bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-β
2
Authors: Paruchuri Sailaja , Yang Jeong-Hee , Aikawa Elena , Melero-Martin Juan M. , Khan Zia A. , Loukogeorgakis Stavros , Schoen Frederick J. , Bischoff Joyce
Published: September 2006

In situ analysis of fetal semilunar valve leaflets has revealed cells coexpressing endothelial and mesenchymal markers along the endothelium, with diminished frequency seen in adult valves. To determine whether such cells are progenitor cells, we isolated clonal populations from human pulmonary valves. The clones expressed endothelial markers but showed potential to further differentiate into endothelium in response to vascular endothelial growth factor (VEGF)-A. When exposed to transforming growth factor (TGF)-β
2
, individual clones adopted a mesenchymal phenotype to varying degrees and expressed markers of endothelial to mesenchymal transformation (EMT). Both VEGF- and TGFβ
2
–induced phenotypic changes were partially reversible, indicating the plasticity of these cells. When challenged with VEGF or TGFβ
2
, a hierarchy of endothelial/mesenchymal potential could be seen among the clonal populations: cells initially closer to an endothelial phenotype showed a strong response to TGFβ
2
that could be inhibited by VEGF, whereas cells closer to a mesenchymal phenotype responded to TGFβ
2
but were resistant to endothelial-inducing effects of VEGF. These findings suggest the presence of bipotential valve progenitor cells with ability to differentiate into either endothelial or interstitial cells of the valve leaflet. Understanding the differentiation potential and function of these cells may be important for understanding heart valve disease and may also be applied to current paradigms for creating tissue-engineered heart valves.
Adenylyl Cyclase Isoform–Selective Regulation of Vascular Smooth Muscle Proliferation and Cytoskeletal Reorganization
Authors: Gros Robert , Ding Qingming , Chorazyczewski Jozef , Pickering J. Geoffrey , Limbird Lee E. , Feldman Ross D.
Published: September 2006

Compartmentation of cAMP signaling been demonstrated to be attributable to the structural association of protein kinase A (PKA) (via association with A-kinase anchoring proteins [AKAPs]) with phosphodiesterase and AKAP-dependent effector molecules. However, other mechanisms contributing to compartmentalization have not been rigorously explored, including the possibility that different isoforms of adenylyl cyclase (AC) may be functionally “compartmentalized” because of differential association with tethering or signaling molecules. To this end, we examined the effect of adenoviral transduction of representative AC isoforms (AC1, AC2, AC5, and AC6) on cellular cAMP production, PKA activation, extracellular signal-regulated kinase (ERK) activation, cell doubling and proliferation, as well as arborization responses (an index of cAMP-mediated cytoskeletal re-organization) in vascular smooth muscle cells. When isoforms were expressed at levels to achieve comparable forskolin-stimulated AC activity, only gene transfer of AC6 significantly enhanced PKA-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation and arborization responses. Treatment of control cells, which express AC6 endogenously, as well as vascular smooth overexpressing the AC6 isoform with small interfering RNA directed against AC6, significantly suppressed both isoproterenol-stimulated cAMP accumulation and arborization. Notably, the selective effects of AC6 expression were abrogated in the presence of phosphodiesterase suppression. In contrast, only the expression of AC1 enhanced forskolin-stimulated association of ERK with AC, demonstrated by coimmuno-isolation of ERK with Flag-tagged AC1, but not with Flag-tagged AC6. To determine whether these isoform-selective effects of AC were unique to differentiated and morphologically compartmentalized vascular smooth muscle cells or were a general property of these isoforms, we examined the consequence of expression of these various isoforms in human embryonic kidney (HEK) cells. Indeed, we observed similar isoform-dependent association of AC1 with ERK, activation of ERK by stimulation of AC1 with forskolin, and AC1-dependent lengthening of doubling time, indicating that these properties of AC1 are cell autologous and likely result from AC1-dependent protein-protein interactions. In aggregate, these findings suggest that isoform-selective signaling complexes likely contribute to various functional consequences of cAMP elevation in vascular smooth muscle cells.
APOE4
-VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2
Authors: DeKroon Robert , Robinette Jennifer B. , Hjelmeland Anita B. , Wiggins Emma , Blackwell Morven , Mihovilovic Mirta , Fujii Makoto , York John , Hart Janet , Kontos Christopher , Rich Jeremy , Strittmatter Warren J.
Published: September 2006

