bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression response of the rat small intestine following oral Salmonella infection
Authors: Rodenburg Wendy , Bovee-Oudenhoven Ingeborg M. J. , Kramer Evelien , van der Meer Roelof , Keijer Jaap
Published: March 2007

Data on the molecular response of the intestine to the food-borne pathogen Salmonella are derived from in vitro studies, whereas in vivo data are lacking. We performed an oral S. enteritidis infection study in Wistar rats to obtain insight in the in vivo response in time. Expression profiles of ileal mucosa (IM) and Peyer's patches (PP) were generated using DNA microarrays at days 1, 3, and 6 postinfection. An overview of Salmonella-regulated processes was obtained and confirmed by quantitative real-time PCR on pooled and individual samples. Salmonella-induced gene expression responses in vivo are fewer and smaller than observed in vitro, and the response develops over a longer period of time. Few effects are seen at day 1 and mainly occur in IM, suggesting the mucosa as the primary site of invasion. Later, a bigger response is observed, especially in PP. Decreased expression of anti-microbial peptides genes (in IM at day 1) suggests inhibition of this process by Salmonella. Newly identified target processes are carbohydrate transport (increased expression in IM at day 1) and phase I and phase II detoxification (decreased expression at days 3 and 6). Increase of cytokine and chemokine expression occurs at later time points, both in PP and IM. Pancreatitis-associated protein, lipocalin 2, and calprotectin, potential inflammatory marker proteins, showed induced expression from day 3 onward. We conclude that the in vivo gene expression response of the ileum to Salmonella differs to a large extent from the response seen in vitro.
Tissue Transglutaminase Inhibits Autophagy in Pancreatic Cancer Cells
Authors: Akar Ugur , Ozpolat Bulent , Mehta Kapil , Fok Jansina , Kondo Yasuko , Lopez-Berestein Gabriel
Published: March 2007

Elevated expression of tissue transglutaminase (TG2) in cancer cells has been implicated in the development of drug resistance and metastatic phenotypes. However, the role and the mechanisms that regulate TG2 expression remain elusive. Here, we provide evidence that protein kinase Cδ (PKCδ) regulates TG2 expression, which in turn inhibits autophagy, a type II programmed cell death, in pancreatic cancer cells that are frequently insensitive to standard chemotherapeutic agents. Rottlerin, a PKCδ-specific inhibitor, and PKCδ small interfering RNA (siRNA) down-regulated the expression of TG2 mRNA and protein and induced growth inhibition without inducing apoptosis in pancreatic cancer cells. Inhibition of PKCδ by rottlerin or knockdown of TG2 protein by a TG2-specific siRNA resulted in a marked increase in autophagy shown by presence of autophagic vacuoles in the cytoplasm, formation of the acidic vesicular organelles, membrane association of microtubule-associated protein 1 light chain 3 (LC3) with autophagosomes, and a marked induction of LC3-II protein, important hallmarks of autophagy, and by electron microscopy. Furthermore, inhibition of TG2 by rottlerin or by the siRNA led to accumulation of green fluorescent protein (GFP)-LC3-II in autophagosomes in pancreatic cancer cells transfected with GFP-LC3 (GFP-ATG8) expression vector. Knockdown of Beclin-1, a specific autophagy-promoting protein and the product of Becn1 (ATG6), inhibited rottlerin-induced and TG2 siRNA–induced autophagy, indicating that Beclin-1 is required for this process. These results revealed that PKCδ plays a critical role in the expression of TG2, which in turn regulates autophagy. In conclusion, these results suggest a novel mechanism of regulation of TG2 and TG2-mediated autophagy in pancreatic cancer cells. (Mol Cancer Res 2007;5(3):241–9)
BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs
Authors: Buckley Niamh E. , Hosey Alison M. , Gorski Julia J. , Purcell James W. , Mulligan Jude M. , Harkin D. Paul , Mullan Paul B.
Published: March 2007

BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-γ, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-γ. We also show that the induction of IRF-7 by BRCA1 and IFN-γ is dependent on the type I IFNs, IFN-α and IFN-β. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-γ. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-α and IFN-β in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-γ regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261–70)
Constitutive Suppressor of Cytokine Signaling 3 Expression Confers a Growth Advantage to a Human Melanoma Cell Line
Authors: Komyod Waraporn , Böhm Markus , Metze Dieter , Heinrich Peter C. , Behrmann Iris
Published: March 2007

The growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, whereas late stage melanoma cells have often been reported to be “multi-cytokine–resistant.” Here, we analyzed the melanoma cell line 1286, resistant towards the growth-inhibitory effects of interleukin 6 (IL-6), and oncostatin M (OSM), to better understand the mechanisms underlying cytokine resistance. Although the relevant receptors gp130 and OSMR are expressed at the cell surface of these cells, cytokine stimulation hardly led to the activation of Janus kinase 1 and signal transducer and activator of transcription (STAT)3 and STAT1. We found a high-level constitutive expression of suppressors of cytokine signaling 3 (SOCS3) that did not further increase after cytokine treatment. Importantly, upon suppression of SOCS3 by short interfering RNA, cells became susceptible towards OSM and IL-6: they showed an enhanced STAT3 phosphorylation and a dramatically increased STAT1 phosphorylation. Moreover, suppression of SOCS3 rendered 1286 cells sensitive to the antiproliferative action of IL-6 and OSM, but not of IFN-α. Interestingly, SOCS3–short interfering RNA treatment also increased the growth-inhibitory effect in cytokine-sensitive WM239 cells expressing SOCS3 in an inducible way. Thus, SOCS3 expression confers a growth advantage to these cell lines. Constitutive SOCS3 mRNA expression, although at lower levels than in 1286 cells, was found in nine additional human melanoma cell lines and in normal human melanocytes, although at the protein level, SOCS3 expression was marginal at best. However, in situ analysis of human melanoma specimens revealed SOCS3 immunoreactivity in 3 out of 10 samples, suggesting that in vivo SOCS3 may possibly play a role in IL-6 resistance in at least a fraction of tumors. (Mol Cancer Res 2007;5(2):271–81)
Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility
Authors: Larsen Alice Bjerregaard , Pedersen Mikkel Wandahl , Stockhausen Marie-Thérése , Grandal Michael Vibo , Deurs Bo van , Poulsen Hans Skovgaard
Published: March 2007

EphA2 overexpression has been reported in many cancers and is believed to play an important role in tumor metastasis and angiogenesis. We show that the activated epidermal growth factor receptor (EGFR) and the cancer-specific constitutively active EGFR type III deletion mutant (EGFRvIII) induce the expression of EphA2 in mammalian cell lines, including the human cancer cell lines A431 and HN5. The regulation is partially dependent on downstream activation of mitogen-activated protein kinase/extracellular signal–regulated kinase kinase and is a direct effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to the plasma membrane and EphA2 coimmunoprecipitates with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a functional role of EphA2 in EGFR-expressing cancer cells. (Mol Cancer Res 2007;5(3):283–93)
The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents
Authors: Tabernero Josep
Published: March 2007

Multiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, redundancy, and the potential for tumors to bypass signaling pathway blockade, resulting in primary or acquired resistance. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have become key therapies in several tumor types. Close relationships between these factors exist: VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor–resistant cell lines. Clinical trials have also produced promising data: combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The potential of this novel approach to anticancer therapy will be elucidated by large, ongoing clinical trials. (Mol Cancer Res 2007;5(3):203–20)
Fluorescence in situ Hybridization Reveals Closely Correlated Results in Cytological and Histological Specimens of Hematological Neoplasias Compared to Conventional Cytogenetics
Authors: Gerr Heidrun , Gadzicki Dorothea , Kreipe Hans , Schlegelberger Brigitte , Wilkens Ludwig
Published: March 2007

Objectives: Fluorescence in situ hybridization (FISH) has become a useful tool to identify chromosomal aberrations in non-dividing cells. Numerous studies have compared chromosomal banding analysis (CBA) and FISH on fixed cultured bone marrow cells. However, up to now, there has been no study comparing two main sources of diagnostic material, i.e. bone marrow aspirates and trephine biopsies. We therefore analyzed these materials by FISH in comparison with CBA. Methods: CBA revealed chromosomal aberrations in 18 patients suffering from myelodysplastic syndrome (n = 13), acute myeloid leukemia (n = 3), or chronic myeloproliferative syndrome (n = 2). FISH was performed on fixed cultured bone marrow cells, aspirates and trephine biopsies from each patient. Results: Percentages of aberrant cells in the different materials correlated highly with Pearson values of 0.909 for biopsy/fixed cultured cells (p < 0.001), 0.830 for biopsy/aspirate (p < 0.001) and 0.768 for aspirate/fixed cultured cells (p < 0.001). Moreover, in bone marrow biopsies peritrabecular and central intertrabecular areas yielded very similar FISH results with a high correlation (r = 0.968, p < 0.001). FISH revealed a lower proportion of aberrant cells than CBA in 90% of the specimens. Conclusions: In summary, the different materials available for the FISH examination are comparable in sensitivity and show similar quantitative results. Therefore, the use of biopsy sections for the routine FISH examination of chromosomal abnormalities is a valid method.
Splenic Rupture, Beyond and Behind: A Histological, Morphometric and Follow-Up Study of 254 Cases
Authors: Sterlacci William , Heiss Simone , Augustin Florian , Tzankov Alexandar
Published: March 2007

