bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathetic Hyperactivity in Hypertensive Chronic Kidney Disease Patients Is Reduced During Standard Treatment
Authors: Neumann Jutta , Ligtenberg Gerry , Klein Inge H.T. , Boer Peter , Oey P. Liam , Koomans Hein A. , Blankestijn Peter J.
Published: January 2007

Standard treatment in chronic kidney disease (CKD) patients includes an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. CKD is often characterized by sympathetic hyperactivity. This study investigates the prevalence of sympathetic hyperactivity (quantified by assessment of muscle sympathetic nerve activity [MSNA]) in a sizable group of patients with CKD and assessed whether chronic angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker normalizes increased MSNA. In 74 CKD patients (creatinine clearance 54±31 mL/min), MSNA, blood pressure, and plasma renin activity were measured in the absence of antihypertensive drugs except for diuretics. In a subgroup of 31 patients, another set of measurements was obtained after ≥6 weeks of enalapril (10 mg PO), losartan (100 mg PO), or eprosartan (600 mg PO). Patients as compared with control subjects (n=82) had higher mean arterial pressure (113±13 versus 89±7 mm Hg), MSNA (31±13 versus 19±7 bursts per minute), and log plasma renin activity (2.67±036 versus 2.40±0.32 fmol/L per second; all
P
<0.001). During angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (n=31), mean arterial pressure (115±11 to 100±9 mm Hg) and MSNA (33±11 to 25±9 bursts per minute) decreased (both
P
<0.01) but were still higher than in control subjects (both
P
<0.01). Multiple regression analysis identified age and plasma renin activity as predictive for MSNA. In conclusion, sympathetic hyperactivity occurs in a substantial proportion of hypertensive CKD patients. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment reduces but does not normalize MSNA.
Sarcoplasmic Reticulum Calcium Overloading in Junctin Deficiency Enhances Cardiac Contractility but Increases Ventricular Automaticity
Authors: Yuan Qunying , Fan Guo-Chang , Dong Min , Altschafl Beth , Diwan Abhinav , Ren Xiaoping , Hahn Harvey H. , Zhao Wen , Waggoner Jason R. , Jones Larry R. , Jones W. Keith , Bers Donald M. , Dorn Gerald W. , Wang Hong-Sheng , Valdivia Héctor H. , Chu Guoxiang , Kranias Evangelia G.
Published: January 2007

Background—

Abnormal sarcoplasmic reticulum calcium (Ca) cycling is increasingly recognized as an important mechanism for increased ventricular automaticity that leads to lethal ventricular arrhythmias. Previous studies have linked lethal familial arrhythmogenic disorders to mutations in the ryanodine receptor and calsequestrin genes, which interact with junctin and triadin to form a macromolecular Ca-signaling complex. The essential physiological effects of junctin and its potential regulatory roles in sarcoplasmic reticulum Ca cycling and Ca-dependent cardiac functions, such as myocyte contractility and automaticity, are unknown.

Methods and Results—

The junctin gene was targeted in embryonic stem cells, and a junctin-deficient mouse was generated. Ablation of junctin was associated with enhanced cardiac function in vivo, and junctin-deficient cardiomyocytes exhibited increased contractile and Ca-cycling parameters. Short-term isoproterenol stimulation elicited arrhythmias, including premature ventricular contractions, atrioventricular heart block, and ventricular tachycardia. Long-term isoproterenol infusion also induced premature ventricular contractions and atrioventricular heart block in junctin-null mice. Further examination of the electrical activity revealed a significant increase in the occurrence of delayed afterdepolarizations. Consistently, 25% of the junctin-null mice died by 3 months of age with structurally normal hearts.

Conclusions—

Junctin is an essential regulator of sarcoplasmic reticulum Ca release and contractility in normal hearts. Ablation of junctin is associated with aberrant Ca homeostasis, which leads to fatal arrhythmias. Thus, normal intracellular Ca cycling relies on maintenance of junctin levels and an intricate balance among the components in the sarcoplasmic reticulum quaternary Ca-signaling complex.
Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs
Authors: Shiroshita-Takeshita Akiko , Sakabe Masao , Haugan Ketil , Hennan James K. , Nattel Stanley
Published: January 2007

Background—

Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction–enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia.

Methods and Results—

Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (
P
=0.003) and increased AF duration (
P
=0.008), with AF lasting >3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (
P
=0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (
P
=0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemia–induced conduction slowing and AF duration increases.

