bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV‐infected viremic long‐term non‐progressors and controllers display different immunological mechanisms for preserved CD4+cell counts
Authors: Gaardbo J , Ronit A , Hartling H , Thorsteinsson K , Ullum H , Andersen A , Nielsen S
Published: November 2012

Purpose

Most HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term Non Progressors (LTNP) and Viremic Controllers (VC) maintain normal CD4 counts and do not progress in the absence of treatment. While VC are able to control viral replication LTNP are not. Thus, lack of viral replication cannot explain non‐progression in LTNP. Therefore we hypothesized that the immunological mechanism responsible for preserved CD4 counts in LTNP is different from that in VC.

Methods

69 treatment naïve HIV‐infected patients were included in a cross‐sectional study. A total of 14 LTNP (viral load, VL>5000 copies/ml, CD4+ cell count>350 cells/ul, infected>10 years), 30 VC (VL<5000 copies/ml, CD4 count>350 cells/ul), and 25 progressors (PR) (VL>5.000 copies/ml, CD4 count>350 cells/ul) were included. Immune activation (CD4+ and CD8+cells co‐expressing CD38+HLA‐DR+), apoptosis (CD8+CD28‐CD95+), Th17 cells (CD4+CD161+), and regulatory T cells (Tregs, CD4+CD25+CD127lowFoxP3+) were evaluated using flow cytometry. For statistics Kruskal‐Wallis test followed by Mann‐Whitney U test were used. Data are given as medians.

Summary of results

LTNP had higher frequency of activated CD4+ and CD8+cells compared to VC (3.4% vs. 1.6%, P=0.007, 21.7% vs. 12.0%, P=0.051) and similar levels to PR (4.2%, 22.4%, P>0.05). Likewise, LTNP had higher frequency of apoptotic cells compared to VC (63.7% vs. 48.6%, P=0.0408) and similar levels to PR (63.8%, P>0.05). Interestingly, borderline significant trends towards lower Th17/Treg ratio in LTNP compared to VC were found (3.8 vs. 5.5, P=0.068) while ratios in LTNP and PR were similar (4.0, P>0.05).

Conclusion

LTNP displayed high levels of immune activation, apoptotic cells and reduced Th17/Treg ratio compared to VC, while LTNP were similar to PR. Thus, the immunological mechanism responsible for preserved CD4 counts in LTNP is still unclear but seems to be different from that in VC.

image
Progression to AIDS or death in HIV‐infected patients initiating cART with CD4<200 cells/µ L: the role of CD4 and viral load changes during follow‐up
Authors: Ferrer E , Curto J , Esteve A , Miro J , Tural C , Riera S , Segura F , Force L , Casabona J , Podzamczer D
Published: November 2012

Purpose of the study

Our aim was to evaluate factors associated with progression to AIDS/death in HIV‐infected naïve pts initiating cART with low CD4 counts.

Methods

Adult HIV‐infected ARV‐naïve pts with CD4 <200 who initiated NNRTI or PI‐containing regimens between 1998 and 2009, were included. Primary end point was progression to AIDS (a first episode or a new AIDS‐defining condition in pts with prior AIDS) or death. Kaplan‐Meier curves were used to determine progression‐free survival and multivariate Cox regression models were used to identify independent predictive factors of progression to AIDS/death.

Summary of results

We included 1427 patients (80% men, median age 38 years, 25% IDU, 37% AIDS, 20% HCV) between 1998 and 2009. At baseline (BL), median (range) CD4 and viral load (VL) was 77 (1–199) cells/µL and 170,000 (19–8,750,000) copies/mL, respectively. After a median follow‐up 4.6 years, 70% of pts reached CD4>200/µL, 65.2% reached undetectable VL and 268 (19%) pts progressed to AIDS/death during follow‐up. The probability of AIDS/death at 5 years was 76%, 34%, 3% and 3%, in pts with BL CD4<100/VL>5 log and CD4<200/VL detectable during FU, BL CD4<100/ VL>5 log and CD4<200/VL undetectable during FU, BL CD4<100 and/or VL>5 log and CD4>200/VL undetectable during FU and BL CD4>100/ VL<5 log and CD4>200/VL undetectable during FU, respectively. In the multivariate analysis, several variables were associated with AIDS/death: CD4< 200 during FU (HR 10.89, p<0.001), detectable VL during FU (HR 3.49, p<0.001), age>50 years (HR 1.75, p=0.001), prior AIDS (HR 1.71, p<0.001) and BL VL>5 log (HR 1.45, p=0.011). If only pts without prior AIDS (n=895) were analyzed, the variables independently associated with AIDS/death were: CD4<200 during FU (HR 9.90, p<0.001), detectable VL during FU (HR 2.78, p<0.001) and BL VL>5 log (HR 1.62, p=0.016).

Conclusions

In immunosuppressed patients initiating cARV therapy, not reaching CD4>200/µL during FU was the strongest variable associated with progression to AIDS/death. VL at BL and mainly at follow up also played a role in patient outcome.
Long‐term therapy with nevirapine and tropism
Authors: Moling O , Andreis S , Bressan S , Basso M , Monticelli J , Menegotto N , Nicolè S , Scaggiante R , Andreoni M , Palù G , Parisi S
Published: November 2012

Objective

A more potent effect on the residual viraemia was ascribed to nevirapine (NVP) with respect to other antiretroviral drugs; moreover a selection of X4 strains was described in patients (pts) with undetectable viraemia; our aim was to study viro‐immunological parameters and tropism for co‐receptor in pts on a long term successful therapy with NVP.

