in human plasma resulted in the disappearance of added full-length recombinant ADAMTS13. This loss was inhibited by hirudin. Using purified proteins, we showed that ADAMTS13 is proteolyzed at several cleavage sites by thrombin in a time- and concentration-dependent manner. Furthermore, this proteolysis ablated ADAMTS13 activity against purified von Willebrand factor. Preincubation of thrombin with soluble thrombomodulin, but not heparin, inhibited the proteolysis of ADAMTS13, suggesting the involvement of thrombin exosite I (and not exosite II) in ADAMTS13 recognition. Plasmin also cleaved ADAMTS13 into similar fragments, resulting in the loss of ADAMTS13 activity. This study demonstrates the susceptibility of ADAMTS13 to proteolytic inactivation and suggests possible roles for thrombin and plasmin at sites of vascular injury.
Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia
Authors: Cario Gunnar , Stanulla Martin , Fine Bernard M. , Teuffel Oliver , Neuhoff Nils v. , Schrauder André , Flohr Thomas , Schäfer Beat W. , Bartram Claus R. , Welte Karl , Schlegelberger Brigitte , Schrappe Martin
Published: September 2004

Treatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.
Mechanistic role of heat shock protein 70 in Bcr-Abl–mediated resistance to apoptosis in human acute leukemia cells
Authors: Guo Fei , Sigua Celia , Bali Purva , George Prince , Fiskus Warren , Scuto Anna , Annavarapu Srinivas , Mouttaki Abdelmoughite , Sondarva Gautam , Wei Sheng , Wu Jie , Djeu Julie , Bhalla Kapil
Published: September 2004

Bcr-Abl–expressing primary or cultured leukemia cells display high levels of the antiapoptotic heat shock protein (hsp) 70 and are resistant to cytarabine (Ara-C), etoposide, or Apo-2L/TRAIL (TNF-related apoptosis-inducing ligand)–induced apoptosis. Conversely, a stable expression of the cDNA of hsp70 in the reverse orientation attenuated not only hsp70 but also signal transducers and activators of transcription 5 (STAT5) and Bcl-xL levels. This increased apoptosis induced by cytarabine, etoposide, or Apo-2L/TRAIL. Ectopic expression of hsp70 in HL-60 cells (HL-60/hsp70) inhibited Ara-C and etoposide-induced Bax conformation change and translocation to the mitochondria; attenuated the accumulation of cytochrome c, Smac, and Omi/HtrA2 in the cytosol; and inhibited the processing and activity of caspase-9 and caspase-3. Hsp70 was bound to death receptors 4 and 5 (DR4 and DR5) and inhibited Apo-2L/TRAIL-induced assembly and activity of the death-inducing signaling complex (DISC). HL-60/hsp70 cells exhibited increased levels and DNA binding activity of STAT5, which was associated with high levels of Pim-2 and Bcl-xL and resistance to apoptosis. Expression of the dominant negative (DN) STAT5 resensitized HL-60/hsp70 cells to cytarabine, etoposide, and Apo-2L/TRAIL–induced apoptosis. Collectively, these findings suggest that hsp70 inhibits apoptosis upstream and downstream of the mitochondria and is a promising therapeutic target for reversing drug-resistance in chronic myeloid leukemia-blast crisis and acute myeloid leukemia cells. (Blood. 2005;105:1246-1255)
Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine
Authors: Shanafelt Tait D. , Lee Yean K. , Bone Nancy D. , Strege Ann K. , Narayanan Ven L. , Sausville Edward A. , Geyer Susan M. , Kaufmann Scott H. , Kay Neil E.
Published: September 2004

B-cell chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. We evaluated the ability of the investigational antileukemic agent adaphostin to induce apoptosis in CLL B cells and synergize with fludarabine in vitro. Analysis by annexin V/propidium iodide (PI) staining revealed that the concentration of adaphostin required to induce 50% cell death (IC50) at 24 hours was 4.2 μM (range, 1.10-11.25 μM; median, 4.25 μM; n = 29) for CLL isolates and more than 10 μM for B and T cells from healthy donors. Immunoblots demonstrated adaphostin induced poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage and cleavage of caspase-3 substrates, suggesting that adaphostin induces apoptosis. Adaphostin increased the level of reactive oxygen species (ROS) within CLL B cells, and the antioxidant N-acetylcysteine blocked both adaphostin-induced ROS generation and apoptosis. Adaphostin also caused a decrease in the level of the antiapoptotic protein Bcl-2. When adaphostin was combined with fludarabine (F-ARA-AMP), a synergistic effect on cell death was observed in all 10 CLL samples. These findings not only indicate that adaphostin induces apoptosis selectively in CLL B cells through a mechanism that involves ROS generation but also demonstrate its ability to augment the effects of fludarabine. Further preclinical development of adaphostin as a novel agent for the treatment of CLL appears warranted.
Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases
Authors: Mesa Ruben A. , Li Chin-Yang , Ketterling Rhett P. , Schroeder Georgene S. , Knudson Ryan A. , Tefferi Ayalew
Published: September 2004

