bluuebunny/crossref_metadata_2025 huggingface dataset:
Store-Operated Ca
2+
Influx and Expression of TRPC Genes in Mouse Sinoatrial Node
Authors: Ju Yue-Kun , Chu Yi , Chaulet Herve , Lai Donna , Gervasio Othon L. , Graham Robert M. , Cannell Mark B. , Allen David G.
Published: May 2007

Store-operated Ca
2+
entry was investigated in isolated mouse sinoatrial nodes (SAN) dissected from right atria and loaded with Ca
2+
indicators. Incubation of the SAN in Ca
2+
-free solution caused a substantial decrease in resting intracellular Ca
2+
concentration ([Ca
2+
]
i
) and stopped pacemaker activity. Reintroduction of Ca
2+
in the presence of cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca
2+
pump inhibitor, led to sustained elevation of [Ca
2+
]
i
, a characteristic of store-operated Ca
2+
channel (SOCC) activity. Two SOCC antagonists, Gd
3+
and SKF-96365, inhibited 72±8% and 65±8% of this Ca
2+
influx, respectively. SKF-96365 also reduced the spontaneous pacemaker rate to 27±4% of control in the presence of CPA. Because members of the transient receptor potential canonical (TRPC) gene family may encode SOCCs, we used RT-PCR to examine mRNA expression of the 7 known mammalian TRPC isoforms. Transcripts for TRPC1, 2, 3, 4, 6, and 7, but not TRPC5, were detected. Immunohistochemistry using anti-TRPC1, 3, 4, and 6 antibodies revealed positive labeling in the SAN region and single pacemaker cells. These results indicate that mouse SAN exhibits store-operated Ca
2+
activity which may be attributable to TRPC expression, and suggest that SOCCs may be involved in regulating pacemaker firing rate.
Digital Map of Posterior Cerebral Artery Infarcts Associated With Posterior Cerebral Artery Trunk and Branch Occlusion
Authors: Phan, MBBS, FRACP Thanh G. , Fong Ashley C. , Donnan Geoffrey , Reutens David C.
Published: May 2007

Background and Purpose—

Knowledge of the extent and distribution of infarcts of the posterior cerebral artery (PCA) may give insight into the limits of the arterial territory and infarct mechanism. We describe the creation of a digital atlas of PCA infarcts associated with PCA branch and trunk occlusion by magnetic resonance imaging techniques.

Methods—

Infarcts were manually segmented on T
2
-weighted magnetic resonance images obtained >24 hours after stroke onset. The images were linearly registered into a common stereotaxic coordinate space. The segmented images were averaged to yield the probability of involvement by infarction at each voxel. Comparisons were made with existing maps of the PCA territory.

Results—

Thirty patients with a median age of 61 years (range, 22 to 86 years) were studied. In the digital atlas of the PCA, the highest frequency of infarction was within the medial temporal lobe and lingual gyrus (probability=0.60 to 0.70). The mean and maximal PCA infarct volumes were 55.1 and 128.9 cm
3
, respectively. Comparison with published maps showed greater agreement in the anterior and medial boundaries of the PCA territory compared with its posterior and lateral boundaries.

Conclusions—

We have created a probabilistic digital atlas of the PCA based on subacute magnetic resonance scans. This approach is useful for establishing the spatial distribution of strokes in a given cerebral arterial territory and determining the regions within the arterial territory that are at greatest risk of infarction.
Lipoprotein (a) and Stroke
Authors: Smolders Barbara , Lemmens Robin , Thijs Vincent
Published: May 2007

Background and Purpose—

The relationship between elevated lipoprotein (a) levels[Lp(a)] and stroke is controversial. We systematically reviewed the literature to determine whether Lp(a) is a risk factor for stroke.

Methods—

We searched MEDLINE (1966 to 2006), EMBASE (1974 to 2006), and Google scholar for articles on Lp(a) and cerebrovascular disease. From potentially relevant references retrieved, we excluded uncontrolled studies, studies of children with stroke, studies investigating carotid atherosclerosis, and studies lacking adequate data.

Results—

Thirty-one studies comprising 56 010 subjects with >4609 stroke events met all inclusion criteria and were included in the meta-analysis. In case-control studies (n=23 with 2600 strokes) unadjusted mean Lp(a) was higher in stroke patients (standardized mean difference, 0.39; 95% CI, 0.23 to 0.54) and was more frequently abnormally elevated (OR, 2.39; 95% CI, 1.57 to 3.63). Sensitivity analysis and meta-regression did not find any influence of study design, measurement period of Lp(a) in relationship to stroke episode, subtype, age, and sex to explain the substantial heterogeneity between studies (I
2
=83.7%;
P
<0.001). There was no evidence of publication bias. In nested case-control studies (n=3 with 364 strokes) Lp(a) was not a risk factor for incident stroke (OR, 1.04; 95% CI, 0.6 to 1.8). In prospective cohort studies (n=5 with >1645 strokes), incident stroke was more frequent in patients in the highest tertile of Lp(a) distribution compared with the lowest tertile of Lp(a) (RR, 1.22; 95% CI, 1.04 to 1.43). There was no publication bias or heterogeneity in the prospective studies (I
2
=0.00%;
P
=0.67).

