bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Neuropeptide Y Y1 Receptors by Testosterone in Vascular Smooth Muscle Cells in Rat Testis
Authors: Kopp Jutta , Collin Ola , Villar Marcelo , Mullins Deborah , Bergh Anders , Hökfelt Tomas
Published: June 2008

It is well established that testosterone and neuropeptide Y (NPY), via its Y1 receptor (Y1R), are involved in the central control of the gonadotrope axis in male rats. Here we examined if a similar interaction also occurs in the male peripheral reproductive target organ, the testes. Expression of the Y1R transcript and protein and changes in testicular microcirculation were studied in normal rats and 12 days following hypophysectomy with and without testosterone substitution (1 or 25 mg s.c.). In situ hybridization and immunohistochemistry showed strong expression of, respectively, Y1R messenger RNA (Y1R mRNA) and Y1R-like immunoreactivity (Y1R-LI) in vascular smooth muscles in the testes of control and hypophysectomized rats treated with testosterone, but was not seen without testosterone substitution. In parallel, control animals and hypophysectomized, testosterone-supplemented rats showed a strong (approximately 40%) decrease in testicular blood flow following intratesticular (i.t.) injection of the Y1-R agonists, [Leu31, Pro34]NPY, [D-Arg25]NPY or NPY, an effect which was completely blocked by prior intravenous administration of the Y1R antagonist, BIBP3226. No significant change in testicular blood flow following i.t. injection of NPY was seen in hypophysectomized rats without testosterone substitution. These findings suggest that the high levels of Y1R mRNA and Y1R-LI in the testes reflect expression of functional Y1Rs mediating vasoconstriction, and that testosterone regulates expression of functional Y1Rs.
Proteolytic Processing of cGMP-Dependent Protein Kinase I Mediates Nuclear cGMP Signaling in Vascular Smooth Muscle Cells
Authors: Sugiura Takahiro , Nakanishi Hidehiko , Roberts Jesse D.
Published: June 2008

Cyclic GMP modulates gene expression in vascular smooth muscle cells (SMCs) in part by stimulating cGMP-dependent protein kinase I (PKGI) and the phosphorylation of transcription factors. In some cells, cGMP increases nuclear translocation of PKGI and PKGI-dependent phosphorylation of transcription regulators; however, these observations have been variable, and the mechanisms mediating nuclear PKGI translocation are incompletely understood. We tested the hypothesis that proteolytic cleavage of PKGI is required for cGMP-stimulated nuclear compartmentation of PKGI and phosphorylation of transcription factors. We detected an NH
2
-terminal PKGI fragment with leucine zipper domain immunoreactivity in the cytosol and endoplasmic reticulum of SMCs, but only a COOH-terminal PKGI fragment containing the catalytic region (now termed
PKGIγ
) was observed in the Golgi apparatus (GA) and nucleoplasm. Posttranslational PKGI processing in the GA was critical for nuclear compartmentation of PKGIγ because GA disruption with nocodazol or brefeldin A inhibited PKGIγ nuclear localization. PKGIγ immunoreactivity was particularly abundant in the nucleolus of interphase SMCs where its colocalization with the nucleolar dense fibrillar component protein fibrillarin closely matched the level of nucleolar assembly. Purified nucleolar PKGIγ enzyme activity was insensitive to cGMP stimulation, which is consistent with its lack of the NH
2
-terminal autoinhibitory domain. Mutation of a putative proteolytic cleavage region in PKGI inhibited cGMP-mediated phosphorylation of cAMP response element-binding protein, cAMP response element-dependent transcription, and nuclear localization of PKGIγ. These observations suggest that posttranslational modification of PKGI critically influences the nuclear translocation of PKGI and activities of cGMP in SMCs.
Brain Lesion Volume and Capacity for Consent in Stroke Trials
Authors: Dani Krishna A. , McCormick Michael T. , Muir Keith W.
Published: June 2008

Background and Purpose—

European directives and legislation in some countries forbid inclusion of subjects incapable of consent in research if recruitment of patients capable of consent will yield similar results. We compared brain lesion volumes in stroke patients deemed to have capacity to consent with those defined as incapacitated.

Methods—

Data were obtained from 3 trials recruiting patients primarily with cortical stroke syndromes. Patients were recruited within 24 hours of onset and used MRI based selection or outcome criteria. Method of recruitment was recorded with stroke severity, age, and brain lesion volumes on Diffusion Weighted Imaging.

