bluuebunny/crossref_metadata_2025 huggingface dataset:
High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients
Authors: Pernodet Nicolas , Hermetet François , Adami Pascale , Vejux Anne , Descotes Françoise , Borg Christophe , Adams Marjorie , Pallandre Jean-René , Viennet Gabriel , Esnard Frédéric , Jouvenot Michèle , Despouy Gilles
Published: October 2012

Introduction

The gene quiescin/sulfhydryl oxidase 1, QSOX1, encodes an enzyme directed to the secretory pathway and excreted into the extracellular space. QSOX1 participates in the folding and stability of proteins and thus could regulate the biological activity of its substrates in the secretory pathway and/or outside the cell. The involvement of QSOX1 in oncogenesis has been studied primarily in terms of its differential expression in systemic studies. QSOX1 is overexpressed in prostate cancers and in pancreatic adenocarcinoma. In contrast, QSOX1 gene expression is repressed in endothelial tumors. In the present study, we investigated the role of QSOX1 in breast cancer.

Methods

We analyzed QSOX1 mRNA expression in a cohort of 217 invasive ductal carcinomas of the breast. Moreover, we investigated QSOX1's potential role in regulating tumor growth and metastasis using cellular models in which we overexpressed or extinguished QSOX1 and xenograft experiments.

Results

We showed that the QSOX1 expression level is inversely correlated to the aggressiveness of breast tumors. Our results show that QSOX1 leads to a decrease in cell proliferation, clonogenic capacities and promotes adhesion to the extracellular matrix. QSOX1 also reduces the invasive potential of cells by reducing cell migration and decreases the activity of the matrix metalloproteinase, MMP-2, involved in these mechanisms. Moreover, in vivo experiments show that QSOX1 drastically reduces the tumor development.

Conclusions

Together, these results suggest that QSOX1 could be posited as a new biomarker of good prognosis in breast cancer and demonstrate that QSOX1 inhibits human breast cancer tumorogenesis.
Quasi-Static Monotonic and Cyclic Tests on Composite Spandrels
Authors: Beyer Katrin , Dazio Alessandro
Published: October 2012

In modern unreinforced masonry (URM) walls, the vertical piers are connected at the story levels by reinforced concrete (RC) ring beams—also known as bond beams—or RC slabs. Particularly, in the outer walls, the spandrel element also includes a masonry spandrel on top of the RC beam or slab (“composite” spandrel). Numerical simulations have shown that spandrels significantly influence the global behavior of the URM building when subjected to seismic loading. Despite their importance, experimental data on the cyclic behavior of composite spandrels were lacking. This paper presents the results of an experimental campaign on five composite spandrels. Each test unit consisted of an RC beam, a masonry spandrel and the adjacent masonry piers required for applying realistic boundary conditions to the spandrel. The investigated parameters included the type of loading, the brick type and the reinforcement content of the RC beam.
Seismic Design Factors for Steel Moment Frames with Masonry Infills: Part 2
Authors: Ravichandran Shiv Shanker , Klingner Richard E.
Published: October 2012

In this second part, archetypical steel moment frames with masonry infills are evaluated using the ATC-63 methodology, which is a systematic procedure for the determination of seismic design factors of structural systems. The ATC-63 methodology is briefly reviewed. Procedures in the ATC-63 methodology are specialized for application to infilled steel moment frames. Results from the ATC-63 evaluation of the archetypical infilled steel moment frames are presented, and are used to propose seismic design factors and design guidelines for steel moment frames with masonry infills. The applicability of the proposed seismic design factors and guidelines for reinforced concrete infilled frames is discussed.
A Simplified Approach to Joint Shear Behavior Prediction of RC Beam-Column Connections
Authors: Kim Jaehong , LaFave James M.
Published: October 2012

An extensive experimental database of reinforced concrete (RC) beam-column connections subjected to cyclic lateral loading has been constructed. All cases within the database experienced joint shear failure, either in conjunction with or without yielding of longitudinal beam reinforcement, representing damage within a joint panel that was the main contributor to total lateral deformation. (Cases having damage within a joint panel caused by other premature failure modes (e.g., anchorage failure) are not included in the database.) Using the experimental database, envelope curves of joint shear stress vs. strain behavior were developed by connecting key points such as cracking, yielding, and peak loading. Joint shear stress and strain models at peak response have been developed by a Bayesian parameter estimation method based on the experimental database. At other key points, important influence parameters are also identified by constructing joint shear stress and strain models in conjunction with the Bayesian parameter estimation method. Then, a complete RC joint shear stress vs. strain model (including post-peak behavior) is suggested using simplified joint shear stress and strain models at peak response; effects of key parameters on the suggested behavior models are evaluated. Finally, the ASCE/SEI 41 joint shear behavior model has been examined using the constructed database—specific joint shear strength factors and plastic joint shear deformation values are recommended for use when following that approach.
Examination of SPT-Based Liquefaction Triggering Correlations
Authors: Idriss I. M. , Boulanger R. W.
Published: October 2012

