bluuebunny/crossref_metadata_2025 huggingface dataset:
The Arabic Vowels: Features and Possible Clinical Application in Communication Disorders
Authors: Kotby M.N. , Saleh M. , Hegazi M. , Gamal N. , Abdel Salam M. , Nabil A. , Fahmi S.
Published: October 2010

Most scholars, old and modern, agree that the vowel system of the Arabic language is composed of 3 vowels only, namely /i/, /Ε/ and /u/. The spoken Cairo dialect suggests that there are 6 identifiable vowels, with a short and long variant for each. Objective: The aim of this study is to test the validity of the notion that there are 6 × 2 distinct vowels, with a more central one. Subjects and Methods: Spectral analysis was used to measure F1 and F2 for the vowels of 14 real words. Data was collected from 60 healthy adult informants, 30 males and 30 females. They were native Egyptians speaking the colloquial Cairene dialect. Results: The values of the 6 long and short vowels plus the central one are presented. A significant difference was found between each of them. The long and short vowels differed only in the duration but did not differ in their formant values. Conclusion: The study illustrates the distinctive features of the vowels of the Arabic language. Each of the 7 vowels represents a distinct entity. This will have important implications in assessment and management of language, speech and voice disorders in children and adults.
A Phase II Study of Antofloxacin Hydrochloride, a Novel Fluoroquinolone, for the Treatment of Acute Bacterial Infections
Authors: Wang Jin , Xiao Yonghong , Huang Wenxiang , Xu Nan , Bai Chunxue , Xiu Qingyu , Mei Changlin , Zheng Qingshan
Published: October 2010

Aims: To evaluate the clinical and bacterial efficacies and the safety of antofloxacin hydrochloride tablets in the treatment of acute exacerbations of chronic bronchitis (AECB) and acute pyelonephritis (AP). Patients and Methods: A randomized, controlled, multicenter, double-blind, double-dummy clinical trial was conducted at 6 hospitals in China. The patients in the investigational group took an oral 400-mg loading dose of antofloxacin on the first day followed by 200 mg daily. Control group patients took 200 mg of levofloxacin orally twice daily for 7–14 days. Results: A total of 284 patients were enrolled into the study, including 140 cases of AECB and 144 cases of AP; 141 patients were in the antofloxacin group and 143 patients were in the levofloxacin group. Two hundred fifty-four patients completed the entire treatment and follow-up and comprised the per-protocol analysis data set; 30 patients were excluded because of informed consent withdrawal, loss to follow-up, protocol violations, or adverse drug events. Treatment was ceased in 3 patients in the antofloxacin group and in 1 patient in the levofloxacin group because of skin rashes, dizziness, or adverse gastrointestinal effects. At the end of the 2-regimen treatment, the observed effectiveness rates for AECB were 90.3 and 87.7% for the treatment and control groups, respectively, and 96.9 and 92.1% for AP. The overall bacterial eradication rates were 95.9 and 92.4%, and drug-related adverse events were observed in 13.1 and 10.1% of patients, respectively. There were no severe adverse effects. No statistical differences in drug efficacy and safety were detected between the 2 treatment groups (p > 0.05). Conclusions: Antofloxacin hydrochloride is an effective and well-tolerated new fluoroquinolone that demonstrates clinical and bacteriological efficacies similar to levofloxacin for the treatment of AECB and AP.
Temporary End Ileostomy with Subcutaneously Buried Efferent Limb: Results and Potential Advantages
Authors: van der Sluis Fabian F.J. , Schouten Nelleke , de Graaf Peter W. , Karsten Tom M. , Stassen Laurents P.
Published: October 2010

Purpose: To evaluate the results of a modified technique of creating a defunctioning end ileostomy. Methods: Medical records of all consecutive patients with a defunctioning end ileostomy with buried efferent limb operated at our hospital between January 2000 and December 2007 were reviewed. The defunctioning end ileostomy with buried efferent limb is created by closing the distal limb and positioning it in the subcutis. Parameters studied were: stomal and reversal related complications. Results: 66 patients were included. Between construction and closure of the stoma, a total of 21 patients (31.8%) developed stoma-related complications. In 1 patient (1.5%) high output occurred, in 6 (9%) stomal retraction and in 4 (6.1%) a parastomal hernia occurred. Peristomal skin problems were observed in 14 patients (21.2%) in the early postoperative period, decreasing to 6 patients (9.1%) after 3 weeks. In 1 patient, stoma closure could not be performed through a local approach and formal laparotomy was necessary. Complications of loop ileostomy as reported in the literature show relatively high rates of peristomal skin and leakage problems. Conclusions: Our results suggest that end ileostomy with subcutaneous buried efferent limb offers advantages over loop ileostomy with regard to the risk of developing peristomal skin and leakage problems.
Vowel Contrast and Speech Intelligibility in Dysarthria
Authors: Kim Heejin , Hasegawa-Johnson Mark , Perlman Adrienne
Published: October 2010

