bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of diet and major depression to incidence of acute myocardial infarction (AMI)
Authors: Yary Teymoor , Soleimannejad Kourosh , Abd Rahim Firdaus , Kandiah Mirnalini , Aazami Sanaz , Poor Seyedehozma Jafar , Wee Wong Teck , Aazami Golnaz
Published: November 2010

Background

Despite significant improvements in the treatment of coronary heart disease (CHD), it is still a major cause of mortality and morbidity among the Iranian population. Epidemiological studies have documented that risk factors including smoking and the biochemical profile are responsible for the development of acute myocardial infarction (AMI). Psychological factors have been discussed as potential risk factors for coronary heart disease. Among emotional factors, depression correlates with coronary heart disease, particularly myocardial infarction.

Methods

This case-control study was conducted on 120 cases (69 males and 51 females) of acute myocardial infarction (AMI) and 120 controls, with a mean age of 62.48 ± 15.39 years. Cases and controls were matched by age, residence and sex.

Results

The results revealed that severe depression was independently associated with the risk of AMI (P = 0.025, OR = 2.6, 95% CI 1.1-5.8). The analysis of variables indicated that risk factors for developing depression were unmarried, low levels of polyunsaturated fatty acids (PUFAs), total dietary fiber (TDF) and carbohydrates. The levels of these dietary factors were lowest in severely depressed patients compared to those categorised as moderate or mild cases. Furthermore, severely depressed subjects were associated with higher levels of total cholesterol, high systolic blood pressure (SBP) and WHR. Age, income, a family history of coronary heart disease, education level, sex, employment and smoking were not associated with severe depression.

Conclusion

The present study demonstrated that severe depression symptoms are independent risk factors for AMI. Furthermore, severe depression was associated with an unhealthy diet and AMI risk factors.
Proteomic analysis of streptomycin resistant and sensitive clinical isolates of Mycobacterium tuberculosis
Authors: Sharma Prashant , Kumar Bhavnesh , Gupta Yash , Singhal Neelja , Katoch Vishwa Mohan , Venkatesan Krishnamurthy , Bisht Deepa
Published: November 2010

Background

Streptomycin (SM) is a broad spectrum antibiotic and is an important component of any anti-tuberculosis therapy regimen. Several mechanisms have been proposed to explain the emergence of resistance but still our knowledge is inadequate. Proteins form a very complex network and drugs are countered by their modification/efflux or over expression/modification of targets. As proteins manifest most of the biological processes, these are attractive targets for developing drugs, immunodiagnostics or therapeutics. The aim of present study was to analyze and compare the protein profile of whole cell extracts from Mycobacterium tuberculosis clinical isolates susceptible and resistant to SM.

Results

Two-dimensional gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was employed for analyzing the protein profiles. Homology and in silico characterization for identified proteins was assessed using BLAST, InterProScan and KEGG database searches. Computational studies on the possible interactions between SM and identified proteins were carried out by a battery of online servers and softwares, namely, CLUSTALW (KEGG), I-TASSER, VMD, PatchDock and FireDock. On comparing 2DE patterns, nine proteins were found consistently overexpressed in SM resistant isolates and were identified as Rv0350, Rv0440, Rv1240, Rv3075c, Rv2971, Rv3028c, Rv2145c, Rv2031c and Rv0569. In silico docking analysis showed significant interactions of SM with essential (Rv0350, Rv0440 and Rv2971) and non essential (Rv1240, Rv3075c and Rv2031c) genes.

Conclusions

The computational results suggest high protein binding affinity of SM and suggested many possible interactions between identified proteins and the drug. Bioinformatic analysis proves attributive for analysis of diversity of proteins identified by whole proteome analysis. In-depth study of the these proteins will give an insight into probable sites of drug action other than established primary sites and hence may help in search of novel chemotherapeutic agents at these new sites as inhibitors.
Primary retroperitoneal carcinosarcoma in a child: a case report
Authors: Xu Feng , Huang Yangqing , Yang Jiamei
Published: November 2010

Carcinosarcoma is a rare biphasic malignancy consisting of intermixed epithelial and mesenchymal elements. Carcinosarcoma is particularly rare among children. We accepted a 7 year old patient with retroperitoneal carcinosarcoma. The tumor was totally resected and no recurrence is found 11 months after operation. Literatures has been reviewed and there are few reports of primary retroperitoneal carcinosarcoma in children up to date. So we report the patient's clinical character, surgical resection, pathological and immunohistochemical analysis.
Zinc in innate and adaptive tumor immunity
Authors: John Erica , Laskow Thomas C , Buchser William J , Pitt Bruce R , Basse Per H , Butterfield Lisa H , Kalinski Pawel , Lotze Michael T
Published: November 2010