The differences between the liquefaction triggering correlations published by Seed et al. (1984) and those published more recently by Cetin et al. (2004) and those by Idriss and Boulanger (2004 , 2008) are examined in this paper. The case histories, which cause the Cetin et al. correlation of the cyclic resistance ratio, adjusted for M = 7.5 and σ v′ = 1 atm, to plot significantly lower than those by Seed et al. and Idriss and Boulanger, are examined in detail. The lower position of the Cetin et al. liquefaction triggering correlation is found to be primarily caused by their interpretations and usage for 8 of the 11 key case histories that had controlled the position of their liquefaction triggering correlation. When properly interpreted, these eight case histories no longer support the position of the published Cetin et al. liquefaction triggering curve.
Experimental Seismic Performance Evaluation of Unreinforced Brick Masonry Buildings
Authors: Shahzada Khan , Khan Akhtar Naeem , Elnashai Amr S. , Ashraf Mohammad , Javed Muhammad , Naseer Amjad , Alam Bashir
Published: October 2012

This paper presents an experimental study on the performance of a full-scale unreinforced brick masonry (URM) building system tested under quasi-static loading at the Earthquake Engineering Centre, University of Engineering and Technology in Peshawar, Pakistan. The configuration and materials used in the single-story URM building are typical of those found in the northern areas of Pakistan affected by the 2005 Kashmir earthquake. This study is a part of ongoing research for the earthquake impact assessment of the city of Abbottabad. Combined shear and flexural behavior was observed during the test. The experimental data was analyzed and is presented in the form of force-deformation hysteresis loops and envelope curves. Based on the measured data, different performance levels have been established. The measured response of the test structure is also compared to the estimated response obtained using three capacity evaluation procedures and the two are found to be in good agreement.
Caffeine Inhibits EGF-Stimulated Trophoblast Cell Motility through the Inhibition of mTORC2 and Akt
Authors: Grant Isobelle , Cartwright Judith E. , Lumicisi Brooke , Wallace Alison E. , Whitley Guy S.
Published: October 2012

Impaired trophoblast invasion is associated with pregnancy disorders such as early pregnancy loss and preeclampsia. There is evidence to suggest that the consumption of caffeine during pregnancy may increase the risk of pregnancy loss; however, little is known about the direct effect of caffeine on normal trophoblast biology. Our objectives were to examine the effect of caffeine on trophoblast migration and motility after stimulation with epidermal growth factor (EGF) and to investigate the intracellular signaling pathways involved in this process. Primary first-trimester extravillous trophoblasts (EVT) and the EVT-derived cell line SGHPL-4 were used to study the effect of caffeine on EGF-stimulated cellular motility using time-lapse microscopy. SGHPL-4 cells were further used to study the effect of caffeine and cAMP on EGF-stimulated invasion of fibrin gels. The influence of caffeine and cAMP on EGF-stimulated intracellular signaling pathways leading to the activation of Akt were investigated by Western blot analysis. Caffeine inhibits both EGF-stimulated primary EVT and SGHPL-4 cell motility. EGF stimulation activates phosphatidylinositol 3-kinase, and Akt and caffeine inhibit this activation. Although cAMP inhibits both motility and invasion, it does not inhibit the activation of Akt, indicating that the effects of caffeine seen in this study are independent of cAMP. Further investigation indicated a role for mammalian target of rapamycin complex 2 (mTORC2) as a target for the inhibitory effect of caffeine. In conclusion, we demonstrate that caffeine inhibits EGF-stimulated trophoblast invasion and motility in vitro and so could adversely influence trophoblast biology in vivo.
Progesterone Directly and Rapidly Inhibits GnRH Neuronal Activity via Progesterone Receptor Membrane Component 1
Authors: Bashour Nicholas Michael , Wray Susan
Published: October 2012

