bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting disease-associated genotype patterns
Authors: Long Quan , Zhang Qingrun , Ott Jurg
Published: August 2009

Background

In addition to single-locus (main) effects of disease variants, there is a growing consensus that gene-gene and gene-environment interactions may play important roles in disease etiology. However, for the very large numbers of genetic markers currently in use, it has proven difficult to develop suitable and efficient approaches for detecting effects other than main effects due to single variants.

Results

We developed a method for jointly detecting disease-causing single-locus effects and gene-gene interactions. Our method is based on finding differences of genotype pattern frequencies between case and control individuals. Those single-nucleotide polymorphism markers with largest single-locus association test statistics are included in a pattern. For a logistic regression model comprising three disease variants exerting main and epistatic interaction effects, we demonstrate that our method is vastly superior to the traditional approach of looking for single-locus effects. In addition, our method is suitable for estimating the number of disease variants in a dataset. We successfully apply our approach to data on Parkinson Disease and heroin addiction.

Conclusion

Our approach is suitable and powerful for detecting disease susceptibility variants with potentially small main effects and strong interaction effects. It can be applied to large numbers of genetic markers.
From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways
Authors: Bauer-Mehren Anna , Furlong Laura I , Rautschka Michael , Sanz Ferran
Published: August 2009

Background

Single nucleotide polymorphisms (SNPs) are the most frequent type of sequence variation between individuals, and represent a promising tool for finding genetic determinants of complex diseases and understanding the differences in drug response. In this regard, it is of particular interest to study the effect of non-synonymous SNPs in the context of biological networks such as cell signalling pathways. UniProt provides curated information about the functional and phenotypic effects of sequence variation, including SNPs, as well as on mutations of protein sequences. However, no strategy has been developed to integrate this information with biological networks, with the ultimate goal of studying the impact of the functional effect of SNPs in the structure and dynamics of biological networks.

Results

First, we identified the different challenges posed by the integration of the phenotypic effect of sequence variants and mutations with biological networks. Second, we developed a strategy for the combination of data extracted from public resources, such as UniProt, NCBI dbSNP, Reactome and BioModels. We generated attribute files containing phenotypic and genotypic annotations to the nodes of biological networks, which can be imported into network visualization tools such as Cytoscape. These resources allow the mapping and visualization of mutations and natural variations of human proteins and their phenotypic effect on biological networks (e.g. signalling pathways, protein-protein interaction networks, dynamic models). Finally, an example on the use of the sequence variation data in the dynamics of a network model is presented.

Conclusion

In this paper we present a general strategy for the integration of pathway and sequence variation data for visualization, analysis and modelling purposes, including the study of the functional impact of protein sequence variations on the dynamics of signalling pathways. This is of particular interest when the SNP or mutation is known to be associated to disease. We expect that this approach will help in the study of the functional impact of disease-associated SNPs on the behaviour of cell signalling pathways, which ultimately will lead to a better understanding of the mechanisms underlying complex diseases.
Matrix gla protein (MGP): an overexpressed and migration-promoting mesenchymal component in glioblastoma
Authors: Mertsch Sonja , Schurgers Leon J , Weber Kathrin , Paulus Werner , Senner Volker
Published: August 2009

Background

Recent studies have demonstrated that a molecular subtype of glioblastoma is characterized by overexpression of extracellular matrix (ECM)/mesenchymal components and shorter survival. Specifically, gene expression profiling studies revealed that matrix gla protein (MGP), whose function has traditionally been linked to inhibition of calcification of arteries and cartilage, is overexpressed in glioblastomas and associated with worse outcome.

Methods

In order to analyze the role of MGP in glioblastomas, we performed expression, migration and proliferation studies.

Results

Real-time PCR and ELISA assays confirmed overexpression of MGP in glioblastoma biopsy specimens and cell lines at mRNA and protein levels as compared to normal brain tissue. Immunohistochemistry verified positivity of glial tumor cells for MGP. RNAi-mediated knockdown of MGP in three glioma cell lines (U343MG, U373MG, H4) led to marked reduction of migration, as demonstrated by wound healing and transwell assays, while no effect on proliferation was seen.

Conclusion

Our data suggest that upregulation of MGP (and possibly other ECM-related components as well) results in unfavorable prognosis via increased migration.
Body satisfaction and body weight: gender differences and sociodemographic determinants
Authors: Austin S Bryn , Haines Jess , Veugelers Paul J
Published: August 2009

Background

Given the documented links between body satisfaction, weight-related behaviors, and weight change in adolescents, we sought to examine the prevalence of poor body satisfaction in prepubescent girls and boys and its associations with body weight, socioeconomic factors, and rural residence.

Methods

We obtained data from 4254 girls and boys participating in a population-based survey of grade five students in the province of Nova Scotia, Canada. We examined gender specific associations between the prevalence of poor body satisfaction and body mass index (BMI) with generalized additive models and applied multilevel logistic regression methods to estimate associations of body satisfaction with BMI, rural residence, parental education and income, and neighborhood household income.

Results

We observed a linear increase in poor body satisfaction with increasing BMI in girls. Among boys, however, we found a U-shape association where boys with low BMI and those with high BMI reported higher levels of poor body satisfaction. We also found that poor body satisfaction was more prevalent among girls whose parents had lower educational attainment and among those who reside in rural areas.