Among 2333 consecutive patients with myelofibrosis with myeloid metaplasia (MMM) seen at our institution, 91 fulfilled the World Health Organization (WHO) criteria for leukemic transformation (LT). All episodes of LT were myeloid in origin (acute myeloid leukemia [AML]) with all French-American-British (FAB) subtypes represented except M3; the most frequent subtypes were M7 (25.4%), M0 (22.4%), and M2 (17.9%). Cytogenetic studies during LT were available in 56 patients and revealed a clonal abnormality in 51 (91%): 30 patients had complex karyotype, 2 had core-binding factor gene lesions, and 18 had abnormalities of chromosome 5 or 7. Karyotypic evolution was documented in the majority of the patients in whom serial analysis was possible. In general, LT was fatal in 98% of the cases after a median of 2.6 months (range, 0-24.2 months). Twenty-four patients received AML-like induction chemotherapy that resulted in no complete remission: 41% reverted into chronic-phase disease and the incidence of treatment-related mortality was 33%. The remaining 67 patients received either supportive care alone (48 patients) or low-intensity chemotherapy (19 patients). Overall, survival was similarly poor in all 3 treatment categories. The outcome of LT in MMM with current therapies is dismal and either supportive care alone or appropriate clinical trials should be considered.
Reconstruction of ancestral protein sequences and its applications
Authors: Cai Wei , Pei Jimin , Grishin Nick V
Published: September 2004

Background

Modern-day proteins were selected during long evolutionary history as descendants of ancient life forms. In silico reconstruction of such ancestral protein sequences facilitates our understanding of evolutionary processes, protein classification and biological function. Additionally, reconstructed ancestral protein sequences could serve to fill in sequence space thus aiding remote homology inference.

Results

We developed ANCESCON, a package for distance-based phylogenetic inference and reconstruction of ancestral protein sequences that takes into account the observed variation of evolutionary rates between positions that more precisely describes the evolution of protein families. To improve the accuracy of evolutionary distance estimation and ancestral sequence reconstruction, two approaches are proposed to estimate position-specific evolutionary rates. Comparisons show that at large evolutionary distances our method gives more accurate ancestral sequence reconstruction than PAML, PHYLIP and PAUP*. We apply the reconstructed ancestral sequences to homology inference and functional site prediction. We show that the usage of hypothetical ancestors together with the present day sequences improves profile-based sequence similarity searches; and that ancestral sequence reconstruction methods can be used to predict positions with functional specificity.

Conclusions

As a computational tool to reconstruct ancestral protein sequences from a given multiple sequence alignment, ANCESCON shows high accuracy in tests and helps detection of remote homologs and prediction of functional sites. ANCESCON is freely available for non-commercial use. Pre-compiled versions for several platforms can be downloaded from ftp://iole.swmed.edu/pub/ANCESCON/.
Comparative genomics of cyclin-dependent kinases suggest co-evolution of the RNAP II C-terminal domain and CTD-directed CDKs
Authors: Guo Zhenhua , Stiller John W
Published: September 2004

Background

Cyclin-dependent kinases (CDKs) are a large family of proteins that function in a variety of key regulatory pathways in eukaryotic cells, including control over the cell cycle and gene transcription. Among the most important and broadly studied of these roles is reversible phosphorylation of the C-terminal domain (CTD) of RNA polymerase II, part of a complex array of CTD/protein interactions that coordinate the RNAP II transcription cycle. The RNAP CTD is strongly conserved in some groups of eukaryotes, but highly degenerate or absent in others; the reasons for these differences in stabilizing selection on CTD structure are not clear. Given the importance of reversible phosphorylation for CTD-based transcription, the distribution and evolutionary history of CDKs may be a key to understanding differences in constraints on CTD structure; however, the origins and evolutionary relationships of CTD kinases have not been investigated thoroughly. Moreover, although the functions of most CDKs are reasonably well studied in mammals and yeasts, very little is known from most other eukaryotes.

