bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Lesions in an Unselected Cohort of the Elderly
Authors: Fernando Malee S. , Simpson Julie E. , Matthews Fiona , Brayne Carol , Lewis Claire E. , Barber Robert , Kalaria Raj N. , Forster Gill , Esteves Filomena , Wharton Stephen B. , Shaw Pamela J. , O’Brien John T. , Ince Paul G.
Published: April 2006

Background and Purpose—

“Incidental” MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved.

Methods—

A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury.

Results—

PVL severity was associated with loss of ventricular ependyma (
P
=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both
P
<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV;
P
<0.001) and microglial activation (CD68 expression;
P
=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1α and HIF2α was elevated in DSCLs (
P
=0.003 and
P
=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs
P
<0.001; DSCLs
P
=0.009) and the number of neuroglobin-positive cells (WMLs
P
=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1α expression in DSCLs (
P
=0.04).

Conclusion—

The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.
Prevention and Treatment of the Metabolic Syndrome
Authors: Daskalopoulou S. S. , Mikhailidis D. P. , Elisaf M.
Published: April 2006

The prevalence of the metabolic syndrome is increasing owing to lifestyle changes leading to obesity. This syndrome is a complex association of several interrelated abnormalities that increase the risk for cardiovascular disease and progression to diabetes mellitus (DM). Insulin resistance is the key factor for the clustering of risk factors characterizing the metabolic syndrome. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III defined the criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. According to these guidelines, treatment involves the improvement of the underlying insulin resistance through lifestyle modification (eg, weight reduction and increased physical activity) and possibly by drugs. The coexistent risk factors (mainly dyslipidemia and hypertension) should also be addressed. Since the main goal of lipid-lowering treatment is to achieve the NCEP low-density lipoprotein cholesterol (LDL-C) target, statins are a good option. However, fibrates (as monotherapy or in combination with statins) are useful for the treatment of the metabolic syndrome that is commonly associated with hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) levels. The blood pressure target is <140/90 mm Hg. The effect on carbohydrate homeostasis should possibly be taken into account in selecting an antihypertensive drug. Patients with the metabolic syndrome commonly have other less well-defined metabolic abnormalities (eg, hyperuricemia and raised C-reactive protein levels) that may also be associated with an increased cardiovascular risk. It seems appropriate to manage these abnormalities. Drugs that beneficially affect carbohydrate metabolism and delay or even prevent the onset of DM (eg, thiazolidinediones or acarbose) could be useful in patients with the metabolic syndrome. Furthermore, among the more speculative benefits of treatment are improved liver function in nonalcoholic fatty liver disease and a reduction in the risk of acute gout.
Assessment of Toe Blood Pressure Is an Effective Screening Method to Identify Diabetes Patients with Lower Extremity Arterial Disease
Authors: Sahli David , Eliasson Björn , Svensson Maria , Blohmé Göran , Eliasson Mats , Samuelsson Pär , Öjbrandt Kristina , Eriksson Jan W.
Published: April 2006

The authors evaluated a screening program for lower extremity arterial disease (LEAD) in diabetic patients and focused on the value of toe blood pressure assessment. They recruited 437 subjects, ages 30-70 years (134 healthy controls, 166 type 1 and 137 type 2 diabetic patients; control [Ctr], DM1, and DM2) with no previous history of LEAD. They were enrolled in a longitudinal study with a planned follow-up of 10 years. Patients were consecutively enrolled from outpatient diabetes units of 2 university hospitals. Subjects were screened with respect to peripheral circulation by use of established noninvasive techniques. These included arm, ankle (AP), and toe (TP) blood pressure measurements; evaluation of peripheral neuropathy; and a standardized physical examination. Results from the baseline examination are presented in this report. The number of patients who presented peripheral pressures or indices below normal (< mean -2 SD for controls) was higher among diabetic patients; 24% of DM1 and 31% of DM2, as compared to 6% of Ctr, had at least 1 lower limb with a low TP, AP, toe/arm index (TI), or ankle/arm index (AI), and these subjects were mainly identified by using the toe/arm index. TI was independently and negatively associated with fasting blood glucose in both patient groups, and with smoking, age, and diabetes duration in DM1. The mean AP was higher in the DM1 and DM2 groups compared to Ctr, whereas overall TP, TI, and AI were similar in the groups. It was also shown that abnormally low TI was significantly more common than low AI among diabetics (p<0.001), and this was true for TP vs AP as well (p<0.05). It is beneficial to include assessment of toe blood pressure and toe/arm blood pressure index to detect early LEAD in diabetic patients. Ankle blood pressure and indices alone are less efficient, owing probably to medial sclerosis in diabetic patients. Up to 30% of diabetic patients with no ischemic symptoms may have signs of impaired arterial circulation.
Effect of Chronic Oral Supplementation with Vitamins on the Endothelial Function in Chronic Smokers
Authors: Takase Bonpei , Etsuda Hirokuni , Matsushima Yoshihiro , Ayaori Makoto , Kusano Hiroyuki , Hamabe Akira , Uehata Akimi , Ohsuzu Fumitaka , Ishihara Masayuki , Kurita Akira
Published: April 2006