Methods

14 pts on HAART from 130 months (GL, median value, range 118–156 months) without occurrence of blips, as assessable with the available methods at that time, were retrospectively selected from a single center cohort (Bolzano). Tropism for V3 was determined by population sequencing on blood, and using geno2pheno algorithm; cellular HIV DNA load was analysed by in‐house Real‐Time. A further eighteen months (mo) follow up was then observed. Data were compared with those obtained from a control group of 50 naïve pts (GS), evaluated after a 36‐mo successful therapy (median, range 12–84) with various drug combinations, with median baseline (BL) CD4 of 50/μl, comparable value with the GL cohort.

Results

In 7 pts a R5‐tropic (GLR5, FPR median 84.8%) and in 7 an X4‐tropic strain (GLX4, FPR median 1.1%) was demonstrated. BL data of GLR5 were 46 y old, CD4 54/l, HIV‐RNA 104,000 cps/ml; HAART from 142 mo, with NVP from 125 (one after 70 mo on NVP switched to protease from 57); at follow up CD4 were 679/l, HIV‐DNA 60 cps/106 PBMCs (range<5–252). GLX4 were 46 y, at BL 38 CD4/l, HIV‐RNA 250,000 cps/ml; in HAART from 121 mo, with NVP from 97; at follow up CD4 902/l, HIV‐DNA 60 cps/106 PBMCs (range<5–225). Six out of seven pts of the two groups were on treatment with abacavir+lamivudine (ABC+3TC) and one with tenofovir+emtricitabine. In the subsequent 18 mo four blips were observed (21–71 cps/ml); the backbone was changed to raltegravir in two GLR5 and one GLX4 for convenience. In the 50 GS pts at follow up an X4 strain was found in 50% of 14 efavirenz‐treated, in 16% of 6 NVP, and 63% of 30 protease.

Discussion

In a group of very long‐term treated pts with NVP plus two NRTI (ABC+3TC in 12 out of 14), a tropism for CXCR4 was demonstrated in 50%, without significant differences in the CD4 gain and in the HIV‐DNA load archived in the peripheral blood. With respect to pts on various therapies from a median of 36 mo, the type of archived virus does not seem to have a role on the outcome of a very long therapy, 130 mo, with NVP+ABC+3TC; this therapy does not seem able to select a special tropism in pts.
A systematic literature review examining soluble and cellular biomarkers in HIV patients receiving antiretroviral therapy
Authors: Byrnes M , Travers K , Burns M , Sapra S
Published: November 2012

The use of antiretroviral therapies (ART) for treatment of human immunodeficiency virus type 1 (HIV‐1) has led to more favorable prognoses for infected individuals, including reduced HIV viral load, improved CD4 + T‐cell recovery, and slower disease progression. However, ART‐treated HIV+patients may have increased risk of adverse outcomes associated with chronic inflammation and immune activation. Molecules associated with chronic immune system activation and inflammatory cytokine production may be useful biomarkers of HIV pathogenesis and/or ART outcomes. We systematically identified MEDLINE‐indexed articles published in the past decade investigating the association of several soluble (IL‐6, CRP, MCP‐1, IP‐10, D‐dimer, soluble CD14, and LPS) and cellular (CD28, CD38, HLA‐DR, PD‐1, caspase‐3, IFNγ and IL‐2 ELISpots) biomarkers with clinical outcomes in ART‐treated HIV positive (HIV+) patients. Seventy publications were included, consisting mainly of observational studies of soluble biomarkers. One quartile elevations in baseline IL‐6, CRP, and D‐dimer were associated with increased risk of disease progression or death (ORs 1.8–2.4; p≤0.01) and all‐cause mortality (ORs 4.1–5.3; p≤0.0001); these elevations were also associated with increased rates of IRIS (ORs 1.59–2.07; p≤0.001). Additionally, IL‐6, CRP, and D‐dimer levels were higher in patients who experienced a cardiovascular event than in controls (p≤0.001). The association between soluble biomarkers and quantitative assessments of HIV viral load has not been studied as thoroughly. However, several studies found an association between D‐dimer and viral load. Research is lacking regarding the relationship between CD4 count and soluble biomarkers. Most studies evaluating cellular biomarkers examined their association with HIV viral load and CD4 count, but did not examine clinical outcomes. The most commonly studied cellular biomarkers were the T cell activation markers CD38 and HLA‐DR. Studies suggest that CD4 and CD8 activation were increased in patients with higher HIV viral load, and that CD8 activation was higher in patients with low CD4 counts. In our review, we found that several soluble biomarkers were related to the risk of adverse clinical outcomes in ART‐treated HIV+patients. More data, particularly regarding cell‐associated biomarkers, is required to characterize their association with outcomes of interest, to describe causality, and to document their prognostic importance.
Factors associated with immune status in the diagnosis of HIV infection
Authors: Cardoso S , Figueiredo C , Santos A , Poínhos R , Piñeiro C , Xerinda S , Soares J , Marques R , Serrão R , Sarmento A
Published: November 2012

Introduction

Current guidelines recommend the start of antiretroviral therapy before advanced immunosuppression, which is not always possible. The purpose of this study is to evaluate factors associated with the degree of immunosuppression at the diagnosis of HIV infection.