Conclusion

Insight into the unique relationships between body satisfaction and BMI experienced by prepubescent children, males, and populations diverse in parental education and geographic location may help to inform public health initiatives designed to improve weight-related behaviors and reduce overweight in children.
Association of a genetic polymorphism (-44 C/G SNP) in the human DEFB1 gene with expression and inducibility of multiple β-defensins in gingival keratinocytes
Authors: Kalus Andrea A , Fredericks L Page , Hacker Beth M , Dommisch Henrik , Presland Richard B , Kimball Janet R , Dale Beverly A
Published: August 2009

Background

Human β-defensins (hBDs) are antimicrobial peptides with a role in innate immune defense. Our laboratory previously showed that a single nucleotide polymorphism (SNP) in the 5' untranslated region of the hBD1 gene (DEFB1), denoted -44 (rs1800972), is correlated with protection from oral Candida. Because this SNP alters the putative mRNA structure, we hypothesized that it alters hBD1 expression.

Methods

Transfection of reporter constructs and evaluation of antimicrobial activity and mRNA expression levels in keratinocytes from multiple donors were used to evaluate the effect of this SNP on constitutive and induced levels of expression.

Results

Transfection of CAT reporter constructs containing the 5' untranslated region showed that the -44 G allele yielded a 2-fold increase in CAT protein compared to other common haplotypes suggesting a cis effect on transcription or translation. The constitutive hBD1 mRNA level in human oral keratinocytes was significantly greater in cells from donors with the -44 GG genotype compared to those with the common CC genotype. Surprisingly, the hBD3 mRNA level as well as antimicrobial activity of keratinocyte extracts also correlated with the -44 G allele. Induced levels of hBD1, hBD2, and hBD3 mRNA were evaluated in keratinocytes challenged with Toll-like receptor 2 and 4 ligands, interleukin-1β, TNFα, and interferon-γ (IFNγ). In contrast to constitutive expression levels, IFNγ-induced keratinocyte hBD1 and hBD3 mRNA expression was significantly greater in cells with the common CC genotype, but there was no clear correlation of genotype with hBD2 expression.

Conclusion

The DEFB1 -44 G allele is associated with an increase in overall constitutive antimicrobial activity and expression of hBD1 and hBD3 in a manner that is consistent with protection from candidiasis, while the more common C allele is associated with IFNγ inducibility of these β-defensins and is likely to be more protective in conditions that enhance IFNγ expression such as chronic periodontitis. These results suggest a complex relationship between genetics and defensin expression that may influence periodontal health and innate immune responses.
Discovery of common marburgvirus protective epitopes in a BALB/c mouse model
Authors: Kalina Warren V , Warfield Kelly L , Olinger Gene G , Bavari Sina
Published: August 2009

Background

Marburg virus (MARV) causes acute hemorrhagic fever that is often lethal, and no licensed vaccines are available for preventing this deadly viral infection. The immune mechanisms for protection against MARV are poorly understood, but previous studies suggest that both antibodies and T cells are required. In our study, we infected BALB/c mice with plaque-purified, nonlethal MARV and used overlapping peptides to map H2d-restricted CD8+ T-cell epitopes.

Methods

Splenocytes from mice infected with nonlethal MARV were harvested and stimulated with multiple overlapping 15-mer peptide pools, and reactive CD8+ T cells were evaluated for antigen specificity by measuring upregulation of CD44 and interferon-γ expression. After confirming positive reactivity to specific 15-mer peptides, we used extrapolated 9-mer epitopes to evaluate the induction of cytotoxic T-cell responses and protection from lethal MARV challenge in BALB/c mice.

Results

We discovered a CD8+ T-cell epitope within both the MARV glycoprotein (GP) and nucleoprotein (NP) that triggered cytotoxic T-cell responses. These responses were also protective when epitope-specific splenocytes were transferred into naïve animals.

Conclusion

Epitope mapping of MARV GP, NP, and VP40 provides the first evidence that specific MARV-epitope induction of cellular immune responses is sufficient to combat infection. Establishment of CD8+ T-cell epitopes that are reactive to MARV proteins provides an important research tool for dissecting the significance of cellular immune responses in BALB/c mice infected with MARV.
Long-term results after Boston brace treatment in adolescent idiopathic scoliosis
Authors: Lange Johan Emil , Steen Harald , Brox Jens Ivar
Published: August 2009

Background

Few studies have evaluated long-term outcome after bracing using validated health related quality of life outcome measures. The aim of the present study was to evaluate the long-term outcome in adolescent idiopathic scoliosis (AIS) 12 years or more after treatment with the Boston brace.

Methods

109 (80%) of 135 patients (7 men) with AIS treated with the Boston brace at a mean of 19.2 (range 12–28) years previously responded to long-term follow-up examination.

All patients (n = 109) answered a standardised questionnaire including demographics, work status, treatment, Global Back Disability Question, Oswestry Disability Index (ODI) (100-worst possible), General Function Score (GFS) (100 – worst possible), EuroQol (EQ-5D) (1 – best possible), EQ-VAS (100 – best possible)) and Scoliosis Research Society -22 (SRS – 22) (5 – best possible). Clinical and radiological examination was obtained in 86 patients.

