bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics and stability analysis of the simplified model for the surface grinder in various worktable positions
Authors: Cha K-C , Wang N-Z , Liao J-Y
Published: September 2011

This study proposes a procedure to evaluate the dynamic performance and the cutting stability of a surface grinder. The governing equations for the 3 degrees of freedom (DOF) lumped-mass model are formulated by the Lagrange energy method. The absolute value of the maximum negative real part of the overall dynamic compliance and the limiting critical chip are the main performance indicators used to assess the machine tool structure’s dynamic characteristics and the cutting stability in various worktable positions. The major factors influencing the system performance is obtained by sensitivity analysis. A computer program which is based on the stability theory of the regenerative chatter model for producing a three-dimensional stability lobe diagram of the multi-DOF system has been developed. The developed program can identify the stable or chatter region defined by the lobe curves. A randomly selected point in the stable or chatter region can also be verified by time domain analysis. The procedure proposed in this study can be applied to analyse dynamic performance for other machine tools.
A note on the use of variational methods for treatment of plate dynamics
Authors: Grossi R O
Published: September 2011

The present note deals with a methodology for development of compact analytical schemes, for the derivation of boundary value problems, which describe the statical and dynamical behaviours of plates with complicating effects. A special set of multi-indices in differentiation symbols and two formulae of integration by parts are introduced to develop compact analytical expressions in the procedures for deriving the governing differential equations and natural boundary conditions.
Modelling of condensed flexible bodies considering non-linear inertia effects resulting from gross motions
Authors: Offner G
Published: September 2011

Besides various other application fields, flexible multi-body dynamics simulation is used in particular during the development process of internal combustion engines and power units. Problems such as crankshaft and engine dynamics, radial slider bearing dynamics or noise, vibration, and harshness can be investigated using this methodology. Any specific engine component, called body, can be represented by different methods. Besides beam-mass representations and structured modelling, finite element models are commonly used. As these imply a large number of degrees of freedom, they cannot be applied directly to multi-body dynamics ensuring computational performance. Therefore, condensation methods need to be applied which result in a reduced model with equivalent dynamical properties. This is particularly important if detailed, highly non-linear contact dynamic models, for instance the well-known Reynolds equation, are considered.

Typically, condensation methods are applied to structural matrices of bodies which perform only vibration motions without any global motions. This study outlines a floating frame of reference formulation for condensed components, which perform global motions in addition to the vibration motions. For this purpose, non-linear inertia terms of the reduced body, which result from the global motions need to be computed considering the applied reduction strategy. Both the theoretical background of the formulation and some application examples of the method will be discussed.
Vibration of a rotating flexible ferromagnetic disc subjected to a solenoid electromagnet
Authors: Pei Yong-Chen , Lu H , Chatwin C
Published: September 2011

A rotating flexible ferromagnetic annular disc with initial unstressed transverse runout subjected to a solenoid electromagnet is modelled and investigated. The total transverse deflection of the steady-state response of the rotating disc is analysed, and the condition of undamped resonance induced by the initial transverse runout and the stiffness of the electromagnetic force is evaluated. A quadratic eigenvalue problem is obtained and employed to study natural frequency and dynamic stability of the rotating disc. Analytical results show that the solenoid electromagnet can cause not only dynamic instability but also system resonance of the rotating disc if it has the initial transverse runout; the instability and resonance tend to occur at a lower rotational speed with the increase of the stiffness of the electromagnetic force.
Opinion expression during social conflict: Comparing online reader comments and letters to the editor
Authors: McCluskey Michael , Hmielowski Jay
Published: September 2011

News outlets serve democratic norms by providing a wide range of viewpoints, including opinions from the public. This study examined opinion expression in online reader posts and letters to the editor in a community facing social conflict. Analysis of opinion expression about the Jena Six showed more balance in both the range and tone of opinions from online reader comments than reader letters. Online posts more often challenged community institutions than did letters. Ability to post anonymous comments, the absence of media gatekeepers and a younger audience are potential reasons why online reader comments differed from reader letters.
California Hispanic Nurses
Authors: Tellez Michelle Sardenberg-Hersh , Black Lisa M. , Tinoco Adelita
Published: September 2011