Conclusion—

This meta-analysis suggests that elevated Lp(a) is a risk factor for incident stroke.
Short-Term Risk for Stroke Is Doubled in Persons With Newly Treated Type 2 Diabetes Compared With Persons Without Diabetes
Authors: Jeerakathil Thomas , Johnson Jeffrey A. , Simpson Scot H. , Majumdar Sumit R.
Published: May 2007

Background and Purpose—

Cardiovascular risk factors are suboptimally treated in diabetes, possibly because of the impression that there is a long delay between diagnosis and the development of macrovascular complications such as stroke. We determined the incidence of stroke in people newly treated for type 2 diabetes.

Methods—

We conducted an inception cohort study with the use of linked administrative databases from Saskatchewan Health. Subjects entered the type 2 diabetes cohort on receipt of their first prescription for an oral antidiabetic drug. We defined incident stroke as any hospital admission with International Classification of Diseases, Ninth Revision, codes 430 to 438 inclusive. Age-standardized incidence rates were compared between the diabetes cohort and the general population.

Results—

There were 12 272 subjects in the diabetes cohort, the mean±SD age was 64±13.6 years, and 55% were male. During a mean 5-year follow-up, 9.1% of the diabetes cohort had a stroke. The age-standardized incidence rate for stroke was 642 per 100 000 person-years in subjects with diabetes, compared with 313 per 100 000 person-years in the general population (rate ratio=2.1, 95% CI=1.8 to 2.3). The relative short-term risk for stroke in the diabetes cohort compared with the general population ranged from 1.8 (95%=CI 1.6 to 1.9) in persons >75 years to 5.6 (95% CI=2.5 to 9.3) in the 30- to 44-year category.

Conclusions—

The risk of stroke is high within 5 years of treatment for type 2 diabetes and more than double the rate for the general population. This further supports the need for aggressive early cardiovascular risk factor management in type 2 diabetes.
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults
Authors: Broderick Joseph , Connolly Sander , Feldmann Edward , Hanley Daniel , Kase Carlos , Krieger Derk , Mayberg Marc , Morgenstern Lewis , Ogilvy Christopher S. , Vespa Paul , Zuccarello Mario
Published: May 2007

Purpose—

The aim of this statement is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.

Methods—

A formal literature search of Medline was performed through the end date of August 2006. The results of this search were complemented by additional articles on related issues known to the writing committee. Data were synthesized with the use of evidence tables. The American Heart Association Stroke Council’s Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 5 expert peer reviewers and by the members of the Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years’ time.

Results—

Evidence-based guidelines are presented for the diagnosis of intracerebral hemorrhage, the management of increased arterial blood pressure and intracranial pressure, the treatment of medical complications of intracerebral hemorrhage, and the prevention of recurrent intracerebral hemorrhage. Recent trials of recombinant factor VII to slow initial bleeding are discussed. Recommendations for various surgical approaches for treatment of spontaneous intracerebral hemorrhage are presented. Finally, withdrawal-of-care and end-of-life issues in patients with intracerebral hemorrhage are examined. (Stroke. 2007;38:2001-2023.)
Test Design Optimization in CAT Early Stage with the Nominal Response Model
Authors: Lima Passos Valeria , Berger Martijn P. F. , Tan Frans E.
Published: May 2007

The early stage of computerized adaptive testing (CAT) refers to the phase of the trait estimation during the administration of only a few items. This phase can be characterized by bias and instability of estimation. In this study, an item selection criterion is introduced in an attempt to lessen this instability: the D-optimality criterion. A polytomous unconstrained CAT simulation is carried out to evaluate this criterion's performance under different test premises. The simulation shows that the extent of early stage instability depends primarily on the quality of the item pool information and its size and secondarily on the item selection criteria. The efficiency of the D-optimality criterion is similar to the efficiency of other known item selection criteria. Yet, it often yields estimates that, at the beginning of CAT, display a more robust performance against instability.
The Passive Compression Test
Authors: Kim Yang-Soo , Kim Jung-Man , Ha Kee-Yong , Choy Soon , Joo Min-Wook , Chung Yang-Guk
Published: May 2007

Background

Even though there are several physical tests available for superior labrum anterior posterior lesions, there have been very few reports on their accuracy, and none can be regarded as completely predictive for the presence of a superior labrum anterior posterior lesion in the shoulder joint.

Hypothesis

This new clinical test is a useful and accurate technique for detecting superior labral tears in the shoulder joint.

Study Design

Cohort study (diagnosis); Level of evidence, 2.

