bluuebunny/crossref_metadata_2025 huggingface dataset:
Retropharyngeal Lymph Node Metastasis in Nasopharyngeal Carcinoma: Prognostic Value and Staging Categories
Authors: Ma Jun , Liu Lizhi , Tang Linglong , Zong Jingfeng , Lin Aihua , Lu Taixiang , Cui Nianji , Cui Chunyan , Li Li
Published: March 2007

Purpose: To investigate the incidence, prognostic value, and staging categories of retropharyngeal lymph node (RLN) metastasis in nasopharyngeal carcinoma (NPC).

Experimental Design: We did a retrospective review of the data from 749 biopsy-proved nonmetastatic NPC patients. All patients had undergone contrast-enhanced computed tomography and had radiotherapy as their primary treatment.

Results: The incidence of RLN metastasis was 51.5%. After adjusting for tumor (T) and node (N) classifications, a borderline significant difference of distant metastasis-free survival (DMFS) rates was observed between patients with or without RLN metastasis. In N0 disease, the presence of RLN metastasis was a significant independent predictor for overall survival (OS), loco-regional relapse-free survival, and DMFS in multivariate Cox modeling analysis. No significant difference was observed in all end points between patients with unilateral and bilateral RLN metastasis. The hazard ratios of death and distant failure for N0 with RLN metastasis were similar to N1. The survival curve of OS and DMFS for N0 disease with RLN metastasis had approximated that of N1 disease. The survival curve of OS for T1 disease with RLN metastasis was approximately the same as T2 disease. However, the survival curve of DMFS for T1 disease with RLN metastasis was approximately the same as in T3 disease.

Conclusions: RLN metastasis has a tendency to affect the DMFS rates of patients with NPC. Retropharyngeal node involvement has a negative effect on the prognosis of N0 disease. RLN metastasis should be classified as N1.
High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer
Authors: Forssell Johan , Öberg Åke , Henriksson Maria L. , Stenling Roger , Jung Andreas , Palmqvist Richard
Published: March 2007

Purpose: The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development.

Experimental Design: Four hundred forty-six colorectal cancer specimens were stained with the pan-monocyte/macrophage marker CD68, and average infiltration along the tumor front was semiquantitatively evaluated using a four-grade scale. Each section was similarly scored for the presence of CD68 hotspots. Some aspects of macrophage-tumor cell interactions were also studied using in vitro coculture systems.

Results: Including all patients, regardless of surgical outcome and localization, survival increased incrementally with CD68TFMean infiltration grade (P = 0.0001) but not in curatively resected colon cancers (P = 0.28). CD68 hotspot score (CD68TFHotspot) was divided into high and low. A high hotspot score conferred a highly significant survival advantage also in curatively resected colon cancer cases (n = 199, P = 0.0002) but not in rectal cancers. CD68TFHotspot high turned out as an independent prognostic marker for colon cancer in multivariate analyses including gender, age, localization, grade, stage, tumor type, and lymphocytes at the tumor front, conferring a relative risk of 0.49 (P = 0.007). In vitro coculture experiments, using phorbol 12-myristate 13-acetate–activated U937 cells as macrophage model, revealed that a high ratio of macrophages to colon cancer cells inhibited cancer cell growth. This was partially dependent on cell-to-cell contact, whereas Boyden chamber cocultivation without cell-to-cell contact promoted cancer cell spread.

Conclusions: In conclusion, our data indicate that a dense macrophage infiltration at the tumor front positively influences prognosis in colon cancer and that the degree of cell-to-cell contact may influence the balance between protumorigenic and antitumorigenic properties of macrophages.
A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children's Oncology Group Study
Authors: Horton Terzah M. , Pati Debananda , Plon Sharon E. , Thompson Patrick A. , Bomgaars Lisa R. , Adamson Peter C. , Ingle Ashish M. , Wright John , Brockman Adam H. , Paton Martin , Blaney Susan M.
Published: March 2007

Purpose: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia.

Experimental Design: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m2 dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor κB (NF-κB) binding activity were evaluated during the first treatment cycle.

Results: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m2 dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m2 revealed a clearance of 11 mL/h/m2, a central volume of distribution of 6.7 L/m2, and a terminal half-life of 12.6 h. NF-κB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses.