Cigarette smoking has been associated with endothelial dysfunction including impaired endothelium-dependent flow-mediated dilation (FMD). In cigarette smokers, increased oxygen-derived free radicals have been suspected of being one of the major causes of endothelial dysfunction, owing possibly to the inactivation of nitric oxide by free radicals. Vitamins C and E are widely used antioxidant vitamins, which have also been reported to effectively improve the endothelial function in several conditions. To test the effect of moderate-term oral antioxidant vitamin supplementation on the endothelial function in smokers, the authors evaluated the combined effect of vitamins C and E, administered in normal dosages, on FMD in young male smokers. A prospective interventional study was performed. In 15 healthy male subjects (mean age, 24.4 ±2.5 years old). They studied FMD in the brachial artery by using high-resolution ultrasound. The vascular effects of moderate-term oral supplementation with vitamin C (1.0 g/day) and vitamin E (500 mg/day) were determined during reactive hyperemia, which causes endothelium-dependent FMD. They performed a vascular function study 3 times including before vitamin supplement, after 25 days of vitamin supplement, and 4 weeks after the cessation of the vitamin supplement. The flow-mediated dilator response measurements were repeated twice a day before vitamin supplements, and the repeatability obtained from these measurements was found acceptable (variability of FMD <2%). The oral antioxidant vitamin supplement significantly restored FMD (3.8 ±2.2% vs 5.9 ±2.5%; p<0.05), however, this effect disappeared 4 weeks after the vitamin supplementations ended. The combined usual dosage of vitamins C and E supplements was found to improve the endothelial function in chronic smokers.
The Role of Valvular and Thoracic Aortic Calcifications in Distinction Between Ischemic and Nonischemic Cardiomyopathy
Authors: Atak Ramazan , Ileri Mehmet , Yetkin Ozkan , Yetkin Ertan , Turhan Hasan , Senen Kubilay , Sahin Onur , Ozbakır Cemal , Demikan Deniz
Published: April 2006

Determination of underlying etiology in patients with dilated and globally hypokinetic left ventricles may sometimes be difficult even after detailed history and complete clinical evaluation. Cardiac valvular and thoracic aortic calcifications have previously been reported to be used as a window to diffuse atherosclerosis of the vascular system. The authors prospectively examined the predictive value of mitral annular calcification (MAC), aortic valve calcification (AVC), and thoracic aortic calcification (TAC) in diagnosis of coronary artery disease as the underlying cause of diffuse left ventricular dilatation and systolic dysfunction. The study included 98 consecutive patients (male/female = 76/22, mean age = 58.9 ±10.7 years, range: 33 to 75 years) over the age of 30 years admitted to their clinics between October 1999 and December 2001 with signs and symptoms of congestive heart failure associated with documented cardiomegaly. Transthoracic echocardiography and coronary angiography were performed in all patients for the evaluation of valvular calcifications and coronary status. Although there was no significant difference between the groups with and without coronary artery stenosis (CAS), with regard to presence of MAC, patients with CAS tended to have MAC more frequently (12/61, 20% vs 4/37, 11%, p>0.05). AVC and TAC were found to be significantly more frequent in patients with CAS compared to those without CAS (AVC, 35/61, 57% vs 4/37, 11%, p<0.001 and TAC, 28/61, 46% vs 2/37, 5%, p<0.001). While all 3 calcifications had sensitivity under 60%, and specificity and positive predictive value over 75% individually, the presence of any of them had a sensitivity of 80%, specificity of 86%, positive predictive value of 91%, and negative predictive value of 73%. Thus the presence of any of these calcifications distinguished patients with coronary artery disease with a sensitivity of 80% and specificity of 86%. The presence of aortic valvular valve and thoracic aortic calcifications seems to be associated with significant coronary arterial stenosis; however, with relatively low negative predictive values these cannot be used in clinical practice for diagnosis of underlying coronary artery disease in patients with dilatated left ventricles and impaired systolic functions.
Losartan Reduces Left Ventricular Hypertrophy Proportionally to Blood Pressure Reduction in Hypertensives, but Does Not Affect Diastolic Cardiac Function
Authors: Zakynthinos E. , Pierutsakos Ch. , Konstantinidis K. , Zakynthinos S. , Papadogiannis D.
Published: April 2006

