bluuebunny/crossref_metadata_2025 huggingface dataset:
MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C
Authors: Dharel Narayan , Kato Naoya , Muroyama Ryosuke , Moriyama Masaru , Shao Run-Xuan , Kawabe Takao , Omata Masao
Published: August 2006

Purpose: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection.

Experimental Design: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region.

Results: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age >60 years, male gender, presence of cirrhosis, serum α-fetoprotein >20 μg/L, and serum albumin <3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively.

Conclusions: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.
Characterization and Expression of CT45 in Hodgkin's Lymphoma
Authors: Heidebrecht Hans-Jürgen , Claviez Alexander , Kruse Marie Luise , Pollmann Marc , Buck Friedrich , Harder Sönke , Tiemann Markus , Dörffel Wolfgang , Parwaresch Reza
Published: August 2006

Purpose: The monoclonal antibody Ki-A10 (IgG1) generated after immunization of mice with Hodgkin's lymphoma cell line L428 detects a nuclear antigen in human tissues with a restricted distribution pattern similar to cancer/testis antigens. The aim of this study was to characterize the antigen and to determine the expression profile in Hodgkin's lymphoma.

Experimental Design: The half-life and phosphorylation of the antigen were determined by radiolabeling. The antigen was characterized by immunopurification and sequencing. Demethylation of genes is used to induce cancer/testis antigens. Ki-A10-negative cells were treated with 5-aza-2′-deoxycytidine. The Ki-A10 expression in paraffin-embedded tumors was determined immunohistochemically.

Results: Immunopurification of the 25/22-kDa antigen and sequencing revealed a peptide of 14 amino acids corresponding to the gene product of the newly described gene family MGC27005, located on chromosome Xq26.3, now termed CT45. CT45 is significantly phosphorylated and down-regulated during mitosis. Demethylation of CT45-negative HeLa cells and stimulated peripheral blood lymphocytes induced CT45 expression. Except testis, immunohistochemical stainings of normal tissues, reactive lymphoid lesions, and most malignant tumors were negative. In comparison, 54 of 99 (55%) samples from pediatric and adolescent Hodgkin's lymphoma patients enrolled in the multicenter trial HD-95 stained Ki-A10 positive. Ki-A10 expression correlated with histologic subtypes (nodular sclerosis Hodgkin's lymphoma 68% versus mixed cellularity Hodgkin's lymphoma 40% versus nodular lymphocyte predominant Hodgkin's lymphoma 9%; P < 0.001).

Conclusions: Ki-A10 is the first monoclonal antibody that detects CT45. As benign lymphoid lesions did not express CT45, the use of Ki-A10 antibody will facilitate the discrimination of Hodgkin's lymphoma from reactive lymphadenopathies.
Presence of Phosphorylated Hepatocyte Growth Factor Receptor/c-Met Is Associated with Tumor Progression and Survival in Patients with Conventional Renal Cell Carcinoma
Authors: Miyata Yasuyoshi , Kanetake Hiroshi , Kanda Shigeru
Published: August 2006

Purpose: Hepatocyte growth factor receptor (HGFR/c-Met) signaling is associated with tumor progression in various cancers. The clinical significance and pathologic roles of phosphorylated HGFR/c-Met in renal cell carcinoma (RCC) are not fully understood; therefore, this study sought to clarify the possible role of two tyrosine residues (pY1234/pY1235 and pY1349) in HGFR/c-Met.

Experimental Design: The kinetics of tyrosine phosphorylation at these two residues was examined in a human renal carcinoma cell line, ACHN cells. In addition, phosphorylated HGFR/c-Met expression (using phosphorylation site-specific antibodies for pY1234/pY1235 and pY1349) was examined in 114 tumor sections of conventional RCC patients by immunohistochemistry. The relationships between these expressions and clinicopathologic features and survival were also investigated.

Results: Although phosphorylation of Y1349 HGFR/c-Met was observed for 120 minutes after HGF treatment of ACHN cells, maximal phosphorylation of Y1234/Y1235 was observed at 30 minutes followed by a rapid inactivation. Median rates (range) of cancer cells immunopositive for pY1234/pY1235 HGFR/c-Met and pY1349 HGFR/c-Met in the tumor sections were 0% (0-5.2%) and 14.3% (0-64.3%), respectively. Positive expression of pY1349 HGFR/c-Met was significantly associated with high pT stage, presence of metastasis, and high-grade carcinoma. Multivariate Cox analysis revealed that the positive expression of pY1349 HGFR/c-Met was a significant and an independent predictor of cause-specific survival (odds ratio, 2.94; 95% confidence interval, 1.12-7.72; P = 0.028).

Conclusions: Phosphorylated HGFR/c-Met may be important in the tumor progression of RCC. Expression of pY1349 HGFR/c-Met is a useful predictor for metastasis and survival of conventional RCC patients.
Tumor-Directed Radiation and the Immunotoxin SS1P in the Treatment of Mesothelin-Expressing Tumor Xenografts
Authors: Hassan Raffit , Williams-Gould Juanita , Steinberg Seth M. , Liewehr David J. , Yokokawa Junko , Tsang Kwong Y. , Surawski Robert J. , Scott Tamalee , Camphausen Kevin
Published: August 2006

Purpose: Mesothelin is a cell surface protein overexpressed in mesotheliomas and pancreatic and ovarian cancers. The goal of this study was to determine if radiation therapy in combination with the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) would result in enhanced antitumor activity against mesothelin-expressing xenografts in nude mice.