Conclusions: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m2/dose. Although bortezomib treatment inhibited NF-κB activity, bortezomib had little activity as a single agent in this population.
Insulin-like Growth Factor Binding Proteins IGFBP3, IGFBP4, and IGFBP5 Predict Endocrine Responsiveness in Patients with Ovarian Cancer
Authors: Walker Graeme , MacLeod Kenneth , Williams Alistair R.W. , Cameron David A. , Smyth John F. , Langdon Simon P.
Published: March 2007

Purpose: This study sought to explore the predictive value of the insulin-like growth factor (IGF) binding proteins (IGFBP) as markers of response in ovarian cancer patients treated with the aromatase inhibitor letrozole.

Experimental Design: IGFBP mRNA expression in cell lines was measured by quantitative reverse transcription-PCR and IGFBP protein expression measured in sections from primary tumors of patients treated with letrozole by semiquantitative immunohistochemistry.

Results: Quantitative reverse transcription-PCR analysis showed that IGFBP3 and IGFBP5 were down-regulated and IGFBP4 was up-regulated by 17β-estradiol (E2) in an estrogen receptor (ER)–positive ovarian cancer cell line. Expressions of IGFBP1, IGFBP2, and IGFBP6 were unaffected by E2. The E2 modulation of these genes was reversed by tamoxifen. Using ERα-specific (propyl pyrazole triol) and ERβ-specific (diarylpropionitrile) agonists, the gene expression modulations produced by E2 could be replicated by propyl pyrazole triol but not by diarylpropionitrile.

For ovarian cancer patients being treated with letrozole, we tested the predictive value of the IGFBPs in paraffin-fixed sections from their primary tumors by semiquantitative immunohistochemistry. Using serum CA125 as an indicator of progression/response, significant differences in expression levels of IGFBPs were observed between tumors from CA125 responding/stable patients compared with tumors from progressing patients. Mean immunoscores for IGFBP3 and IGFBP5 were significantly lower, and mean expression of IGFBP4 was significantly higher in tumors from patients demonstrating CA125 response or stabilization compared with CA125 progression.

Conclusion: These results indicate that expression levels of certain IGFBP family members in ovarian cancers are estrogen regulated and can, thus, help identify patients who could benefit from endocrine therapy.
Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology
Authors: Ratnam Kapila , Low Jennifer A.
Published: March 2007

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.
Cancer Cachexia Signaling Pathways Continue to Emerge Yet Much Still Points to the Proteasome
Authors: Acharyya Swarnali , Guttridge Denis C.
Published: March 2007

Cachexia is a life-threatening consequence of cancer that diminishes both quality of life and survival. It is a syndrome that is characterized by extreme weight loss resulting mainly from the depletion of skeletal muscle. Research from the past decades investigating the mechanisms of tumor-induced muscle wasting has identified several key cachectic factors that act through the ubiquitin-dependent proteasome system. Signaling pathways that mediate the effects of these cachectic factors have also subsequently emerged. Here, we review some of these pathways specific to myostatin, nuclear factor κB, and the newly elucidated dystrophin glycoprotein complex. Although these molecules are likely to employ distinct modes of action, results suggest that they nevertheless maintain a link to the proteasome pathway. Therefore, although the proteasome remains a preferred choice for therapy, the continually emerging upstream signaling molecules serve as additional promising therapeutic targets for the treatment of tumor-induced muscle wasting.
Sperm-Associated Antigen 9, a Novel Cancer Testis Antigen, Is a Potential Target for Immunotherapy in Epithelial Ovarian Cancer
Authors: Garg Manoj , Chaurasiya Dipak , Rana Ritu , Jagadish Nirmala , Kanojia Deepika , Dudha Namrata , Kamran Neha , Salhan Sudha , Bhatnagar Amar , Suri Sushma , Gupta Anju , Suri Anil
Published: March 2007

Purpose: Cancer testis antigens are a group of tumor antigens with gene expression restricted to male germ cells in the testis and in various cancerous tissues. Recently, we reported a novel testis-specific sperm-associated antigen 9 (SPAG9) gene, a new member of the c-Jun NH2-terminal kinase–interacting protein family, having functional role in sperm-egg fusion and mitogen-activated protein kinase signaling pathway. National Center for Biotechnology Information Blast searches revealed SPAG9 nucleotide sequence similarities with expressed sequence tags of various cancerous tissues. In an effort to examine the clinical utility of SPAG9, we investigated the SPAG9 mRNA and protein expression in epithelial ovarian cancer (EOC). Humoral immune response to SPAG9 was also evaluated in EOC patients.

Experimental Design: We determined the expression profile of SPAG9 transcript by reverse transcription-PCR and RNA in situ hybridization and SPAG9 protein expression by immunohistochemistry in EOC specimens and human ovarian cancer cell lines. Using ELISA and Western blotting, we analyzed specific antibodies for SPAG9 in sera from patients with EOC.