GnRH neurons are essential for reproduction, being an integral component of the hypothalamic-pituitary-gonadal axis. Progesterone (P4), a steroid hormone, modulates reproductive behavior and is associated with rapid changes in GnRH secretion. However, a direct action of P4 on GnRH neurons has not been previously described. Receptors in the progestin/adipoQ receptor family (PAQR), as well as progesterone receptor membrane component 1 (PgRMC1) and its partner serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1) mRNA binding protein 1 (SERBP1), have been shown to mediate rapid progestin actions in various tissues, including the brain. This study shows that PgRMC1 and SERBP1, but not PAQR, are expressed in prenatal GnRH neurons. Expression of PgRMC1 and SERBP1 was verified in adult mouse GnRH neurons. To investigate the effect of P4 on GnRH neuronal activity, calcium imaging was used on primary GnRH neurons maintained in explants. Application of P4 significantly decreased the activity of GnRH neurons, independent of secretion of gamma-aminobutyric acidergic and glutamatergic input, suggesting a direct action of P4 on GnRH neurons. Inhibition was not blocked by RU486, an antagonist of the classic nuclear P4 receptor. Inhibition was also maintained after uncoupling of the inhibitory regulative G protein (Gi/o), the signal transduction pathway used by PAQR. However, AG-205, a PgRMC1 ligand and inhibitor, blocked the rapid P4-mediated inhibition, and inhibition of protein kinase G, thought to be activated downstream of PgRMC1, also blocked the inhibitory activity of P4. These data show for the first time that P4 can act directly on GnRH neurons through PgRMC1 to inhibit neuronal activity.
Topiramate Treatment Improves Hypothalamic Insulin and Leptin Signaling and Action and Reduces Obesity in Mice
Authors: Caricilli Andrea M. , Penteado Erica , de Abreu Lélia L. , Quaresma Paula G. F. , Santos Andressa C. , Guadagnini Dioze , Razolli Daniella , Mittestainer Francine C. , Carvalheira Jose B. , Velloso Licio A. , Saad Mario J. A. , Prada Patricia O.
Published: October 2012

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator α and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity.
Chromogranin A Induces the Biogenesis of Granules with Calcium- and Actin-Dependent Dynamics and Exocytosis in Constitutively Secreting Cells
Authors: Elias Salah , Delestre Charlène , Ory Stéphane , Marais Sébastien , Courel Maïté , Vazquez-Martinez Rafael , Bernard Sophie , Coquet Laurent , Malagon Maria M. , Driouich Azeddine , Chan Philippe , Gasman Stéphane , Anouar Youssef , Montero-Hadjadje Maité
Published: October 2012

Chromogranins are a family of acidic glycoproteins that play an active role in hormone and neuropeptide secretion through their crucial role in secretory granule biogenesis in neuroendocrine cells. However, the molecular mechanisms underlying their granulogenic activity are still not fully understood. Because we previously demonstrated that the expression of the major component of secretory granules, chromogranin A (CgA), is able to induce the formation of secretory granules in nonendocrine COS-7 cells, we decided to use this model to dissect the mechanisms triggered by CgA leading to the biogenesis and trafficking of such granules. Using quantitative live cell imaging, we first show that CgA-induced organelles exhibit a Ca2+-dependent trafficking, in contrast to native vesicle stomatitis virus G protein-containing constitutive vesicles. To identify the proteins that confer such properties to the newly formed granules, we developed CgA-stably-expressing COS-7 cells, purified their CgA-containing granules by subcellular fractionation, and analyzed the granule proteome by liquid chromatography-tandem mass spectrometry. This analysis revealed the association of several cytosolic proteins to the granule membrane, including GTPases, cytoskeleton-based molecular motors, and other proteins with actin- and/or Ca2+-binding properties. Furthermore, disruption of cytoskeleton affects not only the distribution and the transport but also the Ca2+-evoked exocytosis of the CgA-containing granules, indicating that these granules interact with microtubules and cortical actin for the regulated release of their content. These data demonstrate for the first time that the neuroendocrine factor CgA induces the recruitment of cytoskeleton-, GTP-, and Ca2+-binding proteins in constitutively secreting COS-7 cells to generate vesicles endowed with typical dynamics and exocytotic properties of neuroendocrine secretory granules.
WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad
Authors: Chassot Anne-Amandine , Bradford Stephen T. , Auguste Aurélie , Gregoire Elodie P. , Pailhoux Eric , de Rooij Dirk G. , Schedl Andreas , Chaboissier Marie-Christine
Published: October 2012

The gonad arises from the thickening of the coelomic epithelium and then commits into the sex determination process. Testis differentiation is activated by the expression of the Y-linked gene Sry, which promotes cell proliferation and differentiation of Sertoli cells, the supporting cells of the testis. In absence of Sry (XX individuals), activation of WNT/CTNNB1 signalling, via the upregulation of Rspo1 and Wnt4, promotes ovarian differentiation. However, Rspo1 and Wnt4 are expressed in the early undifferentiated gonad of both sexes, and Axin2-lacZ, a reporter of canonical WNT/CTNNB1 signalling, is expressed in the coelomic region of the E11.5 gonadal primordium, suggesting a role of these factors in early gonadal development. Here, we show that simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of the cells of the coelomic epithelium, reducing the number of progenitors of Sertoli cells in XY mutant gonads. As a consequence, in XY Wnt4−/−; Rspo1−/− foetuses, this leads to the differentiation of a reduced number of Sertoli cells and the formation of a hypoplastic testis exhibiting few seminiferous tubules. Hence, this study identifies Rspo1 and Wnt4 as two new regulators of cell proliferation in the early gonad regardless of its sex, in addition to the specific role of these genes in ovarian differentiation.
Twist1 mediates repression of chondrogenesis by β-catenin to promote cranial bone progenitor specification
Authors: Goodnough L. Henry , Chang Andrew T. , Treloar Charles , Yang Jing , Scacheri Peter C. , Atit Radhika P.
Published: October 2012