In contrast to the well-recognized salutary effects of angiotensin-converting enzyme inhibition, the value of angiotensin II type I (ATl)-receptor blockade on left ventricular hypertrophy (LVH) is controversial. In addition, the data on the influence of this therapy on cardiac diastolic function are scarce. Thirty-nine patients with moderate primary hypertension, LVH, and normal systolic function received losartan, 50 to 100 mg daily. Transthoracic echocardiography was performed at baseline and after 6 months of treatment. Thirty-one patients completed and were included in the study (16 males, 61.1 ±1.0 years). The patients were divided into responders if mean blood pressure (BP) decreased >5 mm Hg at the end of the study (20 patients) and non-responders (mean BP decrease ≤5 mm Hg, 11 patients). The BP and the LVH were significantly reduced (systolic BP by 10.0%, diastolic BP 6.5%, mean BP 8.2%, left ventricular mass index [LVMI] 6.2%, interventricular septum 5.8%, posterior wall 3.0%) (p≤0.02), attributed to the reduction of BP and LVH in responders; the LVH in non-responders did not alter with treatment. A significant correlation was noted between changes in BP and LVMI ( r =0.60, p<0.001). The systolic cardiac function remained normal. The Doppler parameters usually used to assess the diastolic function of the LV (early diastolic filling velocity [E wave], late diastolic filling velocity [A wave], ratio of E/A waves, isovolumic relaxation time), which were abnormal at baseline, did not change with treatment. The size of the left atrium increased (p<0.05) at the end of the study. In conclusion, a 6-month course with losartan decreased BP and LVH. However, the LVH regression was rather associated with the reduction of the hemodynamic stimulus per se, than any trophic effect of the drug in the myocardium. The diastolic cardiac function remained abnormal with treatment.
Observer Behavior as a Potential Source of Reactivity: Describing and Quantifying Observer Effects in a Large-Scale Observational Study of Police
Authors: Spano Richard
Published: April 2006

One theme in the field research literature is that observer effects (or observer behavior) can act as a source of bias in observational data. This article uses both descriptive and quantitative data on reactivity from a large scale observational study of police to (1) describe and categorize instances of observer effects (in the form of observers helping officers), (2) specify hypothesized effects between rapport and observer effects, and (3) assess the impact of observer effects on patrol officer arrest and use of force behavior. Descriptive accounts indicate that observer behavior at times significantly altered the course of events. In addition, bivariate analyses suggest that observer effects are likely officer initiated rather than observer initiated. Finally, both bivariate and multivariate analyses revealed that observer effects are significant predictors of use of force but not arrest behavior net of a variety of controls for acclimation between officer and observer over the course of fieldwork, officer work orientation, suspect characteristics, and situational factors. The implications of these findings for future research are discussed.
Parenting Behavior, Quality of the Parent-Adolescent Relationship, and Adolescent Functioning in Four Ethnic Groups
Authors: Wissink Inge B. , Dekovic Maja , Meijer Anne Marie
Published: April 2006

The cross-ethnic similarity in the pattern of associations among parenting behavior (support and authoritative and restrictive control), the quality of the parent-adolescent relationship (disclosure and positive and negative quality), and several developmental outcomes (aggressive behavior, delinquent behavior, and global self-esteem) was tested. A sample of 541 Dutch, Moroccan, Turkish, and Surinamese adolescents living in the Netherlands (mean age 14.43) completed questionnaires at school. The results showed ethnic similarities in the mean levels of support, authoritative control, disclosure, positive quality of the parent-adolescent relationship, delinquent behavior, and self-esteem. The quality of the parent-adolescent relationship, especially a negative quality of the relationship, showed significant associations with each adolescent outcome in all ethnic groups. For both aggressive behavior and self-esteem, the same model was applicable to all ethnic groups. The links between the quality of the parent-adolescent relationship and delinquent behavior were also similar. The links between parenting behavior and delinquent behavior, however, differed across groups.
Reconstructing the role of the appropriate adult in England and Wales
Authors: Pierpoint Harriet
Published: April 2006

The definition of the role of the ‘appropriate adult’ for young suspects in the Police and Criminal Evidence Act 1984 Code of Practice C is ambiguous and contradictory. This article argues that the role has been socially constructed by the legislator, the courts, young people, the police and appropriate adults themselves. Following various recommendations to use volunteers as appropriate adults, this article revisits the nature of the role in light of a case study of a volunteer appropriate adult service. The results demonstrate that, in terms of volunteer practice, the role has been constructed to include elements of due process, welfare and crime prevention, but has to operate within the constraints of crime control and managerialism. Hence, this article concludes that the role of the appropriate adult should be reconstructed building on the volunteers’ welfare tendencies and that, although a number of cultural and practical obstacles would have to be overcome, he or she should be joined by a mandatory legal adviser to ensure that due process is respected.
Survival advantage from imatinib compared with the combination interferon-α plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials
Authors: Roy Lydia , Guilhot Joëlle , Krahnke Tillmann , Guerci-Bresler Agnès , Druker Brian J. , Larson Richard A. , O'Brien Steve , So Charlene , Massimini Giorgio , Guilhot François
Published: April 2006

In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.
XcisClique: analysis of regulatory bicliques
Authors: Pati Amrita , Vasquez-Robinet Cecilia , Heath Lenwood S , Grene Ruth , Murali TM
Published: April 2006

Background

Modeling ofcis-elements or regulatory motifs in promoter (upstream) regions of genes is a challenging computational problem. In this work, set of regulatory motifs simultaneously present in the promoters of a set of genes is modeled as a biclique in a suitably defined bipartite graph. A biologically meaningful co-occurrence of multiplecis-elements in a gene promoter is assessed by the combined analysis of genomic and gene expression data. Greater statistical significance is associated with a set of genes that shares a common set of regulatory motifs, while simultaneously exhibiting highly correlated gene expression under given experimental conditions.