Results

Here we identify 123 CDK family members from animals, plants, yeasts, and four protists from which genome sequences have been completed, and 10 additional CDKs from incomplete genome sequences of organisms with known CTD sequences. Comparative genomic and phylogenetic analyses suggest that cell-cycle CDKs are present in all organisms sampled in this study. In contrast, no clear orthologs of transcription-related CDKs are identified in the most putatively ancestral eukaryotes, Trypanosoma or Giardia. Kinases involved in CTD phosphorylation, CDK7, CDK8 and CDK9, all are recovered as well-supported and distinct orthologous families, but their relationships to each other and other CDKs are not well-resolved. Significantly, clear orthologs of CDK7 and CDK8 are restricted to only those organisms belonging to groups in which the RNAP II CTD is strongly conserved.

Conclusions

The apparent origins of CDK7 and CDK8, or at least their conservation as clearly recognizable orthologous families, correlate with strong stabilizing selection on RNAP II CTD structure. This suggests co-evolution of the CTD and these CTD-directed CDKs. This observation is consistent with the hypothesis that CDK7 and CDK8 originated at about the same time that the CTD was canalized as the staging platform RNAP II transcription. Alternatively, extensive CTD phosphorylation may occur in only a subset of eukaryotes and, when present, this interaction results in greater stabilizing selection on both CTD and CDK sequences. Overall, our results suggest that transcription-related kinases originated after cell-cycle related CDKs, and became more evolutionarily and functionally diverse as transcriptional complexity increased.
cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma
Authors: Chen Qing-Rong , Bilke Sven , Wei Jun S , Whiteford Craig C , Cenacchi Nicola , Krasnoselsky Alexei L , Greer Braden T , Son Chang-Gue , Westermann Frank , Berthold Frank , Schwab Manfred , Catchpoole Daniel , Khan Javed
Published: September 2004

Background

Recurrent non-random genomic alterations are the hallmarks of cancer and the characterization of these imbalances is critical to our understanding of tumorigenesis and cancer progression.

Results

We performed array-comparative genomic hybridization (A-CGH) on cDNA microarrays containing 42,000 elements in neuroblastoma (NB). We found that only two chromosomes (2p and 12q) had gene amplifications and all were in the MYCN amplified samples. There were 6 independent non-contiguous amplicons (10.4–69.4 Mb) on chromosome 2, and the largest contiguous region was 1.7 Mb bounded by NAG and an EST (clone: 757451); the smallest region was 27 Kb including an EST (clone: 241343), NCYM, and MYCN. Using a probabilistic approach to identify single copy number changes, we systemically investigated the genomic alterations occurring in Stage 1 and Stage 4 NBs with and without MYCN amplification (stage 1-, 4-, and 4+). We have not found genomic alterations universally present in all (100%) three subgroups of NBs. However we identified both common and unique patterns of genomic imbalance in NB including gain of 7q32, 17q21, 17q23-24 and loss of 3p21 were common to all three categories. Finally we confirm that the most frequent specific changes in Stage 4+ tumors were the loss of 1p36 with gain of 2p24-25 and they had fewer genomic alterations compared to either stage 1 or 4-, indicating that for this subgroup of poor risk NB requires a smaller number of genomic changes are required to develop the malignant phenotype.

Conclusions

cDNA A-CGH analysis is an efficient method for the detection and characterization of amplicons. Furthermore we were able to detect single copy number changes using our probabilistic approach and identified genomic alterations specific to stage and MYCN amplification.
MAPK-dependent regulation of IL-1- and β-adrenoreceptor-induced inflammatory cytokine production from mast cells: Implications for the stress response
Authors: Chi David S , Fitzgerald S Matthew , Pitts Shannon , Cantor Karen , King Ellis , Lee Steven A , Huang Shau-Ku , Krishnaswamy Guha
Published: September 2004

Background

Catecholamines, such as epinephrine, are elaborated in stress responses, and mediate vasoconstriction to cause elevation in systemic vascular resistance and blood pressure. Our previous study has shown that IL-1 can induce mast cells to produce proinflammatory cytokines which are involved in atherogenesis. The aim of this study was to determine the effects of epinephrine on IL-1-induced proatherogenic cytokine production from mast cells.