Results—

Of the 56 subjects included, 38 (68%) were recruited by assent and 18 (32%) by consent. The assent group had a median lesion volume of 18.35 cubic centimetres (cc) (interquartile range [IQR] 8.27–110.31 cc), compared to 2.79 cc (IQR 1.31–12.33 cc) when patients consented (
P
=0.0004). Lesions were smaller than 5 cc in 7/38 (18%) in the assent group and 11/18 (61%) in the consent group (
P
=0.0024). There was good correlation between neurological deficit by NIH stroke scale score and lesion volume (
r
=0.584,
P
<0.0001). Logistic regression demonstrated NIHSS or lesion volume predicted capacity to consent.

Conclusions—

Patients with acute stroke who retain capacity to consent have significantly smaller infarct volumes than those incapable of consent, and these are frequently below the limits where measurement error significantly compromises valid use of volumetric end points. Only a small proportion of patients with capacity to consent would be eligible for, and contribute usefully to, most acute stroke trial protocols.
Intra-Urban Residential Mobility: The Family Lif e Cycle Mo del and the Influence of the Renter/Non-Renter Dichotomy
Authors:   Lee Boon Thong
Published: June 2008

Many factors account for why families or households move from one residence to another in an urban area and it is an enormous and difficult task to attempt to isolate or rank the factors in ordered importance. This is because many of them do not operate singly but often in company with others. Nevertheless, studies in Western cities by Rossi (1955),' Maisel (1966),' and Simmons (1968),' for examples, have shown that one important group of variables that consistently affect intra- urban residential mobility is that associated with the family life cycle. In fact, Simmons (1968) concluded that over half of intra-urban mobility within a moderately growing city in the United States "results from the changing housing needs generated by the life cycle."
Theory, National Policy and the Management of Minority Cultures
Authors: Lee Raymond L.M. , Akerman Susan E.
Published: June 2008

Our examination of the ideas shaping theory, policy and administrative approaches to majority-minority relations will emphasize the role of implicit, unrecognized Anglo-American liberal ideologies in delimiting the parameters of discussion. The theories that provide a basis for national policy are grounded in laissex, feire ideology about the inevitable assimilation of minority cultural groups through individualism and the "natural" functioning of market forces. Policies addressing the economic, educational and political aspirations of minority cultures assume that the due process of the established social order naturally results in harmonious relations among all groups and distributes rewards to any deserving individual who exerts efforts to better himself. This ideology essentially asserts that society operates most effectively when individuals or groups are given the moral privilege of gradual adjustment and mobility. We will pursue this theme of the ideological roots of theory and policy in the next two sections of the paper by considering some general theoretical issues and by critiquing theories relevant to national policies. In the third and fourth sections we will analyze the assimilation model and aspects of national policy derived from this model, with attention to the management of. minority relations using illustrative data from Malaysia.
Battered Women and Their Animal Companions: Symbolic Interaction Between Human and Nonhuman Animals
Authors: Flynnl Clifton P.
Published: June 2008

Only recently have sociologists considered the role of nonhuman animals in human society.The few studies undertaken of battered women and their animal companions have revealed high rates of animal abuse co-existing with domestic violence.This study examines several aspects of the relationship between humans and animals in violent homes.The study explored the role of companion animals in the abusive relationship through in-depth, semi-structured interviews with clients at a battered women's shelter. In particular, the study focused on the use of companion animals by women's violent partners to control, hurt, and intimidate the women; the responses of the animals to the women's victimization; and the role of pets as human surrogates and the resulting symbolic interaction between human and nonhuman family members. The significance of the findings for family violence research and application are discussed, as well as the broader implications for sociological investigation of human-animal interaction.
The Status of Animals in Biblical and Christian Thought: A Study in Colliding Values
Authors: Preece Rod , Fraser David
Published: June 2008

A common contemporary view is that the Bible and subsequent Christian thought authorize humans to exploit animals purely as means to human ends.This paper argues that Biblical and Christian thought have given rise to a more complex ethic of animal use informed by its pastoralist origins, Biblical pronouncements that permit different interpretations, and competing ideas and doctrines that arose during its development, and influenced by the rich and often contradictory features of ancient Hebrew and Greco-Roman traditions. The result is not a uniform ethic but a tradition of unresolved debate. Differing interpretations of the Great Chain of Being and the conflict over animal experimentation demonstrate the colliding values inherent in the complex history of Biblical and Christian thought on animals.
Addressing Animal Abuse: The Complementary Roles of Religion, Secular Ethics, and the Law
Authors: Fraschl Pamela D.
Published: June 2008