Methods

This test was conducted independently by 2 physicians before any other diagnostic evaluation. In all cases, the glenohumeral joint was investigated first, and the appropriate treatments were performed on the lesion. A protocol was established to evaluate the sensitivity, specificity, and positive and negative predictive values of this new clinical test. The reproducibility of this test was evaluated with a κ coefficient.

Results

Sixty-one patients (61 shoulders) were examined with the passive compression test, and all underwent arthroscopic surgery. In 31 patients with a positive passive compression test result, 27 had a superior labrum anterior posterior lesion, and in 30 patients with a negative passive compression test result, 6 had a superior labrum anterior posterior lesion. The sensitivity of the test was 81.8%, and the specificity was 85.7%. The positive predictive value was 87.1%, and the negative predictive value was 80.0%. The κ coefficient was 0.771 between the 2 independent examiners (P < .01).

Conclusion

The passive compression test is a useful and accurate technique for predicting superior labral tears of the shoulder joint.
Achilles Tendinosis
Authors: de Mos Marieke , van El Benno , DeGroot Jeroen , Jahr Holger , van Schie Hans T. M. , van Arkel Ewoud R. , Tol Hans , Heijboer Rien , van Osch Gerjo J. V. M. , Verhaar Jan A. N.
Published: May 2007

Background

Understanding biochemical and structural changes of the extracellular matrix in Achilles tendinosis might be important for developing mechanism-based therapies.

Hypothesis

In Achilles tendinosis, changes occur in biochemical composition and collagen turnover rate.

Study Design

Descriptive laboratory study.

Methods

From 10 patients undergoing surgery for Achilles tendinopathy, 1 tendinosis biopsy specimen and 1 biopsy specimen of macroscopically healthy tendon tissue adjacent to the lesion were collected. Furthermore, biopsy samples were collected from 3 donors with asymptomatic Achilles tendons. Water content, collagen content, percentage of denatured collagen, amount of lysine hydroxylation, number of enzymatic and nonenzymatic crosslinks, matrix metalloproteinase activity, and matrix metalloproteinase and collagen gene-expression levels were analyzed.

Results

In tendinotic lesions, the water content was highest, and collagen content was subnormal with higher amounts of denatured/damaged collagen. Low pentosidine levels in tendinotic tissue indicated the presence of relatively young collagenous matrix. More hydroxylated lysine residues were present in tendinotic samples, but enzymatic crosslinks revealed no differences between tendinotic, adjacent, and healthy samples. In tendinotic specimens, matrix metalloproteinase activity was higher, matrix metalloproteinase gene-expression profile was altered, and collagen type I and III gene expression were upregulated.

Conclusion

In Achilles tendinosis, the collagen turnover rate is increased, and the natural biochemical composition of the collagenous matrix is compromised.

Clinical Relevance

Although tendon tissue directly adjacent to an Achilles tendinosis lesion looks macroscopically healthy, histological and biochemical degenerative changes in adjacent tissue are evident, which may have implications for surgical interventions.
The Effects of Contact on the Prejudice Between Hispanics and Non-Hispanic Whites in the United States
Authors: Weaver Charles N.
Published: May 2007

The growing Hispanic population has come into increasing contact with the larger population of non-Hispanic Whites. It is important to understand the effects of this contact on prejudice. The effects of six kinds of contact were examined for their effects on prejudice between Hispanics ( n = 156) and non-Hispanic Whites ( n = 1,479) who were participants in a recent survey representative of the U.S. population. Both groups were prejudiced, but in different ways. Contact reduced the prejudice of both groups, but it reduced it much more for non-Hispanic Whites. The findings suggested that prejudice between the two groups will almost certainly decline as contact increases. Questions were raised for further research.
¿Derecho u Obligación?
Authors: Alvarez Leticia
Published: May 2007

This study draws from a social domain framework to explore judgments of parental authority in a Mexican origin familial context. The sample included 277 ninth-grade youth ( M = 14.53 years, SD = .61) and one of each of their parents. The average age of mothers was 39.88 years ( SD = 5.85), and for fathers it was 41.65 years ( SD = 5.51). As expected, parents were less acculturated and adhered to familismo and machismo. Results also showed that youth and parents agreed that parents have the right and obligation to authority in the personal domain more than in the conventional. The present findings are discussed in terms of rights and obligations of perceived authority and cultural orientations for parents and youth.
Hope Measurement in Mexican American Youth
Authors: Edwards Lisa M. , Ong Anthony D. , Lopez Shane J.
Published: May 2007

Hope is a motivational construct that has been associated with many positive outcomes in children, adolescents, and adults. Although research with the Children's Hope Scale (CHS) has demonstrated support for the reliability and validity of the CHS with various samples of youth, there is little empirical evidence for its use with Latino youth. The current study examined the psychometric properties of the six-item CHS in a sample of 135 Mexican American youth. Confirmatory factor analyses provided support for a hierarchical representation of the CHS with two underlying factors (pathways and agency). CHS scores were found to be positively correlated with measures of positive affect, life satisfaction, support from family and friends, and optimism. Additional analyses provided evidence supporting convergent validity and measurement invariance across gender. Implications and directions for future research are discussed.
What Does the Public Know About Preventing Cancer? Results From the Health Information National Trends Survey (HINTS)
Authors: Hawkins Nikki A. , Berkowitz Zahava , Peipins Lucy A.
Published: May 2007

