bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroprotection by Hypoxic Preconditioning Involves Oxidative Stress-Mediated Expression of Hypoxia-Inducible Factor and Erythropoietin
Authors: Liu Jing , Narasimhan Purnima , Yu Fengshan , Chan Pak H.
Published: May 2005

Background and Purpose—

Hypoxic preconditioning is an endogenous protection against subsequent lethal hypoxia, but the mechanism involved is not understood. Hypoxia is followed by reactive oxygen species (ROS) production and induces hypoxia-inducible factor (HIF) and its downstream factor erythropoietin (Epo), which is associated with neuroprotection. We hypothesized that these endogenous processes may contribute to hypoxic preconditioning.

Methods—

We used a mouse neuronal culture model, with 2 hours of hypoxia as preconditioning followed by 15 hours of hypoxic insult, and examined the expression of HIF-1α, Epo, and their downstream proteins by Western blotting. Copper/zinc–superoxide dismutase (SOD1) transgenic (Tg) mice were used to detect the effect of ROS. Cell survival and apoptosis were detected by mitogen-activated protein 2 quantification, apoptotic-related DNA fragmentation, and caspase-3 fragmentation. Antisense Epo was used to block endogenously produced Epo.

Results—

Hypoxic preconditioning was protective in wild-type (Wt) neurons but not in neurons obtained from SOD1 Tg mice. In Wt neurons, HIF-1α and Epo expression showed a greater increase after hypoxia compared with Tg neurons and reached a higher level with preconditioned hypoxia, followed by pJak2, pStat5, and nuclear factor κB (NF-κB) expression. Antisense Epo decreased these downstream proteins and the neuroprotection of hypoxic preconditioning.

Conclusions—

Hypoxic preconditioning induces ROS, which may downregulate the threshold for production of HIF-1α and Epo expression during subsequent lethal hypoxia, thus exerting neuroprotection through the Jak2–Stat5 and NF-κB pathways.
Refining the Perfusion–Diffusion Mismatch Hypothesis
Authors: Butcher K.S. , Parsons M. , MacGregor L. , Barber P.A. , Chalk J. , Bladin C. , Levi C. , Kimber T. , Schultz D. , Fink J. , Tress B. , Donnan G. , Davis S.
Published: May 2005

Background and Purpose—

The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)–diffusion-weighted imaging (DWI) mismatch predicts the response to thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients.

Methods—

Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWI
vol
-DWI
vol
) and DWI expansion (T2
Day 90-vol
-DWI
Acute-vol
) were also assessed.

Results—

Mean age was 68±11, time to MRI 4.5±0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (
P
<0.001). Mismatch ≥20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (
R
=−0.51;
P
=0.009).

Conclusions—

Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.
New Concept in Cavernous Sinus Dural Arteriovenous Fistula
Authors: Suh Dae Chul , Lee Jeong Hyun , Kim Sang Joon , Chung Sun Ju , Choi Choong Gon , Kim Hyun Jeong , Kim Chang Jin , Kook Michael , Ahn Hyo-Sook , Kwon Sun Uck , Kim Jong Sung
Published: May 2005

Background and Purpose—

An extradurally located cavernous sinus dural arteriovenous fistula (CSDAVF) exhibits different clinical behavior from other dural arteriovenous fistulas (DAVFs) located between 2 dural leaves. The aim of this study is to define angiographic types of CSDAVF associated with presenting symptom (Sx) and venous drainage patterns.

Methods—

CSDAVFs during a mean of 23-month follow-up period of 58 patients (17 to 73 years, male:female ratio=8:50) were retrospectively analyzed. The 3 types of CSDAF, ie, proliferative (PT), restrictive (RT), and late restrictive (LRT) types, were categorized by the degrees and patterns of prominent arteriovenous shunt as well as venous flow. The status of the venous connection with CS and the presenting Sx patterns classified as orbital (OrbSxP), ocular (OcuSxP), cavernous (CavSxP), and cerebral (CerSxP) were associated with angiographic types as well as symptom onset, age, and gender. Correlations of discrete and categorical variables were statistically analyzed using the χ
2
or Fisher exact test.

Results—

PT (n=23) and RT (n=23) of CSDAVF were more common than LRT (n=12) (
P
=0.016) in patients with younger than 65 years and were related to OrbSxP (
P
=0.015) and CavSxP (
P
=0.038) in contrast to LRT to OcuSxP (
P
=0.004). Early onset of Sxs was related to the OrbSxP (
P
=0.08) and CavSxP (
P
<0.001). CerSxP (5%) was noted in RT or LRT. OrbSxP was related to the superior ophthalmic venous drainage (
P
=0.026) and CavSxP to the inferior petrosal sinus (
P
=0.046) and posterior fossa venous drainages (
P
=0.014). Seven patients revealed chronological progression of CSDAVF from PT to LRT and even to complete healing.