The bones of the mammalian skull vault form through intramembranous ossification. Skull bones ossify directly, in a process regulated by β-catenin, instead of passing through a cartilage intermediate. We tested whether β-catenin is necessary for fate selection of intramembranous bone progenitors in the skull. Here, we show in mice that removal of β-catenin from skull bone progenitors results in the near complete transformation of the skull bones to cartilage, whereas constitutive β-catenin activation inhibits skull bone fate selection. β-catenin directly activated Twist1 expression in skull progenitors, conditional Twist1 deletion partially phenocopied the absence of β-catenin, and Twist1 deletion partially restored bone formation in the presence of constitutive β-catenin activation. Finally, Twist1 bound robustly to the 3′UTR of Sox9, the central initiator of chondrogenesis, suggesting that Twist1 might directly repress cartilage formation through Sox9. These findings provide insight into how β-catenin signaling via Twist1 actively suppresses the formation of cartilage and promotes intramembranous ossification in the skull.
Cell cycle regulates cell type in theArabidopsissepal
Authors: Roeder Adrienne H. K. , Cunha Alexandre , Ohno Carolyn K. , Meyerowitz Elliot M.
Published: October 2012

The formation of cellular patterns during development requires the coordination of cell division with cell identity specification. This coordination is essential in patterning the highly elongated giant cells, which are interspersed between small cells, in the outer epidermis of the Arabidopsis thaliana sepal. Giant cells undergo endocycles, replicating their DNA without dividing, whereas small cells divide mitotically. We show that distinct enhancers are expressed in giant cells and small cells, indicating that these cell types have different identities as well as different sizes. We find that members of the epidermal specification pathway, DEFECTIVE KERNEL1 (DEK1), MERISTEM LAYER1 (ATML1), Arabidopsis CRINKLY4 (ACR4) and HOMEODOMAIN GLABROUS11 (HDG11), control the identity of giant cells. Giant cell identity is established upstream of cell cycle regulation. Conversely, endoreduplication represses small cell identity. These results show not only that cell type affects cell cycle regulation, but also that changes in the cell cycle can regulate cell type.
HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development
Authors: Bentovim Lital , Amarilio Roy , Zelzer Elazar
Published: October 2012

Collagen production is fundamental for the ontogeny and the phylogeny of all multicellular organisms. It depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as a substrate. This dependency is expected to limit collagen production to oxygenated cells. However, during embryogenesis, cells in different tissues that develop under low oxygen levels must produce this essential protein. In this study, using the growth plate of developing bones as a model system, we identify the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central component in a mechanism that underlies collagen hydroxylation and secretion by hypoxic cells. We show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of extracellular matrix proteins, including collagen type II. Reduced collagen hydroxylation and endoplasmic reticulum stress induction in Hif1a-depleted cells suggests that HIF1α regulates collagen secretion by mediating its hydroxylation and consequently its folding. We demonstrate in vivo the ability of Hif1α to drive the transcription of collagen prolyl 4-hydroxylase, which catalyzes collagen hydroxylation. We also show that, concurrently, HIF1α maintains cellular levels of oxygen, most likely by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. Through this two-armed mechanism, HIF1α acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate. As hypoxic conditions occur also during pathological conditions such as cancer, our findings may promote the understanding not only of embryogenesis, but also of pathological processes.
Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome
Authors: Hofmann Jennifer J. , Briot Anais , Enciso Josephine , Zovein Ann C. , Ren Shuxun , Zhang Zhen W. , Radtke Freddy , Simons Michael , Wang Yibin , Iruela-Arispe M. Luisa
Published: October 2012

The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
Matrix stiffness reverses the effect of actomyosin tension on cell proliferation
Authors: Mih Justin D. , Marinkovic Aleksandar , Liu Fei , Sharif Asma S. , Tschumperlin Daniel J.
Published: October 2012

