bluuebunny/crossref_metadata_2025 huggingface dataset:
RADIOGRAPHIC SENSITIVITY AND NEGATIVE PREDICTIVE VALUE FOR ACUTE CANINE SPINAL TRAUMA
Authors: KINNS JENNIFER , MAI WILFRIED , SEILER GABRIELA , ZWINGENBERGER ALLISON , JOHNSON VICTORIA , CÁCERES ANA , VALDÉS‐MARTÍNEZ ALEJANDRO , SCHWARZ TOBIAS
Published: November 2006

The objectives of this study were to establish the sensitivity and negative predictive value of radiography for acute spinal osseous lesions in the canine trauma patient, and to evaluate the interobserver variability in radiographic assessment of the spine in traumatized dogs. This was a retrospective multiple observer blinded study. The study population included 30 canine patients that presented following acute trauma, with clinical signs attributable to the spinal column. Radiography and computed tomography (CT) were performed in all cases. Radiographic interpretation was performed independently by four observers with different experience levels who were blinded to clinical information (other than trauma) and the CT results. CT studies were interpreted by a further three radiologists who formed a consensus opinion on the presence of specific osseous lesions. Using the CT results as a gold standard, the sensitivities and negative predictive values of radiography for specific osseous lesions were calculated. Interobserver agreement was also evaluated. Radiography was found to have only a moderate sensitivity for fractures (72%) and subluxations (77.5%). Low negative predictive values were found for the presence of vertebral canal narrowing (58%) and fracture fragments within the vertebral canal (51%). Interobserver agreement was only moderate to fair for most lesion types. In conclusion, radiography cannot be used to reliably rule out potentially unstable acute vertebral lesions in the canine trauma patient, and further imaging is therefore often indicated in the patient with a high risk of such injuries.
RADIOGRAPHIC FEATURES OF GOLDEN RETRIEVER MUSCULAR DYSTROPHY
Authors: BRUMITT JASON W. , ESSMAN STEPHANIE C. , KORNEGAY JOE N. , GRAHAM JOHN P. , WEBER WILLIAM J. , BERRY CLIFFORD R.
Published: November 2006

Golden Retriever muscular dystrophy is an inherited, degenerative myopathy due to the absence of dystrophin and is used as a model of Duchenne muscular dystrophy of young boys. This report describes the radiographic abnormalities of Golden Retriever muscular dystrophy in 26 dogs. The thoracic abnormalities included diaphragmatic asymmetry (18/26), diaphragmatic undulation (18/26), and gastro‐esophageal hiatal hernia (6/26). Pelvic abnormalities included narrowing of the body of the ilia (14/19), ventral deviation and curvature of the tuber ischii (14/19), elongation of the obturator foramen with a decrease in opacity of the surrounding bone (12/19), and lateral flaring of the wings of the ilia (12/19). Abdominal abnormalities consisted of hepatomegaly (14/22) and poor serosal detail (12/22). The unique thoracic abnormalities were a consistent finding in affected Golden Retriever muscular dystrophy dogs. The diagnosis of muscular dystrophy should be included in the differential list if the combination of diaphragm undulation and asymmetry, and gastro‐esophageal hiatal hernia are identified. These diaphragmatic abnormalities are related to hypertrophy and hyperplasia of the diaphragm. Additionally, the skeletal changes of pelvic tilt, elongation of the pelvis, widening of the obturator foramina and thinning of the ischiatic tables appear to be specific to Golden Retriever muscular dystrophy in dogs. These pelvic abnormalities are most likely secondary to bone remodeling associated with the progressive skeletal myopathy and subsequent contracture/fibrosis.
Historical Trends in Questioning Presidents, 1953‐2000
Authors: CLAYMAN STEVEN E. , ELLIOTT MARC N. , HERITAGE JOHN , MCDONALD LAURIE L.
Published: November 2006

This article develops a system for analyzing the aggressiveness of journalists' questions to public figures and applies that system to a sample of presidential news conferences from Eisenhower through Clinton. The primary objective is to use the phenomenon of aggressive questioning as a window into the White House press corps and its evolving relationship to the presidency. Ten features of question design are examined as indicators of four basic dimensions of aggressiveness: (1) initiative, (2) directness, (3) assertiveness, and (4) adversarialness. The results reveal significant trends for all dimensions, all indicating a long‐term decline in deference to the president and the rise of a more vigorous and at times adversarial posture. While directness has increased gradually over time and is relatively insensitive to the immediate sociopolitical context, initiative, assertiveness, and adversarialness are more volatile and sensitive to local conditions. The volatile dimensions rose from the late 1960s through the early 1980s, declined from the mid‐1980s through the early 1990s, and rose again at century's end. Possible factors contributing to these trends, and their broader ramifications for the evolving relationship between the news media and the presidency, are also discussed.
Polls, Elite Opinion, and the President: How Information and Issue Saliency Affect Approval
Authors: WOLF MICHAEL R. , HOLIAN DAVID B.
Published: November 2006