Experimental Design: Female athymic nude mice bearing s.c. mesothelin-expressing xenografts were treated with SS1P alone, tumor-focused radiation alone, or the combination of the two. Two different regimens of the combination therapy were tested. In the low-dose combination schedule, mice were treated with either 5 Gy radiation alone, 0.2 mg/kg SS1P alone, or the same doses of radiation and SS1P in combination. In the high-dose combination experiments, mice were treated with either 15 Gy radiation alone, 0.3 mg/kg SS1P alone, or the combination of radiation and SS1P.

Results: In the low-dose radiation and SS1P combination studies, mice treated with the combination of radiation and SS1P had a statistically significant prolongation in time to tumor doubling or tripling compared with control, SS1P, or radiation alone. A similar increase in time to tumor doubling or tripling was seen in mice treated with high-dose radiation and SS1P combination.

Conclusions: Combination of SS1P with tumor-directed radiation results in enhanced antitumor activity against mesothelin-expressing tumor xenografts. This effect was seen when either low or high doses of radiation were used.
Peptidome from Renal Cell Carcinoma Contains Antigens Recognized by CD4+ T Cells and Shared among Tumors of Different Histology
Authors: Tassi Elena , Facchinetti Valeria , Seresini Samantha , Borri Anna , Dell'Antonio Giacomo , Garavaglia Claudio , Casorati Giulia , Protti Maria Pia
Published: August 2006

Purpose: Renal cell carcinoma (RCC) is considered immunogenic; nonetheless, rare tumor-associated antigens have been identified or are expressed in RCC. Peptidome (i.e., the total content of natural peptides of whole cells) from other tumors, such as melanoma, has proved to be immunogenic. The aims of this study were to determine whether peptidome from RCC is immunogenic and whether it contains tumor peptides shared among allogenic RCCs.

Experimental Design: Autologous dendritic cells pulsed with RCC peptidome were used to activate in vitro CD4+ T cells from healthy donors and a metastatic RCC patient. CD4+ T-cell polyclonal lines and clones were characterized for tumor cell recognition by proliferation assay, killing activity, and cytokine secretion.

Results: CD4+ T-cell lines and clones recognized HLA-DR-matched allogenic RCC and, for the patient, the autologous tumor. RCC-reactive CD4+ T cells showed a heterogeneous Th1 or Th0/Th2 pattern of cytokine secretion. Moreover, RCC-reactive CD4+ T cells recognized also melanoma, colon carcinoma, cervical carcinoma, pancreas carcinoma, lung carcinoma, gastric carcinoma, and lymphoma cells but not autologous T-cell blasts.

Conclusions: Our results show that (a) the RCC peptidome contain antigens recognized by CD4+ T cells and (b) shared among tumors of different histology and (c) it induces both Th1-type and Th2/Th0-type immune responses. These data support the use of the peptidome from allogenic RCC for specific immunotherapy in RCC and possibly in other neoplastic diseases. Moreover, the CD4+ T-cell clones generated here are useful tools for tumor antigen identification.
Bcl-2 Protein in 518A2 Melanoma Cells In vivo and In vitro
Authors: Benimetskaya Luba , Ayyanar Kanyalakshmi , Kornblum Noah , Castanotto Daniela , Rossi John , Wu Sijian , Lai Johnathan , Brown Bob D. , Popova Natalia , Miller Paul , McMicken Harilyn , Chen Yin , Stein C.A.
Published: August 2006

Purpose: Bcl-2 is an apoptotic protein that is highly expressed in advanced melanoma. Several strategies have been employed to target the expression of this protein, including G3139, an 18-mer phosphorothioate oligodeoxyribonucleotide targeted to the initiation region of the Bcl-2 mRNA. This compound has recently completed phase III global clinical evaluation, but the function of Bcl-2 as a target in melanoma has not been completely clarified. To help resolve this question, we have permanently and stably down-regulated Bcl-2 protein and mRNA expression in 518A2 cells by two different technologies and evaluated the resulting clones both in vitro and in vivo.

Experimental Design: 518A2 melanoma cells were transfected with plasmids engineered to produce either a single-stranded antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA or a short hairpin RNA also targeted to the Bcl-2 mRNA. In vitro growth, the apoptotic response to G3139, and the G3139-induced release of cytochrome c from isolated mitochondria were evaluated. Cells were then xenografted into severe combined immunodeficient mice and tumor growth was measured.

Results: In vitro, down-regulation of Bcl-2 expression by either method produced no change either in the rate of growth or in sensitivity to standard cytotoxic chemotherapeutic agents. Likewise, the induction of apoptosis by G3139 was entirely Bcl-2 independent. In addition, the G3139-induced release from isolated mitochondria was also relatively independent of Bcl-2 expression. However, when xenografted into severe combined immunodeficient mice, cells with silenced Bcl-2, using either technology, either failed to grow at all or grew to tumors of low volume and then completely regressed. In contrast, control cells with “normal” levels of Bcl-2 protein expression expanded to be large, necrotic tumors.