Results

The magnitude of the primary prebrace major curve was in average 33.4° (range 20 – 52). At weaning and at the last follow-up the corresponding values were 28.3° (9–56) and 34.2° (8 – 87), respectively. The mean age at follow-up was 35 (27 – 46) years. Work status was: full time (80%), on sick-leave (3%), on rehabilitation (4%), disability pension (4%), homemaker (7%), students (2%), 7% had changed their job because of back pain. 88% had had delivered a baby, 55% of them had pain in pregnancy. Global back status was excellent or good in 81%. The mean (standard deviation) ODI was 6.4 (9.8), GFS 5.4 (10.5), EQ-5D 0.84 (0.2), SRS-22: pain 4.2 (0.8), mental health 4.2 (0.7), self-image 3.9 (0.7), function 4.1 (0.6), satisfaction with treatment 3.7 (1.0). 28% had taken physiotherapy for back pain the last year and 12% had visited a doctor.

Conclusion

Long-term results were satisfactory in most patients with AIS treated with the Boston brace.
Emerging role of microRNAs in diagnosis and treatment of various diseases including ovarian cancer
Authors: Shah Parag P , Hutchinson Lauren E , Kakar Sham S
Published: August 2009

MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by targeting messenger RNA (mRNA). Recently, it has been demonstrated that miRNA expression is altered in many human diseases including cancers, suggesting that miRNA may play a potential role in the pathogenesis of different diseases. It has also been reported that there is a unique expression pattern of miRNAs in the disease state differing from the normal state. In this review, we focus on the miRNA signatures in different human diseases including cancers. Such signatures may be used as diagnostic and prognostic markers.
Knee stability assessment on anterior cruciate ligament injury: Clinical and biomechanical approaches
Authors: Lam Mak-Ham , Fong Daniel TP , Yung Patrick SH , Ho Eric PY , Chan Wood-Yee , Chan Kai-Ming
Published: August 2009

Anterior cruciate ligament (ACL) injury is common in knee joint accounting for 40% of sports injury. ACL injury leads to knee instability, therefore, understanding knee stability assessments would be useful for diagnosis of ACL injury, comparison between operation treatments and establishing return-to-sport standard. This article firstly introduces a management model for ACL injury and the contribution of knee stability assessment to the corresponding stages of the model. Secondly, standard clinical examination, intra-operative stability measurement and motion analysis for functional assessment are reviewed. Orthopaedic surgeons and scientists with related background are encouraged to understand knee biomechanics and stability assessment for ACL injury patients.
Assisted assembly: how to improve a de novo genome assembly by using related species
Authors: Gnerre Sante , Lander Eric S , Lindblad-Toh Kerstin , Jaffe David B
Published: August 2009

We describe a new assembly algorithm, where a genome assembly with low sequence coverage, either throughout the genome or locally, due to cloning bias, is considerably improved through an assisting process via a related genome. We show that the information provided by aligning the whole-genome shotgun reads of the target against a reference genome can be used to substantially improve the quality of the resulting assembly.
A method for estimating apparent displacement vectors from time-lapse seismic images
Authors: Hale Dave
Published: August 2009

Reliable estimates of vertical, inline, and crossline components of apparent displacements in time-lapse seismic images are difficult to obtain for two reasons. First, features in 3D seismic images tend to be locally planar, and components of displacement within the planes of such features are poorly resolved. Second, searching directly for peaks in 3D crosscorrelations is less robust, more complicated, and computationally more costly than searching for peaks of 1D crosscorrelations. I estimate all three components of displacement with a process designed to mitigate these two problems. I address the first problem by computing for each image sample a local phase correlation instead of a local crosscorrelation. I address the second problem with a cyclic sequence of searches for peaks of correlations computed for lags constrained to one of the three image axes.
Mig-6is required for appropriate lung development and to ensure normal adult lung homeostasis
Authors: Jin Nili , Cho Sung-Nam , Raso M. Gabriela , Wistuba Ignacio , Smith Yvonne , Yang Yanan , Kurie Jonathan M. , Yen Rudolph , Evans Christopher M. , Ludwig Thomas , Jeong Jae-Wook , DeMayo Francesco J.
Published: August 2009

Mitogen-inducible gene 6 [Mig-6; Errfi1 (ErbB receptor feedback inhibitor 1); RALT (receptor-associated late transducer); gene 33] is a ubiquitously expressed adaptor protein containing CRIB,SH3 and 14-3-3 interacting domains and has been shown to negatively regulate EGF signaling. Ablation of Mig-6 results in a partial lethal phenotype in which surviving mice acquire degenerative joint diseases and tumors in multiple organs. We have determined that the early lethality in Mig-6-/- mice occurs in the perinatal period, with mice displaying abnormal lung development. Histological examination of Mig-6-/- lungs (E15.5-P3) revealed reduced septation,airway over-branching, alveolar type II cell hyperplasia, and disturbed vascular formation. In neonatal Mig-6-/- lungs, cell proliferation increased in the airway epithelium but apoptosis increased in the blood vessels. Adult Mig-6-/- mice developed features of chronic obstructive pulmonary disease (COPD); however, when Mig-6was inducibly ablated in adult mice (Mig-6d/d), the lungs were normal. Knockdown of MIG-6 in H441 human bronchiolar epithelial cells increased phospho-EGFR and phospho-AKT levels as well as cell proliferation, whereas knockdown of MIG-6 in human lung microvascular endothelial (HMVEC-L) cells promoted their apoptosis. These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization.
dbxmediates neuronal specification and differentiation through cross-repressive, lineage-specific interactions witheveandhb9
Authors: Lacin Haluk , Zhu Yi , Wilson Beth A. , Skeath James B.
Published: August 2009