Objective: Population-based data regarding splenic rupture causes are sparse. To systematically characterize histology and morphometry of splenic rupture, we performed a retrospective clinicopathological study of 254 patients. Methods: Our electronic data base was reviewed and all splenic rupture cases were morphologically, morphometrically and, where needed, molecularly analyzed. Clinical and follow-up data were gained by reviewing patient charts. A formula to calculate splenic volume based on size was established and results were compared to the actual volumes. Results: Ruptured spleens presented 0.1% of all gross surgical pathology specimens. Nearly 90% were due to trauma and approximately 10% were pathologic, being associated with underlying diseases (5% with unexpected diseases) such as splenic angiomas, granulomatous diseases, infarctions, hepatopathies, cysts, hemorrhagic diatheses, hematological neoplasms, metastatic carcinoma and collagenosis. Men were more often affected than women. Morphometric analysis showed distinct splenic weights, volumes and capsule thicknesses with respect to the different rupture causes. Pathological ruptures were predominantly observed in elderly, male patients with larger spleens. Conclusions: Splenic rupture is due to an often unexpected underlying disease in approximately 10% of the cases. This should be kept in mind when dealing with susceptible patient groups.
Novel Electrical Stimulation Sets the Cultured Myoblast Contractile Function to ‘On’
Authors: Kawahara Yumi , Yamaoka Kaoru , Iwata Masahiro , Fujimura Masahiko , Kajiume Teruyuki , Magaki Takuro , Takeda Masaaki , Ide Toshinori , Kataoka Katsuko , Asashima Makoto , Yuge Louis
Published: March 2007

Objective: In the present study, the effect of electrical stimulation was examined for the ability to induce morphological, physiological, and molecular biological effects on myoblasts during cell differentiation. Methods: L6 rat myoblasts were electrically stimulated by newly developed methods on culture days 6, 8, 10 and 12. Results: This electrical stimulation accelerated the appearance of myotubes, and subsequently produced spontaneously contracting muscle fibers. Measurement of membrane potential showed that the contracting cell had functional ion channels and gap junctional intercellular communication. In the electrically stimulated cells, an enhanced expression of MyoD family and M-cadherin was also observed. Expression of connexin 43 was increased and maintained at a high level in the electrically stimulated cells. Conclusion: This is the first demonstration of in vitro induction of myoblasts in spontaneously contractile muscle fibers by intermittent stimulation. This novel method for induction of myoblast differentiation represents an important advance in cell therapy.
Association between DNA Repair Gene Polymorphisms and p53 Alterations in Japanese Patients with Muscle-Invasive Bladder Cancer
Authors: Sakano Shigeru , Matsumoto Hiroaki , Yamamoto Yoshiaki , Kawai Yoshihisa , Eguchi Satoshi , Ohmi Chietaka , Matsuyama Hideyasu , Naito Katsusuke
Published: March 2007

Objective: DNA repair enzymes play a vital role in protecting the genome from carcinogens, several of which can cause mutations in the TP53 gene in bladder cancer. Some single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate the repair capacity. This study aimed to clarify the effect of these functional SNPs on the alteration of p53 in muscle-invasive bladder cancer. Methods: We investigated the association between SNPs in xeroderma pigmentosum complementation groups C (XPC), D and G and X-ray repair cross-complementing group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus in Japanese patients with muscle-invasive bladder cancer. p53 expression and the allelic imbalance were evaluated using immunohistochemistry and a microsatellite marker, respectively. Results: Positive p53 expression was significantly less frequent in patients with the CC genotype of the XPC gene than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC gene were also less frequent in patients with positive p53 expression (p = 0.01). Conclusion: Our results suggested that the XPC polymorphism might affect p53 alteration and the molecular pathway defined by the p53 alteration in the development of muscle-invasive bladder cancer.
The Inhibitory Effect of Preeclamptic Umbilical Cord Blood Serum on Matrix Metalloproteinase-1 in Arterial Slices Incubated in vitro
Authors: Galewska Zofia , Romanowicz Lech , Gogiel Tomasz , Jaworski Stefan , Bańkowski Edward
Published: March 2007