Methods

XcisClique, the system developed in this work, is a comprehensive infrastructure that associates annotated genome and gene expression data, models knowncis-elements as regular expressions, identifies maximal bicliques in a bipartite gene-motif graph; and ranks bicliques based on their computed statistical significance. Significance is a function of the probability of occurrence of those motifs in a biclique (a hypergeometric distribution), and on the new sum of absolute values statistic (SAV) that uses Spearman correlations of gene expression vectors. SAV is a statistic well-suited for this purpose as described in the discussion.

Results

XcisClique identifies new motif and gene combinations that might indicate as yet unidentified involvement of sets of genes in biological functions and processes. It currently supportsArabidopsis thalianaand can be adapted to other organisms, assuming the existence of annotated genomic sequences, suitable gene expression data, and identified regulatory motifs. A subset of Xcis Clique functionalities, including the motif visualization component MotifSee, source code, and supplementary material are available athttps://bioinformatics.cs.vt.edu/xcisclique/.
Bacterial Lipopolysaccharide Stimulates the Thyrotropin-Dependent Thyroglobulin Gene Expression at the Transcriptional Level by Involving the Transcription Factors Thyroid Transcription Factor-1 and Paired Box Domain Transcription Factor 8
Authors: Vélez María L. , Costamagna Eugenia , Kimura Edna T. , Fozzatti Laura , Pellizas Claudia G. , Montesinos María M. , Lucero Ariel M. , Coleoni Aldo H. , Santisteban Pilar , Masini-Repiso Ana M.
Published: April 2006

The bacterial lipopolysaccharide (LPS) is a biological activator that induces expression of multiple genes in several cell types. LPS has been proposed as an etiopathogenic agent in autoimmune diseases. However, whether LPS affects the expression of autoantigens has not been explored. Thyroglobulin (TG) is a key protein in thyroid hormonogenesis and one of the major thyroid autoantigens. This study aimed to analyze the action of LPS on TG gene expression in Fisher rat thyroid cell line FRTL-5 thyroid cells. We demonstrate that LPS increases the TSH-induced TG protein and mRNA level. Evidence that the effect of LPS is exerted at the transcriptional level was obtained by transfecting the minimal TG promoter. The C element of the TG promoter, which contains sequences for paired box domain transcription factor 8 (Pax8) and thyroid transcription factor (TTF)-1 binding, is essential for full TG promoter expression under TSH stimulation. The transcriptional activity of a construct containing five tandem repeats of the C site is increased by LPS, indicating a possible involvement of the C site in the LPS-induced TG gene transcription. We demonstrate that the TG promoter mutated at the Pax8 or TTF-1 binding element in the C site does not respond to LPS. In band shift assays, binding of Pax8 and TTF-1 to the C site is increased by LPS. The Pax8 and TTF-1 mRNA and protein levels are augmented by LPS. The half-lives of TG, Pax8, and TTF-1 are increased in endotoxin-treated cells. Our results reveal the ability of LPS to stimulate the expression of TG, a finding of potential pathophysiological implication.
Regulation of the Mouse Protein Targeting to Glycogen (PTG) Promoter by the FoxA2 Forkhead Protein and by 3′,5′-Cyclic Adenosine 5′-Monophosphate in H4IIE Hepatoma Cells
Authors: Cheng Alan , Zhang Mei , Crosson Sean M. , Bao Zhao Q. , Saltiel Alan R.
Published: April 2006

The scaffolding protein, protein targeting to glycogen (PTG), orchestrates the signaling of several metabolic enzymes involved in glycogen synthesis. However, little is known concerning the regulation of PTG itself. In this study, we have cloned and characterized the mouse promoter of PTG. We identified multiple FoxA2 binding sites within this region. FoxA2 is a member of the forkhead family of transcription factors that has recently been implicated in the cAMP-dependent regulation of several genes involved in liver metabolism. Using luciferase reporter constructs, we demonstrate that FoxA2 transactivates the PTG promoter in H4IIE hepatoma cells. Nuclear extracts prepared from mouse liver and H4IIE cells were able to bind a FoxA2-specific probe derived within the PTG promoter region. Chromatin immunoprecipitation experiments further demonstrate that FoxA2 binds to the PTG promoter in vivo. Finally, we show that treatment with cAMP analogs activates the PTG promoter and significantly increases PTG levels in H4IIE cells. Our results provide a framework to investigate how additional transcription factors may regulate PTG expression in other cell types.
RGS2 Is Regulated by Angiotensin II and Functions as a Negative Feedback of Aldosterone Production in H295R Human Adrenocortical Cells
Authors: Romero Damian G. , Plonczynski Maria W. , Gomez-Sanchez Elise P. , Yanes Licy L. , Gomez-Sanchez Celso E.
Published: April 2006