Individual neurons adopt and maintain defined morphological and physiological phenotypes as a result of the expression of specific combinations of transcription factors. In particular, homeodomain-containing transcription factors play key roles in determining neuronal subtype identity in flies and vertebrates. dbx belongs to the highly divergent H2.0 family of homeobox genes. In vertebrates, Dbx1 and Dbx2promote the development of a subset of interneurons, some of which help mediate left-right coordination of locomotor activity. Here, we identify and show that the single Drosophila ortholog of Dbx1/2contributes to the development of specific subsets of interneurons via cross-repressive, lineage-specific interactions with the motoneuron-promoting factors eve and hb9 (exex). dbx is expressed primarily in interneurons of the embryonic, larval and adult central nervous system, and these interneurons tend to extend short axons and be GABAergic. Interestingly, many Dbx+ interneurons share a sibling relationship with Eve+ or Hb9+ motoneurons. The non-overlapping expression of dbx and eve, or dbxand hb9, within pairs of sibling neurons is initially established as a result of Notch/Numb-mediated asymmetric divisions. Cross-repressive interactions between dbx and eve, and dbx and hb9, then help maintain the distinct expression profiles of these genes in their respective pairs of sibling neurons. Strict maintenance of the mutually exclusive expression of dbx relative to that of eveand hb9 in sibling neurons is crucial for proper neuronal specification, as misexpression of dbx in motoneurons dramatically hinders motor axon outgrowth.
Spatial and temporal regulation of coronary vessel formation by calcineurin-NFAT signaling
Authors: Zeini Miriam , Hang Calvin T. , Lehrer-Graiwer Joshua , Dao Tiffany , Zhou Bin , Chang Ching-Pin
Published: August 2009

Formation of the coronary vasculature requires reciprocal signaling between endothelial, epicardially derived smooth muscle and underlying myocardial cells. Our studies show that calcineurin-NFAT signaling functions in endothelial cells within specific time windows to regulate coronary vessel development. Mouse embryos exposed to cyclosporin A (CsA), which inhibits calcineurin phosphatase activity, failed to develop normal coronary vasculature. To determine the cellular site at which calcineurin functions for coronary angiogenesis, we deleted calcineurin in endothelial, epicardial and myocardial cells. Disruption of calcineurin-NFAT signaling in endothelial cells resulted in the failure of coronary angiogenesis, recapitulating the coronary phenotype observed in CsA-treated embryos. By contrast, deletion of calcineurin in either epicardial or myocardial cells had no effect on coronary vasculature during early embryogenesis. To define the temporal requirement for NFAT signaling, we treated developing embryos with CsA at overlapping windows from E9.5 to E12.5 and examined coronary development at E12.5. These experiments demonstrated that calcineurin-NFAT signaling functions between E10.5 and E11.5 to regulate coronary angiogenesis. Consistent with these in vivo observations, endothelial cells exposed to CsA within specific time windows in tissue culture were unable to form tubular structures and their cellular responses to VEGF-A were blunted. Thus, our studies demonstrate specific temporal and spatial requirements of NFAT signaling for coronary vessel angiogenesis. These requirements are distinct from the roles of NFAT signaling in the angiogenesis of peripheral somatic vessels, providing an example of the environmental influence of different vascular beds on the in vivo endothelial responses to angiogenic stimuli.
Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo
Authors: Nichols Jennifer , Silva Jose , Roode Mila , Smith Austin
Published: August 2009

Embryonic stem (ES) cells can be derived and propagated from multiple strains of mouse and rat through application of small-molecule inhibitors of the fibroblast growth factor (FGF)/Erk pathway and of glycogen synthase kinase 3. These conditions shield pluripotent cells from differentiation-inducing stimuli. We investigate the effect of these inhibitors on the development of pluripotent epiblast in intact pre-implantation embryos. We find that blockade of Erk signalling from the 8-cell stage does not impede blastocyst formation but suppresses development of the hypoblast. The size of the inner cell mass(ICM) compartment is not reduced, however. Throughout the ICM, the epiblast-specific marker Nanog is expressed, and in XX embryos epigenetic silencing of the paternal X chromosome is erased. Epiblast identity and pluripotency were confirmed by contribution to chimaeras with germline transmission. These observations indicate that segregation of hypoblast from the bipotent ICM is dependent on FGF/Erk signalling and that in the absence of this signal, the entire ICM can acquire pluripotency. Furthermore, the epiblast does not require paracrine support from the hypoblast. Thus,naïve epiblast and ES cells are in a similar ground state, with an autonomous capacity for survival and replication, and high vulnerability to Erk signalling. We probed directly the relationship between naïve epiblast and ES cells. Dissociated ICM cells from freshly harvested late blastocysts gave rise to up to 12 ES cell clones per embryo when plated in the presence of inhibitors. We propose that ES cells are not a tissue culture creation, but are essentially identical to pre-implantation epiblast cells.
Fine-tuning of secondary arbor development: the effects of the ecdysone receptor on the adult neuronal lineages of theDrosophilathoracic CNS
Authors: Brown Heather L. D. , Truman James W.
Published: August 2009