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order.
Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures
Authors: Bovolenta Roberta , Zucchini Silvia , Paradiso Beatrice , Rodi Donata , Merigo Flavia , Mora Graciela Navarro , Osculati Francesco , Berto Elena , Marconi Peggy , Marzola Andrea , Fabene Paolo F , Simonato Michele
Published: November 2010

Under certain experimental conditions, neurotrophic factors may reduce epileptogenesis. We have previously reported that local, intrahippocampal supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) increases neurogenesis, reduces neuronal loss, and reduces the occurrence of spontaneous seizures in a model of damage-associated epilepsy. Here, we asked if these possibly anti-epileptogenic effects might involve anti-inflammatory mechanisms. Thus, we used a Herpes-based vector to supplement FGF-2 and BDNF in rat hippocampus after pilocarpine-induced status epilepticus that established an epileptogenic lesion. This model causes intense neuroinflammation, especially in the phase that precedes the occurrence of spontaneous seizures. The supplementation of FGF-2 and BDNF attenuated various parameters of inflammation, including astrocytosis, microcytosis and IL-1β expression. The effect appeared to be most prominent on IL-1β, whose expression was almost completely prevented. Further studies will be needed to elucidate the molecular mechanism(s) for these effects, and for that on IL-1β in particular. Nonetheless, the concept that neurotrophic factors affect neuroinflammation in vivo may be highly relevant for the understanding of the epileptogenic process.
Evolution of Dengue Virus Type 3 Genotype III in Venezuela: Diversification, Rates and Population Dynamics
Authors: Ramírez Alvaro , Fajardo Alvaro , Moros Zoila , Gerder Marlene , Caraballo Gerson , Camacho Daria , Comach Guillermo , Alarcón Victor , Zambrano Julio , Hernández Rosa , Moratorio Gonzalo , Cristina Juan , Liprandi Ferdinando
Published: November 2010

Background

Dengue virus (DENV) is a member of the genus Flavivirus of the family Flaviviridae. DENV are comprised of four distinct serotypes (DENV-1 through DENV-4) and each serotype can be divided in different genotypes. Currently, there is a dramatic emergence of DENV-3 genotype III in Latin America. Nevertheless, we still have an incomplete understanding of the evolutionary forces underlying the evolution of this genotype in this region of the world. In order to gain insight into the degree of genetic variability, rates and patterns of evolution of this genotype in Venezuela and the South American region, phylogenetic analysis, based on a large number (n = 119) of envelope gene sequences from DENV-3 genotype III strains isolated in Venezuela from 2001 to 2008, were performed.

Results

Phylogenetic analysis revealed an in situ evolution of DENV-3 genotype III following its introduction in the Latin American region, where three different genetic clusters (A to C) can be observed among the DENV-3 genotype III strains circulating in this region. Bayesian coalescent inference analyses revealed an evolutionary rate of 8.48 × 10-4 substitutions/site/year (s/s/y) for strains of cluster A, composed entirely of strains isolated in Venezuela. Amino acid substitution at position 329 of domain III of the E protein (A→V) was found in almost all E proteins from Cluster A strains.

Conclusions

A significant evolutionary change between DENV-3 genotype III strains that circulated in the initial years of the introduction in the continent and strains isolated in the Latin American region in recent years was observed. The presence of DENV-3 genotype III strains belonging to different clusters was observed in Venezuela, revealing several introduction events into this country. The evolutionary rate found for Cluster A strains circulating in Venezuela is similar to the others previously established for this genotype in other regions of the world. This suggests a lack of correlation among DENV genotype III substitution rate and ecological pattern of virus spread.
Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis
Authors: Gu Ling , Zhou Chenyan , Liu Huajun , Gao Ju , Li Qiang , Mu Dezhi , Ma Zhigui
Published: November 2010

Background

Glucocorticoid (GC) resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex) treatment.

Methods

Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and apoptosis associated proteins.

Results

10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G1-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR) expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1.

Conclusion

Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G0/G1 phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting new therapeutic approach for GC resistant T-ALL patients.
A GA microsatellite in the Fli1promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis
Authors: Morris Erin E , Amria May Y , Kistner-Griffin Emily , Svenson John L , Kamen Diane L , Gilkeson Gary S , Nowling Tamara K
Published: November 2010

Introduction

The transcription factor Fli1 is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Recently, a GAn polymorphic microsatellite was characterized in the mouse Fli1 promoter that modulates promoter activity and is truncated in two lupus mouse models compared to non-autoimmune prone mice. In this work, we characterize a homologous GAn microsatellite in the human Fli1 promoter. The purpose of this study is to determine the effect of the microsatellite length on Fli1 promoter activity in vitro and to determine if the length of the GAn microsatellite is associated with SLE and/or specific disease characteristics.

Methods

Constructs with variable lengths of the GAn microsatellite in the Fli1 promoter were generated and analyzed in promoter/reporter (P/R) assays in a human T cell line. Using three SLE patient cohorts and matched controls, microsatellite length was measured and association with the presence of disease and the occurrence of specific disease manifestations was assessed.