Results: SPAG9 mRNA and protein expression was detected in 90% of EOC tissues and in all three human ovarian cancer cell lines. Specific SPAG9 antibodies were detected in 67% of EOC patients and not in sera from healthy individuals.

Conclusions: Our findings indicate that SPAG9 is highly expressed in EOC and immunogenic in patients. Humoral immune response against SPAG9 in early stages of EOC suggests its important role in early diagnostics. These results collectively suggest that SPAG9, a novel member of cancer testis antigen family, could be a potential target for the development of diagnostic and therapeutic methods in EOC.
Plasma and Cerebrospinal Fluid Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420
Authors: Broniscer Alberto , Panetta John C. , O'Shaughnessy Melinda , Fraga Charles , Bai Feng , Krasin Matthew J. , Gajjar Amar , Stewart Clinton F.
Published: March 2007

Purpose: To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420.

Experimental Design: Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC0-24).

Results: This patient was assigned to receive erlotinib at a dose level of 70 mg/m2, but the actual daily dose was 75 mg (78 mg/m2). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC0-24 in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC0-24 in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and ∼9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was ∼130 ng/mL (325 nmol/L).

Conclusions: The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.
Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma
Authors: Worley Lori A. , Onken Michael D. , Person Erica , Robirds Diane , Branson Julie , Char Devron H. , Perry Arie , Harbour J. William
Published: March 2007

Purpose: To compare a gene expression–based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma.

Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios.

Results: The gene expression–based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3.

Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.
Partial Seizures due to Sclerosis of the Right Amygdala Presenting as Panic Disorder
Authors: Picardi Angelo , Di Gennaro Giancarlo , Meldolesi Giulio N. , Grammaldo Liliana G. , Esposito Vincenzo , Quarato Pier P.
Published: March 2007

The differential diagnosis between panic disorder and focal epilepsy may sometimes pose a serious challenge. We report the case of a 32-year-old woman who complained of paroxysmal episodes of acute anxiety that evaded diagnosis for 8 years. Standard EEGs and brain CT scan showed no clear pathologic findings. Antidepressants, support psychotherapy and several courses of antiepileptic drugs were not beneficial. She was referred to our centre for a comprehensive diagnostic assessment. Clinical and standardized personality assessment did not reveal the personality organization typically associated with proneness to develop phobic anxiety disorders. Also, agoraphobic avoidance was absent, and the patient’s main worries during the episodes involved negative social judgments rather than health. A brain MRI revealed a slightly increased signal at FLAIR images in the right amygdala. Video-EEG monitoring was decisive in establishing the diagnosis of drug-resistant right mesial temporal lobe epilepsy. Anteromesial temporal lobectomy was offered and successfully performed. Pathological examination of removed brain tissue revealed amygdalar sclerosis and mild hippocampal neuronal loss. At a 6-month follow-up visit, the paroxysmal episodes had completely disappeared. Depression, anxiety and quality of life were markedly improved. This case suggests that focal epilepsy should be considered in patients with paroxysmal episodes of anxiety, especially if dissociative symptoms and atypical clinical features for panic disorder are present, and if there is no satisfactory response to adequate trials of medication and psychotherapy within one year. A careful psychopathological analysis rather than a descriptive enumeration of symptoms is needed to bring these features to light. In such cases, even if routine EEGs or MRI are inconclusive and there is no response to antiepileptic drugs, it would be advisable to perform video-EEG monitoring to rule out partial seizures.
Associations between the CYBA 242C/T and the MPO –463G/A Polymorphisms, Oxidative Stress and Cardiovascular Disease in Chronic Kidney Disease Patients
Authors: Grahl Debora A. , Axelsson Jonas , Nordfors Louise , Heimbürger Olof , Bárány Peter , Qureshi Abdul Rashid , Kato Sawako , Watanabe Makoto , Suliman Mohamed , Riella Miguel C. , Lindholm Bengt , Stenvinkel Peter , Pecoits-Filho Roberto
Published: March 2007