Background: Our previous studies demonstrated that preeclampsia is accompanied by significant alterations in the amounts of peptide growth factors in the umbilical cord serum. Some of these factors (especially IGF-1) are known as regulators of collagen metabolism. The umbilical cord arteries (UCAs) of newborns delivered by mothers with preeclampsia contain more than twice the amount of collagen in comparison to newborns delivered by healthy mothers. A significant role in collagen degradation is attributed to matrix metalloproteinase (MMP)-1 (collagenase 1) and tissue inhibitors of metalloproteinases (TIMPs). Objective: To compare the effects of umbilical cord (UC) blood serum of control and preeclamptic newborns on the content and activity of MMP-1, TIMP-1 and TIMP-2 in UCA wall slices incubated in vitro. Methods: Polyacrylamide gel electrophoresis (PAGE) followed by Western immunoblotting allowed to detect MMP-1 as well as TIMP-1 and TIMP-2. The amounts of MMP-1, TIMP-1 and TIMP-2 in UCA slices were measured by immunoenzymatic method (ELISA). MMP-1 activity in the arterial wall was measured using a collagenase-1-specific substrate. Results: Western immunoblot analyses detected MMP-1, TIMP-1 and TIMP-2 in the incubation fluids and in extracts from the UCA wall. Both 43- and 55-kDa (a zymogen) bands of MMP-1 were visible. The control UC serum stimulated both the amount as well as actual and potential activities of MMP-1 in the arterial wall in a time-dependent manner. In contrast to controls, the preeclamptic serum did not exert such an effect. Conclusions: The small amount and low activity of MMP-1 accompanied by elevated amounts of TIMPs (especially TIMP-1) decelerate the degradation and enhance the accumulation of collagen in the preeclamptic UCA wall.
Expression of Receptor for Advanced Glycation End Products during Rat Tongue Carcinogenesis by 4-Nitroquinoline 1-Oxide and Effect of a Selective Cyclooxygenase-2 Inhibitor, Etodolac
Authors: Yamamoto Kazuhiko , Kitayama Wakashi , Denda Ayumi , Sasahira Tomonori , Kuniyasu Hiroki , Kirita Tadaaki
Published: March 2007

Objectives: The expression of a receptor for advanced glycation end products (RAGE) in lesions developed during rat tongue carcinogenesis by 4-nitroquinoline 1-oxide (4-NQO) and the effect of a selective cyclooxygenase-2 inhibitor, etodolac, were investigated. Methods: The tongue lesions were induced in Fischer 344 rats given 20–30 ppm 4-NQO in their drinking water for 12 weeks and then fed the basal diet containing 150 and 300 ppm of etodolac for 16 weeks, respectively. Results: The incidence of carcinomas in the 4-NQO-alone group was 100%. Etodolac significantly reduced the incidences of carcinomas to 66.7% (p < 0.05) and 50% (p < 0.01) at doses of 150 and 300 ppm, respectively. RAGE protein was immunohistochemically expressed in dysplastic cells and cancer cells of dysplasias and carcinomas. Etodolac significantly decreased the stainability of RAGE protein in dysplasias (p < 0.02) and carcinomas (p < 0.01). The expression of RAGE mRNA analyzed by RT-PCR was clearly detected in carcinomas developing in the 4-NQO-alone group. In carcinomas developing in the etodolac-treated group, RAGE mRNA expression significantly decreased (p < 0.03). Conclusions: These results indicate that RAGE is involved in rat tongue carcinogenesis by 4-NQO and suggest that the chemopreventive effect exerted by etodolac is partly related to the inhibition of RAGE expression.
Clinical Effects of Treatment for Hypogonadism in Male Adolescents with Prader-Labhart-Willi Syndrome
Authors: Eiholzer Urs , Grieser Jürgen , Schlumpf Michael , l’Allemand Dagmar
Published: March 2007

Background: In boys with Prader-Labhart-Willi syndrome (PWS), hypogonadism causes pubertal arrest and reduces pubertal muscle growth. Formerly, it was assumed that therapy with gonadal hormones accentuates behaviour abnormalities in PWS. Our aim was to assess the clinical effects of human chorionic gonadotropin (hCG) therapy on pubertal development, muscle mass and behaviour in adolescents with PWS. Methods: 6 peripubertal boys with PWS undergoing long-term treatment with growth hormone were examined 6-monthly for at least 2 years before and after pubertal arrest (13.5 ± 0.3 years, mean ± SEM) and the beginning of hCG therapy (500–1,500 IU twice weekly, intramuscularly). Height, weight, pubertal stage, bone age, body composition (by dual-energy X-ray absorptiometry), testosterone levels and behaviour abnormalities (obtained from parents) were assessed. Results: Testicular volume and lean mass were reduced in pubertal boys with PWS. During hCG therapy, testosterone levels and lean mass significantly increased (at the beginning and after 2 years of hCG therapy: 2.3 ± 0.9 and 10.7 ± 1.3 nmol/l, –3.1 ± 0.3 and –1.4 ± 0.6 SD, respectively), and fat mass stabilized at 38%. The characteristically observed PWS-associated problems, mood instability, aggressiveness and difficulties in social interaction, did not deteriorate during therapy. Conclusion: In the present study, timely application of hCG to treat hypogonadism in boys with PWS promoted virilization and normalized muscle mass without detrimental effects on behaviour. Larger studies comparing hCG therapy with testosterone replacement would be useful.
Prediction of Alzheimer’s Disease Using the CSF Aβ42/Aβ40 Ratio in Patients with Mild Cognitive Impairment
Authors: Hansson Oskar , Zetterberg Henrik , Buchhave Peder , Andreasson Ulf , Londos Elisabet , Minthon Lennart , Blennow Kaj
Published: March 2007