Our experiment examines the effect of information and issue saliency on presidential approval. Subjects received either pro‐Bush or anti‐Bush information on the president's Iraq War and Social Security policies in the form of newspaper opinion pieces and/or polls, and then evaluated Bush's overall job performance and his handling of these two issues. Information and polls that supported Bush's Social Security policy led subjects to support Bush on this issue, but attitudes were resistant on the more salient Iraq issue. The experiment demonstrates that poll results, more than simply reflecting aggregate opinion, influence attitudes on less salient issues.
Jimmy Carter and George W. Bush: Faith, Foreign Policy, and an Evangelical Presidential Style
Authors: BERGGREN D. JASON , RAE NICOL C.
Published: November 2006

In this article, we argue that Presidents Jimmy Carter and George W. Bush share a distinctive approach to politics and governing: an “evangelical” style of presidential leadership. Though they differed in terms of party and ideology, we claim, using examples from their foreign policies, that the evangelical faith of Carter and Bush provided them with a particular vision of the presidency and the global role of the United States. Richard Neustadt argued that aptitude for politics is the most essential attribute for contemporary presidential success and that the evangelical approach will inevitably lead to political failure. From our analysis of the Carter and Bush approaches to foreign policy, we conclude, however, that in certain circumstances, the evangelical style can contribute to successful presidential leadership and is worthy of further serious study by presidential scholars.
Avoiding Advice and Consent: Recess Appointments and Presidential Power
Authors: CORLEY PAMELA C.
Published: November 2006

This research note attempts to determine under what conditions presidents will use the unilateral tool of recess appointments, specifically to independent agencies. Multivariate analysis reveals that, after controlling for the effects of other variables, presidents are more likely to make a recess appointment if they lack partisan support in the Senate and when they have high public approval. Recess appointments are not cost free and, consequently, presidents use this power strategically and sparingly.
Conceptualizing and Measuring White House Staff Influence on Presidential Rhetoric
Authors: VAUGHN JUSTIN S. , VILLALOBOS JOSÉ D.
Published: November 2006

Scholars have debated extensively the impact of presidential rhetoric on public opinion and congressional behavior, but have largely ignored the determinants of what the president actually says. This inattention is partly the result of the difficulty of acquiring systematic observations of presidential speech crafting. We devise a method of quantifying White House staff influence over the composition of rhetoric that captures the multistage negotiations between the president's speechwriters and his policy advisors and provides a framework for future studies on the determinants of presidential rhetoric. We employ our method to study influence over the writing of President George H. W. Bush's announcement of his veto of a tax bill.
Prevalence and Correlates of Erectile Dysfunction by Race and Ethnicity Among Men Aged 40 or Older in the United States: From the Male Attitudes Regarding Sexual Health Survey
Authors: Laumann Edward O. , West Suzanne , Glasser Dale , Carson Culley , Rosen Raymond , Kang Jeong-han
Published: November 2006

Introduction

Most U.S. population-based estimates of erectile dysfunction (ED) prevalence restricted upper age, were not nationally representative, or underrepresented minority groups.

Aim

To estimate, by race/ethnicity in the United States, the prevalence of ED and the impact of sociodemographic, health, relationship, psychological, and lifestyle variables.

Methods

This cross-sectional, population-based, nationally representative probability survey conducted between May 2001 and January 2002 in the general community setting facilitated equivalent representation among U.S. non-Hispanic white (N=901), non-Hispanic black (N=596), and Hispanic (N=676) men aged 40 and older by using targeted phone lists to oversample the minority populations.

Main Outcome Measure

Estimated prevalence of moderate or severe ED, defined as a response of “sometimes” or “never” to the question “How would you describe your ability to get and keep an erection adequate for satisfactory intercourse?”

Results

The estimated prevalence was 22.0% (95% confidence interval [CI], 19.4–24.6) overall, 21.9% (95% CI, 18.8–24.9) in whites, 24.4% (95% CI, 18.4–30.5) in blacks, and 19.9% (95% CI, 13.9–25.9) in Hispanics, and increased with increasing age. The odds ratio increased with increasing age. Probability also increased with diabetes, hypertension, and moderate or severe lower urinary tract symptoms (LUTS) overall; age ≥70 years and diabetes in whites; severe LUTS in blacks; and age ≥60 years, moderate LUTS, hypertension, and depression in Hispanics. It decreased with exercise and college vs. less than high school education overall; with exercise, good relationship quality, and according to alcohol intake in blacks; and with high school or college education in Hispanics.