Conclusions—

Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates.
Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death
Authors: Antzelevitch Charles , Pollevick Guido D. , Cordeiro Jonathan M. , Casis Oscar , Sanguinetti Michael C. , Aizawa Yoshiyasu , Guerchicoff Alejandra , Pfeiffer Ryan , Oliva Antonio , Wollnik Bernd , Gelber Philip , Bonaros Elias P. , Burashnikov Elena , Wu Yuesheng , Sargent John D. , Schickel Stefan , Oberheiden Ralf , Bhatia Atul , Hsu Li-Fern , Haïssaguerre Michel , Schimpf Rainer , Borggrefe Martin , Wolpert Christian
Published: January 2007

Background—

Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death.

Methods and Results—

Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant
CACNB2b
(Ca
vβ2b
),
CACNA2D1
(Ca
vα2δ1
), and
CACNA1C
tagged with enhanced yellow fluorescent protein (Ca
v
1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals ≤360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in
CACNA1C
(A39V and G490R) and
CACNB2
(S481L) encoding the α
1
- and β
2b
-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca
v
1.2 channels but normal trafficking of channels containing G490R Ca
v
1.2 or S481L Ca
vβ2b
-subunits.

Conclusions—

This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.
When Good Fences Make Bad Neighbors: Fixed Borders, State Weakness, and International Conflict
Authors: Atzili Boaz
Published: January 2007

Since the end of World War II, the norm of fixed borders—the proscription against foreign conquest and annexation of homeland territory—has gained prevalence in world politics. Although the norm seeks to make the world a more peaceful place, it may instead cause it to become more conflict prone. Among sociopolitically weak states—states that lack legitimate and effective governmental institutions—fixed borders can actually increase instability and conflict. Adherence to the norm of fixed borders can lead to the perpetuation and exacerbation of weakness in states that are already weak or that have just gained independence. It does so by depriving states of what was traditionally the most potent incentive to increase efforts of state building: territorial pressures. By creating conditions that are rife for the spillover of civil wars and by supplying opportunities for foreign predation, sociopolitically weak states in a world of fixed borders have become a major source of interstate conflict in much of the developing world. Investigation into one case, the war in Congo, reveals the plausibility and the potential force of this argument. Good fences indeed can make bad neighbors.
Warlordism in Comparative Perspective
Authors: Marten Kimberly
Published: January 2007

Warlordism creates significant problems in failed states: it impedes the development of stable and secure societies, thwarts economic growth, and creates new threats to international security. Through a comparative study of four seemingly disparate cases—medieval Europe, Republican China, and Somalia and Afghanistan in the mid-2000s—it is possible to develop an inductive, generalizable definition of warlordism. Warlordism emerges when armed men seize small slices of territory in disintegrating states for their own benefit, using charisma and patronage ties to cement their local authority, and disrupting commerce and investment through their fragmentary rule. Two causal factors were necessary for the demise of warlordism in medieval Europe and Republican China: the presence of a powerful and aggrieved economic interest group, and the appearance of a transformative idea from outside the existing system that supported the interest group's actions. If this same causal relationship holds true today, then warlordism will be more quickly eliminated in Somalia than in Afghanistan. The international community can take action to help eliminate warlordism, but change ultimately depends on domestic factors and will likely be violent.
Governance without Government in Somalia: Spoilers, State Building, and the Politics of Coping
Authors: Menkhaus Ken
Published: January 2007

Zones of state failure are assumed to be anarchic. In reality, communities facing the absence of an effective state authority forge systems of governance to provide modest levels of security and rule of law. Nowhere is this phenomenon more evident than in Somalia, where an array of local and regional governance arrangements have emerged since the 1991 collapse of the state. The Somalia case can be used both to document the rise of governance without government in a zone of state collapse and to assess the changing interests of local actors seeking to survive and prosper in a context of state failure. The interests of key actors can and do shift over time as they accrue resources and investments; the shift “from warlord to landlord” gives some actors greater interests in governance and security, but not necessarily in state revival; risk aversion infuses decisionmaking in areas of state failure; and state-building initiatives generally fail to account for the existence of local governance arrangements. The possibilities and problems of the “mediated state model,” in which weak states negotiate political access through existing local authorities, are considerable.
Seeking New Civilizations: Race Normativity in the Star Trek Franchise
Authors: Kwan Allen
Published: January 2007