Using data from the California Board of Registered Nursing Surveys of 1997, 2004, 2006 and 2008, this study explores demographic, human capital, and work environment changes in the Hispanic RN population and compared these changes to those occurring among non-Hispanic Whites. Results find several significant differences between the two groups. The most important finding is that Hispanic RNs enter and leave the profession at younger ages than their non-Hispanic White counterparts. There is an abrupt decrease in the proportion of Hispanic RNs after age 50, while the proportion non-Hispanic White continues to increase until age 65. Decided action is needed to increase recruitment and retention of Hispanic RNs in order to increase nurse-patient concordance and abate the looming nurse shortage.
Staffing Changes Before and After Mandated Nurse-to-Patient Ratios in California’s Hospitals
Authors: Serratt Teresa , Harrington Charlene , Spetz Joanne , Blegen Mary
Published: September 2011

California is the first state to mandate specific nurse-to-patient ratios in general acute care hospitals. These ratios went into effect January 1, 2004 and apply “at all times”. Little is known about the changes in staffing that occurred subsequent to the implementation of this legislation. This study identifies and describes changes in nurse and non-nursing staffing that may have occurred as a result of the enactment of these nurse-to-patient ratios. The results of this study indicate that most hospitals made upward adjustments in their RN and registry nurse staff but decreases in support staff and other non-nurse staff were not evident. These findings suggest that these mandated ratios had the desired effect of increasing the number of nurses caring for acutely ill patients.
Jury Service as Civic Engagement
Authors: Bloeser Andrew J. , McCurley Carl , Mondak Jeffery J.
Published: September 2011

Much like other forms of civic engagement, many Americans apparently perceive jury “duty” as optional, a circumstance that often has left courts struggling to seat juries. Considering how individuals orient themselves to this often neglected form of civic responsibility facilitates a more holistic understanding of citizen behavior and its antecedents. In this article, we explore the possible effects of resources, barriers and personality traits on jury summons compliance. Data are drawn from a field experiment and corresponding survey conducted in the State of Washington. Results reveal that cultural/linguistic factors act as strong barriers to jury service and that people’s personality traits influence summons compliance. Efforts to reduce resource constraints via heightened juror pay brought no positive effect on compliance rates.
Cognitive-Behavioral Therapy for Immigrants Presenting With Social Anxiety Disorder
Authors: Weiss Brandon J. , Singh J. Suzanne , Hope Debra A.
Published: September 2011

Cognitive-behavioral therapy (CBT) for the treatment of social anxiety disorder (SAD) has demonstrated efficacy in numerous randomized trials. However, few studies specifically examine the applicability of such treatment for ethnic minority clients. Thus, the purpose of this article is to present two case studies examining the utility of individualized CBT for SAD with two clients who immigrated to the United States, one from Central America and one from China, for whom English was not the primary language. Both clients demonstrated improvement on a semistructured interview and self-report measures. Necessary adaptations were modest, suggesting that therapy could be conducted in a culturally sensitive manner without much deviation from the treatment protocol. Results are discussed in terms of adapting treatment to enhance acceptability for and better fitting the needs of ethnic minority clients and non-native speakers of English. Implications for treating ethnic minority clients, as well as the practice of culturally sensitive treatment, are discussed.
Extrinsic and intrinsic determinants of nerve regeneration
Authors: Ferguson Toby A. , Son Young-Jin
Published: September 2011

After central nervous system (CNS) injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS) axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.
Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen
Authors: Betts Brian C. , Abdel-Wahab Omar , Curran Shane A. , St Angelo Erin T. , Koppikar Priya , Heller Glenn , Levine Ross L. , Young James W.
Published: September 2011

Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2–mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4+ Tregs to CD8+CD25+ effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell–stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment.
Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors
Authors: Neri Paola , Ren Li , Gratton Kathy , Stebner Erin , Johnson Jordan , Klimowicz Alexander , Duggan Peter , Tassone Pierfrancesco , Mansoor Adnan , Stewart Douglas A. , Lonial Sagar , Boise Lawrence H. , Bahlis Nizar J.
Published: September 2011

