bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz
Authors: Focà Emanuele , Motta Davide , Borderi Marco , Gotti Daria , Albini Laura , Calabresi Alessandra , Izzo Ilaria , Bellagamba Rita , Narciso Pasquale , Sighinolfi Laura , Clò Alberto , Gibellini Davide , Quiros-Roldan Eugenia , Brianese Nigritella , Cesana Bruno Mario , Re Maria Carla , Torti Carlo
Published: February 2012

Background

Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain.

Methods

We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated.

Results

Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated.

Conclusions

These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.
The application of methylation specific electrophoresis (MSE) to DNA methylation analysis of the 5' CpG island of mucin in cancer cells
Authors: Yokoyama Seiya , Kitamoto Sho , Yamada Norishige , Houjou Izumi , Sugai Tamotsu , Nakamura Shin-ichi , Arisaka Yoshifumi , Takaori Kyoichi , Higashi Michiyo , Yonezawa Suguru
Published: February 2012

Background

Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Epigenetic changes in promoter regions appear to be the first step in expression of mucins. Thus, detection of promoter methylation status is important for early diagnosis of cancer, monitoring of tumor behavior, and evaluating the response of tumors to targeted therapy. However, conventional analytical methods for DNA methylation require a large amount of DNA and have low sensitivity.

Methods

Here, we report a modified version of the bisulfite-DGGE (denaturing gradient gel electrophoresis) using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE). The MSE method is comprised of the following steps: (a) bisulfite treatment of genomic DNA, (b) amplification of the target DNA by a nested PCR approach and (c) applying to DGGE. To examine whether the MSE method is able to analyze DNA methylation of mucin genes in various samples, we apply it to DNA obtained from state cell lines, ethanol-fixed colonic crypts and human pancreatic juices.

Result

The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is < 0.1% and the detectable minimum amount of DNA is 20 pg, which can be obtained from only a few cells. We also show that MSE can be used for analysis of challenging samples such as human isolated colonic crypts or human pancreatic juices, from which only a small amount of DNA can be extracted.

Conclusions

The MSE method can provide a qualitative information of methylated sequence profile. The MSE method allows sensitive and specific analysis of the DNA methylation pattern of almost any block of multiple CpG sites. The MSE method can be applied to analysis of DNA methylation status in many different clinical samples, and this may facilitate identification of new risk markers.
Willingness to use and pay for options of care for community-dwelling older people in rural Vietnam
Authors: Van Hoi Le , Thi Kim Tien Nguyen , Van Tien Nguyen , Van Dung Dao , Thi Kim Chuc Nguyen , Goran Sahlen Klas , Lindholm Lars
Published: February 2012

Background

The proportion of people in Vietnam who are 60 years and over has increased rapidly. The emigration of young people and impact of other socioeconomic changes leave more elderly on their own and with less family support. This study assesses the willingness to use and pay for different models of care for community-dwelling elderly in rural Vietnam.

Methods

In 2007, people aged 60 and older and their family representatives, living in 2,240 households, were randomly selected from the FilaBavi Demographic Surveillance Site. They were interviewed using structured questionnaires to assess dependence in activities of daily living (ADLs), willingness to use and to pay for day care centres, mobile care teams, and nursing centres. Respondent socioeconomic characteristics were extracted from the FilaBavi repeated census. Percentages of those willing to use models and the average amount (with 95% confidence intervals) they are willing to pay were estimated. Multivariate analyses were performed to measure the relationship of willingness to use services with ADL index and socioeconomic factors. Four focus group discussions were conducted to explore people's perspectives on the use of services. The first discussion group was with the elderly. The second discussion group was with their household members. Two other discussion groups included community association representatives, one at the communal level and another at the village level.

Results

Use of mobile team care is the most requested service. The fewest respondents intend to use a nursing centre. Households expect to use services for their elderly to a greater extent than do the elderly themselves. Willingness to use services decreases when potential fees increase. The proportion of respondents who require that services be free-of-charge is two to three times higher than the proportion willing to pay full cost. Households are willing to pay more than the elderly for day care and nursing centres. The elderly are more willing to pay for mobile teams than are their households. Age group, sex, literacy, marital status, living arrangement, living area, working status, poverty, household wealth and dependence in ADLs are factors related to willingness to use services.