Conclusion

The odds of ED increased with increasing age across race/ethnicity when controlling for sociodemographic, health, relationship, psychological, and lifestyle variables. These initial analyses suggest further study of the interrelationships among risk factors for ED.
Sexual Function and Obstructive Sleep Apnea–Hypopnea: A Randomized Clinical Trial Evaluating the Effects of Oral-Appliance and Continuous Positive Airway Pressure Therapy
Authors: Hoekema Aarnoud , Stel Anna-Lucia , Stegenga Boudewijn , Van Der Hoeven Johannes H. , Wijkstra Peter J. , Van Driel Mels F. , De Bont Lambert G.M.
Published: November 2006

Introduction

The obstructive sleep apnea–hypopnea syndrome (OSAHS) is associated with sexual dysfunction. Although successful treatment with continuous positive airway pressure (CPAP) has been demonstrated to improve sexual function, the effects of oral-appliance therapy are unknown.

Aim

The aims of this study were to determine to what extent untreated male OSAHS patients experience sexual dysfunctions compared with control subjects, and second, to evaluate the effects of oral-appliance and CPAP therapy on sexual functioning.

Methods

Sexual functioning was determined in 48 OSAHS patients with the Golombok Rust inventory of sexual satisfaction (GRISS) and a testosterone measurement. GRISS outcomes were compared with 48 age-matched male controls without any sexual problems. Patients were randomized for either oral-appliance or CPAP therapy. After 2–3 months of treatment, the GRISS and testosterone measurements were repeated.

Main Outcome Measure

The outcomes on the GRISS were used as the main outcome measure.

Results

Compared with controls, OSAHS patients had significantly more erectile dysfunction (mean ± standard deviation; OSAHS 8.7 ± 3.8 vs. controls 6.8 ± 2.6) and sexual dissatisfaction (mean ± standard deviation; OSAHS 9.7 ± 4.2 vs. controls 8.1 ± 2.6) as indicated by the GRISS. No significant changes in the GRISS or testosterone levels were observed in the 20 and 27 patients completing the follow-up review for oral-appliance and CPAP therapy. A correlation was demonstrated between the extent of erectile dysfunction at baseline and improvements in erectile function following treatment (r =−0.547, P =0.000).

Conclusions

This study confirms that male OSAHS patients show more sexual dysfunctions compared with age-matched control subjects. Although significant improvements in sexual functioning in neither the oral-appliance nor CPAP-treated group could be established, our findings suggest that untreated OSAHS patients with pronounced erectile dysfunction experience some improvement following treatment.
Pilot Study of Sexual Dysfunction Following Abdominal Aortic Aneurysm Surgery
Authors: Koo Vincent , Lau Louis , McKinley Andrew , Blair Paul , Hood John
Published: November 2006

Introduction

The complication of sexual dysfunction as a quality of life (QoL) component after abdominal aortic aneurysm (AAA) surgery in men is poorly studied.

Aims

To investigate the prevalence of sexual dysfunction and to highlight the importance of discussing this issue with patients undergoing AAA repair.

Main Outcome Measures

The self-reported sexual dysfunction prevalence pre- and postoperatively, the effects on sexual QoL, and the postoperative Sexual Health Inventory for Men (SHIM) scores.

Methods

Between April 1999 and July 2002, a questionnaire-based study, including the SHIM, was conducted on male patients 1–2 years after their elective open (EO) and rupture open (RO) or endovascular repair (EVAR) AAA repair. Demographics, risk factors for sexual dysfunction, sexual history, and postoperative sexual QoL data were obtained.

Results

Out of 142 alive male patients surveyed, 56 (40%) patients responded (26 EO, 21 EVAR, and 9 RO repair). The mean age was 69, 73, and 70 years, respectively, and 65%, 66%, and 66%, respectively, admitted to be sexually active postoperatively. The self-reported sexual dysfunction prevalence preoperatively was 27% (EO), 63% (EVAR), and 45% (RO); and postoperatively was 58%, 76%, and 67%, respectively. Detection using SHIM was higher at 70%, 95%, and 78%, respectively. There was a significantly greater increase in the postoperative prevalence of sexual dysfunction in the EO group than in the EVAR group (P <0.05, χ2). The sexual QoL was worsened postoperatively in all groups: 53% (EO), 75% (EVAR), and 50% (RO); but only one-third of EO and EVAR patients, and none in RO patients, would seek treatment for their sexual dysfunction.

Conclusion

There was a negative impact on the sexual QoL in all groups after surgery, and a significantly higher proportion of patients experienced deterioration in sexual QoL following EO surgical repair. Our results demonstrate the need for a prospective study.
A Reproducibility Study of Corpus Cavernosum Electromyography in Young Healthy Volunteers Under Controlled Conditions
Authors: Jiang Xiaogang , Holsheimer Jan , Wagner Gorm , Mulders Peter , Wijkstra Hessel , Meuleman Eric
Published: November 2006

Introduction

Although the corpus cavernosum electromyography (CC-EMG) has been studied already for 16 years, doubts regarding its reproducibility have remained.

Aim

To assess the reproducibility of CC-EMG under controlled conditions and the influence of confounding factors.