Chromosomal instability is a defining feature of clonal myeloma plasma cells that results in the perpetual accumulation of genomic aberrations. In addition to its role in protein homeostasis, the ubiquitin-proteasome system is also involved in the regulation of DNA damage-repair proteins. In the present study, we show that proteasome inhibition induces a “BRCAness” state in myeloma cells (MM), with depletion of their nuclear pool of ubiquitin and abrogation of H2AX polyubiquitylation, an essential step for the recruitment of BRCA1 and RAD51 to the sites of DNA double-stranded breaks (DSBs) and the initiation of homologous recombination (HR)–mediated DNA repair. Inhibition of poly-ADP-ribose-polymerase 1 and 2 (PARP1/2) with ABT-888 induced transient DNA DSBs that were rapidly resolved and thus had no effect on viability of the MM cells. In contrast, cotreatment of MM cell lines and primary CD138+ cells with bortezomib and ABT-888 resulted in the sustained accumulation of unrepaired DNA DSBs with persistence of unubiquitylated γH2AX foci, lack of recruitment of BRCA1 and RAD51, and ensuing MM-cell death. The heightened cytotoxicity of ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice. Our studies indicate that bortezomib impairs HR in MM and results in a contextual synthetic lethality when combined with PARP inhibitors.
AU-rich RNA binding proteins in hematopoiesis and leukemogenesis
Authors: Baou Maria , Norton John D. , Murphy John J.
Published: September 2011

Posttranscriptional mechanisms are now widely acknowledged to play a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation, and tumorigenesis. Although much attention has focused on microRNAs as regulators of mRNA stability/translation, recent data have highlighted the role of several diverse classes of AU-rich RNA-binding protein in the regulation of mRNA decay/stabilization. AU-rich elements are found in the 3′-untranslated region of many mRNAs that encode regulators of cell growth and survival, such as cytokines and onco/tumor-suppressor proteins. These are targeted by a burgeoning number of different RNA-binding proteins. Three distinct types of AU-rich RNA binding protein (ARE poly-U–binding degradation factor-1/AUF1, Hu antigen/HuR/HuA/ELAVL1, and the tristetraprolin/ZFP36 family of proteins) are essential for normal hematopoiesis. Together with 2 further AU-rich RNA-binding proteins, nucleolin and KHSRP/KSRP, the functions of these proteins are intimately associated with pathways that are dysregulated in various hematopoietic malignancies. Significantly, all of these AU-rich RNA-binding proteins function via an interconnected network that is integrated with microRNA functions. Studies of these diverse types of RNA binding protein are providing novel insight into gene-regulatory mechanisms in hematopoiesis in addition to offering new opportunities for developing mechanism-based targeted therapeutics in leukemia and lymphoma.
Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue
Authors: Brambilla Francesca , Lavatelli Francesca , Di Silvestre Dario , Valentini Veronica , Rossi Rossana , Palladini Giovanni , Obici Laura , Verga Laura , Mauri Pierluigi , Merlini Giampaolo
Published: September 2011

Considering the important advances in treating specific types of systemic amyloidoses, unequivocal typing of amyloid deposits is now essential. Subcutaneous abdominal fat aspiration is the easiest, most common diagnostic procedure. We developed a novel, automated approach, based on Multidimensional Protein Identification Technology, for typing amyloidosis. Fat aspirates were obtained from patients with the most common systemic amyloidoses (ALλ, ALκ, transthyretin, and reactive amyloidosis), with Congo red score more than or equal to 3+, and nonaffected controls. Peptides from extracted and digested proteins were analyzed by Multidimensional Protein Identification Technology. On semiquantitative differential analysis (patients vs controls) of mass spectrometry data, specific proteins up-represented in patients were identified and used as deposit biomarkers. An algorithm was developed to classify patients according to type and abundance of amyloidogenic proteins in samples; in all cases, proteomic characterization was concordant with fibril identification by immunoelectron microscopy and consistent with clinical presentation. Our approach allows reliable amyloid classification using readily available fat aspirates.
Memory T cells from minor histocompatibility antigen–vaccinated and virus-immune donors improve GVL and immune reconstitution
Authors: Li Ning , Matte-Martone Catherine , Zheng Hong , Cui Weiguo , Venkatesan Srividhya , Tan Hung Sheng , McNiff Jennifer , Demetris Anthony J. , Roopenian Derry , Kaech Susan , Shlomchik Warren D.
Published: September 2011

Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (TM) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host tissues. One approach to augmenting GVL has been to infuse ex vivo–generated T cells with defined specificities; however, this requires expertise that is not widely available. In the present study, we tested an alternative approach, adoptive immunotherapy with CD8+ TM from donors vaccinated against a single minor histocompatibility antigen (miHA) expressed by leukemia cells. Vaccination against the miHA H60 greatly augmented TM-mediated GVL against mouse chronic-phase (CP-CML) and blast crisis chronic myeloid leukemia (BC-CML). TM-mediated GVL was antigen specific and was optimal when H60 expression was hematopoietically restricted. Even when H60 was ubiquitous, donor H60 vaccination had a minimal impact on GVHD. TM from lymphocytic choriomeningitis virus (LCMV)–immune and H60-vaccinated donors augmented GVL and protected recipients from LCMV. These data establish a strategy for augmenting GVL and immune reconstitution without elaborate T-cell manipulation.
Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma
Authors: Böll Boris , Bredenfeld Henning , Görgen Helen , Halbsguth Teresa , Eich Hans T. , Soekler Martin , Markova Jana , Keller Ulrich , Graeven Ullrich , Kremers Stephan , Geissler Michael , Trenn Guido , Fuchs Michael , von Tresckow Bastian , Eichenauer Dennis A. , Borchmann Peter , Engert Andreas
Published: September 2011

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.
ICOS gene polymorphisms are associated with sporadic breast cancer: a case-control study
Authors: Xu Fengyan , Li Dalin , Zhang Qiujin , Fu Zhenkun , Zhang Jie , Yuan Weiguang , Chen Shuang , Pang Da , Li Dianjun
Published: September 2011

Background

Inducible costimulator (ICOS), a costimulatory molecular of the CD28 family, provides positive signal to enhance T cell proliferation. Its abnormal expression can disturb the immune response and entail an increased risk of cancer. To investigate whether single nucleotide polymorphisms (SNPs) in the ICOS gene are associated with sporadic breast cancer susceptibility and progression in Chinese women, a case-control study was conducted.

Methods

In the study cohort, we genotyped five SNPs (rs11889031, rs10932029, rs4675374, rs10183087 and rs10932037) in ICOS gene among 609 breast cancer patients and 665 age-matched healthy controls. Furthermore, the positive results were replicated in an independent validation cohort of 619 patients and 682 age-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotypes.

Results

In rs10932029, compared with TT genotype and T allele, the CT genotype and C allele showed a significantly increased risk of breast cancer (P = 0.030, OR = 1.467, 95% CI 1.037-2.077; P = 0.017, OR = 1.481, 95% CI 1.070-2.049, respectively), and the associations were also significant in the validation cohort (P = 0.002, OR = 1.693, 95% CI 1.211-2.357; P = 0.003, OR = 1.607, 95% CI 1.171-2.204, respectively). Haplotype analysis showed that CTCAC haplotype containing rs10932029 T allele had a lower frequency in cases than in controls (P = 0.015), whereas haplotype CCCAC containing rs10932029 C allele was more common in cases than in controls (P = 0.013). In the analysis of clinicopathologic features, rs11889031 CT genotype and T allele were associated with progesterone receptor (PR) status and lymph node metastasis, which were further supported by our validation cohort. Moreover, some haplotypes were associated with estrogen receptor (ER) and PR statuses.

Conclusions

These results indicate that ICOS gene polymorphisms may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in a northern Chinese population.
Long term virological, immunological and mortality outcomes in a cohort of HIV-infected female sex workers treated with highly active antiretroviral therapy in Africa
Authors: Huet Charlotte , Ouedraogo Abdoulaye , Konaté Issouf , Traore Isidore , Rouet François , Kaboré Antoinette , Sanon Anselme , Mayaud Philippe , Van de Perre Philippe , Nagot Nicolas
Published: September 2011

Background

Concerns have been raised that marginalised populations may not achieve adequate compliance to antiretroviral therapy. Our objective was to describe the long-term virological, immunological and mortality outcomes of providing highly active antiretroviral therapy (HAART) with strong adherence support to HIV-infected female sex workers (FSWs) in Burkina Faso and contrast outcomes with those obtained in a cohort of regular HIV-infected women.

Methods

Prospective study of FSWs and non-FSWs initiated on HAART between August 2004 and October 2007. Patients were followed monthly for drug adherence (interview and pill count), and at 6-monthly intervals for monitoring CD4 counts and HIV-1 plasma viral loads (PVLs) and clinical events.