This study provides information about the public’s familiarity with cancer prevention strategies and examines the association between this familiarity and actual prevention behavior. Data from interviews with 5,589 adults included in the 2003 Health Information National Trends Survey (HINTS) were analyzed. Most respondents were able to cite one or two strategies for reducing the chances of cancer. On average, the fewest number of strategies were cited by Hispanics, respondents aged 65 years or older, and those with the lowest levels of education and income. Avoiding tobacco and eating a healthy diet were most commonly cited. People who cited the following strategies for preventing cancer were more likely to practice them: eating plenty of fruits and vegetables, exercising regularly, not smoking, and participating in cancer screening. Results indicate that efforts are needed to increase public familiarity with recommended strategies, especially among groups that are least familiar with recommendations for cancer prevention.
Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantion in elderly patients and association with acute graft-versus-host disease
Authors: Mielke Stephan , Rezvani Katayoun , Savani Bipin N. , Nunes Raquel , Yong Agnes S. M. , Schindler John , Kurlander Roger , Ghetie Victor , Read Elizabeth J. , Solomon Scott R. , Vitetta Ellen S. , Barrett A. John
Published: May 2007

Selective depletion (SD) of host-reactive donor T cells from allogeneic stem-cell transplants (SCTs) using an anti-CD25 immunotoxin (IT) is a strategy to prevent acute graft-versus-host disease (aGvHD). There is concern that concurrent removal of regulatory T cells (Tregs) with incomplete removal of alloactivated CD25+ T cells could increase the risk of aGvHD. We therefore measured Tregs in the blood of 16 patients receiving a T-cell–depleted allograft together with anti–CD25-IT–treated SD lymphocytes, in 13 of their HLA-identical donors, and in 10 SD products. Tregs were characterized by intracellular staining for forkhead box protein 3 (FOXP3) and by quantitative reverse-transcription–polymerase chain reaction (qRT-PCR) for FOXP3 gene in CD4+ cells. Patients received a median of 1.0 × 108/kg SD T cells and a stem cell product containing a median of 0.25 × 104/kg residual T cells. Tregs reconstituted promptly after SCT and underwent further expansion. Of the CD4+ T cells in SD products, 1.5% to 4.8% were CD25− Tregs. Acute GvHD (≥ grade II) was restricted to 5 patients whose donors had significantly (P = .019) fewer Tregs compared with those without clinically significant aGvHD. These results suggest that rapid Treg reconstitution can occur following SD allografts, either from CD25− Tregs escaping depletion, or from residual CD25− and CD25+ Tregs contained in the stem-cell product that expand after transplantation and may confer additional protection against GvHD.
Mutations in the SBDS gene in acquired aplastic anemia
Authors: Calado Rodrigo T. , Graf Solomon A. , Wilkerson Keisha L. , Kajigaya Sachiko , Ancliff Philip J. , Dror Yigal , Chanock Stephen J. , Lansdorp Peter M. , Young Neal S.
Published: May 2007

Shwachman-Diamond syndrome (SDS; OMIM 260400), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T>C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had reduced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T>C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism.
The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish
Authors: Hall Chris , Flores Maria Vega , Storm Thilo , Crosier Kathy , Crosier Phil
Published: May 2007

Background

How different immune cell compartments contribute to a successful immune response is central to fully understanding the mechanisms behind normal processes such as tissue repair and the pathology of inflammatory diseases. However, the ability to observe and characterize such interactions, in real-time, within a living vertebrate has proved elusive. Recently, the zebrafish has been exploited to model aspects of human disease and to study specific immune cell compartments using fluorescent reporter transgenic lines. A number of blood-specific lines have provided a means to exploit the exquisite optical clarity that this vertebrate system offers and provide a level of insight into dynamic inflammatory processes previously unavailable.

Results

We used regulatory regions of the zebrafish lysozyme C (lysC) gene to drive enhanced green fluorescent protein (EGFP) and DsRED2 expression in a manner that completely recapitulated the endogenous expression profile of lysC. Labeled cells were shown by co-expression studies and FACS analysis to represent a subset of macrophages and likely also granulocytes. Functional assays within transgenic larvae proved that these marked cells possess hallmark traits of myelomonocytic cells, including the ability to migrate to inflammatory sources and phagocytose bacteria.

Conclusion

These reporter lines will have utility in dissecting the genetic determinants of commitment to the myeloid lineage and in further defining how lysozyme-expressing cells participate during inflammation.
Influenza vaccine supply, 2005–2006: did we come up short?
Authors: Bardenheier Barbara H , Strikas Raymond , Kempe Allison , Stokley Shannon , Ellis Jean
Published: May 2007

Background

Although total influenza vaccine doses available in the 2005/2006 influenza season were over 80 million, CDC received many reports of delayed and diminished vaccine shipments in October to November of 2005. To better understand the supply problems, CDC and partners surveyed several health care professional groups.