Conclusions—

CSDAVF presents as 3 distinctive angiographic types and is associated with presenting Sxs and venous drainage patterns.
Use of Quantitative Magnetic Resonance Angiography to Stratify Stroke Risk in Symptomatic Vertebrobasilar Disease
Authors: Amin-Hanjani Sepideh , Du Xinjian , Zhao Meide , Walsh Katherine , Malisch Tim W. , Charbel Fady T.
Published: May 2005

Background and Purpose—

Symptomatic vertebrobasilar disease (VBD) carries a high risk of recurrent stroke. We sought to determine whether a management algorithm consisting of quantitative hemodynamic assessment could stratify stroke risk and guide the need for intervention.

Methods—

All patients with symptomatic VBD at our institution are evaluated by a standard protocol including quantitative magnetic resonance angiography (QMRA). Patients are stratified on the basis of the presence or absence of distal flow compromise. Those with low distal flow are offered intervention (surgical or endovascular); all patients receive standard medical therapy. We reviewed the clinical outcome of patients managed with this protocol from 1998 to 2003.

Results—

Follow-up was available for 47 of 50 patients over a mean interval of 28 months. Stroke and combined stroke/transient ischemic attack free survival at 2 years was calculated using the Kaplan–Meier curve. Patients with normal distal flow (n=31) had an event-free survival of 100% and 96%, respectively. Comparatively, patients with low distal flow (n=16) experienced a 71% and 53% event-free survival, demonstrating a significantly higher risk of recurrent ischemia (
P
=0.003). Patients with low flow who subsequently underwent treatment (n=12) had an 82% event-free survival. Cox proportional hazards analysis demonstrated that flow status affected event-free survival regardless of covariates.

Conclusions—

Patients with symptomatic VBD demonstrating low distal flow on QMRA appear to have a high risk of stroke; conversely, those with normal flow seem to have a benign course and may be optimally managed with medical therapy alone.
The Metabolic Syndrome Is a Stronger Risk Factor for Early Carotid Atherosclerosis in Women Than in Men
Authors: Iglseder Bernhard , Cip Paula , Malaimare Liane , Ladurner Gunther , Paulweber Bernhard
Published: May 2005

Background and Purpose—

The metabolic syndrome (MetS) is associated with an increased risk for subsequent development of type 2 diabetes mellitus, cardiovascular disease, and stroke. Type 2 diabetes increases the risk of stroke and coronary heart disease in women to a greater extent than in men, and thus the question arises whether there are sex differences in the association of early atherosclerosis and MetS.

Methods—

1588 middle-aged Austrian subjects (1001 males, 587 females) were included in the present study. MetS was defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Early atherosclerosis was assessed by intima-media thickness (IMT) and extent of plaques (B-score) of the carotid arteries.

Results—

B-score and carotid artery IMT parameters were significantly higher in subjects with the MetS. After adjustment for established risk factors, the difference in B-score remained significant only in women. Computed common carotid artery IMT values using general linear model equations with age, body mass index, and low-density lipoprotein cholesterol as covariates displayed the highest values for men with MetS (811.8±9.5 μm). Women with MetS (797.6±15 μm) and men without the syndrome (788.8±5 μm) showed similar IMTs, whereas women without the MetS presented significantly lower values (735.6±7 μm). Among the subcomponents of the MetS, high-density lipoprotein cholesterol showed the strongest impact on IMT in men, whereas blood glucose ranked first in women.

Conclusions—

The effect of MetS on early atherosclerosis is more pronounced in females. The impact of the components of MetS on carotid IMT differs between men and women.
It Isn't Just about Choice: The Potential of a Public Performance Report to Affect the Public Image of Hospitals
Authors: Hibbard Judith H. , Stockard Jean , Tusler Martin
Published: May 2005

Can a well-designed public performance report affect the public image of hospitals? Using a pre/postdesign and telephone interviews, consumer views and reports of their use of public hospital report are examined. The findings show that the report did influence consumer views about the quality of individual hospitals in the community 2 to 4 months after the release of the report.
The Impact of Medical Interpreter Services on the Quality of Health Care: A Systematic Review
Authors: Flores Glenn
Published: May 2005