This paper examines the role that religious belief plays in societies' treatment of nonhuman animals, first asking two questions. Does religious belief continue to play a role today in societies' treatment of nonhuman animals, and should it? The paper discusses the interaction of (a) religion, (b) secular ethics, and (c) the law. As with a three-legged stool, each leg or component relies on the next for support. Religious values and claims, as features of the ethical framework by which many people live, have daily implications for nonhuman animals. On a sliding scale, negative to positive, a religious point of view may affect other animals in different ways. Beliefs - religious in nature and origin - about other animals sometimes stand behind the claims and ethical formulations of avowedly nonreligious people and institutions and may be of some interest to philosophers and historians. The paper concludes that only through consideration and involvement of the three separate, yet inter-connected, components can animal abuse be effectively addressed.
Nothingness and Being A Schelerian Comment
Authors: Frings Manfred
Published: June 2008

Heidegger's central question, "What is the meaning of Being?", is intertwined with the concept of nothingness, as it has been since Pre-Socratic thought. I wish to articulate "nothingness" by restricting myself to three aspects of this concept given by Scheler: 1.) the meanings with which the word "nothing" is used, 2.) the moral implication belonging to the question of "nothing," and 3.) the concept of reality. It is the purpose of this selection of Schelerian thought to furnish some distinctions to be made in Heidegger's central position.
Authenticity Is Not a Real Predicate
Authors: Heim Michael
Published: June 2008

There is a tendency to assume otherwise, to take authenticity for a real predicate, and this is true not only of proponents of existentialism. We find even prominent interpreters of Heidegger using "authenticity" as a real predicate, as a quality applied to a referent present at hand. Let a couple instances suffice.
Twisting Free: Being to an Extent Sensible
Authors: Sallis John
Published: June 2008

I would like to celebrate this beautiful setting, which has been set into the work of one of England's foremost painters, set beautifully, I would want to say. I would like in deed to celebrate it by setting what I shall say within the orbit of a word used by Plato to refer to the beautiful, one to which Heidegger has paid special attention, the word τò εxφαvεστατov, in German, das Hervorscheinendste, in English, the most radiant, that which most shines forth.1 I would like also to offer most sincere thanks to David Krell for arranging this colloquium in this lovely setting; also for many other things, not the least being the phrase that I have borrowed from him and used as the first of the two titles for this lecture, a debt on which I have now, however inadequately, to try to make good.
Editorial
Authors: Macchia Frank D.
Published: June 2008

Barth was not closed to the possibility of glossolalia because he realized in his own experience how powerful the Holy Spirit could be. On a different occasion Barth said to me, 'Almost thou persuadeth me to become an enthusiast, but I must have Scripture.'
Flow Patterns at the Ends of a Street Canyon: Measurements from the Joint Urban 2003 Field Experiment
Authors: Pol Suhas U. , Brown Michael J.
Published: June 2008

During the Joint Urban 2003 experiment held in Oklahoma City, Oklahoma, an east–west-running street canyon was heavily instrumented with wind sensors. In this paper, the flow patterns at the street canyon ends are investigated by looking at sonic anemometers placed near ground level and tethersonde wind vane systems operated in “ladder” mode that were suspended over the sides of the buildings on each side of the street. For southerly flow conditions, the street-level wind sensors often showed what appeared to be a horizontally rotating “corner” or “end” vortex existing at each end of the street canyon near the intersections. It was found that this vortex flow pattern appeared for a wide range of upper-level wind directions but then changed to purely unidirectional flow for wind directions that were outside this range. The tethersonde wind vane measurements show that this vortexlike flow regime occasionally existed through the entire depth of the street canyon. The horizontal extent of the end vortex into the street canyon was found to be different at each end of the street. Under high-wind conditions, the mean wind patterns in the street did not vary appreciably during the day and night. The end vortex may be important in the dispersal of airborne contaminants, acting to enhance lateral and vertical mixing.
A Geographic Information Systems–Based Analysis of Supercells across Oklahoma from 1994 to 2003
Authors: Hocker James E. , Basara Jeffrey B.
Published: June 2008

Oklahoma is a region that is well known for its high frequency of severe thunderstorms, which vary in activity, mode, and coverage. In particular, this region experiences a significant number of highly organized supercell thunderstorms that pose hazards such as high winds, large hail, and tornadoes. This demonstration study focuses on the development and analysis of a 10-yr sample of supercell storms resulting from organized severe weather events in Oklahoma. Geographic information systems (GIS) were used as the primary tool to develop and analyze the 10-yr supercell dataset. The use of GIS technologies within the field of meteorology has increased dramatically in recent years and will likely continue as additional atmospheric science data formats become available in popular GIS software packages such as the Environmental Systems Research Institute’s ArcGIS series. For this specific study, GIS served as a critical component for developing individual georeferenced storm features and analyzing the life span and characteristics of 943 supercell thunderstorms. The results of a series of spatial storm frequency, initiation, termination, and direction analyses are presented. Results revealed that for the period spanning 1994–2003 supercell storms resulting from organized severe weather events were most frequent across several regions, including east-central Oklahoma, southwest Oklahoma, and west-central through northeast Oklahoma, with an overall mean track from the southwest to northeast. Supercell tracks were predominantly southwesterly during the first 5 months of the year, northwesterly from June through September, and once again southwesterly from October through the end of the year. A final set of analyses and examples illustrate the utility of storm feature–based climatologies.
Varus/Valgus and Internal/External Torsional Knee Joint Stiffness Differs between Sexes
Authors: Schmitz Randy J. , Ficklin Travis K. , Shimokochi Yohei , Nguyen Anh-Dung , Beynnon Bruce D. , Perrin David H. , Shultz Sandra J.
Published: June 2008

Background

Torsional joint stiffness is thought to play a role in the observed sex bias in noncontact anterior cruciate ligament injury rates.

Hypothesis

Women will exhibit lower torsional stiffness values of the knee in response to varus/valgus and internal/external rotations than will men.

Study Design

Controlled laboratory study.

Methods

Knee kinematics of 20 university students (10 men, 27.3 ± 3.4 years, 177.3 ± 6.8 cm, 81.1 ± 7.0 kg; 10 women, 22.9 ± 1.5 years, 169.0 ± 7.1 cm, 66.1 ±11.4 kg) were measured while 0 to 10 Nm of varus and valgus torques were applied with the subject nonweightbearing and while 0 to 5 N.m of internal and external torques were applied with the subject nonweightbearing and weightbearing with the use of a custom joint testing device. Joint stiffness values were calculated at 1-N.m increments.

Results

When low magnitudes of torque were applied to the knee, women had significantly lower stiffness values than did men-With the exception of applied external torque with the joint weightbearing and varus torque with the joint nonweightbearing, women demonstrated an increase in joint stiffness as the magnitude of torque increased from lower to higher magnitudes. In contrast, for the men, joint stiffness values remained unchanged as the magnitude of applied torque increased.

Conclusion

Women exhibited lower knee stiffness in response to low magnitudes of applied torque compared to men and demonstrated an increase of joint stiffness as the magnitude of applied torque increased.

Clinical Relevance

The decreased stiffness behavior of the knee in response to low torques that was observed for women may have a role in detrimentally affecting knee biomechanics and resulting neuromuscular function, particularly when an individual transitions from nonweightbearing to weightbearing.
Successful Management of Refractory Neonatal Seizures With Midazolam
Authors: Sirsi Deepa , Nangia Srishti , LaMothe Jacqueline , Kosofsky Barry E. , Solomon Gail E.
Published: June 2008

Seizures are indicative of underlying neurologic dysfunction in neonates. Repeated seizures may be deleterious to the brain even without disturbances of ventilation or perfusion. First-line antiepileptic drugs such as phenobarbital and phenytoin are not very effective in controlling seizures in neonates. Rapid control of status epilepticus with midazolam has been demonstrated in 2 previous studies with complete clinical and electrographic response in neonates who did not respond to phenobarbital and phenytoin. We report our experience with 3 neonates with status epilepticus. Seizures in all 3 neonates did not respond to phenobarbital and phenytoin but responded to midazolam infusion. Midazolam may be considered a safe and effective antiepileptic drug in refractory neonatal seizures of diverse etiologies.
Brain Lesions and IQ: Recovery Versus Decline Depends on Age of Onset
Authors: Duval Julie , Braun Claude M. J. , Montour-Proulx Isabelle , Daigneault Sylvie , Rouleau Isabelle , Bégin Jean
Published: June 2008

A growing literature suggests that early lesions are associated with poorer IQ outcome. Those studies covered a restricted age range in pediatric populations only and did not control for important moderator variables. The present investigation studied IQ change in brain-lesioned children and adults (age 0 to 84 years). Altogether, 725 cases with a documented unilateral focal lesion were gathered from hospital charts and from published cases in the literature, including 240 with repeated IQ testing. Multiple regression analyses isolated the contribution of age at lesion onset to IQ change. Important mediator variables included were lesion side, site, volume, etiology, and so on. An early lesion was significantly associated with poorer postlesion IQ in time and with decline of IQ in time. Later onset lesions were associated with better postlesion IQ and recovery in time. The so-called Kennard principle is refuted, with regard to IQ.
Hormonal regulation of B-cell function and systemic lupus erythematosus
Authors: Cohen-Solal JFG , Jeganathan V , Hill L , Kawabata D , Pinto-Rodriguez D , Grimaldi C , Diamond B
Published: June 2008

The prevalence of systemic lupus erythematosus (SLE) is far higher in females than in males and numerous investigations to understand this gender bias have been performed, which propose as casual actors genetic predispositions and sex hormones effects. We will describe in this review how the sex hormones estrogen and prolactin influence B cell maturation and selection, permitting B cells to mature to immunocompetence in a mouse model of lupus. Finally, we will discuss the relevance and implications of these results for human disease.
Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses
Authors: Petkau J , Reingold SC , Held U , Cutter GR , Fleming TR , Hughes MD , Miller DH , McFarland HF , Wolinsky JS
Published: June 2008

Background

Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes.

Objective

The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS.

Methods

We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database.

Results

Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses.

Conclusions

Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.
Abortion and depression: A population-based longitudinal study of young women
Authors: Pedersen Willy
Published: June 2008

Aim: Induced abortion is an experience shared by a large number of women in Norway, but we know little about the likely social or mental health-related implications of undergoing induced abortion. International studies suggest an increased risk of adverse outcomes such as depression, but many studies are weakened by poor design. One particular problem is the lack of control for confounding factors likely to increase the risk of both abortion and depression. The aim of the study was to investigate whether induced abortion was a risk factor for subsequent depression. Methods: A representative sample of women from the normal population (n=768) was monitored between the ages of 15 and 27 years. Questions covered depression, induced abortion and childbirth, as well as sociodemographic variables, family relationships and a number of individual characteristics, such as schooling and occupational history and conduct problems. Results: Young women who reported having had an abortion in their twenties were more likely to score above the cut-off point for depression (odds ratio (OR) 3.5; 95% confidence interval (CI) 2.0—6.1). Controlling for third variables reduced the association, but it remained significant (OR 2.9; 95% CI 1.7—5.6). There was no association between teenage abortion and subsequent depression. Conclusions: Young adult women who undergo induced abortion may be at increased risk for subsequent depression.
Pulmonary complications in diabetes mellitus
Authors: Kaparianos A , Argyropoulou E , Sampsonas F , Karkoulias K , Tsiamita M , Spiropoulos K
Published: June 2008

Clear decrements in lung function have been reported in patients with diabetes over the past two decades, and many reports have suggested plausible pathophysiological mechanisms. However, there are no reports of functional limitations of activities of daily living ascribable to pulmonary disease in patients with diabetes. This review attempts to summarize the available information from the present literature, to describe the nature of the lung dysfunction in diabetes and the emerging clinical implications of such dysfunction.
Assessing the airways
Authors: Enright P , McCormack M
Published: June 2008

Spirometry is the best test to detect airway obstruction, categorize the severity of obstructive lung diseases, and objectively measure changes in severity because of disease progression or treatment. However, peak flow may be helpful to rule out moderate to severe airway obstruction and for home monitoring in some patients with asthma.
Developing Progress Monitoring Measures for Secondary Mathematics
Authors: Foegen Anne , Olson Jeannette R. , Impecoven-Lind Linda
Published: June 2008

Secondary special educators are in desperate need of progress monitoring measures in mathematics that appropriately reflect their students' instructional content. As educators across the country respond to increasing standards for challenging curricula, growing numbers of students with disabilities are participating in more advanced mathematics courses at the secondary level, including algebra and geometry. Unfortunately, there are few measures in existence specifically designed for these content areas. In this article, the authors describe the work of Project AAIMS (Algebra Assessment and Instruction: Meeting Standards), a federally supported effort to develop and validate progress monitoring measures in algebra. The authors' focus is on describing the process used and offering recommendations for professionals who wish to develop their own measures for secondary mathematics.
Challenges and Opportunities for Promoting Student Achievement Through Large-Scale Assessment Results
Authors: Decker Dawn M. , Bolt Sara E.
Published: June 2008

The intent of large-scale assessment systems is to promote student achievement toward specific standards by holding schools accountable for the performance of all students. However, it is difficult to know whether large-scale assessment systems are having this intended effect as they are currently implemented. In this article, the authors examine the research on intended and unintended consequences of large-scale assessment and accountability systems, highlight critical issues in using large-scale assessment programs to measure student learning and to inform intervention, and provide guidelines for promoting the intervention validity of large-scale assessments.
Affluent parents' advocacy for special-education children's rights vis-a-vis placement-committees in Israel
Authors: Gvion Liora , Luzzatto Diana
Published: June 2008

This article focuses on the strategies that Israeli parents of children with high functioning communication disorders apply in their negotiations with municipal placement-committees, in order to realize their right to be fully involved in matters concerning their children's schooling. Our claim is that the parents introduce into the negotiation process alternatives to the professional discourse inherent in the committee's working culture. The alternative discourse rests on the self-awareness of the parents to their cultural capital and their understanding of a democratic culture, which reinforces their perception of city officials' duties to grant them educational services which accord with their world view. Our study distinguishes between formal and informal strategies of action that assist the parents turning from passive subjects who accept the committee's decisions into active individuals who establish a culture of resistance.
Review: Airway smooth muscle as a model for new investigative drugs in asthma
Authors: Baroffio Michele , Crimi Emanuele , Brusasco Vito
Published: June 2008

Bronchial asthma as such exists because airway smooth muscle (ASM) contracts excessively in response to various stimuli. After several decades during which research was mainly focused on airway inflammation, increasing attention is now being paid to a possible abnormal behaviour of ASM. Thus, ASM is regarded as a major target for anti-asthma treatments. This review first describes the mechanisms of ASM contraction and airway hyperresponsiveness, through cellular, animal and human models. The developments of new drugs targeting extra and/or intracellular pathway of ASM contraction are discussed.
Echocardiography in the Investigation of Cardiomyopathy
Authors: Cubbon Richard M , Kahn Matthew , Rajwani Adil , Gale Christopher P , Kearney Mark T
Published: June 2008

The term cardiomyopathy represents a wide spectrum of myocardial diseases with diverse clinical features and the potential to cause debilitating symptoms, or even death. Echocardiography plays a crucial role in the diagnosis and monitoring of these disorders; contemporary techniques, such as tissue Doppler, contrast echo and 3D echo have added further value to the assessment.
Abdominal Ultrasound Findings in HIV Patients: A Pictorial Review
Authors: Kawooya Michael G. , Muyinda Zeridah , Byanyima Rosemary , Malwadde Elsie Kiguli
Published: June 2008

Human immunodeficiency virus (HIV) is a significant health problem in many developing countries with seroprevalences in the range 5–25%. Ultrasound is the most widely available and affordable method of assessing HIV-related abdominal morbidity. Before antiretroviral therapy is administered, it is imperative that any comorbidity is diagnosed and treated. Awareness of the range of sonographic appearances of abdominal pathology in HIV is important so that a prompt and accurate evaluation can be made. Although ultrasound appearances in HIV vary between different populations and with different grades of immunosuppression, some disease conditions manifest with a characteristic, although not pathognomonic, picture. This aim of this review is to describe the spectrum of ultrasound appearances of the abdominal organs in HIV patients and explain their aetiology.
Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ
Authors: Reddy Raju C. , Narala Venkata R. , Keshamouni Venkateshwar G. , Milam Jami E. , Newstead Michael W. , Standiford Theodore J.
Published: June 2008

Neutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-γ in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-γ, which is up-regulated by the sepsis-induced cytokines TNF-α and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-γ ligands troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-γ construct. Inhibition of chemotaxis by PPAR-γ ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-γ was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-γ antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-γ activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.
A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose
Authors: Cooper Gregory M. , Johnson Julie A. , Langaee Taimour Y. , Feng Hua , Stanaway Ian B. , Schwarz Ute I. , Ritchie Marylyn D. , Stein C. Michael , Roden Dan M. , Smith Joshua D. , Veenstra David L. , Rettie Allan E. , Rieder Mark J.
Published: June 2008

Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n = 181) and 2 independent replication patient populations (n = 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P = 6.2 × 10−13) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ∼ 10−4). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable.
Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer
Authors: Chang David H. , Deng Haiteng , Matthews Phillip , Krasovsky Joseph , Ragupathi Govind , Spisek Radek , Mazumder Amitabha , Vesole David H. , Jagannath Sundar , Dhodapkar Madhav V.
Published: June 2008

CD1d-restricted T cells have been implicated in the pathogenesis of several chronic inflammatory states. However, the nature of the specific ligands recognized by these cells in vivo in patients with inflammatory or malignant diseases remains unknown. We took a biochemical approach to directly isolate and characterize the nature of CD1d-binding ligands from the plasma of myeloma patients. Characterization of these ligands revealed several lysophosphatidylcholine (LPC) species. Human LPC-CD1d dimer binding cells are T-cell receptorαβ+ T cells but predominantly Vα24−Vβ11−. Cytokine secretion by LPC-specific T cells is skewed toward IL-13 secretion, and the frequencies of these cells are increased in myeloma patients relative to healthy donors. These data identify a distinct population of human CD1d-restricted T cells specific for inflammation-associated lysolipids and suggest a novel mechanism for inflammation mediated immune regulation in human cancer.
HIV-1 Tat protein alter the tight junction integrity and function of retinal pigment epithelium: an in vitro study
Authors: Bai Ling , Zhang Zhenping , Zhang Hui , Li Xiumei , Yu Qiurong , Lin Haotian , Yang Wenhui
Published: June 2008

Background

How HIV-1 enter into the eyes remains obscure. We postulated that HIV-1 Tat protein can alter the expression of specific tight-junction proteins and disturb the blood retinal barrier, and contributes to HIV trafficking into the eyes. This study is to determine the effects of HIV-1 Tat proteins on the barrier function and tight-junction protein expression of retinal pigment epithelial cell (RPE).

Methods

A human RPE cell line (D407) cultured on microporous filter-supports was used. After treating with HIV-1 Tat protein, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of the RPE cells to sodium fluorescein was measured. The expressions of the occludin and claudins were determined by real-time polymerase chain reaction, immunofluorescence, and Western blot analysis. Activation of ERK1/2 was detected by Western blot analysis with specific antiphospho protein antibodies. NF-κB DNA binding activity was determined by transcription factor assay. Specific pharmacologic inhibitors directed against the MAPKs were used to analyze the signaling involved in barrier destruction of RPE cells exposed to HIV-1 Tat.

Results

Treating cultured human retinal pigment epithelial cells with 100 nM Tat for 24 hours increased the permeability and decreased the TER of the epithelial monolayer. HIV-1 Tat also disrupted and downregulated the tight-junction proteins claudin-1, claudin-3, and claudin-4 in these cells, whereas claudin-2 was upregulated, and the expression of occludin was unaffected. HIV-1 Tat protein also induced activation of ERK1/2 and NF-κB. HIV-1 Tat protein induced barrier destruction, changes in expression of TJs, and activation of ERK1/2 and NF-κB were abrogated by inhibitor of ERK1/2 and NF-κB.

Conclusion

HIV-1 Tat protein causes increases in the paracellular permeability of RPE cells in vitro concomitant with changes in expression of certain transmembrane proteins associated with the tight junction. The effects of HIV-1 Tat on barrier function of the RPE may be mediated by ERK MAPK and NF-κB activation, which may represent potential targets for novel therapeutic approaches for the retinopathy induced by HIV infection.
Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma
Authors: Chakraborty Sanjukta , Mohiyuddin SM Azeem , Gopinath KS , Kumar Arun
Published: June 2008

Background

Despite extensive research, the five-year survival rate of oral squamous cell carcinoma (OSCC) patients has not improved. Effective treatment of OSCC requires the identification of molecular targets and signaling pathways to design appropriate therapeutic strategies. Several genes from the mTOR signaling pathway are known to be dysregulated in a wide spectrum of cancers. However, not much is known about the involvement of this pathway in tumorigenesis of OSCC. We therefore investigated the role of the tumor suppressor genes, TSC1 and TSC2, and other members of this pathway in tumorigenesis of OSCC.

Methods

Expression of genes at the RNA and protein levels was examined by semi-quantitative RT-PCR and western blot analyses, respectively. Loss of heterozygosity was studied using matched blood and tumor DNA samples and microsatellite markers from the TSC1, TSC2 and PTEN candidate regions. The effect of promoter methylation on TSC gene expression was studied by treating cells with methyltransferase inhibitor 5-azacytidine. Methylation status of the TSC2 promoter in tissue samples was examined by combined bisulfite restriction analysis (COBRA).

Results

The semi-quantitative RT-PCR analysis showed downregulation of TSC1, TSC2, EIF4EBP1 and PTEN, and upregulation of PIK3C2A, AKT1, PDPK1, RHEB, FRAP1, RPS6KB1, EIF4E and RPS6 in tumors. A similar observation was made for AKT1 and RPS6KB1 expression in tumors at the protein level. Investigation of the mechanism of downregulation of TSC genes identified LOH in 36.96% and 39.13% of the tumors at the TSC1 and TSC2 loci, respectively. No mutation was found in TSC genes. A low LOH rate of 13% was observed at the PTEN locus. Treatment of an OSCC cell line with the methyltransferase inhibitor 5-azacytidine showed a significant increase in the expression of TSC genes, suggesting methylation of their promoters. However, the 5-azacytidine treatment of non-OSCC HeLa cells showed a significant increase in the expression of the TSC2 gene only. In order to confirm the results in patient tumor samples, the methylation status of the TSC2 gene promoter was examined by COBRA. The results suggested promoter hypermethylation as an important mechanism for its downregulation. No correlation was found between the presence or absence of LOH at the TSC1 and TSC2 loci in 50 primary tumors to their clinicopathological variables such as age, sex, T classification, stage, grade, histology, tobacco habits and lymph node metastasis.