Evidence supports an important role for β-amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD). Here, we investigate baseline levels of the 40- and 42-amino-acid-long Aβ peptides (Aβ40 and Aβ42) in cerebrospinal fluid (CSF) from a cohort of patients with mild cognitive impairment (MCI, n = 137) in relation to the final diagnosis after 4–6 years of follow-up time. CSF Aβ42 concentration at baseline and the Aβ42/Aβ40 ratio were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients and MCI patients who developed other forms of dementia (p < 0.001). The baseline levels of Aβ40 were similar in all MCI groups but correlated with change in Mini Mental State Examination scores in converters to AD. The Aβ42/Aβ40 ratio was superior to Aβ42 concentration with regard to identifying incipient AD in MCI (p < 0.05). In conclusion, the data provide further support for the view that amyloid precursor protein metabolism is disturbed in early sporadic AD and points to the usefulness of the Aβ42/Aβ40 ratio as a predictive biomarker for AD.
Plasma Homocysteine Is Elevated in Elderly Patients with Memory Complaints and Vascular Disease
Authors: Nilsson Karin , Gustafson Lars , Hultberg Björn
Published: March 2007

Background: There is an association between elevated plasma total homocysteine (tHcy) and vascular disease in elderly patients suffering from organic and non-organic mental disease. The main objective of the present study was to investigate the relationship between plasma tHcy concentration and vascular disease in elderly patients with memory complaints. Methods: In 108 patients with memory complaints the concentration of plasma tHcy was related to the presence of vascular disease. Furthermore, different determinants of plasma tHcy concentration were measured. Results: Patients with confirmed memory complaints (CMC, n = 86) which fulfilled the criteria of mild cognitive impairment were divided into two categories, with and without vascular disease. The CMC group without vascular disease showed similar biochemical and brain imaging findings to patients with subjective memory complaints (SMC, n = 22). The group of CMC patients with vascular disease had higher age, higher plasma tHcy, lower serum folate and lower renal function than patients without vascular disease. Conclusion: The finding of two subgroups of patients with CMC supports the notion that mild cognitive impairment is a heterogenous clinical entity with multiple aetiological factors. The elevated plasma tHcy in the group of CMC patients with vascular disease is likely to be associated with vascular disease.
Increased QT Dispersion in Sickle Cell Disease: Effect of Pulmonary Hypertension
Authors: Akgül Ferit , Seyfeli Ergün , Melek İsmet , Duman Taşkin , Seydaliyeva Tunzale , Gali Edip , Yalçın Fatih
Published: March 2007

Background: QT dispersion has been proposed to be a predictor of adverse outcomes in a variety of cardiac disease states. The objective of this study was to examine QT dispersion in patients with sickle cell disease (SCD) and to assess the effect of pulmonary hypertension (PHT) on QT dispersion. Methods: We performed Doppler echocardiographic assessments of pulmonary artery systolic pressure in 73 (mean age 18.5 ± 8.0 years) steady-state SCD patients and 25 (mean age 19.6 ± 7.2 years) healthy subjects. Resting 12-lead electrocardiogram was recorded and QT dispersion was calculated as the difference between maximum and minimum QT intervals. Bazett’s formula was used to obtain a rate-corrected value of the QT interval (QTc). Results: Maximum QTc, minimum QTc and QTc dispersion were significantly increased in SCD patients compared to the control subjects (p < 0.0001, p < 0.05, p < 0.0001, respectively). Among SCD patients, patients with PHT had higher maximum QTc and QTc dispersion than patients without PHT (p < 0.0001). However, minimum QTc showed no significant differences between the two patient groups. Conclusion: QTc dispersion is significantly increased in SCD patients, especially those with PHT indicating regional inhomogeneity of ventricular repolarization.
Paraneoplastic Hyperamylasaemia in Association with Multiple Myeloma
Authors: Calvo-Villas Jose M. , Alvarez Iván , Carretera Elena , Espinosa Juan , Sicilia Francisco
Published: March 2007

Marked hyperamylasaemia associated with an amylase-producing multiple myeloma appears to be a fairly unusual phenomenon. The present report describes a fatal case of multiple myeloma associated with paraneoplastic hyperamylasaemia without evidence of pancreatic or salivary gland involvement. Serum and urine amylase levels paralleled the myeloma response to chemotherapy and disease progression. The importance of paraneoplastic hyperamylasaemia as a useful myeloma marker to monitor disease progression and treatment response is emphasized. Conventional chemotherapy at diagnosis and salvage treatment with bortezomib at relapse failed to achieve a long-term response and to decrease the serum amylase to a normal level.
Symptomatic Dry Eye Treatment with Autologous Platelet-Rich Plasma
Authors: Alio Jorge L. , Colecha José R. , Pastor Silvia , Rodriguez Alejandra , Artola Alberto
Published: March 2007