Results

P/R assays demonstrated that the presence of a shorter microsatellite resulted in higher Fli1 promoter activity. A significant association was observed in the lupus cohort SLE in Gullah Health (SLEIGH) between the GA26 base pair allele and absence of nephritis.

Conclusions

This study demonstrates that a GAn microsatellite in the human Fli1 promoter is highly polymorphic. The length of the microsatellite is inversely correlated to Fli1 promoter activity in a human T cell line. Although no association between microsatellite length and lupus was observed, an association between a specific microsatellite length and patients without nephritis in the SLEIGH cohort was observed.
Prospective case-control study of premenopausal serum estradiol and testosterone levels and breast cancer risk
Authors: Dorgan Joanne F , Stanczyk Frank Z , Kahle Lisa L , Brinton Louise A
Published: November 2010

Introduction

Breast cancer is frequently a hormonally dependent cancer, and associations of circulating estrogens and androgens with subsequent breast cancer risk are well established in postmenopausal women. Associations of serum estrogens and androgens with breast cancer risk in premenopausal women are less well studied. The objective of this study was to determine whether estradiol and testosterone levels in serum collected before menopause are associated with subsequent breast cancer risk.

Methods

We conducted a prospective case-control study of 266 participants who were registered in the Columbia, Missouri, Serum Bank and not using exogenous hormones at the time of blood collection. Each of 98 insitu or invasive breast cancer cases with prediagnostic serum collected before menopause was matched to two controls by age, date, menstrual cycle day, and time of day of blood collection. Estradiol and testosterone concentrations were quantified by using specific radioimmunoassays, and sex hormone-binding globulin (SHBG) was quantified with a chemiluminescent immunoassay to allow calculation of the non-SHBG bound hormone fractions. Data were analyzed by using conditional logistic regression. All tests of statistical significance were two-sided.

Results

Serum testosterone was strongly and significantly associated with breast cancer risk. The relative odds (OR) for increasing quartiles of total testosterone were 1.0, 2.1 (95% confidence interval (CI) 0.9 to 4.8), 1.5 (95% CI, 0.6 to 3.4), and 3.3 (95% CI, 1.5 to 7.5, Ptrend = 0.006). Comparable ORs for the non-SHBG bound fraction of testosterone that is bioavailable were 1.0, 1.7 (95% CI, 0.7 to 4.2), 1.7 (95% CI, 0.7 to 4.0), and 4.2 (95% CI, 1.6 to 10.9, Ptrend = 0.002). Total and non-SHBG-bound estradiol were not associated with breast cancer, but extreme variation in levels across the menstrual cycle coupled with relatively small numbers, particularly for analyses stratified by cycle phase, limited the power to detect associations.

Conclusions

Results suggest that premenopausal women with elevated serum testosterone levels are at an increased risk of breast cancer.
Acute pancreatitis with organ dysfunction associates with abnormal blood lymphocyte signaling: controlled laboratory study
Authors: Oiva Jani , Mustonen Harri , Kylänpää Marja-Leena , Kyhälä Lea , Kuuliala Krista , Siitonen Sanna , Kemppainen Esko , Puolakkainen Pauli , Repo Heikki
Published: November 2010

Introduction

Severe acute pancreatitis is associated with systemic inflammation, compensatory immune suppression, secondary infections, vital organ dysfunction, and death.

Our study purpose was to delineate signaling profiles of circulating lymphocytes in acute pancreatitis complicated by organ dysfunction.

Methods

Sixteen patients with acute pancreatitis, dysfunction of vital organ(s), and immune suppression (proportion of HLA-DR Human Leukocyte Antigen - DR - positive monocytes < 80%) participated. Healthy volunteers served as reference subjects. Using phospho-specific whole blood flow cytometry we studied lymphocyte phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases p38 and extracellular signal-regulated kinases (ERK)1/2, and signal transducers and activators of transcription (STATs) 1, 3, and 6. Statistical comparisons were performed with the Wilcoxon-Mann-Whitney test.

Results

In blood samples supplemented with tumor necrosis factor, E. coli or S. aureus, phosphorylation levels of NFκB were lower and levels of p38 were higher in patients with acute pancreatitis than healthy subjects. Low NFκB activation involved CD3+CD4+ and CD3+CD8+ lymphocytes. ERK1/2 phosphorylation induced by co-stimulation with phorbol 12-myristate 13-acetate and calcium ionophore A23187 was depressed in patients. STAT3 was constitutively activated in patients' CD3+CD4+ and CD3+CD8+ lymphocytes. Also, IL-6-induced STAT1 phosphorylation was impaired while IL-4-induced STAT6 phosphorylation was enhanced.