As with many science fiction works, the Star Trek franchise uses allegory to address contemporary social issues. Taking a liberal humanistic stance, it addresses race and racism using aliens as allegorical stand-ins for humanity. However, the producers of the Star Trek franchise were inadvertently perpetuating the racism they were advocating against. Operating within the framework of normative Whiteness, the producers privilege the White American male as the average human being. The characters of other racial and cultural backgrounds try to assimilate into the normative Whiteness defined by the producers or they are simply in the background to support the White lead characters. By drawing on previous work on the original series and The Next Generation, this article examines episodes from Deep Space Nine, Voyager, and Enterprise to determine how the Star Trek franchise reinscribes, or sometimes destabilizes, the mode of racial and cultural homogeneity assumed by the producers.
Winning or Losing the West: The Photographic Act
Authors: Paakspuu Kalli
Published: January 2007

The visual public record of the early West represents a site of national, continental, hemispheric, and global configurations of territory, power, and imagination. The early photograph reproduces the contradictory encounters between industry, settlers, and Indigenous communities as a particular future is envisioned and contested. The transformative value of a photograph was quickly recognized for nation building and soon served a political purpose as its uses expanded from surveying lands to promoting population growth and tourism and to artistic expression. The early uses on the frontier, however, created a secondary history: an alteric and alternative history of Indigenous Peoples through an oral storytelling with a perspective of difference in assimilation, disidentification, and resistance. Transcultural photography, however, is never neutral as participants come from different worlds to participate in a contested exchange. This article looks at photographic encounters between Red Cloud, Mathew Brady, and Alexander Gardener as they enact a mediation in international relations.
The Poetics of Pattern Recognition: William Gibson's Shifting Technological Subject
Authors: Wetmore Alex
Published: January 2007

William Gibson's 1984 cyberpunk novel Neuromancer continues to be a touchstone in cultural representations of the impact of new information and communication technologies on the self. As critics have noted, the posthumanist, capital-driven, urban landscape of Neuromancer resembles a Foucaultian vision of a panoptically engineered social space in which no activity (even unofficial and illegal activity) eludes the disciplinary gaze of power. On the other hand, William Gibson's latest novel, Pattern Recognition, marks an important ideological shift from Neuromancer. Though the novel retains a deep ambivalence toward new technologies' potential impact on the self, Pattern Recognition nevertheless locates a new source for hope and agency in embodied everyday experience. This article maintains that the change can best be understood as a complex transition from the worldview of Michel Foucault to that of Michel de Certeau.
The Cultural Phenomenon of Identity Theft and the Domestication of the World Wide Web
Authors: Caeton Daniel A.
Published: January 2007

Through a critique of the rhetorical configurations of identity theft, this article contributes to the emerging body of theory contending with the social effects of digital information technologies (DIT). It demonstrates how the politics of fear manipulate technosocial matrices in order to derive consent for radical changes such as the domestication of the Web and the instrumentalization of identity. Specifically, this critique attends to these tasks by performing a rhetorical reading of three recent television commercials that were heavily circulated by the international financial conglomerate, Citigroup Incorporated. Based on this reading, which is heavily indebted to Foucaldian theories of power and discipline, a distinction is drawn between identity theft as it is configured in juridico-political discourse and the cultural phenomenon of identity theft, which functions as a technosocial myth.
From Fears of Entropy to Comfort in Chaos: Arcadia, The Waste Land, Numb3rs, and Man's Relationship With Science
Authors: Miller Kristen
Published: January 2007

Through the use of some purposeful anachronisms, Tom Stoppard uses his 1993 play Arcadia to explore the effects on man's psyche of the transition from Newton's Laws to the laws of thermodynamics and from thermodynamics to chaos theory. However, remarkably similar reactions to these changes are also reflected in works from the actual time periods following these shifts in scientific understanding. Modernist literature is believed by many to reflect a sense of depression about the implications of the second law of thermodynamics, which is exemplified in T. S. Eliot's 1922 poem The Waste Land. Likewise, the comfort provided by the revisions to thermodynamics made by chaos theory are reflected frequently in contemporary popular culture, such as in the current television series Numb3rs. Through the invocation of science, all three works suggest that man is uncomfortable with too much predictability and that comfort can instead be found in chaos and unpredictability.
Antinuclear antibody testing in pleural fluid for the diagnosis of lupus pleuritis
Authors: Porcel J M , Ordi-Ros J , Esquerda A , Vives M , Madroñero A B , Bielsa S , Vilardell-Tarrés M , Light R W
Published: January 2007