Regulator of G protein signaling (RGS) proteins interact with Gα-subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. Angiotensin (Ang) II interacts with its G protein-coupled receptor in zona glomerulosa adrenal cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. We studied Ang II-mediated regulation of RGS2, the role of RGS2 in steroidogenesis, and the intracellular signal events involved in H295R human adrenal cells. We report that both H295R cells and human adrenal gland express RGS2 mRNA. In H295R cells, Ang II caused a rapid and transient increase in RGS2 mRNA levels quantified by real-time RT-PCR. Ang II effects were mimicked by calcium ionophore A23187 and blocked by calcium channel blocker nifedipine. Ang II effects also were blocked by calmodulin antagonists (W-7 and calmidazolium) and calcium/calmodulin-dependent kinase antagonist KN-93. RGS2 overexpression by retroviral infection in H295R cells caused a decrease in Ang II-stimulated aldosterone secretion but did not modify cortisol secretion. In reporter assays, RGS2 decreased Ang II-mediated aldosterone synthase up-regulation. These results suggest that Ang II up-regulates RGS2 mRNA by the calcium/calmodulin-dependent kinase pathway in H295R cells. RGS2 overexpression specifically decreases aldosterone secretion through a decrease in Ang II-mediated aldosterone synthase-induced expression. In conclusion, RGS2 expression is induced by Ang II to terminate the intracellular signaling cascade generated by Ang II. RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland.
Deoxyribonucleic Acid Damage and Spontaneous Mutagenesis in the Thyroid Gland of Rats and Mice
Authors: Maier J. , van Steeg H. , van Oostrom C. , Karger S. , Paschke R. , Krohn K.
Published: April 2006

Thyroid tumors are a frequent finding not only in iodine-deficient regions. They are predominantly characterized by somatic genetic changes (e.g. point mutations or rearrangements). Because slow thyroid proliferation is a apparent contradiction to a high frequency of tumor initiation, we characterized mutational events in thyroid. First we studied the frequency of certain base exchanges in somatic TSH receptor (TSHR) mutations and determined the spontaneous mutation rate in thyroid and liver. Then we applied different protocols of the comet assay to quantify genomic DNA damage and conducted immunohistochemistry for 8-oxoguanine as a molecular marker for oxidative stress. Among 184 somatic mutations of the human TSHR found in thyroid tumors, C→T transitions had a unexpectedly high frequency (>32%). The mutation rate in thyroid is 8–10 times higher than in other organs. The comet assay detected increased levels of oxidized pyrimidine (2- to 3-fold) and purine (2- to 4-fold) in thyroid, compared with liver and lung, and a 1.6-fold increase of oxidized purine, compared with spleen. Immunohistochemistry revealed high levels of 8-oxoguanine in thyroid epithelial cells. We have shown a strikingly high mutation rate in the thyroid. Furthermore, results of the comet assay as well as immunohistochemistry suggest that oxidative DNA modifications are a likely cause of the higher mutation rate. It is possible that free radicals resulting from reactive oxygen species in the thyroid generate mutations more frequently. This is also supported by the spectrum of somatic mutations in the TSHR because more frequent base changes could stem from oxidized base adducts that we detected in the comet assay and with immunohistochemistry.
Gonadotropin-Releasing Hormone Activation of C-jun, But Not Early Growth Response Factor-1, Stimulates Transcription of a Luteinizing Hormone β-Subunit Gene
Authors: Melamed Philippa , Zhu Yunhua , Tan Siew Hoon , Xie Min , Koh Mingshi
Published: April 2006