Results

95 women, including 47 FSWs, were followed for a median of 32 months (interquartile range [IQR], 20-41). At HAART initiation, the median CD4 count was 147 cells/μl (IQR, 79-183) and 144 cells/μl (100-197), and the mean PVLs were 4.94 log10copies/ml (95% confidence interval [CI], 4.70-5.18) and 5.15 log10copies/ml (4.97-5.33), in FSWs and non-FSWs, respectively. Four FSWs died during follow-up (mortality rate: 1.7 per 100 person-years) and none among other women. At 36 months, the median CD4 count increase was 230 cells/μl (IQR, 90-400) in FSWsvs. 284 cells/μl (193-420) in non-FSWs; PVL was undetectable in 81.8% (95% CI, 59.7-94.8) of FSWsvs. 100% (83.9-100) of non-FSWs; and high adherence to HAART (> 95% pills taken) was reported by 83.3% (95% CI, 67.2-93.6), 92.1% (95% CI, 78.6-98.3), and 100% (95% CI, 54.1-100) of FSWs at 6, 12, and 36 months after HAART initiation, respectively, with no statistical difference compared to the pattern observed among non-FSWs.

Conclusions

Clinical and biological benefits of HAART can be maintained over the long term among FSWs in Africa and could also lead to important public health benefits.
Optimisation of surface expression using the AIDA autotransporter
Authors: Gustavsson Martin , Bäcklund Emma , Larsson Gen
Published: September 2011

Background

Bacterial surface display is of interest in many applications, including live vaccine development, screening of protein libraries and the development of whole cell biocatalysts. The goal of this work was to understand which parameters result in production of large quantities of cells that at the same time express desired levels of the chosen protein on the cell surface. For this purpose, staphylococcal protein Z was expressed using the AIDA autotransporter in Escherichia coli.

Results

The use of an OmpT-negative E. coli mutant resulted in successful expression of the protein on the surface, while a clear degradation pattern was found in the wild type. The expression in the mutant resulted also in a more narrow distribution of the surface-anchored protein within the population. Medium optimisation showed that minimal medium with glucose gave more than four times as high expression as LB-medium. Glucose limited fed-batch was used to increase the cell productivity and the highest protein levels were found at the highest feed rates. A maintained high surface expression up to cell dry weights of 18 g l-1 could also be achieved by repeated glucose additions in batch cultivation where production was eventually reduced by low oxygen levels. In spite of this, the distribution in the bacterial population of the surface protein was narrower using the batch technique.

Conclusions

A number of parameters in recombinant protein production were seen to influence the surface expression of the model protein with respect both to the productivity and to the display on the individual cell. The choice of medium and the cell design to remove proteolytic cleavage were however the most important. Both fed-batch and batch processing can be successfully used, but prolonged batch processing is probably only possible if the chosen strain has a low acetic acid production.
Increased interleukin-10 and interferon-γ levels in Plasmodium vivax malaria suggest a reciprocal regulation which is not altered by IL-10 gene promoter polymorphism
Authors: Medina Tiago S , Costa Sheyla PT , Oliveira Maria D , Ventura Ana M , Souza José M , Gomes Tassia F , Vallinoto Antonio CR , Póvoa Marinete M , Silva João S , Cunha Maristela G
Published: September 2011

Background

In human malaria, the naturally-acquired immune response can result in either the elimination of the parasite or a persistent response mediated by cytokines that leads to immunopathology. The cytokines are responsible for all the symptoms, pathological alterations and the outcome of the infection depends on the reciprocal regulation of the pro and anti-inflammatory cytokines. IL-10 and IFN-gamma are able to mediate this process and their production can be affected by single nucleotide polymorphisms (SNPs) on gene of these cytokines. In this study, the relationship between cytokine IL-10/IFN-gamma levels, parasitaemia, and their gene polymorphisms was examined and the participation of pro-inflammatory and regulatory balance during a natural immune response inPlasmodium vivax-infected individuals was observed.

Methods

The serum levels of the cytokines IL-4, IL-12, IFN-gamma and IL-10 from 132 patients were evaluated by indirect enzyme-linked immunosorbent assays (ELISA). The polymorphism at position +874 of the IFN-gamma gene was identified by allele-specific polymerase chain reaction (ASO-PCR) method, and the polymorphism at position -1082 of the IL-10 gene was analysed by PCR-RFLP (PCR-Restriction Fragment Length Polymorphism).

Results

The levels of a pro- (IFN-gamma) and an anti-inflammatory cytokine (IL-10) were significantly higher inP. vivax-infected individuals as compared to healthy controls. The IFN-gamma levels in primoinfected patients were significantly higher than in patients who had suffered only one and more than one previous episode. The mutant alleles of both IFN-gamma and IL-10 genes were more frequent than the wild allele. In the case of the IFNG+874 polymorphism (IFN-gamma) the frequencies of the mutant (A) and wild (T) alleles were 70.13% and 29.87%, respectively. Similar frequencies were recorded in IL-10-1082, with the mutant (A) allele returning a frequency of 70.78%, and the wild (G) allele a frequency of 29.22%. The frequencies of the alleles associated with reduced production of both IFN-gamma and IL-10 were high, but this effect was only observed in the production of IFN-gamma.