We sought to determine whether measuring antinuclear antibodies (ANA) and their specificities [dsDNA, extractable nuclear antigens (ENA)] on pleural fluid may contribute to the differential diagnosis of pleural effusions. ANA were tested by indirect immunofluorescence on Hep-2 cells in the pleural fluid of 266 patients with effusions of different etiologies, including 15 lupus pleuritis. The cutoff value for diagnostic use was set at 1: 160. Pleural fluid analysis of specific autoantibodies, such as anti-dsDNA and anti-ENA, was also performed if a positive ANA test was obtained. All patients with lupus pleurisy and 16 of 251 (6.4%) patients with pleural effusions secondary to other causes were ANA positive. Fifty-six percent of the positive ANAs in non-lupus pleural fluids were due to neoplasms. The pleural fluid ANA titers were low (≤1: 80) or absent in two patients with systemic lupus erythematosus (SLE) and effusions due to other factors. Whereas ANA staining patterns in pleural fluid did not help to discriminate lupus pleuritis from non-lupus etiologies, the absence of pleural fluid anti-dsDNA or anti-ENA favored the latter. ANAs in pleural fluid provided no additional diagnostic information beyond that obtained by the measurement in serum and, therefore, these tests need not be routinely performed on pleural fluid samples. However, in patients with SLE and a pleural effusion of uncertain etiology, lack of ANAs or specific autoantibodies in pleural fluid argues against the diagnosis of lupus pleuritis.
Systemic lupus erythematosus and exercise
Authors: Ayán C , Martín V
Published: January 2007

Systemic lupus erythematosus (SLE) is a rheumatic disease characterized by a variety of symptoms, especially fatigue, pain and reduced quality of life. Physical exercise is a useful tool for improving cardiovascular fitness, reducing metabolic abnormalities and fatigue and improving quality of life. However, very few studies have focused on the relationship between SLE and physical exercise. This paper reviews the main SLE symptoms that can be alleviated by exercising, as well as the results of studies seeking to analyse the exercise capacity and physical training possibilities of SLE patients. Considerations for future research are also discussed.
Scanning transmission electron microscopy using a SEM: Applications to mineralogy and petrology
Authors: Lee M. R. , Smith C. L.
Published: January 2007

High-resolution imaging of electron-transparent samples using a scanning electron microscope, here termed low voltage (LV) STEM, is a new and valuable technique for studying Earth and planetary materials. The most effective method of LV-STEM imaging uses a pair of electron detectors positioned side-by-side beneath the thin sample. The detector directly underlying the sample forms bright-field images dominated by mass-thickness contrast. Activation of the detector offset from the sample yields dark-field images with a greater component of atomic number contrast. LV-STEM images with significant diffraction contrast can also be obtained, but require careful positioning of the sample relative to the electron detectors. In this study LV-STEM was used successfully to image sub-μm sized kaolinite crystals and tens of nm-sized etch pits on the gold-coated surfaces of weathered feldspar grains. Dark-field LV-STEM was also especially effective for characterizing very fine-scale intergrowths of Mg- and Fe-rich phyllosilicates within uniformly thin samples of the Murchison meteorite prepared using the focused ion beam (FIB) technique. LV-STEM is a quick and easy method for characterizing the morphology and internal structure of mineral and rock samples and may prove to be especially useful in geomicrobiology research.
Evidence for metre-scale variations in hematite composition within the Palaeoproterozoic Itabira Iron Formation, Minas Gerais, Brazil
Authors: Cabral A. R. , Lehmann B. , Galbiatti H. F. , Rocha Filho O. G.
Published: January 2007

Hematite is a mineral the chemical composition of which rarely differs significantly from stoichiometric Fe2O3. As such, little attention has been paid to the mineral chemistry of hematite in Precambrian iron formations, where hematite forms monomineralic high-grade orebodies. Electron microprobe analysis of hematite from two iron-ore deposits, Cauê (Itabira district) and Gongo Soco, in the Palaeoproterozoic Itabira Iron Formation, Quadrilátero Ferrífero of Minas Gerais, Brazil, has revealed distinct variations in chemical composition with respect to Ti and Cr. Hematite containing Ti and/or Cr is of very local occurrence in the itabirite unit and shows a spatial relationship to hematitic, palladiferous gold-bearing veins (known as ‘jacutinga’), occurring either within the veins (adjacent to, or included in, palladiferous gold grains) or in their vicinity. Where present, titaniferous hematite (to ∼1.3 wt.% TiO2) is lepidoblastic and defines a pervasive tectonic foliation (S1). In contrast, Ti-free, chromiferous hematite (to ∼6.4 wt.% Cr2O3) characteristically occurs as inclusions in palladiferous gold within S1-truncating ‘jacutinga’. Replacement of granoblastic, Ti-free, chromiferous martite with relicts of magnetite by lepidoblastic, Cr-depleted, titaniferous hematite proves that Cr and Ti were mobile during metamorphism. Chromium was ultimately fractionated into the hematite found in auriferous aggregates within cross-cutting ‘jacutinga’. A positive correlation between Cr and Pt in bulk-rock samples from the Itabira district suggests that Cr is a potential prospective guide for Au-Pd-Pt-bearing hematitic veins (‘jacutinga’).
Hydrolytic weakening of jadeite in UHP jadeite-quartzites from the Dabie Mountains, eastern China
Authors: Su Wen , Ye Kai , Liu Jingbo
Published: January 2007