Genetic variations in the NADPH/MPO system in chronic kidney disease (CKD) patients might lead to altered activity of these enzymes, and thus to altered risk for oxidative stress (OS) and cardiovascular disease (CVD). We evaluated the impact of 242C/T CYBA and –463G/A MPO polymorphisms on OS and CVD mortality in stage 5 CKD patients starting dialysis. Two hundred and fifty-seven patients were genotyped using Pyrosequencing. Plasmalogen [dimethylacetal (DMA) 16/C16:0] was used as OS marker. CVD was assessed from patient history and clinical symptoms. Prevalence of CVD was higher (35%) in GG patients (MPO) compared to AG (26%) and AA (0%) patients (p < 0.01). Patients with CC genotype (CYBA) had lower levels of DMA 16/C16:0 (ratio 0.071 ± 0.003) compared to TT patients (0.089 ± 0.006; p < 0.05). These patients also had increased CVD mortality compared to CT and TT patients (χ2 2.19; p < 0.05). We conclude that genetic variations in the NADPH/MPO system are associated with OS, presence of CVD and CVD-related mortality in CKD patients.
Long-Term Efficacy of Tonsillectomy in Chinese Patients with IgA Nephropathy
Authors: Chen Yu , Tang Zheng , Wang Qingwen , Yu Yusheng , Zeng Caihong , Chen Huiping , Liu Zhi-hong , Li Lei-shi
Published: March 2007

Background: To investigate the clinical efficacy of tonsillectomy on long-term clinical remission and renal survival of immunoglobulin A nephropathy (IgAN) patients in China. Methods: We performed a 130-month retrospective case-control study of 112 patients with idiopathic biopsy-diagnosed IgAN from 1983 to 1999. Fifty-four patients underwent tonsillectomy and 58 patients did not. The clinical remission rate during follow-up and variables to predict clinical remission were estimated by χ2 test and multivariate Cox regression analysis; renal survival was evaluated by Kaplan-Meier analysis. Results: Up to 2006, the follow-up period lasted 130 ± 50.3 months (60–276 months). The clinical remission rate was 46.3% in patients with tonsillectomy and 27.6% in those without tonsillectomy during follow-up. Multivariate analysis demonstrated that tonsillectomy was not an independent impact factor for renal clinical remission (p = 0.386). By Kaplan-Meier analysis, there was no significant difference in renal survival rate between patients with tonsillectomy and those without tonsillectomy (p = 0.059). Conclusion: The clinical remission rate in IgAN patients with tonsillectomy was higher than that in patients without tonsillectomy during follow-up. But within 130 months, it was difficult to find statistical difference in renal survival between IgAN patients with and without tonsillectomy.
Plaque Rupture in Humans and Mice
Authors: Schwartz Stephen M. , Galis Zorina S. , Rosenfeld Michael E. , Falk Erling
Published: March 2007

Despite the many studies of murine atherosclerosis, we do not yet know the relevance of the natural history of this model to the final events precipitated by plaque disruption of human atherosclerotic lesions. The literature has become particularly confused because of the common use of terms such as “instability”, “vulnerable”, “rupture”, or even “thrombosis” for features of plaques in murine model systems not yet shown to rupture spontaneously and in an animal surprisingly resistant to formation of thrombi at sites of atherosclerosis. We suggest that use of conclusory terms like “vulnerable” and “stable” should be discouraged. Similarly, terms such as “buried fibrous caps” that imply preceding events that are unproven tend to create confusion. We will argue that such terminology may mislead readers by implying knowledge that does not yet exist. We suggest, instead, a focus on specific processes that various forms of data have implicated in plaque progression. For example, formation of the fibrous cap, protease activation, and cell death in the necrotic core can be well described and have all been modeled in well-defined experiments. The relevance of such well-defined, objective, descriptive observations in the mouse can be tested for relevance against data from human pathology.
Genetic Dissection of a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 and Gene Expression Analysis Identifies
SPON1
As a Novel Candidate Hypertension Gene
Authors: Clemitson Jenny-Rebecca , Dixon Richard J. , Haines Steve , Bingham Andrew J. , Patel Bhakti R. , Hall Laurence , Lo Ming , Sassard Jean , Charchar Fadi J. , Samani Nilesh J.
Published: March 2007

A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene,
Spon1
that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the
Spon1
gene product in SHR kidneys.
Spon1
belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.
Granulocyte-Macrophage Colony-Stimulating Factor–Induced Vessel Growth Restores Cerebral Blood Supply After Bilateral Carotid Artery Occlusion
Authors: Schneider Ulf C. , Schilling Lothar , Schroeck Helmut , Nebe C. Thomas , Vajkoczy Peter , Woitzik Johannes
Published: March 2007

Background and Purpose—

Hemodynamic compromise due to occlusive cerebrovascular disease is associated with an increased stroke risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been suggested to stimulate collateral blood vessel growth in various models of hemodynamic compromise. The purpose of this study was to investigate the effects of GM-CSF on cerebral hemodynamics and vessel growth in a rat model of chronically impaired cerebral blood flow (CBF).