Transcription of mammalian LH β-subunit genes (LHβ) is regulated by GnRH through activation of early growth response factor-1 (Egr-1), which interacts synergistically with steroidogenic factor-1 (Sf-1) and pituitary homeobox-1 (Pitx1) at the promoter; Egr-1 is thought to comprise the major mediator of this effect. However, the proximal promoters of LHβ genes in lower vertebrates lack an Egr-1 response element yet are responsive to GnRH; we demonstrate here that the promoter of the Chinook salmon LHβ (csLHβ) gene is also unresponsive to Egr-1. The homologous LHβ promoters in other fish contain a conserved estrogen response element-like sequence, which we recently demonstrated is not required for estrogen receptor (ER) α association with the csLHβ gene. Here we show that the estrogen response element-like element is required for the GnRH effect and for a response to c-jun overexpression. Using plasmid immunoprecipitation, we show that after GnRH exposure, c-jun associates with the intact csLHβ gene promoter through this element. We further show that the effect of c-jun requires its DNA-binding domain and that c-jun interacts with Sf-1 and ERα and exerts synergistic effects on promoter activity with Sf-1, ERα, and Pitx1. Finally, we demonstrate the role of c-jun in mediating the GnRH effect on this gene through knockdown of c-jun expression or use of a dominant negative. We conclude that c-jun mediation of the GnRH effect on the LHβ gene may be common in lower vertebrates and may have preceded an evolutionary divergence in the cis-regulatory elements that led to its function being replaced in mammals by Egr-1.
Leonardo Bruni and Biography: The Vita Aristotelis
Authors: Ianziti Gary
Published: April 2006

This article presents theVita Aristotelis(1429) as an extension of Bruni's campaign to win acceptance for his new view of Aristotle as an independently valid guide to the secular life. The dynamics and structure of theVitaare traced to Brum's attempt to counter the impact of the imminent publication of theLivesof Diogenes Laertius in a Latin translation by Ambrogio Traversari. In refuting the negative aspects of the portrait offered by Diogenes, Bruni developed and defended a selective, rhetorically based approach to biography that was novel in relation to classical and medieval interpretations of the genre.
The ‘Opicius’ Poems (British Library, Cotton Vespasian B.iv) and the Humanist Anti-Literature in Early Tudor England
Authors: Carlson David R.
Published: April 2006

Following the format of a catalogue manuscript description, this study analyses the design and contents of a manuscript presented to king Henry VII of England about 1492-93. Featuring an epic account of the 1492 English invasion of France and a pastoral dialogue praising the domestic peace imposed by the Tudor regime, the five poems are the work of a little-known Italian writer “Johannes Opicius, “ in a stylishly written and decorated copy. Like other contemporary presentations, especially the works of the early Tudor laureate Bernard Andre”, the verse is as classicizing as the design is Italianate and humanist, innovative features for English literary culture. Like other cognate products, however, Opicius’ performance lacks properties usually associated with literature. The work was not for reading nor for recirculation, owing its inspiration solely to a wish to gratify the monarch. The presentation was chiefly a matter of performing the magnificence of the king.
The Short, Lascivious Lives of Two Venetian Theaters, 1580-85
Authors: Johnson Eugene J.
Published: April 2006

Theteatro all'italiana, or Italian opera house with boxes, was one of the most successful building types invented during the Renaissance, but fragmentary and ambiguous evidence has made locating its origins difficult. This article proposes that those origins are to be found in two theaters forcommedia dell'artebuilt in Venice in 1580 and destroyed by order of the Council of Ten in 1585 (m.v.). The history of these two theaters is sketched here for the first time by means of documents recently found in the Archivio di Stato, Venice, that also include new information related to Palladia's Teatro Olimpico in Vicenza. The role the two Venetian theaters played in the economic, political and social history of the city is suggested.
FemaleComplaintes: Laments of Venus, Queens, and City Women in Late Sixteenth-Century France*
Authors: van Orden Kate
Published: April 2006

This essay studies a large repertory of French laments (complaintes,) written in the voices of women. As a feminine counterpart to masculine love lyric, thecomplaintearose from an alternative poetics, treating subjects excluded fromfin amors, such as death, crime, and war. Essentially, lyric assigned erotic longing to men and mourning to women. The unusual subject matter accommodated by thecomplaintes, coupled with a set of material and musical forms locating them amid the cultures of cheap print, psalmody, and street song, ultimately embroiled them in the battles of the religious wars. Thus female voices came to trumpet confessional politics in songs that levied lyric, gender, and faith to serve in civil war.
George Herbert's Sacramental Puritanism*
Authors: Whalen Robert
Published: April 2006

The relationship in the early Stuart church between doctrine and discipline — between formal theological belief and outward matters including church governance, polity and ceremonial practice — is important for our understanding of George Herbert's devotional lyrics. Eucharistic theories which entertained notions of “real presence “ tended to support a sacerdotal style of divinity in which priest, ceremony and outward conformity were key features. Belief in the centrality of inward spiritual life, on the other hand, was reinforced by a theology in which the external elements are less effectual instruments than mere signs of a strictly invisible grace. This paper elucidates a sacramental poetics through which Herbert sought to reconcile the ideologically contrary imperatives of public ceremony and private religious devotion. The two are brought together successfully inThe Temple, but this success consists largely in the drama resulting from the conflict the poems trace. Unmistakably inward in focus, Herbert's devotional enthusiasm is cultivated nonetheless through a fully sacramental and sacerdotal apparatus.
The Diabolical Adventures of Don Quixote, or Self-Exorcism and the Rise of the Novel
Authors: Kallendorf Hllaire
Published: April 2006