Methods

We evaluated demographic and epidemiological data of HIV‐infected patients observed at the Department of Infectious Diseases diagnosed between 2006–2011, and analyzed the relationship between these data and the immune status at diagnosis. Statistical analysis was performed using SPSS version 20.0 for Windows.

Results

Data from 600 new patients were analyzed. 584 (97.3%) infected by HIV‐1. 426 (71%) male. Mean age=42 years (SD=14). Risk factor for HIV infection: sexual in 548 patients (91.3%) (22.8% homo/bisexual). 153 (25.5%) patients had AIDS ‐defining illness. Origin of patients: general practitioner ‐ 153 (25.5%), hospitalization in the Department of Infectious Diseases ‐ 110 (18.3%), diagnostic screening after partner's diagnosis ‐ 69 (11.5%), hospital consultation ‐ 68 (11 3%), emergency room ‐ 61 (10.2%), anonymous diagnostic testing center ‐ 46 (7.7%), other hospital inpatient services ‐ 31 (5.2%), hospitalization in another hospital ‐ 30 (5%), attempted blood donation ‐ 15 (2.5%), drug addiction treatment center ‐ 8 (1.3%), pregnancy screening ‐ 3 (0.5%) and patient's own initiative ‐ 6 (1%). The mean CD4+ cell count was 319 cells/cmm (SD=274; range: 2–1416). Women were diagnosed at significantly higher CD4+ cell count levels (p=0.005), as well as younger patients (p<0.001). Homo/bisexual patients had CD4+ cell counts significantly higher than the other groups (p<0.001). There were differences in CD4+ cell count depending on the origin of the patients (p<0.001): patients diagnosed at anonymous diagnostic center, drug addiction treatment center, blood donors, pregnant women and coming on their own initiative, had higher CD4+ cell count levels (p<0.001). Patients admitted in the Department of Infectious Diseases were those with the lower CD4+ cell counts. No relationship was found between CD4+ cell count level and year of diagnosis.

Conclusion

These results indicate the importance of early HIV screening even in individuals without a perceived risk of acquisition of this infection, so they can benefit from antiretroviral treatment before having advanced immunosuppression.
HIV elite controllers as a key to novel strategies in treatment of HIV infection
Authors: Pronin A , Zukova E , Orlova‐Morozova E , Serkov I , Kaminskiy G
Published: November 2012

Purpose of the study

To identify and primarily characterize the elite controllers (EC) in Moscow Regional HIV Living People Cohort (Russia).

Methods

2682 HIV‐1‐positive individuals with A1 (asymptomatic) stage of HIV infection were under regular physician observation continuously for at least 5 years. Verification antibody testing was performed with “New Love Blot” and “Autoblot 2000” (Biorad). Patients underwent scheduled HIV viral load and T‐lymphocyte subpopulation measurement (twice a year) and did not have indications to HAART (viral load less then 5 log10/ml, CD4+ counts more then 500 cells/mm3). HIV viral load was detected by PCR m2000rt Abbott Biosystems analyzer, “RealTime HIV‐1” sets with 20 copies per ml sensitivity) and major subpopulation of T‐lymphocytes were analyzed by flow cytometer BD FACSCount, sets of antibodies ÑD3/CD4/CD8/CD45) [1].

image

Summary of results

Average log10 viral load was defined in each patient for 5‐year period, and the distribution appeared to have a bimodal character (Figure 1). 106 EC were primarily identified as having average viral load less then 1.7 log10 (50) HIV copies/ml.

The incidence of EC appeared to be 3.95% (95% CI: 3.2%; 4.7%) of population with A1 (asymptomatic) disease with no indications to HAART, that corresponds to literary data [2]. Belonging to EC was then proved by laboratory dynamics. In EC 3 types of viral load dynamics were identified: 1) absence of detectable viremia, 2) single spikes, 3) episodic temporary elevation(s) (at mean 500‐900 copies) lasting half a year. All these emphasize the control of virus. In EC 3 types of ÑD4+T‐lymphocyte dynamics were defined: 1) CD4+ elevation (in case beginning from the acute stage of the disease), 2) stable ÑD4+ cells, 3) CD4+ cell depletion with very small velocity. 12 EC had “minimal change disease” defined additionally by the absence or trace appearance of pol 68/66, 52/51, 34/31 antibodies (Table 1) and non‐detectable PCR levels in all measurements. These represent 11.32% (95% CI: 5.17%; 17.47%) from EC and 0.45% (95% CI: 0.19%; 0.71%) from population with A1 (asymptomatic) HIV‐disease.