Methods

Surveys were sent to representative samples of influenza vaccine providers including pediatricians, internists, federally qualified health centers, visiting nurse organizations, and all 64 state and other health departments receiving federal immunization funds directly. In November and December, 2005, providers were asked questions about their experience in ordering influenza vaccine, sources where orders were placed, proportion of orders received, and referral of patients to other vaccination sites.

Results

The number of providers surveyed (median: 154; range: 64 – 308) and response rates (median: 62%; range: 51% – 77%) varied among groups. Less than half of the providers in most groups placed a single order that was accepted (median: 31%; range: 8% – 53%), and most placed multiple orders. Only 57% of federally qualified health centers and 60% of internists reported they received at least 40% of their orders by the middle of December; the other provider groups received a greater proportion of their orders. Most internists (80%) and federally qualified health centers (54%) reported that they had referred priority group patients to other locations to receive the influenza vaccine due to inadequate supplies. Vaccine providers who ordered only from Chiron received a lower proportion of their orders than providers that ordered from another source or ordered from multiple sources.

Conclusion

Most of the providers surveyed received only part of their orders by the middle of December. Disruptions in receipt of influenza vaccine during the fall of 2005 were due primarily to shortfalls in vaccine from Chiron and also due to delays and partial shipments from other distributors.
Effects of nebulized ketamine on allergen-induced airway hyperresponsiveness and inflammation in actively sensitized Brown-Norway rats
Authors: Zhu Min Min , Zhou Qin Hai , Zhu Mei Hua , Bo Rong Hai , Xu Yu Ming , Qian Yan Ning , Fu Cheng Zhang
Published: May 2007

Since airway hyperresponsiveness (AHR) and allergic inflammatory changes are regarded as the primary manifestations of asthma, the main goals of asthma treatment are to decrease inflammation and maximize bronchodilation. These goals can be achieved with aerosol therapy. Intravenous administration of the anesthetic, ketamine, has been shown to trigger bronchial smooth muscle relaxation. Furthermore, increasing evidence suggests that the anti-inflammatory properties of ketamine may protect against lung injury. However, ketamine inhalation might yield the same or better results at higher airway and lower ketamine plasma concentrations for the treatment of asthma. Here, we studied the effect of ketamine inhalation on bronchial hyperresponsiveness and airway inflammation in a Brown-Norway rat model of ovalbumin(OVA)-induced allergic asthma. Animals were actively sensitized by subcutaneous injection of OVA and challenged by repeated intermittent (thrice weekly) exposure to aerosolized OVA for two weeks. Before challenge, the sensitizened rats received inhalation of aerosol of phosphate-buffered saline (PBS) or aerosol of ketamine or injection of ketamine respectivity. Airway reactivity to acetylcholine (Ach) was measured in vivo, and various inflammatory markers, including Th2 cytokines in bronchoalveolar lavage fluid (BALF), as well as induciable nitric oxide synthase (iNOS) and nitric oxide (NO) in lungs were examined. Our results revealed that delivery of aerosolized ketamine using an ultrasonic nebulizer markedly suppressed allergen-mediated airway hyperreactivity, airway inflammation and airway inflammatory cell infiltration into the BALF, and significantly decreased the levels of interleukin-4 (IL-4) in the BALF and expression of iNOS and the concentration of NO in the inflamed airways from OVA-treated rats. These findings collectively indicate that nebulized ketamine attenuated many of the central components of inflammatory changes and AHR in OVA-provoked experimental asthma, potentially providing a new therapeutic approach against asthma.
B-Type Natriuretic Peptide Inhibited Angiotensin II-Stimulated Cholesterol Biosynthesis, Cholesterol Transfer, and Steroidogenesis in Primary Human Adrenocortical Cells
Authors: Liang Faquan , Kapoun Ann M. , Lam Andrew , Damm Debby L. , Quan Diana , O’Connell Maile , Protter Andrew A.
Published: May 2007

In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC50 of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Δ-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3β-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2). Consistent with the microarray and real-time PCR results, BNP also blocked Ang II-induced binding of 125I-labeled low-density lipoprotein and 125I-labeled high-density lipoprotein to human adrenocortical cells. Furthermore, BNP markedly inhibited Ang II-stimulated release of estradiol, aldosterone, and cortisol from cultured primary human adrenocortical cells. These findings demonstrate that BNP opposes Ang II-induced steroidogenesis via multiple steps from cholesterol supply and transfer to the final formation of steroid hormones. This study provides new insights into the cellular mechanisms by which BNP modulates Ang II-induced steroidogenesis in the adrenal gland.
Location Strategies and Knowledge Spillovers
Authors: Alcácer Juan , Chung Wilbur
Published: May 2007