Deformed jadeite grains in the UHP jadeite-quartzites from the Dabie Mountains, eastern China show evidence (by transmission electron microscopy, TEM) of plastic deformation: free dislocations, dislocation loops, dislocation networks, dislocation arrays and regularly spaced subgrain boundaries by dislocation walls. Electron energy-loss spectroscopy and TEM studies reveal the existence of water-rich bubbles within dislocations and imply a relationship with water-defect dislocation by water weakening in the jadeites. These observations suggest that the water-rich bubbles are a major weakening effect facilitating plastic deformation of jadeite by dislocation creep.
Effect of polyamines and synthetic polyamine-analogues on the expression of antizyme (AtoC) and its regulatory genes
Authors: Filippou Panagiota S , Lioliou Efthimia E , Panagiotidis Christos A , Athanassopoulos Constantinos M , Garnelis Thomas , Papaioannou Dionyssios , Kyriakidis Dimitrios A
Published: January 2007

Background

In bacteria, the biosynthesis of polyamines is modulated at the level of transcription as well as post-translationally. Antizyme (Az) has long been identified as a non-competitive protein inhibitor of polyamine biosynthesis in E. coli. Az was also revealed to be the product of the atoC gene. AtoC is the response regulator of the AtoS-AtoC two-component system and it functions as the positive transcriptional regulator of the atoDAEB operon genes, encoding enzymes involved in short chain fatty acid metabolism. The antizyme is referred to as AtoC/Az, to indicate its dual function as both a transcriptional and post-translational regulator.

Results

The roles of polyamines on the transcription of atoS and atoC genes as well as that of atoDAEB(ato) operon were studied. Polyamine-mediated induction was tested both in atoSC positive and negative E. coli backgrounds by using β-galactosidase reporter constructs carrying the appropriate promoters patoDAEB, patoS, patoC. In addition, a selection of synthetic polyamine analogues have been synthesized and tested for their effectiveness in inducing the expression of atoC/Az, the product of which plays a pivotal role in the feedback inhibition of putrescine biosynthesis and the transcriptional regulation of the ato operon. The effects of these compounds were also determined on the ato operon expression. The polyamine analogues were also tested for their effect on the activity of ornithine decarboxylase (ODC), the key enzyme of polyamine biosynthesis and on the growth of polyamine-deficient E. coli.

Conclusion

Polyamines, which have been reported to induce the protein levels of AtoC/Az in E. coli, act at the transcriptional level, since they cause activation of the atoC transcription. In addition, a series of polyamine analogues were studied on the transcription of atoC gene and ODC activity.
Efficient classification of complete parameter regions based on semidefinite programming
Authors: Kuepfer Lars , Sauer Uwe , Parrilo Pablo A
Published: January 2007

Background

Current approaches to parameter estimation are often inappropriate or inconvenient for the modelling of complex biological systems. For systems described by nonlinear equations, the conventional approach is to first numerically integrate the model, and then, in a second a posteriori step, check for consistency with experimental constraints. Hence, only single parameter sets can be considered at a time. Consequently, it is impossible to conclude that the "best" solution was identified or that no good solution exists, because parameter spaces typically cannot be explored in a reasonable amount of time.

Results

We introduce a novel approach based on semidefinite programming to directly identify consistent steady state concentrations for systems consisting of mass action kinetics, i.e., polynomial equations and inequality constraints. The duality properties of semidefinite programming allow to rigorously certify infeasibility for whole regions of parameter space, thus enabling the simultaneous multi-dimensional analysis of entire parameter sets.