Conclusions

This study has shown evidence of reciprocal regulation of the levels of IL-10 and IFN-gamma cytokines inP. vivaxmalaria, which is not altered by the presence of polymorphism in the IL-10 gene.
Improved protein arrays for quantitative systems analysis of the dynamics of signaling pathway interactions
Authors: Wang Xiaoyu , Dong Ying , Jiwani Ameena J , Zou Yonglong , Pastor Johanne , Kuro-o Makoto , Habib Amyn A , Ruan Minzi , Boothman David A , Yang Chin-Rang
Published: September 2011

An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states is presented. The signals are amplified linearly by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots, but are not linear by the enzyme-based amplification. Software is developed to facilitate the quantitative readouts of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.
Cancer/Testis antigens as potential predictors of biochemical recurrence of prostate cancer following radical prostatectomy
Authors: Shiraishi Takumi , Terada Naoki , Zeng Yu , Suyama Takahito , Luo Jun , Trock Bruce , Kulkarni Prakash , Getzenberg Robert H
Published: September 2011

Background

The Cancer/Testis Antigens (CTAs) are an important group of proteins that are typically restricted to the testis in the normal adult but are aberrantly expressed in several types of cancers. As a result of their restricted expression patterns, the CTAs could serve as unique biomarkers for cancer diagnosis/prognosis. The aim of this study was to identify promising CTAs that are associated with prostate cancer (PCa) recurrence following radical prostatectomy (RP).

Methods

The expression of 5 CTAs was measured by quantitative multiplex real-time PCR using prostate tissue samples obtained from 72 patients with apparently clinically localized PCa with a median of two years follow-up (range, 1 to 14 years).

Results

The expression of CTAs namely, CEP55, NUF2, PBK and TTK were significantly higher while PAGE4 was significantly lower in patients with recurrent disease. All CTAs with the exception of TTK were significantly correlated with the prostatectomy Gleason score, but none were correlated with age, stage, or preoperative PSA levels. In univariate proportional hazards models, CEP55 (HR = 3.59, 95% CI: 1.50-8.60), p = 0.004; NUF2 (HR = 2.28, 95% CI: 1.11-4.67), p = 0.024; and PAGE4 (HR = 0.44, 95% CI: 0.21-0.93), p = 0.031 were significantly associated with the risk of PCa recurrence. However, the results were no longer significant after adjustment for prostatectomy Gleason score.

Conclusions

To our knowledge, this is the first study to identify CTAs as biomarkers that can differentiate patients with recurrent and non-recurrent disease following RP and underscores its potential impact on PCa prognosis and treatment.
EARLYDRAIN- outcome after early lumbar CSF-drainage in aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial
Authors: Bardutzky Jürgen , Witsch Jens , Jüttler Eric , Schwab Stefan , Vajkoczy Peter , Wolf Stefan
Published: September 2011

Background

Aneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.

In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage has not been evaluated prospectively in a randomized controlled trial yet.

Methods/Design

This is a protocol for a 2-arm randomized controlled trial to compare an intervention group receiving early continuous lumbar CSF-drainage and standard neurointensive care to a control group receiving standard neurointensive care only. Adults suffering from a first aneurysmal subarachnoid hemorrhage whose aneurysm has been secured by means of coiling or clipping are eligible for trial participation. The effect of early CSF drainage (starting < 72 h after securing the aneurysm) will be measured in the following ways: the primary endpoint will be disability after 6 months, assessed by a blinded investigator during a personal visit or standardized telephone interview using the modified Rankin Scale. Secondary endpoints include mortality after 6 months, angiographic vasospasm, transcranial Doppler sonography (TCD) mean flow velocity in both middle cerebral arteries and rate of shunt insertion at 6 months after hospital discharge.

Discussion

Here, we present the study design of a multicenter prospective randomized controlled trial to investigate whether early application of a lumbar drainage improves clinical outcome after aneurysmal subarachnoid hemorrhage.