Given the importance of proximity for knowledge spillovers, we examine firms’ location choices expecting differences in firms’ strategies. Firms will locate to maximize their net spillovers as a function of locations’ knowledge activity, their own capabilities, and competitors’ anticipated actions. Using new entrants into the United States from 1985 to 1994, we find that firms favor locations with academic innovative activity. Other results highlight differences in firms’ location strategies suggesting that firms consider not only gains from inward knowledge spillovers but also the possible cost of outward spillovers. While less technologically advanced firms favor locations with high levels of industrial innovative activity, technologically advanced firms choose only locations with high levels of academic activity and avoid locations with industrial activity to distance themselves from competitors.
Dynamic Agency with Renegotiation and Managerial Tenure
Authors: Şabac Florin
Published: May 2007

This paper proves the renegotiation-proofness principle for a dynamic LEN (linear contracts, exponential utility, normal distributions) model and examines the impact of repeated renegotiation on incentives and managerial tenure when performance information is serially correlated. In addition to providing a general solution to a multiperiod agency problem with serially correlated performance measures, this paper characterizes optimal managerial tenure/turnover policies as a function of the time-series properties of performance measures. With negatively correlated performance measures, the principal prefers longer managerial tenure, and no turnover is optimal. With positively correlated performance measures, absent a switching cost, turnover every period is optimal. In the presence of a fixed switching cost, interior optimal turnover policies exist if the performance measures are positively correlated. Switching costs are necessary, but not sufficient for interior optimal tenure. The optimal turnover policies present an alternative to theories of performance-driven managerial turnover and are consistent with evidence that a majority of managerial turnovers are (age-related) normal retirements.
Managerial Motivation Dynamics and Incentives
Authors: Kocabıyıkoğlu Ayşe , Popescu Ioana
Published: May 2007

Firms can increase profitability by appropriately motivating managers. We investigate drivers of managerial motivation, and propose how firms can use performance pay to alter motivational patterns. We focus on the agent’s optimal effort decision in trading off compensation utility with effort cost in a static and dynamic setting. Surprisingly, we find that lower risk aversion or increased pay are not necessarily motivating factors, and identify the relevant effort drivers underlying the agent’s utility and compensation plan. We characterize properties of agents’ preferences for output lotteries (risk aversion, aggressiveness, prudence) that trigger systematic motivational patterns with respect to a variety of factors, such as the agent’s productivity and past performance, time to evaluation, the firm’s capabilities, and market factors. Our insights are robust, holding under very general modeling assumptions on preferences, rewards, and the stochastic effort-output function.
Temporary and Permanent Buyout Prices in Online Auctions
Authors: Gallien Jérémie , Gupta Shobhit
Published: May 2007

Buyout options allow bidders to instantly purchase at a specified price an item listed for sale through an online auction. A temporary buyout option disappears once a regular bid is submitted, whereas a permanent option remains available until it is exercised or the auction ends. Such buyout price may be static and remain constant throughout the auction, or dynamic and vary as the auction progresses. We formulate a game-theoretic model featuring time-sensitive bidders with independent private values and Poisson arrivals but endogenous bidding times to answer the following questions: How should a seller set the buyout price (if at all)? What are the implications of using a temporary buyout option relative to a permanent one? What is the potential benefit associated with using a dynamic buyout price? For all buyout option types we exhibit a Nash equilibrium in bidder strategies, argue that this equilibrium constitutes a plausible outcome prediction, and study the problem of maximizing the corresponding seller revenue. Our numerical experiments suggest that when any participant is time sensitive, the seller may significantly increase his utility by introducing a buyout option, but that dynamic buyout prices may not provide a substantial advantage over static ones. Furthermore, whereas permanent buyout options yield higher predicted revenue than temporary options, they also provide additional incentives for late bidding and may therefore not be always more desirable.
Pricing and Lead Time Decisions in Decentralized Supply Chains
Authors: Liu Liming , Parlar Mahmut , Zhu Stuart X.
Published: May 2007

This paper studies a decentralized supply chain consisting of a supplier and a retailer facing price- and lead-time-sensitive demands. A Stackelberg game is constructed to analyze the price and lead time decisions by the supplier as the leader and the retailer as the follower. The equilibrium strategies of the two players are obtained. Using the performance of the corresponding centralized system as a benchmark, we show that decentralized decisions in general are inefficient and lead to inferior performance due to the double marginalization effect. However, further analysis shows that the decision inefficiency is strongly influenced by market and operational factors, and if the operational factors are dominating, it may not be significant. This shows that before pursuing a coordination strategy with retailers, a supplier should first improve his or her own internal operations.
The Strategic Perils of Delayed Differentiation
Authors: Anand Krishnan S. , Girotra Karan
Published: May 2007