Results

Two ml of HMC-1 (0.75 × 106 cells/ml) were cultured with epinephrine (1 × 10-5 M) in the presence or absence of IL-1β (10 ng/ml) for 24 hrs. HMC-1 cultured alone produced none to trace amounts of IL-6, IL-8, and IL-13. IL-1β significantly induced production of these cytokines in HMC-1, while epinephrine alone did not. However, IL-6, IL-8, and IL-13 production induced by IL-1β were significantly enhanced by addition of epinephrine. The enhancing effect appears to involve NF-κB and p38 MAPK pathways. Flow cytometry showed the presence of β1 and β2 adrenoreceptors on resting mast cells. The enhancing effect of proatherogenic cytokine production by epinephrine was down regulated by the β1 and β2 adrenoceptor antagonist, propranolol, but not by the β1 adrenoceptor antagonist, atenolol, suggesting the effect involved β2 adrenoceptors. The enhancing effect of epinephrine on proatherogenic cytokine production was also down regulated by the immunosuppressive drug, dexamethasone.

Conclusions

These results not only confirm that an acute phase cytokine, IL-1β, regulates mast cell function, but also show that epinephrine up regulates the IL-1β induction of proatherogenic cytokines in mast cells. These data provide a novel role for epinephrine, a stress hormone, in inflammation and atherogenesis.
A comparative ultrastructural and molecular biological study on Chlamydia psittaci infection in alpha-1 antitrypsin deficiency and non-alpha-1 antitrypsin deficiency emphysema versus lung tissue of patients with hamartochondroma
Authors: Theegarten Dirk , Anhenn Olaf , Hotzel Helmut , Wagner Mathias , Marra Alessandro , Stamatis Georgios , Mogilevski Grigori , Sachse Konrad
Published: September 2004

Background

Chlamydiales are familiar causes of acute and chronic infections in humans and animals. Human pulmonary emphysema is a component of chronic obstructive pulmonary disease (COPD) and a condition in which chronic inflammation manifested as bronchiolitis and intra-alveolar accumulation of macrophages is common. It is generally presumed to be of infectious origin. Previous investigations based on serology and immunohistochemistry indicated Chlamydophila pneumoniae infection in cases of COPD. Furthermore, immunofluorescence with genus-specific antibodies and electron microscopy suggested involvement of chlamydial infection in most cases of pulmonary emphysema, but these findings could not be verified by PCR. Therefore, we examined the possibility of other chlamydial species being present in these patients.

Methods

Tissue samples from patients having undergone lung volume reduction surgery for advanced alpha-1 antitrypsin deficiency (AATD, n = 6) or non-alpha-1 antitrypsin deficiency emphysema (n = 34) or wedge resection for hamartochondroma (n = 14) were examined by transmission electron microscopy and PCR.

Results

In all cases of AATD and 79.4% of non-AATD, persistent chlamydial infection was detected by ultrastructural examination. Intra-alveolar accumulation of macrophages and acute as well as chronic bronchiolitis were seen in all positive cases. The presence of Chlamydia psittaci was demonstrated by PCR in lung tissue of 66.7% AATD vs. 29.0% non-AATD emphysema patients. Partial DNA sequencing of four positive samples confirmed the identity of the agent as Chlamydophila psittaci. In contrast, Chlamydophila pneumoniae was detected only in one AATD patient. Lung tissue of the control group of non-smokers with hamartochondroma was completely negative for chlamydial bodies by TEM or chlamydial DNA by PCR.

Conclusions

These data indicate a role of Chlamydophila psittaci in pulmonary emphysema by linking this chronic inflammatory process to a chronic infectious condition. This raises interesting questions on pathogenesis and source of infection.
Ability to perform activities of daily living is the main factor affecting quality of life in patients with dementia
Authors: Andersen Christian K , Wittrup-Jensen Kim U , Lolk Anette , Andersen Kjeld , Kragh-Sørensen Per
Published: September 2004

Background

Dementia is a chronic illness associated with a progressive loss of cognitive and intellectual abilities, such as memory, judgment and abstract thinking.

The objective of this study was to assess the health utilities of patients with dementia in Europe and identify the key factors influencing their Health-Related Quality of Life (HRQol).