Conclusion

Our algorithm reduces the computational effort of parameter estimation by several orders of magnitude, as illustrated through conceptual sample problems. Of particular relevance for systems biology, the approach can discriminate between structurally different candidate models by proving inconsistency with the available data.
Worked examples of alternative methods for the synthesis of qualitative and quantitative research in systematic reviews
Authors: Lucas Patricia J , Baird Janis , Arai Lisa , Law Catherine , Roberts Helen M
Published: January 2007

Background

The inclusion of qualitative studies in systematic reviews poses methodological challenges. This paper presents worked examples of two methods of data synthesis (textual narrative and thematic), used in relation to one review, with the aim of enabling researchers to consider the strength of different approaches.

Methods

A systematic review of lay perspectives of infant size and growth was conducted, locating 19 studies (including both qualitative and quantitative). The data extracted from these were synthesised using both a textual narrative and a thematic synthesis.

Results

The processes of both methods are presented, showing a stepwise progression to the final synthesis. Both methods led us to similar conclusions about lay views toward infant size and growth. Differences between methods lie in the way they dealt with study quality and heterogeneity.

Conclusion

On the basis of the work reported here, we consider textual narrative and thematic synthesis have strengths and weaknesses in relation to different research questions. Thematic synthesis holds most potential for hypothesis generation, but may obscure heterogeneity and quality appraisal. Textual narrative synthesis is better able to describe the scope of existing research and account for the strength of evidence, but is less good at identifying commonality.
Increased cardiovascular mortality more than fifteen years after radiotherapy for breast cancer: a population-based study
Authors: Roychoudhuri Rahul , Robinson David , Putcha Venkata , Cuzick Jack , Darby Sarah , Møller Henrik
Published: January 2007

Background

Breast radiotherapy as practised in the 1970s and 1980s resulted in significant myocardial exposure, and this was higher when the left breast was treated. It has been proposed that this difference might result in greater cardiovascular mortality following irradiation of the left breast when compared with the right.

Methods

All cases of female breast cancer diagnosed between 1971 and 1988 and recorded on the Thames Cancer Registry database were followed up to the end of 2003 to identify cases who had died from ischaemic heart disease (IHD) or any cardiovascular disease (CVD). A proportional hazards regression analysis was performed, stratified by time since diagnosis, using as the baseline group those women with right-sided disease who did not receive radiotherapy, and adjusting for age at diagnosis.

Results

A total of 20,871 women with breast cancer were included in the analysis, of which 51% had left-sided disease. Mortality at 15+ years after diagnosis was increased in recipients of left-breast radiotherapy compared to non-irradiated women with right-sided breast cancer, both for IHD (hazard ratio 1.59; 95% confidence interval 1.21–2.08; p = 0.001) and all CVD (hazard ratio 1.27; 95% confidence interval 1.07–1.51; p = 0.006). When irradiated women with left-sided breast cancer were compared with irradiated women with right-sided breast cancer, cardiovascular mortality at 15+ years after diagnosis was raised by around 25% (IHD: hazard ratio 1.23; 95% confidence interval 0.95–1.60; p = 0.114; CVD: hazard ratio 1.25; 95% confidence interval 1.05–1.49; p = 0.014).

Conclusion

We have found an elevation in cardiovascular mortality more than 15 years after breast radiotherapy in women diagnosed with breast cancer between 1971 and 1988. The risk was greater following irradiation of the left breast compared with the right. This confirms that radiotherapy as practised in the 1970s and 1980s has resulted in significant long-term cardiac toxicity. In absolute terms, the increase in cardiovascular mortality induced by radiotherapy may be substantial, as these mortality events are relatively common.
Use of patient flow analysis to improve patient visit efficiency by decreasing wait time in a primary care-based disease management programs for anticoagulation and chronic pain: a quality improvement study
Authors: Potisek Nicholas M , Malone Robb M , Shilliday Betsy Bryant , Ives Timothy J , Chelminski Paul R , DeWalt Darren A , Pignone Michael P
Published: January 2007

Background

Patients with chronic conditions require frequent care visits. Problems can arise during several parts of the patient visit that decrease efficiency, making it difficult to effectively care for high volumes of patients. The purpose of the study is to test a method to improve patient visit efficiency.

Methods

We used Patient Flow Analysis to identify inefficiencies in the patient visit, suggest areas for improvement, and test the effectiveness of clinic interventions.