Conclusions

Community-centric elderly care will be used and partly paid for by individuals if it is provided by the government or associations. Capacity building for health professional networks and informal caregivers is essential for developing formal care models. Additional support is needed for the most vulnerable elderly to access services.
Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum
Authors: Pascual Aurélie , Parola Philippe , Benoit-Vical Françoise , Simon Fabrice , Malvy Denis , Picot Stéphane , Delaunay Pascal , Basset Didier , Maubon Danièle , Faugère Bernard , Ménard Guillaume , Bourgeois Nathalie , Oeuvray Claude , Didillon Eric , Rogier Christophe , Pradines Bruno
Published: February 2012

Background

The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN).

Methods

The susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method.

Results

The IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM) and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM). A significant positive correlation was shown between responses to PPQ and PND responses (rho = 0.46) and between PPQ and MDAQ (rho = 0.30). No significant correlation was shown between PPQ IC50 and responses to other anti-malarial drugs. A significant positive correlation was shown between responses to PND and MDAQ (rho = 0.37), PND and LMF (rho = 0.28), PND and QN (rho = 0.24), PND and AS (rho = 0.19), PND and DHA (rho = 0.18) and PND and CQ (rho = 0.16). All these coefficients of correlation are too low to suggest cross-resistance between PPQ or PND and the other drugs.

Conclusions

In this study, the excellent anti-malarial activity of PPQ and PND was confirmed. The absence of cross-resistance with quinolines and artemisinin derivatives is consistent with the efficacy of the combinations of PPQ and DHA or PND and AS in areas where parasites are resistant to conventional anti-malarial drugs.
Detection of the third and fourth heart sounds using Hilbert-Huang transform
Authors: Tseng Yi-Li , Ko Pin-Yu , Jaw Fu-Shan
Published: February 2012

Background

The third and fourth heart sound (S3 and S4) are two abnormal heart sound components which are proved to be indicators of heart failure during diastolic period. The combination of using diastolic heart sounds with the standard ECG as a measurement of ventricular dysfunction may improve the noninvasive diagnosis and early detection of myocardial ischemia.

Methods

In this paper, an adaptive method based on time-frequency analysis is proposed to detect the presence of S3 and S4. Heart sound signals during diastolic periods were analyzed with Hilbert-Huang Transform (HHT). A discrete plot of maximal instantaneous frequency and its amplitude was generated and clustered. S3 and S4 were recognized by the clustered points, and performance of the method was further enhanced by period definition and iteration tracking.

Results

Using the proposed method, S3 and S4 could be detected adaptively in a same method. 90.3% of heart sound cycles with S3 were detected using our method, 9.6% were missed, and 9.6% were false positive. 94% of S4 were detected using our method, 5.5% were missed, and 16% were false positive.

Conclusions

The proposed method is adaptive for detecting low-amplitude and low-frequency S3 and S4 simultaneously compared with previous detection methods, which would be practical in primary care.
Low-density nanoporous iron foams synthesized by sol-gel autocombustion
Authors: Hua Zhenghe , Deng Yu , Li Kenan , Yang Shaoguang
Published: February 2012

Nanoporous iron metal foams were synthesized by an improved sol-gel autocombustion method in this report. It has been confirmed to be pure phase iron by X-ray diffraction measurements. The nanoporous characteristics were illustrated through scanning electron microscope and transmission electron microscope images. Very low density and quite large saturation magnetization has been performed in the synthesized samples.
Methods for depth-map filtering in view-plus-depth 3D video representation
Authors: Smirnov Sergey , Gotchev Atanas , Egiazarian Karen
Published: February 2012