This study explores Cervantes’ appropriations of the terminology and imagery of Catholic exorcists and demonologists in the Spanish Golden Age. The “lucid intervals” of Don Quixote, his constant sense that someone pursues him, and his explicit voicing of the words of the exorcism ritual can only be understood fully in relation to contemporaneous religious belief. This essay also argues that the devilishly-described Don Quixote exorcized himself. This action anticipated self-exorcism as preached by the Franciscan Diego Gómez Lodosa. In Cervantes studies, Don Quixote's selfexorcism will become paradigmatic of the autonomous action of this first novelistic character.
Form and Substance in International Agreements
Authors: Raustiala Kal
Published: April 2006

International agreements exhibit a wide range of variation. Many are negotiated as legally binding agreements, while others are expressly nonbinding. Some contain substantive obligations requiring deep, demanding policy changes; others demand little or simply ratify the status quo ante. Some specify institutions to monitor and sanction noncompliance; others create no review structure at all. Thus, there is considerable variation both in the form of international agreements—in their legal bindingness, as well as in the range of structural provisions for monitoring and addressing noncompliance—and in the substantive obligations they impose. This variation in form and substance raises several fundamental questions about the role of international agreements in world politics.’ Why do states differentiate commitments into those which are legally binding and those which are not? What relationship exists between legality and the substantive provisions of an accord, and between legality and structural provisions for monitoring behavior? What is the relationship between substantive obligations and monitoring provisions? Finally, what difference, if any, do these choices make as to the effectiveness of an agreement?
International Administrative Law and National Sovereignty
Authors: Reinsch Paul S.
Published: April 2006

The conception of a law common to the entire civilized world has received a new content and a practical interpretation through the recent development of international unions. The numerous private unions and associations for international purposes constitute a spontaneous grouping of men throughout the world who are interested in certain lines of enterprise — industrial, political, or scientific — which are not limited by national boundaries, but have the whole world for their field of action. The number of such associations already created is indeed surprising. Nearly every type of social effort for the promotion of the broader interests of mankind has been organized in this manner, so that there are literally hundreds of international unions and associations. These bodies hold periodical conferences for the interchange of opinions and the comparison of results, and in many cases they have established permanent bureaus or offices.
The Intercantonal Law of Switzerland (Swiss Interstate Law)
Authors: Huber Max
Published: April 2006

Interstate law is the law governing the relations between the members of a confederation of states with each other, in so far as these are opposed to each other as states. It is distinguished from international law because its subjects are not sovereigns, but belong to a governed body of a superordinate commonwealth. As opposed to federal state law it is characterized by having for its object not relations of supremacy and subordination between the federation and its members, but relations of coordination between the members of the federal state. Interstate law is an intermediary conception between the law of confederations and the law of nations.
The Need of Popular Understanding of
International Law
Authors: Root Elihu
Published: April 2006

The increase of popular control over
national conduct, which marks the political
development of our time, makes it constantly more
important that the great body of the people in
each country should have a just conception of
their international rights and duties.
Albericus Gentilis
Authors: Balch Thomas Willing
Published: April 2006

Modern international law is generally regarded as beginning with the Peace of Westphalia in 1648. But it is necessary to go much further back in the history of the world for the beginnings of the law governing the intercourse of nations. The Greek states had a rudimentary inter-state law that regulated their relations. Thus they practiced arbitration in a way among themselves: they recognized the sanctity of the person of heralds, and they followed other recognized customs in their dealings one with another. When Rome and Carthage and other nations were struggling for the mastery of the world, the beginnings of a law of nations were recognized and practiced between them. Upon, however, practically all the known world coming under the sway of imperial Rome, all possibility as well as need of a law of nations was wanting, and as a result the faltering beginnings of an international law as recognized among the Greek states and then by the Powers surrounding the Mediterranean, were extinguished by the extension of the Pax Romana to all the known world.
Military Tribunals and their Jurisdiction
Authors: Halleck Henry Wager
Published: April 2006

The early Romans had their præfecti prætorio, or military judges, afterwards replaced by magistri militum, who exercised a jurisdiction somewhat corresponding to modern courts-martial and military commissions. It is true that there has been much dispute in regard to the exact limits of this jurisdiction, as conferred by the laws which have been handed down to us, yet its general outlines have been pretty well agreed upon.
Convention for the Peaceful Adjustment of International Differences
Authors: Hershey Amos S.
Published: April 2006

The First Hague Conference had as its main object a consideration of a “ possible reduction of the excessive armaments which weigh upon all nations,” or, at least, a discussion of the possibility of “ putting an end to the progressive development of the present armaments.” The conference early realized that even a limitation of the increase of military and naval expenditure was impracticable at that time, and devoted its chief energies to the secondary purpose for which it was called, viz., to discuss and devise “ the most effectual means of insuring to all peoples the benefits of a real and durable peace.”
Hague Convention Restricting the use of Force to Recover on Contract Claims
Authors: Scott George Winfield
Published: April 2006