The adult central nervous system (CNS) of Drosophila is largely composed of relatively homogenous neuronal classes born during larval life. These adult-specific neuron lineages send out initial projections and then arrest development until metamorphosis, when intense sprouting occurs to establish the massive synaptic connections necessary for the behavior and function of the adult fly. In this study, we identified and characterized specific lineages in the adult CNS and described their secondary branch patterns. Because prior studies show that the outgrowth of incumbent remodeling neurons in the CNS is highly dependent on the ecdysone pathway, we investigated the role of ecdysone in the development of the adult-specific neuronal lineages using a dominant-negative construct of the ecdysone receptor(EcR-DN). When EcR-DN was expressed in clones of the adult-specific lineages,neuroblasts persisted longer, but we saw no alteration in the initial projections of the lineages. Defects were observed in secondary arbors of adult neurons, including clumping and cohesion of fine branches, misrouting,smaller arbors and some defasciculation. The defects varied across the multiple neuron lineages in both appearance and severity. These results indicate that the ecdysone receptor complex influences the fine-tuning of connectivity between neuronal circuits, in conjunction with other factors driving outgrowth and synaptic partnering.
Overselling in a Competitive Environment: Boon or Bane?
Authors: Lim Wei Shi
Published: August 2009

In this paper, we study the practice of overselling in a competitive environment where late-arriving consumers value the good higher than early-arriving ones but the former's arrival is uncertain. We show that overselling is a dominant strategy for the firms. However, it can lead to a prisoners' dilemma situation in which all firms are worse off overselling. We further show that only when demand from the late consumers far exceeds the supply and there is a sufficiently high profit margin from reselling does overselling result in a Pareto-dominant outcome for the firms.
A Viral Branching Model for Predicting the Spread of Electronic Word of Mouth
Authors: van der Lans Ralf , van Bruggen Gerrit , Eliashberg Jehoshua , Wierenga Berend
Published: August 2009

In a viral marketing campaign, an organization develops a marketing message and encourages customers to forward this message to their contacts. Despite its increasing popularity, there are no models yet that help marketers to predict how many customers a viral marketing campaign will reach and how marketers can influence this process through marketing activities. This paper develops such a model using the theory of branching processes. The proposed viral branching model allows customers to participate in a viral marketing campaign by (1) opening a seeding e-mail from the organization, (2) opening a viral e-mail from a friend, and (3) responding to other marketing activities such as banners and offline advertising. The model parameters are estimated using individual-level data that become available in large quantities in the early stages of viral marketing campaigns. The viral branching model is applied to an actual viral marketing campaign in which over 200,000 customers participated during a six-week period. The results show that the model quickly predicts the actual reach of the campaign. In addition, the model proves to be a valuable tool to evaluate alternative what-if scenarios.
Composite Reference Interval for Thyroid-Stimulating Hormone and Free Thyroxine, Comparison with Common Cutoff Values, and Reconsideration of Subclinical Thyroid Disease
Authors: Ross H Alec , den Heijer Martin , Hermus Ad R M M , Sweep Fred C G J
Published: August 2009

Background: Examination of the 2-dimensional probability distribution of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) shows that the widths of the TSH and FT4 reference intervals derived from this bivariate distribution are mutually interdependent, an aspect commonly ignored when interpreting thyroid testing results with separate reference intervals for TSH and FT4. We desired to establish and critically evaluate a composite reference interval for TSH and FT4 to allow bivariate classification of biochemical thyroid conditions.

Methods: FT4 and TSH results of 871 healthy individuals [361 women and 510 men, 18–40 years old, without history of thyroid-related disease or medication, negative for anti–thyroid peroxidase (anti-TPO) antibody] were transformed to standard normal variables by logarithmic transformation with correction for skewness and subsequent normalization. We established a 95% reference interval of the distance of each FT4/TSH pair of values to the center of the 2-dimensional probability distribution.

Results: The bivariate 95% reference interval is enclosed by a circular profile with radius 2.45 SD. By contrast, conventional reference intervals comprise a square with the boundaries of −1.96 and +1.96 SD for both FT4 and TSH that enclose only 90% of all data. Compared with the ±1.96 SD square, the bivariate reference interval classified 4% fewer of 3651 healthy individuals older than 40 years as subclinically hyperthyroid and 14% fewer of 712 anti-TPO–positive healthy individuals as subclinically hypothyroid.

Conclusions: Conventional application of separate cutoff values for FT4 and TSH leads to overestimation of the incidence of subclinical thyroid disease. Application of a composite overall reference interval is recommended.
Cystatin C and Cardiovascular Risk
Authors: Taglieri Nevio , Koenig Wolfgang , Kaski Juan Carlos
Published: August 2009

Background: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular disease (CVD) and cardiovascular events. Cystatin C, a protease inhibitor synthesized in all nucleated cells, has been proposed as a replacement for serum creatinine for the assessment of renal function, particularly to detect small reductions in glomerular filtration rate.