Background/Aims: This study examined the spectral characteristics of American English vowels in dysarthria associated with cerebral palsy (CP), and investigated the relationship between a speaker’s overall speech intelligibility and vowel contrast. Methods: The data were collected from 12 American English native speakers (9 speakers with a diagnosis of CP and 3 controls). Primary measures were F1 and F2 frequencies of 3 corner vowels /i, a, u/ and 3 noncorner vowels /I, 3, */. Six acoustic variables were derived from the formant measures, and were regressed against intelligibility: corner vowel space, noncorner vowel space, mean distance between vowels, F1 and F2 variability, and overlap degree among vowels. Results: First, the effect of vowel was significant for both F1 and F2 measures for all speakers, but post hoc analysis revealed a reduced distinction at lower intelligibility. Second, regression functions relating intelligibility and acoustic variables were significant for overlap degree among vowels, F1 variability, corner vowel space and mean distance between vowels. Overlap degree among vowels accounted for the greatest amount of variance in intelligibility scores. Conclusion: A speaker’s overall intelligibility in dysarthric speech is better represented by the overlap degree among vowels than by the vowel space.
β-Globin Gene Cluster Haplotypes in a Cohort of 221 Children with Sickle Cell Anemia or Sβ⁰-Thalassemia and Their Association with Clinical and Hematological Features
Authors: Belisário André Rolim , Martins Marina Lobato , Brito Ana Mercy Siebra , Rodrigues Cibele Velloso , Silva Célia Maria , Viana Marcos Borato
Published: October 2010

Background/Aims: βS-Haplotype prevalence and its associations with clinical and hematological characteristics were assessed in Brazilian children with sickle cell anemia or Sβ⁰-thalassemia. Methods: A retrospective randomized cohort study was undertaken with 208 SS and 13 Sβ⁰-thalassemia children derived from the Newborn Screening Program of the state of Minas Gerais. βS-Haplotypes were determined by PCR-RFLP. Results: Thirty-nine percent of the SS subjects had the CAR/CAR genotype, 33% had CAR/Ben, 24% had Ben/Ben, 1% had CAR/Atp, 1% had Ben/Atp, and 1% had Arab-Indian/Ben; 1% could not be characterized. Of the Sβ⁰-thalassemia children, 5 were CAR/undefined, 2 were Ben/undefined, and 1 was CAM/undefined. There was no significant association between βS-haplotypes and the total Hb, Hb F, MCV, MCH, WBC, and reticulocyte count among the SS children. Likewise, no significant association was detected between βS-haplotypes and the frequency of acute chest syndrome episodes, blood transfusions, splenic sequestration, or cerebrovascular disease (high-risk/conditional transcranial Doppler ultrasonography or clinical stroke). A limited number of Sβ⁰-thalassemia children precluded valid analyses. Conclusions: The prevalence of βS-haplotypes in this study is in agreement with the historical records of African slaves brought to the state of Minas Gerais. Furthermore, βS-haplotypes CAR and Ben were not associated with any analyzed feature of children with sickle cell anemia.
Genistein Prevents Myocardial Hypertrophy in 2-Kidney 1-Clip Renal Hypertensive Rats by Restoring eNOS Pathway
Authors: Li Jie , Xie Zhi-Zhong , Tang Yong-Bo
Published: October 2010