Methods—

Male Sprague-Dawley rats underwent sequential bilateral carotid artery occlusion (BCO) and were treated with GM-CSF or saline for 6 weeks. Sham-occluded animals served as a control group. Baseline CBF was measured by iodo[
14
C]antipyrine autoradiography, and cerebrovascular reserve capacity was assessed by laser-Doppler flowmetry after application of 20 mg/kg body weight acetazolamide. The capillary density and arterioles immunopositive for α-smooth muscle actin were counted on brain sections. The cerebral angioarchitecture was visualized with a latex perfusion technique.

Results—

Baseline CBF as measured by iodo[
14
C]antipyrine autoradiography was not affected by BCO. The cerebrovascular reserve capacity, however, was significantly impaired 1 week after BCO. CBF and cerebrovascular reserve capacity recovered completely in GM-CSF–treated animals but not in solvent-treated animals. Histologic analysis of the hippocampus revealed integrity of the hypoxia-vulnerable neurons in all animals. The capillary density showed a very mild increase in GM-CSF–treated animals. However, the number of intraparenchymal and leptomeningeal arterioles was significantly higher in GM-CSF–treated animals than in both other groups.

Conclusions—

Long-term GM-CSF treatment in a BCO model in rats leads to restoration of impaired cerebral hemodynamics and accompanies structural changes in the resistance-vessel network.
Novel Protein Transduction Method by Using 11R
Authors: Ogawa Tomoyuki , Ono Shigeki , Ichikawa Tomotsugu , Arimitsu Seiji , Onoda Keisuke , Tokunaga Koji , Sugiu Kenji , Tomizawa Kazuhito , Matsui Hideki , Date Isao
Published: March 2007

Background and Purpose—

A motif of 11 consecutive arginines (11R) is reported to be one of the most effective protein transduction domains for introducing proteins into the cell membrane. We therefore examined the transduction efficiency of 11R in cerebral arteries.

Methods—

Basilar arteries (BAs) obtained from rats were incubated with either 11R-enhanced green fluorescent protein (11R-EGFP) or EGFP without 11R. After incubation, expression of 11R-EGFP or EGFP in BA serial sections was observed by fluorescence microscope. In an additional in vivo experiment, 11R-EGFP or EGFP was injected into the cisterna magna with or without subarachnoid hemorrhage. The 11R-EGFP or EGFP was injected just after the autologous blood injection, and then the expression of 11R-EGFP or EGFP in BA sections was also observed by fluorescence microscope.

Results—

The 11R-EGFP signal was much stronger than that of EGFP in all layers of the rat BA, in both in vivo and ex vivo experiments. Moreover, the 11R-EGFP was transduced into the BA immediately (2 hours after the injection). Interestingly, 11R-fused fluorescent protein was transduced especially into the tunica media of the BA.

Conclusions—

The 11R-fused fluorescent protein effectively penetrates into all layers of the rat BA, especially into the tunica media. This is the first study to our knowledge to demonstrate the successful transduction of a protein transduction domain fused protein into the cerebral arteries.
Attitudes and Current Practice of Primary Care Physicians in Acute Stroke Management
Authors: Roebers Sabine , Wagner Markus , Ritter Martin A. , Dornbach Frank , Wahle Klaus , Heuschmann Peter U.
Published: March 2007

Background and Purpose—

Stroke patients often report that primary care physicians (PCPs) are their first medical contact after onset of symptoms. We studied PCP attitudes and current practice in early management of suspected stroke patients.

Methods—

A cross-sectional survey was conducted among 714 general practitioners, internists, and neurologists providing acute primary care for stroke patients in 4 different regions in Germany. PCP attitudes and practices were assessed with standardized questionnaires and case vignettes presenting suspected stroke patients contacting PCPs either by phone or in practice. Factors influencing the decision of the PCPs to admit patients with clear stroke symptoms as medical emergency to hospital were assessed using multivariate analysis.

Results—

In total, 395 PCPs participated in the study (55.3%). Most PCPs agreed that stroke (94.7%) and transient ischemic attack (84.8%) were medical emergencies. In case vignettes, admission to hospital as medical emergency was preferred management after first contact to patients with clear stroke symptoms by phone or in practice (68.9% and 65.6%, respectively). Outpatient clarification was the preferred option of PCPs in patients with unclear stroke symptoms contacting PCPs by phone or in practice (54.7% and 75.5%, respectively) and in transient ischemic attack patients (50.9%). Working as general practitioner (odds ratio, 0.3; 95% confidence interval, 0.2 to 0.6) and practice location outside metropolitan area (
P
=0.002) independently decreased probability of admitting suspected stroke patients as medical emergency when first contact to PCPs was by phone. PCP agreement that all stroke and transient ischemic attack patients must be admitted to hospital increased probability for early hospitalization of stroke and transient ischemic attack patients when first contact was in practice (odds ratio, 2.0; 95% confidence interval, 1.2 to 3.3, and odds ratio, 1.8; 95% confidence interval, 1.1 to 2.8, respectively).