Content: This report presents a review of the role of cystatin C as a predictor of cardiovascular risk.

Summary: Patients with higher circulating cystatin C concentrations appear to have an increased cardiovascular risk profile, i.e., they are older and have a higher prevalence of systemic hypertension, dyslipidemia, documented CVD, increased body mass index, and increased concentrations of C-reactive protein. Prospective studies have shown, in various clinical scenarios, that patients with increased cystatin C are at a higher risk of developing both CVD and CKD. Importantly, cystatin C appears to be a useful marker for identifying individuals at a higher risk for cardiovascular events among patients belonging to a relatively low-risk category as assessed by both creatinine and estimated glomerular filtration rate values. Of interest, elastolytic proteases and their inhibitors, in particular cystatin C, have been shown to be directly involved in the atherosclerotic process. Increased concentrations of cystatin C appear to be indicative of preclinical kidney disease associated with adverse outcomes. Clinical studies involving direct glomerular filtration rate measurements are required to ascertain both the true role of this promising marker in renal disease and whether atherogenic factors like inflammation can account for increases in cystatin C concentrations, thus explaining its predictive value in CVD.
The impact of ovarian stimulation for IVF on the developing embryo
Authors: Santos Margarida Avo , Kuijk Ewart W , Macklon Nick S
Published: August 2009

The use of assisted reproductive technologies (ART) has been increasing over the past three decades, and, in developed countries, ART account for 1–3% of annual births. In an attempt to compensate for inefficiencies in IVF procedures, patients undergo ovarian stimulation using high doses of exogenous gonadotrophins to allow retrieval of multiple oocytes in a single cycle. Although ovarian stimulation has an important role in ART, it may also have detrimental effects on oogenesis, embryo quality, endometrial receptivity and perinatal outcomes. In this review, we consider the evidence for these effects and address possible underlying mechanisms. We conclude that such mechanisms are still poorly understood, and further knowledge is needed in order to increase the safety of ovarian stimulation and to reduce potential effects on embryo development and implantation, which will ultimately be translated into increased pregnancy rates and healthy offspring.
Diagnosis and therapy of depression in primary care
Authors: Torzsa Péter , Szeifert Lilla , Dunai Klaudia , Kalabay László , Novák Márta
Published: August 2009

A depresszió a külföldi és hazai felmérések szerint is a leggyakoribb pszichiátriai tünetegyüttes. Nyugat-Európában a major depresszió élettartam-prevalenciája 13%, egyéves prevalenciája 4% körül alakul. Magyarországon is hasonló a súlyos depresszió előfordulási aránya; a családorvosnál megjelenő betegek mintegy 5–8%-ánál diagnosztizálható valamilyen depresszív zavar. A megbetegedés nők körében és az életkor előrehaladtával gyakrabban fordul elő. Az Egészségügyi Világszervezet szerint a depresszió jelenleg a harmadik leggyakoribb munkaképesség-csökkenésért felelős betegség. A kórkép jelentőségét növeli, hogy nagymértékben rontja az életminőséget, gyakran társul szorongással, alvászavarokkal, alkohol- és drogfüggőséggel, valamint egyes szomatikus kórképekkel. A depresszió az öngyilkosság legfőbb rizikófaktora. A depresszió szűrésében, diagnosztizálásában nagy szerep jut a családorvosnak. Nemcsak a levert hangulatról, szomorúságról, öngyilkossági gondolatokról panaszkodó beteg esetén kell depresszióra gondolni, hanem szervi betegséggel nem magyarázható egyéb tünetek, fejfájás, fáradékonyság, hasi fájdalom, gastrointestinalis panaszok, testsúlyváltozás esetén is. A családorvosnak megfelelő ismeretekkel kell rendelkeznie a különböző terápiás lehetőségekről – pszichoterápiás módszerekről, antidepresszív gyógyszerekről, egyéb terápiás lehetőségekről –, hogy betegét hatékonyan tudja kezelni, szükség esetén a pszichológussal, pszichiáter szakorvossal együttműködve. Jelen közleményünkben bemutatjuk a depresszió jelentőségét és előfordulási gyakoriságát vizsgáló irodalmi adatokat, valamint összefoglaljuk a depresszió diagnosztikus és terápiás lehetőségeit a családorvosi gyakorlatban.
The efficacy of class III D,L sotalol in treatment of left atrial tachycardia after pulmonary vein isolation
Authors: Mihálcz Attila , Földesi Csaba , Kardos Attila , Ladunga Károly , Szili-Török Tamás
Published: August 2009