Genistein has been shown to increase nitric oxide (NO) production derived from endothelial nitric oxide synthase (eNOS). This study was to investigate whether genistein could prevent myocardial hypertrophy in the 2-kidney 1-clip (2K1C) renohypertensive rat through the NO pathway and to clarify the underlying mechanisms. After the 2K1C operation, plasma angiotensin II increased, and the rats developed significant left ventricular hypertrophy (LVH) and increased collagen I expression. Phosphorylated eNOS, NOS activity, NO production and cGMP contents were markedly decreased in ventricular tissues of 2K1C rats. Chronic administration of genistein to 2K1C rats restored NO, NOS activity, phosphorylated eNOS expression, cGMP in ventricular tissues, and the restoration was parallel with the improvement of LVH and attenuated the excessive ventricular collagen I expression. Genistein also elevated angiotensin II type 2 receptor (AT2) expression, and the effects of genistein on LVH could be completely abolished by an AT2 antagonist, PD123319. The antagonist also reversed the increase in eNOS activity, NO and cGMP restored by genistein in hypertensive rats. We further explored the mechanisms by which genistein restored NO in hypertension and found that genistein significantly enhanced phosphorylated eNOS but left relatively unchanged total eNOS and the eNOS dimer/monomer ratio. In addition, genistein decreased the binding of eNOS with caveolin 3 and simultaneously promoted its binding with calmodulin and heat shock protein 90. We conclude that the preventive effects of genistein on cardiac remodeling induced by 2K1C hypertension are mediated by AT2-dependent NO production.
Hypoxia and Upregulation of Hypoxia-Inducible Factor 1α Stimulate Venous Thrombus Recanalization
Authors: Evans Colin Edward , Humphries Julia , Mattock Katherine , Waltham Matthew , Wadoodi Ashar , Saha Prakash , Modarai Bijan , Maxwell Patrick J. , Smith Alberto
Published: October 2010

Objective—

Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization.

Methods and Results—

Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS]=−0.77,
P
<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R]=0.85,
P
<0.0005), during resolution in a murine model. HIF1α (
P
<0.005), VEGF (
P
<0.005), and VEGF receptor 1 (VEGFR1) (
P
<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor
l
-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (
P
<0.001) and volume (
P
<0.05) were reduced by a third in
l
-mimosine–treated mice compared with controls, whereas vein recanalization (
P
<0.005) and thrombus neovascularization (
P
<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content.

Conclusion—

Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.
String-to-Dependency Statistical Machine Translation
Authors: Shen Libin , Xu Jinxi , Weischedel Ralph
Published: October 2010

We propose a novel string-to-dependency algorithm for statistical machine translation. This algorithm employs a target dependency language model during decoding to exploit long distance word relations, which cannot be modeled with a traditional n-gram language model. Experiments show that the algorithm achieves significant improvement in MT performance over a state-of-the-art hierarchical string-to-string system on NIST MT06 and MT08 newswire evaluation sets.
TLR-signaling Networks
Authors: Brown J. , Wang H. , Hajishengallis G.N. , Martin M.
Published: October 2010

Toll-like receptors play a critical role in innate immunity by detecting invading pathogens. The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response. The present review will cover the fundamental signaling pathways utilized by TLRs and how these pathways regulate the innate immune response to pathogens. Abbreviations: TLR, Toll-like receptor; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; APC, antigen-presenting cell; IL, interleukin; TIR, Toll/IL-1R homology; MyD88, myeloid differentiation factor 88; IFN, interferon; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRAK, IL-1R-associated kinase; TAK1, TGF-β-activated kinase; TAB1, TAK1-binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MAPK, mitogen-activated protein kinase; NLR, NOD-like receptors; LRR, leucine-rich repeats; DC, dendritic cell; PI3K, phosphoinositide 3-kinases; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; DAF, decay-accelerating factor; IKK, IκB kinase; IRF, interferon regulatory factors; TBK1, TANK-binding kinase 1; CARD, caspase activation and recruitment domain; PYD, pyrin N-terminal homology domain; ATF, activating transcription factor; and PTEN, phosphatase and tensin homolog.
A New Hypo/Oligodontia Syndrome
Authors: Chalabreysse L. , Senni F. , Bruyère P. , Aime B. , Ollagnier C. , Bozio A. , Bouvagnet P.
Published: October 2010