Results

At baseline, the mean visit time for 93 anticoagulation clinic patient visits was 84 minutes (+/- 50 minutes) and the mean visit time for 25 chronic pain clinic patient visits was 65 minutes (+/- 21 minutes). Based on these data, we identified specific areas of inefficiency and developed interventions to decrease the mean time of the patient visit. After interventions, follow-up data found the mean visit time was reduced to 59 minutes (+/-25 minutes) for the anticoagulation clinic, a time decrease of 25 minutes (t-test 39%; p < 0.001). Mean visit time for the chronic pain clinic was reduced to 43 minutes (+/- 14 minutes) a time decrease of 22 minutes (t-test 34 %; p < 0.001).

Conclusion

Patient Flow Analysis is an effective technique to identify inefficiencies in the patient visit and efficiently collect patient flow data. Once inefficiencies are identified they can be improved through brief interventions.
High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma
Authors: Hebert Carla , Norris Kathleen , Scheper Mark A , Nikitakis Nikolaos , Sauk John J
Published: January 2007

Background

HMGA2 expression has been shown to be associated with enhanced selective chemosensitivity towards the topoisomerase (topo) II inhibitor, doxorubicin, in cancer cells. Although the roles of signaling cascades and proteins as regulatory factors in development, neoplasia and adaptation to the environment are becoming well established, evidence for the involvement of regulatory small RNA molecules, such as microRNAs (miRNAs) as important regulators of both transcriptional and posttranscriptional gene silencing is presently mounting.

Results

Here we report that HMGA2 expression in head and neck squamous cell carcinoma (HNSCC) cells is regulated in part by miRNA-98 (miR-98). Albeit HMGA2 is associated with enhanced selective chemosensitivity towards topoisomerase (topo) II inhibitor, doxorubicin in HNSCC, the expression of HMGA2 is thwarted by hypoxia. This is accompanied by enhanced expression of miRNA-98 and other miRNAs, which predictably target HMGA2. Moreover, we show that transfection of pre-miR-98™ during normoxia diminishes HMGA2 and potentiates resistance to doxorubicin and cisplatin. These findings implicate the role of a miRNA as a key element in modulating tumors in variable microenvironments.

Conclusion

These studies validate the observation that HMGA2 plays a prominent role in governing genotoxic responses. However, this may only represent cells growing under normal oxygen tensions. The demonstration that miRNA profiles are altered during hypoxia and repress a genotoxic response indicates that changes in microenvironment in eukaryotes mimic those of lower species and plants, where, for example, abiotic stresses regulate the expression of thousands of genes in plants at both transcriptional and posttranscriptional levels through a number of miRNAs and other small regulatory RNAs.
Urine carcinoembryonic antigen levels are more useful than serum levels for early detection of Bilharzial and non-Bilharzial urinary bladder carcinoma: Observations of 43 Egyptian cases
Authors: Saied Gamal M , El-Metenawy Wafaa H , Elwan Mohamed S , Dessouki Nazar R
Published: January 2007

Background

Both urinary bilharziasis and urothelial neoplasia are associated with increased production of tissue carcinoembryonic antigen (CEA).

Patients and methods

Urine and serum CEA were determined in 43 patients with urinary bladder carcinoma including 22 post bilharzial and 21 nonbiharzial cases, in addition to 10 normal control cases.

Results

A significant increase was detected in both urine and serum CEA levels with bladder carcinoma compared to control cases. Urinary CEA was significantly elevated in 86% of bilharzial, versus 62% in nonbilharzial bladder carcinoma. Only 10.5% of control cases had urinary CEA elevation. The mean urinary CEA in bilharzial, was higher than that of nonbilharzial carcinoma, but the difference was not statistically significant. There was a definite relationship between urine CEA and the stage of malignancy; the higher the stage, the higher the level of urine CEA. No relationship could be detected between the stage of malignancy and serum CEA, or between the grades of malignancy and urine or serum CEA levels.

Conclusion

Urinary CEA is more useful than serum CEA in the early detection of urotherlial carcinoma particularly if provoked by bilharziasis. Its level is also correlated with the tumor stage.
Interaction between Bluetongue virus outer capsid protein VP2 and vimentin is necessary for virus egress
Authors: Bhattacharya Bishnupriya , Noad Rob J , Roy Polly
Published: January 2007

Background

The VP2 outer capsid protein Bluetongue Virus (BTV) is responsible for receptor binding, haemagglutination and eliciting host-specific immunity. However, the assembly of this outer capsid protein on the transcriptionally active viral core would block transcription of the virus. Thus assembly of the outer capsid on the core particle must be a tightly controlled process during virus maturation. Earlier studies have detected mature virus particles associated with intermediate filaments in virus infected cells but the viral determinant for this association and the effect of disrupting intermediate filaments on virus assembly and release are unknown.