Conclusions

Lymphocytes of patients with acute pancreatitis, organ dysfunction and immune suppression show impaired NFκB activation, which increases infection risk and enhanced p38 activation, which sustains inflammation. Secondly, they indicate constitutive STAT3 activation, which may favor Th17 lineage of CD4+ lymphocyte differentiation. Thirdly, they reveal impaired STAT1 activation and enhanced STAT6 activation, denoting a shift from Th1 towards Th2 differentiation.
The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-β-mediated antiviral activity in vitro and in vivo
Authors: Shirey Kari Ann , Nhu Quan M , Yim Kevin C , Roberts Zachary J , Teijaro John R , Farber Donna L , Blanco Jorge C , Vogel Stefanie N
Published: November 2010

The 2009 outbreak of pandemic H1N1 influenza, increased drug resistance, and the significant delay in obtaining adequate numbers of vaccine doses have heightened awareness of the need to develop new antiviral drugs that can be used prophylactically or therapeutically. Previously, we showed that the experimental anti-tumor drug DMXAA potently induced IFN-β but relatively low TNF-α expression in vitro. This study confirms these findings in vivo and demonstrates further that DMXAA induces potent antiviral activity in vitro and in vivo. In vitro, DMXAA protected RAW 264.7 macrophage-like cells from VSV-induced cytotoxicity and moreover, inhibited replication of influenza, including the Tamiflu®-resistant H1N1 influenza A/Br strain, in MDCK cells. In vivo, DMXAA protected WT C57BL/6J but not IFN-β−/− mice from lethality induced by the mouse-adapted H1N1 PR8 influenza strain when administered before or after infection. Protection was accompanied by mitigation of weight loss, increased IFN-β mRNA and protein levels in the lung, and significant inhibition of viral replication in vivo early after DMXAA treatment. Collectively, this study provides data to support the use of DMXAA as a novel antiviral agent.
Rhesus macaque θ-defensin isoforms: expression, antimicrobial activities, and demonstration of a prominent role in neutrophil granule microbicidal activities
Authors: Tongaonkar Prasad , Tran Patti , Roberts Kevin , Schaal Justin , Ösapay George , Tran Dat , Ouellette André J , Selsted Michael E
Published: November 2010

Mammalian defensins are cationic, antimicrobial peptides that play a central role in innate immunity. The peptides are composed of three structural subfamilies: α-, β-, and θ-defensins. θ-Defensins are macrocyclic octadecapeptides expressed only in Old World monkeys and Orangutans and are produced by the pair-wise, head-to-tail splicing of nonapeptides derived from their respective precursors. The existence of three active θ-defensin genes predicts that six different RTDs (1–6) are produced in this species. In this study, we isolated and quantified RTDs 1–6 from the neutrophils of 10 rhesus monkeys. RTD-1 was the most abundant θ-defensin, constituting ∼50% of the RTD content; total RTD content varied by as much as threefold between animals. All peptides tested were microbicidal at ∼1 μM concentrations. The contribution of θ-defensins to macaque neutrophil antimicrobial activity was assessed by analyzing the microbicidal properties of neutrophil granule extracts after neutralizing θ-defensin content with a specific antibody. θ-Defensin neutralization markedly reduced microbicidal activities of the corresponding extracts. Macaque neutrophil granule extracts had significantly greater microbicidal activity than those of human neutrophils, which lack θ-defensins. Supplementation of human granule extracts with RTD-1 markedly increased the microbicidal activity of these preparations, further demonstrating a prominent microbicidal role for θ-defensins.
Enhancing seismic data resolution using the prestack blueing technique: An example from the Ketzin C O2 injection site, Germany
Authors: Kazemeini Sayed Hesammoddin , Yang Can , Juhlin Christopher , Fomel Sergey , Cosma Calin
Published: November 2010

Restricted resolution imposes limits on the detection of subsurface geologic features using surface seismic data. Despite great improvements in acquisition and processing techniques in recent years, seismic data still suffer from limited resolution. Detailed subsurface information on the geologic conditions at depth cannot always be attained from conventional surface seismic data. For the area of this study, the carbon dioxide [Formula: see text] storage site at Ketzin, Germany, high seismic resolution is required for mapping the internal structure of the main target reservoir. Processing of the 3D surface seismic data using conventional methods did not provide optimum resolution. The spectral blueing technique attempts to enhance the surface seismic data resolution. Well-log data generally show a blue spectrum with higher-amplitudes at the higher frequencies than the commonly assumed white reflection series. By designing and applying one or several operators to poststack data, it has been possible to better match the reflectivity series and improve resolution. Applying the blueing operator to prestack data was investigated to possibly improve seismic resolution, produce more consistent results, and cause fewer ringing artifacts than when applied to poststack data. Prestack blueing, poststack blueing, and no blueing of the Ketzin 3D seismic data were compared with zero-offset vertical seismic profile (VSP) and synthetic seismograms. The comparison shows that prestack spectral blueing can indeed enhance seismic resolution with fewer artifacts associated with it than the poststack technique. The prestack and poststack spectral blueing approaches improve the well to seismic tie.
Semiautomated suppression of above-surface diffractions in GPR data
Authors: Carpentier Stefan F. , Horstmeyer Heinrich , Green Alan G. , Doetsch Joseph , Coscia Ilaria
Published: November 2010