Background: Autologous platelet-rich plasma (PRP) has been proven to be very effective on tissue regeneration and wound healing. Here we investigate the potential use of PRP in the treatment of symptomatic dry eye. Methods: Eighteen consecutive patients with symptomatic dry eye were treated with topical PRP and followed up for 1 month. Disappearance of subjective symptoms, increase in best corrected visual acuity, tear meniscus, tear breakup time, decrease in inflammation, fluorescein staining and improvement in impression cytology were measured. Results: Symptoms improved significantly in 89% of the patients, 28% improved at least 1 line of best corrected visual acuity. A significant improvement on lachrymal meniscus and conjunctival hyperemia and a decrease or disappearance of corneal fluorescein staining were observed. Impression cytology revealed a significant increase in conjunctival goblet cells. Conclusion: Treatment of patients suffering from significant dry eye symptoms with autologous RPR proved to be very effective, improving both patient symptoms and major clinical signs.
Role of Inositol 1,4,5-Triphosphate and p38 Mitogen-Activated Protein Kinase in Reactive Oxygen Species Generation by Granulocytes in a Cyclic AMP-Dependent Manner: An Age-Related Phenomenon
Authors: Martins Chaves Míriam , Caldeira Costa Daniela , Costa Telhado Pereira Cristina , Andrade Thiago Rabelo , Horta Bernardo Coelho , Nogueira-Machado José Augusto
Published: March 2007

Background: It is generally agreed that elderly subjects undergo progressive deterioration of their immune responsiveness, which leads to an increased susceptibility to autoimmune processes, neoplasm and inflammation. Thus there is a general consensus that regulation of inflammation results from a balance between pro-inflammatory and anti-inflammatory pathways. Objective: The present study aimed to investigate the possible alterations of cyclic AMP/protein kinase A (cAMP/PKA) and p38 mitogen-activated protein kinase (p38 MAPK) pathway signaling (reactive oxygen species (ROS) generation) and inositol 1,4,5-triphosphate (InsP3) production by neutrophils during the aging process. Methods: Age-induced ROS generation and InsP3 production were studied in healthy subjects ranging in age from 20 to 80 years. The subjects were divided into six age groups: (I) 20–29, (II) 30–39, (III) 40–49, (IV) 50–59, (V) 60–69, and (VI) 70–80 years old. The effect of cAMP, H89 (inhibitor PKA), and PD169316 (inhibitor p38 MAPK) on ROS production was quantified in a luminol-dependent chemiluminescence assay (relative light units/min) and by InsP3 release (cpm). Results: Our results demonstrated a lack of dibutyryl cAMP inhibitory effects on ROS generation and InsP3 production by granulocytes from PKA-dependent 50-year-olds. However, the inhibitory effect of cAMP is restored in neutrophils after the age of 50 years when p38 MAPK signaling is inhibited. Conclusions: The present study may be important towards a better understanding of the high susceptibility to infections and age-related inflammatory and deregulation diseases. The alteration of cAMP/PKA and p38 MAPK signaling pathways enhances the inflammatory process.
Increased Risk of Colorectal Adenomas in Italian Subjects Carrying the p53 PIN3 A2-Pro72 Haplotype
Authors: Perfumo Chiara , Bonelli Luigina , Menichini Paola , Inga Alberto , Gismondi Viviana , Ciferri Enrico , Percivale Pierluigi , Bianchi Scarrà Giovanna , Nasti Sabina , Fronza Gilberto , Varesco Liliana
Published: March 2007

Background: Few reports have investigated the association of two p53 polymorphisms (Arg72Pro and PIN3-A2) with colorectal cancer (CRC) risk, and no previous study has analyzed their role as susceptibility alleles for colorectal adenoma. Aim: To explore the impact of the p53 PIN3-Arg72Pro haplotype on colorectal adenoma formation and progression to cancer. Methods: One hundred and eighty-four colorectal tumor patients (124 with adenomas and 60 with adenocarcinoma) and 188 controls (42 subjects with a clean colon, 54 hospital controls and 92 blood donors) from the Italian population were tested for PIN3-Arg72Pro haplotype status. Results: A significantly increased risk of colorectal adenomas was observed in patients carrying the PIN3 A2-Pro72 haplotype (OR = 2.02, 95% CI: 1.17–3.48; p = 0.01), while those carrying the PIN3 A1-Pro72 haplotype had a significantly increased risk of developing CRC (OR = 3.33; 95% CI: 1.40–7.89; p = 0.006). Comparisons of cases with the clean colon control group provided stronger evidence of the associations. A family history of CRC did not affect the risk estimates. No association was observed between the pathologic features of adenomas, the Arg72Pro and PIN3 polymorphisms, and the PIN3-Arg72Pro haplotype. Conclusions: Our finding that two different p53 haplotypes are associated with colorectal adenoma and cancer, respectively, suggests that each of these haplotypes may independently impact on p53 function(s) within different genetic pathways of colorectal carcinogenesis.
Clinical Significance of Lobar Atrophy in Frontotemporal Dementia: Application of an MRI Visual Rating Scale
Authors: Kipps Christopher M. , Davies R. Rhys , Mitchell Joanna , Kril Jillian J. , Halliday Glenda M. , Hodges John R.
Published: March 2007

