bluuebunny/crossref_metadata_2025 huggingface dataset:
Silent Myocardial Ischemia in Patients With Symptomatic Intracranial Atherosclerosis
Authors: Arenillas Juan F. , Candell-Riera Jaume , Romero-Farina Guillermo , Molina Carlos A. , Chacón Pilar , Aguadé-Bruix Santiago , Montaner Joan , de León Gustavo , Castell-Conesa Joan , Álvarez-Sabín José
Published: May 2005

Background and Purpose—

Optimization of coronary risk evaluation in stroke patients has been encouraged. The relationship between symptomatic intracranial atherosclerosis and occult coronary artery disease (CAD) has not been evaluated sufficiently. We aimed to investigate the prevalence of silent myocardial ischemia in patients with symptomatic intracranial atherosclerosis and to identify factors associated with its presence.

Methods—

From 186 first-ever transient ischemic attack or ischemic stroke patients with intracranial stenoses, 65 fulfilled selection criteria, including angiographic confirmation of a symptomatic atherosclerotic stenosis and absence of known CAD. All patients underwent a maximal-stress myocardial perfusion single-photon emission computed tomography (SPECT). Lipoprotein(a) [Lp(a)], C-reactive protein, and homocysteine (Hcy) levels were determined before SPECT.

Results—

Stress-rest SPECT detected reversible myocardial perfusion defects in 34 (52%) patients. Vascular risk factors associated with a pathologic SPECT were hypercholesterolemia (
P
=0.045), presence of >2 risk factors (
P
=0.004) and high Lp(a) (
P
=0.023) and Hcy levels (
P
=0.018). Ninety percent of patients with high Lp(a) and Hcy levels had a positive SPECT. Existence of a stenosed intracranial internal carotid artery (ICA; odds ratio [OR], 7.22, 2.07 to 25.23;
P
=0.002) and location of the symptomatic stenosis in vertebrobasilar arteries (OR, 4.89, 1.19 to 20.12;
P
=0.027) were independently associated with silent myocardial ischemia after adjustment by age, sex, and risk factors.

Conclusions—

More than 50% of the patients with symptomatic intracranial atherosclerosis and not overt CAD show myocardial perfusion defects on stress-rest SPECT. Stenosed intracranial ICA, symptomatic vertebrobasilar stenosis and presence of high Lp(a) and Hcy levels may characterize the patients at a higher risk for occult CAD.
Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention
Authors: Schrader Joachim , Lüders Stephan , Kulschewski Anke , Hammersen Frank , Plate Kerstin , Berger Jürgen , Zidek Walter , Dominiak Peter , Diener Hans Christoph ,   the MOSES Study Group
Published: May 2005

Background and Purpose—

In hypertensive stroke patients, for the same level of blood pressure control, eprosartan will be more effective than nitrendipine in reducing cerebrovascular and cardiovascular morbidity and mortality.

Methods—

A total of 1405 well-defined, high-risk hypertensives with cerebral event during the last 24 months (proven by cerebral computed tomography scan or nuclear magnetic resonance) were randomized to eprosartan or nitrendipine (mean follow-up 2.5 years). Primary end point was the composite of total mortality and all cardiovascular and cerebrovascular events, including all recurrent events.

Results—

Randomization was successful without significant differences in the baseline characteristics. Blood pressure was reduced to a comparable extent without any significant differences between the 2 groups during the whole study period (150.7/84 mm Hg and 152.0/87.2 mm Hg with eprosartan and nitrendipine therapy to 137.5/80.8 mm Hg and 136.0/80.2 mm Hg, respectively, confirmed by ambulatory blood pressure monitoring). Moreover, already after 3 months, normotensive mean values were achieved, and 75.5% reached values <140/90 mm Hg with the eprosartan regimen and 77.7% with the nitrendipine regimen. During follow-up, in total, 461 primary events occurred: 206 eprosartan and 255 nitrendipine (incidence density ratio [IDR], 0.79; 95% CI, 0.66 to 0.96;
P
=0.014). Cardiovascular events were: 77 eprosartan and 101 nitrendipine (IDR, 0.75; 95% CI, 0.55 to 1.02;
P
=0.06); cerebrovascular events: 102 eprosartan and134 nitrendipine (IDR, 0.75; 95% CI, 0.58 to 0.97;
P
=0.03).

Conclusions—

The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study was the first to compare an angiotensin II type 1 receptor antagonist with a calcium antagonist in secondary stroke prevention. In these high-risk hypertensive stroke patients, an early normotensive and comparable blood pressure was achieved. The combined primary end point was significantly lower in the eprosartan group.
Vampire Bat Salivary Plasminogen Activator (Desmoteplase) Inhibits Tissue-Type Plasminogen Activator-Induced Potentiation of Excitotoxic Injury
Authors: Reddrop Courtney , Moldrich Randal X. , Beart Philip M. , Farso Mark , Liberatore Gabriel T. , Howells David W. , Petersen Karl-Uwe , Schleuning Wolf-Dieter , Medcalf Robert L.
Published: May 2005

Background and Purpose—

In contrast to tissue-type plasminogen activator (tPA), vampire bat (
Desmodus rotundus
) salivary plasminogen activator (desmoteplase [DSPA]) does not promote excitotoxic injury when injected directly into the brain. We have compared the excitotoxic effects of intravenously delivered tPA and DSPA and determined whether DSPA can antagonize the neurotoxic and calcium enhancing effects of tPA.

Methods—

The brain striatal region of wild-type c57 Black 6 mice was stereotaxically injected with N-methyl-
d
-Aspartate (NMDA); 24 hour later, mice received an intravenous injection of tPA or DSPA (10 mg/kg) and lesion size was assessed after 24 hours. Cell death and calcium mobilization studies were performed using cultures of primary murine cortical neurons.

Results—

NMDA-mediated injury was increased after intravenous administration of tPA, whereas no additional toxicity was seen after administration of DSPA. Unlike DSPA, tPA enhanced NMDA-induced cell death and the NMDA-mediated increase in intracellular calcium levels in vitro. Moreover, the enhancing effects of tPA were blocked by DSPA.

Conclusions—

Intravenous administration of tPA promotes excitotoxic injury, raising the possibility that leakage of tPA from the vasculature into the parenchyma contributes to brain damage. The lack of such toxicity by DSPA further encourages its use as a thrombolytic agent in the treatment of ischemic stroke.
Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke
Authors: Marini Carmine , De Santis Federica , Sacco Simona , Russo Tommasina , Olivieri Luigi , Totaro Rocco , Carolei Antonio
Published: May 2005

Background and Purpose—

Atrial fibrillation (AF) is a major risk factor for ischemic stroke and its prevalence increases steeply with age. Population-based data on its influence on stroke outcome are scarce.

Methods—

We evaluated the prevalence of AF and its influence on prognosis in patients with a first-ever ischemic stroke from a population-based registry.

Results—

The presence of AF at stroke onset and during the acute phase was confirmed by a standard electrocardiogram in 869 (24.6%) of 3530 patients with ischemic stroke. With respect to patients without the arrhythmia, those with AF were more frequently women, aged 80 years and older, with coronary heart disease and peripheral arterial disease. The presence of AF was associated with high 30-day (32.5%; 95% CI, 29.3 to 35.6) and 1-year case-fatality rates (49.5%; 95% CI, 46.2 to 52.8), with a higher stroke recurrence rate within the first year of follow-up (6.6% versus 4.4%;
P
=0.046) and with the worst survival after an average follow-up of 45.2 months (
P
<0.0001). At the multivariate Cox regression analysis, AF was an independent predictor of 30-day and 1-year mortality. Approximately 17% of all deaths were attributable to the presence of AF.

Conclusions—

We found a high prevalence of AF in patients with a first-ever ischemic stroke, especially among elderly women. The overall contribution of AF to stroke mortality was relevant, suggesting that together with new strategies to prevent the development of the arrhythmia more appropriate treatments are needed, mostly in elderly women.
Increased Plasma Levels of 15-Deoxy Δ Prostaglandin J
2
Are Associated With Good Outcome in Acute Atherothrombotic Ischemic Stroke
Authors: Blanco Miguel , Moro María Ángeles , Dávalos Antonio , Leira Rogelio , Castellanos Mar , Serena Joaquín , Vivancos José , Rodríguez-Yáñez Manuel , Lizasoain Ignacio , Castillo José
Published: May 2005

Background and Purpose—

The 15-deoxy Δ prostaglandin J
2
(15-dPGJ
2
) is an anti-inflammatory prostaglandin that has been proposed to be the endogenous ligand of peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor that can exert potent anti-inflammatory actions by repressing inflammatory genes when activated. It has been suggested that 15-dPGJ
2
could be beneficial in neurological disorders in which inflammation contributes to cell death such as stroke.

Methods—

We investigated the relationship between plasma levels of 15-dPGJ
2
and early neurological deterioration (END), infarct volume, and neurologic outcome in 552 patients with an acute stroke admitted within 24 hours after symptoms onset.

Results—

Median [quartiles] plasma 15-dPGJ
2
levels on admission were significantly higher in patients than in controls (60.5 [11.2 to 109.4] versus 5.0 [3.8 to 7.2] pg/mL;
P
<0.0001). Levels of this prostaglandin were also significantly higher in patients with vascular risk factors (history of hypertension or diabetes) and with atherothrombotic infarcts (113.9 [81.6 to 139.7] pg/mL), than in those with lacunar (58.7 [32.7 to 86.2] pg/mL), cardioembolic (12.1 [6.5 to 39.2] pg/mL), or undetermined origin infarcts (11.4 [5.6 to 24.3] pg/mL) (
P
<0.0001). In the subgroup of patients with atherothrombotic infarcts, the adjusted odds ratio of END and poor outcome for 1 pg/mL increase in 15-dPGJ
2
were 0.95 (95% CI, 0.94 to 0.97) and 0.97 (95% CI, 0.96 to 0.98), respectively. In a generalized linear model, by 1 U increase in 15-dPGJ
2
, there was a reduction of 0.47 mL (95% CI, 0.32 to 0.63) in the mean estimated infarct volume.

Conclusions—

Increased plasma 15-dPGJ
2
concentration is associated with good early and late neurological outcome and smaller infarct volume. These findings suggest a neuroprotective effect of 15-dPGJ
2
in atherothrombotic ischemic stroke.
Embolic Signals And Prediction of Ipsilateral Stroke or Transient Ischemic Attack in Asymptomatic Carotid Stenosis
Authors: Abbott Anne L. , Chambers Brian R. , Stork Jacinda L. , Levi Christopher R. , Bladin Christopher F. , Donnan Geoffrey A.
Published: May 2005

Background and Purpose—

We tested the hypothesis that transcranial Doppler embolic signal (ES) detection identifies an increased risk of ipsilateral carotid stroke or transient ischemic attack (TIA) in subjects with asymptomatic severe carotid stenosis.

Methods—

Subjects with duplex-determined 60% to 99% carotid stenosis, without other apparent cerebroembolic sources, underwent 6-monthly neurological assessment and 60-minute ES monitoring. ES positivity was defined as ≥1 ES detected in ≥1 study, ES negativity as no ES in any study, and consistent ES negativity as no ES in any study where ≥6 studies were performed. Rates of ipsilateral carotid stroke/TIA were calculated using Kaplan–Meier analysis and correlated with ES status using odds ratios (ORs) and Cox proportional hazards regression analysis.

Results—

A total of 202 subjects (138 male; mean age 74 years; mean follow-up 34 months) were recruited. The average annual rate of ipsilateral carotid stroke/TIA was 3.1%. A total of 231 arteries were monitored at least once (mean 4.3 studies/artery). Six of 60 (10.0%) ES-positive arteries had an ipsilateral carotid stroke/TIA compared with 12 of 171 (7.0%) ES-negative arteries (OR, 1.47; 95% CI, 0.43, 4.48;
P
=0.624) and 2 of 41 (4.9%) consistently ES-negative arteries (OR, 2.17; 95% CI, 0.36, 22.90;
P
=0.59). Differences in survival free of ipsilateral carotid stroke/TIA according to ES status were not statistically significant.

Conclusions—

Although there were more ipsilateral carotid cerebrovascular events among ES-positive arteries, this was not statistically significant. Less labor-intensive techniques are required to make further study and clinical application practical.
Regional Impairment of Cerebrovascular Reactivity and BOLD Signal in Adults After Stroke
Authors: Krainik Alexandre , Hund-Georgiadis Margret , Zysset Stefan , von Cramon D. Yves
Published: May 2005

Background and Purpose—

Comparative studies across populations using functional magnetic resonance imaging (fMRI) rely on a similar relationship between blood oxygen level-dependent (BOLD) signal and neural activity. However, in elderly and patients with cerebrovascular disease, impaired cerebrovascular dynamics and neurovascular coupling may explain differences in BOLD contrast across populations and brain regions. The purpose of the study was to determine whether poststroke patients have regional heterogeneities of cerebrovascular reactivity (CVR) and their potential influence on voxel-wise motor-related BOLD signal.

Methods—

Using fMRI, 8 fully recovered patients from stroke in the frontal lobe without cortical lesion in the regions of interest located in the primary sensorimotor cortex (SMC), supplementary motor area (SMA), and cerebellum (CRB) were compared with 8 healthy subjects. Motor-related BOLD signal changes (%SC) were evaluated during simple unimanual and bimanual tasks, and CVR was evaluated during hyperventilation (HV). Analyses were performed using Lipsia software in SMC, SMA, and CRB.

Results—

In controls, amplitudes of BOLD signal were symmetrical in all regions of interest during all motor tasks and HV. In patients, %SC was decreased in SMC and SMA of the lesioned hemisphere despite their apparent anatomical integrity for all tasks. Impaired CVR was a predictor of impaired motor-related BOLD response in the SMC during contralateral movements (β=−1.87;
R
=−0.75;
P
=0.03).

Conclusions—

These preliminary findings suggest that CVR heterogeneities may account for task-related BOLD signal changes in patients after stroke.
Enriched Environment Increases Neural Stem/Progenitor Cell Proliferation and Neurogenesis in the Subventricular Zone of Stroke-Lesioned Adult Rats
Authors: Komitova Mila , Mattsson Bengt , Johansson Barbro B. , Eriksson Peter S.
Published: May 2005

Background and Purpose—

The subventricular zone in the adult brain is identified as an endogenous resource of neuronal precursors that can be recruited to adjacent lesioned areas. The hypothesis was tested that postischemic environmental enrichment might enhance subventricular zone cell genesis.

Methods—

A cortical infarct was induced in adult spontaneously hypertensive rats by ligating the middle cerebral artery distal to the striatal branches, after which animals were housed in either standard or enriched environment and allowed to survive for 5 weeks. The thymidine analogue bromodeoxyuridine was administered during the first postischemic week. The generation of neural stem/progenitor cells and neuronal precursors in the subventricular zone were studied with cell specific markers such as Ki67 and phosphorylated histone H3 (cell proliferation), Sox-2 (neural stem/progenitor cells), bromodeoxyuridine (slowly cycling, nonmigratory putative neural stem cells), and doublecortin (newborn immature neurons).

Results—

Proliferating cells in the subventricular zone were identified as chiefly neural progenitors but also putative neural stem cells and neuronal precursors. Five weeks after stroke, proliferation in the subventricular zone was lower in stroke-lesioned rats housed in standard environment compared with nonlesioned rats. Postischemic environmental enrichment normalized cell proliferation levels, increased the numbers of putative neural stem cells as assessed with bromodeoxyuridine, and increased doublecortin-positive neuroblasts, which extended in migratory chains toward the infarct.

Conclusions—

Enriched environment increased the neural stem/progenitor cell pool and neurogenesis in the adult subventricular zone 5 weeks after a cortical stroke. This might be of potential importance for tissue regeneration.
Steps After Stroke
Authors: Shaughnessy Marianne , Michael Kathleen M. , Sorkin John D. , Macko Richard F.
Published: May 2005

Background and Purpose—

Nearly two thirds of stroke survivors have deficits impairing ambulatory recovery. Conventional mobility outcome measures such as timed walks and functional independence measure (FIM) do not quantify free-living ambulatory behavior. This study compared step activity monitoring (SAM) with established instruments to assess ambulatory recovery across the outpatient subacute stroke rehabilitation phase.

Methods—

We measured FIM mobility subscale, SAM-derived daily steps, Stroke Impact Scale (SIS) mobility scores, and timed walks in 11 subjects after discharge from inpatient rehabilitation and again 3 months later.

Results—

Significant improvement was measured in free-living step activity (mean gain 80%;
P
=0.001) but not with timed walks (
P
=0.4), FIM (
P
=0.08), or SIS mobility scales (
P
=0.3).

Conclusions—

Microprocessor-linked SAM is a sensitive indicator of ambulatory recovery that measures improvements not captured by other conventional outcome instruments.
Negative feedback regulation of T helper type 1 (Th1)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions
Authors: Minami Keita , Yanagawa Yoshiki , Iwabuchi Kazuya , Shinohara Nobuo , Harabayashi Toru , Nonomura Katsuya , Onoé Kazunori
Published: May 2005

The ability of extracellular stimuli to modulate dendritic cell (DC) activation of natural killer T (NKT) cells was not well understood. We investigated the effects of the T helper type 1 (Th1)/Th2-cytokine environment on DC induction of NKT cell-mediated cytokine production in mice. Pretreatment of myeloid DCs with Th1 or Th2 cytokines, interleukin (IL)-4 or interferon (IFN)-γ, led to the enhanced production of reciprocal cytokines by NKT cells (eg, IL-4 pretreatment led to the enhanced production of Th1 cytokines) in vitro and in vivo. Thus, the recognition of Th1 or Th2 cytokines by DCs acts as a negative feedback loop to maintain Th1/Th2-cytokine balance via NKT cell functions. Using these data, we manipulated cytokine levels and innate cytolytic activity in vivo to increase an antitumor response. This is the first description of a novel regulation system governing Th1/Th2 cytokine balance involving DCs and NKT cells. (Blood. 2005;106:1685-1693)
Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody
Authors: Tacken Paul J. , de Vries I. Jolanda M. , Gijzen Karlijn , Joosten Ben , Wu Dayang , Rother Russell P. , Faas Susan J. , Punt Cornelis J. A. , Torensma Ruurd , Adema Gosse J. , Figdor Carl G.
Published: May 2005

Current dendritic cell (DC)–based vaccines are based on ex vivo–generated autologous DCs loaded with antigen prior to readministration into patients. A more direct and less laborious strategy is to target antigens to DCs in vivo via specific surface receptors. Therefore, we developed a humanized antibody, hD1V1G2/G4 (hD1), directed against the C-type lectin DC-specific intercellular adhesion molecule 3–grabbing nonintegrin (DC-SIGN) to explore its capacity to serve as a target receptor for vaccination purposes. hD1 was cross-linked to a model antigen, keyhole limpet hemocyanin (KLH). We observed that the chimeric antibody-protein complex (hD1-KLH) bound specifically to DC-SIGN and was rapidly internalized and translocated to the lysosomal compartment. To determine the targeting efficiency of hD1-KLH, monocyte-derived DCs and peripheral blood lymphocytes (PBLs) were obtained from patients who had previously been vaccinated with KLH-pulsed DCs. Autologous DCs pulsed with hD1-KLH induced proliferation of patient PBLs at a 100-fold lower concentration than KLH-pulsed DCs. In addition, hD1-KLH–targeted DCs induced proliferation of naive T cells recognizing KLH epitopes in the context of major histocompatibility complex (MHC) classes I and II. We conclude that antibody-mediated targeting of antigen to DCs via DC-SIGN effectively induces antigen-specific naive as well as recall T-cell responses. This identifies DC-SIGN as a promising target molecule for DC-based vaccination strategies.
IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma
Authors: Ehrlich Lori A. , Chung Ho Yeon , Ghobrial Irene , Choi Sun Jin , Morandi Francesca , Colla Simona , Rizzoli Vittorio , Roodman G. David , Giuliani Nicola
Published: May 2005

Bone destruction in multiple myeloma is characterized both by markedly increased osteoclastic bone destruction and severely impaired osteoblast activity. We reported that interleukin-3 (IL-3) levels are increased in bone marrow plasma of myeloma patients compared with healthy controls and that IL-3 stimulates osteoclast formation. However, the effects of IL-3 on osteoblasts are unknown. Therefore, to determine if IL-3 inhibits osteoblast growth and differentiation, we treated primary mouse and human marrow stromal cells with IL-3 and assessed osteoblast differentiation. IL-3 inhibited basal and bone morphogenic protein-2 (BMP-2)-stimulated osteoblast formation in a dose-dependent manner without affecting cell growth. Importantly, marrow plasma from patients with high IL-3 levels inhibited osteoblast differentiation, which could be blocked by anti-IL-3. However, IL-3 did not inhibit osteoblast differentiation of osteoblastlike cell lines. In contrast, IL-3 increased the number of CD45+ hematopoietic cells in stromal-cell cultures. Depletion of the CD45+ cells abolished the inhibitory effects of IL-3 on osteoblasts, and reconstitution of the cultures with CD45+ cells restored the capacity of IL-3 to inhibit osteoblast differentiation. These data suggest that IL-3 plays a dual role in the bone destructive process in myeloma by both stimulating osteoclasts and indirectly inhibiting osteoblast formation. (Blood. 2005;106:1407-1414)
Paramagnetic artifact and safety criteria for human brain mapping
Authors: Seiyama Akitoshi , Seki Junji , Iwamoto Mari , Yanagida Toshio
Published: May 2005

Biological effects of magnetic field and their safety criteria, especially effects of gradient magnetic field on the cerebral and pulmonary circulation during functional brain mapping are still unclear. Here we estimated that magnetically induced artifacts for the blood oxygenation level- and flow- based functional magnetic resonance imaging are less than 0.1%, and disturbance in the pulmonary circulation is less than 1.3% even if the field strength of magnetic resonance system is risen up to 10 tesla. These paramagnetic effects are considered to be small and harmless during human brain mapping.
TP53-binding protein variants and breast cancer risk: a case-control study
Authors: Frank Bernd , Hemminki Kari , Bermejo Justo Lorenzo , Klaes Rüdiger , Bugert Peter , Wappenschmidt Barbara , Schmutzler Rita K , Burwinkel Barbara
Published: May 2005

Introduction

The TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk.

Methods

Allelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals.

Results

No significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34).

Conclusion

The lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing.
Strain-Dependent Influences on the Hypothalamo-Pituitary-Adrenal Axis Profoundly Affect the 7B2 and PC2 Null Phenotypes
Authors: Peinado Juan R. , Laurent Virginie , Lee Sang-Nam , Peng Bonnie W. , Pintar John E. , Steiner Donald F. , Lindberg Iris
Published: May 2005

Two null mouse models have previously been created to study the role of the prohormone convertase (PC2) and its helper protein 7B2; unexpectedly, the phenotypes of these two nulls differ profoundly, with the 7B2 but not the PC2 null dying at 5 wk. The genetic backgrounds of these two models differ, with the 7B2 null in a 129/SvEv (129) background and the PC2 null in a mixed C57BL/N6:129/SvEv (B6:129) background. Because background can contribute greatly to phenotype, we have here examined strain influence on the hypothalamo-pituitary-adrenal (HPA) axis and glucose levels in wild-type, 7B2 null, and PC2 null mice. Wild-type B6 and 129 mice differed in basal corticosterone and glucose levels. When 7B2 nulls were transferred onto the B6 background, they survived and showed greatly decreased circulating corticosterone and increased blood glucose levels, most likely due to the comparatively higher adrenal resistance of the B6 strain to ACTH stimulation. Circulating ACTH levels were increased over wild-type in the B6 7B2 null but did not reach levels as high as the 129 7B2 null. Conversely, when the mixed-strain PC2 nulls were bred into the 129 background at the N6 generation, they began to exhibit the Cushing’s-like phenotype characteristic of 129 7B2 null mice and died before 6 wk of age. Taken together, these results indicate that background effects are critical because they increase the phenotypic differences between the 7B2 and PC2 nulls and play a life-or-death role in the ACTH hypersecretion syndrome present in both 129 nulls.
Integrin Activates Receptor-Like Protein Tyrosine Phosphatase α, Src, and Rho to Increase Prolactin Gene Expression through a Final Phosphatidylinositol 3-Kinase/Cytoskeletal Pathway that Is Additive with Insulin
Authors: Vulin Anthony I. , Jacob Kirsten K. , Stanley Frederick M.
Published: May 2005

We previously showed that receptor-like protein tyrosine phosphatase (RPTP)-α inhibited insulin-increased prolactin gene transcription. Others suggested that RPTPα was a key intermediary between integrins and activation of Src. We present evidence that inhibition of insulin-increased prolactin gene transcription was secondary to RPTPα activation of Src, reflecting its role as mediator of integrin responses. Src kinase activity was increased in GH4 cells transiently or stably expressing RPTPα and cells plated on the integrin-α5β1 ligand fibronectin. C-terminal Src kinase inactivated Src and blocked RPTPα inhibition of insulin-increased prolactin gene transcription. Expression of dominant-negative Src also prevented the RPTPα-mediated inhibition of insulin-increased prolactin gene expression. Low levels of a constitutively active Src mutant (SrcY/F) stimulated whereas higher expression levels of Src Y/F inhibited prolactin gene expression. Src-increased prolactin gene transcription was inhibited by expression of a blocking Rho-mutant (RhoN19), suggesting that Src acted through or required active Rho. Experiments with an activated Rho-mutant (RhoL63) demonstrated a biphasic activation/repression of prolactin gene transcription that was similar to the effect of Src. The effects of both Src and Rho were phosphatidylinositol 3-kinase dependent. Expression of SrcY/F or RhoL63 altered the actin cytoskeleton and morphology of GH4 cells. Taken together, these data suggest a physiological pathway from the cell matrix to increased prolactin gene transcription mediated by RPTPα/Src/Rho/phosphatidylinositol 3-kinase and cytoskeletal change that is additive with effects of insulin. Over activation of this pathway, however, caused extreme alteration of the cytoskeleton that blocked activation of the prolactin gene.
Peroxisome Proliferator-Activated Receptor α (PPARα) Potentiates, whereas PPARγ Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells
Authors: Ravnskjaer Kim , Boergesen Michael , Rubi Blanca , Larsen Jan K. , Nielsen Tina , Fridriksson Jakob , Maechler Pierre , Mandrup Susanne
Published: May 2005

Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic β-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of β-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARα and retinoid X receptor α (RXRα) in INS-1E β-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARα target genes and enhances FA uptake and β-oxidation. In contrast, ectopic expression of PPARγ/RXRα increases FA uptake and deposition as triacylglycerides. Although the expression of PPARα/RXRα leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARγ/RXRα attenuates GSIS, the expression of PPARα/RXRα potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes α and γ on lipid partitioning and insulin secretion when systematically compared in a β-cell context.
Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor α
Authors: Seely Jeremiah , Amigh Karla Saner , Suzuki Takashi , Mayhew Bobbie , Sasano Hironobu , Giguere Vincent , Laganière Josée , Carr Bruce R. , Rainey William E.
Published: May 2005

The estrogen-related receptors (ERRα, -β, and -γ) are a subfamily of orphan nuclear receptors (designated NR3B1, NR3B2, and NR3B3) that are structurally and functionally related to estrogen receptors α and β. Herein we test the hypothesis that ERRα regulates transcription of the genes encoding the enzymes involved in adrenal steroid production. Real-time RT-PCR was first used to determine the levels of ERRα mRNA in various human tissues. Adult adrenal levels of ERRα transcript were similar to that seen in heart, which is known to highly express ERRα. Expression of ERRα in the adult adrenal was then confirmed using Western blotting and immunohistochemistry. To examine the effects of ERRα on steroidogenic capacity we used reporter constructs with the 5′-flanking regions of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage (CYP11A), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 17α-hydroxylase/17,20-lyase (CYP17), and dehydroepiandrosterone sulfotransferase (SULT2A1). Cotransfection of these reporter constructs with wild-type ERRα or VP16-ERRα expression vectors demonstrated ERRα enhanced reporter activity driven by flanking DNA from CYP17 and SULT2A1. SULT2A1 promoter activity was most responsive to the ERRα and VP16-ERRα, increasing activity 2.6- and 79.5-fold, respectively. ERRα effects on SULT2A1 were greater than the stimulation seen in response to steroidogenic factor 1 (SF1). Transfection of serial deletions of the 5′-flanking DNA of the SULT2A1 gene and EMSA experiments indicated the presence of three functional regulatory cis-elements which shared sequence similarity to binding sites for SF1. Taken together, the expression of ERRα in the adrenal and its regulation of SULT2A1 suggest an important role for this orphan receptor in the regulation of adrenal steroid production.
Deficiency of the Very Low-Density Lipoprotein (VLDL) Receptors in Streptozotocin-Induced Diabetic Rats: Insulin Dependency of the VLDL Receptor
Authors: Iwasaki Tadao , Takahashi Sadao , Takahashi Masao , Zenimaru Yasuo , Kujiraoka Takeshi , Ishihara Mitsuaki , Nagano Makoto , Suzuki Jinya , Miyamori Isamu , Naiki Hironobu , Sakai Juro , Fujino Takahiro , Miller Norman E. , Yamamoto Tokuo T. , Hattori Hiroaki
Published: May 2005

Hyperlipidemia is a common feature of diabetes and is related to cardiovascular disease. The very low-density lipoprotein receptor (VLDL-R) is a member of the low-density lipoprotein receptor (LDL-R) family. It binds and internalizes triglyceride-rich lipoproteins with high specificity. We examined the etiology of hyperlipidemia in the insulin-deficient state. VLDL-R expression in heart and skeletal muscle were measured in rats with streptozotocin (STZ)-induced diabetes. STZ rats showed severe hyperlipidemia on d 21 and 28, with a dramatic decline in VLDL-R protein in skeletal muscle (>90%), heart (∼50%) and a loss of adipose tissues itself on d 28. The reduction of VLDL-R protein in skeletal muscle could not be explained simply by a decrease at the transcriptional level, because a dissociation between VLDL-R protein and mRNA expression was observed. The expression of LDL-R and LDL-R-related protein in liver showed no consistent changes. Furthermore, no effect on VLDL-triglyceride production in liver was observed in STZ rats. A decrease in postheparin plasma lipoprotein lipase activity started on d 7 and continued to d 28 at the 50% level even though severe hyperlipidemia was detected only on d 21 and 28. In rat myoblast cells, serum deprivation for 24 h induced a reduction in VLDL-R proteins. Insulin (10−6m), but not IGF-I (10 ng/ml), restored the decreased VLDL-R proteins by serum deprivation. These results suggest that the combination of VLDL-R deficiency and reduced plasma lipoprotein lipase activity may be responsible for severe hyperlipidemia in insulin-deficient diabetes.
Cloning and Characterization of a Functional Type II Gonadotropin-Releasing Hormone Receptor with a Lengthy Carboxy-Terminal Tail from an Ancestral Vertebrate, the Sea Lamprey
Authors: Silver Matthew R. , Nucci Nathaniel V. , Root Adam R. , Reed Karen L. , Sower Stacia A.
Published: May 2005

A full-length transcript encoding a functional type II GnRH receptor was cloned from the pituitary of the sea lamprey, Petromyzon marinus. The current study is the first to identify a pituitary GnRH receptor transcript in an agnathan, which is the oldest vertebrate lineage. The cloned receptor retains the conserved structural features and amino acid motifs of other known GnRH receptors and notably includes a C-terminal intracellular tail of approximately 120 amino acids, the longest C-terminal tail of any vertebrate GnRH receptor identified to date. The lamprey GnRH receptor was shown to activate the inositol phosphate (IP) signaling system; stimulation with either lamprey GnRH-I or lamprey GnRH-III led to dose-dependent responses in transiently transfected COS7 cells. Furthermore, analyses of serially truncated lamprey GnRH receptor mutants indicate perturbations of the C-terminal tail disrupts IP accumulation, however, the tailless lamprey GnRH receptor was not only functional but was also capable of stimulating IP levels equal to wild type. Expression of the receptor transcript was demonstrated in the pituitary and testes using RT-PCR, whereas in situ hybridization showed expression and localization of the transcript in the proximal pars distalis of the pituitary. The phylogenetic placement and structural and functional features of this GnRH receptor suggest that it is representative of an ancestral GnRH receptor. In addition to having an important role in lamprey reproductive processes, the extensive C-terminal tail of this lamprey GnRH receptor may have great significance for understanding the evolutionary change of this vital structural feature within the GnRH receptor family.
Hedgehog Signaling in Mouse Ovary: Indian Hedgehog and Desert Hedgehog from Granulosa Cells Induce Target Gene Expression in Developing Theca Cells
Authors: Wijgerde Mark , Ooms Marja , Hoogerbrugge Jos W. , Grootegoed J. Anton
Published: May 2005