Env
Env
Env
Gag
Gag
Gag
Gag
Pol
Pol
Pol

Patient number
160
120
41
55
40
24/25
18
68/66
52/51
34/31

1
+
*
+
+
+
+
−
−
−
−

2
+
+
+
+
*
+
−
*
*
+

3
+
*
+
*
‐
*
−
*
*
*

4
+
+
+
+
+
+
−
+
*
+

5
+
+
+
+
−
+
−
+
+
−

6
+
+
+
+
+
+
*
+
+
*

7
+
+
+
+
+
+
*
*
*
+

8
+
*
+
*
‐
*
*
*
−
*

9
+
+
+
+
‐
+
*
−
−
−

10
+
‐
+
*
‐
+
−
−
−
−

11
+
+
+
+
+
+
*
−
−
−

12
+
*
+
+
+
+
−
*
−
−

Signs of antibodies: +, presence; *, traces; −, absence

Conclusions

Among EC patients with “minimal change disease” were identified. They may represent: (i) primarily persistent HIV infection (with reduced productive cycle), (ii) low dose (localized) HIV‐infection, (iii) rare successful immune‐mediated elimination of HIV that could be the model for novel elimination strategies.
Test for CCR5 tropism and treatment with maraviroc in Sicily: an observational retrospective multicentre study
Authors: Celesia B , Gussio M , Franco A , Scifo G , Prestileo T , Di Lorenzo F , La Rosa R , Nigro L , Colomba C , Ingrassia D , Galvagna S , Mannino G , Storaci N , Migliore S , Salvo A , Todaro G , Portelli V , Sturniolo G , Davi’ A , Bruno S , Bellissima P , Guarneri L , Palermo F , Zagami A , Nunnari G , Cosentino S
Published: November 2012

Purpose of the study

Maraviroc (MVC) is the first CCR5 inhibitor licensed for clinical use. A pre‐treatment test is mandatory to identify R5 tropic patients. Aim of this study is to detect indications and results of tropism test and to evaluate efficacy and tolerability of MVC‐based regimen.

Methods

An observational retrospective multicentre study was performed in Sicily in 15 Infectious Diseases Units. Clinical records of 213 screened for tropism HIV+ subjects were reviewed for age, sex, risk, clinical stage (CDC, CD4 cell count, HIV RNA viral load), therapeutic line, indication and result of test for tropism; within subjects treated with MVC, HIV RNA, CD4 cell count and metabolic parameters trend and adverse events were analysed.

Summary of results

Median age 44 (IQR 30–50) years, 67.1% males; 46.3% heterosexuals, 28.6% MSMs, 21.4% IVDUs; 23.7% CDC A, 32.1% CDC B, 44.2% CDC C; median CD4 was 217 (IQR 121–374) cells/µl and mean of HIV RNA was 4.72 (Cl 95% 4.07–4.67) log10 copies/ml; median therapeutic line was 4 (IQR 2–7). 80.8% were submitted to Trofile™ test, 19.2% to genotypic test, 75.5% after a therapeutic failure. 56.8% of subjects screened were R5, 7.5% X4, 21.6% DM, 14% undefined. All X4 patients were tested after a therapeutic failure; patients screened for toxicity were more frequently R5 (75%) (p<0.01). 76 (35.7%) multi‐experienced (at baseline 8% HIV RNA<50 copies/ml, median CD4 cell count 219 (IQR 124–345) cells/µl) subjects were treated with MVC plus an optimized background treatment: MVC was associated in 74% of cases with a protease inhibitors (56% darunavir/ritonavir), in 42% with raltegravir, in 56% with a NUC‐sparing regimen. After 12 months of treatment 56.8% (ITT analysis) and 61.7% (AT) of patients had HIV RNA<50 copies/ml; median CD4 cell count was 387 (IQR 222–455) cells/µl. After 24 months 64.8% (ITT) 80% (AT) had HIV‐RNA<50 copies/ml. Median CD4 cell count was 381 (IQR 218.515) cells/µl with a median increase of 168 (IQR 54–274) cells/µl. At 24 months median value of total and HDL cholesterol and triglycerides were within the normal range. 7 patients stopped the treatment: 2 died, 1 adverse event, 4 virological failure.

Conclusions

Although the test has been proposed to patients with long treatment history and failure, only 3/5 of R5 tropic patients were treated with MVC. An high number of multi‐experienced subjects treated with a MVC‐based regimen obtained HIV RNA<50 copies/ml and a satisfactory increase of CD4 cell count.
Recent Advances in the Construction of Polycyclic Compounds by Palladium‐Catalyzed Atom‐Economical Cascade Reactions
Authors: Ohno Hiroaki
Published: November 2012

The development of cascade reactions that realize step‐economical syntheses of complex compounds by multiple bond formation is one of the most attractive subjects in modern organic chemistry. Another important challenge in this area is to improve atom economy by minimizing waste product formation and avoiding prefunctionalization of the substrates. Because palladium catalysts are well known to promote a variety of atom‐economical elementary reactions, many useful palladium‐catalyzed cascade reactions have been developed. In this Focus Review, recent advances in palladium‐catalyzed atom‐economical cascade reactions for the construction of polycyclic compounds are summarized. Especially, the cascade reactions reported in the past decade, which include carbopalladation onto alkyne/alkene/allenes, nucleophilic reaction, and direct arylation/CH bond functionalization, are highlighted.
Synergetic Effects of In Situ Formed CaH2 and LiBH4 on Hydrogen Storage Properties of the Li–Mg–N–H System
Authors: Li Bo , Liu Yongfeng , Gu Jian , Gao Mingxia , Pan Hongge
Published: November 2012