Conclusions: The presence of Bcl-2 protein profoundly affects the ability of 518A2 melanoma cells to grow as human tumor xenografts in severe combined immunodeficient mice. The in vivo role of Bcl-2 in melanoma cells thus differs significantly from its in vitro role, and these experiments further suggest that Bcl-2 may be an important therapeutic target even in tumors that do not contain the t14:18 translocation.
Treatment of High-Risk Peripheral T-Cell Lymphomas other than Anaplastic Large-Cell Lymphoma with a Dose-Intensified CHOP Regimen Followed by High-Dose Chemotherapy
Authors: Yamazaki Tetsuo , Sawada Umihiko , Kura Yoshimasa , Ito Takeyoshi , Takeuchi Jin , Hatta Yoshihiro , Aikawa Shingo , Takei Kazuhiro , Ishizuka Hikaru , Saiki Minoru , Uenogawa Kumi
Published: August 2006

We investigated the efficacy of a dose-intensified double-CHOP regimen followed by high-dose chemotherapy with or without peripheral blood stem cell transplantation (PBSCT) in 11 patients with four types of peripheral T-cell lymphoma (PTCL). Three of the 4 patients with unspecified PTCL (PTCLu) achieved complete response (CR); 1 patient relapsed and 1 died of secondary leukemia after consolidation therapy. All angioimmunoblastic T-cell lymphoma (AILT) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients achieved CR; 5 of 6 have remained disease free for more than 3 years. The patient with hepatosplenic lymphoma did not achieve CR even after PBSCT and underwent allogenic bone marrow transplantation (allo-BMT). Thus, our regimen appears to be effective for high-risk AILT and SPTCL. However, allo-BMT should be considered for high-risk of PTCLu and hepatosplenic T-cell lymphoma.
Natural History of Southeast Asian Chronic Myeloid Leukemia Patients with Different BCR-ABL Gene Variants
Authors: Auewarakul C.U. , Huang S. , Yimyam M. , Boonmoh S.
Published: August 2006

Little evidence exists regarding the prognostic impact of the major BCR-ABL gene variants (e13a2 and e14a2) in chronic myeloid leukemia (CML) patients diagnosed and treated in the developing Asian countries. In this study, 139 Thai CML patients were followed for a median period of 3 years (range 18–43 months). Clinical presentations of both BCR-ABL gene variant groups (73% e14a2+ and 27% e13a2+) were similar, although e14a2+ patients tended to be older (42 vs. 37 years) and had higher white blood cell counts than e13a2+ patients. The majority of patients in both groups presented with Sokal stage 2–3 (score >0.8) and were categorized as Hasford’s intermediate- to high-risk groups (score >780). All patients received oral chemotherapy and 13% underwent allogeneic stem cell transplantation. None received oral tyrosine kinase inhibitors. In the conventional chemotherapy group, the overall survival (OS) rate was slightly better in e14a2+ than in e13a2+ patients (p = n.s.). The median survival in e14a2+ and e13a2+ patients who did not receive stem cell transplantation was 49 and 33 months, respectively (p = n.s.). The type of blastic crisis in e14a2+ and e13a2+ patients was similar, being predominantly myeloid. In conclusion, CML patients in Thailand, despite being much younger, had a comparable OS with those in the Western countries, with no different OS between e14a2+ and e13a2+ patients. Future studies should focus on the impact of novel oral BCR-ABL tyrosine kinase inhibitors on the outcome of Thai CML patients with different BCR-ABL gene variants.
Myocardial Infarction and Other Arterial Occlusions in Hemophilia A Patients
Authors: Girolami A. , Ruzzon E. , Fabris F. , Varvarikis C. , Sartori R. , Girolami B.
Published: August 2006

Myocardial infarction and other arterial occlusions are considered to be rare in hemophilia A. However, a systematic study of the subject has never been attempted. All case reports of myocardial infarction or other arterial occlusions have been now gathered and properly evaluated from a cardiological point of view. Thirty-six patients with myocardial infarction and 6 patients with documented cerebrovascular event were retrieved from the literature. The age of the patients varied between 7 and 79 years, with a mean of 44 years. In 16 cases, the arterial occlusion occurred in men <40 years of age. The majority of myocardial infarctions (MIs) were anterolateral (12 cases). Posterior-inferior MI was present in 6 cases whereas it was of the non-Q type in 4 patients. It was multiple in 6 cases, and in the remaining patients the type of infarction could not be determined. In 26 cases, the thrombotic event (22 myocardial infarctions and 4 ischemic cerebrovascular accidents) occurred during or after the infusion of factor VIII concentrates and, more frequently, after prothrombin complex concentrates (activated or non-activated ones) or recombinant factor VIIa preparations. In 3 cases, the vascular complication occurred after intravenous desmopressin administration. MI was fatal in 7 instances. After the event, signs and symptoms of heart failure were seen as sequels in 7 patients. One patient had to undergo cardiac transplant 5 months after the MI. No death occurred after ischemic cerebrovascular accidents. Since not all hemophilia patients develop inhibitors and therefore are not usually treated with activated concentrates, this series of patients is somewhat biased and does not allow general conclusions. The high prevalence of MI and other arterial complications which occurred after transfusion therapy, usually in patients with inhibitors, clearly indicates the need for a careful evaluation of the appropriate therapeutic approach in each single patient.
Non-Invasive Detection of Fetal Rhesus D Status: A Comparison between Polymerase Chain Reaction and Flow Cytometry
Authors: Di Simone Nicoletta , Lai Marco , Rumi Carlo , Riccardi Patrizia , D’Asta Marco , Leone Giuseppe , Mancuso Salvatore , Caruso Alessandro
Published: August 2006