Twenty-one million Americans are limited in English proficiency (LEP), but little is known about the effect of medical interpreter services on health care quality. Asystematic literature review was conducted on the impact of interpreter services on quality of care. Five database searches yielded 2,640 citations and a final database of 36 articles, after applying exclusion criteria. Multiple studies document that quality of care is compromised when LEP patients need but do not get interpreters. LEP patients' quality of care is inferior, and more interpreter errors occur with untrained ad hoc interpreters. Inadequate interpreter services can have serious consequences for patients with mental disorders. Trained professional interpreters and bilingual health care providers positively affect LEP patients' satisfaction, quality of care, and outcomes. Evidence suggests that optimal communication, patient satisfaction, and outcomes and the fewest interpreter errors occur when LEP patients have access to trained professional interpreters or bilingual providers.
The Impact of Managed Care on Publicly Funded Outpatient Adolescent Substance Abuse Treatment: Service Use and Six-Month Outcomes in Oregon and Washington
Authors: Carlson Matthew J. , Gabriel Roy M. , Deck Dennis D. , Laws Katherine E. , D'Ambrosio Ryan
Published: May 2005

This study assessed the impact of managed care on publicly funded adolescent substance abuse treatment by comparing differences in service utilization and outcomes across prospective samples from two states: Oregon, which uses managed care practices in service financing and delivery, and Washington, which does not. One hundred and six adolescents from Washington and 94 from Oregon, who entered outpatient substance abuse treatment in 1998 and 1999, completed self-report surveys about their substance use before and after receiving treatment (follow-up rate = 75 percent). In addition, clinical chart reviews conducted at the 6-month follow-up assessed the type and amount of treatment these adolescents received during the study period. It was found that service utilization and treatment outcomes were comparable across the two state samples. The evidence presented here suggests that managed care is capable of delivering substance abuse treatment services of comparable quality to state-administered substance abuse treatment services.
Explaining Variation in Physician Practice Patterns and Their Propensities to Recommend Services
Authors: O’Neill Liam , Kuder John
Published: May 2005

Variations in physician practice patterns have important implications for quality and cost. The purpose of this article is to explain variation in physicians' practice patterns in terms of physician personal characteristics, practice setting, patient population, and managed care involvement. Data on 2,455 primary care physicians were derived from the Community Tracking Study Physician Survey (1996-1997). Factor scores were determined based on responses to three clinical scenarios that represent discretionary medical decisions. These scenarios include a specialist referral for benign prostatic hyperplasia, prescription drugs for elevated cholesterol, and an office visit for vaginal discharge. Physician age, being a foreign medical school graduate, being a solo practitioner, and having a larger proportion of Medicaid patients were all associated with higher factor scores, a greater likelihood of ordering a service. Being board certified was associated with lower factor scores. Managed care involvement was not a significant predictor of factor scores.
Searching for Evidence: The Value of a Librarian-Clinician Collaboration—The Librarian’s Role
Authors: Vrabel Mark
Published: May 2005

More than ever before, home health care practitioners are expected to support their clinical decision making with the best available scientific evidence. It is important for these practitioners to understand the process involved and possess the necessary resources and skills. Librarians and other information professionals trained in performing extensive literature and database searches are ideal partners during the search for evidence. This article identifies and describes those databases most likely to include citations and reviews of research relevant to the home health care practitioner engaging in the evidence search phase of the EBP process, including the Cochrane Library, MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and others, and provides practical suggestions for devising search strategies and optimizing retrieval based upon a well-built clinical question.
Evidence Based Practice: A Nursing Research Assignment
Authors: Simko Lynn Coletta
Published: May 2005

Teaching a graduate-level nursing research course can be quite challenging, especially one that is offered online and asynchronously. One of the assignments required of master of science in nursing (MSN) students is to develop a paper that examines a clinical problem that might be improved by using research knowledge. Students are then required to review the studies in this problem area, summarize what is known and not known regarding this problem, and summarize the gaps in the literature. They then are to write a critique supporting or refuting this practice. This assignment has proven to be both challenging and rewarding for the MSN students. They often comment that they had no idea that the research was or was not available to support (or refute) their clinical practice. The lack of research in these clinical problem areas has led some students to conduct research in these areas.
How to Promote or Implement Evidenced-Based Practice in a Clinical Setting
Authors: Couvillon Jennifer S.
Published: May 2005

How does one promote or implement evidenced-based practice in a clinical setting? This question is often raised, and without a step-by-step plan, the answer is often left unanswered. Research can be theoretical, abstract, and often confusing to the registered nurse who is in the field and busy providing for patients. Imagine that at the beginning of the shift the home health care nurse is organizing the planned patient visits and at the end of the shift is hurriedly writing the plan to meet the needs identified that day. When and how does using evidence from research come into play? How can it be prioritized into the day without taking time away from the patient-nurse interaction? This article offers suggestions for the independent home health care nurse who knows the importance of implementing evidence-based practice in the clinical setting but who cannot seem to find the time.
Evidence-Based Assessment and Treatment of Persistent Pain in the Community-Dwelling Elderly Receiving Home Health Services: A Pathway
Authors: Minner Donna M. , Marek Karen Dorman
Published: May 2005