Endothelial cell dysfunction and apoptosis are critical in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Both endothelial cell apoptosis and atherosclerosis are reduced by high-density lipoprotein (HDL). Low HDL levels increase the risk of CVD and are also a key characteristic of the metabolic syndrome. The apolipoprotein E4 (
APOE4
) allele also increases the risk of atherosclerosis and CVD. We previously demonstrated that the antiapoptotic activity of HDL is inhibited by
APOE4
very-low-density lipoprotein (
APOE4
-VLDL) in endothelial cells, an effect similar to reducing the levels of HDL. Here we establish the intracellular mechanism by which
APOE4
-VLDL inhibits the antiapoptotic pathway activated by HDL. We show that
APOE4
-VLDL diminishes the phosphorylation of Akt by HDL but does not alter phosphorylation of c-Jun N-terminal kinase, p38, or Src family kinases by HDL. Furthermore
APOE4
-VLDL inhibits Akt phosphorylation by reducing the phosphatidylinositol 3-kinase product phosphatidylinositol-(3,4,5)-triphosphate (PI[3,4,5]P
3
). We further demonstrate that
APOE4
-VLDL reduces PI(3,4,5)P
3
, through the phosphoinositol phosphatase SHIP2, and not through PTEN. SHIP2 is already implicated as an independent risk factor for type II diabetes, hypertension and obesity, which are also all components of the metabolic syndrome and independent risk factors for CVD. Significantly, the association between CVD and type 2 diabetes or hypertension is further increased by the
APOE4
allele. Therefore the activation of SHIP2 by
APOE4
-VLDL, with the subsequent inhibition of the HDL/Akt pathway, is a novel and significant biological mechanism and may be a critical intermediate by which
APOE4
increases the risk of atherosclerotic CVD.
Oxidized Phospholipids Stimulate Angiogenesis Via Autocrine Mechanisms, Implicating a Novel Role for Lipid Oxidation in the Evolution of Atherosclerotic Lesions
Authors: Bochkov Valery N. , Philippova Maria , Oskolkova Olga , Kadl Alexandra , Furnkranz Alexander , Karabeg Erduan , Afonyushkin Taras , Gruber Florian , Breuss Johannes , Minchenko Alexander , Mechtcheriakova Diana , Hohensinner Philipp , Rychli Kathrin , Wojta Johann , Resink Therese , Erne Paul , Binder Bernd R. , Leitinger Norbert
Published: September 2006

Angiogenesis is a common feature observed in advanced atherosclerotic lesions. We hypothesized that oxidized phospholipids (OxPLs), which accumulate in atherosclerotic vessels can stimulate angiogenesis. We found that oxidized 1-palmitoyl-2-arachidonoyl-
sn
-glycero-3-phosphocholine (OxPAPC) stimulated the formation of sprouts from endothelial cell spheroids and promoted growth of capillaries into Matrigel plugs in mice. OxPLs stimulated expression of vascular endothelial growth factor (VEGF) in vivo and in several normal and tumor cell types in vitro. In addition, OxPAPC upregulated cyclooxygenase (COX)-2 and interleukin (IL)-8. COX-2 inhibitors, as well as blocking antibodies to IL-8 suppressed activation of sprouting by OxPAPC. We conclude that OxPAPC stimulates angiogenesis via autocrine mechanisms involving VEGF, IL-8, and COX-2–generated prostanoids. Our data suggest that accumulation of OxPLs may contribute to increased growth of blood capillaries in advanced lesions, thus leading to progression and destabilization of atherosclerotic plaques.
Meniscal Repair with Biofix Arrows
Authors: Gifstad Tone , Grøntvedt Torbjørn , Drogset Jon Olav
Published: September 2006

Background

Absorbable meniscus arrows have, since they were introduced in 1993, become a common all-inside technique in meniscal repair. Potential advantages are conserving the meniscus, simplifying the surgical technique, reducing operating time, and reducing the risk of neurovascular damage. Despite extensive use all over the world, few long-term follow-up studies have been published.

Hypothesis

Meniscus arrows have, based on published material, a rate of success around 80% to 90%.

Study Design

Case series; Level of evidence, 4.

Methods

The Biofix arrow fixation technique was used in 123 patients in need of meniscal repair from January 1997 to December 2002 at our hospital. The patients underwent an interview by phone, mail, or e-mail during autumn 2004 that included questions about reoperation and Lysholm score. In addition, the operative charts were reviewed.

Results

There were 118 patients (96%) available for the questionnaire, and 45 of these (38%) had had reoperations done because of meniscal rerupture during the follow-up period. Another 3 patients were waiting for meniscal reoperations. In addition, the charts of 2 of those unavailable for the study showed that they had been reoperated, resulting in a total of 41% verified failures. The Lysholm score for the whole study group at follow-up was 85 (range, 36-100). The mean Lysholm score for those who had a second operation was 81 (range, 36-100), and it was 88 (range, 55-100) for the others (P = .009). The mean time between primary operation and reoperation was 17 months (range, 1-75 months). Mean postoperative follow-up was 4.7 years (range, 1.8-7.7 years).

Conclusion

Meniscal repair with Biofix arrows has an unacceptably low rate of success.
Pitching Biomechanics as a Pitcher Approaches Muscular Fatigue during a Simulated Baseball Game
Authors: Escamilla Rafael F. , Barrentine Steven W. , Fleisig Glenn S. , Zheng Naiquan , Takada Yoshihiro , Kingsley David , Andrews James R.
Published: September 2006

Background

The effects of approaching muscular fatigue on pitching biomechanics are currently unknown. As a pitcher fatigues, pitching mechanics may change, leading to a decrease in performance and an increased risk of injury.

Hypothesis

As a pitcher approaches muscular fatigue, select pitching biomechanical variables will be significantly different than they were before muscular fatigue.

Study Design

Controlled laboratory study.

Methods

Ten collegiate baseball pitchers threw 15 pitches per inning for 7 to 9 innings off an indoor throwing mound during a simulated baseball game. A pitching session ended when each pitcher felt he could no longer continue owing to a subjective perception of muscular fatigue. A 6-camera 3D automatic digitizing system collected 200-Hz video data. Twenty kinematic and 11 kinetic variables were calculated throughout 4 phases of the pitch. A repeated-measure analysis of variance (P < .01) was used to compare biomechanical variables between innings.

Results

Compared with the initial 2 innings, as a pitcher approached muscular fatigue during the final 2 innings he was able to pitch, there was a significant decrease in ball velocity, and the trunk was significantly closer to a vertical position. There were no other significant differences in kinematics or kinetics variables.

Conclusion

The relatively few differences observed imply that pitching biomechanics remained remarkably similar between collegiate starting pitchers who threw between 105 and 135 pitches for 7 to 9 innings and approached muscular fatigue.

Clinical Relevance

This study did not support the idea that there is an increase in shoulder and elbow forces and torques as muscular fatigue is approached. It is possible that if a pitcher remained in a fatigued state for a longer period of time, additional changes in pitching mechanics may occur and the risk of injury may increase.
Achilles Tendon Elongation after Rupture Repair
Authors: Kangas Jarmo , Pajala Ari , Ohtonen Pasi , Leppilahti Juhana
Published: September 2006

Background

A few prospective controlled trials comparing early functional rehabilitation after Achilles tendon repair and non-operative immobilization have been reported.

Hypotheses

There is no difference in Achilles tendon elongation between early motion and immobilization after Achilles tendon repair. Tendon elongation does not correlate with the clinical outcome.

Study Design

Randomized clinical trial; Level of evidence, 2.

Methods

Fifty patients with acute Achilles tendon rupture were randomized postoperatively to receive either early movement of the ankle between neutral and plantar flexion in a brace for 6 weeks or immobilization in tension using a below-knee cast with the ankle in a neutral position for 6 weeks. Full weightbearing was allowed after 3 weeks in both groups. Standardized radiographs to measure previously placed radiographic markers were taken on the first day postoperatively and at 1, 3, 6, 12, 24 weeks postoperatively, with the final radiograph a mean of 60 (SD, 6.4) weeks postoperatively. The outcome was assessed at the 3-month and final checkups by the clinical scoring method described by Leppilahti et al and included subjective factors and objective factors.

Results

Tendon elongation occurred in both groups but was somewhat less in the early motion group (median 2 mm in the early motion group vs median 5 mm in the cast group a mean of 60 weeks postoperatively, P = .054). The elongation curves first rose and then slowly fell in both groups. The patients who had less elongation achieved a better clinical outcome (ρ= -.42, P = .017). Tendon elongation did not correlate significantly with age, body mass index, or isokinetic peak torques.

Conclusion

Achilles tendon elongation was somewhat less in the early motion group and correlated with the clinical outcome scores. We recommend early functional postoperative treatment after Achilles rupture repair.
Radiographic Adaptations to the Stress of High-Level Rock Climbing in Junior Athletes
Authors: Schöffl Volker Rainer , Hochholzer Thomas , Imhoff Andreas B. , Schöffl Isabelle
Published: September 2006

Background

Radiographic adaptations and changes in adult climbers are a well-known fact, but few data are available for young climbers.

Hypothesis

Radiographic adaptations have been shown for highly active young climbers. The question arises whether these adaptations may lead to an early onset of osteoarthrosis in the fingers.

Study Design

Cohort study; Level of evidence, 2.

Methods

Ten members of the German Junior National Team (GJNT; 21.0 ± 1.6 years) and 10 recreational climbers (RC; 19.9 ± 1.9 years) were examined using a standard questionnaire and radiographs of the hand. For comparison, radiographs of 12 young nonclimbers (control group [CG]) were evaluated.

Results

The climbing level of GJNT increased significantly during the 5-year evaluation period (P < .01) and was significantly higher than that of the RC (1999: P < .01, 2004: P < .01). There was no increase in finger contractures or finger joint capsular width during the 5 years. Stress reactions were found in 8 of 10 of GJNT (1999 and 2004) and increased in RC from 2 of 10 (1999) to 3 of 10 (2004). No osteoarthrotic changes were found in 2004. There was no significant difference for the Barnett-Nordin Index between GJNT, RC, and CG. Years of climbing (P < .01), participation in climbing competitions (P < .01), hours of training per week (P < .01), number of training units per week (P < .05), and climbing level (2004) (P < .01) were significant factors for development of radiographic stress reaction in all athletes (GJNT and RC).

Conclusion

Intensive training and climbing leads to adaptive reactions such as cortical hypertrophy and broadened joint bases in the fingers. Nevertheless, osteoarthrotic changes are rare in young climbers. A longer follow-up is necessary to evaluate whether these adaptive stress reactions may lead to an early onset of osteoarthritis.
Chronic Illness Management: Changing the System
Authors: Haskett Tim
Published: September 2006

A growing elderly population, affected primarily by chronic diseases such as diabetes and hypertension, requires a different response from the health care system traditionally oriented toward the delivery of acute care services. It is time to shift to a delivery system oriented toward chronic illness management. With the right tools—evidence based decision support at the point of care, electronic clinical information available at all times to the health care team, support and education to facilitate self management for clients with chronic illness, and a health care system design and payment system to create and maintain these tools—it can be done. By applying evidence based standards of care within such a system, we should be able to provide effective health care for everyone who needs it, improve the general level of function of the population, and reduce or control cost at the same time.
Impact of Home-Based Monitoring on the Care of Patients with Congestive Heart Failure
Authors: Myers Sue , Grant Richard W. , Lugn Nancy E. , Holbert Beth , Kvedar Joseph C.
Published: September 2006

Congestive heart failure (CHF) affects nearly 5 million people in the United States with an annual cost of $30 billion. Home-based telemonitoring is a therapeutic tool that may reduce costs and improve patient satisfaction. This article assesses the effectiveness of home telemonitoring in patients with class III or IV CHF recently discharged from the hospital. A cohort of patients (n=83) were provided home telemonitoring for a 2-month period following hospital discharge. Home visit frequency, patient rehospitalization rate, emergency department use, quality of life, and health care costs were compared to a similar usual care cohort (n=83). Patients in the telemonitor group transmitted their weight, blood pressure, and oxygen saturation daily to a telemonitor nurse who evaluated each patient with a follow-up telephone call. Daily home care telemonitoring reduced the frequency of home nursing visits, provided cost savings, and was associated with improved self-perceived quality of life.
Policy Approaches to Chronic Disease Management
Authors: Wipf Kim R. , Langner Barbara
Published: September 2006

As health care costs continue rising and the elderly population steadily grows, our health care system's ability to cost-effectively care for the nation's elderly population with chronic disease presents a daunting challenge to the country's health care system. Our government is searching for the most costefficient and quality-driven methods to effectively manage the complex health care needs of a growing elder population with chronic disease states. The Medicare Prescription, Drug, Improvement, and Modernization Act of 2003 provided for phased-in development, testing, evaluation, and implementation of chronic care improvement programs in the traditional Medicare fee-for-service program meeting specific criteria. This article reviews the limitations of the current demonstration project and the policy changes necessary to facilitate and promote the home care industry's and the nursing profession's participation and provision of chronic disease management services in our nation.
Engaging the Emotional, Financial, and Physical Ramifications of Long-Distance Caregiving
Authors: Smith Cheryl
Published: September 2006

This article examines the profound impact of longdistance caregiving on family members and the loved ones for whom they are caring. It discusses the physical, emotional, and financial issues associated with long-distance caregiving and how longdistance caregivers can be better supported. The article also examines how the home care industry is addressing the specialized needs of these men and women who make up 15% of all long-distance caregivers as well as what is being done to supply the emotional and financial support necessary to maintain a better quality of life for all concerned.
Productivity Versus Case Management in Hospice
Authors: Vogt Kristine
Published: September 2006

Many factors influence the quality and efficiency of the service provided by a hospice. In end-of-life care, the quality of service is measured by the experiences of patients and families. Although cost containment is important, there are many opportunities to save money and most do not involve cutting labor costs. Productivity and caseload affect the cost of labor and both measurements affect the quality of care. A review of all costs and processes including areas such as off-hours staffing can uncover areas for savings. Many factors must be considered. If customer responsiveness by the hospice agency is perceived as poor, referrals will drop. No matter what reductions are implemented, care quality as well as cost containment outcomes must be measured to determine the impact. Case management is one strategy that provides oversight for efficient and effective care but caseloads for professional staff must be established at reasonable levels.
The actin cloud induced by LFA-1–mediated outside-in signals lowers the threshold for T-cell activation
Authors: Suzuki Jun-ichiro , Yamasaki Sho , Wu Jennifer , Koretzky Gary A. , Saito Takashi
Published: September 2006

The dynamic rearrangement of the actin cytoskeleton plays critical roles in T-cell receptor (TCR) signaling and immunological synapse (IS) formation in T cells. Following actin rearrangement in T cells upon TCR stimulation, we found a unique ring-shaped reorganization of actin called the “actin cloud,” which was specifically induced by outside-in signals through lymphocyte function–associated antigen-1 (LFA-1) engagement. In T-cell–antigen-presenting cell (APC) interactions, the actin cloud is generated in the absence of antigen and localized at the center of the T-cell–APC interface, where it accumulates LFA-1 and tyrosine-phosphorylated proteins. The LFA-1–induced actin cloud formation involves ADAP (adhesion- and degranulation-promoting adaptor protein) phosphorylation, LFA-1/ADAP assembly, and c-Jun N-terminal kinase (JNK) activation, and occurs independent of TCR and its proximal signaling. The formation of the actin cloud lowers the threshold for subsequent T-cell activation. Thus, the actin cloud induced by LFA-1 engagement may serve as a possible platform for LFA-1–mediated costimulatory function for T-cell activation.
Rapid quantification of naive alloreactive T cells by TNF-α production and correlation with allograft rejection in mice
Authors: Brehm Michael A. , Mangada Julie , Markees Thomas G. , Pearson Todd , Daniels Keith A. , Thornley Thomas B. , Welsh Raymond M. , Rossini Aldo A. , Greiner Dale L.
Published: September 2006

Allograft transplantation requires chronic immunosuppression, but there is no effective strategy to evaluate the long-term maintenance of immunosuppression other than assessment of graft function. The ability to monitor naive alloreactive T cells would provide an alternative guide for drug therapy at early, preclinical stages of graft rejection and for evaluating tolerance-inducing protocols. To detect and quantify naive alloreactive T cells directly ex vivo, we used the unique ability of naive T cells to rapidly produce TNF-α but not IFN-γ. Naive alloreactive T cells were identified by the production of TNF-α after a 5-hour in vitro stimulation with alloantigen and were distinguished from effector/memory alloreactive T cells by the inability to produce IFN-γ. Moreover, naive alloreactive T cells were not detected in mice tolerized against specific alloantigens. The frequency of TNF-α–producing cells was predictive for rejection in an in vivo cytotoxicity assay and correlated with skin allograft rejection. Naive alloreactive T cells were also detected in humans, suggesting clinical relevance. We conclude that rapid production of TNF-α can be used to quantify naive alloreactive T cells, that it is abrogated after the induction of tolerance, and that it is a potential tool to predict allograft rejection.
Chemokines CCL19 and CCL21 promote activation-induced cell death of antigen-responding T cells
Authors: Yasuda Takuwa , Kuwabara Taku , Nakano Hideki , Aritomi Kentaro , Onodera Takashi , Lipp Martin , Takahama Yousuke , Kakiuchi Terutaka
Published: September 2006

Secondary lymphoid organs (SLOs) provide a niche for the initiation and regulation of T-cell responses, but the mechanisms have been poorly understood. We investigated the influence of chemokines CCL19 and CCL21 constitutively expressed in SLOs on activation-induced cell death (AICD) of CD4+ T cells. When paucity of lymph node T cells (plt) mutant mice lacking expression of CCL19/CCL21 were primed with OVA/CFA, both expansion of OVA-responding CD4+ T cells in the draining lymph nodes and an in vitro recall response were prolonged as compared with responses in wild-type (WT) mice. The apoptotic cell frequency among OVA-responding CD4+ T cells was similarly low in plt/plt and WT mice during the clonal expansion phase. However, during the clonal contraction phase, the frequency never increased in plt/plt mice, whereas in WT mice it continuously increased to a peak 18 days after immunization. The presence of CCL19/CCL21 during the in vitro stimulation of CD4+ T cells with anti-CD3 plus anti-CD28 significantly enhanced in vitro AICD induction of the restimulated T cells, partially through enhancing expression of Fas ligand. Our results suggest that CCL19/CCL21 produced by stromal cells and antigen-presenting cells regulate CD4+ T-cell immune responses in SLOs by promoting AICD.
Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands
Authors: Cheng Pingyan , Nefedova Yulia , Corzo Cesar A. , Gabrilovich Dmitry I.
Published: September 2006

Notch is a major factor mediating interaction between hematopoietic progenitor cells (HPCs) and bone marrow stroma (BMS). However its contribution to dendritic cell (DC) differentiation is controversial. We found that main Notch ligands Delta-1 and Jagged-1 had the opposite effect on DC differentiation. Delta-1 promoted generation of fully differentiated DCs, whereas Jagged-1 stimulated accumulation of DC precursors but prevented their transition to terminally differentiated DCs. BMS expressed a substantially higher level of Jagged-1 than Delta-1. Just the opposite expression pattern was observed in spleen stroma (SS). The BMS effect on DC differentiation was similar to that of Jagged-1, whereas the effect of SS was similar to the effect of Delta-1. Down-regulation of Jagged-1 in BMS substantially increased DC differentiation. Experiments in vivo with adoptive transfer of DC precursors further supported the different roles of BMS and SS in DC development. Jagged-1 and Delta-1 equally activated CBF-1/RBPJκ transcription factor, which is a major Notch target. However, they produced a different pattern of activation of Notch target gene Hes1. Overexpression of Hes1 resulted in increased DC differentiation from HPCs. Thus, this study not only revealed the different role of Notch ligands in DC differentiation but also may provide a new insight into regulation of DC differentiation by BMS.
Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-β
Authors: Zhu Jiangao , Martinez Jennifer , Huang Xiaopei , Yang Yiping
Published: September 2006

Vaccinia virus (VV) has been used extensively as a vaccine vehicle in the clinical application for infectious diseases and cancer. Previous studies have suggested that the unique potency of VV-based vaccine lies in its effective activation of the innate immune system. However, how VV activates innate immune pathways remains largely unknown. In this study, we showed that VV elicited innate immune response through both Toll-like receptor (TLR)–dependent and –independent pathways. The TLR pathway was mediated by TLR2 and MyD88, leading to the production of proinflammatory cytokines, whereas activation of the TLR-independent pathway resulted in the secretion of IFN-β. More importantly, both TLR-dependent and -independent pathways were required for activating innate and adaptive immunity to VV in vivo. These findings represent the first evidence that innate immune recognition of VV is mediated by TLR2, demonstrate that one pathogen can target both TLR and non-TLR innate immune pathways to work together in achieving efficient activation of host defense, and suggest potential new strategies for the design of effective vaccines.
Expansion of Vδ1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16–binding proteins
Authors: Catellani Silvia , Poggi Alessandro , Bruzzone Andrea , Dadati Patrizia , Ravetti Jean Louis , Gobbi Marco , Zocchi Maria Raffaella
Published: September 2006

Data on 23 patients with low-grade non-Hodgkin lymphomas (NHLs), 4 mantle (MT), 4 marginal zone (MZ), and 15 follicular (FL), were analyzed and compared with 10 high-risk (HR) B-cell chronic lymphocytic leukemias (B-CLLs) with lymph node involvement and 4 diffuse large-cell lymphomas (DLCLs). A significant increase in circulating Vδ1 T lymphocytes producing interleukin-4 (IL-4) was found in patients with FL, MT, and MZ NHL, at variance with DLCL and HR B-CLL. IL-4 was also detectable in the sera and lymph nodes of the same patients. In 19 of the 23 patients with NHL with increased circulating Vδ1 T lymphocytes, B cells expressing the UL-16–binding proteins (ULBPs) ULBP2 or ULBP3 or both were found in peripheral blood, bone marrow, or lymph nodes. Of note, in HR B-CLL or in DLCL, where leukemic cells were negative for ULBPs, no Vδ1 T-cell increase was found. Moreover, Vδ1 T lymphocytes from patients with FL NHL proliferate in response to ULBP2+ and ULBP3+ lymphoma cells. Finally, patients with high expression of ULBPs, increased circulating Vδ1 T lymphocytes, and high levels of serum IL-4 showed stable disease in a 1-year follow-up in contrast to patients with low circulating Vδ1 T cells and undetectable IL-4 or ULBPs.
Hematologic manifestations of celiac disease
Authors: Halfdanarson Thorvardur R. , Litzow Mark R. , Murray Joseph A.
Published: September 2006

Celiac disease is a common systemic disorder that can have multiple hematologic manifestations. Patients with celiac disease may present to hematologists for evaluation of various hematologic problems prior to receiving a diagnosis of celiac disease. Anemia secondary to malabsorption of iron, folic acid, and/or vitamin B12 is a common complication of celiac disease and many patients have anemia at the time of diagnosis. Celiac disease may also be associated with thrombocytosis, thrombocytopenia, leukopenia, venous thromboembolism, hyposplenism, and IgA deficiency. Patients with celiac disease are at increased risk of being diagnosed with lymphoma, especially of the T-cell type. The risk is highest for enteropathy-type T-cell lymphoma (ETL) and B-cell lymphoma of the gut, but extraintestinal lymphomas can also be seen. ETL is an aggressive disease with poor prognosis, but strict adherence to a gluten-free diet may prevent its occurrence.
Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis
Authors: Hamacher Alexandra , Weigt Mathias , Wiese Michael , Hoefgen Barbara , Lehmann Jochen , Kassack Matthias U
Published: September 2006

Background

Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile.

Results

Regardless of using affinity data (pK
i values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity.

Conclusion

In conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented.
Detection of 65 kD heat shock protein in cerebrospinal fluid of tuberculous meningitis patients
Authors: Mudaliar Anju V , Kashyap Rajpal S , Purohit Hemant J , Taori Girdhar M , Daginawala Hatim F
Published: September 2006

Background

Diagnosis of tuberculous meningitis (TBM) is difficult. Rapid confirmatory diagnosis is essential to initiate required therapy. There are very few published reports about the diagnostic significance of 65 kD heat shock protein (hsp) in TBM patients, which is present in a wide range of Mycobacterium tuberculosis species and elicits a cellular and humoral immune response. In the present study we have conducted a prospective evaluation for the demonstration of 65 kD hsp antigen in cerebrospinal fluid (CSF) of TBM patients, by indirect ELISA method using monoclonal antibodies (mAb) against the 65 kD hsp antigen, for the diagnosis of TBM.

Methods

A total of 160 CSF samples of different groups of patients (confirmed TBM {n = 18}, clinically suspected TBM {n = 62}, non TBM infectious meningitis {n = 35} and non-infectious neurological diseases {n = 45}) were analyzed by indirect ELISA method using mAb to 65 kD hsp antigen. The Kruskal Wallis test (Non-Parametric ANOVA) with the Dunnett post test was used for statistical analysis.

Results

The indirect ELISA method yielded 84% sensitivity and 90% specificity for the diagnosis of TBM using mAb to 65 kD hsp antigen. The mean absorbance value of 65 kD hsp antigen in TBM patients was [0.70 ± 0.23 (0.23–1.29)], significantly higher than the non-TBM infectious meningitis group [0.32 ± 0.14 (0.12–0.78), P < 0.001] and also higher than the non-infectious neurological disorders group [0.32 ± 0.13 (0.20–0.78), P < 0.001]. A significant difference in the mean absorbance of 65 kD hsp antigen was noted in the CSF of culture-positive TBM patients [0.94 ± 0.18 (0.54–1.29)] when compared with clinically suspected TBM patients [0.64 ± 0.20 (0.23–0.98), P < 0.05].

Conclusion

The presence of 65 kD hsp antigen in the CSF of confirmed and suspected cases of TBM would indicate that the selected protein is specific to M. tuberculosis and could be considered as a diagnostic marker for TBM.
Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line
Authors: Zhang Ping , Zhang Zhiyuan , Zhou Xiaojian , Qiu Weiliu , Chen Fangan , Chen Wantao
Published: September 2006

Background

Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells.

Methods

A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated.

Results

Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 μM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells.

Conclusion

The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in cisplatin resistance.
California Men's Health Study (CMHS): a multiethnic cohort in a managed care setting
Authors: Enger Shelley M , Van Den Eeden Stephen K , Sternfeld Barbara , Loo Ronald K , Quesenberry Charles P , Rowell Sarah , Sadler Marianne C , Schaffer Donna M , Habel Laurel A , Caan Bette J
Published: September 2006

Background

We established a male, multiethnic cohort primarily to study prostate cancer etiology and secondarily to study the etiologies of other cancer and non-cancer conditions.

Methods/Design

Eligible participants were 45-to-69 year old males who were members of a large, prepaid health plan in California. Participants completed two surveys on-line or on paper in 2002 – 2003. Survey content included demographics; family, medical, and cancer screening history; sexuality and sexual development; lifestyle (diet, physical activity, and smoking); prescription and non-prescription drugs; and herbal supplements. We linked study data with clinical data, including laboratory, hospitalization, and cancer data, from electronic health plan files.

We recruited 84,170 participants, approximately 40% from minority populations and over 5,000 who identified themselves as other than heterosexual. We observed a wide range of education (53% completed less than college) and income. PSA testing rates (75% overall) were highest among black participants. Body mass index (BMI) (median 27.2) was highest for blacks and Latinos and lowest for Asians, and showed 80.6% agreement with BMI from clinical data sources. The sensitivity and specificity can be assessed by comparing self-reported data, such as PSA testing, diabetes, and history of cancer, to health plan data. We anticipate that nearly 1,500 prostate cancer diagnoses will occur within five years of cohort inception.

Discussion

A wide variety of epidemiologic, health services, and outcomes research utilizing a rich array of electronic, biological, and clinical resources is possible within this multiethnic cohort. The California Men's Health Study and other cohorts nested within comprehensive health delivery systems can make important contributions in the area of men's health.
The validity of self-rated health as a measure of health status among young military personnel: evidence from a cross-sectional survey
Authors: Haddock Christopher K , Poston Walker SC , Pyle Sara A , Klesges Robert C , Vander Weg Mark W , Peterson Alan , Debon Margaret
Published: September 2006

Background

Single item questions about self ratings of overall health status are widely used in both military and civilian surveys. Limited information is available to date that examines what relationships exist between self-rated health, health status and health related behaviors among relatively young, healthy individuals.

Methods

The current study uses the population of active duty United States Air Force recruits (N = 31,108). Participants completed surveys that asked about health behaviors and health states and were rated their health on a continuum from poor to excellent.

Results

Ratings of health were consistently lower for those who used tobacco (F = 241.7, p < .001), reported binge drinking (F = 69.0, p < .001), reported drinking and driving (F = 19.4, p < .001), reported taking health risks (F = 109.4, p < .001), were depressed (F = 256.1, p < .001) and were overweight (F = 39.5, p < .001).

Conclusion

Given the consistent relationship between self-rated overall health and factors important to military health and fitness, self-rated health appears to be a valid measure of health status among young military troops.
Colonic carcinoma with multiple small bowel perforations mimicking intestinal obstruction
Authors: Tiwary Satyendra K , Singh Manish K , Khanna Rahul , Khanna Ajay K
Published: September 2006

Background

Carcinoma of the colon may present with perforation proximal to the site of malignancy. Caecum is the commonest site of perforation if the ileocecal valve is patent and the jejunal and ileal perforations are very rare.

Case presentation

A 35 year male presented with intestinal obstruction. Emergency laparotomy revealed carcinoma of the transverse colon with multiple pinpoint perforations along antimesenteric border of ileum, which were wrapped with omentum, and no peritoneal contamination was present. Extended right hemicolectomy with jejunocolic anastomosis was done. Patient made uneventful recovery in postoperative period and was treated with adjuvant chemotherapy.

Conclusion

Patients with colonic carcinoma and incompetent ileocecal valve may present with intestinal perforation. Increased intraluminal pressure and closed loop obstruction may lead to ischemia and perforation of the small bowel.
PhyloFacts: an online structural phylogenomic encyclopedia for protein functional and structural classification
Authors: Krishnamurthy Nandini , Brown Duncan P , Kirshner Dan , Sjölander Kimmen
Published: September 2006

The Berkeley Phylogenomics Group presents PhyloFacts, a structural phylogenomic encyclopedia containing almost 10,000 'books' for protein families and domains, with pre-calculated structural, functional and evolutionary analyses. PhyloFacts enables biologists to avoid the systematic errors associated with function prediction by homology through the integration of a variety of experimental data and bioinformatics methods in an evolutionary framework. Users can submit sequences for classification to families and functional subfamilies. PhyloFacts is available as a worldwide web resource from http://phylogenomics.berkeley.edu/phylofacts.
Pivotal Advance: Vasoactive intestinal peptide inhibits up-regulation of human monocyte TLR2 and TLR4 by LPS and differentiation of monocytes to macrophages
Authors: Foster N , Lea S R , Preshaw P M , Taylor J J
Published: September 2006

Vasoactive intestinal peptide (VIP) is an immunoregulatory peptide, which inhibits LPS-induced cytokine secretion in myeloid cells and has beneficial effects in animal models of inflammatory diseases. We show for the first time that VIP decreases LPS-induced up-regulation of TLR2 and TLR4 by human monocytic THP1 cells and peripheral blood monocytes (PBM). VIP inhibited up-regulation of TLR4 expression in THP1 cells in response to LPS from Escherichia coli or the periodontal pathogen Porphyromonas gingivalis within 6 h poststimulation but had less of an effect on TLR2. After 24 h, P. gingivalis LPS-stimulated monocytic THP1 cells to differentiate into macrophages, which predominantly expressed TLR2, and E. coli LPS-stimulated THP1 differentiation to predominantly TLR4-expressing macrophages. VIP decreased monocyte differentiation to macrophages induced by LPS from either species and also reduced overall TLR2 and TLR4 expression in these cells. VIP had a similar effect on human PBM. The transcription factor PU.1 regulates TLR expression and has a central role in myeloid cell differentiation. VIP inhibited the nuclear translocation of PU.1 in LPS-stimulated THP-1 monocytes. VIP also inhibited the expression of the M-CSF receptor, which is regulated by PU.1. In summary, VIP inhibited LPS-induced differentiation of monocytes with a concomitant reduction in TLR2 and TLR4 expression. Although there was differential induction of TLR expression by LPS from P. gingivalis and E. coli, VIP inhibited the action of both of these LPS types on monocytes. The mechanism of action of VIP on monocyte differentiation may be via inhibition of the transcription factor PU.1.
Effects of LPS-mediated bystander activation in the innate immune system
Authors: Yadav Rajwardhan , Zammit David J , Lefrancois Leo , Vella Anthony T
Published: September 2006

LPS induces dendritic cell (DC) activation, but the precise in vivo mechanism is unclear since DCs express low levels of TLR4. Here, it is shown that DCs can be activated in response to LPS through a bystander mechanism. This result was obtained using chimeric mice reconstituted with LPS-responsive and nonresponsive bone marrow cells. Thus, after indirect in vivo conditioning by LPS, bystander-activated DCs (LPS nonresponsive) up-regulated CD86. This up-regulation occurred even when LPS-responsive cells were MyD88 deficient. Functional analysis demonstrated that in vivo LPS conditioning endowed both the LPS-responsive and bystander cells with the ability to produce IFN-γ in response to TLR9 stimulation in vitro. IFN-γ production was also shown to be important for enhanced T-bet gene expression but not important for up-regulation of CD86. To investigate aspects of the mechanism, we used intracellular cytokine staining and found that NKDCs were responsible for at least some of the IFN-γ production. Thus, our in vivo results demonstrated that bacterial LPS can bridge activation of various cellular populations of the innate immune system through a bystander mechanism.
Transgenic expression of CSF-1 in CSF-1 receptor-expressing cells leads to macrophage activation, osteoporosis, and early death
Authors: Wei Suwen , Dai Xu-Ming , Stanley E Richard
Published: September 2006

CSF-1 is the primary mononuclear phagocyte and osteoclast growth factor. Autocrine regulation by CSF-1 has been reported in macrophages during inflammatory responses and in neoplastic cells. To investigate whether inflammatory disease or neoplasia was the dominant consequence of autocrine regulation by CSF-1 in CSF-1 receptor (CSF-1R)-expressing cells, we created mice that express CSF-1 under the control of the CSF-1R promoter/first intron driver [transgene TgN(Csf1r-Csf1)Ers (TgRC) mice], which have reduced thymic size, a short lifetime, and low body weight and develop osteoporosis. In 4-week-old TgRC mice, osteoclast numbers are elevated, and macrophage densities are increased in bone marrow, spleen, liver, and brain. Cultured TgRC macrophages express CSF-1 and proliferate without exogenous CSF-1 and in the presence of neutralizing antimouse CSF-1 antibody. Compared with macrophages from nontransgenic littermates, TgRC macrophages exhibit a stellate morphology, express elevated mRNAs for proinflammatory cytokines, and despite a lower, steady-state cytokine secretion, secrete elevated levels of inflammatory cytokines in response to LPS, indicating that TgRC macrophages are functionally primed through the CSF-1R. Thus, autocrine regulation of CSF-1R-expressing cells by CSF-1 leads to a severe phenotype that emphasizes the importance of the known, local production of CSF-1 in inflammatory disease.