bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Co-morbidity of Oral Appliances in the Treatment of Obstructive Sleep Apnea-Hypopnea: a Systematic Review
Authors: Hoekema A. , Stegenga B. , de Bont L.G.M.
Published: January 2009

The Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common sleep-related breathing disorder characterized by repetitive obstructions of the upper airway during sleep. Modification of pharyngeal patency by Oral Appliance (OA) therapy has been suggested as an alternative to various treatment modalities for OSAHS. To determine the evidence base with respect to the efficacy and co-morbidity of OA therapy in OSAHS, we conducted a systematic review of the available literature. Primary outcome measures were the reduction in number of upper-airway obstructions and co-morbidity related to the craniomandibular or craniofacial complex, respectively. Eligible studies regarding efficacy were independently assessed by two assessors using a quality assessment scale. Effect sizes of methodologically sound studies were calculated. In identical interventions, effect sizes were pooled with the use of a random-effects model. Given the scarcity of controlled studies related to co-morbidity, appraisal was confined to a description of eligible studies. Sixteen controlled trials related to efficacy were identified. With respect to the primary outcome measure, OA therapy was clearly more effective than control therapy (pooled effect size, −0.96; 95% confidence interval [CI], −1.49 to −0.42) and possibly more effective than uvulopalatopharyngoplasty. Although patients generally preferred OA therapy, improvement of respiratory variables, such as the number of upper-airway obstructions, was usually better in Continuous Positive Airway Pressure (CPAP) therapy (pooled effect size, 0.83; 95% CI, 0.59 to 1.06). Moreover, specific aspects related to OA design may influence patient-perceived efficacy and preference. Twelve patient-series and one controlled trial related to co-morbidity were identified. Analysis of the data suggests that OA therapy may have adverse effects on the craniomandibular and craniofacial complex. Although CPAP is apparently more effective and adverse effects of OA treatment have been described, it can be concluded that OA therapy is a viable treatment for, especially, mild to moderate OSAHS. Controlled studies addressing the specific indication and co-morbidity of OA therapy are warranted.
Altered Autoantigen Structure in Sjögren’s Syndrome: Implications for the Pathogenesis of Autoimmune Tissue Damage
Authors: Rosen A. , Casciola-Rosen L.
Published: January 2009

The etiology and pathogenic mechanisms underlying Sjögren’s syndrome (SS) remain unclear. Recent studies have emphasized that the specific autoantibodies that occur in a high proportion of patients with SS may provide important insights into the circumstances that initiate and propagate tissue damage in this disease. Although autoantigens targeted in systemic autoimmune diseases share little in common in terms of structure, subcellular distribution, or function in normal cells, these molecules are unified by becoming clustered and concentrated in the surface blebs of apoptotic cells. Furthermore, their structure is altered during some types of cell death to generate structures not previously generated during development and homeostasis. This review highlights the susceptibility of SS autoantigens to undergoing such structural changes during activation of immune effector pathways, and synthesizes a model of SS incorporating these concepts. An understanding of the mechanisms responsible for activating the specific immune response in SS, and the role of specific immune effector pathways in propagating both the autoimmune response and tissue damage, is of potential therapeutic importance. Abbreviations used in this paper are: CTL, cytotoxic T-lymphocytes; ER, endoplasmic reticulum; GluR3, subunit III of the glutamate receptor; GrB, granzyme B; M3R, type III muscarinic receptor; NK cells, natural killer cells; PARP, poly(ADP-ribose)polymerase; SS, Sjögren’s syndrome; SLE, systemic lupus erythematosus; and UV, ultraviolet.
Connective Tissue Metabolism and Gingival Overgrowth
Authors: Trackman P. C. , Kantarci A.
Published: January 2009

Gingival overgrowth occurs mainly as a result of certain anti-seizure, immunosuppressive, or antihypertensive drug therapies. Excess gingival tissues impede oral function and are disfiguring. Effective oral hygiene is compromised in the presence of gingival overgrowth, and it is now recognized that this may have negative implications for the systemic health of affected patients. Recent studies indicate that cytokine balances are abnormal in drug-induced forms of gingival overgrowth. Data supporting molecular and cellular characteristics that distinguish different forms of gingival overgrowth are summarized, and aspects of gingival fibroblast extracellular matrix metabolism that are unique to gingival tissues and cells are reviewed. Abnormal cytokine balances derived principally from lymphocytes and macrophages, and unique aspects of gingival extracellular matrix metabolism, are elements of a working model presented to facilitate our gaining a better understanding of mechanisms and of the tissue specificity of gingival overgrowth.
Alternatives in Polymerization Contraction Stress Management
Authors: Braga R.R. , Ferracane J.L.
Published: January 2009

Polymerization contraction stress of dental composites is often associated with marginal and interfacial failures of bonded restorations. The magnitude of stress depends on composite composition (filler content and matrix composition) and its ability to flow before gelation, which is related to the cavity configuration and curing characteristics of the composite. This article reviews variations among studies regarding contraction-stress-testing methods and contraction stress values of current composites, and discusses the validity of contraction stress studies in relation to results from microleakage tests. The effects of lower curing rates and alternative curing routines on contraction stress values are also discussed, as well as the use of low-elastic-modulus liners. Moreover, studies with experimental dimethacrylate-based composites and recent developments in low-shrinkage monomers are described.
Chemotaxis-guided Movements in Bacteria
Authors: Lux Renate , Shi Wenyuan
Published: January 2009

Motile bacteria often use sophisticated chemotaxis signaling systems to direct their movements. In general, bacterial chemotactic signal transduction pathways have three basic elements: (1) signal reception by bacterial chemoreceptors located on the membrane; (2) signal transduction to relay the signals from membrane receptors to the motor; and (3) signal adaptation to desensitize the initial signal input. The chemotaxis proteins involved in these signal transduction pathways have been identified and extensively studied, especially in the enterobacteria Escherichia coli and Salmonella enterica serovar typhimurium. Chemotaxis-guided bacterial movements enable bacteria to adapt better to their natural habitats via moving toward favorable conditions and away from hostile surroundings. A variety of oral microbes exhibits motility and chemotaxis, behaviors that may play important roles in bacterial survival and pathogenesis in the oral cavity.
Zinc Finger Transcription Factors in Skeletal Development
Authors: Ganss Bernhard , Jheon Andrew
Published: January 2009

Cellular and molecular processes that regulate the development of skeletal tissues resemble those required for regeneration. Given the prevalence of degenerative skeletal disorders in an increasingly aging population, the molecular mechanisms of skeletal development must be understood in detail if novel strategies are to be developed in regenerative medicine. Research in this area over the past decade has revealed that cell differentiation is largely controlled at the level of gene transcription, which in turn is regulated by transcription factors. Transcription factors usually recognize and bind to specific DNA sequences in the promoter of target genes via characteristic DNA-binding domains. Although the gene family containing C2H2 zinc fingers as DNA-binding motifs is the largest family of transciptional regulators, with several hundred individual members in mammals, only a small but increasing number of zinc finger genes have been implicated in bone, cartilage, or tooth development. These zinc finger proteins (ZFPs) contain multiple structural motifs that require zinc to maintain their structural integrity and function. Interestingly, zinc deficiency is known to result in skeletal growth retardation and has been identified as a risk factor in the pathogenesis of osteoporosis. This review attempts to summarize our current state of knowledge regarding the role of ZFPs in the molecular regulation of skeletogenesis.
Signal Transducers and Activators of Transcription: Insights into the Molecular Basis of Oral Cancer
Authors: Siavash H. , Nikitakis N.G. , Sauk J.J.
Published: January 2009

Recent efforts on developing more direct and effective targets for cancer therapy have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins are latent cytoplasmic transcription factors that become activated in response to extracellular signaling proteins. STAT proteins have been convincingly reported to possess oncogenic properties in a plethora of human cancers, including oral and oropharyngeal cancer. Signal transduction pathways mediated by these oncogenic transcription factors and their regulation in oral cancer are the focus of this review.
TGF-β Signal Transduction in Oro-facial Health and Non-malignant Disease (Part I)
Authors: Prime S.S. , Pring M. , Davies M. , Paterson I.C.
Published: January 2009

The transforming growth factor-beta (TGF-β) family of cytokines consists of multi-functional polypeptides that regulate a variety of cell processes, including proliferation, differentiation, apoptosis, extracellular matrix elaboration, angiogenesis, and immune suppression, among others. In so doing, TGF-β plays a key role in the control of cell behavior in both health and disease. In this report, we review what is known about the mechanisms of activation of the peptide, together with details of TGF-β signal transduction pathways. This review summarizes the evidence implicating TGF-β in normal physiological processes of the craniofacial complex—such as palatogenesis, tooth formation, wound healing, and scarring—and then evaluates its role in non-malignant disease processes such as scleroderma, submucous fibrosis, periodontal disease, and lichen planus.
The Role of TGF-β in Epithelial Malignancy and its Relevance to the Pathogenesis of Oral Cancer (Part II)
Authors: Prime S.S. , Davies M. , Pring M. , Paterson I.C.
Published: January 2009

The role of transforming growth factor-β (TGF-β) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-β can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-β are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-β signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-β to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.
Oral Health, Atherosclerosis, and Cardiovascular Disease
Authors: Meurman Jukka H. , Sanz Mariano , Janket Sok-Ja
Published: January 2009

During the last two decades, there has been an increasing interest in the impact of oral health on atherosclerosis and subsequent cardiovascular disease (CVD). The advent of the inflammation paradigm in coronary pathogenesis stimulated research in chronic infections caused by a variety of micro-organisms—such as Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus—as well as dental pathogens, since these chronic infections are thought to be involved in the etiopathogenesis of CVD by releasing cytokines and other pro-inflammatory mediators ( e.g., C-reactive protein [CRP], tumor necrosis factor [TNF-α]) that may initiate a cascade of biochemical reactions and cause endothelial damage and facilitate cholesterol plaque attachment. Yet, due to the multi-factorial nature of dental infection and CVD, confirming a causal association is difficult, and the published results are conflicting. The main deficit in the majority of these studies has been the inadequate control of numerous confounding factors, leading to an overestimation and the imprecise measurement of the predictor or overadjustment of the confounding variables, resulting in underestimation of the risks. A meta-analysis of prospective and retrospective follow-up studies has shown that periodontal disease may increase the risk of CVD by approximately 20% (95% confidence interval [CI], 1.08–1.32). Similarly, the reported risk ratio between periodontal disease and stroke is even stronger, varying from 2.85 (CI 1.78–4.56) to 1.74 (CI 1.08–2.81). The association between peripheral vascular disease and oral health parameters has been explored in only two studies, and the resultant relative risks among individuals with periodontitis were 1.41 (CI 1.12–1.77) and 2.27 (CI 1.32–3.90), respectively. Overall, it appears that periodontal disease may indeed contribute to the pathogenesis of cardiovascular disease, although the statistical effect size is small.
Forced, Not Voluntary, Exercise Improves Motor Function in Parkinson's Disease Patients
Authors: Ridgel Angela L. , Vitek Jerrold L. , Alberts Jay L.
Published: January 2009

Background. Animal studies indicate forced exercise (FE) improves overall motor function in Parkinsonian rodents. Global improvements in motor function following voluntary exercise (VE) are not widely reported in human Parkinson's disease (PD) patients. Objective. The aim of this study was to compare the effects of VE and FE on PD symptoms, motor function, and bimanual dexterity. Methods. Ten patients with mild to moderate PD were randomly assigned to complete 8 weeks of FE or VE. With the assistance of a trainer, patients in the FE group pedaled at a rate 30% greater than their preferred voluntary rate, whereas patients in the VE group pedaled at their preferred rate. Aerobic intensity for both groups was identical, 60% to 80% of their individualized training heart rate. Results. Aerobic fitness improved for both groups. Following FE, Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved 35%, whereas patients completing VE did not exhibit any improvement. The control and coordination of grasping forces during the performance of a functional bimanual dexterity task improved significantly for patients in the FE group, whereas no changes in motor performance were observed following VE. Improvements in clinical measures of rigidity and bradykinesia and biomechanical measures of bimanual dexterity were maintained 4 weeks after FE cessation. Conclusions. Aerobic fitness can be improved in PD patients following both VE and FE interventions. However, only FE results in significant improvements in motor function and bimanual dexterity. Biomechanical data indicate that FE leads to a shift in motor control strategy, from feedback to a greater reliance on feedforward processes, which suggests FE may be altering central motor control processes.
Local Cancellous Bone Grafting for Osteonecrosis of the Femoral Head
Authors: Yuhan Chang  , Hu Chi-Chien , Chen Dave W. , Ueng Steve W. N. , Shih Chun-Hsiung , Lee Mel S.
Published: January 2009

Objective. This study reports a novel local bone graft technique for the treatment of osteonecrosis of femoral head (ONFH). Materials and methods. From 1998 to 2005, a procedure using local bone grafting was performed for the treatment of ONFH in 11 patients. The local bone grafts were obtained from the intertrochanteric region and then impacted into the necrotic lesion. A wire coil was inserted into the remaining space after the grafting. Results. At a mean follow-up of 61 months (range, 30 to 103 months), all 5 ARCO stage IIC hips survived but 3 of the 6 ARCO stage IIIA hips failed. The overall clinical success rate was 73%. Conclusions. This study demonstrates that local cancellous bone grafting combined with a space-filling device implanted into the ONFH is a promising procedure and the wire coil showed no interference to the remodeling of the femoral head after grafting.
Schooling: History as Handmaiden
Authors: Hilbink Thomas
Published: January 2009

An attempt to “make sense of the past” leaves many paths to explore. In this article the author looks back at his work on a constitutional law case challenging the state of Alabama's ban on the sale of “sexual devices.” His role in the case was to research and draft a brief that laid out the history of government “interference or non-interference” in private sexual activities. Frustrated by how courts had misused and abused history in the past, the author set out to “school” the court in the “proper” use of history. While the trial court embraced his interpretation of the past, the appeals court mockingly tossed it aside. The article grapples not only with how courts have made sense of the past, but how the author has come to understand the role of history in law, both for good and for bad. At the same time, the author reassesses his own “graduate student hubris” in seeking to defend the purity of history from legal “history-lite” from new perspectives as professional historian and advocate.
Balancing integrity vs. risk of falling – nurses’ experiences of caring for elderly people with dementia in nursing homes
Authors: Johansson Inger , Bachrach-Lindström Margareta , Struksnes Solveig , Hedelin Birgitta
Published: January 2009

Abstract

Dementia is recognized as being a major risk for falls that cause suffering and increase dependency for the individual. The purpose of this study was to explore registered nurses’ and nurse assistants’ experiences of caring for elderly people with dementia who are at risk of falling, and factors that contribute or reduce falls in this group. A phenomenographic design was chosen. Ten nurses and 18 nurse assistants with experience of fall events were strategically selected for a recorded interview. The informants were chosen from 10 nursing homes in Sweden and Norway. They were asked to describe a fall situation they had been involved in when caring for elderly people with dementia. The findings shed light on an ethical dilemma in the main category ‘Balancing integrity and autonomy versus risk of falling’ which was comprehensively related to two descriptive categories. The first one was ‘Adjusting to the older person’s condition’ with the concepts of forgetfulness, anxiety and confusion, ability to express oneself and understand, bodily build and function. The second category was ‘Adjusting the care environment’, comprising these conceptions: the physical environment, the psychosocial environment, organization and human resources. Based on the staff’s perceived difficulties in preventing falls in elderly people with dementia, there is a need for additional support or professional supervision in their work to enhance possibilities for successful fall prevention.
The Effect of Q Angle on Ankle Sprain Occurrence
Authors: Pefanis Nikolaos , Papaharalampous Xenofon , Tsiganos Georgios , Papadakou Eugenia , Baltopoulos Panagiotis
Published: January 2009

The intersegmental joint forces and the structures that must resist them (articular surfaces, ligaments, and musculature) are related through anatomical alignment of the joints and skeletal system. Ankle joint structure can affect or be affected by bony malformations of the surrounding areas, including the knee and hip. The aim of the current study is to examine the possible relationship between the quadriceps (Q) angle and other factors (anthropometric characteristics, medical history, and age) on the occurrence of ankle sprains, because its value, when assessed correctly, provides useful information for the anatomical alignment of the lower extremity. The study sample consisted of 45 high-level athletes, evenly distributed among 3 sports (basketball, soccer, and volleyball). Q angle measurements were made on radiographs. The study lasted for 2 years. A logistic regression was used to determine the importance of each factor on the probability in question. A significance level of P = .1 was used. The factors contributing more to an ankle sprain were a previous injury of the same type ( P < .01) followed by body mass index (BMI; P < .10) and age (P < .10). On the contrary, Q angle was proven to be statistically nonsignificant (P > .10). The results were valid even when the BMI variable was substituted by body inertia propensity, a derived variable. The Q angle remained statistically nonsignificant ( P > .10). The Q angle magnitude does not seem to be a decisive factor that could increase the probability of spraining an ankle. The most important factors that could affect the probability of sustaining an ankle sprain are the athlete's age, anthropometric characteristics, and prior injuries.
Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG
Authors: Braess Jan , Spiekermann Karsten , Staib Peter , Grüneisen Andreas , Wörmann Bernhard , Ludwig Wolf-Dieter , Serve Hubert , Reichle Albrecht , Peceny Rudolf , Oruzio Daniel , Schmid Christoph , Schiel Xaver , Hentrich Marcus , Sauerland Christina , Unterhalt Michael , Fiegl Michael , Kern Wolfgang , Buske Christian , Bohlander Stefan , Heinecke Achim , Baurmann Herrad , Beelen Dietrich W. , Berdel Wolfgang E. , Büchner Thomas , Hiddemann Wolfgang
Published: January 2009

Dose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction. (European Leukemia Trial Registry LN_AMLINT_2004_230.)
Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital
Authors: Rubnitz Jeffrey E. , Onciu Mihaela , Pounds Stanley , Shurtleff Sheila , Cao Xueyuan , Raimondi Susana C. , Behm Frederick G. , Campana Dario , Razzouk Bassem I. , Ribeiro Raul C. , Downing James R. , Pui Ching-Hon
Published: January 2009

To characterize the biology and optimal therapy of acute mixed-lineage leukemia in children, we reviewed the pathologic and clinical features, including response to therapy, of 35 patients with mixed-lineage leukemia. The majority of cases (91%) had blasts cells that simultaneously expressed either T-lineage plus myeloid markers (T/myeloid, n = 20) or B-lineage plus myeloid markers (B/myeloid, n = 12). Overall survival rates for the B/myeloid and T/myeloid subgroups were not significantly different from each other or from the rate for acute myeloid leukemia (AML) but were inferior to the outcome in children with acute lymphoblastic leukemia (ALL). Patients who failed to achieve complete remission with AML-directed therapy could often be induced with a regimen of prednisone, vincristine, and L-asparaginase. Analysis of gene-expression patterns identified a subset of biphenotypic leukemias that did not cluster with T-cell ALL, B-progenitor ALL, or AML. We propose that treatment for biphenotypic leukemia begin with one course of AML-type induction therapy, with a provision for a switch to lymphoid-type induction therapy with a glucocorticoid, vincristine, and L-asparaginase if the patient responds poorly. We also suggest that hematopoietic stem cell transplantation is often not required for cure of these patients.
Estimation of tumor heterogeneity using CGH array data
Authors: Wang Kai , Li Jian , Li Shengting , Bolund Lars , Wiuf Carsten
Published: January 2009

Background

Array-based comparative genomic hybridization (CGH) is a commonly-used approach to detect DNA copy number variation in whole genome-wide screens. Several statistical methods have been proposed to define genomic segments with different copy numbers in cancer tumors. However, most tumors are heterogeneous and show variation in DNA copy numbers across tumor cells. The challenge is to reveal the copy number profiles of the subpopulations in a tumor and to estimate the percentage of each subpopulation.

Results

We describe a relation between experimental data and exact DNA copy number and develop a statistical method to reveal the heterogeneity of tumors containing a mixture of different-stage cells. Furthermore, we validate the method on simulated data and apply the method to 29 pairs of breast primary tumors and their matched lymph node metastases.

Conclusion

We demonstrate a new method for CGH array analysis that allows a tumor sample to be classified according to its heterogeneity. The method gives an interpretable series of copy number profiles, one for each major subpopulation in a tumor. The profiles facilitate identification of copy number alterations in cancer development.
Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries
Authors: Cagnin Stefano , Biscuola Michele , Patuzzo Cristina , Trabetti Elisabetta , Pasquali Alessandra , Laveder Paolo , Faggian Giuseppe , Iafrancesco Mauro , Mazzucco Alessandro , Pignatti Pier Franco , Lanfranchi Gerolamo
Published: January 2009

Background

Atherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. There may be common molecular pathways sustaining this process. Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis.

Results

We used DNA microarrays and meta-analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression. We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis. Caveolae and JAK/STAT pathways, and S100A9/S100A8 interacting proteins are certainly involved in the development of vascular disease. We found that the system of caveolae is directly connected with genes that respond to hormone receptors, and indirectly with the apoptosis pathway.

Cytokines, chemokines and growth factors released in the blood flux were investigated in parallel. High levels of RANTES, IL-1ra, MIP-1alpha, MIP-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-17, PDGF-BB, VEGF and IFN-gamma were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels.

Conclusion

The pattern of cytokine and S100A9/S100A8 up-regulation characterizes atherosclerosis as a proinflammatory disorder. Activation of the JAK/STAT pathway is confirmed by the up-regulation of IL-6, STAT1, ISGF3G and IL10RA genes in coronary and carotid plaques. The functional network constructed in our research is an evidence of the central role of STAT protein and the caveolae system to contribute to preserve the plaque. Moreover, Cav-1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype.
Modulators of arginine metabolism support cancer immunosurveillance
Authors: Capuano Giusy , Rigamonti Nicolò , Grioni Matteo , Freschi Massimo , Bellone Matteo
Published: January 2009

Background

Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.

Results

We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.

Conclusion

Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.
High expression of 5-lipoxygenase in normal and malignant mantle zone B lymphocytes
Authors: Mahshid Yilmaz , Lisy Marcus-René , Wang Xiao , Spanbroek Rainer , Flygare Jenny , Christensson Birger , Björkholm Magnus , Sander Birgitta , Habenicht Andreas JR , Claesson Hans-Erik
Published: January 2009

Background

Human B lymphocytes can produce leukotriene B4but the biological function of the 5-lipoxygenase (5-LO) pathway in B cells is unclear. In order to better understand and define the role of 5-LO in B cells, we investigated the expression of 5-LO mRNA and protein in subsets of B cells from human tonsils and different types of B cell lymphoma.

Results

Based on RT-PCR and western blot/immunohistochemical staining, with a polyclonal antibody raised against 5-LO, high expression of 5-LO was found in mantle zone B cells from tonsils. By contrast, only a weak expression of 5-LO was detected in germinal centre cells and no expression in plasma cells from tonsils. This pattern of 5-LO expression was preserved in malignant lymphoma with high expression in mantle B cell lymphoma (MCL) and weak or no expression in follicular lymphoma. Primary leukemized MCL, so called B-prolymphocytic leukaemia cells, and MCL cell lines also expressed 5-LO and readily produced LTB4after activation.

Conclusion

The present report demonstrates the expression of 5-LO mainly in normal and malignant mantle zone B cells while the expression is low or absent in germinal centre B cells and plasma cells, indicating a role of the 5-LO pathway in B cells before the cells finally differentiate to plasma cells.
Characterization of the meningococcal DNA glycosylase Fpg involved in base excision repair
Authors: Tibballs Katrina L , Ambur Ole Herman , Alfsnes Kristian , Homberset Håvard , Frye Stephan A , Davidsen Tonje , Tønjum Tone
Published: January 2009

Background

Neisseria meningitidis, the causative agent of meningococcal disease, is exposed to high levels of reactive oxygen species inside its exclusive human host. The DNA glycosylase Fpg of the base excision repair pathway (BER) is a central player in the correction of oxidative DNA damage. This study aimed at characterizing the meningococcal Fpg and its role in DNA repair.

Results

The deduced N. meningitidis Fpg amino acid sequence was highly homologous to other Fpg orthologues, with particularly high conservation of functional domains. As for most N. meningitidis DNA repair genes, the fpg gene contained a DNA uptake sequence mediating efficient transformation of DNA. The recombinant N. meningitidis Fpg protein was over-expressed, purified to homogeneity and assessed for enzymatic activity. N. meningitidis Fpg was found to remove 2,6-diamino-4-hydroxy-5-formamidopyrimidine (faPy) lesions and 7,8-dihydro-8-oxo-2'-deoxyguanosine (8oxoG) opposite of C, T and G and to a lesser extent opposite of A. Moreover, the N. meningitidis fpg single mutant was only slightly affected in terms of an increase in the frequency of phase variation as compared to a mismatch repair mutant.

Conclusion

Collectively, these findings show that meningococcal Fpg functions are similar to those of prototype Fpg orthologues in other bacterial species.
Linkage mapping of putative regulator genes of barley grain development characterized by expression profiling
Authors: Pietsch Christof , Sreenivasulu Nese , Wobus Ulrich , Röder Marion S
Published: January 2009

Background

Barley (Hordeum vulgare L.) seed development is a highly regulated process with fine-tuned interaction of various tissues controlling distinct physiological events during prestorage, storage and dessication phase. As potential regulators involved within this process we studied 172 transcription factors and 204 kinases for their expression behaviour and anchored a subset of them to the barley linkage map to promote marker-assisted studies on barley grains.

Results

By a hierachical clustering of the expression profiles of 376 potential regulatory genes expressed in 37 different tissues, we found 50 regulators preferentially expressed in one of the three grain tissue fractions pericarp, endosperm and embryo during seed development. In addition, 27 regulators found to be expressed during both seed development and germination and 32 additional regulators are characteristically expressed in multiple tissues undergoing cell differentiation events during barley plant ontogeny. Another 96 regulators were, beside in the developing seed, ubiquitously expressed among all tissues of germinating seedlings as well as in reproductive tissues. SNP-marker development for those regulators resulted in anchoring 61 markers on the genetic linkage map of barley and the chromosomal assignment of another 12 loci by using wheat-barley addition lines. The SNP frequency ranged from 0.5 to 1.0 SNP/kb in the parents of the various mapping populations and was 2.3 SNP/kb over all eight lines tested. Exploration of macrosynteny to rice revealed that the chromosomal orders of the mapped putative regulatory factors were predominantly conserved during evolution.

Conclusion

We identified expression patterns of major transcription factors and signaling related genes expressed during barley ontogeny and further assigned possible functions based on likely orthologs functionally well characterized in model plant species. The combined linkage map and reference expression map of regulators defined in the present study offers the possibility of further directed research of the functional role of regulators during seed development in barley.
Multiple splice defects in ABCA1cause low HDL-C in a family with Hypoalphalipoproteinemia and premature coronary disease
Authors: Rhyne Jeffrey , Mantaring Myrna M , Gardner David F , Miller Michael
Published: January 2009

Background

Mutations at splice junctions causing exon skipping are uncommon compared to exonic mutations, and two intronic mutations causing an aberrant phenotype have rarely been reported. Despite the high number of functional ABCA1 mutations reported to date, splice variants have been reported infrequently. We screened DNA from a 41 year-old male with low HDL-C (12 mg/dL [0.31 mmol/L]) and a family history of premature coronary heart disease (CHD) using polymerase chain reaction single-strand conformation polymorphism (SSCP) analysis.

Methods

Family members with low levels of HDL-C (n = 6) were screened by SSCP for mutations in ABCA1. Samples with altered SSCP patterns were sequenced directly using either an ABI 3700 or ABI3730Xl DNA Analyzer. To screen for splicing defects, cDNA was isolated from the proband's RNA and was sequenced as above. A series of minigenes were constructed to determine the contribution of normal and defective alleles.

Results

Two novel splice variants in ABCA1 were identified. The first mutation was a single base pair change (T->C) in IVS 7, 6 bps downstream from the exon7/intron7 junction. Amplification of cDNA and allelic subcloning identified skipping of Exon 7 that results in the elimination of 59 amino acids from the first extracellular loop of the ABCA1 protein. The second mutation was a single base pair change (G->C) at IVS 31 -1, at the intron/exon junction of exon 32. This mutation causes skipping of exon 32, resulting in 8 novel amino acids followed by a stop codon and a predicted protein size of 1496 AA, compared to normal (2261 AA). Bioinformatic studies predicted an impact on splicing as confirmed by in vitro assays of constitutive splicing.

Conclusion

In addition to carnitine-acylcarnitine translocase (CACT) deficiency and Hermansky-Pudlak syndrome type 3, this represents only the third reported case in which 2 different splice mutations has resulted in an aberrant clinical phenotype.
Structural factors associated with an increased risk of HIV and sexually transmitted infection transmission among street-involved youth
Authors: Marshall Brandon DL , Kerr Thomas , Shoveller Jean A , Montaner Julio SG , Wood Evan
Published: January 2009

Background

The prevalence of HIV and sexually transmitted infections (STIs) among street-involved youth greatly exceed that of the general adolescent population; however, little is known regarding the structural factors that influence disease transmission risk among this population.

Methods

Between September 2005 and October 2006, 529 street-involved youth were enroled in a prospective cohort known as the At Risk Youth Study (ARYS). We examined structural factors associated with number of sex partners using quasi-Poisson regression and consistent condom use using logistic regression.

Results

At baseline, 415 (78.4%) were sexually active, of whom 253 (61.0%) reported multiple sex partners and 288 (69.4%) reported inconsistent condom use in the past six months. In multivariate analysis, self-reported barriers to health services were inversely associated with consistent condom use (adjusted odds ratio [aOR] = 0.52, 95%CI: 0.25 – 1.07). Structural factors that were associated with greater numbers of sex partners included homelessness (adjusted incidence rate ratio [aIRR] = 1.54, 95%CI: 1.11 – 2.14) and having an area restriction that affects access to services (aIRR = 2.32, 95%CI: 1.28 – 4.18). Being searched or detained by the police was significant for males (aIRR = 1.36, 95%CI: 1.02 – 1.81).

Conclusion

Although limited by its cross-sectional design, our study found several structural factors amenable to policy-level interventions independently associated with sexual risk behaviours. These findings imply that the criminalization and displacement of street-involved youth may increase the likelihood that youth will engage in sexual risk behaviours and exacerbate the negative impact of resultant health outcomes. Moreover, our findings indicate that environmental-structural interventions may help to reduce the burden of these diseases among street youth in urban settings.
Incidence and risk factors of exacerbations among COPD patients in primary health care: APMPOC study
Authors: Borrell Eulàlia , Rodríguez Mar , Torán Pere , Muñoz Laura , Pera Guillem , Montellà Núria , Monteagudo Mònica , Urrea Magalí , Puigfel Yolanda , Negrete Antonio , Mezquiriz Xavier , Domènech Cristina , Lacasta Anna , García Ma Llum , Maneus Sandra , Tintoré Glòria
Published: January 2009

Background

Worldwide, chronic obstructive pulmonary disease (COPD) is the fourth cause of death. Exacerbations have a negative impact on the prognosis of COPD and the frequency and severity of these episodes are associated with a higher patient mortality. Exacerbations are the first cause of decompensation, hospital admission and death in COPD. The incidence of exacerbations has mainly been estimated in populations of patients with moderate-severe COPD requiring hospital care. However, little is known regarding the epidemiology of exacerbations in patients with less severe COPD forms. It is therefore possible that a high number of these less severe forms of exacerbations are underdiagnosed and may, in the long-term, have certain prognostic importance for the COPD evolution. The aim of this study was to know the incidence and risk factors associated with exacerbations in patients with COPD in primary care.

Methods and design

A prospective, observational, 3-phase, multicentre study will be performed involving: baseline evaluation, follow up and final evaluation. A total of 685 smokers or ex-smokers from 40 to 80 years of age with COPD, without acute respiratory disease or any other long-term respiratory disease will be randomly selected among the population assigned to 21 primary care centres. The diagnosis of COPD and its severity will be confirmed by spirometry. Information regarding the baseline situation, quality of life and exposure to contaminants or other factors potentially related to exacerbations will be collected. A group of 354 patients with confirmed COPD of varying severity will be followed for one year through monthly telephone calls and daily reporting of symptoms with the aim of detecting all the exacerbations which occur. These patients will be evaluated again at the end of the study and the incidence of exacerbations and associated relative risks will be estimated by negative binomial regression.

Discussion

The results will be relevant to provide knowledge about natural history of the initial phases of the COPD and the impact and incidence of the exacerbations on the patients with mild-moderate forms of the disease. These data may be important to know the milder forms of exacerbation wich are often silent or very little expressed clinically.
Contribution of the C-terminal region within the catalytic core domain of HIV-1 integrase to yeast lethality, chromatin binding and viral replication
Authors: Xu Zaikun , Zheng Yingfeng , Ao Zhujun , Clement Martin , Mouland Andrew J , Kalpana Ganjam V , Belhumeur Pierre , Cohen Éric A , Yao XiaoJian
Published: January 2009

Background

HIV-1 integrase (IN) is a key viral enzymatic molecule required for the integration of the viral cDNA into the genome. Additionally, HIV-1 IN has been shown to play important roles in several other steps during the viral life cycle, including reverse transcription, nuclear import and chromatin targeting. Interestingly, previous studies have demonstrated that the expression of HIV-1 IN induces the lethal phenotype in some strains of Saccharomyces cerevisiae. In this study, we performed mutagenic analyses of the C-terminal region of the catalytic core domain of HIV-1 IN in order to delineate the critical amino acid(s) and/or motif(s) required for the induction of the lethal phenotype in the yeast strain HP16, and to further elucidate the molecular mechanism which causes this phenotype.

Results

Our study identified three HIV-1 IN mutants, V165A, A179P and KR186,7AA, located in the C-terminal region of the catalytic core domain of IN that do not induce the lethal phenotype in yeast. Chromatin binding assays in yeast and mammalian cells demonstrated that these IN mutants were impaired for the ability to bind chromatin. Additionally, we determined that while these IN mutants failed to interact with LEDGF/p75, they retained the ability to bind Integrase interactor 1. Furthermore, we observed that VSV-G-pseudotyped HIV-1 containing these IN mutants was unable to replicate in the C8166 T cell line and this defect was partially rescued by complementation with the catalytically inactive D64E IN mutant.

Conclusion

Overall, this study demonstrates that three mutations located in the C-terminal region of the catalytic core domain of HIV-1 IN inhibit the IN-induced lethal phenotype in yeast by inhibiting the binding of IN to the host chromatin. These results demonstrate that the C-terminal region of the catalytic core domain of HIV-1 IN is important for binding to host chromatin and is crucial for both viral replication and the promotion of the IN-induced lethal phenotype in yeast.
Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling
Authors: Apopa Patrick L , Qian Yong , Shao Rong , Guo Nancy Lan , Schwegler-Berry Diane , Pacurari Maricica , Porter Dale , Shi Xianglin , Vallyathan Val , Castranova Vincent , Flynn Daniel C
Published: January 2009

Background

Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human.

Results

The confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS) and the stabilization of microtubules. We also showed Akt/GSK-3β signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3β – mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery.

Conclusion

Our results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.