Trial registration

www.clinicaltrials.gov Identifier: NCT01258257
Reducing the exome search space for Mendelian diseases using genetic linkage analysis of exome genotypes
Authors: Smith Katherine R , Bromhead Catherine J , Hildebrand Michael S , Shearer A Eliot , Lockhart Paul J , Najmabadi Hossein , Leventer Richard J , McGillivray George , Amor David J , Smith Richard J , Bahlo Melanie
Published: September 2011

Many exome sequencing studies of Mendelian disorders fail to optimally exploit family information. Classical genetic linkage analysis is an effective method for eliminating a large fraction of the candidate causal variants discovered, even in small families that lack a unique linkage peak. We demonstrate that accurate genetic linkage mapping can be performed using SNP genotypes extracted from exome data, removing the need for separate array-based genotyping. We provide software to facilitate such analyses.
Targeted analysis of nucleotide and copy number variation by exon capture in allotetraploid wheat genome
Authors: Saintenac Cyrille , Jiang Dayou , Akhunov Eduard D
Published: September 2011

Background

The ability of grass species to adapt to various habitats is attributed to the dynamic nature of their genomes, which have been shaped by multiple rounds of ancient and recent polyploidization. To gain a better understanding of the nature and extent of variation in functionally relevant regions of a polyploid genome, we developed a sequence capture assay to compare exonic sequences of allotetraploid wheat accessions.

Results

A sequence capture assay was designed for the targeted re-sequencing of 3.5 Mb exon regions that surveyed a total of 3,497 genes from allotetraploid wheat. These data were used to describe SNPs, copy number variation and homoeologous sequence divergence in coding regions. A procedure for variant discovery in the polyploid genome was developed and experimentally validated. About 1% and 24% of discovered SNPs were loss-of-function and non-synonymous mutations, respectively. Under-representation of replacement mutations was identified in several groups of genes involved in translation and metabolism. Gene duplications were predominant in a cultivated wheat accession, while more gene deletions than duplications were identified in wild wheat.

Conclusions

We demonstrate that, even though the level of sequence similarity between targeted polyploid genomes and capture baits can bias enrichment efficiency, exon capture is a powerful approach for variant discovery in polyploids. Our results suggest that allopolyploid wheat can accumulate new variation in coding regions at a high rate. This process has the potential to broaden functional diversity and generate new phenotypic variation that eventually can play a critical role in the origin of new adaptations and important agronomic traits.
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families
Authors: Brownstein Zippora , Friedman Lilach M , Shahin Hashem , Oron-Karni Varda , Kol Nitzan , Rayyan Amal Abu , Parzefall Thomas , Lev Dorit , Shalev Stavit , Frydman Moshe , Davidov Bella , Shohat Mordechai , Rahile Michele , Lieberman Sari , Levy-Lahad Ephrat , Lee Ming K , Shomron Noam , King Mary-Claire , Walsh Tom , Kanaan Moien , Avraham Karen B
Published: September 2011

Background

Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.

Results

A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.

Conclusions

Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
Unique Gene Expression Profile Associated with an Early-Onset Multiple Endocrine Neoplasia (MEN1)-Associated Pituitary Adenoma
Authors: Farrell William E. , Azevedo Monalisa F. , Batista Dalia L. , Smith Alastair , Bourdeau Isabelle , Horvath Anelia , Boguszewski Margaret , Quezado Martha , Stratakis Constantine A.
Published: September 2011

Context:

Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown.

Objective:

The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome.

Patients and Methods:

A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes.

Results:

In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed.

Conclusions:

We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.
Lower Free Thyroxin Associates with a Less Favorable Metabolic Phenotype in Healthy Pregnant Women
Authors: Bassols Judit , Prats-Puig Anna , Soriano-Rodríguez Pilar , García-González María Mar , Reid Joanna , Martínez-Pascual María , Mateos-Comerón Fátima , de Zegher Francis , Ibáñez Lourdes , López-Bermejo Abel
Published: September 2011

Context:

A lower free T4 (fT4), within the euthyroid range, has been shown in adults to associate with an adverse metabolic phenotype. Thyroid physiology changes significantly during gestation and affects maternal and fetal well-being.

Objective:

The aim of the study was to test the hypothesis that a lower serum fT4 in healthy euthyroid pregnant women is related to a less favorable metabolic phenotype and to fetal or placental weight.