View-plus-depth is a scene representation format where each pixel of a color image or video frame is augmented by per-pixel depth represented as gray-scale image (map). In the representation, the quality of the depth map plays a crucial role as it determines the quality of the rendered views. Among the artifacts in the received depth map, the compression artifacts are usually most pronounced and considered most annoying. In this article, we study the problem of post-processing of depth maps degraded by improper estimation or by block-transform-based compression. A number of post-filtering methods are studied, modified and compared for their applicability to the task of depth map restoration and post-filtering. The methods range from simple and trivial Gaussian smoothing, to in-loop deblocking filter standardized in H.264 video coding standard, to more comprehensive methods which utilize structural and color information from the accompanying color image frame. The latter group contains our modification of the powerful local polynomial approximation, the popular bilateral filter, and an extension of it, originally suggested for depth super-resolution. We further modify this latter approach by developing an efficient implementation of it. We present experimental results demonstrating high-quality filtered depth maps and offering practitioners options for highest-quality or better efficiency.
Mycotic pseudoaneurysms complicating renal transplantation: a case series and review of literature
Authors: Leonardou Polytimi , Gioldasi Sofia , Zavos George , Pappas Paris
Published: February 2012

Introduction

Kidney transplantation can be complicated by infection and subsequent development of mycotic aneurysm, endangering the survival of the graft and the patient. Management of this condition in five cases is discussed, accompanied by a review of the relevant literature.

Case presentations

Five patients, three men 42-, 67- and 57-years-old and two women 55- and 21-years-old (mean age of 48 years), all Caucasians, developed a mycotic aneurysm in the region of the anastomosis between renal graft artery and iliac axes. Four patients presented with systemic fever and iliac fossa pain and one presented with hemorrhagic shock. Morphologic investigation by color doppler ultrasonography revealed a pseudoaneurysm at the anastomotic site. A combination of antibiotic therapy, surgery and interventional procedures was required as all kidney transplants had to be removed. No recurrence was recorded during the follow-up period.

Conclusions

A high index of suspicion is required for the timely diagnosis of a mycotic aneurysm; aggressive treatment with cover stents and/or surgical excision is necessary in order to prevent potentially fatal complications.
Therapeutic strategies in epithelial ovarian cancer
Authors: Kim Ayako , Ueda Yutaka , Naka Tetsuji , Enomoto Takayuki
Published: February 2012

Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube.

Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma.

The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.
Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging
Authors: Fournier Patrick , Dumulon-Perreault Véronique , Ait-Mohand Samia , Langlois Réjean , Bénard François , Lecomte Roger , Guérin Brigitte
Published: February 2012

Background

Gastrin-releasing peptide receptors [GRPR] are highly over-expressed in multiple cancers and have been studied as a diagnostic target. Multimeric gastrin-releasing peptides are expected to have enhanced tumor uptake and affinity for GRPR. In this study, a 64Cu-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-monomer and two NOTA-dimers of [D-Tyr6,βAla11, Thi13, Nle14]bombesin(6-14) ] [BBN(6-14)] were compared.

Methods

Monomeric and dimeric peptides were synthesized on solid phase support and radiolabeled with 64Cu. NOTA-dimer 1 consists of asymmetrically linked BBN(6-14), while NOTA-dimer 2 has similar spacer between the two BBN(6-14) ligands and the chelator. In vitro GRPR-binding affinities were determined with competitive binding assays on PC3 human prostate cancer cells. In vivo stability and biodistribution of radiolabeled compounds were assessed in Balb/c mice. Cellular uptake and efflux were measured with radiolabeled NOTA-monomer and NOTA-dimer 2 on PC3 cells for up to 4 h. In vivo biodistribution kinetics were measured in PC3 tumor-bearing Balb/c nude mice by μ-positron emission tomography [μPET] imaging and confirmed by dissection and counting.