Dental agenesis is either syndromic or non-syndromic. Here, we describe a familial case with Carvajal/Naxos syndrome associating woolly hair, palmoplantar keratoderma, and biventricular dilated cardiomyopathy. In addition to these signs, all three affected family members had hypo/oligodontia ranging from absence of the lower left second molar to 15 missing teeth, the typical pattern of oligodontia being absent 2nd premolars and absent 2nd and 3rd molars. Mutation screening in the desmoplakin gene ( DSP) revealed a de novo missense mutation (c.1790 C>T, p.Ser597Leu) changing a serine residue conserved in all vertebrates. In addition, this variation was absent from 100 control DNA samples. There were no mutations in the plakoglobin gene. This familial case report and two other previous reports demonstrate that autosomal-dominant mutations in the DSP gene are associated with hypo/oligodontia in the setting of Carvajal/Naxos syndrome. This study suggests that dentists discovering oligo/hypodontia should screen for woolly hair and palmoplantar keratoderma because of the probable cardiac involvement with an inherent high risk of severe cardiomyopathy. In addition, this study reveals the role of desmosomes in the development of teeth and suggests that other genes encoding proteins of the desmosome could be involved in oligo/hypodontia.
Biomimetic Analogs for Collagen Biomineralization
Authors: Gu L. , Kim Y.K. , Liu Y. , Ryou H. , Wimmer C.E. , Dai L. , Arola D.D. , Looney S.W. , Pashley D.H. , Tay F.R.
Published: October 2010

Inability of chemical phosphorylation of sodium trimetaphosphate to induce intrafibrillar mineralization of type I collagen may be due to the failure to incorporate a biomimetic analog to stabilize amorphous calcium phosphates (ACP) as nanoprecursors. This study investigated adsorption/desorption characteristics of hydrolyzed and pH-adjusted sodium trimetaphosphate (HPA-Na3P3O9) to collagen. Based on those results, a 5-minute treatment time with 2.8 wt% HPA-Na3P3O9 was used in a single-layer reconstituted collagen model to confirm that both the ACP-stabilization analog and matrix phosphoprotein analog must be present for intrafibrillar mineralization. The results of that model were further validated by complete remineralization of phosphoric-acid-etched dentin treated with the matrix phosphoprotein analog and lined with a remineralizing lining composite, and with the ACP-stabilization analog supplied in simulated body fluid. An understanding of the basic processes involved in intrafibrillar mineralization of reconstituted collagen fibrils facilitates the design of novel tissue engineering materials for hard tissue repair and regeneration.
Virulence Factors of the Oral Spirochete Treponema denticola
Authors: Dashper S.G. , Seers C.A. , Tan K.H. , Reynolds E.C.
Published: October 2010

There is compelling evidence that treponemes are involved in the etiology of several chronic diseases, including chronic periodontitis as well as other forms of periodontal disease. There are interesting parallels with other chronic diseases caused by treponemes that may indicate similar virulence characteristics. Chronic periodontitis is a polymicrobial disease, and recent animal studies indicate that co-infection of Treponema denticola with other periodontal pathogens can enhance alveolar bone resorption. The bacterium has a suite of molecular determinants that could enable it to cause tissue damage and subvert the host immune response. In addition to this, it has several non-classic virulence determinants that enable it to interact with other pathogenic bacteria and the host in ways that are likely to promote disease progression. Recent advances, especially in molecular-based methodologies, have greatly improved our knowledge of this bacterium and its role in disease.
Differences in Legal Outcomes for Male and Female Children Who Have Been Sexually Abused
Authors: Goldberg Edelson Meredyth , Joa Debbie
Published: October 2010

The goal of the present study was to determine whether or not there were sex differences in legal outcomes for children who were sexually abused. Using the methodology of Joa and Edelson (2004), the results indicated that males who were sexually abused had poorer legal outcomes than females. Specifically, it was found that cases involving male victims were less likely to be filed with the District Attorney (DA) than cases involving female victims and had fewer criminal counts charged. For those children seen at a Child Abuse Assessment Center, cases involving female victims were significantly more likely to be filed by the DA’s office than were cases involving male victims. Finally, there were differences in whether guilty defendants pled guilty or were found guilty at trial depending on whether the defendant sexually abused a male or female. The implications of the findings are discussed.
Predictors of Child Pornography Offenses and Child Sexual Abuse in a Community Sample of Pedophiles and Hebephiles
Authors: Neutze Janina , Seto Michael C. , Schaefer Gerard A. , Mundt Ingrid A. , Beier Klaus M.
Published: October 2010