Methods

This study used cross-sectional data from the Odense study; a Danish cohort of patients aged 65–84 living in Odense, Denmark. A total of 244 patients with mild to severe dementia were interviewed together with a caregiver about their health status and activities of daily living (ADL). Alzheimer's disease was diagnosed according to the NINCDS-ADRDA criteria for probable dementia. Vascular dementia and other types of dementia were diagnosed according to the DSM-IIIR criteria. Severity of dementia was defined by score intervals on the Mini Mental State Examination score: mild (MMSE 20–30), moderate (MMSE 10–19), and severe (MMSE 0–9). Based on the ADL information, the patients' dependency level was defined as either dependent or independent. Questions from the Odense Study were mapped into each of the five dimensions of the EQ-5D in order to assess patients' HRQol. Danish EQ-5D social tariffs were used to value patients' HRQol.

A regression analysis of EQ-5D values was conducted with backward selection on gender, age, severity, ADL level and setting in order to determine the main factor influencing HRQoL.

Results

The EQ-5D weight in patients independent upon others in ADL was 0.641 (95% CI: [0.612–0.669]), and in those dependent upon others was 0.343 (95% CI: [0.251–0.436]).

Conclusion

Dependency upon others to perform ADL was the main factor affecting HRQoL.
Identification of rehabilitation needs after a stroke: an exploratory study
Authors: Talbot Lise R , Viscogliosi Chantal , Desrosiers Johanne , Vincent Claude , Rousseau Jacqueline , Robichaud Line
Published: September 2004

Background

Services to meet adequate rehabilitation needs of elderly stroke survivors are not always provided. Indeed, since 1995, in the wake of the Quebec shift to ambulatory care, home care services, mainly those related to rehabilitation of the elderly, are either unavailable or incomplete. The aim of this study was to examine the rehabilitation needs of this clientele from their hospitalization to their reintegration into the community.

Methods

The "Handicap Production Process" conceptual approach was chosen to help identify the rehabilitation needs of persons affected by physical or cognitive disabilities due to the interactions between personal and environmental factors, and (activities of daily living, social roles). This qualitative exploratory study was performed in 2003. Data were collected among four groups of experts: patients, caregivers, health care providers and administrators. Data triangulation was used to ensure a rigorous analysis and validity of the results.

Results

Unfulfilled needs could be found in the categories of pertaining to residence, community living, psychological and emotional needs. Indeed, it appears that a psychological follow-up to discuss acceptance and consequences of non-acceptance would facilitate mid-to long-term rehabilitation.

Conclusion

Improving accessibility to healthcare services, respecting priority parking spaces for the disabled as well as promoting public awareness would enable a better social reintegration and recovery of social roles, thus limiting the onset of handicap situations.
BRCA1-mediated repression of select X chromosome genes
Authors: Jazaeri Amir A , Chandramouli Gadisetti VR , Aprelikova Olga , Nuber Ulrike A , Sotiriou Christos , Liu Edison T , Ropers H Hilger , Yee Cindy J , Boyd Jeff , Barrett J Carl
Published: September 2004

Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling). Significance was determined using parametric statistics with P < 0.005 as a cutoff. Forty of 178 total X-chromosome transcripts were differentially expressed between the BRCA1-associated tumors and sporadic cancers with a BRCA2-like molecular profile. Thirty of these 40 genes showed higher mean expression in the BRCA1-associated samples including all 11 transcripts that mapped to Xp11. In contrast, four of 178 total X chromosome transcripts showed significant differential expression between BRCA1-associated and sporadic tumors with a BRCA1-like molecular profile. All four mapped to Xp11 and showed higher mean expression in BRCA1-associated tumors. Re-expression of BRCA1 in HCC1937 BRCA1-deficient breast cancer cell resulted in the repression of 21 transcripts. Eleven of the 21 (54.5%) transcripts mapped to Xp11. However, there was no significant overlap between these Xp11 genes and those found to be differentially expressed between BRCA1-associated and sporadic ovarian cancer samples. These results demonstrate that BRCA1 mediates the repression of several X chromosome genes, many of which map to the Xp11 locus.
A knowledgebase system to enhance scientific discovery: Telemakus
Authors: Fuller Sherrilynne S , Revere Debra , Bugni Paul F , Martin George M
Published: September 2004

Background

With the rapid expansion of scientific research, the ability to effectively find or integrate new domain knowledge in the sciences is proving increasingly difficult. Efforts to improve and speed up scientific discovery are being explored on a number of fronts. However, much of this work is based on traditional search and retrieval approaches and the bibliographic citation presentation format remains unchanged.

Methods

Case study.

Results

The Telemakus KnowledgeBase System provides flexible new tools for creating knowledgebases to facilitate retrieval and review of scientific research reports. In formalizing the representation of the research methods and results of scientific reports, Telemakus offers a potential strategy to enhance the scientific discovery process. While other research has demonstrated that aggregating and analyzing research findings across domains augments knowledge discovery, the Telemakus system is unique in combining document surrogates with interactive concept maps of linked relationships across groups of research reports.

Conclusion

Based on how scientists conduct research and read the literature, the Telemakus KnowledgeBase System brings together three innovations in analyzing, displaying and summarizing research reports across a domain: (1) research report schema, a document surrogate of extracted research methods and findings presented in a consistent and structured schema format which mimics the research process itself and provides a high-level surrogate to facilitate searching and rapid review of retrieved documents; (2) research findings, used to index the documents, allowing searchers to request, for example, research studies which have studied the relationship between neoplasms and vitamin E; and (3) visual exploration interface of linked relationships for interactive querying of research findings across the knowledgebase and graphical displays of what is known as well as, through gaps in the map, what is yet to be tested. The rationale and system architecture are described and plans for the future are discussed.
Collagen type II (CII)-specific antibodies induce arthritis in the absence of T or B cells but the arthritis progression is enhanced by CII-reactive T cells
Authors: Nandakumar Kutty Selva , Bäcklund Johan , Vestberg Mikael , Holmdahl Rikard
Published: September 2004

Antibodies against type II collagen (anti-CII) are arthritogenic and have a crucial role in the initiation of collagen-induced arthritis. Here, we have determined the dependence of T and B cells in collagen-antibody-induced arthritis (CAIA) during different phases of arthritis. Mice deficient for B and/or T cells were susceptible to the CAIA, showing that the antibodies induce arthritis even in the absence of an adaptive immune system. To determine whether CII-reactive T cells could have a role in enhancing arthritis development at the effector level of arthritis pathogenesis, we established a T cell line reactive with CII. This T cell line was oligoclonal and responded to different post-translational forms of the major CII epitope at position 260–270 bound to the Aq class II molecule. Importantly, it cross-reacted with the mouse peptide although it is bound with lower affinity to the Aq molecule than the corresponding rat peptide. The T cell line could not induce clinical arthritis per se in Aq-expressing mice even if these mice expressed the major heterologous CII epitope in cartilage, as in the transgenic MMC (mutated mouse collagen) mouse. However, a combined treatment with anti-CII monoclonal antibodies and CII-reactive T cells enhanced the progression of severe arthritis.
Analysis of HLA DR, HLA DQ, C4A, FcγRIIa, FcγRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcγRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility
Authors: Jönsen Andreas , Bengtsson Anders A , Sturfelt Gunnar , Truedsson Lennart
Published: September 2004

Dysfunction in various parts of immune defence, such as immune response, immune complex clearance, and inflammation, has an impact on pathogenesis in systemic lupus erythematosus (SLE). We hypothesised that combinations of common variants of genes involved in these immune functions are associated with susceptibility to SLE. The following variants were analysed: HLA DR3, HLA DQ2, C4AQ0, Fcγ receptor IIa (FcγRIIa) genotype R/R, Fcγ receptor IIIa (FcRγIIIa) genotype F/F, mannan-binding lectin (MBL) genotype conferring a low serum concentration of MBL (MBL-low), and interleukin-1 receptor antagonist (IL-1Ra) genotype 2/2. Polymorphisms were analysed in 143 Caucasian patients with SLE and 200 healthy controls. HLA DR3 in SLE patients was in 90% part of the haplotype HLA DR3-DQ2-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7–4.5). Analysis of combinations of gene variants revealed that the strong association with SLE for HLA DR3-DQ2-C4AQ0 remained after combination with FcγRIIa R/R, FcγRIIIa F/F, and MBL-low (OR>2). Furthermore, the combination of the FcγRIIa R/R and IL-1Ra 2/2 genotypes yielded a strong correlation with SLE (OR 11.8, 95% CI 1.5–95.4). This study demonstrates that certain combinations of gene variants may increase susceptibility to SLE, suggesting this approach for future studies. It also confirms earlier findings regarding the HLA DR3-DQ2-C4AQ0 haplotype.
Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement
Authors: Trysberg Estelle , Blennow Kaj , Zachrisson Olof , Tarkowski Andrej
Published: September 2004

Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8 – two cytokines that are known to upregulate MMP-9 – both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.