Results

NOTA-monomer, NOTA-dimers 1 and 2 were prepared with purity of 99%. The inhibition constants of the three BBN peptides were comparable and in the low nanomolar range. All 64Cu-labeled peptides were stable up to 24 h in mouse plasma and 1 h in vivo. 64Cu/NOTA-dimer 2 featuring a longer spacer between the two BBN(6-14) ligands is a more potent GRPR-targeting probe than 64Cu/NOTA-dimer 1. PC3 tumor uptake profiles are slightly different for 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2; the monomeric BBN-peptide tracer exhibited higher tumor uptake during the first 0.5 h and a fast renal clearance resulting in higher tumor-to-muscle ratio when compared to 64Cu/NOTA-dimer 2. The latter exhibited higher tumor-to-blood ratio and was retained longer at the tumor site when compared to 64Cu/NOTA-monomer. Lower ratios of tumor-to-blood and tumor-to-muscle in blocking experiments showed GRPR-dependant tumor uptake for both tracers.

Conclusion

Both 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2 are suitable for detecting GRPR-positive prostate cancer in vivo by PET. Tumor retention was improved in vivo with 64Cu/NOTA-dimer 2 by applying polyvalency effect and/or statistical rebinding.
Phase II Study of Imatinib in Advanced Chordoma
Authors: Stacchiotti Silvia , Longhi Alessandra , Ferraresi Virginia , Grignani Giovanni , Comandone Alessandro , Stupp Roger , Bertuzzi Alexia , Tamborini Elena , Pilotti Silvana , Messina Antonella , Spreafico Carlo , Gronchi Alessandro , Amore Paola , Vinaccia Vincenza , Casali Paolo Giovanni
Published: February 2012

Purpose

To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)–positive chordomas.

Patients and Methods

In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score.

Results

Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months). A minor dimensional response (< 20%) was detected in nine patients. A maximum standard uptake value decrease ≥ 25% was observed in 10 (39%) of 26 patients evaluable for PET response at 3 months. Changes in the Brief Pain Inventory score were consistent with the response assessment. Median PFS (intention-to-treat population, 56 patients) was 9 months. No unexpected toxicities were observed.

Conclusion

This is the largest phase II study in chordoma to date. It confirms anecdotal evidence that imatinib has antitumor activity in this orphan disease, and therefore, it is worth further investigation.
New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge
Authors: Schanz Julie , Tüchler Heinz , Solé Francesc , Mallo Mar , Luño Elisa , Cervera José , Granada Isabel , Hildebrandt Barbara , Slovak Marilyn L. , Ohyashiki Kazuma , Steidl Christian , Fonatsch Christa , Pfeilstöcker Michael , Nösslinger Thomas , Valent Peter , Giagounidis Aristoteles , Aul Carlo , Lübbert Michael , Stauder Reinhard , Krieger Otto , Garcia-Manero Guillermo , Faderl Stefan , Pierce Sherry , Le Beau Michelle M. , Bennett John M. , Greenberg Peter , Germing Ulrich , Haase Detlef
Published: February 2012

Purpose

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients.

Patients and Methods

Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results.

Results

In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score.

Conclusion

In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.
Minimal Residual Disease Quantification Is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial
Authors: Böttcher Sebastian , Ritgen Matthias , Fischer Kirsten , Stilgenbauer Stephan , Busch Raymonde M. , Fingerle-Rowson Günter , Fink Anna Maria , Bühler Andreas , Zenz Thorsten , Wenger Michael Karl , Mendila Myriam , Wendtner Clemens-Martin , Eichhorst Barbara F. , Döhner Hartmut , Hallek Michael J. , Kneba Michael
Published: February 2012

Purpose

To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial.

Patients and Methods

MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10−4), intermediate- (≥ 10−4 to <10−2), and high-level (≥ 10−2) groups.

Results

Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC.

Conclusion

MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer
Authors: Henry N. Lynn , Azzouz Faouzi , Desta Zereunesay , Li Lang , Nguyen Anne T. , Lemler Suzanne , Hayden Jill , Tarpinian Karineh , Yakim Elizabeth , Flockhart David A. , Stearns Vered , Hayes Daniel F. , Storniolo Anna Maria
Published: February 2012

Purpose

Aromatase inhibitors (AIs) are effective for treatment of hormone receptor–positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another.

Patients and Methods

Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period.

Results

Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months.