The stiffness of the extracellular matrix exerts powerful effects on cell proliferation and differentiation, but the mechanisms transducing matrix stiffness into cellular fate decisions remain poorly understood. Two widely reported responses to matrix stiffening are increases in actomyosin contractility and cell proliferation. To delineate their relationship, we modulated cytoskeletal tension in cells grown across a physiological range of matrix stiffnesses. On both synthetic and naturally derived soft matrices, and across a panel of cell types, we observed a striking reversal of the effect of inhibiting actomyosin contractility, switching from the attenuation of proliferation on rigid substrates to the robust promotion of proliferation on soft matrices. Inhibiting contractility on soft matrices decoupled proliferation from cytoskeletal tension and focal adhesion organization, but not from cell spread area. Our results demonstrate that matrix stiffness and actomyosin contractility converge on cell spreading in an unexpected fashion to control a key aspect of cell fate.
Can HIV-1 incidence be estimated from plasma viral load and sexual behaviour?
Authors: Chan D J
Published: October 2012

To estimate the impact of sexual practices and HIV-1 viral load status on HIV-1 incidence, we surveyed 38 men who have sex with men (MSM) on their sexual practices in the past three months. HIV-1 RNA load was measured in semen and blood contemporaneously. A Bernoulli model was developed incorporating seminal plasma viral load (SPVL), number and serostatus of partners, and number of protected and unprotected episodes of anal intercourse. Probability of transmission according to SPVL was determined by sensitivity analysis based on the correlation between blood plasma viral load (BPVL) and SPVL. There was a BPVL threshold below which SPVL was low or undetectable and above which SPVL increased geometrically. Seven subjects infected 0.93 HIV-1-negative partners and 13 subjects infected 4.28 unknown serostatus partners. Probability estimates were heavily skewed by a small number of subjects with high rates of unprotected sex and multiple sexual partners. We conclude that more HIV-1 infections may occur from increased episodes of unprotected sex with multiple partners of unknown HIV-1 serostatus. The model can be used to counsel individuals or predict epidemics, and to assess behaviour change or the impact of public health interventions.
Anticipated changes in sexual risk behaviour following vaccination with a low-efficacy HIV vaccine: survey results from a South African township
Authors: Andersson K M , Vardas E , Niccolai L M , Van Niekerk R M , Mogale M M , Holdsworth I M , Bogoshi M , McIntyre J A , Gray G E
Published: October 2012

We assessed the potential for anticipated changes in sexual risk-taking behaviour following hypothetical administration of a low-efficacy preventive HIV vaccine. We developed a survey and collected self-reported data from 158 HIV-negative volunteers in a cohort undergoing prescreening for Phase I/II HIV vaccine trials in Soweto. Overall, 22% reported they might use condoms less frequently; 9% reported that they might increase their frequency of sex with casual/anonymous partners; and 55% reported their sexual partners might want to use condoms less frequently knowing they were vaccinated. Multivariate analyses revealed that anticipated decrease in condom use was predicted by poor comprehension and by young age. Individuals may increase their risk-taking behaviour knowing that a vaccine would provide only incomplete protection against HIV transmission. In HIV vaccine trials and future vaccination programmes, education and risk-reduction counselling will be needed for vaccinated individuals and their partners, and mass media education campaigns may be necessary.
Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990–2009
Authors: Heitzinger K , Sow P S , Dia Badiane N M , Gottlieb G S , N'Doye I , Toure M , Kiviat N B , Hawes S E
Published: October 2012

We assessed trends in the relative prevalences of HIV-1, HIV-2 and dual HIV-1/HIV-2 infection in 10,321 women attending outpatient clinics in Senegal between 1990 and 2009. The relative prevalence of HIV-1 (defined as the proportion of seropositive subjects having HIV-1) rose sharply from 38% in 1990 until 1993 ( P < 0.001), whereupon it continued to rise, but at a slower rate, reaching 72% of HIV infections in 2009. As compared with HIV-1, the relative prevalence of HIV-2 decreased sharply from 54% in 1990 until 1993 ( P < 0.001) and continued to decrease at a slower rate through 2009. The relative prevalence of dual infection, as compared with HIV-1, was stable from 1990 to 1993, but decreased slightly thereafter ( P < 0.001). These study findings indicate that during the early 1990s, the relative prevalence of HIV-1 increased markedly, while the relative prevalence of HIV-2 decreased and the relative prevalence of dual infection remained stable in Senegal. From 1993 to 2009, the relative prevalence of HIV-1 increased at a slower rate, while the relative prevalences of HIV-2 and dual infection decreased. These results confirm trends in HIV prevalence observed in other West African populations and provide a critical update on HIV transmission risk among women in Senegal.
Associations between drug use and risk behaviours for HIV and sexually transmitted infections among female sex workers in Yunnan, China
Authors: Yao Y , Yang F , Chu J , Siame G , Lim H J , Jin X , Ding G , Sun Y , Wang G , Yu Y , Wang N
Published: October 2012

This is a cross-sectional study of 399 subjects conducted to explore the association between drug use and risk behaviour for HIV and sexually transmitted infections (STIs) among female sex workers (FSWs), and also to study the prevalence of HIV/STIs among drug-using FSWs (DUFSWs) and non-DUFSWs in Yunnan province of China. Demographic information, mobility, sexual and drug-using behaviours were collected and subjects were tested for HIV/STIs. Mean age was 27 years (SD = ±7.8) and 94 (23.6%) tested positive for recent opiate use. Compared with non-DUFSWs, DUFSWs had a significantly higher prevalence of HIV (38% versus 4%, P ≤ 0.001), herpes simplex virus type 2 (HSV-2; 92% versus 60%, P ≤ 0.001) and STIs (95.7% versus 69.2%, P ≤ 0.001). DUFSWs had a significantly longer duration of commercial sex work compared with non-DUFSWs (median 5 versus 1 years, P ≤ 0.001), and had at least two clients in the last working day. DUFSWs were also more likely to work in low-end commercial sex venues and frequented a greater number of work locations than non-DUFSWs. Compared with non-DUFSWs, DUFSWs were more likely to exhibit riskier sexual behaviours and greater workplace mobility. Interventions targeting drug-related behavioural changes are needed urgently in this population in order to reduce rates of HIV and STIs.
Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit
Authors: Amâncio F F , Lambertucci J R , Cota G F , Antunes C M
Published: October 2012

The outcomes of HIV-infected patients requiring critical care have improved. However, in developing countries, information about HIV-infected patients admitted to intensive care units (ICUs) is scarce. We describe the prognosis of HIV-infected patients admitted to a Brazilian ICU and the factors predictive of short- and long-term survival. A historical cohort study, including HIV-infected patients admitted to a Brazilian ICU at an HIV/AIDS reference hospital, was conducted. Survivors were followed up for 24 months after ICU discharge. Demographic, clinical and laboratory data, disease severity scores and mortality were evaluated. Data were analysed using survival and regression models. One hundred and twenty-five patients were studied. In-ICU and in-hospital mortality rates were 46.4% and 68.0%, respectively. Multivariate analysis showed that the in-ICU mortality was significantly associated with APACHE (Acute Physiology and Chronic Health Evaluation) II scores (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.03–1.11), mechanical ventilation (OR, 6.39; 95% CI, 1.29–31.76), tuberculosis treatment (OR, 2.62; 95% CI, 1.03–6.71), use of antiretroviral therapy (OR, 0.19; 95% CI, 0.05–0.77) and septic shock (OR, 4.38; 95% CI, 1.78–10.76). Septic shock was also associated with long-term survival (hazard ratio, 3.0; 95% CI, 1.31–6.90). In-hospital and in-ICU mortality were higher than those reported for developed countries. ICU admission mostly due to AIDS-related diseases may explain these differences.
Performance of absolute CD4+ count in predicting co-infection with human T-lymphotropic virus type 1 in antiretroviral-naïve HIV-infected patients
Authors: Gudo E S , Bhatt N B , Augusto O , Semá C , Savino W , Ferreira O C , Jani I V
Published: October 2012

Early identification of patients co-infected with HIV and human T-lymphotropic virus type 1 (HTLV-1) is essential to improve care, as CD4+ T-cell counts have been revealed to be an unreliable laboratory parameter to monitor HIV infection in co-infection. Unfortunately, HTLV-1 testing is not currently available in sub-Saharan Africa. We conducted this study to determine the performance of absolute CD4+ T-cell count estimation in guiding the clinical suspicion of co-infection. A cross-sectional survey was conducted in antiretroviral-naïve HIV (AN-HIV) patients attending an HIV outpatient clinic in Maputo city, Mozambique. Seven hundred and one AN-HIV patients were enrolled in the study. The prevalence of HTLV-1 co-infection was 4.5% (95% confidence interval [CI] 3.0–6.0%). Logistic regression analysis showed that CD4+ T-cell count was an independent predictor of co-infection ( P value: 0.000). The performance of absolute CD4+ T-cell counts in predicting co-infection was higher in symptomatic HIV patients when compared with asymptomatic HIV patients. The best performance was achieved with the cut-off of CD4+ count of 500 cells/mm3, which gave sensitivity, specificity, positive and negative predictive values of 54.2%, 87.2%, 24.0% and 96.2%, respectively. In conclusion, our data provide evidence that the absolute CD4+ T-cell count is of moderate accuracy in guiding the clinical suspicion of co-infection in AN-HIV and its implementation could improve the care provided to a significant number of HIV patients in Mozambique.
Speaking the truth: an analysis of gender differences in serostatus disclosure practices among HIV-infected patients in St Petersburg, Russia
Authors: Davidson A S , Zaller N , Dukhovlinova E , Toussova O , Feller E , Heimer R , Kozlov A
Published: October 2012

The Russian HIV epidemic is primarily fuelled by injection drug use, but heterosexual spread may be playing an increasing role in transmission. Government-funded AIDS clinics provide most HIV treatment in Russia, and represent an important contact point between the medical community and infected population. Little is known about the population actively seeking HIV treatment. To describe demographics, perceived mode of acquisition and serostatus disclosure practices of HIV-infected individuals seeking treatment in St Petersburg, Russia, we conducted a cross-sectional study of 204 HIV-infected patients presenting to the St Petersburg City AIDS Center between May and June 2007. Mean age of respondents was 28 years old, 51% were women and two-thirds (67%) reported a history of injection drug use. Men were more likely to report injection (62% versus 45%) while women were more likely to identify sexual transmission (45% versus 32%) as their perceived infection route. Predictors of serostatus disclosure were female gender, married status and higher education. Women represent half of all patients seeking HIV treatment in St Petersburg, and are more likely than men to have disclosed their HIV-positive serostatus to sexual partners. While this population may not represent the burden of HIV disease in Russia, it is an important target group for secondary prevention.
Chlamydial partner notification in the British Association for Sexual Health and HIV (BASHH) 2011 UK national audit against the BASHH Medical Foundation for AIDS and Sexual Health Sexually Transmitted Infections Management Standards
Authors: McClean H , Carne C A , Sullivan A K , Radcliffe K W , Ahmed-Jushuf I
Published: October 2012

This paper reports on chlamydial partner notification (PN) performance in the 2011 BASHH national audit against the British Association for Sexual Health and HIV (BASHH) Medical Foundation for AIDS Sexual Health (MedFASH) Sexually Transmitted Infection Management Standards (STIMS). There was wide regional variation in level 3 clinic PN performance against the current standard of index case-reported chlamydial PN, with 43% (regional range 0–80%) of clinics outside London meeting the ≥0.6 contacts seen per index standard, and 85% of clinics (regional range 82–88%) in London meeting the ≥0.4 standard. For level 2 clinics, 39% (regional range 0–100%) of clinics outside London met the ≥0.6 standard, and 43% (regional range 40–50%) of clinics in London met the ≥0.4 standard. Performance for health-care worker (HCW)-verified contact attendance is also reported. New standards for each of these performance measures are proposed for all level 3 clinics: ≥0.6 contacts seen per index case based on index case report, and ≥0.4 contacts seen per index case based on HCW verification, both within four weeks of the first partner notification interview. The results are discussed with regard to the importance of adoption of standards by commissioners of services, relevance to national quality agendas, and the need for development of a national system of PN quality assurance measurement and reporting.
Gender differences in enrolment in an HIV-treatment programme in rural Lesotho, 2006–2008: a brief report
Authors: Furin J , Miller A C , Lesia N , Cancedda C , Haidar M , Joseph K , Ramanagoaela L , Rigodon J
Published: October 2012

The southern African nation of Lesotho has an HIV seroprevalence of approximately 25%. To address the need for HIV care in rural Lesotho, a project called the Rural Health Initative (RHI) was launched in seven clinics in 2006. Data on enrolment were collected retrospectively and analysed for trends in gender enrolment over time. Of 6001 enrolled, 3904 were women (65.1%) and 2097 (34.9%) were men. When analysed by month of enrolment, there was a higher percentage of men enrolled in December compared with the other months of the year (χ2 = 15.98, P < 0.001). This may be due to the migratory work of the men in the mines of South Africa and suggests a need for targeted interventions to increase male enrolments over the entire calendar year.
A systematic review and meta-analysis of the cardioprotective effects of remote ischaemic preconditioning in open cardiac surgery
Authors: Pilcher Janine M , Young Paul , Weatherall Mark , Rahman Ishtiaq , Bonser Robert S , Beasley Richard W
Published: October 2012

Objective

To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery.

Design

We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC.

Setting

Randomized controlled trials of RIPC in open cardiac surgery patients.

Main outcome measures

Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta-regression.

Results

Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33).

Conclusions

Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty.
Laparoscopic surgery for rectal cancer
Authors: Chand Manish , Bhoday Jemma , Brown Gina , Moran Brendan , Parvaiz Amjad
Published: October 2012

Laparoscopic surgery for colonic cancer is a safe and established alternative to traditional open colectomy. The potential advantages of shorter length of stay, faster recovery and fewer operative complications are well documented. The last 5 years has seen an increase in the number of laparoscopic colorectal operations as more surgeons learn this technique. Short and medium term results have been encouraging with respect to oncological outcomes. However, laparoscopic surgery for rectal cancer remains a contentious issue. The increased complexity of operating within the confines of the pelvis and the greater risk of oncological compromise, have led to some surgeons urging caution. We present the challenges associated with laparoscopic rectal cancer surgery and explain that appropriate patient selection, surgical planning and laparoscopic experience are the key to successful outcomes.
Cotranscriptional splicing efficiency differs dramatically between Drosophila and mouse
Authors: Khodor Yevgenia L. , Menet Jerome S. , Tolan Michael , Rosbash Michael
Published: October 2012