Results

In this study it is demonstrated that BTV VP2 associates with vimentin in both virus infected cells and in the absence of other viral proteins. Further, the determinants of vimentin localisation are mapped to the N-terminus of the protein and deletions of aminio acids between residues 65 and 114 are shown to disrupt VP2-vimentin association. Site directed mutation also reveals that amino acid residues Gly 70 and Val 72 are important in the VP2-vimentin association. Mutation of these amino acids resulted in a soluble VP2 capable of forming trimeric structures similar to unmodified protein that no longer associated with vimentin. Furthermore, pharmacological disruption of intermediate filaments, either directly or indirectly through the disruption of the microtubule network, inhibited virus release from BTV infected cells.

Conclusion

The principal findings of the research are that the association of mature BTV particles with intermediate filaments are driven by the interaction of VP2 with vimentin and that this interaction contributes to virus egress. Furthermore, i) the N-terminal 118 amino acids of VP2 are sufficient to confer vimentin interaction. ii) Deletion of amino acids 65–114 or mutation of amino acids 70–72 to DVD abrogates vimentin association. iii) Finally, disruption of vimentin structures results in an increase in cell associated BTV and a reduction in the amount of released virus from infected cells.
Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra
Authors: Grammatopoulos Tom N , Jones Susan M , Ahmadi Ferogh A , Hoover Brian R , Snell Lawrence D , Skoch Jesse , Jhaveri Vimal V , Poczobutt Andy M , Weyhenmeyer James A , Zawada W Michael
Published: January 2007

Background

Recent attention has focused on understanding the role of the brain-renin-angiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. In this study, we show that an antagonist of the angiotensin II (Ang II) type 1 (AT1) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1).

Results

In the presence of exogenous Ang II, losartan reduced MPP+(5 μM) induced DA neuronal loss by 72%in vitro. Mice challenged with MPTP showed a 62% reduction in the number of DA neurons in the SNpc and a 71% decrease in tyrosine hydroxylase (TH) immunostaining of the striatum, whereas daily treatment with losartan lessened MPTP-induced loss of DA neurons to 25% and reduced the decrease in striatal TH+immunostaining to 34% of control.

Conclusion

Our study demonstrates that the brain-RAS plays an important neuroprotective role in the MPTP model of PD and points to AT1receptor as a potential novel target for neuroprotection.
Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas
Authors: Chanock Stephen J , Burdett Laurie , Yeager Meredith , Llaca Victor , Langerød Anita , Presswalla Shafaq , Kaaresen Rolf , Strausberg Robert L , Gerhard Daniela S , Kristensen Vessela , Perou Charles M , Børresen-Dale Anne-Lise
Published: January 2007

Introduction

Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA.

Methods

We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples.

Results

Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed.

Conclusion

The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns.
Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships
Authors: Mégarbane Bruno , Declèves Xavier , Bloch Vanessa , Bardin Christophe , Chast François , Baud Frédéric J
Published: January 2007

Introduction

Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.

Methods

We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.

Results

Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R- methadone concentrations fitted well a sigmoidal E
max
model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.

Conclusion

After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.
Prediction of effective genome size in metagenomic samples
Authors: Raes Jeroen , Korbel Jan O , Lercher Martin J , von Mering Christian , Bork Peer
Published: January 2007

We introduce a novel computational approach to predict effective genome size (EGS; a measure that includes multiple plasmid copies, inserted sequences, and associated phages and viruses) from short sequencing reads of environmental genomics (or metagenomics) projects. We observe considerable EGS differences between environments and link this with ecologic complexity as well as species composition (for instance, the presence of eukaryotes). For example, we estimate EGS in a complex, organism-dense farm soil sample at about 6.3 megabases (Mb) whereas that of the bacteria therein is only 4.7 Mb; for bacteria in a nutrient-poor, organism-sparse ocean surface water sample, EGS is as low as 1.6 Mb. The method also permits evaluation of completion status and assembly bias in single-genome sequencing projects.
Excessive Over-Voltage in Long Cables of Large Offshore Windfarms
Authors: Akhmatov Vladislav
Published: January 2007

Large offshore windfarms are connected to onshore transmission grids through long high-voltage cables. When a large offshore windfarm goes into isolated operation with its high-voltage cable, for example by an action of the on-shore main-circuit breaker, there is a risk of significant over-voltage in the cable and the windfarm transformer. This paper analyses such a situation for both an existing and a planned large offshore windfarm in Denmark.