Conclusions—

Stroke and transient ischemic attack were well recognized as medical emergencies by PCPs in our study. However, only two-thirds of PCP would immediately admit stroke suspected patients with clear symptoms to hospital as medical emergency.
Toll Receptor Polymorphisms and Carotid Artery Intima-Media Thickness
Authors: Labrum Robyn , Bevan Steve , Sitzer Matthias , Lorenz Matthias , Markus Hugh S.
Published: March 2007

Background and Purpose—

Inflammation is a key mechanism in atherosclerosis. Variation in genes encoding inflammatory responses may therefore influence atherosclerosis risk possibly through interaction with chronic infections and proinflammatory environmental risk factors such as smoking, diabetes, and obesity. The Toll-like receptor family (TLRs) genes TLR2 and TLR4, both involved in the inflammatory process, are potential candidates and TLR-4 has been previously associated with cardiovascular disease, although other studies have failed to confirm this.

Methods—

A total of 3000 individuals from the prospective community-based Carotid Atherosclerosis Progression Study (CAPS) were genotyped for single nucleotide polymorphisms: TLR2 (Arg753Gln, −16934 A/T) and TLR4 (D299G, T399I). Associations were determined with common carotid artery intima-media thickness (IMT) at baseline and also progression of IMT over the 3-year follow-up period. Gene–environment interactions with high sensitive C-reactive protein, smoking, body mass index, and diabetes were determined.

Results—

There was no association between single nucleotide polymorphisms or haplotypes in either TLR4 or TLR2 and either baseline IMT or progression of IMT over the 3-year follow up. There were no interactions among the three proinflammatory risk factors. No genotype or haplotype was associated with high sensitive C-reactive protein.

Conclusions—

In this large community population, we found no evidence for genetic variation in these two TLRs being risk factors for increased IMT either directly or through interaction with proinflammatory risk factors. We were unable to confirm associations with the TLR4 polymorphisms reported in previous smaller studies.
A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages
Authors: Ohwaki Kenji , Bujo Hideaki , Jiang Meizi , Yamazaki Hiroyuki , Schneider Wolfgang J. , Saito Yasushi
Published: March 2007

Objective—

Macrophages play a key role in lipid-rich unstable plaque formation and interact with intimal smooth muscle cells (SMCs) in early and progressive stages of atherosclerosis. LR11 (also called sorLA), a member of low-density lipoprotein receptor family, is highly and specifically expressed in intimal SMCs, and causes urokinase-type plasminogen activator receptor-mediated degradation of extracellular matrices. Here we investigated whether the secreted soluble form of LR11 (solLR11) enhances adhesion, migration, and lipid accumulation in macrophages using animal models and cultured systems.

Methods and Results—

Immunohistochemistry showed solLR11 expression in thickened intima of balloon-denuded rat artery. Macrophage infiltration into the cuff-injured artery was markedly reduced in LR11-deficient mice. In vitro functional assays using THP-1-derived macrophages showed that solLR11 (1 μg/mL) significantly increased acetylated low-density lipoprotein uptake by THP-1 cells and cell surface levels of scavenger receptor SR-A 1.7- and 2.8-fold, respectively. SolLR11 dose-dependently increased the migration activity of THP-1 macrophages and adhesion to extracellular matrices 2.0- and 2.1-fold, respectively, at 1 μg/mL. These effects of solLR11 were almost completely inhibited by a neutralizing anti-urokinase-type plasminogen activator receptor antibody.

Conclusion—

SolLR11, secreted from intimal SMCs, regulates adhesion, migration, and lipid accumulation in macrophages through activation of urokinase-type plasminogen activator receptor. The formation of lipid-laden macrophages in atherosclerotic plaques possibly is regulated by SolLR11 of intimal SMCs.
Toll-Like Receptors 2-Deficient Mice Are Protected Against Postischemic Coronary Endothelial Dysfunction
Authors: Favre Julie , Musette Philippe , Douin-Echinard Victorine , Laude Karine , Henry Jean-Paul , Arnal Jean-François , Thuillez Christian , Richard Vincent
Published: March 2007

Objectives—

Toll-like receptors (TLR) 2 are expressed in cardiac and inflammatory cells, and regulate leukocyte function. Because leukocyte adhesion is a critical event in endothelial injury induced by ischemia/reperfusion (I/R), we assessed whether TLR2 were involved in I/R - induced coronary endothelial injury.