Little is known about factors that distinguish men who act upon their self-identified sexual interest in prepubescent or pubescent children from those who do not. Even less is known about pedophiles or hebephiles who are not involved with the criminal justice system. In this study, a sample of 155 self-referred pedophiles and hebephiles was recruited from the community. All participants met DSM-IV-TR criteria for pedophilia (or paraphilia not otherwise specified for those who were sexually attracted to pubescent children). Two sets of group comparisons were conducted on sociodemographic variables and measures of dynamic risk factors. The first set was based on recent activity and compared men who had committed child pornography only or child sexual abuse offenses in the past six months with men who remained offense-free during the same period. The second set was based on lifetime offense history (excluding the most recent six months) and compared child pornography offenders with child sexual abuse offenders and men who had committed both kinds of offenses. Overall, there were more similarities than differences between groups.
Abdominal massage for the alleviation of constipation symptoms in people with multiple sclerosis: a randomized controlled feasibility study
Authors: McClurg Doreen , Hagen Suzanne , Hawkins Stanley , Lowe-Strong Andrea
Published: October 2010

Background: Constipation affects many people with multiple sclerosis (MS), negatively impacting on their quality of life. The use of abdominal massage has been reported in several populations and has been shown to increase the frequency of defaecation.

Objective: The objective of this study was to determine the feasibility of undertaking abdominal massage in people with MS.

Methods: Following ethical approval, 30 patients with MS and constipation were recruited. After providing informed written consent and completion of baseline outcome measures, participants were randomly allocated to a massage group or a control group. The massage group participants were provided with advice on bowel management, and they or their carers were taught how to deliver abdominal massage and were recommended to perform it daily during the 4-week intervention period. The control group received bowel management advice only. Outcomes were measured pre (Week 0) and post treatment (Week 4), and at Week 8 and included: the Constipation Scoring System (CSS) (primary outcome), the Neurogenic Bowel Dysfunction Score, and a bowel diary.

Results: Both groups demonstrated a decrease in CSS score from Week 0 to Week 4, indicating an improvement in constipation symptoms; however, the massage group improved significantly more than the control groups (mean difference between groups in score change −5.0 (SD 1.5), 95% CI −8.1, −1.8; t = −3.28, df = 28, p = 0.003).

Conclusion: The results of this small study suggest a positive effect of the intervention on the symptoms of constipation, and support the feasibility of a substantive trial of abdominal massage for the alleviation of the symptoms of constipation in people with MS.
Communicating thin: A grounded model of Online Negative Enabling Support Groups in the pro-anorexia movement
Authors: Haas Stephen M. , Irr Meghan E. , Jennings Nancy A. , Wagner Lisa M.
Published: October 2010

The pro-anorexia movement provides support for those with anorexia and adopts an ‘anti-recovery’ view of the disease.The internet has allowed pro-anorexia followers (proanas) to exchange messages in anonymous virtual communities where they encourage one another to be thin. Through the analysis of pro-ana websites using grounded theory, four themes encompassing eight communicative strategies were identified: 1) co-constructing an ana personal identity; 2) self-loathing ana; 3) advising ana; and, 4) group ana encouragement. An emergent grounded model explicates underlying theoretical principles that indicate a new type of social support group, the Online Negative Enabling Support Group (ONESG), in which members encourage negative or harmful behaviors, accept ‘self’ or ‘other’ negative messages without correction from others and co-construct an affectionate ‘enabling in-group’ that evolves online ‘weak-tie’ support into ‘strong ties’ used to combat stigma in their offline world.
Activation and Effective Connectivity Changes Following Explicit-Memory Training for Face–Name Pairs in Patients With Mild Cognitive Impairment
Authors: Hampstead Benjamin M. , Stringer Anthony Y. , Stilla Randall F. , Deshpande Gopikrishna , Hu Xiaoping , Moore Anna Bacon , Sathian K.
Published: October 2010