Conclusion

Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.
Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements
Authors: Kumar Shaji , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis K. , Colby Colin , Laumann Kristina , Zeldenrust Steve R. , Leung Nelson , Dingli David , Greipp Philip R. , Lust John A. , Russell Stephen J. , Kyle Robert A. , Rajkumar S. Vincent , Gertz Morie A.
Published: February 2012

Purpose

Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification.

Patients and Methods

We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials.

Results

We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets.

Conclusion

Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.
Differential regulation of actin microfilaments by human MICAL proteins
Authors: Giridharan Sai Srinivas Panapakkam , Rohn Jennifer L. , Naslavsky Naava , Caplan Steve
Published: February 2012

The Drosophila melanogaster MICAL protein is essential for the neuronal growth cone machinery that functions through plexin- and semaphorin-mediated axonal signaling. Drosophila MICAL is also involved in regulating myofilament organization and synaptic structures, and serves as an actin disassembly factor downstream of plexin-mediated axonal repulsion. In mammalian cells there are three known isoforms, MICAL1, MICAL2 and MICAL3, as well as the MICAL-like proteins MICAL-L1 and MICAL-L2, but little is known of their function, and information comes almost exclusively from neural cells. In this study we show that in non-neural cells human MICALs are required for normal actin organization, and all three MICALs regulate actin stress fibers. Moreover, we provide evidence that the generation of reactive oxygen species by MICAL proteins is crucial for their actin-regulatory function. However, although MICAL1 is auto-inhibited by its C-terminal coiled-coil region, MICAL2 remains constitutively active and affects stress fibers. These data suggest differential but complementary roles for MICAL1 and MICAL2 in actin microfilament regulation.
Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function
Authors: Bergmann Jan H. , Jakubsche Julia N. , Martins Nuno M. , Kagansky Alexander , Nakano Megumi , Kimura Hiroshi , Kelly David A. , Turner Bryan M. , Masumoto Hiroshi , Larionov Vladimir , Earnshaw William C.
Published: February 2012

Human kinetochores are transcriptionally active, producing very low levels of transcripts of the underlying alpha-satellite DNA. However, it is not known whether kinetochores can tolerate acetylated chromatin and the levels of transcription that are characteristic of housekeeping genes, or whether kinetochore-associated ‘centrochromatin’, despite being transcribed at a low level, is essentially a form of repressive chromatin. Here, we have engineered two types of acetylated chromatin within the centromere of a synthetic human artificial chromosome. Tethering a minimal NF-κB p65 activation domain within kinetochore-associated chromatin produced chromatin with high levels of histone H3 acetylated on lysine 9 (H3K9ac) and an ~10-fold elevation in transcript levels, but had no substantial effect on kinetochore assembly or function. By contrast, tethering the herpes virus VP16 activation domain produced similar modifications in the chromatin but resulted in an ~150-fold elevation in transcripts, approaching the level of transcription of an endogenous housekeeping gene. This rapidly inactivated kinetochores, causing a loss of assembled CENP-A and blocking further CENP-A assembly. Our data reveal that functional centromeres in vivo show a remarkable plasticity – kinetochores tolerate profound changes to their chromatin environment, but appear to be critically sensitive to the level of centromeric transcription.
Management strategies for acute proximal deep vein thrombosis: a Delphi consensus
Authors: Patterson B O , Karthikesalingam A , Morgan R , Hunt B J , Thompson M M , Holt P J E
Published: February 2012

Objectives

Deep vein thrombosis (DVT) is a leading cause of cardiovascular disease. We tested the hypothesis that there is a consensus regarding the treatment of acute DVT among clinicians experienced in DVT management.

Method

A Delphi consensus approach was used to gather expert opinion regarding attitudes towards the treatment of acute proximal DVT and management of specific cases. Strength of preference for various treatment strategies across a number of case scenarios was quantified. Univariate and multivariate analyses were performed to quantify the influence of various factors on treatment modality selected.

Results

Respondents strongly agreed that DVT was a significant health problem and that further research was a priority. A multidisciplinary team approach with access to various treatment strategies was encouraged. Pregnancy and recent surgery independently predicted preference for medical treatment, whereas proximal DVT and May–Thurner syndrome were associated with interventional strategies.

Conclusion

Acute proximal DVT is a significant health problem for which a variety of treatments are available. This study demonstrates that no consensus exists as to the optimum strategy for certain patient groups. Trends in opinion based on local experience and case-series exist, but the results of ongoing randomized trials will ultimately inform best practice.
Max-k-Cut by the Discrete Dynamic Convexized Method
Authors: Zhu Wenxing , Lin Geng , Ali M. M.
Published: February 2012

In this paper, we propose a “multistart-type” algorithm for solving the max-k-cut problem. Central to our algorithm is an auxiliary function we propose. We formulate the max-k-cut problem as an explicit mathematical form, which allows us to use an easy implementable local search. The construction of the auxiliary function requires a local maximizer of the max-k-cut problem. If the best local maximizer obtained is used in the construction of the auxiliary function, then the local maximization of the auxiliary function leads to a better maximizer of the max-k-cut problem. This proves to be a good strategy to escape from the current local optima and to search a broader solution space. Indeed, we have shown, both numerically and theoretically, that the maximization of the auxiliary function by the local search method can escape successfully from previously converged discrete local maximizers by taking increasing values of a parameter. Computational results on many test instances with different sizes and densities show that the proposed algorithm is efficient and stable to find approximate global solutions for the max-k-cut problems. Although we have presented results for k ≥ 2, the robustness of our algorithm is shown for k = 2 by comparisons with a number of recent methods. A number of theoretical results are also presented, which justify the design of our algorithm.
Nucleus Accumbens Response to Incentive Stimuli Anticipation in Children of Alcoholics: Relationships with Precursive Behavioral Risk and Lifetime Alcohol Use
Authors: Yau Wai-Ying Wendy , Zubieta Jon-Kar , Weiland Barbara J. , Samudra Preeti G. , Zucker Robert A. , Heitzeg Mary M.
Published: February 2012

Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond previous substance use confounds and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied 20 18- to 22-year-old COAs and 20 controls, developmentally well characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (ages 12–14 years) externalizing behavioral risk. None met criteria for Diagnostic and Statistical Manual of Mental Disorders IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared with controls. However, additional analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest that a close association between motivational responses, alcohol consumption, and behavioral risk may underlie addiction vulnerability in COAs.
Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region
Authors: Zhang Zhang J. , Koifman Julius , Shin Damian S. , Ye Hui , Florez Carlos M. , Zhang Liang , Valiante Taufik A. , Carlen Peter L.
Published: February 2012

How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg2+/high-K+perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a “preictal phase,” which abruptly turns into a higher frequency “ictal” phase. Blockade of GABAAreceptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABAAresponses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABAAreversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.
Incorporating Cross-Modal Statistics in the Development and Maintenance of Multisensory Integration
Authors: Xu Jinghong , Yu Liping , Rowland Benjamin A. , Stanford Terrence R. , Stein Barry E.
Published: February 2012

Development of multisensory integration capabilities in superior colliculus (SC) neurons was examined in cats whose visual–auditory experience was restricted to a circumscribed period during early life (postnatal day 30–8 months). Animals were periodically exposed to visual and auditory stimuli appearing either randomly in space and time, or always in spatiotemporal concordance. At all other times animals were maintained in darkness. Physiological testing was initiated at ∼2 years of age. Exposure to random visual and auditory stimuli proved insufficient to spur maturation of the ability to integrate cross-modal stimuli, but exposure to spatiotemporally concordant cross-modal stimuli was highly effective. The multisensory integration capabilities of neurons in the latter group resembled those of normal animals and were retained for >16 months in the absence of subsequent visual–auditory experience. Furthermore, the neurons were capable of integrating stimuli having physical properties differing significantly from those in the exposure set. These observations suggest that acquiring the rudiments of multisensory integration requires little more than exposure to consistent relationships between the modality-specific components of a cross-modal event, and that continued experience with such events is not necessary for their maintenance. Apparently, the statistics of cross-modal experience early in life define the spatial and temporal filters that determine whether the components of cross-modal stimuli are to be integrated or treated as independent events, a crucial developmental process that determines the spatial and temporal rules by which cross-modal stimuli are integrated to enhance both sensory salience and the likelihood of eliciting an SC-mediated motor response.
Local Dendrodendritic Inhibition Regulates Fast Synaptic Transmission in Visual Thalamus
Authors: Crandall Shane R. , Cox Charles L.
Published: February 2012