Methods and Results—

Ischemia - reperfusion markedly decreased NO-mediated coronary relaxations to acetylcholine assessed ex vivo. In contrast, in TLR2 deficient mice, I/R paradoxically
improved
the NO-mediated responses to acetylcholine. To precise the cellular compartment expressing TLR2 which is involved in endothelial injury, we developed bone-marrow chimeric mice by transplanting TLR2
−/−
bone marrow to WT mice or WT bone marrow to TLR2
−/−
mice and submitted them to I/R 5 weeks after transplant. Both chimeric mice displayed similar protection as TLR2
−/−
mice against I/R-induced endothelial dysfunction, suggesting a role of TLR2 expressed on both non-bone marrow cells (in our case presumably endothelial cells and/or cardiomyocytes) and cells of bone marrow origin (presumably neutrophils). TLR2 deficiency was also associated with a smaller infarct size, and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration.

Conclusions—

TLR2 contribute to coronary endothelial dysfunction after I/R, possibly through stimulation of neutrophil- (and free radical-) mediated endothelial injury.
Impaired Executive Control Is Associated with a Variation in the Promoter Region of the Tryptophan Hydroxylase 2 Gene
Authors: Reuter Martin , Ott Ulrich , Vaitl Dieter , Hennig Jürgen
Published: March 2007

Current models of attention describe attention not as a homogenous entity but as a set of neural networks whose measurement yields a set of three endophenotypes—alerting, orienting, and executive control. Previous findings revealed different neuroanatomical regions for these subsystems, and data from twin studies indicate differences in their heritability. The present study investigated the molecular genetic basis of attention in a sample of 100 healthy subjects. Attention performance was assessed with the attention network test that distinguishes alerting, orienting, and executive control (conflict) using a simple reaction time paradigm with different cues and congruent and incongruent flankers. Two gene loci on candidate genes for cognitive functioning, the functional catechol-O-methyltransferase (COMT) VAL158MET and the tryptophan hydroxylase 2 (TPH2) −703 G/T promoter polymorphism, were tested for possible associations with attention. COMT is involved in the catabolism of dopamine, and TPH is the rate-limiting enzyme for serotonin synthesis. Results showed no effect of the COMT polymorphism on attention performance. However, the TT genotype of TPH2 −03 G/T was significantly associated with more errors (a possible indicator of impaired impulse control; p = .001) and with decreased performance in executive control (p = .001). This single-nucleotide polymorphism on the TPH2 gene explained more than 10% of the variance in both indicators of attention stressing the role of the serotonergic system for cognitive functions.
Beta-adrenergic Modulation of Cognitive Flexibility during Stress
Authors: Alexander Jessica K. , Hillier Ashleigh , Smith Ryan M. , Tivarus Madalina E. , Beversdorf David Q.
Published: March 2007

Stress-induced activation of the locus ceruleus-norepinephrine (LC-NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC-NE system may produce deleterious effects. The aim of the present study was to determine the effect of pharmacological modulation of the LC-NE system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuo-spatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system.
Male Friendship in Ming China: An Introduction
Authors: Huang Martin
Published: March 2007

This introduction provides a historical and theoretical context for the four articles on Ming male friendship. It reviews relevant scholarship and tries to show how the four articles contribute to a better appreciation of the complexities of friendship as it was theorized and practiced by Chinese males in Ming China.
Placing the Wild in the City: "Thinking with" Melbourne's Bats
Authors: Thomson Melanie
Published: March 2007

This paper uses academic and lay discourses to examine the ways in which "the city" is constructed in its relationship to "wildlife." The paper examines the negative and essentialized ways in which the city's relationship to wildlife has been represented in postcolonial theory and animal geography. The paper further explores these theoretical framings of the city in the empirical context of the relocation of an urban, flying fox colony, which provides opportunities to reconsider these bounded conceptualizations of the city.
Keeping the Force: Retaining Military Careerists
Authors: Quester Aline O. , Thomason James S.
Published: March 2007

Despite major recent recruiting and reenlistment successes, serious concerns are growing that the all-volunteer force will face severe tests in the nineties. This article explores one of the threatening prospects: far stronger civilian sector competition for technically trained military personnel. In particular, the authors first emK pirically estimate the magnitude of the pull of the civilian economy on the career military; then these estimates are used to gauge the impact of likely future civilian job growth on the chances that military personnel will reenlist or leave.
Congressional Perspectives On Defense Manpower Issues
Authors: Hale Robert F.
Published: March 2007