Background. Mild cognitive impairment (MCI) is often a precursor to Alzheimer disease. Little research has examined the efficacy of cognitive rehabilitation in patients with MCI, and the relevant neural mechanisms have not been explored. The authors previously showed the behavioral efficacy of cognitive rehabilitation using mnemonic strategies for face–name associations in patients with MCI. Here, the authors used functional magnetic resonance imaging (fMRI) to test whether there were training-specific changes in activation and connectivity within memory-related areas. Methods. A total of 6 patients with amnestic, multidomain MCI underwent pretraining and posttraining fMRI scans, during which they encoded 90 novel face–name pairs and completed a 4-choice recognition memory test immediately after scanning. Patients were taught mnemonic strategies for half the face–name pairs during 3 intervening training sessions. Results. Training-specific effects comprised significantly increased activation within a widespread cerebral cortical network involving medial frontal, parietal, and occipital regions; the left frontal operculum and angular gyrus; and regions in the left lateral temporal cortex. Increased activation common to trained and untrained stimuli was found in a separate network involving inferior frontal, lateral parietal, and occipital cortical regions. Effective connectivity analysis using multivariate, correlation-purged Granger causality analysis revealed generally increased connectivity after training, particularly involving the middle temporal gyrus and foci in the occipital cortex and the precuneus. Conclusion. The authors’ findings suggest that the effectiveness of explicit-memory training in patients with MCI is associated with training-specific increases in activation and connectivity in a distributed neural system that includes areas involved in explicit memory.
A potential role for α-actinin in inside-out αIIbβ3 signaling
Authors: Tadokoro Seiji , Nakazawa Tsuyoshi , Kamae Tsuyoshi , Kiyomizu Kazunobu , Kashiwagi Hirokazu , Honda Shigenori , Kanakura Yuzuru , Tomiyama Yoshiaki
Published: October 2010

Many different biochemical signaling pathways regulate integrin activation through the integrin cytoplasmic tail. Here, we describe a new role for α-actinin in inside-out integrin activation. In resting human platelets, α-actinin was associated with αIIbβ3, whereas inside-out signaling (αIIbβ3 activation signals) from protease-activated receptors (PARs) dephosphorylated and dissociated α-actinin from αIIbβ3. We evaluated the time-dependent changes of the αIIbβ3 activation state by measuring PAC-1 binding velocity. The initial velocity analysis clearly showed that PAR1-activating peptide stimulation induced only transient αIIbβ3 activation, whereas PAR4-activating peptide induced long-lasting αIIbβ3 activation. When αIIbβ3 activation signaling dwindled, α-actinin became rephosphorylated and reassociated with αIIbβ3. Compared with control platelets, the dissociation of α-actinin from αIIbβ3 was only transient in PAR4-stimulated P2Y12-deficient platelets in which the sustained αIIbβ3 activation was markedly impaired. Overexpression of wild-type α-actinin, but not the mutant Y12F α-actinin, increased its binding to αIIbβ3 and inhibited PAR1-induced initial αIIbβ3 activation in the human megakaryoblastic cell line, CMK. In contrast, knockdown of α-actinin augmented PAR-induced αIIbβ3 activation in CMK. These observations suggest that α-actinin might play a potential role in setting integrins to a default low-affinity ligand-binding state in resting platelets and regulating αIIbβ3 activation by inside-out signaling.
Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease
Authors: Hulbert Monica L. , McKinstry Robert C. , Lacey JoAnne L. , Moran Christopher J. , Panepinto Julie A. , Thompson Alexis A. , Sarnaik Sharada A. , Woods Gerald M. , Casella James F. , Inusa Baba , Howard Jo , Kirkham Fenella J. , Anie Kofi A. , Mullin Jonathan E. , Ichord Rebecca , Noetzel Michael , Yan Yan , Rodeghier Mark , DeBaun Michael R.
Published: October 2010

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.
The phylogenetic position of Acoela as revealed by the complete mitochondrial genome of Symsagittifera roscoffensis
Authors: Mwinyi Adina , Bailly Xavier , Bourlat Sarah J , Jondelius Ulf , Littlewood D Timothy J , Podsiadlowski Lars
Published: October 2010

Background

Acoels are simply organized unsegmented worms, lacking hindgut and anus. Several publications over recent years challenge the long-held view that acoels are early offshoots of the flatworms. Instead a basal position as sister group to all other bilaterian animals was suggested, mainly based on molecular evidence. This led to the view that features of acoels might reflect those of the last common ancestor of Bilateria, and resulted in several evo-devo studies trying to interpret bilaterian evolution using acoels as a proxy model for the "Urbilateria".