Inhibition from thalamic interneurons plays a critical role in modulating information transfer between thalamus and neocortex. Interestingly, these neurons yield inhibition via two distinct outputs: presynaptic dendrites that innervate thalamocortical relay neurons and axonal outputs. Since the dendrites of thalamic interneurons are the primary targets of incoming synaptic information, it has been hypothesized that local synaptic input could produce highly focused dendritic output. To gain additional insight into the computational power of these presynaptic dendrites, we have combined two-photon laser scanning microscopy, glutamate uncaging, and whole-cell electrophysiological recordings to locally activate dendritic terminals and study their inhibitory contribution to rat thalamocortical relay neurons. Our findings demonstrate that local dendritic release from thalamic interneurons is controlled locally by AMPA/NMDA receptor-mediated recruitment of L-type calcium channels. Moreover, by mapping these connections with single dendrite resolution we not only found that presynaptic dendrites preferentially target proximal regions, but such actions differ significantly across branches. Furthermore, local stimulation of interneuron dendrites did not result in global excitation, supporting the notion that these interneurons can operate as multiplexors, containing numerous independently operating input–output devices.
Biglycan Is an Extracellular MuSK Binding Protein Important for Synapse Stability
Authors: Amenta Alison R. , Creely Hilliary E. , Mercado Mary Lynn T. , Hagiwara Hiroki , McKechnie Beth A. , Lechner Beatrice E. , Rossi Susana G. , Wang Qiang , Owens Rick T. , Marrero Emilio , Mei Lin , Hoch Werner , Young Marian F. , McQuillan David J. , Rotundo Richard L. , Fallon Justin R.
Published: February 2012

The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for prepatterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn−/o) muscle is indistinguishable from wild-type controls. However, by 5 weeks after birth, nerve-muscle synapses in bgn−/omice are abnormal as judged by the presence of perijunctional folds, increased segmentation, and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied presynaptic and postsynaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn−/osynapses. In bgn−/omyotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability.
Role of Amygdala Central Nucleus in Aversive Learning Produced by Shock or by Unexpected Omission of Food
Authors: Purgert Robert J. , Wheeler Daniel S. , McDannald Michael A. , Holland Peter C.
Published: February 2012

Many psychological learning theories have noted commonalities between aversive states produced by presentation of negative reinforcers, such as electric shock, and the omission of expected positive reinforcers, such as food. Here, three groups of rats received training with one auditory cue paired with shock and another with the omission of expected food, a shock-paired cue and a food-omission control cue, or a food-omission cue and a shock control cue. Food-omission cues were established by contrast with food delivery; after extensive light–food pairings, the light was followed by the food-omission cue instead of food. Aversiveness of the food-omission cue was assessed with a conditioned punishment procedure, in which presentation of that cue was made contingent on performance of one previously trained instrumental response, whereas a second response had no consequences. We found that rats with lesions of amygdala central nucleus (CeA) showed impaired acquisition of freezing to the cue paired with shock and no evidence for acquisition of aversive properties by the cue that accompanied the omission of expected food. Furthermore, analyses ofArcandHomer1amRNAs after rats were exposed to a two-epoch test procedure that allowed assessment of gene expression produced by two different test stimuli showed that both food-omission and shock-paired cues generated more neuronal activity in CeA than appropriate control cues. However, the number of neurons that were activated by both shock and food-omission cues was not significantly greater than expected by chance. Thus, under these test conditions, different subsets of CeA neurons represented these two aversive states.