Diffractions from above-surface objects can be a major problem in the processing and interpretation of ground-penetrating radar (GPR) data. Whereas methods to reduce random and many other types of source-generated noise are available, the efficient suppression of above-surface diffractions (ASDs) continues to be challenging. We have developed a scheme for semiautomatically detecting and suppressing ASDs. Initially, an accurate representation of ASDs is obtained by (1) Stolt [Formula: see text] migrating the GPR data using the air velocity to focus ASDs, (2) multichannel filtering to minimize other signals, (3) setting an amplitude threshold that targets the high-amplitude ASDs and effectively eliminates other signals, and (4) Stolt [Formula: see text] demigrating the ASDs using the air velocity, and remigrating them using the ground velocity. By excluding the obliquity correction in the Stolt algorithms and avoiding intermediate amplitude scaling, we preserve the ASDs’ amplitude and phase information. The final stepinvolves subtracting this image of ASDs from a standard migrated version of the original data. This scheme, which includes some important extensions to a previously proposed method, makes it possible to semiautomatically process large volumes of GPR data characterized by numerous highly clustered and overlapping ASDs. The user has control over the tradeoff between ASD suppression and undesired removal of useful signal. It achieves nearly complete removal of ASDs in synthetic data and significant suppression in field data. Once ASDs have been suppressed, their influence can be reduced further by applying relatively gentle multichannel filters. It is not possible to remove line diffractions that resemble subhorizontal reflections or retrieve subsurface signals from data saturated by ASDs, such that some blank regions may be left after applying the suppression scheme. Nevertheless, subsequent processing and interpretation of the GPR data benefit significantly from the suppression of ASDs, which otherwise would clutter the final images.
Fundamental discussions on seismic vibrators
Authors: Wei Zhouhong , Phillips Thomas F. , Hall Michael A.
Published: November 2010

Vibrators are the most widely used sources in land seismic exploration. Successful application of vibroseis technology requires evaluating each element in the vibrator system and ensuring that each part of the system contributes to the success of the method. To obtain a high-quality image of the subsurface using the vibroseis method, it is beneficial to know: the frequency bandwidth the vibrator and its control system can deliver; the outgoing signal from the vibrator and the repeatability of the source signature; and the harmonic distortion level on the vibrator force output and the limits the vibrator is subject to. Fundamental discussions on the vibrator system that have been forgotten over time are presented.
GH-Dependent STAT5 Signaling Plays an Important Role in Hepatic Lipid Metabolism
Authors: Barclay Johanna L. , Nelson Caroline N. , Ishikawa Mayumi , Murray Lauren A. , Kerr Linda M. , McPhee Timothy R. , Powell Elizabeth E. , Waters Michael J.
Published: November 2010

GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b−/− mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identified putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used DN-STAT5a/b, DN-STAT1, constitutively active (CA)-STAT3, or addition of oleate/palmitate in the hepatoma line to assign which of these apply to individual targets in STAT5 signaling deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/β expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because activated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.
Gene Expression Profiling Reveals Cyp26b1 to Be an Activin Regulated Gene Involved in Ovarian Granulosa Cell Proliferation
Authors: Kipp Jingjing L. , Golebiowski Ann , Rodriguez Guadalupe , Demczuk Michael , Kilen Signe M. , Mayo Kelly E.
Published: November 2010

Activin, a member of the TGF-β superfamily, is an important modulator of FSH synthesis and secretion and is involved in reproductive dysfunctions and cancers. It also regulates ovarian follicle development. To understand the mechanisms and pathways by which activin regulates follicle function, we performed a microarray study and identified 240 activin regulated genes in mouse granulosa cells. The gene most strongly inhibited by activin was Cyp26b1, which encodes a P450 cytochrome enzyme that degrades retinoic acid (RA). Cyp26b1 has been shown to play an important role in male germ cell meiosis, but its expression is largely lost in the ovary around embryonic d 12.5. This study demonstrated that Cyp26b1 mRNA was expressed in granulosa cells of follicles at all postnatal developmental stages. A striking inverse spatial and temporal correlation between Cyp26b1 and activin-βA mRNA expression was observed. Cyp26b1 expression was also elevated in a transgenic mouse model that has decreased activin expression. The Cyp26 inhibitor R115866 stimulated the proliferation of primary cultured mouse granulosa cells, and a similar effect was observed with RA and activin. A pan-RA receptor inhibitor, AGN194310, abolished the stimulatory effect of either RA or activin on granulosa cell proliferation, indicating an involvement of RA receptor-mediated signaling. Overall, this study provides new insights into the mechanisms of activin action in the ovary. We conclude that Cyp26b1 is expressed in the postnatal mouse ovary, regulated by activin, and involved in the control of granulosa cell proliferation.
Targeted Inactivation of the Androgen Receptor Gene in Murine Proximal Epididymis Causes Epithelial Hypotrophy and Obstructive Azoospermia
Authors: Krutskikh Anton , De Gendt Karel , Sharp Victoria , Verhoeven Guido , Poutanen Matti , Huhtaniemi Ilpo
Published: November 2010