The convention of the Second Hague Conference respecting the subject of contract claims alleged to be due by one state to the subjects of another has a special interest to the citizens of the twentyone American republics, particularly the first article of the convention, which reads as follows:
The Science of International Law: Its Task and Method
Authors: Oppenheim L.
Published: April 2006

The first volume of this American Journal of International Law has shown urbi et orbi that America possesses a number of prominent international jurists who are of equal rank to those of Europe as regards learning, idealism, constructive power, and literary skill.
Neutralization
Authors: Winslow Erving
Published: April 2006

A Justice of the Supreme Court of the United States, who has inherited a taste for epigrammatic expression, made a notable statement on a public occasion not long ago.
The Most-Favored-Nation Clause
Authors: Hornbeck Stanley K.
Published: April 2006

Before turning to consider the views of several of the leading writers who have discussed the theory and practice of the most-favored-nation clause, it will he well to get clearly in mind certain circumstances which have attended its use in different periods. A knowledge of the time when a treaty was made will be found to be absolutely essential in many cases if we wish to arrive at a proper interpretation of some of its clauses.

In the first place, and of primary importance, most-favored-nation treatment has now, and had in the eighteenth century, a different meaning in European policy from that which attached to it between 1825 and 1860. While European countries now give the clause a form and an interpretation corresponding approximately to that in vogue in the eighteenth century, the universalizing of favors, which, through the intricacy of modern treaty systems, that old form might be expected to entail, is largely modified by the mechanism of modern tariff policy.
International Unions and Their Administration
Authors: Reinsch Paul S.
Published: April 2006

The dominant note of political development during the nineteenth century was undoubtedly nationalism, and the political forces of the century, intricate and involved as their action was, may be understood and analyzed with the greatest clearness from the point of view of the struggle for complete national existence and unity which was going on in all the principal countries of the earth. Nations are readily personified, and there is a unity and sequence in their action which makes it appear very concrete when compared with other political influences and movements. Thus, when toward the end of the century, after the great struggles in the United States, Germany, and Italy had been decided in favor of the national principle, it seemed as if the latter were bound to exercise an almost exclusive sway over the future destinies of humanity, as if the twentieth century would be taken up with a fierce economic and military competition among the nationalities who had achieved a complete political existence. Under such conditions, international or diplomatic action would have had for its main function the maintenance of a political balance or equilibrium which would prevent the undue aggrandizement of any one state or nation. Such indeed had been the original and continuing purpose of diplomatic action.
Cardinal Alberoni: An Italian Precursor of Pacifism and International Arbitration
Authors: Vesnitch Mil. R.
Published: April 2006

In a previous study I had occasion to state that the pacifist idea, as well as that of the juridical settlement of international conflicts, dates much farther back than is generally believed, and that it has had sincere advocates in all nations. And what is of even greater importance, international arbitration was practiced to a large extent, both in the Middle Ages and at the time of the Renaissance. I would now present to the enlightened readers of this Journal an Italian personage as one of these advocates, by stating however at the outset, that he lyas not the first among his compatriots, since four centuries before his time, the Venetian Marin Sanudo had consecrated his life to that idea, while the adherents of pacifism can even claim a Dante Alighieri among their number! For many reasons, however, which will be convincingly set forth in the course of these pages, Cardinal Alberoni is deserving of especial attention. The German Gerhoch, the Frenchmen Pierre Dubois and Eméric Crucé, the Czech king George Podiebrad, the Englishman W. Penn, the Portuguese Suarez, the Spaniard Vittoria, the Hollander H. Grotius, and many others, have in him a worthy associate, a fact which I hope will be made clear by the publication of his scheme, as an appendix hereof.
The New British Imperial Law of Nationality
Authors: Flournoy Richard W.
Published: April 2006

The law of nationality, which determines the relation borne by private individuals to sovereign states, is a distinct branch of public law. Being necessarily somewhat technical and detailed in its provisions, it does not ordinarily attract popular interest and attention in times of peace. However, when war breaks out, the question of nationality is seen to be one of vital importance to the state. In times of peace the population of a country presents an appearance of uniformity, and citizens and aliens mingle freely, carrying on the ordinary business of life with each other, apparently regardless of the question of allegiance. Especially has this been so in modern times, with their extensive intercourse between nations and liberal laws governing the rights of aliens. But, nevertheless, when a country is cast into the crucible of war, the component parts of its population are quickly separated into citizens or subjects, allies, alien enemies and neutrals. For some years the theory has been growing that divisions of nationality are being obliterated and replaced by economic and class divisions. The great war now being waged has proven that, whether or not the change mentioned is in a process of development, it has not yet reached the stage where it effectively controls the relation between separate countries. Divisions of nationality are still predominant.