Methods

Three CC-EMG recording sessions were performed in 13 healthy young men under the same conditions. Furthermore, the effects of potentially confounding factors, such as intake of caffeine, alcohol and smoking, and sexual activity, were investigated in the same population. Using auto- and cross-correlation techniques, CC-potentials were characterized with parameters amplitude (A), duration (D), dominant frequency (DF), maximum cross-correlation coefficient of longitudinal and bilateral CC-potential pairs (Rmax-lon. and Rmax-bi.), and propagation velocity (PV).

Main Outcome Measures

Comparison of CC-EMG parameters A, D, DF, Rmax-lon., and Rmax-bi. between three recording sessions and assessment of the impact of confounding factors on these parameters.

Results

DF, D, A, and Rmax-lon. showed significant correlations among three sessions; PV showed significant correlations between two sessions performed within the same day but not between those performed on different days; Rmax-bi. did not show significant correlations between any two sessions. Intake of caffeine, alcohol, and smoking did not affect CC-potentials, while the recordings shortly after ejaculation showed more irregular oscillations and less CC-potentials with smaller A.

Conclusion

CC-potential parameters DF, D, A, and Rmax-lon. have been demonstrated to be reproducible. The results provide a basis for the clinical and scientific application of CC-EMG. CC-potentials are not sensitive to confounding factors such as intake of caffeine, alcohol, and smoking, while measurements shortly after ejaculation should be avoided.
Reporter Metabolite Analysis of Transcriptional Profiles of a
Staphylococcus aureus
Strain with Normal Phenotype and Its Isogenic
hemB
Mutant Displaying the Small-Colony-Variant Phenotype
Authors: Seggewiß Jochen , Becker Karsten , Kotte Oliver , Eisenacher Martin , Yazdi Mohammad Reza Khoschkhoi , Fischer Andreas , McNamara Peter , Al Laham Nahed , Proctor Richard , Peters Georg , Heinemann Matthias , von Eiff Christof
Published: November 2006

In this study, full-genome DNA microarrays based on the sequence of
Staphylococcus aureus
N315 were used to compare the transcriptome of a clinical
S. aureus
strain with a normal phenotype to that of its isogenic mutant with a stable small-colony-variant (SCV) phenotype (
hemB
::
ermB
). In addition to standard statistical analyses, systems biology advances were applied to identify reporter metabolites and to achieve a more detailed survey of genome-wide expression differences between the
hemB
mutant and its parental strain. Genes of enzymes involved in glycolytic and fermentative pathways were found to be up-regulated in the
hemB
mutant. Furthermore, our analyses allowed identification of additional differences between the normal-phenotype
S. aureus
and the SCV, most of which were related to metabolism. Profound differences were identified especially in purine biosynthesis as well as in arginine and proline metabolism. Of particular interest, a hypothetical gene of the Crp/Fnr family (SA2424) that is part of the arginine-deiminase (AD) pathway, whose homologue in
Streptococcus suis
is assumed to be involved in intracellular persistence, showed significantly increased transcription in the
hemB
mutant. The
hemB
mutant potentially uses the up-regulated AD pathway to produce ATP or (through ammonia production) to counteract the acidic environment that prevails intracellularly. Moreover, genes involved in capsular polysaccharide and cell wall synthesis were found to be significantly up-regulated in the
hemB
mutant and therefore potentially responsible for the changed cell morphology of SCVs. In conclusion, the identified differences may be responsible for the SCV phenotype and its association with chronic and persistent infections.
High-Molecular-Weight Complexes of RsbR and Paralogues in the Environmental Signaling Pathway ofBacillus subtilis
Authors: Delumeau Olivier , Chen Chien-Cheng , Murray James W. , Yudkin Michael D. , Lewis Richard J.
Published: November 2006

Bacillus subtilishas developed an intricate signal transduction cascade to respond to the imposition of a variety of stresses on the cell. Reversible protein phosphorylation and the formation of alternative protein-protein complexes modulate the activity of σB, the RNA polymerase sigma factor subunit responsible for the transcription of the general stress response genes. Some of the regulators of σB, such as RsbR and RsbS, are known to associate in a 25S complex, called the stressosome, that can bind RsbT until RsbT phosphorylates target residues in RsbR and RsbS. To date, the RsbR-RsbS complex appears to be the most upstream component of the σBregulatory pathway. This large structure is thought to play an important role in sensing and/or integrating signals from different physical stresses. The roles of the paralogues of RsbR that are found inB. subtilisremain unclear. We describe here how the RsbR paralogues copurify with RsbR fromB. subtiliscell lysates, and we demonstrate in vitro that the paralogues form large complexes either with RsbS or with a prepurified RsbR-RsbS binary complex. We conclude from these biochemical studies that stressosomes inB. subtiliscells contain minimally RsbS and all of the RsbT-phosphorylatable RsbR paralogues.
Two Chemosensory Operons of
Rhodobacter sphaeroides
Are Regulated Independently by Sigma 28 and Sigma 54
Authors: Martin Angela C. , Gould Marcus , Byles Elaine , Roberts Mark A. J. , Armitage Judith P.
Published: November 2006