Persistent pain is a problem for a significant portion of the community-dwelling elderly. Many elderly are reluctant to admit to pain because of fears related to areas such as loss of independence and possible addiction. Cognitively impaired elders may have difficulty expressing persistent pain and understanding pain assessment questions. Because of these and other concerns, the home health nurse faces many challenges when assessing persistent pain in the community-dwelling elderly. A persistent pain pathway was developed to assist home health nurses at Senior Care in the assessment and treatment of persistent pain. Evaluation of its use after 3 months showed an agency-wide increase in client assessment and treatment of pain.
Using Evidence in Home Care: The Value of a Librarian-Clinician Collaboration—the Clinician’s Role
Authors: DePalma Judith A.
Published: May 2005

Evidence-based practice is a natural process for the inquiring home care nurse who wants to provide the highest quality of care. A critical step in the process is finding the best evidence and employing appropriate expertise and resources to facilitate the search. This critical step can be more easily accomplished with a collaborative partnership involving a reference librarian and the clinician. In this process, each uses his or her unique expertise to search for the best evidence to support practice decisions. Examples are given of current relevant evidence for health care clinicians and suggestions for how to use the evidence in decision making.
Home Health Social Work: Obstacles to Evidence-Based Practice
Authors: Dyeson Timothy B.
Published: May 2005

This article briefly describes the mandate for evidence-based practice in social work, the basic principles of evidence-based social work practice, systemic obstacles to evidence-based social work practice in home care, and suggestions for removing these obstacles.
c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells
Authors: Gururajan Murali , Chui Roger , Karuppannan Anbu K. , Ke Jiyuan , Jennings C. Darrell , Bondada Subbarao
Published: May 2005

Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family. Proliferation of murine B lymphomas CH31, CH12.Lx, BKS-2, and WEHI-231 and the human B lymphomas BJAB, RAMOS, RAJI, OCI-Ly7, and OCI-Ly10 was strongly inhibited by SP600125, an anthrapyrazolone inhibitor of JNK, in a dose-dependent manner. The lymphoma cells underwent apoptosis and arrested at the G2/M phase of cell cycle. Furthermore, JNK-specific small interfering RNA (siRNA) inhibited the growth of both murine and human B lymphomas. Thus in the B-lymphoma model, JNK appears to have a unique prosurvival role. Survival signals provided by CD40 and interleukin-10 (IL-10) together reversed the growth inhibition induced by the JNK inhibitor. c-Myc protein levels were reduced in the presence of both SP600125 and JNK-specific siRNA, and CD40 ligation restored c-Myc levels. Moreover, Bcl-xL rescued WEHI-231 cells from apoptosis induced by the JNK inhibitor. The JNK inhibitor also reduced levels of early growth response gene-1 (Egr-1) protein, and overexpressing Egr-1 partially rescued lymphoma cells from apoptosis. Thus, JNK may act via c-Myc and Egr-1, which were shown to be important for B-lymphoma survival and growth. (Blood. 2005;106:1382-1391)
Malaria-specific transgenic CD4+ T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance
Authors: Stephens Robin , Albano Frank R. , Quin Stuart , Pascal Benjamin J. , Harrison Vicky , Stockinger Brigitta , Kioussis Dimitris , Weltzien Hans-Ulrich , Langhorne Jean
Published: May 2005

T cells are important in the immune response to malaria, both for their cytokines and their help for antibody production. To look at the relative importance of these roles, a T-cell receptor (TCR) transgenic mouse has been generated carrying a TCR specific for an epitope of the merozoite surface protein 1 (MSP-1) of the malaria parasite, Plasmodium chabaudi. In adoptive transfer experiments, malaria-specific CD4+ T cells expand and produce interferon γ (IFN-γ) early in infection, but the population contracts quickly despite prolonged persistence of the parasite. MSP-1-specific CD4+ cells can protect immunodeficient mice from lethal infection; however, the parasite is only completely cleared in the presence of B cells showing that T helper cells are critical. Levels of malaria-specific antibody and the speed of their production clearly correlate with the time of resolution of infection, indicating that a critical threshold of antibody production is required for parasite clearance. Furthermore, T cells specific for a shed portion of MSP-1 are able to provide help for antibody to the protective region, which remains bound to the infected erythrocyte, suggesting that MSP-1 has all of the components necessary for a good vaccine. (Blood. 2005;106:1676-1684)
Chimeric NK-receptor–bearing T cells mediate antitumor immunotherapy
Authors: Zhang Tong , Lemoi Bethany A. , Sentman Charles L.
Published: May 2005

NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. The aim of this study was to determine whether chimeric NK-receptor—bearing T cells would directly kill tumor cells and lead to induction of host immunity against tumors. Chimeric NK receptors were produced by linking NKG2D or DNAX activating protein of 10 kDa (Dap10) to the cytoplasmic portion of the CD3ζ chain. Our results showed that chimeric (ch) NKG2D-bearing T cells responded to NKG2D-ligand–bearing tumor cells (RMA/Rae-1β, EG7) but not to wild-type tumor cells (RMA). This response was dependent upon ligand expression on the target cells but not on expression of major histocompatibility complex (MHC) molecules, and the response could be blocked by anti-NKG2D antibodies. These T cells produced large amounts of T-helper 1 (Th1) cytokines and proinflammatory chemokines and killed ligand–expressing tumor cells. Adoptive transfer of chNKG2D-bearing T cells inhibited RMA/Rae-1β tumor growth in vivo. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.
Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression
Authors: Le Scolan Erwan , Pchejetski Dimitri , Banno Yoshiko , Denis Nicole , Mayeux Patrick , Vainchenker William , Levade Thierry , Moreau-Gachelin Françoise
Published: May 2005

The erythroleukemia developed by spi-1/PU.1-transgenic mice is a model of multistage oncogenic process. Isolation of tumor cells representing discrete stages of leukemic progression enables the dissection of some of the critical events required for malignant transformation. To elucidate the molecular mechanisms of multistage leukemogenesis, we developed a microarray transcriptome analysis of nontumorigenic (HS1) and tumorigenic (HS2) proerythroblasts from spi-1-transgenic mice. The data show that transcriptional up-regulation of the sphingosine kinase gene (SPHK1) is a recurrent event associated with the tumorigenic phenotype of these transgenic proerythroblasts. SPHK1 is an enzyme of the metabolism of sphingolipids, which are essential in several biologic processes, including cell proliferation and apoptosis. HS1 erythroleukemic cells engineered to overexpress the SPHK1 protein exhibited growth proliferative advantage, increased clonogenicity, and resistance to apoptosis in reduced serum level by a mechanism involving activation of the extracellular signal-related kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In addition, SPHK1-overexpressing HS1 cells acquired tumorigenicity when engrafted in vivo. Finally, enforced expression of a dominant-negative mutant of SPHK1 in HS2 tumorigenic cells or treatment with a pharmacologic inhibitor reduced both cell growth and apoptosis resistance. Altogether, these data suggest that overexpression of the sphingosine kinase may represent an oncogenic event during the multistep progression of an erythroleukemia. (Blood. 2005;106:1808-1816)
Inhibition of APC anticoagulant activity on oxidized phospholipid by anti–β2-glycoprotein I monoclonal antibodies
Authors: Safa Omid , Esmon Charles T. , Esmon Naomi L.
Published: May 2005

Activated protein C (APC) anticoagulant activity and the ability to be inhibited by auto-antibodies associated with thrombosis are strongly augmented by the presence of phosphatidylethanolamine (PE) and phospholipid oxidation. β2-glycoprotein I (β2-GPI) is a major antigen for antiphospholipid antibodies present in patients with the antiphospholipid syndrome. We therefore investigated whether anti–β2-GPI monoclonal antibodies (mAbs) could inhibit APC with similar membrane specificity. Five mouse mAbs that reacted with different epitopes on β2-GPI were examined. Each inhibited the PE-, phospholipid oxidation–dependent enhancement of APC anticoagulant activity and required antibody divalency. A chimeric APC that retains anticoagulant activity but is relatively unaffected by protein S, PE, or oxidation was not inhibited by the antibodies. In purified systems, anti–β2-GPI mAb inhibition of factor Va inactivation was greater in the presence of protein S and required β2-GPI. Surprisingly, although the mAbs did increase β2-GPI affinity for membranes, PE and oxidation had little influence on the affinity of the β2-GPI antibody complex for the membrane vesicles. We conclude that antibodies to β2-GPI inhibit APC function specifically and contribute to a hypercoaguable state by disrupting specific protein-protein interactions induced by oxidation of PE-containing membranes.
How do stem cells find their way home?
Authors: Lapidot Tsvee , Dar Ayelet , Kollet Orit
Published: May 2005