The epithelial lining of the epididymal duct expresses the androgen receptor (Ar) along its entire length and undergoes rapid and profound degeneration when androgenic support is withdrawn. However, experiments involving orchidectomy with systemic testosterone replacement, and testicular efferent duct ligation, have indicated that structural and functional integrity of the initial segment cannot be maintained by circulating androgen alone, leaving the role of androgen in this epididymal zone unclear. We addressed this question in a mouse model with intact testicular output and selective Ar inactivation in the proximal epididymis by creating double-transgenic males carrying a conditional ArloxP allele and expressing Cre recombinase under the promoter of Rnase10, a gene specifically expressed in proximal epididymis. At 20–25 d of life, on the onset of Rnase10 expression, Ar became selectively inactivated in the principal cells of proximal epididymis, resulting in epithelial hypoplasia and hypotrophy. Upon the subsequent onset of spermiation, epididymal obstruction ensued, with the consequent development of spermatic granulomata, back pressure-induced atrophy of the seminiferous epithelium, orchitis, and fibrosis of the testicular parenchyma. Consistent with these findings, the mice were infertile. When the effect of Ar knockout on gene expression in the proximal epididymis was compared with that of efferent duct ligation and orchidectomy, we identified genes specifically regulated by androgen, testicular efferent fluid, and both. Our findings demonstrate that the development and function of the epididymal initial segment is critically dependent on direct androgen regulation. The phenotype of the produced knockout mouse provides a novel model for obstructive azoospermia.
Inflammatory and Oxidative Stress Markers after Intravenous Insulin in Percutaneous Coronary Intervention with Stent in Type 2 Diabetes Mellitus: A Randomized Controlled Trial
Authors: de Souza Fantin Simone , Wainstein Marco Vugman , Polanczyk Carísi Anne , Ledur Priscila , Lazzari Carmen Maria , Klein Cristini , Hackenhaar Fernanda Schäfer , Benfato Mara Silveira , Schaan Beatriz D'Agord
Published: November 2010

abstract

Context/Objective:

The objective of the study was to evaluate the effects of normalizing glycemia through iv insulin per 24 h on markers of oxidative stress and inflammation in patients with diabetes submitted to percutaneous coronary intervention (PCI) with stent.

Patients/Methods:

This was a prospective, open-label, randomized controlled trial, comparing continuous iv insulin per 24 h targeting glycemia less than 110 mg/dl iv insulin treatment (IIT; n = 35) to standard treatment (ST; n = 35, regular insulin if glycemia was greater than 200 mg/dl). Blood samples for glycemia, glycated hemoglobin, lipids, inflammatory markers [C-reactive protein (CRP), soluble CD40 ligand, IL-6, and endothelin 1 (ET-1)] and oxidative stress (total antioxidant status, carbonyl) were collected immediately after and 24 h after PCI.

Results:

Seventy patients were included. Mean age was 60.5 ± 10 yr, 60% were men, glycated hemoglobin was 8.1 ± 1.8 (IIT) vs. 7.6 ± 1.6% (ST) (P = 0.39). The intensive insulin group had lower glycemia (P = 0.006) and higher insulinemia (P < 0.001). Insulin did not change CRP [4.5 (2.1–11.7) vs. 6.8 (2.4–10.3), P = 0.35], soluble CD40 ligand [402 (191–843) vs. 610 (230–1200), P = 0.68], IL-6 [6.21 (3.1.–10.4) vs. 10.37 (5.9–15.3), P = 0.09], and ET-1 [1.02 (0.7–1.8) vs. 1.10 (0.7–1.9), P = 0.657]. CRP, IL-6, and ET-1 increased after PCI in both groups (P < 0.05). No change was observed on protein oxidation (carbonyl, P = 0.70; total antioxidant status, P = 0.33). There was a positive correlation between CRP and glycemia (r = 0.29, P = 0.002).

Conclusions:

Continuous iv insulin for 24 h increased insulin levels and prevented hyperglycemia. Insulin infusion did not prevent the rise in inflammatory and oxidative stress markers, and no differences were observed between IIT and ST after PCI with a stent.
Small Intestinal Alterations in Severely Obese Hyperglycemic Subjects
Authors: Verdam Froukje J. , Greve Jan Willem M. , Roosta Sedigheh , van Eijk Hans , Bouvy Nicole , Buurman Wim A. , Rensen Sander S.
Published: November 2010

abstract

Context:

Type 2 diabetes mellitus (DM2) is associated with small intestinal hyperplasia and hypertrophy in rodents. Moreover, the small intestine is increasingly acknowledged to play a role in the pathophysiology of DM2.