Spliceosome assembly and/or splicing of a nascent transcript may be crucial for proper isoform expression and gene regulation in higher eukaryotes. We recently showed that cotranscriptional splicing occurs efficiently in Drosophila, but there are not comparable genome-wide nascent splicing data from mammals. To provide this comparison, we analyze a recently generated, high-throughput sequencing data set of mouse liver nascent RNA, originally studied for circadian transcriptional regulation. Cotranscriptional splicing is approximately twofold less efficient in mouse liver than in Drosophila, i.e., nascent intron levels relative to exon levels are ∼0.55 in mouse versus 0.25 in the fly. An additional difference between species is that only mouse cotranscriptional splicing is optimal when 5′-exon length is between 50 and 500 bp, and intron length does not correlate with splicing efficiency, consistent with exon definition. A similar analysis of intron and exon length dependence in the fly is more consistent with intron definition. Contrasted with these differences are many similarities between the two systems: Alternatively annotated introns are less efficiently spliced cotranscriptionally than constitutive introns, and introns of single-intron genes are less efficiently spliced than introns from multi-intron genes. The most striking common feature is intron position: Cotranscriptional splicing is much more efficient when introns are far from the 3′ ends of their genes. Additionally, absolute gene length correlates positively with cotranscriptional splicing efficiency independently of intron location and position, in flies as well as in mice. The gene length and distance effects indicate that more “nascent time” gives rise to greater cotranscriptional splicing efficiency in both systems.
Human tRNASecassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers
Authors: Janas Teresa , Janas Tadeusz , Yarus Michael
Published: October 2012

We have shown previously that simple RNA structures bind pure phospholipid liposomes. However, binding of bona fide cellular RNAs under physiological ionic conditions is shown here for the first time. Human tRNASeccontains a hydrophobic anticodon-loop modification: N6-isopentenyladenosine (i6A) adjacent to its anticodon. Using a highly specific double-probe hybridization assay, we show mature human tRNASecspecifically retained in HeLa intermediate-density membranes. Further, isolated human tRNASecrebinds to liposomes from isolated HeLa membrane lipids, to a much greater extent than an unmodified tRNASectranscript. To better define this affinity, experiments with pure lipids show that liposomes forming rafts or including positively charged sphingosine, or particularly both together, exhibit increased tRNASecbinding. Thus tRNASecresidence on membranes is determined by several factors, such as hydrophobic modification (likely isopentenylation of tRNASec), lipid structure (particularly lipid rafts), or sphingosine at a physiological concentration in rafted membranes. From prior work, RNA structure and ionic conditions also appear important. tRNASecdissociation from HeLa liposomes implies a mean membrane residence of 7.6 min at 24°C (t½ = 5.3 min). Clearly RNA with a 5-carbon hydrophobic modification binds HeLa membranes, probably favoring raft domains containing specific lipids, for times sufficient to alter biological fates.
Post-developmental microRNA expression is required for normal physiology, and regulates aging in parallel to insulin/IGF-1 signaling in C. elegans
Authors: Lehrbach Nicolas J. , Castro Cecilia , Murfitt Kenneth J. , Abreu-Goodger Cei , Griffin Julian L. , Miska Eric A.
Published: October 2012

Regulation of gene expression by microRNAs (miRNAs) is essential for normal development, but the roles of miRNAs in the physiology of adult animals are poorly understood. We have isolated a conditional allele of DGCR8/pash-1, which allows reversible and rapid inactivation of miRNA synthesis in vivo in Caenorhabditis elegans. This is a powerful new tool that allows dissection of post-developmental miRNA functions. We demonstrate that continuous synthesis of miRNAs is dispensable for cellular viability but critical for the physiology of adult animals. Loss of miRNA synthesis in the adult reduces lifespan and results in rapid aging. The insulin/IGF-1 signaling pathway is a critical determinant of lifespan, and is modulated by miRNAs. We find that although miRNA expression is required for some mechanisms of lifespan extension, it is not essential for the longevity of animals lacking insulin/IGF-1 signaling. Further, misregulated insulin/IGF-1 signaling cannot account for the reduced lifespan caused by disruption of miRNA synthesis. We show that miRNAs act in parallel with insulin/IGF-1 signaling to regulate a shared set of downstream genes important for physiological processes that determine lifespan. We conclude that coordinated transcriptional and post-transcriptional regulation of gene expression promotes longevity.