Follicle development in the mammalian ovary requires interactions among the oocyte, granulosa cells, and theca cells, coordinating gametogenesis and steroidogenesis. Here we show that granulosa cells of growing follicles in mouse ovary act as a source of hedgehog signaling. Expression of Indian hedgehog and desert hedgehog mRNAs initiates in granulosa cells at the primary follicle stage, and we find induced expression of the hedgehog target genes Ptch1 and Gli1, in the surrounding pre-theca cell compartment. Cyclopamine, a highly specific hedgehog signaling antagonist, inhibits this induced expression of target genes in cultured neonatal mouse ovaries. The theca cell compartment remains a target of hedgehog signaling throughout follicle development, showing induced expression of the hedgehog target genes Ptch1, Ptch2, Hip1, and Gli1. In periovulatory follicles, a dynamic synchrony between loss of hedgehog expression and loss of induced target gene expression is observed. Oocytes are unable to respond to hedgehog because they lack expression of the essential signal transducer Smo (smoothened). The present results point to a prominent role of hedgehog signaling in the communication between granulosa cells and developing theca cells.
Progesterone Receptor Isoforms A and B: Temporal and Spatial Differences in Expression during Murine Mammary Gland Development
Authors: Aupperlee Mark D. , Smith Kyle T. , Kariagina Anastasia , Haslam Sandra Z.
Published: May 2005

Progesterone is a potent mitogen in the mammary gland. Based on studies using cells and animals engineered to express progesterone receptor (PR) isoforms A or B, PRA and PRB are believed to have different functions. Using an immunohistochemical approach with antibodies specific for PRA only or PRB only, we show that PRA and PRB expression in mammary epithelial cells is temporally and spatially separated during normal mammary gland development in the BALB/c mouse. In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA. PRA levels were significantly lower during pregnancy, suggesting a minor role at this stage of development. PRB was abundantly expressed only during pregnancy, during alveologenesis. PRA and PRB colocalization occurred in only a small percentage of cells. During pregnancy there was extensive colocalization of PRB with 5-bromo-2′-deoxyuridine (BrdU) and cyclin D1; 95% of BrdU-positive cells and 83% of cyclin D1-positive cells expressed PRB. No colocalization of PRA with either BrdU or cyclin D1 was observed at pregnancy. In the virgin gland, PRA colocalization with BrdU or cyclin D1 was low; only 27% of BrdU-positive cells and 4% of cyclin D1-positive cells expressed PRA. The implication of these findings is that different actions of progesterone are mediated in PRB positive vs. PRA-positive cells in vivo. The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo.
Essential Role of the Oocyte in Estrogen Amplification of Follicle-Stimulating Hormone Signaling in Granulosa Cells
Authors: Otsuka Fumio , Moore R. Kelly , Wang Xia , Sharma Shweta , Miyoshi Tomoko , Shimasaki Shunichi
Published: May 2005

The establishment of dominant ovarian follicles that are capable of ovulating fertilizable oocytes is a fundamental determinant of female fertility. This process is governed by pituitary gonadotropins as well as local ovarian factors. Within the follicle, estrogen acts in an autocrine/paracrine manner to enhance FSH action in the granulosa cells. These effects include the augmentation of P450aromatase expression and estradiol production. This feed-forward effect of estrogen is believed to play a key role in follicle dominance. Here we found the essential role of the oocyte in this physiological process using primary cultures of rat granulosa cells. In the presence, but not absence, of oocytes, estrogen amplified FSH-stimulated increases in mRNA expression of P450aromatase, FSH receptor, LH receptor, and inhibin α-, βA-, and βB-subunits as well as cAMP production. Thus, oocytes mediate the estrogen enhancement of FSH action in the granulosa cells. In comparison with FSH, cotreatment with estrogen and oocytes failed to amplify the stimulatory effects of forskolin or 8-bromoadenosine-cAMP on granulosa cell responses including P450aromatase mRNA expression and cAMP production, indicating that estrogen/oocytes amplify FSH action at a site upstream of adenylate cyclase. These findings support the novel conclusion that communication between the oocyte and granulosa cells plays a crucial role in mediating estrogen action during FSH-dependent folliculogenesis.
Myostatin Inhibits Myogenesis and Promotes Adipogenesis in C3H 10T(1/2) Mesenchymal Multipotent Cells
Authors: Artaza Jorge N. , Bhasin Shalender , Magee Thomas R. , Reisz-Porszasz Suzanne , Shen Ruoquin , Groome Nigel P. , Fareez Meerasaluh M. , Gonzalez-Cadavid Nestor F.
Published: May 2005