Objective:

The objective of the study was to investigate the relation between plasma markers of small intestinal function and chronic hyperglycemia in man.

Design, Setting, and Participants:

We conducted a cross-sectional observational study of 40 severely obese subjects with chronic hyperglycemia and 30 severely obese subjects without chronic hyperglycemia who were indicated for bariatric surgery.

Main Outcome Measures:

We assessed plasma levels of citrulline, representing small intestinal enterocyte mass, intestinal fatty acid binding protein (I-FABP), a marker of enterocyte loss, and glucagon-like peptide-2, an intestinotrophic factor, and related them to glycated hemoglobin (HbA1c) levels.

Results:

Plasma citrulline and I-FABP levels were both significantly elevated in subjects with chronic hyperglycemia (HbA1c > 6.0%) compared with subjects with a normal HbA1c (≤ 6.0%) (citrulline, 35 ± 2.1 μmvs. 26 ± 1.4 μm, P = 0.001; I-FABP, 140 ± 22 pg/ml vs. 69 ± 14 pg/ml, P = 0.001). Moreover, plasma citrulline and I-FABP levels correlated with HbA1c levels (citrulline, rs = 0.30, P = 0.02; I-FABP, rs = 0.33, P = 0.005). The I-FABP to citrulline ratio was higher in subjects with an elevated HbA1c (4.0 vs. 3.1, P = 0.03). Plasma glucagon-like peptide-2 levels were not related to citrulline or I-FABP levels (rs = 0.06, P = 0.67; rs 0.08, P = 0.54, respectively).

Conclusion:

Chronically elevated glucose levels in obese individuals are associated with increased small intestinal enterocyte mass and increased enterocyte loss. These findings argue for the further exploration of the role of the intestine in the pathophysiology of DM2.
Energy Management Challenges in a Small Island Economy: The Case of Mauritius
Authors: Elahee Khalil
Published: November 2010

Energy Management, in the context of small island economies depending heavily on imported fossil fuels, is here analyzed. Mauritius, vulnerable also in terms of high population density and fragile ecosystems, is the focus of a national project called Maurice Ile Durable (MID or Mauritius Sustainable Island). The economic development over the past decade has been significant in the country and the national income tends to continue increasing. However, the supply, distribution and utilization of energy are critical issues for the future of the country. In this context, the challenges of Energy Management are found to be particularly of a politico-economic nature. Solutions are proposed towards overcoming the obstacles identified in order to achieve defined objectives.
Nomenclature, Radiative Forcing and Temperature Projections in IPCC Climate Change 2007: The Physical Science Basis (AR4)
Authors: Lightfoot H. Douglas
Published: November 2010

By not following standard scientific nomenclature for parts per million by volume (ppmv) and parts per million by mass (ppm), the authors of Climate Change 2007: The Physical Science Basis ( AR4), introduced confusion between these units. This confusion in AR4 has spread to the scientific community and has potential to create problems. Carbon dioxide contributed approximately 11% of the change in atmospheric warming during the period from the ice ages to the pre-industrial level of 275 ppmv. This is consistent with the current proportion of warming by carbon dioxide, and casts doubt on carbon dioxide being almost 100% of the cause of atmospheric warming from 275 to 378 ppmv. The climate sensitivity parameter calculated for the projected temperature change range of 2.9°C to 6.4°C is physically impossible to achieve. The lower temperature range is unreliable. The Intergovernmental Panel on Climate Change has an important obligation to make these problems known to policymakers and the public.
Sea Level in the Southwest Pacific is Stable
Authors: Ollier Cliff
Published: November 2010

Graphs of sea level for twelve locations in the southwest Pacific show stable sea level for about ten years over the region. The data are compared with results from elsewhere, all of which suggest that any rise of global sea level is negligible. The Darwin theory of coral formation, and subsidence ideas for guyots would suggest that we should see more land subsidence, and apparent sea level rise, than is actually occurring. Sea level studies have not been carried out for very long, but they can indicate major tectonic components such as isostatic rebound in Scandinavia. Attempts to manipulate the data by modelling to show alarming rates of sea level rise (associated with alleged global warming) are not supported by primary regional or global data. Even those places frequently said to be in grave danger of drowning, such as the Maldives, Tuvalu and Holland, appear to be safe.
Development of North American Consensus Guidelines for Medical Laboratories That Perform and Interpret Platelet Function Testing Using Light Transmission Aggregometry
Authors: Hayward Catherine P.M. , Moffat Karen A. , Raby Anne , Israels Sara , Plumhoff Elizabeth , Flynn Greg , Zehnder James L.
Published: November 2010