Rhodobacter sphaeroides
has a complex chemosensory system, with several loci encoding multiple homologues of the components required for chemosensing in
Escherichia coli.
The operons
che
Op2 and
che
Op3 each encode complete pathways, and both are essential for chemosensing. The components of
che
Op2 are predominantly localized to the cell pole, whereas those encoded by
che
Op3 are predominantly targeted to a discrete cluster in the cytoplasm. Here we show that the expression of the two pathways is regulated independently. Overlapping promoters recognized by σ
28
and σ
70
RNAP holoenzyme transcribe
che
Op2, whereas
che
Op3 is regulated by one of the four σ
54
homologues, RpoN3. The different regulation of these operons may reflect the need for balancing responses to extra- and intracellular signals under different growth conditions.
Bile-Induced Curing of the Virulence Plasmid in
Salmonella enterica
Serovar Typhimurium
Authors: García-Quintanilla Meritxell , Prieto Ana I. , Barnes Laurent , Ramos-Morales Francisco , Casadesús Josep
Published: November 2006

Exposure to bile induces curing of the virulence plasmid in
Salmonella enterica
serovar Typhimurium (pSLT). Disruption of the
ccdB
gene increases pSLT curing, both spontaneous and induced by bile, suggesting that the pSLT
ccdAB
genes may encode a homolog of the CcdAB addiction module previously described in the F sex factor. Unlike the F sex factor, synthesis of pSLT-encoded pili does not confer bile sensitivity. These observations may provide insights into the evolution of virulence plasmids in
Salmonella
subspecies I, as well as the causes of virulence plasmid loss in other
Salmonella
subspecies.
Kidney Disease and Cardiovascular Risk
Authors: Tonelli Marcello , Pfeffer Marc A.
Published: November 2006

Kidney failure and chronic kidney disease (CKD) are associated with accelerated cardiovascular disease, apparently because of a high burden of traditional vascular risk factors and possibly nontraditional risk factors such as inflammation, chronic volume overload, and abnormal calcium-phosphate metabolism. Although the burden of cardiovascular disease in CKD patients is well documented, potentially beneficial therapies appear to be underused in mild to moderate CKD and are relatively understudied in those with kidney failure. This review describes the epidemiology and pathophysiology of cardiovascular disease in CKD. We also discuss the clinical and public health implications of current knowledge and outline opportunities for further research.
Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation
Authors: Nilsson Lisa M. , Sun Zheng-Wu , Nilsson Jenny , Nordström Ina , Chen Yung-Wu , Molkentin Jeffery D. , Wide-Swensson Dag , Hellstrand Per , Lydrup Marie-Louise , Gomez Maria F.
Published: November 2006

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [35S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.
Hypothermia reduces ischemia- and stimulation-induced myocardial interstitial norepinephrine and acetylcholine releases
Authors: Kawada Toru , Kitagawa Hirotoshi , Yamazaki Toji , Akiyama Tsuyoshi , Kamiya Atsunori , Uemura Kazunori , Mori Hidezo , Sugimachi Masaru
Published: November 2006

Although hypothermia is one of the most powerful modulators that can reduce ischemic injury, the effects of hypothermia on the function of the cardiac autonomic nerves in vivo are not well understood. We examined the effects of hypothermia on the myocardial interstitial norepinephrine (NE) and ACh releases in response to acute myocardial ischemia and to efferent sympathetic or vagal nerve stimulation in anesthetized cats. We induced acute myocardial ischemia by coronary artery occlusion. Compared with normothermia ( n = 8), hypothermia at 33°C ( n = 6) suppressed the ischemia-induced NE release [63 nM (SD 39) vs. 18 nM (SD 25), P < 0.01] and ACh release [11.6 nM (SD 7.6) vs. 2.4 nM (SD 1.3), P < 0.01] in the ischemic region. Under hypothermia, the coronary occlusion increased the ACh level from 0.67 nM (SD 0.44) to 6.0 nM (SD 6.0) ( P < 0.05) and decreased the NE level from 0.63 nM (SD 0.19) to 0.40 nM (SD 0.25) ( P < 0.05) in the nonischemic region. Hypothermia attenuated the nerve stimulation-induced NE release from 1.05 nM (SD 0.85) to 0.73 nM (SD 0.73) ( P < 0.05, n = 6) and ACh release from 10.2 nM (SD 5.1) to 7.1 nM (SD 3.4) ( P < 0.05, n = 5). In conclusion, hypothermia attenuated the ischemia-induced NE and ACh releases in the ischemic region. Moreover, hypothermia also attenuated the nerve stimulation-induced NE and ACh releases. The Bezold-Jarisch reflex evoked by the left anterior descending coronary artery occlusion, however, did not appear to be affected under hypothermia.
Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism
Authors: Tsang John Y. C. , Lamm Wayne J. E. , Neradilek Blazej , Polissar Nayak L. , Hlastala Michael P.
Published: November 2006