No single influence or perspective dominates congressional attitudes toward defense manpower issues. Reducing growth in defense spending will play a role as will other factors like public attitudes and political inclinations of key committee members. Despite diverse influences, some likely trends emerge. The Congress will probably not debate seriously-let alone enact-a return to conscription while recruiting is doing well, but there remains a willingness to reconsider the all-volunteer force should recruiting falter. Growth in active-duty forces will probably be limited, both to save money and to foster reliance on reserves. Military pay raises, too, may be limited so long as recruiting and retention remain good, but the Congress seems likely to grant catch-up raises if problems recur. Congressional debate over military retirement will continue. Unless agreement can be reached on comprehensive reform, continued piecemeal changessuch as modification of cost-of-living provisions-seem likely.
Gender Integration and Unit Deployment: A Study of GI Jo
Authors: Devilbiss M. C.
Published: March 2007

This study reports on women and men performing operational combat support functions alongside each other in a field-deployed military unit. The research specifically focuses on the gender integration process. Several major issues are addressed: (1) What feelings does one experience in a field environment under simulated combat conditions and are these feelings gender-specific? (2) What about feminine hygiene concerns and availability of personal care facilities for women in the field? (3) Are women capable of surviving and working effectively under these kinds of conditions? (4) How does incorporating women into a unit affect its combat readiness? After surveying the current literature on these issues, the author reports her own findings as a participantobserver in this combat exercise. Major findings include an explanation of the awareness and experience of the salience of gender in this environment (the "gender consciousness" phenomenon) and the "commonality of experience" hypothesis, which suggests that bonding and cohesion are based on commonality of experience, shared risk, and mutual experiences of hardship, not on gender distinctions. Questions and suggestions for future research are also presented.
Antecareer Crisis: Military Recruiting and the Youthful Job Applicant
Authors: Baker Herbert George
Published: March 2007

Generally, young job applicants have not been adequately prepared by either family or school to make wise occupations decisions. Further, today's occupations structure has an increasingly broad array of job alternatives that must be considered. "Antecareer crisis" denotes the dilemma that confronts the person seeking entry into his or her first full-time work experience: it is a crisis of unpreparedness. Help in the sense of vocational guidance is needed by our youth to resolve the antecareer crisis and effect a smoother entry into the adult world of work. Nowhere is this more true than during entry into the very special occupation milieu of the armed services. However, although the Department of Defense is the largest vocational training establishment in the world and depends inordinately upon youthful workers, the military recruiting services have not adequately addressed the problem.
The Chinese Military: Political Demands and Control
Authors: Ng-Quinn Michael
Published: March 2007

Using Deng Xiaoping's military reform in China as an empirical case, this article discusses how the military uses five attributes as its power base from which to make three types of political demands. The top leadership in turn can exert a certain degree of political control, eight tactics of which are discussed. The three sets of variables (power base, political demands, and political control) are seen in a state of interaction and flux. Political control can be effectively applied if the primary authority patterns that make up the political system (party-state) remain intact. The critical variables here are internal and external order, ideology, socialization, leadership, and tradition. Finally, the paper suggests that the importance of national security forces the leadership to make compromises and put the relationships among the three sets of variables into some kind of workable order.
The U.S. and Ethiopia: The Politics of Military Assistance
Authors: Agyeman-Duah Baffour
Published: March 2007

This article concerns the military assistance relationship between the United States and Ethiopia, especially during the early years of the Ethiopian revolution, from 1974 to 1977. The interaction between the outbreak of the uprising and American military assistance and the impact of one upon the other are our main concerns. Besides the objective needs of the revolution to reorient Ethiopia's domestic and external politics, other important forces contributed to the abrogation of the U.S.-Ethiopia Mutual Defense Assistance Agreement that had tied the two countries together for nearly three decades. Both the process and substance of the assistance relationship are analyzed-from the moment the Ethiopian armed forces intervened in the unfolding revolution to the time Menghistu Haile Mariam captured the political leadership. Such forces as the radicalization of Ethiopia's domestic politics, the American shift of its assistance policy from grant aid to foreign military cash and credit sales, the Soviet decision to embrace Menghistu, and American perceptions and reactions to the revolution were all important contributary factors to the MDAA's demise. In the face of new political realities in Ethiopia, the assumptions upon which the U.S.-Ethiopia relationship was built could no longer hold.