Hydrogen storage properties and mechanisms of the Ca(BH4)2‐doped Mg(NH2)2–2 LiH system are systematically investigated. It is found that a metathesis reaction between Ca(BH4)2 and LiH readily occurs to yield CaH2 and LiBH4 during ball milling. The Mg(NH2)2–2 LiH–0.1 Ca(BH4)2 composite exhibits optimal hydrogen storage properties as it can reversibly store more than 4.5 wt % of H2 with an onset temperature of about 90 °C for dehydrogenation and 60 °C for rehydrogenation. Isothermal measurements show that approximately 4.0 wt % of H2 is rapidly desorbed from the Mg(NH2)2–2 LiH–0.1 Ca(BH4)2 composite within 100 minutes at 140 °C, and rehydrogenation can be completed within 140 minutes at 105 °C and 100 bar H2. In comparison with the pristine sample, the apparent activation energy and the reaction enthalpy change for dehydrogenation of the Mg(NH2)2–2 LiH–0.1 Ca(BH4)2 composite are decreased by about 16.5 % and 28.1 %, respectively, and thus are responsible for the lower operating temperature and the faster dehydrogenation/hydrogenation kinetics. The fact that the hydrogen storage performances of the Ca(BH4)2‐doped sample are superior to the individually CaH2‐ or LiBH4‐doped samples suggests that the in situ formed CaH2 and LiBH4 provide a synergetic effect on improving the hydrogen storage properties of the Mg(NH2)2–2 LiH system.
Biocatalytic reduction of short‐chain carboxylic acids into their corresponding alcohols with syngas fermentation
Authors: Perez Jose M. , Richter Hanno , Loftus Sarah E. , Angenent Largus T.
Published: November 2012

Short‐chain carboxylic acids generated by various mixed‐ or pure‐culture fermentation processes have been considered valuable precursors for production of bioalcohols. While conversion of carboxylic acids into alcohols is routinely performed with catalytic hydrogenation or with strong chemical reducing agents, here, a biological conversion route was explored. The potential of carboxydotrophic bacteria, such as Clostridium ljungdahlii and Clostridium ragsdalei, as biocatalysts for conversion of short‐chain carboxylic acids into alcohols, using syngas as a source of electrons and energy is demonstrated. Acetic acid, propionic acid, n‐butyric acid, isobutyric acid, n‐valeric acid, and n‐caproic acid were converted into their corresponding alcohols. Furthermore, biomass yields and fermentation stoichiometry from the experimental data were modeled to determine how much metabolic energy C. ljungdahlii generated during syngas fermentation. An ATP yield of 0.4–0.5 mol of ATP per mol CO consumed was calculated in the presence of hydrogen. The ratio of protons pumped across the cell membrane versus electrons transferred from ferredoxin to NAD+ via the Rnf complex is suggested to be 1.0. Based on these results, we provide suggestions how n‐butyric acid to n‐butanol conversion via syngas fermentation can be further improved. Biotechnol. Bioeng. 2013; 110: 1066–1077. © 2012 Wiley Periodicals, Inc.
Risk of metachronous breast cancer after BRCA mutation–associated ovarian cancer
Authors: Domchek Susan M. , Jhaveri Komal , Patil Sujata , Stopfer Jill E. , Hudis Clifford , Powers Jacquelyn , Stadler Zsofia , Goldstein Laura , Kauff Noah , Khasraw Mustafa , Offit Kenneth , Nathanson Katherine L. , Robson Mark
Published: November 2012

BACKGROUND:

This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA‐OC).

METHODS:

The Memorial Sloan‐Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA‐OC who participated in genetic testing and follow‐up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA‐OC. Overall survival (OS) and BC‐free survival (BCFS) were determined by the Kaplan‐Meier method; patients were censored at the time of last follow‐up.

RESULTS:

A total of 164 patients had BRCA‐OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01‐55 years]). Median follow‐up from OC for those not developing BC was 5.8 years (0.25‐55.6 years). There were 46 deaths, but none were due to BC. The 5‐ and 10‐year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5‐ and 10‐year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA‐OC. In this pseudo‐incident subset, 5‐ and 10‐ year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5‐ and 10‐year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively.

CONCLUSIONS:

OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA‐OC. Cancer 2013. © 2012 American Cancer Society.
Basal bodies exhibit polarized positioning in zebrafish cone photoreceptors
Authors: Ramsey Michelle , Perkins Brian D.
Published: November 2012