We studied the roles of endothelins in determining ventilation (V̇a) and perfusion (Q̇) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (∼23 kg) received autologous clots (∼20 g) via a central venous catheter at time = 0 min. The distribution of V̇a and Q̇ at five different time points (−30, −5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets ( group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets ( group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean V̇a/Q̇ was increased, as was V̇a/Q̇ heterogeneity (log SD V̇a/Q̇), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial Po2 or V̇a/Q̇ mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high V̇a/Q̇ regions.
Responses of Reticulospinal Neurons in the Lamprey to Lateral Turns
Authors: Karayannidou A. , Zelenin P. V. , Orlovsky G. N. , Deliagina T. G.
Published: November 2006

When swimming, the lamprey maintains a definite orientation of its body in the vertical planes, in relation to the gravity vector, as the result of postural vestibular reflexes. Do the vestibular-driven mechanisms also play a role in the control of the direction of swimming in the horizontal (yaw) plane, in which the gravity cannot be used as a reference direction? In the present study, we addressed this question by recording responses to lateral turns in reticulospinal (RS) neurons mediating vestibulospinal reflexes. In intact lampreys, the activity of axons of RS neurons was recorded in the spinal cord by implanted electrodes. Vestibular stimulation was performed by periodical turns of the animal in the yaw plane (60° peak to peak). It was found that the majority of responding RS neurons were activated by the contralateral turn. By removing one labyrinth, we found that yaw responses in RS neurons were driven mainly by input from the contralateral labyrinth. We suggest that these neurons, when activated by the contralateral turn, will elicit the ipsilateral turn and thus will compensate for perturbations of the rectilinear swimming caused by external factors. It is also known that unilateral eye illumination elicits a contralateral turn in the yaw plane (negative phototaxis). We found that a portion of RS neurons were activated by the contralateral eye illumination. By eliciting an ipsilateral turn, these neurons could mediate the negative phototaxis.
Differential Contributions of Shaker and Shab K+Currents to Neuronal Firing Patterns inDrosophila
Authors: Peng I-Feng , Wu Chun-Fang
Published: November 2006

Different K+currents participate in generating neuronal firing patterns. The Drosophila embryonic “giant” neuron culture system has facilitated current- and voltage-clamp recordings to correlate distinct excitability patterns with the underlying K+currents and to delineate the mutational effects of identified K+channels. Mutations of Sh and Shab K+channels removed part of inactivating IAand sustained IK, respectively, and the remaining IAand IKrevealed the properties of their counterparts, e.g., Shal and Shaw channels. Neuronal subsets displaying the delayed, tonic, adaptive, and damping spike patterns were characterized by different profiles of K+current voltage dependence and kinetics and by differential mutational effects. Shab channels regulated membrane repolarization and repetitive firing over hundreds of milliseconds, and Shab neurons showed a gradual decline in repolarization during current injection and their spike activities became limited to high-frequency, damping firing. In contrast, Sh channels acted on events within tens of milliseconds, and Sh mutations broadened spikes and reduced firing rates without eliminating any categories of firing patterns. However, removing both Sh and Shal IAby 4-aminopyridine converted the delayed to damping firing pattern, demonstrating their actions in regulating spike initiation. Specific blockade of Shab IKby quinidine mimicked the Shab phenotypes and converted tonic firing to a damping pattern. These conversions suggest a hierarchy of complexity in K+current interactions underlying different firing patterns. Different lineage-defined neuronal subsets, identifiable by employing the GAL4-UAS system, displayed different profiles of spike properties and K+current compositions, providing opportunities for mutational analysis in functionally specialized neurons.
Existence criteria and classification schemes for positive solutions of second‐order nonlinear difference systems
Authors: Li Wan-Tong , Huang Can-Yun , Cheng Sui Sun
Published: November 2006

Classification schemes for positive solutions of a class of second‐order nonlinear difference systems are given in terms of their asymptotic magnitudes; and necessary as well as sufficient conditions for the existence of these solutions are also provided. Finally, some examples are given to illustrate the main results.
Genetic Reclassification of Histologic Grade Delineates New Clinical Subtypes of Breast Cancer
Authors: Ivshina Anna V. , George Joshy , Senko Oleg , Mow Benjamin , Putti Thomas C. , Smeds Johanna , Lindahl Thomas , Pawitan Yudi , Hall Per , Nordgren Hans , Wong John E.L. , Liu Edison T. , Bergh Jonas , Kuznetsov Vladimir A. , Miller Lance D.
Published: November 2006

Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression. (Cancer Res 2006; 66(21): 10292-301)
A Repressive Epigenetic Domino Effect Confers Susceptibility to Breast Epithelial Cell Transformation: Implications for Predicting Breast Cancer Risk
Authors: Bistulfi Gaia , Pozzi Silvia , Ren MingQiang , Rossetti Stefano , Sacchi Nicoletta
Published: November 2006