Inactivating mutations of the mammalian myostatin gene are associated with increased muscle mass and decreased fat mass; conversely, myostatin transgenic mice that overexpress myostatin in the skeletal muscle have decreased muscle mass and increased fat mass. We investigated the effects of recombinant myostatin protein and antimyostatin antibody on myogenic and adipogenic differentiation of mesenchymal multipotent cells. Accordingly, 10T(1/2) cells were incubated with 5′-azacytidine for 3 d to induce differentiation and then treated with a recombinant protein for myostatin (Mst) carboxy terminal 113 amino acids or a polyclonal anti-Mst antibody for 3, 7, and 14 d. Cells were also cotransfected with a Mst cDNA plasmid expressing the full-length 375-amino acid protein (pcDNA-Mst375) and the silencer RNAs for either Mst (pSil-Mst) or a random sequence (pSil-RS) for 3 or 7 d, and Mst expression was determined. Adipogenesis was evaluated by quantitative image analysis of fat cells before and after oil-red-O staining, immunocytochemistry of adiponectin, and Western blot for CCAAT/enhancer binding protein-α. Myogenesis was estimated by quantitative image analysis-immunocytochemistry for MyoD (Myo differentiation protein), myogenin, and myosin heavy chain type II, or by Western blot for myogenin. 5′-azacytidine-mediated differentiation induced endogenous full-length Mst expression. Recombinant Mst carboxy terminal 113 amino acids inhibited both early and late markers of myogenesis and stimulated both early and late markers of adipogenesis, whereas the antibody against Mst exerted the reverse effects. Myogenin levels at 7 d after transfection of pcDNA-Mst375 were reduced as expected and elevated by pSil-Mst, which blocked efficiently Mst375 expression. In conclusion, myostatin promotes the differentiation of multipotent mesenchymal cells into the adipogenic lineage and inhibits myogenesis.
The Case for Open-Market Purchases in a Liquidity Trap
Authors: Auerbach Alan J , Obstfeld Maurice
Published: May 2005

Prevalent thinking about liquidity traps suggests that the perfect substitutability of money and bonds at a zero short-term nominal interest rate renders open-market operations ineffective for achieving macroeconomic stabilization goals. We show that even were this the case, there remains a powerful argument for large-scale open market operations as a fiscal policy tool. As we also demonstrate, however, this same reasoning implies that open-market operations will be beneficial for stabilization as well, even when the economy is expected to remain mired in a liquidity trap for some time. Thus, the microeconomic fiscal benefits of open-market operations in a liquidity trap go hand in hand with standard macroeconomic objectives. Motivated by Japan’s recent economic experience, we use a dynamic general-equilibrium model to assess the welfare impact of open-market operations for an economy in Japan’s predicament. We argue Japan can achieve a substantial welfare improvement through large open-market purchases of domestic government debt.
Employment Fluctuations with Equilibrium Wage Stickiness
Authors: Hall Robert E
Published: May 2005

Following a recession, the aggregate labor market is slack–employment remains below normal and recruiting efforts of employers, as measured by help-wanted advertising and vacancies, are low. A model of matching friction explains the qualitative responses of the labor market to adverse shocks, but requires implausibly large shocks to account for the magnitude of observed fluctuations. The incorporation of wage stickiness vastly increases the sensitivity of the model to driving forces. I develop a new model of the way that wage stickiness affects unemployment. The stickiness arises in an economic equilibrium and satisfies the condition that no worker-employer pair has an unexploited opportunity for mutual improvement. Sticky wages neither interfere with the efficient formation of employment matches nor cause inefficient job loss. Thus the model provides an answer to the fundamental criticism previously directed at sticky-wage models of fluctuations.
An Empirical Assessment of the Comparative Advantage Gains from Trade: Evidence from Japan
Authors: Bernhofen Daniel M , Brown John C
Published: May 2005

We provide an empirical assessment of the comparative advantage gains from trade argument. We use Japan’s nineteenth-century opening up to world commerce as a natural experiment to answer the following counterfactual: “By how much would real income have had to increase in Japan during its final autarky years of 1851–1853 to afford the consumption bundle the economy could have obtained if it were engaged in international trade during that period?” Using detailed historical data on trade flows, autarky prices, and Japan’s real GDP, we obtain upper bounds on the gains from trade of about 8 to 9 percent of Japan’s GDP.
How to Protect Future Generations Using Tax-Base Restrictions
Authors: Rangel Antonio
Published: May 2005

This paper studies how to protect future generations from expropriation and to induce optimal investment in intergenerational public goods (IPGs), by introducing constitutional restrictions on the tax base. The type of tax-base restrictions that we consider places limits on the tax instruments that the government can use to raise revenue, but not on the level of expenditures or debt. We show that the introduction of a constitutional amendment requiring that IPGs and debt be financed with land taxes makes intergenerational expropriation impossible and, for many cases of interest, induces optimal investment in IPGs. We also show that a weaker constitutional amendment requiring that IPGs be financed with land taxes, but imposing no restrictions on how to finance the debt, has a positive impact on IPGs, but not on expropriation. The paper also studies the political feasibility of these reforms. We show that the first reform is not politically feasible since it hurts current generations, but the weaker reform can induce a Pareto improvement.
Extracting Inflation from Stock Returns to Test Purchasing Power Parity
Authors: Chowdhry Bhagwan , Roll Richard , Xia Yihong
Published: May 2005

Relative purchasing power parity (PPP) holds for pure price inflations, which affect prices of all goods and services by the same proportion, while leaving relative prices unchanged. Pure price inflations also affect nominal returns of all traded financial assets by exactly the same amount. Recognizing that relative PPP may not hold for the official inflation data constructed from commodity price indices because of relative price changes and other frictions that cause prices to be “sticky,” we provide a novel method for extracting a proxy for realized pure price inflation from stock returns. We find strong support for relative PPP in the short run using the extracted inflation measures.