Background/Aims: The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain; while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large sample of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. Methods: We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. Results: The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. Conclusions: MRI findings should form part of the diagnostic criteria for SD; the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.
Cognitive Functioning and Brain MRI in Patients with Type 1 and Type 2 Diabetes Mellitus: A Comparative Study
Authors: Brands Augustina M.A. , Biessels Geert Jan , Kappelle L. Jaap , de Haan Edward H.F. , de Valk Harold W. , Algra Ale , Kessels Roy P.C.
Published: March 2007

Background/Aims: Diabetes mellitus (DM) may affect the central nervous system, resulting in cognitive impairments. It has been suggested that cognitive impairments are more pronounced in DM2 than in DM1, but studies that directly compare the effects of these 2 types of DM on cognition are lacking. Methods: Forty patients with DM1 (mean duration: 34 years) were compared with 40 age- and education-matched patients who were known to have DM2 (mean duration: 7 years). Extensive neuropsychological assessment focussed on abstract reasoning, memory, attention and executive function, visuoconstruction and information processing speed. Psychological well-being was measured and brain MRIs were obtained. Results:No systematic between-group differences were observed in neuropsychological measures or levels of psychological well-being. DM2 patients showed significantly more deep white matter lesions and cortical atrophy on MRI (p < 0.01). Conclusion: DM1 patients with more than 30 years of DM have a similar cognitive profile and better MRI ratings than age- and education-matched DM2 patients with only 7 years of DM.
Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke
Authors: Caso Javier R. , Pradillo Jesús M. , Hurtado Olivia , Lorenzo Pedro , Moro María A. , Lizasoain Ignacio
Published: March 2007

Background—

Stroke is the second to third leading cause of death. Toll-like receptor 4 (TLR4) is a signaling receptor in innate immunity that is a specific immunologic response to systemic bacterial infection and cerebral injury. The role of TLR4 in brain ischemia has not been examined yet. We have therefore investigated whether cerebral ischemia and inflammation produced by permanent occlusion of the middle cerebral artery differ in mice that lack a functional TLR4 signaling pathway.

Methods and Results—

Permanent occlusion of the middle cerebral artery was performed on 2 strains of TLR4-deficient mice (C3H/HeJ and C57BL/10ScNJ) and respective controls (C3H/HeN and C57BL/10ScSn). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected 24 hours and 7 days after stroke. When compared with control mice, TLR4-deficient mice had lower infarct volumes and better outcomes in neurological and behavioral tests. Mice that lacked TLR4 had minor expression of stroke-induced interferon regulatory factor-1, inducible nitric oxide synthase, and cyclooxygenase-2, mediators implicated in brain damage. The levels of interferon-β and of the lipid peroxidation marker malondialdehyde were also lower in brains from TLR4-deficient mice than in those from control mice. In addition, the expression of matrix metalloproteinase-9, which is induced and mediates brain damage, was also reduced in TLR4-deficient mice after experimental stroke.

Conclusions—

TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult. These data demonstrate that TLR4 signaling and innate immunity are involved in brain damage and in inflammation triggered by ischemic injury.
Usefulness of 64-Slice Cardiac Computed Tomographic Angiography for Diagnosing Acute Coronary Syndromes and Predicting Clinical Outcome in Emergency Department Patients With Chest Pain of Uncertain Origin
Authors: Rubinshtein Ronen , Halon David A. , Gaspar Tamar , Jaffe Ronen , Karkabi Basheer , Flugelman Moshe Y. , Kogan Asia , Shapira Reuma , Peled Nathan , Lewis Basil S.
Published: March 2007

Background—

Multidetector computed tomography (MDCT) has high diagnostic value for detecting or excluding coronary artery stenosis. We examined performance characteristics of MDCT for diagnosing or excluding an acute coronary syndrome in patients presenting to the emergency department (ED) with possible ischemic chest pain and examined relation to clinical outcome during a 15-month follow-up period.