Retinoic acid (RA) is a master epigenetic regulator that plays a pivotal role in both breast morphogenesis and development. Here, we show for the first time that RA, via the RA receptor α (RARα), epigenetically regulates in a concerted fashion the transcription of two RA-responsive genes, the RA receptor β2 (RARβ2) and the cellular retinol-binding protein 1 (CRBP1). Specifically, an impaired RA signal through RARα in human breast epithelial cells triggers a repressive epigenetic domino effect, involving first RARβ2 and second CRBP1. The phenotype acquired by breast epithelial cells clearly implies that the resistance to RA-mediated growth inhibition precedes the acquisition of morphological epithelial transformation, thus supporting the occurrence of sequential transcriptional silencing of first RARβ2 and second CRBP1. The identification of this epigenetic network mechanistically linking RARβ2 and CRBP1 transcription provides the basis for devising more accurate epigenetic tests for the prediction of breast cancer risk.(Cancer Res 2006; 66(21): 10308-14)
Combined Stimulation with Interleukin-18 and CpG Induces Murine Natural Killer Dendritic Cells to Produce IFN-γ and Inhibit Tumor Growth
Authors: Chaudhry Umer I. , Kingham T. Peter , Plitas George , Katz Steven C. , Raab Jesse R. , DeMatteo Ronald P.
Published: November 2006

Natural killer dendritic cells (NKDC) are a novel subtype of dendritic cells with natural killer (NK) cell properties. IFN-γ is a pleiotropic cytokine that plays an important role in the innate immune response to tumors. Based on our previous finding that the combination of Toll-like receptor 9 ligand CpG and interleukin (IL)-4 stimulates NKDC to produce IFN-γ, we hypothesized that NKDC are the major IFN-γ-producing dendritic cell subtype and may play a significant role in the host antitumor response. We found that under several conditions in vitro and in vivo NKDC accounted for the majority of IFN-γ production by murine spleen CD11c+ cells. IL-18 alone induced NKDC to secrete IFN-γ, and the combination of IL-18 and CpG resulted in a synergistic increase in IFN-γ production, both in vitro and in vivo. NK cells made 26-fold less IFN-γ under the same conditions in vitro, whereas dendritic cells produced a negligible amount. The mechanism of IFN-γ secretion by NKDC depended on IL-12. NKDC selectively proliferated in vitro and in vivo in response to the combination of IL-18 and CpG. Systemic treatment with IL-18 and CpG reduced the number of B16F10 melanoma lung metastases. The mechanism depended on NK1.1+ cells, as their depletion abrogated the effect. IL-18 and CpG activated NKDC provided greater tumor protection than NK cells in IFN-γ−/− mice. Thus, NKDC are the major dendritic cell subtype to produce IFN-γ. The combined use of IL-18 and CpG is a viable strategy to potentiate the antitumor function of NKDC. (Cancer Res 2006; 66(21): 10497-504)
TMPRSS2 Fusions with Oncogenic ETS Factors in Prostate Cancer Involve Unbalanced Genomic Rearrangements and Are Associated with HDAC1 and Epigenetic Reprogramming
Authors: Iljin Kristiina , Wolf Maija , Edgren Henrik , Gupta Santosh , Kilpinen Sami , Skotheim Rolf I. , Peltola Mari , Smit Frank , Verhaegh Gerald , Schalken Jack , Nees Matthias , Kallioniemi Olli
Published: November 2006

Translocations fusing the strong androgen-responsive gene, TMPRSS2, with ERG or other oncogenic ETS factors may facilitate prostate cancer development. Here, we studied 18 advanced prostate cancers for ETS factor alterations, using reverse transcription-PCR and DNA and RNA array technologies, and identified putative ERG downstream gene targets from the microarray data of 410 prostate samples. Out of the 27 ETS factors, ERG was most frequently overexpressed. Seven cases showed TMPRSS2:ERG gene fusions, whereas the TMPRSS2:ETV4 fusion was seen in one case. In five out of six tumors with high ERG expression, array-CGH analysis revealed interstitial 2.8 Mb deletions between the TMPRSS2 and ERG loci, or smaller, unbalanced rearrangements. In silico analysis of the ERG gene coexpression patterns revealed an association with high expression of the histone deacetylase 1 gene, and low expression of its target genes. Furthermore, we observed increased expression of WNT-associated pathways and down-regulation of tumor necrosis factor and cell death pathways. In summary, our data indicate that the TMPRSS2:ERG translocation is common in advanced prostate cancer and occurs by virtue of unbalanced genomic rearrangements. Activation of ERG by fusion with TMPRSS2 may lead to epigenetic reprogramming, WNT signaling, and down-regulation of cell death pathways, implicating ERG in several hallmarks of cancer with potential therapeutic importance. (Cancer Res 2006; 66(21): 10242-6)
Chromosomal Breakpoints Affecting Immunoglobulin Loci Are Recurrent in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma
Authors: Martín-Subero José I. , Klapper Wolfram , Sotnikova Anna , Callet-Bauchu Evelyne , Harder Lana , Bastard Christian , Schmitz Roland , Grohmann Susanne , Höppner Jorge , Riemke Jennifer , Barth Thomas F.E. , Berger Françoise , Bernd Heinz-Wolfram , Claviez Alexander , Gesk Stefan , Frank Georgiy A. , Kaplanskaya Irina B. , Möller Peter , Parwaresch Reza M. , Rüdiger Thomas , Stein Harald , Küppers Ralf , Hansmann Martin L. , Siebert Reiner ,   for the Deutsche Krebshilfe Network Project “Molecular Mechanisms in Malignant Lymphomas”
Published: November 2006