Conclusion

Our study suggests the involvement of TSC genes and other members of the mTOR signaling pathway in the pathogenesis of OSCC. LOH and promoter methylation are two important mechanisms for downregulation of TSC genes. We suggest that known inhibitors of this pathway could be evaluated for the treatment of OSCC.
Resource use and outcome in critically ill patients with hematological malignancy: a retrospective cohort study
Authors: Merz Tobias M , Schär Pascale , Bühlmann Michael , Takala Jukka , Rothen Hans U
Published: June 2008

Introduction

The paucity of data on resource use in critically ill patients with hematological malignancy and on these patients' perceived poor outcome can lead to uncertainty over the extent to which intensive care treatment is appropriate. The aim of the present study was to assess the amount of intensive care resources needed for, and the effect of treatment of, hemato-oncological patients in the intensive care unit (ICU) in comparison with a nononcological patient population with a similar degree of organ dysfunction.

Methods

A retrospective cohort study of 101 ICU admissions of 84 consecutive hemato-oncological patients and 3,808 ICU admissions of 3,478 nononcological patients over a period of 4 years was performed.

Results

As assessed by Therapeutic Intervention Scoring System points, resource use was higher in hemato-oncological patients than in nononcological patients (median (interquartile range), 214 (102 to 642) versus 95 (54 to 224), P < 0.0001). Severity of disease at ICU admission was a less important predictor of ICU resource use than necessity for specific treatment modalities. Hemato-oncological patients and nononcological patients with similar admission Simplified Acute Physiology Score scores had the same ICU mortality. In hemato-oncological patients, improvement of organ function within the first 48 hours of the ICU stay was the best predictor of 28-day survival.

Conclusion

The presence of a hemato-oncological disease per se is associated with higher ICU resource use, but not with increased mortality. If withdrawal of treatment is considered, this decision should not be based on admission parameters but rather on the evolutional changes in organ dysfunctions.
Cancer Stem Cells and the Ontogeny of Lung Cancer
Authors: Peacock Craig D. , Watkins D. Neil
Published: June 2008

Lung cancer is the leading cause of cancer death in the world today and is poised to claim approximately 1 billion lives during the 21st century. A major challenge in treating this and other cancers is the intrinsic resistance to conventional therapies demonstrated by the stem/progenitor cell that is responsible for the sustained growth, survival, and invasion of the tumor. Identifying these stem cells in lung cancer and defining the biologic processes necessary for their existence is paramount in developing new clinical approaches with the goal of preventing disease recurrence. This review summarizes our understanding of the cellular and molecular mechanisms operating within the putative cancer-initiating cell at the core of lung neoplasia.
Multiple Myeloma Cancer Stem Cells
Authors: Huff Carol Ann , Matsui William
Published: June 2008

Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease.
Invincible, but Not Invisible: Imaging Approaches Toward In Vivo Detection of Cancer Stem Cells
Authors: Hart Lori S. , El-Deiry Wafik S.
Published: June 2008

With evidence emerging in support of a cancer stem-cell model of carcinogenesis, it is of paramount importance to identify and image these elusive cells in their natural environment. The cancer stem-cell hypothesis has the potential to explain unresolved questions of tumorigenesis, tumor heterogeneity, chemotherapeutic and radiation resistance, and even the metastatic phenotype. Intravital imaging of cancer stem cells could be of great value for determining prognosis, as well as monitoring therapeutic efficacy and influencing therapeutic protocols. Cancer stem cells represent a rare population of cells, as low as 0.1% of cells within a human tumor, and the phenotype of isolated cancer stem cells is easily altered when placed under in vitro conditions. This represents a challenge in studying cancer stem cells without manipulation or extraction from their natural environment. Advanced imaging techniques allow for the in vivo observation of physiological events at cellular resolution. Cancer stem-cell studies must take advantage of such technology to promote a better understanding of the cancer stem-cell model in relation to tumor growth and metastasis, as well as to potentially improve on the principles by which cancers are treated. This review examines the opportunities for in vivo imaging of putative cancer stem cells with regard to currently accepted cancer stem-cell characteristics and advanced imaging technologies.