The value of delayed differentiation (also known as postponement) for a monopolist has been extensively studied in the operations literature. We analyze the case of (imperfectly) competitive markets with demand uncertainty, wherein the choice of supply chain configuration (i.e., early or delayed differentiation) is endogenous to the competing firms. We characterize firms’ choices in equilibrium and analyze the effects of these choices on quantities sold, profits, consumer surplus, and welfare. We demonstrate that purely strategic considerations not previously identified in the literature play a pivotal role in determining the value of delayed differentiation. In the face of either entry threats or competition, these strategic effects can significantly diminish the value of delayed differentiation. In fact, under plausible conditions, these effects dominate the traditional risk-pooling benefits associated with delayed differentiation, in which case early differentiation is the dominant strategy for firms, even under cost parity with delayed differentiation. We extend the main model to study the effects of alternate market structures, asymmetric markets, and inventory holdback. Our results—in particular that for a broad range of parameter values, early differentiation is a dominant strategy even under cost parity with delayed differentiation—are robust to these relaxations.
Immunohistochemical Analysis of Regulatory T Cell Markers FOXP3 and GITR on CD4+CD25+ T Cells in Normal Skin and Inflammatory Dermatoses
Authors: Boer Onno J. de , Loos Chris M. van der , Teeling Peter , Wal Allard C. van der , Teunissen Marcel B.M.
Published: May 2007

Regulatory T cells (Treg) are a subset of T lymphocytes that play a central role in immunologic tolerance and in the termination of immune responses. The identification of these cells in normal and inflammatory conditions may contribute to a better understanding of underlying pathology. We investigated the expression of FOXP3 and GITR in normal skin and in a panel of different inflammatory dermatoses. Immunohistochemical double stainings in skin tissue sections revealed that FOXP3 and GITR were almost exclusively present on T cells that express both CD4 and CD25. Further, immunohistochemical double staining, as well as fluorescence-activated cell sorter analysis, on peripheral blood T cells showed that most FOXP3+ cells expressed GITR and vice versa, whereas a minority were single-positive for these markers. The mean frequency of FOXP3+ T cells in spongiotic dermatitis, psoriasis, and lichen planus was in the same range (25-29%), but the frequency of these cells in leishmaniasis appeared to be lower (∼15%), although this was not statistically significant. The mean frequency of GITR+ T cells was fairly similar in all conditions studied (14-20%). Normal human skin also contained FOXP3+ and GITR+ cells in the same frequency range as in diseased skin, but the absolute numbers were, of course, much lower. In conclusion, frequencies of FOXP3+ and GITR+ T cells were similar in all inflammatory skin diseases studied and normal skin, despite the well-known differences among the inflammatory conditions under investigation.
Epithelial Phenotypes in the Developing Human Prostate
Authors: Letellier Guy , Perez Marie-José , Yacoub Mokrane , Levillain Pierre , Cussenot Olivier , Fromont Gaëlle
Published: May 2007

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.
Loss of Caveolin-1 in Bronchiolization in Lung Fibrosis
Authors: Odajima Nao , Betsuyaku Tomoko , Nasuhara Yasuyuki , Nishimura Masaharu
Published: May 2007

Bronchiolization is a key process in fibrosing lung in which the proliferative status of bronchiolar epithelium changes, leading to abnormal epithelial morphology. Within the context that caveolin-1 acts to suppress epithelial proliferation, we postulated that stimulating epithelial injury would lead to caveolin-1 downregulation and encourage proliferation. The present study evaluates the expression of caveolin-1, especially in bronchiolization, in C57BL/6J mice with bleomycin-induced lung fibrosis and in various types of re-epithelialization in human interstitial pneumonias (IPs). Immunohistochemically, levels of caveolin-1 decreased in the bronchiolar epithelium of mice treated with bleomycin. Levels of caveolin-1 mRNA in the whole lung were decreased at 7 and 14 days. Caveolin-1 mRNA was also decreased in laser-capture microdissection- retrieved bronchiolar epithelial cells at 7 days. Among patients with 12 IPs, including four usual IPs (UIPs) and eight nonspecific IPs (NSIPs), whole lung caveolin-1 was significantly decreased compared with 12 controls at both mRNA and protein levels. By scoring immunointensity, caveolin-1 was significantly reduced in bronchiolization and squamous metaplasia as well as in bronchiolar epithelium in 23 IPs (12 UIPs and 11 NSIPs) compared with bronchiolar epithelium from seven controls. These data suggested that loss of caveolin-1 is associated with abnormal re-epithelialization in lung fibrosis.
Combined Staining of TAG-72, MUC1, and CA125 Improves Labeling Sensitivity in Ovarian Cancer
Authors: Chauhan Subhash C. , Vinayek Namita , Maher Diane M. , Bell Maria C. , Dunham Katrina A. , Koch Michael D. , Lio Yuhlong , Jaggi Meena
Published: May 2007

Single antigen-targeted intraperitoneal radioimmunotherapy for ovarian cancer has shown limited success. Due to the heterogeneous expression of tumor antigens on cancer cells, a multi-antigen targeting approach appears logical to augment the therapeutic efficacy of antibody-guided therapy. In the interest of developing this novel approach, ovarian cancer tissue microarray slides containing cancer and benign/non-neoplastic tissue samples ( n = 92) were processed for single-, double-, and triple-antigen labeling using antibodies for the tumor-associated antigens TAG-72, MUC1, and CA125. Among all ovarian cancer types, 72%, 61%, and 50% of the samples showed immunolabeling for TAG-72, MUC1, and CA125, respectively. Expression level of these antigens was significantly ( p<0.005) higher in advanced stage carcinomas compared with early stage. Of the 48 epithelial ovarian cancer samples, individual anti-TAG-72, MUC1, and CA125 antibody probing showed labeling in 89.5%, 87.5%, and 73.0% of the cases, respectively. In the majority of the cancer samples (>70%), a heterogeneous labeling pattern was observed (only 30–40% of the cancer cells within the sample were labeled). However, upon combining the three antigens (triple-antigen labeling), 98% of the epithelial ovarian cancer samples were labeled and >95% of the cancer cells within each sample were labeled. Our data indicate that the heterogeneous expression of cancer antigens appears to be a major obstacle in antibody-guided therapy, and this can be overcome by multiple antigen targeting. Therapeutic efficacy of antibody-guided therapy for ovarian cancer treatment will be enhanced by the combined targeting of TAG-72, MUC1, and CA125. (J Histochem Cytochem 55: 867–875, 2007)
An Improved Method for Three-dimensional Reconstruction of Protein Expression Patterns in Intact Mouse and Chicken Embryos and Organs
Authors: Ahnfelt-Rønne Jonas , Jørgensen Mette C. , Hald Jacob , Madsen Ole D. , Serup Palle , Hecksher-Sørensen Jacob
Published: May 2007

We have developed a wholemount immunofluorescence protocol for the simultaneous detection of up to three proteins in mouse and chicken embryos. Combined with Murray's clearing reagent (BABB) and microscope objectives with long working ranges and high numerical apertures mounted on a confocal microscope, cellular resolution can be obtained in depths offering the possibility of examining expression patterns in entire organs or embryos. Three-dimensional projections of the optical confocal sections can be computed with computer software allowing rotation around any axis. The protocol is robust and we find that most antibodies working on tissue sections also work with this protocol. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
Concentrations of TIMP1 mRNA Splice Variants and TIMP-1 Protein Are Differentially Associated with Prognosis in Primary Breast Cancer
Authors: Sieuwerts Anieta M , Usher Pernille A , Meijer-van Gelder Marion E , Timmermans Mieke , Martens John WM , Brünner Nils , Klijn Jan GM , Offenberg Hanne , Foekens John A
Published: May 2007

Background: TIMP-1 protein is a prognostic factor for recurrence-free and overall survival (OS) time in breast cancer. We evaluated the prognostic value of TIMP1 mRNA and a novel TIMP1 mRNA splice variant in 1301 primary breast cancer patients.

Methods: We measured mRNA transcripts of full-length TIMP1 (TIMP1-v1) and the novel splice variant lacking exon 2 (TIMP1-v2) by use of real-time RT-PCR in frozen primary tumor samples. Transcript concentrations are correlated with histomorphological and biological factors, TIMP-1 protein, and distant metastasis-free survival (MFS) and OS time.

Results: TIMP1-v1 and TIMP1-v2 alone were not informative with respect to predicting prognosis. However, the PCR assay designed to measure the combination of v1 + v2 showed that high concentrations of this combination were associated with good prognosis. In Cox multivariate regression analysis, which also included the traditional prognostic factors, increasing concentrations were independently associated with prolonged MFS (P = 0.004) and OS (P = 0.048). Including TIMP-1 protein and TIMP1-v1+v2 mRNA together in the multivariate model revealed that protein and mRNA were both independently associated with prognosis, with hazard ratios pointing in opposite directions.

Conclusion: High concentrations of TIMP1-v1+2 mRNA are associated with good prognosis in patients with primary breast cancer. Since high concentrations of TIMP-1 protein are associated with poor prognosis, the presence of possible posttranscriptional mechanisms requires further investigation.
Parent–Child Feedback Predicts Sibling Contrast: Using Twin Studies to Test Theories of Parent–Offspring Interaction in Infant Behavior
Authors: Eaves Lindon J. , Silberg Judy L.
Published: May 2007

Several studies report apparent sibling contrast effects in analyses of twin resemblance. In the presence of genetic differences, contrast effects reduce the dizygotic (DZ) twin correlation relative to that in monozygotic (MZ) twins and produce higher DZ than MZ variance. Explanations of contrast effects are typically cast in terms of direct social interaction between twins or an artifact of the process of rating children by their parents. We outline a model for sibling imitation and contrast effects that depends on social interaction between parents and children. In addition to predicting the observed pattern of twin variances and covariances, the parental mediation of child imitation and contrast effects leads to differences in the variance of parents of MZ and DZ twins and differences between the correlations of parents with their MZ and DZ children.