Chromosomal breakpoints affecting immunoglobulin (IG) loci are recurrent in many subtypes of B-cell lymphomas. However, despite the predominant B-cell origin of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL), the presence of chromosomal translocations in IG loci has not yet been systematically explored. Therefore, we have investigated a series of cHL for chromosomal breakpoints in the IGH (n = 230), IGL (n = 139), and IGK (n = 138) loci by interphase cytogenetics. Breakpoints in the IGH, IGL, or IGK locus were observed in the HRS cells of 26 of 149 (17%), 2 of 70, and 1 of 77 evaluable cHLs, respectively. The IG partners could be identified in eight cHLs and involved chromosomal bands 2p16 (REL), 3q27 (BCL6, two cases), 8q24.1 (MYC), 14q24.3, 16p13.1, 17q12, and 19q13.2 (BCL3/RELB). In 65 of 85 (76%) cHLs evaluable for an IGH triple-color probe, the HRS cells showed evidence for a (partial) deletion of the IGH constant region, suggesting the presence of class switch recombination (CSR). Furthermore, analyses with this probe in cases with IGH breakpoints indicated that at least part of them seem to be derived from CSR defects. Our results show that chromosomal breakpoints affecting the IG loci are recurrent in cHL. (Cancer Res 2006; 66(21): 10332-8)
Adaptation to the Ionizing Radiation–Induced G2 Checkpoint Occurs in Human Cells and Depends on Checkpoint Kinase 1 and Polo-like Kinase 1 Kinases
Authors: Syljuåsen Randi G. , Jensen Sanne , Bartek Jiri , Lukas Jiri
Published: November 2006

Checkpoint adaptation was originally defined in yeast as the ability to divide despite the presence of damaged DNA. An important unanswered question is whether checkpoint adaptation also occurs in human cells. Here, we show that following the ionizing radiation–induced G2 checkpoint, human osteosarcoma cells entered mitosis with γ-H2AX foci, a marker for unrepaired DNA double-strand breaks. Exit from the G2 checkpoint was accelerated by inhibiting the checkpoint kinase 1 (Chk1) and delayed by overexpressing wild-type Chk1 or depleting the Polo-like kinase 1 (Plk1). Chk1 and Plk1 controlled this process, at least partly, via independent signaling pathways. Our results suggest that human cells are able to exit the checkpoint arrest and divide before the damage has been fully repaired. Such cell division in the presence of damaged DNA may be detrimental for genetic stability and could potentially contribute to cancer development. (Cancer Res 2006; 66(21): 10253-7)
Expression and Regulatory Role of GAIP-Interacting Protein GIPC in Pancreatic Adenocarcinoma
Authors: Muders Michael H. , Dutta Shamit K. , Wang Ling , Lau Julie S. , Bhattacharya Resham , Smyrk Thomas C. , Chari Suresh T. , Datta Kaustubh , Mukhopadhyay Debabrata
Published: November 2006

Regulator of G-protein signaling–GAIP-interacting protein COOH terminus (GIPC) is involved in protein trafficking, endocytosis, and receptor clustering and is associated with insulin-like growth factor I receptor (IGF-IR), a receptor important for proliferation and anchorage-independent growth. Here, we described GIPC expression in different human pancreatic adenocarcinoma (PCA) cell lines and we examined the role of GIPC in the regulation of IGF-IR protein levels in PCA. Interestingly, inhibition of GIPC expression by RNA interference led to reduced IGF-IR protein levels and a subsequent decrease in proliferation of PCA cells. We also determined that the PDZ domain of GIPC is essential for the post-translational regulation and the binding of IGF-IR. The importance of GIPC in pancreatic cancer development and progression is supported by tissue microarray data of 300 pancreatic cancer specimens where GIPC is highly expressed in PCA. Taken together, our data suggest that GIPC is a central molecule for the stability of IGF-IR and could be a target for future therapy. (Cancer Res 2006; 66(21): 10264-8)
Potentiation of the Effect of Erlotinib by Genistein in Pancreatic Cancer: The Role of Akt and Nuclear Factor-κB
Authors: El-Rayes Basil F. , Ali Shadan , Ali Ifrah F. , Philip Philip A. , Abbruzzese James , Sarkar Fazlul H.
Published: November 2006

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-κB (NF-κB). The expression of EGFR, Akt, and NF-κB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-κB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-κB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-κB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-κB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein. (Cancer Res 2006; 66(21): 10553-9)