Migration of hematopoietic stem cells through the blood, across the endothelial vasculature to different organs and to their bone marrow (BM) niches, requires active navigation, a process termed homing. Homing is a rapid process and is the first and essential step in clinical stem cell transplantation. Similarly, homing is required for seeding of the fetal BM by hematopoietic progenitors during development. Homing has physiological roles in adult BM homeostasis, which are amplified during stress-induced recruitment of leukocytes from the BM reservoir and during stem cell mobilization, as part of host defense and repair. Homing is thought to be a coordinated, multistep process, which involves signaling by stromal-derived factor 1 (SDF-1) and stem cell factor (SCF), activation of lymphocyte function–associated antigen 1 (LFA-1), very late antigen 4/5 (VLA-4/5) and CD44, cytoskeleton rearrangement, membrane type 1 (MT1)–matrix metalloproteinase (MMP) activation and secretion of MMP2/9. Rolling and firm adhesion of progenitors to endothelial cells in small marrow sinusoids under blood flow is followed by trans-endothelial migration across the physical endothelium/extracellular matrix (ECM) barrier. Stem cells finalize their homing uniquely, by selective access and anchorage to their specialized niches in the extravascular space of the endosteum region and in periarterial sites. This review is focused on mechanisms and key regulators of human stem cell homing to the BM in experimental animal models and clinical transplantation protocols.
Visualization methods for statistical analysis of microarray clusters
Authors: Hibbs Matthew A , Dirksen Nathaniel C , Li Kai , Troyanskaya Olga G
Published: May 2005

Background

The most common method of identifying groups of functionally related genes in microarray data is to apply a clustering algorithm. However, it is impossible to determine which clustering algorithm is most appropriate to apply, and it is difficult to verify the results of any algorithm due to the lack of a gold-standard. Appropriate data visualization tools can aid this analysis process, but existing visualization methods do not specifically address this issue.

Results

We present several visualization techniques that incorporate meaningful statistics that are noise-robust for the purpose of analyzing the results of clustering algorithms on microarray data. This includes a rank-based visualization method that is more robust to noise, a difference display method to aid assessments of cluster quality and detection of outliers, and a projection of high dimensional data into a three dimensional space in order to examine relationships between clusters. Our methods are interactive and are dynamically linked together for comprehensive analysis. Further, our approach applies to both protein and gene expression microarrays, and our architecture is scalable for use on both desktop/laptop screens and large-scale display devices. This methodology is implemented in GeneVAnD (Genomic Visual ANalysis of Datasets) and is available at http://function.princeton.edu/GeneVAnD.

Conclusion

Incorporating relevant statistical information into data visualizations is key for analysis of large biological datasets, particularly because of high levels of noise and the lack of a gold-standard for comparisons. We developed several new visualization techniques and demonstrated their effectiveness for evaluating cluster quality and relationships between clusters.
Predicting functional sites with an automated algorithm suitable for heterogeneous datasets
Authors: La David , Livesay Dennis R
Published: May 2005

Background

In a previous report (La et al.,Proteins, 2005), we have demonstrated that the identification of phylogenetic motifs, protein sequence fragments conserving the overall familial phylogeny, represent a promising approach for sequence/function annotation. Across a structurally and functionally heterogeneous dataset, phylogenetic motifs have been demonstrated to correspond to a wide variety of functional site archetypes, including those defined by surface loops, active site clefts, and less exposed regions. However, in our original demonstration of the technique, phylogenetic motif identification is dependent upon a manually determined similarity threshold, prohibiting large-scale application of the technique.

Results

In this report, we present an algorithmic approach that determines thresholds without human subjectivity. The approach relies on significant raw data preprocessing to improve signal detection. Subsequently, Partition Around Medoids Clustering (PAMC) of the similarity scores assesses sequence fragments where functional annotation remains in question. The accuracy of the approach is confirmed through comparisons to our previous (manual) results and structural analyses. Triosephosphate isomerase and arginyl-tRNA synthetase are discussed as exemplar cases. A quantitative functional site prediction assessment algorithm indicates that the phylogenetic motif predictions, which require sequence information only, are nearly as good as those from evolutionary trace methods that do incorporate structure.

Conclusion

The automated threshold detection algorithm has been incorporated into MINER, our web-based phylogenetic motif identification server. MINER is freely available on the web athttp://www.pmap.csupomona.edu/MINER/. Pre-calculated functional site predictions of the COG database and an implementation of the threshold detection algorithm, in the R statistical language, can also be accessed at the website.
Robust detection of periodic time series measured from biological systems
Authors: Ahdesmäki Miika , Lähdesmäki Harri , Pearson Ron , Huttunen Heikki , Yli-Harja Olli
Published: May 2005

Background

Periodic phenomena are widespread in biology. The problem of finding periodicity in biological time series can be viewed as a multiple hypothesis testing of the spectral content of a given time series. The exact noise characteristics are unknown in many bioinformatics applications. Furthermore, the observed time series can exhibit other non-idealities, such as outliers, short length and distortion from the original wave form. Hence, the computational methods should preferably be robust against such anomalies in the data.