Methods and Results—

We prospectively studied 58 patients (56±10 years of age, 36% female) with chest pain possibly ischemic in origin and no new ECG changes or elevated biomarkers. The patients underwent 64-slice contrast-enhanced MDCT, which showed normal coronary vessels (no or trivial atheroma) in 15 patients, nonobstructive plaque in 20 (MDCT-negative patients), and obstructive coronary disease (≥50% luminal narrowing) in 23 (MDCT-positive group). By further investigation (new elevation of cardiac biomarkers, abnormal myocardial perfusion scintigraphy and/or invasive angiography), acute coronary syndrome was diagnosed in 20 of the 23 MDCT-positive patients (ED MDCT sensitivity 100% [20/20], specificity 92% [35/38], positive predictive value 87% [20/23], negative predictive value 100% [35/35]). During a 15-month follow-up period, no deaths or myocardial infarctions occurred in the 35 patients discharged from the ED after initial triage and MDCT findings. One patient underwent late percutaneous coronary intervention (late major adverse cardiovascular events rate, 2.8%). Overall, ED MDCT sensitivity for predicting major adverse cardiovascular events (death, myocardial infarction, or revascularization) during hospitalization and follow-up was 92% (12/13), specificity was 76% (34/45), positive predictive value was 52% (12/23), and negative predictive value was 97% (34/35).

Conclusions—

We found that 64-slice cardiac MDCT is a potentially valuable diagnostic tool in ED patients with chest pain of uncertain origin, providing early direct noninvasive visualization of coronary anatomy. ED MDCT had high positive predictive value for diagnosing acute coronary syndrome, whereas a negative MDCT study predicted a low rate of major adverse cardiovascular events and favorable outcome during follow-up.
Comparison of Noncontact and Electroanatomic Mapping to Identify Scar and Arrhythmia Late After the Fontan Procedure
Authors: Abrams Dominic J. , Earley Mark J. , Sporton Simon C. , Kistler Peter M. , Gatzoulis Michael A. , Mullen Michael J. , Till Janice A. , Cullen Seamus , Walker Fiona , Lowe Martin D. , Deanfield John E. , Schilling Richard J.
Published: March 2007

Background—

The right atrium late after the Fontan procedure is characterized by multiple complex arrhythmia circuits. We performed simultaneous electroanatomic and noncontact mapping to assess the accuracy of both systems to identify scar and arrhythmia.

Methods and Results—

Mapping was performed in 26 patients aged 26.8±8.9 years, 18.7±4.4 years after Fontan surgery. The area and site of abnormal endocardium defined by electroanatomic mapping (bipolar contact electrogram <0.5 mV) were compared with those defined by noncontact mapping during sinus rhythm and by dynamic substrate mapping. Contact and reconstructed unipolar electrograms at a known distance from the multielectrode array, recorded by the noncontact system simultaneously at 452 endocardial sites, were compared for morphological cross correlation, timing difference, and amplitude. Mapping of arrhythmias was performed with both systems when possible. The median patient abnormal endocardium as defined by electroanatomic mapping covered 38.0% (range 16.7% to 97.8%) of the right atrial surface area, as opposed to 60.9% (range 21.3% to 98.5%) defined by noncontact mapping during sinus rhythm and 11.9% (range 0.4% to 67.3%) by dynamic substrate mapping. A significant decrease in electrogram cross correlation (
P
=0.003), timing (
P
=0.012), and amplitude (
P
=0.003) of reconstructed electrograms, but not of contact electrograms (
P
=0.742), was seen at endocardial sites >40 mm from the multielectrode array. Successful arrhythmia mapping by electroanatomic versus noncontact mapping was superior in 15 patients (58%), the same in 6 (23%), and inferior in 5 (19%;
P
=0.044).

Conclusions—

Electroanatomic mapping is the superior modality for arrhythmia mapping late after the Fontan procedure. Noncontact mapping is limited by a significant reduction in reconstructed electrogram correlation, timing, and amplitude >40 mm from the multielectrode array and cannot accurately define areas of scar and low-voltage endocardium.
A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance
Authors: Tanner M.A. , Galanello R. , Dessi C. , Smith G.C. , Westwood M.A. , Agus A. , Roughton M. , Assomull R. , Nair S.V. , Walker J.M. , Pennell D.J.
Published: March 2007

Background—

Cardiac complications secondary to iron overload are the leading cause of death in β-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect.

Methods and Results—

Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24;
P
=0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%;
P
=0.05), and absolute endothelial function (8.8% versus 3.3%;
P
=0.02). There was also a significantly greater improvement in serum ferritin in the combined group (−976 versus −233 μg/L;
P
<0.001).

Conclusions—

In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.
Prognostic Significance of the Centers for Disease Control/American Heart Association High-Sensitivity C-Reactive Protein Cut Points for Cardiovascular and Other Outcomes in Patients With Stable Coronary Artery Disease
Authors: Sabatine Marc S. , Morrow David A. , Jablonski Kathleen A. , Rice Madeline Murguia , Warnica J. Wayne , Domanski Michael J. , Hsia Judith , Gersh Bernard J. , Rifai Nader , Ridker Paul M , Pfeffer Marc A. , Braunwald Eugene
Published: March 2007

Background—

Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored.

Methods and Results—

We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even >1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81;
P
=0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02;
P
=0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted
P
<0.001 for trend) and new diabetes (adjusted
P
<0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes.

Conclusions—

In stable coronary artery disease, an elevated hs-CRP level, even >1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition.