bluuebunny/crossref_metadata_2025 huggingface dataset:
PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication
Authors: Chauhan Dharminder , Hideshima Teru , Anderson Kenneth C.
Published: January 2005

▪ Abstract  Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade™), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.
Host-specific differences in the physiology of acid secretion related to prostaglandins may play a role in gastric inflammation and injury
Authors: Padol Ireneusz T. , Hunt Richard H.
Published: January 2005

Immune mediators are involved in strain-specific manifestations of Helicobacter pylori infection, and the type of immune response is associated with production of PGE2, which in turn influences gastric acid secretion. Acid secretion plays a pivotal role, not only in the pattern of H. pylori-induced gastritis and its consequences, but also in nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathies. Mice and their transgenic modifications are widely used in Helicobacter and eicosanoid research. Using [14C]aminopyrine accumulation and pylorus ligation, we aimed to study acid secretion in gastric gland preparations from the commonly used strains of BALB/c and C57BL/6 mice. We found that PGE2does not inhibit acid secretion in gastric glands from C57BL/6 mice, in contrast to the expected antisecretory effect of PGE2observed in BALB/c mice. In BALB/c mice the effect of histamine and carbachol was reduced by PGE2, whereas in C57BL/6 mice dose-response curves to these secretagogues were not affected. EP3receptors are not involved in acid secretion in C57BL/6 mice, as confirmed by significantly lower expression of mRNA for the EP3receptor. These contrary findings are important to the interpretation of the antisecretory role of eicosanoids in BALB/c and C57BL/6 mouse strains and the involvement of prostanoids in the etiology of Helicobacter-induced inflammation and NSAID-induced gastropathies. We propose that the lack of antisecretory effect of PGE2observed in C57BL/6 mice could reflect the extent of Helicobacter-induced inflammation and status of acid secretion in response to anti-inflammatory drugs.
A mouse model provides evidence that genetic background modulates anemia and liver injury in erythropoietic protoporphyria
Authors: Abitbol Marie , Bernex Florence , Puy Hervé , Jouault Hélène , Deybach Jean-Charles , Guénet Jean-Louis , Montagutelli Xavier
Published: January 2005

Erythropoietic protoporphyria is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin (PP) overproduction by erythrocytes. In humans, it is responsible for painful skin photosensitivity and, occasionally, liver failure due to accumulation of PP in the liver. The ferrochelatase deficiency mouse mutation is the best animal model available for human erythropoietic protoporphyria. The original description, based on mice with a BALB/cByJCrl genetic background, reported a disease resembling the severe form of the human disease, with anemia, jaundice, and liver failure. Using congenic strains, we investigated the effect of genetic background on the severity of the phenotype. Compared with BALB/cByJCrl, C57BL/6JCrl mice developed moderate but increasing anemia and intense liver accumulation of PP with severe hepatocyte damage and loss. Bile excretory function was not affected, and bilirubin remained low. Despite the highest PP concentration in erythrocytes, anemia was mild and there were few PP deposits in the liver in SJL/JOrlCrl homozygotes. Discriminant analysis using six hematologic and biochemical parameters showed that homozygotes of the three genetic backgrounds could be clustered in three well-separated groups. These three congenic strains provide strong evidence for independent genetic control of bone marrow contribution of PP overproduction to development of liver disease and biliary PP excretion. They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences and to identify modifying genes.
Effect of a high or low ambient perinatal temperature on adult obesity in Osborne-Mendel and S5B/Pl rats
Authors: White Christy L. , Braymer H. Doug , York David A. , Bray George A.
Published: January 2005

Perinatal environment is an important determinant of health status of adults. We tested the hypothesis that perinatal ambient temperature alters sympathetic activity and affects body composition in adult life and that this effect differs between S5B/Pl (S5B) and Osborne-Mendel (OM) strains of rat that were resistant (S5B) or susceptible (OM) to dietary obesity. From 1 wk before birth, rat litters were raised at either 18 or 30°C until 2 mo of age while consuming a chow diet. Rats were then housed at normal housing temperature (22°C) and provided either high-fat or low-fat diet. OM rats initially reared at 18°C gained more weight on both diets than those reared at 30°C. Perinatal temperature had no effect on body weight gain of the S5B rats on either diet. At 12 wk of age, OM and S5B rats reared at 18°C had higher intakes of the high-fat diet than those reared at 30°C but lower β3-adrenergic receptor (β3-AR) and uncoupling protein-1 (UCP1) mRNA levels in brown adipose tissue (BAT). The increase in metabolic rate in response to the β3-agonist CL-316243, was greater in both OM and S5B rats reared at 18°C than in those reared at 30°C. Perinatal temperature differentially affects body weight in OM and S5B rats while having similar effects on food intake, response to a β3-agonist, and BAT β3-AR and UCP-1. The data suggest that OM rats are more susceptible to epigenetic programming than S5B rats.
Effects of two cooling strategies on thermoregulatory responses of tetraplegic athletes during repeated intermittent exercise in the heat
Authors: Webborn N. , Price M. J. , Castle P. C. , Goosey-Tolfrey V. L.
Published: January 2005

Athletes with spinal cord injury (SCI), and in particular tetraplegia, have an increased risk of heat strain and consequently heat illness relative to able-bodied individuals. Strategies that reduce the heat strain during exercise in a hot environment may reduce the risk of heat illness. To test the hypotheses that precooling or cooling during intermittent sprint exercise in a heated environment would attenuate the rise in core temperature in tetraplegic athletes, eight male subjects with SCI (lesions C5–C7; 2 incomplete lesions) undertook four heat stress trials (32.0 ± 0.1°C, 50 ± 0.1% relative humidity). After assessment of baseline thermoregulatory responses at rest for 80 min, subjects performed three intermittent sprint protocols for 28 min. All trials were undertaken on an arm crank ergometer and involved a no-cooling control (Con), 20 min of precooling (Pre), or cooling during exercise (Dur). Trials were administered in a randomized order. After the intermittent sprint protocols, mean core temperature was higher during Con (37.3 ± 0.3°C) compared with Pre and Dur (36.5 ± 0.6°C and 37.0 ± 0.5°C, respectively; P < 0.01). Moreover, perceived exertion was lower during Pre (13 ± 2; P < 0.01) and Dur (12 ± 1; P < 0.01) compared with Con (14 ± 2). These results suggest that both precooling and cooling during intermittent sprint exercise in the heat reduces thermal strain in tetraplegic athletes. The cooling strategies also appear to show reduced perceived exertion at equivalent time points, which may translate into improved functional capacity.
Chronic strain alters the passive and contractile properties of rabbit airways
Authors: Tepper R. S. , Ramchandani R. , Argay E. , Zhang L. , Xue Z. , Liu Y. , Gunst S. J.
Published: January 2005

Pathophysiological conditions of the lung may shift the balance of forces so as to chronically alter the amount of strain imposed on the airways. This chronic strain could result in changes in the structure and/or function of the airways that affect its physiological properties. We evaluated the effects of imposing physiological levels of chronic mechanical strain on the passive and active physiological properties of intraparenchymal rabbit airways. Isolated bronchial segments were cultured for 48 h at transmural pressures of 0 cmH2O (No Strain) or 7 cmH2O (Strain). Effects of strain on small parenchymal airways were evaluated in lung tissue slices cultured under conditions of No Strain or ∼50% increased in diameter (Strain). Chronic strain resulted in a higher passive compliance of the bronchial segments and larger airway lumen size. In addition, bronchi not subjected to chronic Strain were more responsive to ACh than bronchi subjected to chronic Strain, and airways in lung slices subjected to No Strain narrowed more in response to ACh than airways in lung slices subjected to Strain. The greatest effects of chronic strain occurred in the smallest sized airways. Our results suggest that chronic distension of the airways has physiologically important effects on their passive and active properties, which are most prominent in the smaller, more peripheral airways.
Frequency of the C34T mutation of theAMPD1gene in world-class endurance athletes: does this mutation impair performance?
Authors: Rubio Juan C. , Martín Miguel A. , Rabadán Manuel , Gómez-Gallego Félix , San Juan Alejandro F. , Alonso Juan M. , Chicharro José L. , Pérez Margarita , Arenas Joaquín , Lucia Alejandro
Published: January 2005

The C34T mutation in the gene encoding for the skeletal muscle-specific isoform of AMP deaminase ( AMPD1) is a common mutation among Caucasians (i.e., one of five individuals) that can impair exercise capacity. The purpose of this study was twofold. First, we determined the frequency distribution of the C34T mutation in a group of top-level Caucasian (Spanish) male endurance athletes (cyclists and runners, n = 104). This group was compared with randomly selected Caucasian (Spanish) healthy (asymptomatic) nonathletes ( n = 100). The second aim of this study was to compare common laboratory indexes of endurance performance (maximal oxygen uptake or ventilatory thresholds) within the group of athletes depending on their C34T AMPD1 genotype. The frequency of the mutant T allele was lower ( P < 0.05) in the group of athletes (4.3%) compared with controls (8.5%). On the other hand, indexes of endurance performance did not differ ( P > 0.05) between athlete carriers or noncarriers of the C34T mutation (e.g., maximal oxygen uptake 72.3 ± 4.6 vs. 73.5 ± 5.9 ml·kg−1·min−1, respectively). In conclusion, although the frequency distribution of the mutant T allele of the AMPD1 genotype is lower in Caucasian elite endurance athletes than in controls, the C34T mutation does not significantly impair endurance performance once the elite-level status has been reached in sports.
Mucocele of the Vermiform Appendix with Sonographic Appearance of an Adnexal Mass
Authors: Dragoumis K. , Mikos T. , Zafrakas M. , Assimakopoulos E. , Venizelos I. , Demertzidis H. , Bontis J.
Published: January 2005

Mucocele of the vermiform appendix is caused by mucus retention in its lumen, due to obstruction or hyperproduction. Appendiceal malignancy can be the underlying cause, making accurate preoperative diagnosis imperative. In women, it can sometimes present as an adnexal mass. A rare case of an appendiceal mucocele is presented, mimicking a cystic tumor of the right adnexum, both clinically and ultrasonographically. In addition, serum levels of CA-125 were increased. This is the first case of a mucocele of the appendix simulating an adnexal mass on ultrasound with increased levels of CA-125 to be reported. This clinical entity should be considered in patients presenting on ultrasound with a right-sided adnexal mass as a rare potential diagnosis.
Involvement of JAM-A in Mononuclear Cell Recruitment on Inflamed or Atherosclerotic Endothelium
Authors: Ostermann Georg , Fraemohs Line , Baltus Thomas , Schober Andreas , Lietz Michael , Zernecke Alma , Liehn Elisa A. , Weber Christian
Published: January 2005

Objective—The junctional adhesion molecule (JAM)-A on endothelium contributes to the inflammatory recruitment of mononuclear cells involving engagement of its integrin receptor lymphocyte function-associated antigen (LFA)-1. It is unknown whether these functions can be inhibited by soluble forms of JAM-A, whether JAM-A is expressed on atherosclerotic endothelium, and whether it participates in atherogenic recruitment of mononuclear cells.

Methods and Results—Adhesion assays revealed that LFA-1–mediated binding of mononuclear cells to intercellular adhesion molecule (ICAM)-1 or cytokine-costimulated endothelium was dose-dependently inhibited by soluble JAM-A.Fc (sJAM-A.Fc). Similarly, sJAM-A.Fc reduced stromal cell-derived factor (SDF)-1α–triggered transendothelial chemotaxis of activated T cells and their SDF-1α–triggered arrest on cytokine-costimulated endothelium under flow conditions. Immunofluorescence analysis revealed an upregulation of JAM-A on early atherosclerotic endothelium of carotid arteries from apolipoprotein E-deficient (apoE−/−) mice fed an atherogenic diet. In ex vivo perfusion assays, pretreatment of mononuclear cells with sJAM-A.Fc inhibited their very late antigen (VLA)-4–independent accumulation on atherosclerotic endothelium of these arteries.

Conclusions—Soluble forms of JAM-A can be effectively applied to inhibit distinct steps of mononuclear cell recruitment on inflamed or atherosclerotic endothelium. In conjunction with its expression on atherosclerotic endothelium, this suggests a functional contribution of JAM-A to atherogenesis.
Powerful Inflammatory Properties of Large Vein Endothelium In Vivo
Authors: Eriksson Einar E. , Karlof Eva , Lundmark Karin , Rotzius Pierre , Hedin Ulf , Xie Xun
Published: January 2005

Objective—

Inflammatory responses of large vein endothelium are of importance in pathological processes such as venous thrombosis, chronic venous congestion, and vein graft atherosclerosis. However, the inflammatory properties of large vein endothelium are unclear.

Methods and Results—

In this study, we used several microscopy techniques to investigate the inflammatory properties of large vein endothelium in vivo. We show that the endothelium in the mouse inferior vena cava (IVC) possesses powerful inflammatory properties that are distinct from the less inflammatory reactive aortic endothelium and virtually identical to endothelial responses in postcapillary venules. Inflammatory stimulation with tumor necrosis factor-α induced strong expression of cell adhesion molecules (CAMs) in the IVC. These CAMs promoted recruitment of leukocytes, platelets, and erythrocytes to the vein wall. The inflammatory responses altered endothelial structure and increased endothelial permeability in the IVC. Accumulation of blood cells and endothelial damage were markedly reduced in mice deficient in the endothelial leukocyte recruitment molecules E-selectin and P-selectin, indicating a central role for these molecules in driving structural and functional changes of IVC endothelium.

Conclusions—

These findings provide the first comprehensive demonstration of the inflammatory capacity of large vein endothelium and emphasize the actions of endothelial cells as targets in large vein disease.
Inhibition of Neointima Formation by a Novel Drug-Eluting Stent System That Allows for Dose-Adjustable, Multiple, and On-Site Stent Coating
Authors: Wessely Rainer , Hausleiter Jörg , Michaelis Cornelia , Jaschke Birgit , Vogeser Michael , Milz Stefan , Behnisch Boris , Schratzenstaller Thomas , Renke-Gluszko Magdalena , Stöver Michael , Wintermantel Erich , Kastrati Adnan , Schömig Albert
Published: January 2005

Objective—

The risk of in-stent restenosis can be considerably reduced by stents eluting cytostatic compounds. We created a novel drug-eluting stent system that includes several new features in the rapidly evolving field of stent-based drug delivery.

Methods and Results—

The aim of the present study was the preclinical evaluation of a stent-coating system permitting individual, on-site coating of stents with a unique microporous surface allowing for individualizable, dose-adjustable, and multiple coatings with identical or various compounds, designated ISAR (
i
ndividualizable drug-eluting
s
tent system to
a
brogate
r
estenosis). Stents were coated with 0.75% rapamycin solution, and high-performance liquid chromatography (HPLC)-based determination of drug release profile indicated drug release for >21 days. Rapamycin-eluting microporous (REMP) stents implanted in porcine coronary arteries were safe. To determine the efficacy of REMP stents, this novel drug-eluting stent platform was compared with the standard sirolimus-eluting stent. At 30 days, in-stent neointima formation in porcine coronary arteries was similar in both groups, yielding a significant decrease of neointimal area and injury-dependent neointimal thickness compared with bare-metal stents.

Conclusion—

The ISAR drug-eluting stent platform as a novel concept for stent coating allows for a safe, effective, on-site stent coating process, thus justifying further clinical evaluation to decrease in-stent restenosis in humans.
Expression of 12/15-Lipoxygenase Attenuates Intracellular Lipid Deposition During In Vitro Foam Cell Formation
Authors: Belkner Jutta , Chaitidis Pavlos , Stender Hannelore , Gerth Christa , Kuban Ralf J. , Yoshimoto Tanihiro , Kuhn Hartmut
Published: January 2005

Objectives—

Lipoxygenases with different positional specificity have been implicated in atherogenesis, but the precise roles of the various isoforms remain unclear. Because of its capability of oxidizing low-density lipoprotein (LDL) to an atherogenic form, 12/15-lipoxygenases have been suggested to initiate LDL oxidation in vivo; thus, these enzymes may exhibit pro-atherogenic activities. However, in several rabbit atherosclerosis models, the enzyme appears to act atheroprotective.

Methods and Results—

To test the impact of 12/15-lipoxygenase expression on early atherogenesis, we established an in vitro foam cell model, which is based on the uptake of acetylated LDL by murine macrophages. In this system, we found that 12/15-lipoxygenase expression protects the cells from intracellular lipid deposition. This effect was related to an attenuated uptake of modified LDL, as indicated by impaired expression of scavenger receptor A and to accelerated intracellular lipid metabolism.

Conclusions—

Our results indicate that the role of 12/15-lipoxygenase in atherogenesis may not be restricted to oxidative LDL modification. Expression of this lipid-peroxidizing enzyme may impact both lipid uptake and intracellular lipid turnover. These data provide a plausible explanation for the antiatherogenic effect of 12/15-LOX in rabbit atherosclerosis models.
Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries
Authors: Johnson Thomas W. , Wu Yin Xiong , Herdeg Christian , Baumbach Andreas , Newby Andrew C. , Karsch Karl R. , Oberhoff Martin
Published: January 2005

Background—

Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries.

Methods and Results—

Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using β-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3–coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with β-galactosidase–expressing adenovirus (RAd
lac
Z). Neointimal area after 28 days was significantly reduced to 1.27±0.19 mm
2
with RAdTIMP-3 versus 2.61±0.31 mm
2
with RAd
lac
Z stents (
P
<0.001) and 2.12±0.20 mm
2
with bare stents (
P
<0.005).

Conclusions—

Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation.
Association Between a Functional Variant of the
KLOTHO
Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity
Authors: Arking Dan E. , Atzmon Gil , Arking Albert , Barzilai Nir , Dietz Harry C.
Published: January 2005

We previously identified a functional variant of
KLOTHO
, termed KL-VS, that is associated with human aging and early-onset occult coronary artery disease. Here, we determine whether the KL-VS allele influences cardiovascular disease risk factors, cardiovascular events, and ultimately, mortality. A total of 525 Ashkenazi Jews composed of 216 probands (age ≥95 years) and 309 unrelated individuals (ages 51 to 94) were genotyped for the KL-VS allele. In concordance with our previous data in Czech individuals (age ≥79;
P
<0.01), a heterozygous advantage for longevity was observed for individuals ≥79 years of age (
P
<0.004). Combined analysis indicates a 1.57-fold (95% CI, 1.23 to 1.98) increased odds ratio (OR) for 5-year survival in two independent populations (
P
<0.0002). Cardiovascular disease risk factors were assessed through multivariate regression analysis, demonstrating that high-density lipoprotein cholesterol (HDL-C;
P
<0.05) and systolic blood pressure (SBP;
P
<0.008) are associated with KL-VS genotype. History of vascular events was analyzed using logistic regression, indicating that after adjustment for traditional risk factors, heterozygous individuals were at significantly lower risk for stroke than wild-type individuals (OR, 5.88; 95% CI, 1.18 to 29.41), whereas homozygous KL-VS individuals had the highest risk (OR, 30.65; 95% CI, 2.55 to 368.00). Similarly, prospective analysis of mortality in probands using Cox regression indicates that wild-type individuals have a 2.15-fold (95% CI, 1.18 to 3.91) and homozygous KL-VS individuals a 4.49-fold (95% CI, 1.35 to 14.97) increase in relative risk for mortality after adjusting for potential confounders. Thus, cross-sectional and prospective studies confirm a genetic model in which the KL-VS allele confers a heterozygous advantage in conjunction with a marked homozygous disadvantage for HDL-C levels, SBP, stroke, and longevity.
Assessment of Cardiac Structure and Left Atrial Appendage Functions in Primary Antiphospholipid Syndrome
Authors: Erdogan Dogan , Goren M. Taner , Diz-Kucukkaya Reyhan , Inanc Murat
Published: January 2005

Background and Purpose—

Although thromboembolic events are the major complication of primary antiphospholipid syndrome (PAPS), cardiac involvement is commonly present. Left atrial appendage (LAA) is recognized as an important source for thrombus formation and thromboembolism. The purpose of the study was to assess the structure and function of LAA with transesophageal echocardiography (TEE) in PAPS patients.

Methods—

Thirty-one PAPS patients (22 women, mean age 36±9 years) in sinus rhythm and 31 (17 women, mean age 37±7 years) controls with normal TEE examination were investigated.

Results—

Eighty-four percent of the PAPS patients had functional and structural valvular defect predominantly in the mitral valve. Valvular lesions were especially frequent in PAPS patients with a history of cerebrovascular events, patients with history of arterial thrombosis (91.6%), and patients with high titers of IgG anticardiolipin antibodies (100%). Intracardiac thrombus was present in 5 patients and in 1 of them it was located in LAA. The structure of LAA was similar between groups. Left atrial appendix ejection fraction (51.8±4 versus 48.6±5.5%;
P
<0.05) and LAA peak outflow velocity (87±10.9 versus 80.6±10.3 cm/s;
P
=0.02) was significantly higher in PAPS group compared with controls. In PAPS patients with mitral regurgitation (MR), LAA outflow peak velocity (84.3±10 versus 98.6±6.5 cm/s;
P
=0.002) and LAA inflow peak velocity (67.8±10.5 versus 80.8±8.6 cm/s;
P
=0.009) were significantly lower compared with PAPS patients without MR.

Conclusions—

It was concluded that disease process in PAPS frequently involved cardiac valves especially mitral valve but spared LAA function. LAA function was normal, but intracardiac thrombus was present in 5 patients and 1 of them was located in LAA. MR in PAPS patients seems to impair LAA function.
Gudmunder Alfredsson and Katarina Tomaševski (eds.), A Thematic Guide to Documents on the Human Rights of Women: Global and Regional Standards adopted by Intergovernmental Organizations, International Non-Governmental Organizations and Professional Associations, The Raoul Wallenberg Institute Human Rights Guides, Volume 1, The Hague: Martinus Nijhoff, 1995
Authors: Thorburn
Published: January 2005

No Abstract
Note from the Editor-in-Chief
Authors: Yonah
Published: January 2005

No Abstract
Fiscal Policy: Institutions versus Rules
Authors: Wyplosz Charles
Published: January 2005

Fiscal discipline is as much needed as monetary discipline. Many countries have attempted to counter the deficit bias by adopting fiscal rules that typically set a limit to their annual budget deficits. The record is not satisfactory; rules are either too lax or too tight and then ignored. This article suggests that the solution is to adopt the approach followed by inflation targeting central banks, with great success. Independent and accountable Fiscal Policy Committees, given the task of achieving debt targets and the authority to decide - or recommend - annual deficits, will be free from the deficit bias. This will allow them to exercise discretion in the short run while delivering debt sustainability in the long run.
Paying for University: The Impact of Increasing Costs on Student Employment, Debt and Satisfaction
Authors: Metcalf Hilary
Published: January 2005

The costs of higher education in the UK have shifted increasingly from the state to the student (and students' families). In 1998, a fee contribution of £1,000 per annum was introduced for new entrants to full-time degree courses. This paper examines its effect on debt, term-time employment and student satisfaction. The analysis uses data from a survey of two cohorts of students and identifies how the impact varied with student and course characteristics. Fees led to an increase in student debt (particularly for disabled students and for students who did not receive financial support from their families) and a decline in student satisfaction. No general impact on term-time employment was identified, but term-time employment increased for students who did not receive financial support from their families. Whilst for these two groups inequality was increased, fees appeared to lead to greater equality, in terms of term-time employment, between children of graduate and non-graduate parents. The paper discusses the implications for the introduction of top-up fees in 2006.
Lessons from Biology for Philosophy of the Human Sciences
Authors: Rosenberg Alex
Published: January 2005

The social sciences must be biological ones, owing simply to the fact that they focus on the causes and effects of the behavior of members of a biological species, Homo sapiens. Our improved understanding of biology as a science and of the biological realm should enable us therefore to solve several of the outstanding problems of the philosophy of social science. The solution to these problems leaves most of the social and behavioral sciences pretty much as it finds them, though it does provide improved understanding of their scope, limits, and methods.
How to Explain Oppression
Authors: Cudd Ann E.
Published: January 2005

This article discusses explanatory theories of normative concepts and argues for a set of criteria of adequacy by which such theories may be evaluated. The criteria offered fall into four categories: ontological, theoretical, pragmatic, and moral. After defending the criteria and discussing their relative weighting, this article uses them to prune the set of available explanatory theories of oppression. Functionalist theories, including Hegelian recognition theory and Foucauldian social theory, are rejected, as are psychoanalytic theory and social dominance theory. Finally, the article defends structural rational choice theory as the most promising methodology for explaining oppression.
Galilean Reflections on Milton Friedman’s “Methodology of Positive Economics,” with Thoughts on Vernon Smith’s “Economics in the Laboratory”
Authors: Schliesser Eric
Published: January 2005

In this article, the author offers a discussion of the evidential role of the Galilean constant in the history of physics. The author argues that measurable constants help theories constrain data. Theories are engines for research, and this helps explain why the Duhem-Quine thesis does not undermine scientific practice. The author connects his argument to discussion of two famous papers in the history of economic methodology, Milton Friedman’s “Methodology of Positive Economics,” which appealed to example of Galilean Law of Fall in its argument; and Vernon Smith’s “Economics in the Laboratory.” While the author offers some criticism of Friedman and Smith, most of the article is a friendly reinterpretation of their insights.
Beliefs, Attitudes, and Practices of Breastfeeding Mothers From a Periurban Community in South Africa
Authors: Sibeko Lindiwe , Dhansay Mohammed Ali , Charlton Karen E. , Johns Timothy , Gray-Donald Katherine
Published: January 2005

The aim of this study was to document the breastfeeding practices, beliefs, and attitudes of periurban South African lactating mothers with infants younger than 6 months. None of the mothers (n = 115, mean age 26 ± 6.3 years) reported exclusively breastfeeding their infants, with complementary breastfeeding being the most practiced (78%) feeding mode. Complementary foods were fed to 32% of infants by their first month of life. Perceived inadequate production of breast milk was the most common (90%) reason cited for adding foods and liquids to breastfeeds. Mothers valued use of traditional herbal preparations (muthi), with more then half (56%) of the infants having received their first dose of muthi before 1 month of age. Our study provides important data on breastfeeding practices of women living within resource-poor settings. Development of successful infant-feeding interventions aimed at promoting overall infant health can benefit from knowledge of these breastfeeding patterns.
Breastfeeding of a Medically Fragile Foster Child
Authors: Gribble Karleen D.
Published: January 2005

A case is presented in which a medically fragile baby was breastfed by her foster mother. As a result, the child’s physical and emotional health were improved. The mechanisms whereby human milk improves health are well known. The act of breastfeeding may also have an analgesic and relaxant effect as a result of hormonal influences and skin-to-skin contact. Many foster babies may benefit from human milk or breastfeeding. However, the risk of disease transmission must be minimized. Provision of human milk to all medically fragile foster babies is desirable. Breastfeeding by the foster mother may be applicable in cases in which the child is likely to be in long-term care, the child has been previously breastfed, or the child’s mother expresses a desire that the infant be breastfed. However, social barriers must be overcome before breastfeeding of foster babies can become more common.
The Development of a Research Human Milk Bank
Authors: Geraghty Sheela R. , Davidson Barbara S. , Warner Barbara B. , Sapsford Amy L. , Ballard Jeanne L. , List Betsy A. , Akers Rachel , Morrow Ardythe L.
Published: January 2005

Although there are well-established clinical human milk banks in the United States, there are no milk banks specifically intended to foster research on human milk. The authors’goalwas to establish a milk bank with a core data set to support exploratory and hypothesis-driven studies on human milk. Donations to the Cincinnati Children’s Research Human Milk Bank are accepted within the context of ongoing, hypothesis-driven research or on an ad hoc basis. Donors must give informed consent, and scientists wishing to use the samples must have Institutional review board approval for their use. Development of more research human milk banks can potentially provide resources for multidisciplinary collaboration and advance the study of human milk and lactation.
Diffusion Tensor Imaging of Frontal White Matter Microstructure in Early Alzheimer’s Disease: A Preliminary Study
Authors: Choi Steven J. , Lim Kelvin O. , Monteiro Isabel , Reisberg Barry
Published: January 2005

Several investigators have suggested that the pathological progression of Alzheimer’s disease appears to recapitulate the developmental maturation pattern, a process termed retrogenesis. Diffusion tensor imaging was used to test the hypothesis that the microstructural integrity of superior frontal and temporal white matter, one of the last regions to mature, would be reduced in vivo in early Alzheimer’s disease. Five consecutive slices, from the orbitofrontal to periventricular frontal regions, as well as temporal and corpus callosal white matter regions, were sampled. Fractional anisotropy, mean diffusivity, axial diffusion, and radial diffusion of 10 patients with early Alzheimer’s disease and 10 age-similar healthy control subjects were compared. Patients with Alzheimer’s disease were found to have significantly reduced fractional anisotropy, increased mean diffusivity, and increased radial diffusion in superior frontal white matter. These data suggest that the integrity of periventricular frontal white matter rather than orbitofrontal white matter appears to be altered in early Alzheimer’s disease and that the white matter abnormalities involve compromised myelin, consistent with the retrogenesis theory. ( J Geriatr Psychiatry Neurol 2005; 18:12-19)
Poststroke Depression in Chinese Patients: Frequency, Psychosocial, Clinical, and Radiological Determinants
Authors: Tang Wai Kwong , Chan Sandra S. M. , Chiu Helen F. K. , Ungvari Gabor S. , Wong Ka Sing , Kwok Timothy C. Y. , Mok Vincent , Wong K. T. , Richards Polly S. , Ahuja Anil T.
Published: January 2005

This study attempted to evaluate the psychosocial, clinical, and radiological predictors of poststroke depression (PSD) in Chinese patients. One hundred eighty-nine patients participated in the study. Three months after the index stroke, a psychiatrist administered the Structured Clinical Interview for DSM-IV to all of the patients and made a DSM-IV diagnosis of depression. In addition, a host of demographic, clinical, and radiological variables were examined. Thirty-one (16.4%) of the patients had a diagnosis of PSD that included major depression (n = 11, 5.8%,), minor depression (n = 16, 8.5%), or dysthymia (n = 4, 2.1%). Univariate analysis revealed that PSD was associated with female gender, a lower level of education, a lower Lubben Social Network Scale (LSNS) score, subcortical infarcts, and lesions in the anterior cerebral artery (ACA) territory, and the Modified Life Event Scale (MLES) score was borderline for statistical significance. Multivariate logistic regression analysis suggested that female gender, a high MLES score, and subcortical and ACA lesions were independent risk factors for PSD and that a high LSNS score was a protective factor. ( J Geriatr Psychiatry Neurol 2005; 18:45-51)
Neuropsychology of Vitamin B₁₂ Deficiency in Elderly Dementia Patients and Control Subjects
Authors: Osimani Alicia , Berger Andrea , Friedman Joshua , Porat-Katz Bat-Sheba , Abarbanel Jacob M.
Published: January 2005

Cobalamin deficiency may cause cognitive deficits and even dementia. In Alzheimer’s disease, the most frequent cause of dementia in elderly persons, low serum levels of vitamin B12, may be misleading. The aim of this work was to characterize the cognitive pattern of B12 deficiency and to compare it with that of Alzheimer’s disease. Nineteen patients with low levels of vitamin B12 were neuropsychologically evaluated before treatment and a year later. Results were compared with those of 10 healthy control subjects. Final results suggest that there is a different pattern in both diseases. Twelve elderly patients with dementia improved with treatment. Seven elderly demented patients did not improve; they deteriorated after 1 year although their levels of cobalamin were normal. Analysis of the initial evaluation showed that the 2 groups of patients had a different neuropsychological profile. The group that improved had initially more psychotic problems and more deficits in concentration, visuospatial performance, and executive functions. They did not show language problems and ideomotor apraxia, which were present in the second group. Their memory pattern was also different. These findings suggest that cobalamin deficiency may cause a reversible dementia in elderly patients. This dementia may be differentiated from that of Alzheimer’s disease by a thorough neuropsychological evaluation. ( J Geriatr Psychiatry Neurol 2005; 18:33-38)
Frontotemporal Dementia, Semantic Dementia, and Alzheimer’s Disease: The Contribution of Standard Neuropsychological Tests to Differential Diagnosis
Authors: Diehl J. , Monsch A. U. , Aebi C. , Wagenpfeil S. , Krapp S. , Grimmer T. , Seeley W. , Förstl H. , Kurz A.
Published: January 2005

CERAD-NAB (Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer’s disease. There were statistically significant differences between the 3 groups. Compared with patients with Alzheimer’s disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer’s disease. Multiple logistic regression analysis revealed that in the differentiation between frontotemporal dementia and Alzheimer’s disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer’s disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. These findings demonstrate that the Mini Mental State Examination and the language subtests of the CERAD-NAB are valuable clinical instruments for the differential diagnosis between early frontotemporal dementia, semantic dementia, and Alzheimer’s disease.(J Geriatr Psychiatry Neurol 2005;18:39-44)
Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD
Authors: Claessens Yann-Erick , Park Sophie , Dubart-Kupperschmitt Anne , Mariot Virginie , Garrido Carmen , Chrétien Stany , Dreyfus François , Lacombe Catherine , Mayeux Patrick , Fontenay Michaëla
Published: January 2005

Myelodysplastic syndromes (MDSs) are characterized by peripheral blood cytopenia including anemia. We have investigated the implication of the extrinsic pathway of apoptosis in MDS-ineffective erythropoiesis by in vitro expansion of erythroid precursors from early stage (low and intermediate-1 International Prognosis Scoring System [IPSS]) MDS, advanced stage (intermediate-2 IPSS) MDS, and control bone marrow samples. We have previously shown that Fas and its ligand were overexpressed in early stage MDS erythroid cells. Here, we show that caspase-8 activity is significantly increased, whereas the expression of death receptors other than Fas, including the type 1 receptor for tumor necrosis factor α (TNF-α) and the receptors for the TNF-related apoptosis-inducing ligand (TRAIL), DR4 and DR5, was normal. We also observed that the adapter Fas-associated death domain (FADD) was overexpressed in early stage MDS erythroid cells. Transduction of early stage MDS-derived CD34+ progenitors with a FADD-encoding construct increased apoptosis of erythroid cells and dramatically reduced erythroid burst-forming unit (BFU-E) growth. Transduction of a dominant-negative (dn) mutant of FADD inhibited caspase-8 activity and cell death and rescued BFU-E growth without abrogating erythroid differentiation. These results extend the observation that Fas-dependent activation of caspase-8 accounts for apoptosis of early stage MDS erythroid cells and demonstrate for the first time that FADD is a valuable target to correct ineffective erythropoiesis in these syndromes.
SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells
Authors: Dupré Loïc , Andolfi Grazia , Tangye Stuart G. , Clementi Rita , Locatelli Franco , Aricò Maurizio , Aiuti Alessandro , Roncarolo Maria-Grazia
Published: January 2005

The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)–family receptors expressed on T and natural killer (NK) cells. In patients affected by X-linked lymphoproliferative (XLP) disease, mutations in the SH2D1A gene result in defective lytic activity. However, the mechanism by which SAP controls cytotoxic activity remains unclear. T-cell–receptor (TCR) activation of CD8+ cytotoxic T cells (CTLs) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTLs from patients with XLP and hemophagocytic lymphohistiocytosis (HLH) display a specific lytic defect against autologous and allogeneic Epstein-Barr virus (EBV)–positive B cells. This defect is associated with the defective polarization of 2B4, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2B4 in normal CTLs reproduces the defects in lysis and polarization observed in SAP-deficient CTLs. Expression and regulation of the SLAM-family receptors SLAM, CD84, and 2B4, as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTLs. In addition, TCR stimulation leads to normal proliferation and production of interleukin 2 (IL-2), IL-4, and interferon-γ (IFN-γ). These results demonstrate that the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.
SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development
Authors: D'Souza Sunita L. , Elefanty Andrew G. , Keller Gordon
Published: January 2005

In this report, we have defined the stage at which Scl functions in the establishment of the hematopoietic system and provide evidence that its primary role is in the generation of the hematopoietic lineages from a progenitor called the blast colony-forming cell (BL-CFC), a cell considered to be the in vitro equivalent of the hemangioblast. Using an embryonic stem (ES) cell line in which lacZ cDNA has been targeted to the Scl locus, we show that most of the BL-CFCs are detected in the SCL/lacZ- population, indicating that this progenitor does not express Scl. In the blast colony assay, Scl-/- cells initiate colony growth but are unable to generate endothelial and hematopoietic progeny and thus form colonies consisting of vascular smooth muscle cells only. The capacity to give rise to blast colonies can be rescued by retroviral transduction of a wild-type Scl gene into Scl-/- FLK-1+ cells, suggesting that the BL-CFC is generated in this population. Finally, we show that Scl-/- endothelial cells display a growth deficiency in monolayer cultures that can be partially overcome by maintaining this population as 3-dimensional aggregates indicating that specific cellular interactions are required for maintenance of the Scl-/- endothelial lineage in vitro.
Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients
Authors: Keats Jonathan J. , Maxwell Christopher A. , Taylor Brian J. , Hendzel Michael J. , Chesi Marta , Bergsagel P. Leif , Larratt Loree M. , Mant Michael J. , Reiman Tony , Belch Andrew R. , Pilarski Linda M.
Published: January 2005

Multiple myeloma (MM) is a B-lineage malignancy characterized by diverse genetic subtypes and clinical outcomes. The recurrent immunoglobulin heavy chain (IgH) switch translocation, t(4;14)(p16;q32), is associated with poor outcome, though the mechanism is unclear. Quantitative reverse-transcription–polymerase chain reaction (RT-PCR) for proposed target genes on a panel of myeloma cell lines and purified plasma cells showed that only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in all t(4;14)POS patients. The different transcripts detected, multiple myeloma SET domain containing protein (MMSET I), MMSET II, Exon 4a/MMSET III, and response element II binding protein (RE-IIBP), are produced by alternative splicing and alternative transcription initiation events. Translation of the various transcripts, including those from major breakpoint region 4-2 (MB4-2) and MB4-3 breakpoint variants, was confirmed by transient transfection and immunoblotting. Green fluorescent protein (GFP)–tagged MMSET I and II, corresponding to proteins expressed in MB4-1 patients, localized to the nucleus but not nucleoli, whereas the MB4-2 and MB4-3 proteins concentrate in nucleoli. Cloning and localization of the Exon 4a/MMSET III splice variant, which contains the protein segment lost in the MB4-2 variant, identified a novel protein domain that prevents nucleolar localization. Kinetic studies using photobleaching suggest that the breakpoint variants are functionally distinct from wild-type proteins. In contrast, RE-IIBP is universally dysregulated and also potentially functional in all t(4;14)POS patients irrespective of fibroblast growth factor receptor 3 (FGFR3) expression or breakpoint type.
New trends in umbilical cord blood transplantation
Authors: Ballen Karen K.
Published: January 2005

Since the first report of a successful umbilical cord blood transplantation in 1988, there has been great interest in the use of cord blood as an alternative stem cell source to treat cancer and genetic diseases. More than 4000 cord blood transplantations have been performed worldwide. In this review, the scientific rationale for this therapy, as well as related preclinical studies, cord blood banking issues, and ethical concerns, will be addressed. Results of studies in both pediatric and adult transplantation will be discussed. Finally, new indications for cord blood use and emerging technologies will be addressed.