Platelet function testing is important for the diagnostic evaluation of common and rare bleeding disorders. Our study goals were to promote best practices and reduce unnecessary testing variances by developing North American guidelines on platelet function testing. Guidelines were developed by consensus for expert recommendations (minimum level for approval, 70%) that included recommendations on the evaluation and interpretation of light transmission platelet aggregometry (LTA). To assess consensus, medical opinions on recommendations were gathered from diagnostic laboratories that perform LTA, in collaboration with the Quality Management Program–Laboratory Services (QMP-LS) in Ontario, Canada (10 laboratories), and the North American Specialized Coagulation Laboratory Association (NASCOLA; 47 laboratories, 5 overlapping the QMP-LS group). Adequate consensus was achieved for all and 89% of recommendations for the QMP-LS and NASCOLA groups, respectively. The recommendations adopted provide North American laboratories with additional guidance on platelet function testing, including how to interpret LTA abnormalities.
Transformation of Follicular Lymphoma to Plasmablastic Lymphoma With c-myc Gene Rearrangement
Authors: Ouansafi Ihsane , He Bing , Fraser Cory , Nie Kui , Mathew Susan , Bhanji Rumina , Hoda Rana , Arabadjief Melissa , Knowles Daniel , Cerutti Andrea , Orazi Attilio , Tam Wayne
Published: November 2010

Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/ BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.
The effect of covariate mean differences on the standard error and confidence interval for the comparison of treatment means
Authors: Liu Xiaofeng Steven
Published: November 2010

The use of covariates is commonly believed to reduce the unexplained error variance and the standard error for the comparison of treatment means, but the reduction in the standard error is neither guaranteed nor uniform over different sample sizes. The covariate mean differences between the treatment conditions can inflate the standard error of the covariate‐adjusted mean difference and can actually produce a larger standard error for the adjusted mean difference than that for the unadjusted mean difference. When the covariate observations are conceived of as randomly varying from one study to another, the covariate mean differences can be related to a Hotelling's T2. Using this Hotelling's T2 statistic, one can always find a minimum sample size to achieve a high probability of reducing the standard error and confidence interval width for the adjusted mean difference.
Characterization of a mutant R11H αB-crystallin associated with human inherited cataract
Authors: Chen Qiang , Yan Ming , Xiang Feiyan , Zhou Xin , Liu Yuanyuan , Zheng Fang
Published: November 2010

αB-Crystallin plays an important part in cataract development. A novel mutation (R11H) was previously detected by our group. In the present study, we set out to investigate the possible molecular mechanism by which the R11H mutation causes cataract. We found that the mutant αB-crystallin exhibits folding defects, decreased surface hydrophobicity and enhanced chaperone-like activity compared with the wild-type αB-crystallin. The mutant protein shows nearly the same molecular mass and thermal stability as the wild-type form. Transfection studies revealed that the R11H mutant was remarkably similar to the wild-type protein in its subcellular distribution, but has an abnormal ability to induce cell apoptosis. These results suggest that the changes in hydrophobic exposure and the abnormal ability to induce programmed cell death of the mutant protein are likely to be responsible for the onset of cataract.
Secretion of hepatoma-derived growth factor is regulated by N-terminal processing
Authors: Thakar Ketan , Kröcher Tim , Savant Soniya , Gollnast Doron , Kelm Sørge , Dietz Frank
Published: November 2010

Hepatoma-derived growth factor (HDGF) was first purified as a growth factor secreted by hepatoma cells. It promotes angiogenesis and has been related to tumorigenesis. To date, little is known about the molecular mechanisms of HDGF functions and especially its routes or regulation of secretion. Here we show that secretion of HDGF requires the N-terminal 10 amino acids and that this peptide can mediate secretion of other proteins, such as enhanced green fluorescent protein, if fused to their N-terminus. Our results further demonstrate that cysteine residues at positions 12 and 108 are linked via an intramolecular disulfide bridge. Surprisingly, phosphorylation of serine 165 in the C-terminal part of HDGF plays a critical role in the secretion process. If this serine is replaced by alanine, the N-terminus is truncated, the intramolecular disulfide bridge is not formed and the protein is not secreted. In summary, these observations provide a model of how phosphorylation, a disulfide bridge and proteolytic cleavage are involved in HDGF secretion.
Physiology and pathophysiology of the RANKL/RANK system
Authors: Hanada Reiko , Hanada Toshikatsu , Penninger Josef M.
Published: November 2010

The TNF family molecule RANKL and its receptor RANK are key regulators of bone remodeling, lymph node formation, and mammary gland development during pregnancy. RANKL and RANK are also expressed in the central nervous systems (CNS). However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Recently, our group reported that the RANKL/RANK signaling pathway has an essential role in the central regulation of body temperature via the prostaglandin axis. This review discusses novel aspects of the RANKL/RANK system as key regulators of fever and female basal body temperature in the CNS.