Objective: A non-invasive prenatal determination of the fetal RhD status might be useful for the management of pregnancies in RhD-negative women whose partners are RhD positive. Methods: Maternal peripheral blood of 32 RhD-negative women (17–24 weeks of gestation) was collected, and circulating fetal cells were enriched by CD71 mini-magnetic activated cell sorting. The RhD status of the fetuses was assessed using multiparametric flow cytometry, and results were compared to those of reverse transcriptase (RT)-polymerase chain reaction (PCR), or PCR, which acted as control. Flow-cytometric study of fetal cells employed monoclonal antibodies directed against CD71, glycophorin A (GPA) and RhD antigens. Results: The median percentage of CD71- and RhD-positive cells was 0.83% (range 0.14–6.44%), and that of CD71 and GPA-positive cells was 10.07% (range 0.52–45.84%). Flow-cytometric analysis correlated with RT-PCR results of RNA obtained from whole maternal blood. In 1 case, an incorrect result was due to the failure of the amplification of the specific RhD band on RNA extracted from the CD71-positive fraction. In two instances, we observed false-positive results for RhD in PCR of DNA obtained from maternal plasma. Conclusion: Based on our results, flow-cytometric analysis might be proposed as a clinical tool for the non-invasive prenatal determination of the fetal RhD status independently of fetal gender.
Low Incidence of Subdural Grid-Related Complications in Prolonged Pediatric EEG Monitoring
Authors: Musleh Wael , Yassari Reza , Hecox Kurt , Kohrman Michael , Chico Maria , Frim David
Published: August 2006

Invasive EEG monitoring is one of the best tools available for localization of epileptogenic foci in the brain. However, published data in mixed series of adult and pediatric patients show high incidence of epidural bacterial contamination, cerebrospinal fluid leakage, and skin infection after subdural electrode implantation. We sought to determine whether the complication rate from prolonged subdural electrode implantation would be lower in a purely pediatric series. Thirty-three subdural electrode implantation procedures were performed in 29 pediatric patients (age range 4–19) for an average of 7.2 days (range 3–14 days). Electrode number varied from 32 to >128 with a range of 4–11 electrode wires piercing the skin >1 cm from the primary incision. Of the 33 implantations and resections (66 craniotomies), 5 were for reimplantation. There were no permanent complications related to grid implantation. Transient complications included 1 case of prolonged prothrombin time and 1 patient with unexplained fever, both of which resolved upon removal of the grids. There were two culture-positive infections, one epidural and one superficial, both in patients undergoing reimplantation. There was no percutaneous cerebrospinal fluid leakage noted and no operation was aborted due to bleeding caused by grid placement. Our data suggest that subdural grid implantation in children is remarkably safe even for prolonged implantation, though infectious risk is significantly higher in reoperation (p = 0.019). This observation may contribute to lowering the threshold for two-stage invasive monitoring approaches in children with epilepsy.
Surgical Treatment Outcome of Subdural Empyema: A Clinical Study
Authors: Yilmaz Nebi , Kiymaz Nejmi , Yilmaz Cahide , Bay Ali , Yuca Sevil Ari , Mumcu Cigdem , Caksen Huseyin
Published: August 2006

A retrospective study of 28 patients identified with subdural empyema (SE) at the Department of Neurosurgery between the years 1995 and 2005 was carried out. SE occurred in all patients following bacterial meningitis. The six most frequently encountered clinical features included: (1) fever in 22 (79%) patients; (2) disturbed consciousness in 16 (57%) patients; (3) papilledema in 11 (39%) patients; (4) hemiparesis in 4 (14%) patients; (5) meningismus or meningeal signs in 4 (14%) patients, and (6) seizures in 3 (11%) patients. In the majority of cases, the most frequent causative pathogen of SE was Staphylococcus aureus. Surgery was performed on all patients, which included craniotomy in a group of 20 patients and burr hole drainage in a group of 8 patients. In conclusion, we believe that infants and young children should be carefully monitored following meningitis, in case of SE development, and that surgical intervention in patients presenting with meningitis may facilitate the development of SE. Furthermore, from a surgical point of view, our experience has led us to believe that craniotomy in comparison with burr hole surgery is the best surgical modality for management of SE as the recurrence rate of SE associated with burr hole surgery is high.
Seven Distinct Coexistent Cranial and Spinal Anomalies
Authors: Emmez Hakan , Tokgöz Nil , Dogulu Fikret , Yilmaz Muhammed Bahadır , Kale Aydemir , Baykaner M. Kemali
Published: August 2006

Existence of multiple cranial and spinal anomalies in spina bifida is well known; however, coexistence of seven different severe anomalies is extremely rare. The location of the anomalies, the patient’s age and presentation are other interesting aspects of the presented case. Case Report: A 1-year-old girl with an enlarged head and big, infected lumbosacral myelomeningocele (MMC) was admitted to the emergency department in a comatose state. Further investigations revealed hydrocephalus, Chiari malformation, syringohydromyelia, split cord malformation, dermal sinus tract, lumbosacral MMC, and tethered cord. Unfortunately, the patient died 3 days after admission because of meningitis and sepsis. Discussion: Coexistence of seven different craniospinal anomalies is extremely unusual. Further investigations with magnetic resonance imaging for associated anomalies, early shunt placement and MMC repair are required to prevent this life-threatening condition in spina bifida.
Cystic Meningioangiomatosis
Authors: Kobayashi Hiroyuki , Ishii Nobuaki , Murata Jun-Ichi , Saito Hisatoshi , Kubota Kanako C. , Nagashima Kazuo , Iwasaki Yoshinobu
Published: August 2006