Results

We describe the first complete mitochondrial genome sequence of a member of the Acoela, Symsagittifera roscoffensis. Gene content and circular organization of the mitochondrial genome does not significantly differ from other bilaterian animals. However, gene order shows no similarity to any other mitochondrial genome within the Metazoa. Phylogenetic analyses of concatenated alignments of amino acid sequences from protein coding genes support a position of Acoela and Nemertodermatida as the sister group to all other Bilateria. Our data provided no support for a sister group relationship between Xenoturbellida and Acoela or Acoelomorpha. The phylogenetic position of Xenoturbella bocki as sister group to or part of the deuterostomes was also unstable.

Conclusions

Our phylogenetic analysis supports the view that acoels and nemertodermatids are the earliest divergent extant lineage of Bilateria. As such they remain a valid source for seeking primitive characters present in the last common ancestor of Bilateria. Gene order of mitochondrial genomes seems to be very variable among Acoela and Nemertodermatida and the groundplan for the metazoan mitochondrial genome remains elusive. More data are needed to interpret mitochondrial genome evolution at the base of Bilateria.
Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis
Authors: Zheng Jian , Yu Xiao , Jiang Lan , Xiao Mang , Bai Bing , Lu Jiachun , Zhou Yifeng
Published: October 2010

Background

As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting.

Methods

We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between theCTLA-4+49G > A polymorphism and cancer risk.

Results

Compared with the commonCTLA-4+49G > A GG genotype, the carriers of variant genotypes (CTLA-4+49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32,P< 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of theCTLA-4+49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48,P< 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52,P= 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33,P< 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48,P= 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32,P< 0.00001) and 1.29 (95% CI = 1.17-1.41,P< 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated withCTLA-4+49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47,P= 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32,P< 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31,P< 0.00001).

Conclusion

Our meta-analysis suggests that theCTLA-4+49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.
The serine protease inhibitor serpinE2 is a novel target of ERK signaling involved in human colorectal tumorigenesis
Authors: Bergeron Sébastien , Lemieux Etienne , Durand Véronique , Cagnol Sébastien , Carrier Julie C , Lussier Jacques G , Boucher Marie-Josée , Rivard Nathalie
Published: October 2010

Background

Among the most harmful of all genetic abnormalities that appear in colorectal cancer (CRC) development are mutations of KRAS and its downstream effector BRAF as they result in abnormal extracellular signal-related kinase (ERK) signaling. In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in normal rat intestinal epithelial cells (IECs) induced morphological transformation associated with epithelial to mesenchymal transition, growth in soft agar, invasion and metastases in nude mice. Results from microarrays comparing control to caMEK-expressing IECs identified the gene encoding for serpinE2, a serine protease inhibitor, as a potential target of activated MEK1.

Results

1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF. 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in KRAS and BRAF. 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice. 4- Treatment of CRC cell lines with U0126 markedly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 is likely dependent of ERK activity. 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade.

Conclusions

Our data indicate that serpinE2 is up-regulated by oncogenic activation of Ras, BRAF and MEK1 and contributes to pro-neoplastic actions of ERK signaling in intestinal epithelial cells. Hence, serpinE2 may be a potential therapeutic target for colorectal cancer treatment.
Screening for Distress in Lung and Breast Cancer Outpatients: A Randomized Controlled Trial
Authors: Carlson Linda E. , Groff Shannon L. , Maciejewski Olga , Bultz Barry D.
Published: October 2010

Purpose

Distress has been recognized as the sixth vital sign in cancer care and several guidelines recommend routine screening. Despite this, screening for distress is rarely conducted and infrequently evaluated.

Methods

A program of routine online screening for distress was implemented for new patients with breast and lung cancer. Patients were randomly assigned to one of three conditions: (1) minimal screening: the distress thermometer (DT) only plus usual care; (2) full screening: DT, problem checklist, Psychological Screen for Cancer part C measuring anxiety and depression, a personalized report summarizing concerns and the report on the medical file; or (3) triage: full screening plus optional personalized phone triage with referral to resources. Patients in all conditions received an information packet and were reassessed 3 months later with the full screening battery.