Design, Setting, Patients, and Outcome Measures:

We examined associations of thyroid function tests (TSH and fT4) and the free T3 (fT3)-to-fT4 ratio (as a proxy of deiodinase activity) with a metabolic profile [preload and postload glucose, glycosylated hemoglobin (HbA1c), high molecular-weight (HMW)-adiponectin, homeostasis model of assessment for insulin resistance (HOMA-IR), and serum lipids] in 321 healthy pregnant women. All women were euthyroid and had negative anti-thyroid peroxidase antibodies. None received thyroid hormone replacement. Blood tests were performed in women between 24 and 28 wk gestation. Placentas and newborns were weighed at birth.

Results:

Circulating TSH did not relate to metabolic parameters, but decreasing fT4 and increasing fT3-to-fT4 ratio associated with a less favorable metabolic phenotype, as judged by higher postload glucose, HbA1c, fasting insulin, HOMA-IR, and triglycerides, and by a lower HMW-adiponectinemia (all P ≤ 0.005). In multiple regression analyses, fT4 was independently associated with HbA1c (β = −0.135; P = 0.038), HMW-adiponectin (β = 0.218; P < 0.001), and placental weight (β = −0.185; P < 0.005), whereas the fT3-to-fT4 ratio was independently associated with maternal body mass index (β = 0.265; P < 0.001), HMW-adiponectinemia (β = −0.237; P < 0.002), HOMA-IR (β = 0.194; P = 0.014), and placental weight (β = 0.174; P = 0.020).

Conclusion:

In pregnant women without a history of thyroid dysfunction, lower concentrations of fT4 and a higher conversion of fT4 to fT3, as inferred by changes in the fT3-to-fT4 ratio, were found to be associated with a less favorable metabolic phenotype and with more placental growth.
A Note on “The 1001 Seances”
Authors: Sedgwick H. A.
Published: September 2011

This note summarizes what I know of the history of Eve Kosofsky Sedgwick's essay “The 1001 Seances.” I suggest that it was primarily as a poet herself that she was drawn to study and to write about the poetry of James Merrill, and I go on to suggest that her writing in this essay is shaped by the complex and changing relation between her identity as a poet and her developing profession as a literary critic.
The 1001 Seances
Authors: Sedgwick Eve Kosofsky
Published: September 2011

This essay, written in 1976–77, is concerned primarily with James Merrill's long poem “The Book of Ephraim,” which was published in 1976. The poem tells of many nights spent by Merrill and his partner, David Jackson, in communication with a spirit named Ephraim, whose messages they spell out on a Ouija board. The poem also includes fragments of a second story, a retelling of a lost novel of Merrill's.

In her essay Sedgwick talks about the poem's structure, likening the spacing of fragments of Ephraim's voice throughout the poem with the spacing of fragments of the lost novel, but she contrasts the pointedness of the novel's plot with the looser repetitious structure of the poem's nightly séances. To show that this pointedness is characteristic of Merrill's novelistic writing, Sedgwick also looks at two actual novels that Merrill had published years earlier, The Seraglio (1957) and The (Diblos) Notebook (1965). In both novels, as well as in the lost novel embedded in the poem, the plot is dominated by a central, climactic, sadomasochistic scene of real or symbolic castration.

Sedgwick distinguishes the fixity of this novelistic theme of castration from a different thematic range in the poem's language, which has to do “with the behaviors of liquids, with currents, obstruction, diffusion, and circulation.” She explores this thematic range in the relation between Ephraim and his mediums, Merrill and Jackson, in which there is more play, variously shifting among flattery, voyeurism, gossip, pedagogy, love, fear, and neglect. The thematics of liquids, she suggests, includes the thematics of fixation but does not synthesize it. “It spaces, distributes, circulates it.”

There is, she says, a formal impartiality to the distribution throughout this long poem of its many disparate elements, but there is also an awareness of wastage, of moments “intently and beautifully” improved, “then how quickly squandered.” Sedgwick suggests that Merrill's long poem is formally exciting because it is “so knowing, so inventive, and so trusting about that wastage.” Sedgwick is describing the poem itself when she quotes it as saying that Merrill and Jackson, through their Ouija board séances with Ephraim, became “a set of / Quasi-grammatical constructions which / Could utter some things clearly, forcibly, / Others not.”
“Surprising Recognition”
Authors: Kent Kathryn R.
Published: September 2011

This essay places Eve Kosofsky Sedgwick's later writings on poetry alongside her early unpublished piece “The 1001 Seances” to illustrate how the latter theorizes the connection between poetic form (and its relation to the novelistic) and male-male homoerotics. I then consider Sedgwick's continuing interest as both a critic and a poet in the erotics of genre, especially as it reappears in A Dialogue on Love.