A case of cerebral meningioangiomatosis with rare cyst formation is reported. A 14-year-old boy without any stigmata of neurofibromatosis type 2 presented intractable complex partial and generalized seizures since the age of 12 years. Neuroradiological studies showed an abnormal cystic mass with calcification in the left frontal lobe of the cerebrum. The tumor was located in the leptomeninges and cerebral cortex. The patient underwent surgical treatment because medical treatment with phenytoin and sodium valproate was not sufficient to control the seizures. An intraoperative electrocorticogram revealed that epileptic foci were recorded from the cortex, which was adjacent to the lesion. Histopathology showed specific features of meningioangiomatosis with meningioma-like nodules. The patient did not have any seizures with anticonvulsants after surgery. It is important to distinguish meningioangiomatosis from other possible cortical lesions and epileptic foci should be carefully considered before resection, because it is a benign and surgically manageable cause of seizures.
Internal Reduction Established by Occiput-C2 Pedicle Polyaxial Screw Stabilization in Pediatric Atlantoaxial Rotatory Fixation
Authors: Belen Deniz , Simsek Serkan , Yigitkanli Kazim , Bavbek Murad
Published: August 2006

Atlantoaxial rotatory fixation is an uncommon disorder of childhood, which can be treated conservatively whendiagnosed early. Although spontaneous correction occasionally occurs, most of the patients usually benefit from collar or traction therapies. If there is no intervention or if all external therapeutic modalities fail, the deformity may become chronic and irreducible. In such rare cases, surgical correction and stabilization are needed to prevent future head and neck deformity or facial asymmetry. In this report we describe a novel surgical technique used in a pediatric case presenting with delayed type 2 atlantoaxial rotatory fixation, in whom all external reduction methods had failed. The patient’s deformity was treated by occiput-C2 pedicle polyaxial screw stabilization. This technique is effective for reducing the atlantoaxial fixation in children.
Association of Clinic Vascular Access Monitoring Practices with Clinical Outcomes in Hemodialysis Patients
Authors: Plantinga Laura C. , Jaar Bernard G. , Astor Brad , Fink Nancy E. , Eustace Joseph A. , Klag Michael J. , Powe Neil R.
Published: August 2006

Background: Early identification of access dysfunctions may be associated with improved patient outcomes. We examined whether patient outcomes were associated with vascular access monitoring practices in an incident dialysis cohort. Methods: We conducted a national prospective cohort study and analyzed 363 hemodialysis patients who had a first permanent vascular access (arteriovenous fistula or graft) by 6 months after the start of dialysis. Multivariate methods were used to examine associations between monitoring practices and 6-month Kt/V (reaching Kt/V ≧1.2), access intervention, access failure, and 2-year septicemia and all-cause hospitalization and mortality. Results: Patients who received monitoring weekly or more often (49%) were more likely to have an access intervention (adjusted RH = 1.40, 95% CI, 1.07–1.84) than those who received monitoring less frequently. Additionally, patients treated at clinics that reported performing regular access monitoring (80% of patients) were less likely to be hospitalized for septicemia (IRR = 0.35, 95% CI, 0.21–0.61) or for any cause (IRR = 0.77, 95% CI, 0.60–0.99). There were no statistically significant differences between patients exposed to different vascular access monitoring practices in access failure, achievement of Kt/V, or survival. Conclusion: Frequent monitoring of dialysis access may initially increase the number of interventions but is beneficial to longer-term outcomes, including septicemia-related and all-cause hospitalization.
Evidence that the Mouse Osteocalcin-Related Gene Does Not Encode Nephrocalcin
Authors: Petrucci Martin , Paquette Yves , Leblond François A. , Pichette Vincent , Bonnardeaux Alain
Published: August 2006

Background/Aims: The osteocalcin-related gene (ORG) is a mouse-specific member of the osteocalcin gene cluster predicted to encode a γ-carboxyglutamic acid-rich protein. ORG mRNA has been predicted to encode nephrocalcin and shown to be expressed in the kidney where it could serve as an important crystallization inhibitor. To determine whether ORG encodes mouse nephrocalcin, we investigated its in vivo and in vitro expression. Methods: We expressed fluorescent fusion ORG proteins in kidney cell lines and generated transgenic mice expressing enhanced green fluorescent protein under the control of the ORG promoter. Results:ORG mRNA was shown to be expressed in mouse kidneys and in a variety of other tissues. Fusion constructs transfected in opossum kidney cells demonstrated integrity of the open reading frame with the presence of a protein of the expected molecular weight. However, kidneys from transgenic mice carrying the enhanced green fluorescent protein gene under the control of the ORG promoter (5.8 kb fragment) demonstrated no expression of the transgene in kidneys or other tissues. Conclusion: We conclude that ORG, the third gene of the mouse osteocalcin gene cluster is silent and unlikely to play a major role in mouse renal physiology.
Renoprotective Effect of Breviscapine through Suppression of Renal Macrophage Recruitment in Streptozotocin-Induced Diabetic Rats
Authors: Qi Xiang Ming , Wu Guo Zhong , Wu Yong Gui , Lin Hui , Shen Ji Jia , Lin Shan Yan
Published: August 2006