Results

Five hundred eighty-five patients with breast cancer and 549 patients with lung cancer were assessed at baseline (89% of all patients), and 75.5% retained for follow-up. High prevalence of baseline distress was found across patients. Twenty percent fewer patients with lung cancer in triage continued to have high distress at follow-up compared to those in the other two groups, and patients with breast cancer in the full screening and triage conditions showed lower distress at follow-up than those in minimal screening. The best predictor of decreased anxiety and depression in full screening and triage conditions was receiving a referral to psychosocial services.

Conclusion

Routine online screening is feasible in a large cancer center and may help to reduce future distress levels, particularly when coupled with uptake of appropriate resources.
Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial
Authors: Palumbo Antonio , Bringhen Sara , Rossi Davide , Cavalli Maide , Larocca Alessandra , Ria Roberto , Offidani Massimo , Patriarca Francesca , Nozzoli Chiara , Guglielmelli Tommasina , Benevolo Giulia , Callea Vincenzo , Baldini Luca , Morabito Fortunato , Grasso Mariella , Leonardi Giovanna , Rizzo Manuela , Pia Falcone Antonietta , Gottardi Daniela , Montefusco Vittorio , Musto Pellegrino , Petrucci Maria Teresa , Ciccone Giovannino , Boccadoro Mario
Published: October 2010

Purpose

The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase III study examined the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with bortezomib-thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous stem-cell transplantation.

Patients and Methods

A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival.

Results

The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio [HR], 0.67; 95% CI, 0.50 to 0.90; P = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; P = .007). Complete response rates were 38% in the VMPT-VT group and 24% in the VMP group (P < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P = .77). Grade 3 to 4 neutropenia (38% v 28%; P = .02), cardiologic events (10% v 5%; P = .04), and thromboembolic events (5% v 2%; P = .08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP.

Conclusion

VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation.
Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08
Authors: Allegra Carmen J. , Yothers Greg , O'Connell Michael J. , Sharif Saima , Petrelli Nicholas J. , Colangelo Linda H. , Atkins James N. , Seay Thomas E. , Fehrenbacher Louis , Goldberg Richard M. , O'Reilly Seamus , Chu Luis , Azar Catherine A. , Lopa Samia , Wolmark Norman
Published: October 2010

Purpose

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 (mFOLFOX6; ie, infusional/bolus fluorouracil, leucovorin, and oxaliplatin) for the adjuvant treatment of patients with stages II to III colon cancer.

Methods

Patients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab (5 mg/kg every 2 weeks for 52 weeks [ie, experimental group]). The primary end point was disease-free survival (DFS).

Results

Among 2,672 analyzed patients, demographic factors were well balanced by treatment. With a median follow-up of 35.6 months, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.89; 95% CI, 0.76 to 1.04; P = .15). The point estimates for 3-year DFS for the overall population were 77.4% and 75.5% for the experimental and control arms, respectively. For patients with stages II and III diseases, these same estimates were 87.4% and 84.7%, respectively, for stage II and 74.2% and 72.4%, respectively, for stage III. Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 15-month landmark (time-by-treatment interaction P value < .0001). Bevacizumab had a strong effect before the landmark (HR, 0.61; 95% CI, 0.48 to 0.78; P < .001) but no significant effect after (HR, 1.22; 95% CI, 0.98 to 1.52; P = .076).

Conclusion

Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.
Cinacalcet HCl Reduces Hypercalcemia in Primary Hyperparathyroidism across a Wide Spectrum of Disease Severity
Authors: Peacock Munro , Bilezikian J. P. , Bolognese M. A. , Borofsky Michael , Scumpia Simona , Sterling L. R. , Cheng Sunfa , Shoback Dolores
Published: October 2010

Context: Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations.

Objective: The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity.

Design and Setting: The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT.

Patients : Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15).

Intervention: The intervention in this study was treatment with cinacalcet for up to 4.5 yr.

Outcomes: Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period.

Results: The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories.

Conclusions: Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.
Familial Focal Congenital Hyperinsulinism
Authors: Ismail Dunia , Smith Virpi V. , de Lonlay Pascale , Ribeiro Maria-Joao , Rahier Jacques , Blankenstein Oliver , Flanagan Sarah E. , Bellanné-Chantelot Christine , Verkarre Virginie , Aigrain Yves , Pierro Agostino , Ellard Sian , Hussain Khalid
Published: October 2010

Background:

Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare.

Aim:

We describe the first familial form of focal CHI in two siblings.

Patients and Methods:

The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia.

Conclusion:

This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.