Pitvarfibrilláció miatt végzett pulmonalis vena izolációját követően a betegek egy részénél iatrogén bal pitvari tachycardia jelentkezik.
Cél:
A sotalolterápia hatásosságának összehasonlítása az 1C tip. propafenonnal szemben, a postablatiós arrhythmiák kezelésében.
Módszer és eredmények:
A vizsgálatba 75, pitvarfibrillációban szenvedő beteget (átlagéletkor 55,4 ± 7,14 év) választottunk, akiknél a pulmonalis vénák valódi elektromos izolálását végeztük. A beavatkozás során az elektromos izolációt körkörös multipoláris katéterrel ellenőriztük. Az ablatiót követően folytattuk az antiarrhythmiás terápiát még minimum 6 hétig, de célunk annak leépítése volt. Az utánkövetést 1, majd 3 havonta tervezett, ambuláns vizsgálatok alapján végeztük. A 12. hónap végén 67 betegnél tudtuk a protokoll szerint gyűjtött adatokat elemezni. 21 betegnél jelentkezett 3 hónapot követően tartósan bal pitvari tachycardia (31,3%). 11 beteg propafenon-, 4 beteg amiodaron- és 6 beteg sotalolterápiában részesült. Az első két csoportnál sotalolterápiára váltottunk, míg az utolsó csoportnál propafenonterápiát kezdtünk. A 12. hónap végére a sotalol hatásossága 80%, a propafenon hatásossága 20% volt.
Következtetések:
Adataink alapján PV-izolációt követően a sotalolterápia nem hatásosabb a bal pitvari tachycardiák megelőzésében, mint a propafenon. A 3 hónapon túl fellépő postablatiós bal pitvari tachycardiák kezelésében a sotalol hatásosabb, mint az IC-csoportba tartozó propafenon.
Surgical robotics in neurosurgery
Authors: Haidegger Tamás , Benyó Zoltán
Published: August 2009

Robotizált rendszereket az egészségügyben elsőként rehabilitációra és végtagpótlásra használtak, majd fokozatosan megjelentek az invazív beavatkozásokat segítő eszközök. Az Amerikai Egyesült Államokban 2008-ban becslések szerint a radikális prosztataeltávolítások több mint 70%-át robottal végezték, és jelentős áttörést értek el veseeltávolításoknál, gastrointestinalis és ortopédiai beavatkozásoknál, valamint szív- és gyereksebészetnél is. Az idegsebészet volt a sebészrobotok legelső alkalmazási területe, és mára már több tucat különböző rendszert fejlesztettek, amelyek eltérő módokon igyekeznek megfelelni a szigorú biztonsági és pontossági követelményeknek. Jelen közlemény célja, hogy röviden ismertesse a manapság leginkább elterjedt idegsebészeti robotokat, fő előnyeiket és korlátaikat. Egy-egy konkrét példán keresztül ismertetjük a legfontosabb fejlesztési stratégiákat, amelyek révén új beavatkozások végrehajtására nyílik lehetőség. Részletesen tárgyaljuk az amerikai Johns Hopkins Universityn fejlesztett új, agyalapi műtétek hatékony támogatására szolgáló rendszert, amely jól példázza, milyen előnyökkel járhat a modern technika megfelelő alkalmazása. E kutatás célja a koponyafúrással járó operációk pontosabbá és biztonságosabbá tétele egy NeuroMate sztereotaktilis robot és StealthStation műtéti navigációs rendszer integrálásával. Laboratóriumi körülmények között végzett kísérletek azt mutatták, hogy a rendszer hatékony segítséget adhat. A robotra szerelt fúró erő/nyomaték irányítás révén, érzékelők segítségével folyamatosan követi a sebész kezének mozgását. A betegek preoperatív orvosi képein meghatározott virtuális határok és fejlett valós idejű vizualizáció segítik a műtétet. Ezek a funkciók együttesen nagymértékben javítják a beavatkozások pontosságát, csökkentik azok idejét, és jelentősen megkönnyítik a sebész feladatát.
Expression and function of G-protein-coupled receptorsin the male reproductive tract
Authors: Avellar Maria Christina W. , Lázari Maria Fatima M. , Porto Catarina S.
Published: August 2009

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.
A glimpse on biological activities of tellurium compounds
Authors: Cunha Rodrigo L. O. R. , Gouvea Iuri E. , Juliano Luiz
Published: August 2009

Tellurium is a rare element which has been regarded as a toxic, non-essential trace element and its biological role is not clearly established to date. Besides of that, the biological effects of elemental tellurium and some of its inorganic and organic derivatives have been studied, leading to a set of interesting and promising applications. As an example, it can be highlighted the uses of alkali-metal tellurites and tellurates in microbiology, the antioxidant effects of organotellurides and diorganoditellurides and the immunomodulatory effects of the non-toxic inorganic tellurane, named AS-101, and the plethora of its uses. Inasmuch, the nascent applications of organic telluranes (organotelluranes) as protease inhibitors and its applications in disease models are the most recent contribution to the scenario of the biological effects and applications of tellurium and its compounds discussed in this manuscript.
Effects of FGF-2 and EGF removal on the differentiationof mouse neural precursor cells
Authors: Schwindt Telma T. , Motta Fabiana L. , Gabriela F. Barnabé , Cristina G. Massant , Guimarães Alessander O. , Calcagnotto Maria Elisa , Pesquero João B. , Mello Luiz E.
Published: August 2009