Background/Aims: Experimental and clinical evidence has consistently demonstrated that renal macrophage infiltration is one of the most important events for the progression of diabetic nephropathy. Breviscapine is a flavonoid extracted from the Chinese herb Erigeron breviscapus. Previously, it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study is to investigate whether the renoprotective effect of breviscapine is through suppression of renal macrophage recruitment in diabetic rats. Methods: Diabetes was induced bystreptozotocin injection, and breviscapine was administered orally at a dose of 20 mg/kg/day for 8 weeks. Control rats received vehicle or breviscapine with the same schedule. Results: Breviscapine treatment markedly inhibited both an increase of albuminuria and glomeruli hypertrophy and tubulointerstitial injury without modifying mean arterial blood pressure and creatinine clearance. Levels of malondialdehyde and protein kinase C activities were markedly higher and antioxidant enzyme activities such as superoxide dismutase, catalase as well as glutathione peroxidase were significantly lower in the kidneys of diabetic rats than of the control group, breviscapine administration markedly remitted these changes. ED-1-positive cells and expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) in glomeruli and tubulointerstitium were all markedly elevated but were significantly reduced by breviscapine. Western blot analysis noted that the expression of transforming growth factor β1 protein was increased 1.8-fold in the kidney in diabetic rats, breviscapine treatment could reduce increased expression of TGF-β1 protein by 47%. Conclusion: This study describes a novel mechanism by which breviscapine confers a renoprotective effect.
Cognitive Deficits in Familial Alzheimer’s Disease Associated with M239V Mutation of Presenilin 2
Authors: Giovagnoli Anna Rita , Marcon Gabriella , Giaccone Giorgio , Confaloni Anna Maria , Tagliavini Fabrizio
Published: August 2006

The neuropsychological assessment of non-demented subjects with gene mutation of familial Alzheimer’s disease (AD) provides a model for exploring the early cognitive features of the disease. We evaluated 1 patient and 6 non-demented subjects belonging to a family with AD with M239V mutation of the presenilin 2 gene, aiming to verify the contribution of specific cognitive patterns to the characterization of familial AD. One patient, 3 non-demented subjects with M239V mutation and 3 subjects without mutation from the same family underwent neuropsychological testing. The patient’s cognitive profile was characterized by anosognosia, visuospatial agnosia, apraxia and fluent aphasia. Of the 3 non-demented subjects with mutation, 1 showed no deficits, another constructive apraxia and the third spatial perception and memory deficits. The 3 subjects without mutation showed normal abilities. The cognitive deficits of the non-demented subjects with mutations indicate focal dysfunction of the posterior cortical areas, resembling the more extended parieto-occipito-temporal dysfunction of the demented patient. Such grading of visuospatial, praxis, and language impairments highlights a distinctive pattern related to the M239V mutation of the presenilin 2 gene.
Rethinking the Dementia Diagnoses in a Population-Based Study: What Is Alzheimer’s Disease and What Is Vascular Dementia?
Authors: Agüero-Torres Hedda , Kivipelto Miia , von Strauss Eva
Published: August 2006

Objective: To explore the hypothesis that older adults often are affected by more than one disease, making the differential diagnosis between Alzheimer’s disease (AD) and vascular dementia (VaD) difficult. Methods: Incident dementia cases (n = 308) from a population-based longitudinal study of people 75+ years were investigated. The DSM-III-R criteria were used for the clinical diagnosis of dementia. Data on vascular disorders (hypertension, cerebrovascular and ischemic heart diseases, heart failure, atrial fibrillation, diabetes) as well as type of onset/course of dementia were used retrospectively to reclassify dementias. Results: Only 47% of the AD cases were reclassified as pure AD without any vascular disorder. Among subjects with AD and with a vascular component, cerebrovascular disease was the most common (41%). Only 25% of VaD were reclassified as pure VaD. Further, 26% of the pure AD subjects developed a vascular disorder in the following 3 years. Conclusions: Both vascular and degenerative mechanisms may often contribute to the expression of dementia among the elderly. Most of the AD cases have vascular involvements, and pure dementia types in very old subjects constitute only a minority of dementia cases.
Acute Abdominal Pain among Elderly Patients
Authors: Laurell H. , Hansson L.-E. , Gunnarsson U.
Published: August 2006