Results

We propose a general-purpose robust testing procedure for finding periodic sequences in multiple time series data. The proposed method is based on a robust spectral estimator which is incorporated into the hypothesis testing framework using a so-calledg-statistic together with correction for multiple testing. This results in a robust testing procedure which is insensitive to heavy contamination of outliers, missing-values, short time series, nonlinear distortions, and is completely insensitive to any monotone nonlinear distortions. The performance of the methods is evaluated by performing extensive simulations. In addition, we compare the proposed method with another recent statistical signal detection estimator that uses Fisher's test, based on the Gaussian noise assumption. The results demonstrate that the proposed robust method provides remarkably better robustness properties. Moreover, the performance of the proposed method is preferable also in the standard Gaussian case. We validate the performance of the proposed method on real data on which the method performs very favorably.

Conclusion

As the time series measured from biological systems are usually short and prone to contain different kinds of non-idealities, we are very optimistic about the multitude of possible applications for our proposed robust statistical periodicity detection method.

Availability

The presented methods have been implemented in Matlab and in R. Codes are available on request. Supplementary material is available at:http://www.cs.tut.fi/sgn/csb/robustperiodic/.
Computing expectation values for RNA motifs using discrete convolutions
Authors: Lambert André , Legendre Matthieu , Fontaine Jean-Fred , Gautheret Daniel
Published: May 2005

Background

Computational biologists use Expectation values (E-values) to estimate the number of solutions that can be expected by chance during a database scan. Here we focus on computing Expectation values for RNA motifs defined by single-strand and helix lod-score profiles with variable helix spans. Such E-values cannot be computed assuming a normal score distribution and their estimation previously required lengthy simulations.

Results

We introduce discrete convolutions as an accurate and fast mean to estimate score distributions of lod-score profiles. This method provides excellent score estimations for all single-strand or helical elements tested and also applies to the combination of elements into larger, complex, motifs. Further, the estimated distributions remain accurate even when pseudocounts are introduced into the lod-score profiles. Estimated score distributions are then easily converted into E-values.

Conclusion

A good agreement was observed between computed E-values and simulations for a number of complete RNA motifs. This method is now implemented into the ERPIN software, but it can be applied as well to any search procedure based on ungapped profiles with statistically independent columns.
The integrins of the urochordate Ciona intestinalis provide novel insights into the molecular evolution of the vertebrate integrin family
Authors: Ewan Richard , Huxley-Jones Julie , Mould A Paul , Humphries Martin J , Robertson David L , Boot-Handford Raymond P
Published: May 2005

Background

Integrins are a functionally significant family of metazoan cell surface adhesion receptors. The receptors are dimers composed of an alpha and a beta chain. Vertebrate genomes encode an expanded set of integrin alpha and beta chains in comparison with protostomes such as drosophila or the nematode worm. The publication of the genome of a basal chordate, Ciona intestinalis, provides a unique opportunity to gain further insight into how and when the expanded integrin supergene family found in vertebrates evolved.

Results

The Ciona genome encodes eleven α and five β chain genes that are highly homologous to their vertebrate homologues. Eight of the α chains contain an A-domain that lacks the short alpha helical region present in the collagen-binding vertebrate alpha chains. Phylogenetic analyses indicate the eight A-domain containing α chains cluster to form an ascidian-specific clade that is related to but, distinct from, the vertebrate A-domain clade. Two Ciona α chains cluster in laminin-binding clade and the remaining chain clusters in the clade that binds the RGD tripeptide sequence. Of the five Ciona β chains, three form an ascidian-specific clade, one clusters in the vertebrate β1 clade and the remaining Ciona chain is the orthologue of the vertebrate β4 chain.

Conclusion

The Ciona repertoire of integrin genes provides new insight into the basic set of these receptors available at the beginning of vertebrate evolution. The ascidian and vertebrate α chain A-domain clades originated from a common precursor but radiated separately in each lineage. It would appear that the acquisition of collagen binding capabilities occurred in the chordate lineage after the divergence of ascidians.
Characterization of TRZ1, a yeast homolog of the human candidate prostate cancer susceptibility gene ELAC2 encoding tRNase Z
Authors: Chen Yang , Beck Audrey , Davenport Christina , Chen Yuan , Shattuck Donna , Tavtigian Sean V
Published: May 2005

Background

In humans, mutation of ELAC2 is associated with an increased risk of prostate cancer. ELAC2 has been shown to have tRNase Z activity and is associated with the γ-tubulin complex.

Results

In this work, we show that the yeast homolog of ELAC2, encoded by TRZ1 (tRNase Z 1), is involved genetically in RNA processing. The temperature sensitivity of a trz1 mutant can be rescued by multiple copies of REX2, which encodes a protein with RNA 3' processing activity, suggesting a role of Trz1p in RNA processing in vivo. Trz1p has two putative nucleotide triphosphate-binding motifs (P-loop) and a conserved histidine motif. The histidine motif and the putative nucleotide binding motif at the C-domain are important for Trz1p function because mutant proteins bearing changes to the critical residues in these motifs are unable to rescue deletion of TRZ1. The growth defect exhibited by trz1 yeast is not complemented by the heterologous ELAC2, suggesting that Trz1p may have additional functions in yeast.