Cell therapy for neurological disorders has advanced, and neural precursor cells (NPC) may become the ideal candidates for neural transplantation in a wide range of diseases. However, additional work has to be done to determine either the ideal culture environment for NPC expansion in vitro, without altering their plasticity, or the FGF-2 and EGF mechanisms of cell signaling in neurospheres growth, survival and differentiation. In this work we evaluated mouse neurospheres cultured with and without FGF-2 and EGF containing medium and showed that those growth factors are responsible for NPC proliferation. It is also demonstrated that endogenous production of growth factors shifts from FGF-2 to IGF-1/PDGFb upon EGF and FGF-2 withdrawal. Mouse NPC cultured in suspension showed different patterns of neuronal localization (core versus shell) for both EGF and FGF-2 withdrawal and control groups. Taken together, these results show that EGF and FGF-2 removal play an important role in NPC differentiation and may contribute to a better understanding of mechanisms of NPC differentiation. Our findings suggest that depriving NPC of growth factors prior to grafting might enhance their chance to effectively integrate into the host.
Metabolism and secretory function of white adipose tissue: effect of dietary fat
Authors: Nascimento Cláudia M. Oller do , Ribeiro Eliane B. , Oyama Lila M.
Published: August 2009

Approximately 40% of the total energy consumed by western populations is represented by lipids, most of them being ingested as triacylglycerols and phospholipids. The focus of this review is to analyze the effect of the type of dietary fat on white adipose tissue metabolism and secretory function, particularly on haptoglobin, TNF-α, plasminogen activator inhibitor-1 and adiponectin secretion. Previous studies have demonstrated that the duration of the exposure to the high-fat feeding, amount of fatty acid present in the diet and the type of fatty acid may or may not have a significant effect on adipose tissue metabolism. However, the long-term or short-term high fat diets, especially rich in saturated fatty acids, probably by activation of toll-like receptors, stimulated the expression of proinflammatory adipokines and inhibited adiponectin expression. Further studies are needed to investigate the cellular mechanisms by which dietary fatty acids affect white adipose tissue metabolism and secretory functions.
Current relevance of fungal and trypanosomatid glycolipids and sphingolipids: studies defining structures conspicuously absent in mammals
Authors: Takahashi Helio K. , Toledo Marcos S. , Suzuki Erika , Tagliari Loriane , Straus Anita H.
Published: August 2009

Recently, glycosphingolipids have been attracting attention due to their role on biological systems as second messengers or modulators of signal transduction, affecting several events, which range from apoptosis to regulation of the cell cycle. In pathogenic fungi, glycolipids are expressed in two classes: neutral monohexosylceramides (glucosyl-or galactosylceramide) and acidic glycosylinositol phosphorylceramides (the latter class carries longer glycan chains). It is worth to mention that monohexosylceramides exhibit significant structural differences in their lipid moieties compared to their mammalian counterparts, whereas the glycosylinositol phosphorylceramides exhibit remarkable structural differences in their carbohydrate moieties in comparison to mammal glycosphingolipids counterpart. We observed that glycosylinositol phosphorylceramides are capable of promoting immune response in infected humans. In addition, inhibiting fungal glycosphingolipid biosynthetic pathways leads to an inhibition of colony formation, spore germination, cell cycle, dimorphism and hyphal growth. Other pathogens, such as trypanosomatids, also present unique glycolipids, which may have an important role for the parasite development and/or disease establishment. Regarding host-pathogen interaction, cell membrane rafts, which are enriched in sphingolipids and sterols, participate in parasite/fungal infection. In this review, it is discussed the different biological roles of (glyco) (sphingo)lipids of pathogenic/opportunistic fungi and trypanosomatids.
The role of research methodology in the rational use of technology in monitoring and preventing communication disorders
Authors: Chiari Brasília M. , Goulart Bárbara N. G.
Published: August 2009

Studies showing stronger scientific evidence related to speech, language and hearing pathology (SLP) have an impact on the prevention and rehabilitation of human communication and gained ground in SLP research agenda. In this paper we discuss some aspects and directions that should be considered for in-depth knowledge about speech, language and hearing needs in different population groups (age group, gender and other variables according to specific related disorders) for improved comprehensive care, successful efforts and effective use of financial and human resources. It is also discussed the decision making process for requesting complementary evaluations and tests, from routine to highly complex ones, that should be based on each test and/or procedure and their contribution to the diagnosis and therapeutic planning. In fact, it is crucial to have reliable parameters for planning, preventing and treating human communication and its related disorders. Epidemiology, biostatistics and social sciences can contribute with more specific information in human communication sciences and guide more specific studies on the international science and technology agenda, improving communication sciences involvement in the international health-related scientific scenario.
Paradoxical sleep deprivation: neurochemical, hormonal and behavioral alterations. Evidence from 30 years of research
Authors: Tufik Sergio , Andersen Monica L. , Bittencourt Lia R. A. , Mello Marco T. de
Published: August 2009

Sleep comprises approximately one-third of a person's lifetime, but its impact on health and medical conditions remains partially unrecognized. The prevalence of sleep disorders is increasing in modern societies, with significant repercussions on people's well-being. This article reviews past and current literature on the paradoxical sleep deprivation method as well as data on its consequences to animals, ranging from behavioral changes to alterations in the gene expression. More specifically, we highlight relevant experimental studies and our group's contribution over the last three decades.