Background: Diagnosis of acute abdominal pain in older persons is a challenge, with the age-related increase in concurrent diseases. In most western countries the number of elderly people is constantly rising, which means that an increasing proportion of patients admitted for abdominal pain at the emergency department are elderly. Objective: To characterize differences in clinical presentation and diagnostic accuracy between younger and more elderly patients with acute abdominal pain. Methods: Patients admitted to Mora Hospital with abdominal pain of up to seven days’ duration were registered according to a detailed schedule. From 1st February 1997 to 1st June 2000, 557 patients aged 65–79 years and 274 patients aged ≧80 years were registered. Patients aged 20–64 years (n = 1,458) served as a control group. Results: A specific diagnosis, i.e. other than ‘nonspecific abdominal pain’, was established in 76 and 78% of the patients aged 65–79 and ≧80 years respectively, and in 64% of those aged 20–64 (p < 0.001). Pain duration before admission increased with age (p < 0.003), as did frequency and duration of hospitalization (p < 0.0001). Hospital stay increased from 170 days per 100 emergency admissions in the control group to 320 and 458 days in the younger and older study groups, respectively. At the emergency department, older patients were more often misdiagnosed than control patients (52 vs. 45%; p = 0.002). At discharge the diagnosis was more accurate in the control group (86 vs. 77%; p < 0.0001). Hospital mortality was higher among older patients (23/831 vs. 2/1,458; p < 0.001). The admission-to-surgery interval was increased (1.8 vs. 0.9 days, p < 0.0001) in patients ≧65 years. Rebound tenderness (p < 0.0001), local rigidity (p = 0.003) and rectal tenderness (p = 0.004) were less common in the older than in the control patients with peritonitis. In patients ≧65 years, C-reactive protein did not differ between patients operated on and those not, contrary to the finding in patients <65 years (p < 0.0001). Conclusion: Both the preliminary diagnosis at the emergency department and the discharge diagnosis were less reliable in elderly than in younger patients. Elderly patients more often had specific organic disease and arrived at the emergency department after a longer history of abdominal pain compared to younger patients.
Bilateral Anterior Cingulotomy for Refractory Obsessive-Compulsive Disorder: Long-Term Follow-Up Results
Authors: Jung Hyun Ho , Kim Chan-Hyung , Chang Jong Hee , Park Yong Gou , Chung Sang Sup , Chang Jin Woo
Published: August 2006

Objective: To investigate the long-term efficacy and adverse cognitive effects of stereotactic bilateral anterior cingulotomy as a treatment for refractory obsessive-compulsive disorder (OCD) patients. Materials and Methods: Seventeen patients suffering from refractory OCD underwent stereotactic bilateral anterior cingulotomies and were followed for 24 months. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Clinical Global Impression and other neuropsychological tests were used to assess the efficacy and cognitive changes of cingulotomy. The tests were taken before and 12 and 24 months after surgery. Results: The mean improvement rate of the Y-BOCS score achieved from the baseline was 48%. Eight patients out of 17 met the responder criteria. During the 24-month follow-up, there were no significant adverse effects observed after surgery. Conclusions: Bilateral anterior cingulotomy was effective for the treatment of refractory OCD, and no other significant adverse cognitive effects on long-term follow-up were found.
Effect of a Selective Cyclooxygenase-2 Inhibitor on Renal Scarring
Authors: Kucuk Hasan Fehmi , Bingul Sadık Mehmet , Kurt Necmi , Kaptanoglu Levent , Akyol Huseyin , Torlak Oguzhan Aziz , Colak Elif
Published: August 2006

Background: Scarring is one of the steps of excessive wound healing, causing dysfunction of the involved tissues and clinically poor cosmetics. The aim of this study was to examine the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor on renal scar formation in experimental pyelonephritis. Materials and Methods: Four groups of 10 Balb/C mice were formed. In groups I and II following the inoculation of lipopolysaccharide (LPS) into both kidneys, 0.18 and 0.36 mg/day of rofecoxib was given respectively via intraperitoneal route for 5 days. No medication was applied following physiological saline solution injection to both kidneys of the mice in group III (negative control group). After group IV’s LPS inoculation on the first day, saline solution (1 ml/day) was given intraperitoneally for 5 days (positive control group). Following the exposure of both kidneys, LPS of Escherichia coli (5 mg/kg) was injected into the kidneys of groups I, II, and IV. In group III, saline solution (0.1 ml) was used instead of LPS. Three days after the inoculation of LPS, solutions containing 0.18 and 0.36 mg of COX-2 inhibitor were given intraperitoneally for 5 days in groups I and II. No medication was used for the mice in group III. Six weeks after the inoculation of LPS and saline solution, all mice were humanely euthanized. Bilateral nephrectomies were done on each group of mice, and histopathological examination was performed. Results: Inoculation of LPS into the renal parenchyma caused pyelonephritis and scar formation in all groups. The degree of pyelonephritis and scar formation was lesser in groups in which COX-2 inhibitors were used. The degree of scar formation was lesser in group II, in which 0.36 mg more of COX-2 inhibitor was used than in group I (0.18 mg of COX-2 inhibitor). Conclusion: In our study model, direct inoculation of LPS to kidneys caused experimentally induced pyelonephritis. Renal scar formation was effectively prevented through the utilization of rofecoxib at 0.36-mg doses.
Effects of High-Frequency Cranial Electrostimulation on the Rest-Activity Rhythm and Salivary Cortisol in Alzheimer’s Disease
Authors: Scherder Erik , Knol Dirk , van Tol Marie-Jose , van Someren Eus , Deijen Jan-Berend , Swaab Dick , Scheltens Philip
Published: August 2006

Objective: In a previous study, low-frequency (0.5 Hz) cranial electrostimulation (CES) neither improved the rest-activity rhythm nor reduced the level of salivary cortisol in patients with probable Alzheimer’s disease (AD). To investigate whether the frequency of CES was responsible for these negative findings, we set out to examine the effects of high-frequency CES on the rest-activity rhythm and salivary cortisol of patients with probable AD. We hypothesized that a decreased level of cortisol would parallel a positive effect of high-frequency CES on nocturnal restlessness in AD patients. Methods: Twenty AD patients were randomly assigned to an experimental group (n = 10) and a control group (n = 10). The experimental group was treated with high-frequency CES, the control group received sham stimulation, for 30 min a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Level of cortisol was measured by means of salivette tubes. Results: The rest-activity rhythm and the level of salivary cortisol did not react positively to high-frequency CES. In contrast, both groups showed an increase in the level of cortisol after the 6-week treatment period. Conclusions: High-frequency CES appeared to be ineffective in AD patients.
Hepatocyte Growth Factor Regulates E Box–Dependent Plasminogen Activator Inhibitor Type 1 Gene Expression in HepG2 Liver Cells
Authors: Imagawa Shogo , Fujii Satoshi , Dong Jie , Furumoto Tomoo , Kaneko Takeaki , Zaman Tarikuz , Satoh Yuki , Tsutsui Hiroyuki , Sobel Burton E
Published: August 2006