The asymmetric positioning of basal bodies, and therefore cilia, is often critical for proper cilia function. This planar polarity is critical for motile cilia function but has not been extensively investigated for nonmotile cilia or for sensory cilia such as vertebrate photoreceptors. Zebrafish photoreceptors form an organized mosaic ideal for investigating cilia positioning. We report that, in the adult retina, the basal bodies of red‐, green‐, and blue‐sensitive cone photoreceptors localized asymmetrically on the cell edge nearest the optic nerve. In contrast, no patterning was seen in the basal bodies of ultraviolet‐sensitive cones or in rod photoreceptors. The asymmetric localization of basal bodies was consistent in all regions of the adult retina. Basal body patterning was unaffected in the cones of the XOPS‐mCFP transgenic line, which lacks rod photoreceptors. Finally, the adult pattern was not seen in 7‐days‐postfertilization (dpf) larvae; basal bodies were randomly distributed in all the photoreceptor subtypes. These results establish the asymmetrical localization of basal bodies in red‐, green‐, and blue‐sensitive cones in adult zebrafish retinas but not in larvae. This pattern suggests an active cellular mechanism regulated the positioning of basal bodies after the transition to the adult mosaic and that rods do not seem to be necessary for the patterning of cone basal bodies. J. Comp. Neurol. 521:1803–1816, 2013. © 2012 Wiley Periodicals, Inc.
Designed Synthesis of Functionalized Two‐Dimensional Metal–Organic Frameworks with Preferential CO2 Capture
Authors: Yan Qiuju , Lin Yichao , Wu Pengyan , Zhao Li , Cao Lujie , Peng Luming , Kong Chunlong , Chen Liang
Published: November 2012

In metal–organic framework (MOF) chemistry, polar functionalities greatly affect the gas adsorption properties. However, synthesis of MOFs with desired functionality is very challenging because many chemical functionalities cannot be achieved under the conditions for MOF assembly. Herein, a facile synthesis of new functionalized two‐dimensional MOFs with preferential CO2 capture is presented, which uses two successive synthesis steps: 1) rational design and template‐free synthesis of the parent MOF with designated pendant amino groups and 2) postsynthetic modification of the active amino groups with acetic acid and trimesoyl chloride functionalities. The only variation in structure arises from the functional groups of these materials. Experimental results demonstrate that the three 2D layered MOFs have remarkable thermal stability and moisture resistance, which are particularly advantageous for practical CO2 capture. Although their surface areas are moderate (270–340 m2 g−1), they still have excellent CO2 adsorption capacity (up to 2.9 mmol g−1 at 1 bar and 273 K) comparable to that of previously reported MOFs with much higher surface areas. Based on first‐principles calculations, it is shown that the acidic carbonyl functionalities in addition to the amino groups are also favorable to bind CO2 molecules. The adsorption sites generated from polar functionalities are key factors leading to high CO2 uptake.
Cytological features of clear cell thyroid tumors, including a papillary thyroid carcinoma with prominent hobnail features
Authors: Yang Grace C. H. , Fried Karen , Scognamiglio Theresa
Published: November 2012

Primary thyroid tumors with extensive clear cell changes are extremely rare. More than 10,000 ultrasound‐guided thyroid fine needle aspirations examined over a period of 17 years by the first author, only one of the 530 (<0.2%) papillary thyroid carcinomas (PTCs) and three of the 42 (7.1%) follicular thyroid carcinomas (FTCs) had extensive cytoplasmic clearing. Thyroidectomies were performed for these cases at four different hospitals in New York City. Final pathology was available for review in each of the four cases. Histology showed a 1.5‐cm PTC with prominent hobnail features and clear cell change in a 31‐year‐old woman, a 4.3‐cm FTC without angioinvasion in a 31‐year‐old woman, a 4.5‐cm angioinvasive FTC in a 45‐year‐old man, and a 2‐cm FTC with extensive angioinvasion in a 41‐year‐old woman with McCune–Albright syndrome (previously published). On ultrasound, the FTCs were solid circumscribed nodules and the PTC had an irregular margin. In these cases, the etiology for the cytoplasmic clearing included accumulation of glycogen in the PTC, accumulation of vesicles in two of the FTCs, and accumulation of lipid droplets in a FTC with extensive angioinvasion. Review of the cytologic literature showed 17 cases of follicular‐derived thyroid tumors with extensive clear cell change. To the best of our knowledge, this is the first cytologic report of PTC with hobnail features and extensive clear cell change. Diagn. Cytopathol. 2013;41:757–761. © 2012 Wiley Periodicals, Inc.
Toxicity evaluation of two typical surfactants to Dunaliella bardawil, an environmentally tolerant alga
Authors: Qv Xiao-Ying , Jiang Jian-Guo
Published: November 2012

Sodium dodecyl benzene sulfonate (SDBS) and cetyl trimethyl ammonium chloride (CTAC) are two kinds of surfactants widely applied in various industries. The tremendous direct discharge of these surfactants into natural waters has posed a significant threat to ecosystems. Dunaliella bardawil was employed in the present research to test the toxic effects of SDBS, CTAC, and their mixture on cell growth, cellular morphology, β-carotene accumulation, and enzymatic activities of superoxide dismutase (SOD) and catalase (CAT). The results showed that SDBS at 200, 550, 900, 1,350, 1,800, and 2,400 mg/L and CTAC at 0.4, 0.7, 1.0, 1.3, 2.8, and 3.5 mg/L inhibited algal growth and β-carotene accumulation, both of which declined and then increased. In particular, CTAC (median inhibitory concentration at 10 days [IC50]10 d = 2.8 ± 1.49 mg/L) was more hazardous than SDBS (IC5010 d = 2,044 ± 637.3 mg/L). The additive index (AI) calculated from carotene content data was (−4.10, −1.67) < 0, indicating an antagonistic effect between SDBS and CTAC. Algae cultivated at level 6 of the binary system showed hormesis due to the mitigated toxicity; SDBS at 2,400 mg/L, CTAC at 3.5 mg/L, and combined surfactants at level 6 exerted lethal effects on D. bardawil. Both SOD and CAT activities showed similar associations with varied concentrations of surfactants: SOD was significantly promoted by 550 to 1,800 mg/L SDBS, 0.7 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4; CAT was clearly promoted by 900 mg/L SDBS, 0.4 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4. Environ. Toxicol. Chem. 2013;32:426–433. © 2012 SETAC
Effect of geometrical structure on the in vivo quality change of a three‐dimensionally perforated porous bone cell scaffold made of apatite/collagen composite
Authors: Otsuka Makoto , Nakagawa Hidenori , Otsuka Kuniko , Ito Atsuo , Higuchi William I.
Published: November 2012

Biodegradable artificial bone blocks with interconnective pores were prepared using a self‐setting apatite/collagen composite cement as a cell scaffold for bone regenerative medicine. The biological behavior of the blocks was tested in rats, and the change in their properties after implantation was measured. One cubic block [10 mm X10 mm X10 mm; porous composite (PC)] was obtained from apatite cement (apatite/collagen cement; 80% of apatite:20% of collagen) with 60 interconnecting holes, 500 um in diameter. The other blocks (NC and NN) without holes were obtained from the apatite/collagen and plain apatite cements, respectively. All blocks were implanted in the rats for 56 days. Changes in the amount and density (block mineral mass and block mineral density) of the blocks were evaluated based on dual energy X‐ray absorptiometry images, and the order of biodegradation was PC < NC < NN. After implantation, the blocks were removed, and subjected to an X‐ray diffraction (XRD) analysis, Fourier‐transformed infrared (FT‐IR) spectroscopy and thermogravimetry (TG). The XRD peaks of all blocks increased significantly. TG revealed that the amount of carbonated apatite also increased with time. However, the organic component of PC depended on the implantation period, consistent with the FT‐IR results. Because PC had interconnective macro‐ and micropores in the apatite/collagen matrices, the results indicated that soft tissue penetrated the block carbonated apatite was generated, bone remodeling was accelerated in the implant. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.
Stiffness‐ and wettability‐dependent myoblast cell compatibility of transparent poly(vinyl alcohol) hydrogels
Authors: Gupta Siddhi , T Greeshma , Basu Bikramjit , Goswami Sudipta , Sinha Arvind
Published: November 2012

This study reports the in vitro compatibility of muscle cells (C2C12 mouse myoblast cell line) with the transparent poly(vinyl alcohol) (PVA) hydrogels and the results are explained on the basis of surface wettability, crystallinity, and nanoscale elastic stiffness property. Nanoindentation was carried out with a maximum load of 100 μN for all the hydrogel compositions and the properties such as elastic stiffness, hardness and total work done during indentation were computed. The difference in cell viability as well as adhesion of cultured myoblast cells on the investigated hydrogel substrates were discussed in reference to the difference in the nanoscale elastic properties, crystallinity, and surface wettability. An important result has been that both elastic stiffness and surface wettability synergistically influence myoblast viability/adhesion on PVA hydrogels. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.
Biophysical Study on the Interaction of Ceftriaxone Sodium with Bovine Serum Albumin Using Spectroscopic Methods
Authors: Pan Jiongwei , Ye Zaiting , Cai Xiaoping , Wang Liangxing , Cao Zhuo
Published: November 2012

The interaction of ceftriaxone sodium (CS), a cephalosporin antibiotic, with the major transport protein, bovine serum albumin (BSA), was investigated using different spectroscopic techniques such as fluorescence, circular dichroism (CD), and UV–vis spectroscopy. Values of binding parameters for BSA–CS interaction in terms of binding constant and number of binding sides were found to be 9.00 × 103, 3.24 × 103, and 2.30 × 103 M−1 at 281, 301, and 321 K, respectively. Thermodynamic analysis of the binding data obtained at different temperatures showed that the binding process was spontaneous and was primarily mediated by van der Waals force or hydrogen bonding. CS binding to BSA caused secondary structural alterations in the protein as revealed by CD results. The distance between CS and Trp of BSA was determined as 3.23 nm according to the Förster resonance energy transfer theory. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:487‐492, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21446
Simultaneous removal of carbon, nitrogen and phosphorus in a multi‐zone wastewater treatment system
Authors: Alimahmoodi Mahmood , Yerushalmi Laleh , Mulligan Catherine N.
Published: November 2012

Background

The simultaneous removal of carbon, nitrogen and phosphorus under variable operating conditions during the start‐up period of a new multi‐environment hybrid wastewater treatment technology called BioCAST is reported in this paper. The presence of both suspended‐growth and immobilized microorganisms, as well as the continuous circulation of mixed liquor between the three zones of aerobic, microaerophilic and anoxic, supported high removal efficiencies of organic and inorganic contaminants.

Results

The removal efficiencies of carbon, nitrogen and phosphorus reached 99.3%, 98.0% and 92.3%, respectively, under varying organic loading rates in the range 0.4–3.0 kg m‐3 d‐1, and nitrogen and phosphorus loading rates of 0.03–0.14 kg m‐3 d‐1 and 0.008–0.028 kg m‐3 d‐1, respectively. Phosphorus removal increased steadily with the increase of nitrogen loading rate, producing a final effluent concentration of 2.9 mg L‐1. Low sludge generation was obtained along with a low biomass yield of 11.5%.

