bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of Gαq Transgenic Mice
Authors: Hayakawa Yukihiro , Chandra Madhulika , Miao Wenfeng , Shirani Jamshid , Brown Joan Heller , Dorn Gerald W. , Armstrong Robert C. , Kitsis Richard N.
Published: November 2003

Background—

Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gαq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gαq peripartum cardiomyopathy model.

Methods and Results—

The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gαq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3–like activity (86.5%;
P
<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3% to 0.2±0.1% (
P
<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm;
P
<0.01), fractional shortening (vehicle, 30.7±1.2%; IDN-1965, 38.9±1.0%;
P
<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295;
P
<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201;
P
<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died;
P
<0.05).

Conclusions—

Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gαq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.
Milrinone Facilitates Resuscitation From Cardiac Arrest and Attenuates Postresuscitation Myocardial Dysfunction
Authors: Niemann James T. , Garner Daniel , Khaleeli Emad , Lewis Roger J.
Published: November 2003

Background—

Left ventricular (LV) dysfunction with a low cardiac index after successful CPR contributes to early death attributable to multiorgan failure, and an effective treatment has not been identified. The purpose of this study was to investigate the use of milrinone, a selective phosphodiesterase III inhibitor, as treatment for LV dysfunction after resuscitation.

Methods and Results—

Ventricular fibrillation (VF) was induced electrically in 32 swine. After 5 minutes of VF, CPR was initiated and animals were randomized to receive either saline (control group, n=16) as a bolus and infusion or milrinone 50 μg/kg as a bolus and then 0.5 μg/kg per min for 60 minutes (treatment group, n=16). After 2 minutes of CPR (total VF time, 7 minutes), countershocks were given. Coronary perfusion pressures during CPR were similar for the groups (24±2 versus 21±4 mm Hg). All animals were defibrillated; 6 of 16 control animals developed refractory postcountershock pulseless electrical activity compared with 0 of 16 treated animals (
P
=0.018). At 30 minutes after restoration of spontaneous circulation, stroke volume (16±3 versus 26±7 mL,
P
<0.01) and LV dp/dt (793±197 versus 1108±316 mm Hg/s,
P
<0.02) were higher in the treatment group. Similar differences were observed 60 minutes after restoration of spontaneous circulation. Significant differences in heart rates between groups were not observed, and peripheral vascular resistance was significantly greater in the control group 30 and 60 minutes after resuscitation.

Conclusions—

Milrinone facilitates resuscitation from prolonged VF and attenuates LV dysfunction after resuscitation without worsening major determinants of myocardial oxygen demand.
Impact of Renal Insufficiency in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction
Authors: Sadeghi H. Mehrdad , Stone Gregg W. , Grines Cindy L. , Mehran Roxana , Dixon Simon R. , Lansky Alexandra J. , Fahy Martin , Cox David A. , Garcia Eulogio , Tcheng James E. , Griffin John J. , Stuckey Thomas D. , Turco Mark , Carroll John D.
Published: November 2003

Background—

The prognostic importance of renal insufficiency (RI) in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) has not been well characterized.

Methods and Results—

PCI was performed in 2082 AMI patients without shock presenting within 12 hours of symptom onset in a prospective, multicenter randomized trial. RI was defined as a calculated (Cockroft-Gault) creatinine clearance (CrCl) ≤60 mL/min. RI at baseline was present in 18% of patients. Compared with patients without RI, patients with RI were older and were more likely to be female; to have hypertension, peripheral vascular disease, or cerebrovascular disease; and to present in heart failure. Mortality was markedly increased in patients with versus without baseline RI both at 30 days (7.5% versus 0.8%,
P
<0.0001) and at 1 year (12.7% versus 2.4%,
P
<0.0001). Mortality rates increased incrementally for every 10-mL/min decrease in baseline CrCl. By multivariate analysis, reduced baseline CrCl was a powerful independent predictor of 30-day mortality (hazard ratio, 5.77;
P
<0.0001) and remained associated with reduced survival at 1 year (hazard ratio, 1.98;
P
=0.08). Hemorrhagic complications and transfusion requirements were also increased more than 2-fold in patients with RI, as were severe restenosis (diameter stenosis ≥70%; 20.6% versus 11.8%,
P
=0.024) and infarct artery reocclusion (14.7% versus 7.3%,
P
=0.02).

Conclusions—

Baseline RI in patients with AMI undergoing primary PCI is associated with a markedly increased risk of mortality, as well as bleeding and restenosis. Novel approaches are needed to improve the otherwise poor prognosis of patients with RI and AMI.
Inflammatory/Antiinflammatory Properties of High-Density Lipoprotein Distinguish Patients From Control Subjects Better Than High-Density Lipoprotein Cholesterol Levels and Are Favorably Affected by Simvastatin Treatment
Authors: Ansell Benjamin J. , Navab Mohamad , Hama Susan , Kamranpour Naeimeh , Fonarow Gregg , Hough Greg , Rahmani Shirin , Mottahedeh Rachel , Dave Ravi , Reddy Srinivasa T. , Fogelman Alan M.
Published: November 2003

Background—

The inflammatory/antiinflammatory properties of HDL were compared with HDL cholesterol in 2 groups of patients and in age- and sex-matched control subjects.

Methods and Results—

Group 1 consisted of 26 patients not yet taking a statin who presented with coronary heart disease (CHD) or CHD equivalents by National Cholesterol Education Program Adult Treatment Panel III criteria studied before and 6 weeks after 40 mg/d of simvastatin. Group 2 consisted of 20 patients with documented CHD and HDL cholesterol ≥84 mg/dL. The inflammatory/antiinflammatory properties of HDL were determined by the ability of the subject’s HDL to alter LDL-induced monocyte chemotactic activity (MCA) in a human artery wall coculture. Induction of MCA by a control LDL was determined in the absence or presence of the subject’s HDL. Values in the absence of HDL were normalized to 1.0. Values >1.0 after the addition of HDL indicated proinflammatory HDL; values <1.0 indicated antiinflammatory HDL. Group 1 values before simvastatin were LDL cholesterol, 118±24 mg/dL; HDL cholesterol, 57±13 mg/dL; triglycerides, 125±64 mg/dL; and high-sensitivity C-reactive protein (hs-CRP), 1.7±1.9 mg/L; and MCA values were 1.38±0.91, compared with 0.38±0.14 for control subjects (
P
=1.5×10
−5
). After simvastatin, values were LDL cholesterol, 73±24 mg/dL; HDL cholesterol, 61±14 mg/dL; triglycerides, 99±52 mg/dL; and hs-CRP, 1.3±1.3 mg/L; and MCA values were 1.08±0.71. In group 2, values were LDL cholesterol, 108±34 mg/dL; HDL cholesterol, 95±14 mg/dL; triglycerides, 89±44 mg/dL; and hs-CRP, 0.8±0.7 mg/L; and MCA values were 1.28±0.29, compared with 0.35±0.11 for control subjects (
P
=1.7×10
−14
). Similar results were obtained with the cell-free assay.

Conclusions—

The inflammatory/antiinflammatory properties of HDL distinguished patients from control subjects better than HDL cholesterol and were improved with simvastatin.
Noninvasive Evaluation of Coronary Reperfusion by Transthoracic Doppler Echocardiography in Patients With Anterior Acute Myocardial Infarction Before Coronary Intervention
Authors: Lee Souki , Otsuji Yutaka , Minagoe Shinichi , Hamasaki Shuichi , Toyonaga Koichi , Negishi Midori , Tsurugida Masanori , Toda Hitoshi , Tei Chuwa
Published: November 2003

Background—

Transthoracic Doppler echocardiography (TTDE) enables evaluation of distal left anterior descending coronary artery (LAD) flow. The purpose of this study was to test whether TTDE can differentiate coronary reperfusion with Thrombolysis in Myocardial Infarction (TIMI) grade 3 from TIMI grade ≤2 in patients with anterior acute myocardial infarction (AMI).

Methods and Results—

In 46 consecutive patients with a first anterior AMI in the acute phase before emergent coronary intervention, the presence of antegrade distal LAD flow and its diastolic peak velocity were evaluated by color and pulsed TTDE and compared with TIMI grades by subsequent coronary angiography performed 29±12 minutes later. Nineteen patients had TIMI 0 reperfusion, 4 had TIMI 1, 10 had TIMI 2, and 13 had TIMI 3. Visual antegrade distal LAD flow was present in 22 of the 46 patients. TIMI 2 and 3 reperfusions were both generally visualized by color TTDE. However, peak distal LAD flow velocity by pulsed TTDE was significantly greater in patients with TIMI 3 compared with those with TIMI 2 (40±10 vs 20±6 cm/s,
P
<0.0001). The diagnosis of TIMI 3 based on diastolic peak distal LAD flow velocity ≥25 cm/s by TTDE had a sensitivity, specificity, and accuracy of 77%, 94%, and 89%, respectively.

Conclusion—

TTDE enables noninvasive differentiation of TIMI 3 from TIMI ≤2 coronary reperfusion in patients with AMI in the acute phase before emergent coronary intervention.
Missense Mutations and Gene Interruption in
PROSIT240
, a Novel
TRAP240
-Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)
Authors: Muncke Nadja , Jung Christine , Rüdiger Heinz , Ulmer Herbert , Roeth Ralph , Hubert Annette , Goldmuntz Elizabeth , Driscoll Deborah , Goodship Judith , Schön Karin , Rappold Gudrun
Published: November 2003

Background—

Congenital heart disease represents the most common severe birth defect, affecting 0.7% to 1% of all neonates, among whom 5% to 7% display transposition of the great arteries (TGA). TGA represents a septation defect of the common outflow tract of the heart, manifesting around the fifth week during embryonic development. Despite its high prevalence, very little is known about the pathogenesis of this disease.

Methods and Results—

Using a positional cloning approach, we isolated a novel gene,
PROSIT240
(also termed
THRAP2
), that is interrupted in a patient with a chromosomal translocation and who displays TGA and mental retardation. High expression of
PROSIT240
within the heart (aorta) and brain (cerebellum) was well correlated with the malformations observed in the patient and prompted further analyses.
PROSIT240
shows significant homology to the nuclear receptor coactivator
TRAP240
, suggesting it to be a new component of the thyroid hormone receptor-associated protein (TRAP) complex. Interestingly, several TRAP components have been previously shown to be important in early embryonic development in various organisms, making
PROSIT240
an excellent candidate gene to be correlated to the patient’s phenotype. Subsequent mutational screening of 97 patients with isolated dextro-looped TGA revealed 3 missense mutations in
PROSIT240
, which were not detected in 400 control chromosomes.

Conclusions—

Together, these genetic data suggest that
PROSIT240
is involved in early heart and brain development.
Implication of an AGT Haplotype in a Multigene Association Study With Pregnancy Hypertension
Authors: Lévesque Sébastien , Moutquin Jean-Marie , Lindsay Carmen , Roy Marie-Claude , Rousseau François
Published: November 2003

Several association studies of candidate genes for preeclampsia and essential hypertension have led to discordant results, partly because of small sample sizes. Using a large population-based sample of pregnant women, we conducted an association study of 10 polymorphisms in 9 genes and aimed (1) to validate 10 published associations with preeclampsia or essential hypertension, (2) to investigate candidate polymorphisms previously associated with preeclampsia for association with essential hypertension and similarly with polymorphisms previously associated with essential hypertension. From a prospective sample of 3391 nulliparous French Canadian pregnant women, we identified 180 cases of preeclampsia, 203 cases of essential hypertension that were matched with normotensive control subjects (n=310 and 357, respectively). Polymorphisms were genotyped by allele-specific PCR. Among our candidate polymorphisms, the Met allele of Thr174Met of
AGT
was associated with preeclampsia (
P
=0.0033). Haplotype analysis revealed that the A-Met-Thr (G1035A-Thr174Met-Met235Thr) haplotype was associated with a 2.1-fold increased risk of preeclampsia (95% CI, 1.4 to 3.4;
P
=0.0008). In conclusion, we observed a strong association between a specific
AGT
haplotype and preeclampsia in our population, without replicating previous published associations with either preeclampsia or essential hypertension. Our data support a role for
AGT
in genetic susceptibility to preeclampsia.
Serum Neuron-Specific Enolase and S-100B Protein in Cardiac Arrest Patients Treated With Hypothermia
Authors: Tiainen Marjaana , Roine Risto O. , Pettilä Ville , Takkunen Olli
Published: November 2003

Background and Purpose—

High serum levels of neuron-specific enolase (NSE) and S-100B protein are known to be associated with ischemic brain injury and poor outcome after cardiac arrest. Therapeutic hypothermia has been shown to improve neurological outcome after cardiac arrest. The aim of this study was to evaluate the effect of therapeutic hypothermia on levels of serum NSE and S-100B protein, their time course, and their prognostic value in predicting unfavorable outcome after out-of-hospital cardiac arrest.

Methods—

Seventy patients resuscitated from ventricular fibrillation were randomly assigned to hypothermia of 33±1°C for 24 hours or to normothermia. Serum NSE and S-100B were sampled at 24, 36, and 48 hours after cardiac arrest. Neurological outcome was dichotomized into good or poor at 6 months after cardiac arrest.

Results—

The levels of NSE (
P
=0.007 by analysis of variance for repeated measurements) but not S-100B were lower in hypothermia- than normothermia-treated patients. A decrease in NSE values between 24 and 48 hours was observed in 30 of 34 patients (88%) in the hypothermia group and in 16 of 32 patients (50%) in the normothermia group (
P
<0.001). The decrease in NSE values was associated with good outcome at 6 months after cardiac arrest (
P
=0.005), recovery of consciousness (
P
<0.001), and survival for at least 6 months after cardiac arrest (
P
=0.012).

Conclusions—

Decreasing levels of serum NSE but not S-100B over time may indicate selective attenuation of delayed neuronal death by therapeutic hypothermia in victims of cardiac arrest.
Leukoaraiosis More Than Dementia Is a Predictor of Stroke Recurrence
Authors: Hénon H. , Vroylandt P. , Durieu I. , Pasquier F. , Leys D.
Published: November 2003

Background and Purpose—

It has been suggested that poststroke dementia is associated with a higher risk of stroke recurrence. Leukoaraiosis, however, might be a confounding factor because it is a risk factor for stroke recurrence and cognitive decline. Our aim was to determine the influence of prestroke and poststroke dementia on the 3-year risk of stroke recurrence.

Methods—

We evaluated prestroke cognitive functions in 202 stroke patients ≥40 years of age using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), with a cutoff of 104 for the diagnosis of dementia. Patients were followed up for 3 years. Dementia was diagnosed on the basis of
International Classification of Diseases
, 10th revision, criteria in survivors who underwent a neurologist visit or from the IQCODE score in survivors who did not. The severity of leukoaraiosis was assessed with a visual rating scale on CT scans without contrast performed at the acute stage of stroke. At each follow-up contact, stroke recurrences were recorded.

Results—

During 385 person-years of follow-up, a total of 29 patients developed 33 stroke recurrences, resulting in an incidence rate of 8.6 per 100 person-years. We did not find any influence of dementia on the risk of stroke recurrence. Leukoaraiosis, however, was a strong predictor of stroke recurrence within 3 years after stroke.

Conclusions—

Dementia was not a predictor of stroke recurrence, but leukoaraiosis was strongly associated with stroke recurrence. Special attention in the secondary prevention of stroke must be given to patients with leukoaraiosis with or without dementia.
A Prophet Tested: Elisha, the Great Woman of Shunem, and the Story's Double Message
Authors: Amit Yairah
Published: November 2003

On casual reading, the story of Elisha and the Shunammite appears to belong to the genre of prophetic legends in praise of the prophets. A closer look, however, reveals marked differences between this story and the usual laudatory tales from the lives of the prophets, and places it in quite a different category. Though Elisha performs miracles—showing that he possessed super-human powers—the story exposes his limitations and human errors. It is, therefore, not so much a laudatory story as one of development. In a development story the miracles are meant not only to impress the prophet's surroundings and the readers of the story, but also to teach the prophet a lesson and to imply to the readers that although he possesses super-human powers, the prophet is only a human being with the failings of his kind. In other words, the prophetic stories of development have a double ambivalent message, and this article attempts to answer the question; what is the purpose and the importance of this complicated message, or of this elaboration of the story.
Israel's Indigenous Origins: Cultural Hybridity and the Formation of Israelite Ethnicity
Authors: Brett Mark
Published: November 2003

This paper addresses the question of whether Iron I settlements in the central Levantine hill country can properly be termed 'Israelite'. Drawing on anthropological theory to interpret the recent archaeological debates, the argument suggests that an Israelite ethnic 'network' arose in the early Iron Age—albeit with a low degree of incorporation—by a process of social fission. In contrast to the Philistine incursion of the same period, there was no imposition of a foreign cultural system. The historical evidence implies that in the course of time the worship of Yhwh, an exodus story, and a 'pig taboo', were added to the indigenous culture in the making of Israelite identity. Yhwh worship was probably not originally seen as a separate religion, but in the Iron II period, it came to be interpreted by some as antagonistic to other gods.
Ezra-Nehemiah as a Narrative of (Re-Invented) Israelite Identity
Authors: Esler Philip
Published: November 2003

This article applies notions of ethnic identity deriving from the work of Fredrik Barth to Ezra-Nehemiah that highlight the processes of boundary formation and maintenance. In particular, it focuses on one of the common indicia of ethnic boundaries, a shared history, here in the form of a 'narrative of ethnic identity' as explained by Stephen Cornell. Such a narrative is a story with a subject (the ethnic group in question), with action, normally in the past, and a value attached to it which bears upon the group's sense of its own worth. It covers the selection, plotting and interpretation of events. The post-exilic return of the Israelites to the land beginning under Cyrus, the erection of the Temple and the re-construction of the walls of Jerusalem described in Ezra-Nehemiah are usefully illuminated and explained when set within such a perspective. A central element of the Barthian understanding of ethnic boundaries, that they are patterns of prescription and proscription, is graphically illustrated in the account of the newly re-installed gates of the city being closed during the sabbath to keep out non-Israelite traders. A model focusing on the creation of a narrative of ethnic identity sheds considerable light on the re-invention of Israelite identity that is arguably the dominant theme in Ezra-Nehemiah.
Evil at Odds with Itself (Matthew 12:22-29): Demonising Rhetoric and Deconstructive Potential in the Matthean Narrative
Authors: Longenecker Bruce
Published: November 2003

Deconstructive analysis assumes that every text inevitably contains within itself the seeds of its own rhetorical self-destruction. The Matthean Gospel threatens to undermine its own rhetorical legitimisation in its depiction of evil, the cohorts of evil and evil's strategic incoherence. In Matt. 12:22-29 the story's central protagonist (Jesus) and his main antagonists (the Pharisees) are shown to hold different views on the character of evil. Within the course of the Matthean narrative, the view of the antagonists proves itself to be accurate, with the protagonist's view proving itself to be deficient. The reliability of the protagonist's discernment of things central to his own career and identity is thereby undermined. Comparison of the Matthean narrative with that of Mark suggests that this deconstructive tendency is to be credited to the Matthean evangelist in his efforts to demonise the synagogue of his contemporaries by means of a rhetoric of evil.
Biblical Scholarship in Public Discourse
Authors: Gottwald Norman
Published: November 2003

While various scholarly strategies for engaging in or avoiding public discourse are recognized as valid, several factors conspire to induce, even compel, biblical scholars to speak their minds in public. This essay examines the various forums in which biblical scholars enter public discourse and the issues they typically address, both in biblical studies and current affairs. It further assesses the net effect of biblical scholars in shaping public policy. Finally, it focuses on the special challenges and dilemmas biblical scholars face when they engage in public discourse, or decline to do so.
"Ja, bin denn ich an Gottes Stelle?" (Genesis 50:19): Beobachtungen und Überlegungen zu einem Schlüsselsatz der Josefsgeschichte und den vielfachen Konsequenzen aus einer rhetorischen Frage
Authors: Ebach Jürgen
Published: November 2003

Die Passage Gen. 50:15-21 (fast) am Ende der Josefsgeschichte ist lesbar als Schlüsseltext der gesamten Genesis 37–50 in all ihren Teilen umfassenden Erzählung. Hier kommen die großen Themen der in der Josefsgeschichte fokussierten "Familiengeschichte Jakobs" zusammen. Der zentrale Satz in dieser Passage ist aber nicht die oft hervorgehobene Formulierung in V. 20 (in der Luther-Bibel: "Ihr gedachtet es böse mit mir zu machen, aber Gott gedachte es gut zu machen"), sondern die Frage Josefs in V. 19: "Ja, bin denn ich an Gottes Stelle?" Als rhetorische Frage zielt sie nicht auf die naheliegende Antwort, sondern auf die Konsequenzen, die aus dieser Antwort zu ziehen sind. Der Satz markiert die Grenzen der Herrschaft Josefs, indem sich der Traum aus Genesis 37 ebenso erfüllt wie er korrigiert wird, er markiert aber auch die Grenzen der Vergebung. Brüder sollen einander nicht Knechte sein—das ist das eine. Josefs Rechnung kann nicht Gottes Rechnung sein—das ist das andere. Ob die Geschichte gut ausgeht, ist stets eine Frage der Lektüre und ihrer Perspektive. Josef kann Familie und werdendes Volk retten, weil er in gewisser Weise zum Ägypter geworden ist. Das Rettende wird aber auch zum Trennenden. In dieser Dialektik scheint über Genesis 50 und die Jakob-Josef-Geschichten hinaus ein Dauerthema jüdischer Existenz auf. Diesen Aspekten geht der Aufsatz exegetisch, systematisch-theologisch und geschichtsphilosophisch nach.
Dendritic cell differentiation potential of mouse monocytes: monocytes represent immediate precursors of CD8- and CD8+ splenic dendritic cells
Authors: León Beatriz , Martínez del Hoyo Gloria , Parrillas Verónica , Vargas Héctor Hernández , Sánchez-Mateos Paloma , Longo Natividad , López-Bravo María , Ardavín Carlos
Published: November 2003

The monocyte capacity to differentiate into dendritic cells (DCs) was originally demonstrated by human in vitro DC differentiation assays that have subsequently become the essential methodologic approach for the production of DCs to be used in DC-mediated cancer immunotherapy protocols. In addition, in vitro DC generation from monocytes is a powerful tool to study DC differentiation and maturation. However, whether DC differentiation from monocytes occurs in vivo remains controversial, and the physiologic counterparts of in vitro monocyte-derived DCs are unknown. In addition, information on murine monocytes and monocyte-derived DCs is scarce. Here we show that mouse bone marrow monocytes can be differentiated in vitro into DCs using similar conditions as those defined in humans, including in vitro cultures with granulocyte-macrophage colony-stimulating factor and interleukin 4 and reverse transendothelial migration assays. Importantly, we demonstrate that after in vivo transfer monocytes generate CD8- and CD8+ DCs in the spleen, but differentiate into macrophages on migration to the thoracic cavity. In conclusion, we support the hypothesis that monocytes generate DCs not only on entry into the lymph and migration to the lymph nodes as proposed, but also on extravasation from blood and homing to the spleen, suggesting that monocytes represent immediate precursors of lymphoid organ DCs. (Blood. 2004;103:2668-2676)
Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease
Authors: Wood John C. , Tyszka J. Michael , Carson Susan , Nelson Marvin D. , Coates Thomas D.
Published: November 2003

Cardiac T2* (magnetic resonance imaging relaxation parameter) is abnormally low in approximately 40% of adults with thalassemia major (TM), suggesting myocardial iron deposition, but it is unknown at what age this occurs. To address this question, we measured cardiac T2* and function in 19 young patients (aged 7-26 years) with TM as well as 17 patients receiving long-term transfusions for sickle cell anemia (SCA) matched for age, sex, and liver iron content. Cardiac T2* was normal in all of the SCA patients but was low (high iron) in 8 of 19 TM patients. Abnormal T2* was observed only in the TM patients receiving transfusions for 13 years or longer and was correlated with ferritin but not liver iron levels. Cardiac dysfunction was present in 3 of the 8 patients with low T2*. Cardiac T2* changes have a long latency relative to liver iron accumulation. Total transfusional burden is a significant independent risk factor for low cardiac T2* and may partially account for differences observed between patients with SCA and TM.
Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients
Authors: Cugno Massimo , Cabibbe Mara , Galli Monica , Meroni Pier Luigi , Caccia Sonia , Russo Rosaria , Bottasso Bianca , Mannucci Pier Mannuccio
Published: November 2003

The causes of thrombosis and pregnancy loss in antiphospholipid syndrome (APS) are still unknown, although several hypotheses have been proposed and hypofibrinolysis has been implicated. Anti–tissue-type plasminogen activator (tPA) antibodies may induce fibrinolytic defects and preliminary data indicate an association with thrombosis in APS. We measured plasma anti-tPA antibody levels in 91 consecutive patients with APS, 91 healthy controls, 40 patients with antiphospholipid antibodies without APS symptoms, and 23 patients with systemic lupus erythematosus (SLE) without antiphospholipid antibodies and APS symptoms. Patients with APS had anti-tPA antibody levels higher than controls (P = .0001), patients with SLE (P = .0001), and asymptomatic antiphospholipid patients (P = .05). A subgroup of 53 patients had plasma levels of tPA antigen higher (P = .0001) and tPA activity lower (P = .05) than controls, with an inverse correlation (r = –0.454; P = .003) between anti-tPA antibody levels and tPA activity and no correlation with tPA antigen. The 2 patients with the highest antibody levels had tPA activity below the normal range. Their antibodies were, respectively, IgG1 and IgG3; both recognized human tPA, recombinant tPA, and the catalytic domain of tPA, but not β2-glycoprotein I, prothrombin, or plasminogen. Our data indicate that anti-tPA antibodies specifically interacting with the catalytic domain of tPA can be found in patients with APS, representing a possible cause of hypofibrinolysis.
VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia
Authors: Egle Alexander , Harris Alan W. , Bath Mary L. , O'Reilly Lorraine , Cory Suzanne
Published: November 2003

In human follicular lymphoma the t(14; 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (Eμ) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike Eμ-Bcl2 mice, many VavP-Bcl2 mice older than 10 months developed follicular lymphoma. Young VavP-Bcl2 mice had an overabundance of enlarged germinal centers and greatly elevated numbers of cycling B cells that had undergone IgH class switching and V-gene hypermutation. The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in Eμ-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal. The germinal center hyperplasia required CD4 T cells, because it could be abolished by anti-CD4 antibody in vivo. VavP-Bcl2 mice also had a propensity to develop kidney disease of the autoimmune type. We suggest that the increased survival capacity of B and T cells fosters prolonged germinal center reactions, and that autoreactivity and hypermutation conspire to generate follicular lymphoma.
BAFF/BLyS can potentiate B-cell selection with the B-cell coreceptor complex
Authors: Hase Hidenori , Kanno Yumiko , Kojima Masaru , Hasegawa Kaoru , Sakurai Daisuke , Kojima Hidefumi , Tsuchiya Naoyuki , Tokunaga Katsushi , Masawa Nobuhide , Azuma Miyuki , Okumura Ko , Kobata Tetsuji
Published: November 2003

The tumor necrosis factor (TNF)–like ligand BAFF/BLyS (B-cell activating factor of the TNF family/B-lymphocyte stimulator) is a potent B-cell survival factor, yet its functional relationship with other B-cell surface molecules such as CD19 and CD40 is poorly understood. We found that follicular dendritic cells (FDCs) in human lymph nodes expressed BAFF abundantly. BAFF up-regulated a B cell–specific transcription factor Pax5/BSAP (Pax5/B cell–specific activator protein) activity and its target CD19, a major component of the B-cell coreceptor complex, and synergistically enhanced CD19 phosphorylation by B-cell antigen receptor (BCR). BAFF further enhanced B-cell proliferation, immunoglobulin G (IgG) production, and reactivity to CD154 by BCR/CD19 coligation and interleukin-15 (IL-15). Our results suggest that BAFF may play an important role in FDC–B-cell interactions through the B-cell coreceptor complex and a possibly sequential link between the T cell–independent and –dependent B-cell responses in the germinal centers.
Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions
Authors: Coppinger Judith A. , Cagney Gerard , Toomey Sinead , Kislinger Thomas , Belton Orina , McRedmond James P. , Cahill Dolores J. , Emili Andrew , Fitzgerald Desmond J. , Maguire Patricia B.
Published: November 2003

Proteins secreted by activated platelets can adhere to the vessel wall and promote the development of atherosclerosis and thrombosis. Despite this biologic significance, however, the complement of proteins comprising the platelet releasate is largely unknown. Using a proteomics approach, we have identified more than 300 proteins released by human platelets following thrombin activation. Many of the proteins identified were not previously attributed to platelets, including secretogranin III, a potential monocyte chemoattractant precursor; cyclophilin A, a vascular smooth muscle cell growth factor; calumenin, an inhibitor of the vitamin K epoxide reductase-warfarin interaction, as well as proteins of unknown function that map to expressed sequence tags. Secretogranin III, cyclophilin A, and calumenin were confirmed to localize in platelets and to be released upon activation. Furthermore, while absent in normal vasculature, they were identified in human atherosclerotic lesions. Therefore, these and other proteins released from platelets may contribute to atherosclerosis and to the thrombosis that complicates the disease. Moreover, as soluble extracellular proteins, they may prove suitable as novel therapeutic targets.
RhoA activation promotes transendothelial migration of monocytes via ROCK
Authors: Honing Henk , van den Berg Timo K , van der Pol Susanne M A , Dijkstra Christine D , van der Kammen Rob A , Collard John G , de Vries Helga E
Published: November 2003

Monocyte infiltration into inflamed tissue requires the initial arrest of the cells on the endothelium followed by firm adhesion and their subsequent migration. Migration of monocytes and other leukocytes is believed to involve a coordinated remodeling of the actin cytoskeleton. The small GTPases RhoA, Rac1, and Cdc42 are critical regulators of actin reorganization. In this study, we have investigated the role of Rho-like GTPases RhoA, Rac1, and Cdc42 in the adhesion and migration of monocytes across brain endothelial cells by expressing their constitutively active or dominant-negative constructs in NR8383 rat monocytic cells. Monocytes expressing the active form of Cdc42 show a reduced migration, whereas Rac1 expression did not affect adhesion or migration. In contrast, expression of the active form of RhoA in monocytes leads to a dramatic increase in their adhesion and migration across endothelial cells. The effect of RhoA was found to be mediated by its down-stream effector Rho kinase (ROCK), as pretreatment with the selective ROCK inhibitor Y-27632 prevented this enhanced adhesion and migration. These results demonstrate that RhoA activation in monocytes is sufficient to enhance adhesion and migration across monolayers of endothelial cells.
Desialylation of glycoconjugates on the surface of monocytes activates the extracellular signal-related kinases ERK 1/2 and results in enhanced production of specific cytokines
Authors: Stamatos Nicholas M , Curreli Sabrina , Zella Davide , Cross Alan S
Published: November 2003

Modulation of the sialic acid content of cell-surface glycoproteins and glycolipids influences the functional capacity of cells of the immune system. The role of sialidase(s) and the consequent desialylation of cell surface glycoconjugates in the activation of monocytes have not been established. In this study, we show that desialylation of glycoconjugates on the surface of purified monocytes using exogenous neuraminidase (NANase) activated extraellular signal-regulated kinase 1/2 (ERK 1/2), an intermediate in intracellular signaling pathways. Elevated levels of phosphorylated ERK 1/2 were detected in desialylated monocytes after 2 h of NANase treatment, and increased amounts persisted for at least 2 additional hours. Desialylation of cell surface glycoconjugates also led to increased production of interleukin (IL)-6, macrophage inflammatory protein (MIP)-1α, and MIP-1β by NANase-treated monocytes that were maintained in culture. Neither increased levels of phosphorylated ERK 1/2 nor enhanced production of cytokines were detected when NANase was heat-inactivated before use, demonstrating the specificity of NANase action. Treatment of monocytes with gram-negative bacterial lipopolysaccharide (LPS) also led to enhanced production of IL-6, MIP-1α, and MIP-1β. The amount of each of these cytokines that was produced was markedly increased when monocytes were desialylated with NANase before exposure to LPS. These results suggest that changes in the sialic acid content of surface glycoconjugates influence the activation of monocytes.
Acute ethanol exposure inhibits macrophage IL-6 production: role of p38 and ERK1/2 MAPK
Authors: Goral Joanna , Choudhry Mashkoor A , Kovacs Elizabeth J
Published: November 2003

Acute ethanol consumption has been linked to an increase in infectious complications in trauma and burn patients. Ethanol modifies production of a variety of macrophage-derived immunoregulatory mediators. Lipopolysaccharide (LPS), a potent stimulator of inflammatory responses in macrophages, activates several intracellular signaling pathways, including mitogen-activated protein kinases (MAPK). In the current study, we investigated the effect of acute ethanol exposure on in vivo activation of p38 and extracellularly regulated kinases 1 and 2 (ERK1/2) MAPK in murine macrophages and the corresponding, LPS-stimulated interleukin (IL)-6 production. We demonstrated that a single dose of ethanol transiently down-regulated p38 and ERK1/2 activation levels (3–24 h after treatment) and impaired IL-6 synthesis. Ethanol-related reduction in IL-6 production was not further affected by the presence of inhibitors of p38 and ERK1/2 (SB 202190 and PD 98059, respectively). These results demonstrate that acute ethanol exposure can impair macrophage IL-6 production and indicate that this effect may result from ethanol-induced alterations in intracellular signaling through p38 and ERK1/2.
Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms
Authors: Toennies Holly M , Green Jonathan M , Arch Robert H
Published: November 2003

Members of the TNF receptor (TNFR) superfamily are cell-surface proteins that can be found on most cell types including lymphocytes. Although some TNFR-related molecules are constitutively expressed, others, such as CD30 and Ox40, are induced upon activation of lymphocytes. CD30 and Ox40 are predominantly expressed on activated T helper (Th)2 cells. Both receptors can activate c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) and have been suggested to play costimulatory roles in lymphocyte activation. To gain further insight into events triggered by both TNFR-related molecules, a detailed analysis of their expression patterns has been prformed. We found that CD30 and Ox40 were coexpressed on Th2 cells. However, in contrast to CD30, Ox40 was also expressed on Th1 cells. Although expression of both receptors is augmented by interleukin-4, only CD30 expression is dependent on signal transducer and activator of transcription (STAT)-6-mediated signaling. Differences in the regulatory pathways controlling expression of CD30 and Ox40 suggest distinct, functional effects triggered by the two TNFR-related molecules during lymphocyte activation.
Gene expression in mature neutrophils: early responses to inflammatory stimuli
Authors: Zhang Xueqing , Kluger Yuval , Nakayama Yasuhiro , Poddar Ranjana , Whitney Constance , DeTora Adam , Weissman Sherman M , Newburger Peter E
Published: November 2003

Neutrophils provide an essential defense against bacterial and fungal infection and play a major role in tissue damage during inflammation. Using oligonucleotide microarrays, we have examined the time course of changes in gene expression induced by stimulation with live, opsonized Escherichia coli, soluble lipopolysaccharide, and the chemoattractant formyl-methionyl-leucyl-phenylalanine. The results indicate that activated neutrophils generate a broad and vigorous set of alterations in gene expression. The responses included changes in the levels of transcripts encoding 148 transcription factors and chromatin-remodeling genes and 95 regulators of protein synthesis or stability. Clustering analysis showed distinct temporal patterns with many rapid changes in gene expression within the first hour of exposure. In addition to the temporal clustering of genes, we also observed rather different profiles associated with each stimulus, suggesting that even a nonvirulent organism such as E. coli is able to play a dynamic role in shaping the inflammatory response. Principal component analysis of transcription factor genes demonstrated clear separation of the neutrophil-response clusters from those of resting and stimulated human monocytes. The present study indicates that combinatorial transcriptional regulation including alterations of chromatin structure may play a role in the rapid changes in gene expression that occur in these terminally differentiated cells.
Series introduction: molecular and cellular basis of septic shock
Authors: Bucala Rick
Published: November 2003

This series of overviews was contributed by participants of a Keystone Symposium, which was convened in early 2003 to address the topic of septic shock in an interdisciplinary manner. This occasion reflects a resurgence of interest in septic shock as a disease that may soon be approachable by new therapeutic interventions.
Transcriptional Regulation of Human Sodium/Iodide Symporter Gene: A Role for Redox Factor-1
Authors: Puppin Cinzia , Arturi Franco , Ferretti Elisabetta , Russo Diego , Sacco Rosario , Tell Gianluca , Damante Giuseppe , Filetti Sebastiano
Published: November 2003

The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue in attempting to restore iodide uptake and use radioiodine as a therapeutic treatment of thyroid cancer. Previous investigations have shown that the multifunctional protein apurinic apyrimidinic endonuclease/redox factor 1 (APE/Ref-1) plays an important role in regulation of thyroid-specific gene transcription. In this study, we investigated the effects of APE/Ref-1 on human NIS promoter activity. Cotransfection experiments performed in nonthyroid HeLa cells demonstrated that APE/Ref-1 exerts both PAX8-dependent and PAX8-independent effects. In fact, in the absence of PAX8, overexpression of APE/Ref-1 enhanced NIS promoter activity 2-fold. When the expression plasmid of APE/Ref-1 was transfected together with an expression plasmid for PAX8, a strong cooperative effect was detected with an increase of NIS promoter activity 9-fold over control. The PAX8-independent effect of APE/Ref-1 was specific for the NIS promoter, resulting not present for the promoter of the thyroperoxidase (TPO) gene. It was, at least in part, due to the up-regulation of the transcriptional activity of the ubiquitous factor early growth response-1 (Egr-1). In the thyroid tumor cell lines TPC-1 and B-CPAP, APE/Ref-1 was not effective by itself, and it also failed to increase PAX8 stimulation on NIS promoter activity. These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. However, restoring the PAX8-APE/Ref-1 expression in tumor cells may not be sufficient to obtain adequate levels of NIS gene expression.
Morpholino-based gene knockdown screen of novel genes with developmental function inCiona intestinalis
Authors: Yamada Lixy , Shoguchi Eiichi , Wada Shuichi , Kobayashi Kenji , Mochizuki Yasuaki , Satou Yutaka , Satoh Nori
Published: November 2003

In the present study, we conducted an extensive analysis to identify novel genes with developmental function among Ciona intestinalis genes discovered by cDNA projects. Translation of a total of 200 genes expressed during embryogenesis was suppressed by using specific morpholino antisense oligonucleotides. Suppression of the translation of any of 40 genes (one-fifth of the genes tested) was thereby shown to cause specific embryonic defects. Most of these genes have counterpart(s) in mouse and human, suggesting that the present approach will be useful for identifying candidate genes essential for the development of vertebrates. Suppression of translation of 14 of these 40 genes resulted in the `disorganized body plan' phenotype characterized by gross morphological abnormalities caused by early defects in embryogenesis. These genes encode zinc-finger, transmembrane or Pbx homeodomain proteins. The morphological features of larvae of this phenotypic class varied according to the gene suppressed, suggesting that a distinct developmental event such as tissue specification or cell cycle progression was affected in each type of larva. Suppression of the remaining 26 genes resulted in the `abnormal tail'phenotype. Some of these genes encode proteins with known functional structures such as Zn-finger and HLH motifs. Twelve genes among them are especially interesting, because their suppression produced defects in the nervous system, as demonstrated by the loss of the sensory pigment cells or palps of the adhesive organ in the knockdown larvae. These results suggest that screening for developmental genes by the reverse genetic approach in Ciona intestinalis embryos is effective for identifying novel genes with developmental functions required for the development of chordates.
Phox2bcontrols the development of peripheral chemoreceptors and afferent visceral pathways
Authors: Dauger Stéphane , Pattyn Alexandre , Lofaso Frédéric , Gaultier Claude , Goridis Christo , Gallego Jorge , Brunet Jean-François
Published: November 2003

We report that the afferent relays of visceral (cardiovascular, digestive and respiratory) reflexes, differentiate under the control of the paired-like homeobox gene Phox2b: the neural crest-derived carotid body, a chemosensor organ, degenerates in homozygous mutants, as do the three epibranchial placode-derived visceral sensory ganglia (geniculate, petrosal and nodose), while their central target, the nucleus of the solitary tract,which integrates all visceral information, never forms. These data establish Phox2b as an unusual `circuit-specific' transcription factor devoted to the formation of autonomic reflex pathways. We also show that Phox2b heterozygous mutants have an altered response to hypoxia and hypercapnia at birth and a decreased tyrosine hydroxylase expression in the petrosal chemosensory neurons, thus providing mechanistic insight into congenital central hypoventilation syndrome, which is associated with heterozygous mutations in PHOX2B.