Objective—

We sought to determine the etiologic mechanism of pleiotropic growth factor, hepatocyte growth factor (HGF), as a regulator of hepatic synthesis of plasminogen activator inhibitor (PAI)-1, the physiological inhibitor of fibrinolysis and a potential inducer of atherothrombosis.

Methods and Results—

HGF increased PAI-1 mRNA expression and PAI-1 protein accumulation in the conditioned media of human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. HGF-inducible PAI-1 mRNA was attenuated by U0126, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, and genistein, an inhibitor of tyrosine kinase. HGF increased the human PAI-1 promoter (−829 to +36 bp) activity, and deletion and mutation analysis uncovered a functional E box (5′-CACATG-3′) at positions −158 to −153 bp. Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways. Co-transfection of USF1 expression vector increased PAI-1 promoter activity. Sterol regulatory element-binding protein-1 attenuated HGF-inducible PAI-1 promoter activity.

Conclusions—

Because USFs are involved in the regulation of carbohydrates and lipid metabolism, HGF-mediated PAI-1 production may provide a novel link between atherothrombosis and metabolic derangements. Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients.
Individual Measurement and Significance of Carotid Intima, Media, and Intima–Media Thickness by B-Mode Ultrasonographic Image Processing
Authors: Bae Jang-Ho , Kim Wuon-Shik , Rihal Charanjit S. , Lerman Amir
Published: August 2006

Objective—

We assessed the clinical significance of intima (IT), media (MT), and intima–media (IMT) thickness of the common carotid artery using B-mode ultrasonographic image processing.

Methods and Results—

One hundred seventy consecutive patients underwent common carotid artery scanning using high-resolution ultrasonography. A total of 150 patients could be analyzed off-line using ultrasonographic image processing, devised for individual measurement of IT, MT, and IMT. By univariate analysis, IT (range, 0.27 to 0.41 mm) was associated with age, whereas MT (range, 0.27 to 0.74 mm) and IMT (range, 0.49 to 1.12 mm) were associated with age, fibrinogen, and creatinine. Among atherosclerosis risk factors, hypertension was associated with thickness of all 3 layers, whereas smoking was associated with IT only. By multivariate analysis, IT was associated with age, hypertension, and smoking, whereas MT and IMT were associated with age, hypertension, and blood urea nitrogen level.

Conclusions—

Carotid IT is associated with smoking, whereas age and hypertension are associated with thickness of all 3 arterial layers. Our results suggest a differential response of the vasculature to systemic risk factors.
An Angiotensin II Type 1 Receptor Mutant Lacking Epidermal Growth Factor Receptor Transactivation Does Not Induce Angiotensin II–Mediated Cardiac Hypertrophy
Authors: Zhai Peiyong , Galeotti Jonathan , Liu Jing , Holle Eric , Yu Xianzhong , Wagner Thomas , Sadoshima Junichi
Published: August 2006

We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT
1
Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein–coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT
1
R (Tg-WT) and an AT
1
R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of Gαq/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice. In conclusion, overexpression of AT
1
-Y319F in cardiac myocytes diminished EGFR transactivation and inhibited a pathological form of cardiac hypertrophy. The YIPP motif in the AT
1
R plays an important role in mediating cardiac hypertrophy in vivo.
Myocyte-Restricted Focal Adhesion Kinase Deletion Attenuates Pressure Overload–Induced Hypertrophy
Authors: DiMichele Laura A. , Doherty Jason T. , Rojas Mauricio , Beggs Hilary E. , Reichardt Louis F. , Mack Christopher P. , Taylor Joan M.
Published: August 2006

Focal adhesion kinase (FAK) is a ubiquitously expressed cytoplasmic tyrosine kinase strongly activated by integrins and neurohumoral factors. Previous studies have shown that cardiac FAK activity is enhanced by hypertrophic stimuli before the onset of overt hypertrophy. Herein, we report that conditional deletion of FAK from the myocardium of adult mice did not affect basal cardiac performance, myocyte viability, or myofibrillar architecture. However, deletion of FAK abolished the increase in left ventricular posterior wall thickness, myocyte cross-sectional area, and hypertrophy-associated atrial natriuretic factor induction following pressure overload. Myocyte-restricted deletion of FAK attenuated the initial wave of extracellular signal-regulated kinase activation and cFos expression induced by adrenergic agonists and biomechanical stress. In addition, we found that persistent challenge of mice with myocyte-restricted FAK inactivation leads to enhanced cardiac fibrosis and cardiac dysfunction in comparison to challenged genetic controls. These studies show that loss of FAK impairs normal compensatory hypertrophic remodeling without a concomitant increase in apoptosis in response to cardiac pressure overload and highlight the possibility that FAK activation may be a common requirement for the initiation of this compensatory response.