Conclusion

Our results provide genetic evidence that prostate cancer susceptibility gene ELAC2 may be involved in RNA processing, especially rRNA processing and mitochondrial function.
The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760]
Authors: Schwenkreis Peter , Witscher Katja , Pleger Burkhard , Malin Jean-Pierre , Tegenthoff Martin
Published: May 2005

Background

Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions.

Results

We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels.

Conclusion

We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation.
Hippocampal lesions facilitate instrumental learning with delayed reinforcement but induce impulsive choice in rats
Authors: Cheung Timothy HC , Cardinal Rudolf N
Published: May 2005

Background

Animals must frequently act to influence the world even when the reinforcing outcomes of their actions are delayed. Learning with action-outcome delays is a complex problem, and little is known of the neural mechanisms that bridge such delays. When outcomes are delayed, they may be attributed to (or associated with) the action that caused them, or mistakenly attributed to other stimuli, such as the environmental context. Consequently, animals that are poor at forming context-outcome associations might learn action-outcome associations better with delayed reinforcement than normal animals. The hippocampus contributes to the representation of environmental context, being required for aspects of contextual conditioning. We therefore hypothesized that animals with hippocampal lesions would be better than normal animals at learning to act on the basis of delayed reinforcement. We tested the ability of hippocampal-lesioned rats to learn a free-operant instrumental response using delayed reinforcement, and what is potentially a related ability – the ability to exhibit self-controlled choice, or to sacrifice an immediate, small reward in order to obtain a delayed but larger reward.

Results

Rats with sham or excitotoxic hippocampal lesions acquired an instrumental response with different delays (0, 10, or 20 s) between the response and reinforcer delivery. These delays retarded learning in normal rats. Hippocampal-lesioned rats responded slightly less than sham-operated controls in the absence of delays, but they became better at learning (relative to shams) as the delays increased; delays impaired learning less in hippocampal-lesioned rats than in shams. In contrast, lesioned rats exhibited impulsive choice, preferring an immediate, small reward to a delayed, larger reward, even though they preferred the large reward when it was not delayed.

Conclusion

These results support the view that the hippocampus hinders action-outcome learning with delayed outcomes, perhaps because it promotes the formation of context-outcome associations instead. However, although lesioned rats were better at learning with delayed reinforcement, they were worse at choosing it, suggesting that self-controlled choice and learning with delayed reinforcement tax different psychological processes.
Non-isotropic noise correlation in PET data reconstructed by FBP but not by OSEM demonstrated using auto-correlation function
Authors: Razifar Pasha , Lubberink Mark , Schneider Harald , Långström Bengt , Bengtsson Ewert , Bergström Mats
Published: May 2005

Background

Positron emission tomography (PET) is a powerful imaging technique with the potential of obtaining functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules in a biological system, bothin vitroandin vivo. PET images can be used directly or after kinetic modelling to extract quantitative values of a desired physiological, biochemical or pharmacological entity. Because such images are generally noisy, it is essential to understand how noise affects the derived quantitative values. A pre-requisite for this understanding is that the properties of noise such as variance (magnitude) and texture (correlation) are known.

Methods

In this paper we explored the pattern of noise correlation in experimentally generated PET images, with emphasis on the angular dependence of correlation, using the autocorrelation function (ACF). Experimental PET data were acquired in 2D and 3D acquisition mode and reconstructed by analytical filtered back projection (FBP) and iterative ordered subsets expectation maximisation (OSEM) methods. The 3D data was rebinned to a 2D dataset using FOurier REbinning (FORE) followed by 2D reconstruction using either FBP or OSEM. In synthetic images we compared the ACF results with those from covariance matrix. The results were illustrated as 1D profiles and also visualized as 2D ACF images.

Results

We found that the autocorrelation images from PET data obtained after FBP were not fully rotationally symmetric or isotropic if the object deviated from a uniform cylindrical radioactivity distribution. In contrast, similar autocorrelation images obtained after OSEM reconstruction were isotropic even when the phantom was not circular. Simulations indicated that the noise autocorrelation is non-isotropic in images created by FBP when the level of noise in projections is angularly variable. Comparison between 1D cross profiles on autocorrelation images obtained by FBP reconstruction and covariance matrices produced almost identical results in a simulation study.

Conclusion

With asymmetric radioactivity distribution in PET, reconstruction using FBP, in contrast to OSEM, generates images in which the noise correlation is non-isotropic when the noise magnitude is angular dependent, such as in objects with asymmetric radioactivity distribution. In this respect, iterative reconstruction is superior since it creates isotropic noise correlations in the images.