Conclusions

The start‐up period of the BioCAST system demonstrated its potential for simultaneous removal of organic material, as well as nitrogen and phosphorus. Phosphorus removal demonstrated a strong dependence on nitrogen loading rate. Moreover, theoretical analysis of the liquid flow and energy balances in different zones of the treatment system showed that the pressure difference across the air diffuser is the governing force for the flow of liquid towards the aerobic zone and the controlling factor for the continuous circulation of mixed liquor among various zones. © 2012 Society of Chemical Industry
The disulfide bond of an RGD4C motif inserted within the Hi loop of the adenovirus type 5 fiber protein is critical for retargeting to αv‐integrins
Authors: Majhen Dragomira , Richardson Jennifer , Vukelić Bojana , Dodig Ivana , Cindrić Mario , Benihoud Karim , Ambriović‐Ristov Andreja
Published: November 2012

Background

The αv‐integrin binding motif RGD4C (CDCRGDCFC) has been used extensively to circumvent inefficient adenovirus type 5 (Ad5) transduction of cells expressing low levels of the coxsackie and adenovirus receptor. However, until now, it has been unclear whether disulfide bonds in the RGD4C motif influence the retargeting potential of RGD4C‐modified Ad5.

Methods

Replication deficient Ad5 bearing wild‐type fiber (Ad5wt) or RGD4G, RGD4C and RGD2C2G insertions within the HI loop of the fiber protein (Ad5RGD4G, Ad5RGD4C and Ad5RGD2C2G, respectively) were used to transduce a panel of cancer cell lines, with or without previous treatment of these Ad5s with the reducing agent dithiothreitol (DTT). In parallel, native and DTT‐treated fiber proteins isolated from purified Ad5RGD4C were compared by mass spectrometry.

Results

Ad5RGD4C transduced all studied cell lines much more efficiently than Ad5wt, whereas Ad5RGD4G transduced cells only slightly more efficiently than Ad5wt. DTT treatment had no effect on cell transduction by wild‐type Ad5wt and Ad5RGD4G but abolished the increased transduction efficacy of Ad5RGD4C in a dose‐dependent manner. The mass spectra of native and DTT‐reduced tryptic digests of the Ad5RGD4C fiber protein are consistent with the presence of a C547–C549 linkage in the C547DC549RGDC553FC555 motif. Finally, the high transduction efficacy of Ad5RGD4C is conserved in Ad5RGD2C2G.

Conclusions

We provide genetic and biochemical data strongly suggesting that cysteines C547 and C549 from the C547DC549RGDC553FC555 motif inserted in the HI loop of the Ad5 fiber form a single disulfide bond, with this disulfide bond being crucial for Ad5RGD4C retargeting to av‐integrins. Copyright © 2012 John Wiley & Sons, Ltd.
From Wald to Savage: Homo Economicus Becomes a Bayesian Statistician
Authors: Giocoli Nicola
Published: November 2012

Bayesian rationality is the paradigm of rational behavior in neoclassical economics. An economic agent is deemed rational when she maximizes her subjective expected utility and consistently revises her beliefs according to Bayes's rule. The paper raises the question of how, when and why this characterization of rationality came to be endorsed by mainstream economists. Though no definitive answer is provided, it is argued that the question is of great historiographic importance. The story begins with Abraham Wald's behaviorist approach to statistics and culminates with Leonard J. Savage's elaboration of subjective expected utility theory in his 1954 classic The Foundations of Statistics. The latter's acknowledged fiasco to achieve a reinterpretation of traditional inference techniques along subjectivist and behaviorist lines raises the puzzle of how a failed project in statistics could turn into such a big success in economics. Possible answers call into play the emphasis on consistency requirements in neoclassical theory and the impact of the postwar transformation of U.S. business schools.
A stress MRI of the shoulder for evaluation of ligamentous stabilizers in acute and chronic acromioclavicular joint instabilities
Authors: Izadpanah Kaywan , Winterer Jan , Vicari Marco , Jaeger Martin , Maier Dirk , Eisebraun Leonie , Ute Will Jutta , Kotter Elmar , Langer Mathias , Südkamp Norbert P. , Hennig Jürgen , Weigel Mathias
Published: November 2012

Purpose:

To show the feasibility of a stress magnetic resonance imaging (MRI) as a new method for simultaneous evaluation of the morphology and the functional integrity of the acromioclavicular joint (ACJ) ligamentous stabilizers.

Materials and Methods:

MRI of four volunteers, 10 patients with acute, and six with chronic ACJ injuries was performed using a 0.25 T open MRI scanner. A 2D‐proton‐density and a 3D‐gradient‐echo sequence at rest and under 6.5 kg shoulder traction were performed. Comparative measurements of the coracoclavicular and the acromioclavicular distance were performed. Additionally, the conoid and trapezoid ligament lengths were measured with multiplanar reconstructions.

Results:

MRI at rest correctly identified tears of the coracoclavicular and the acromioclavicular ligaments in eight patients suffering acute ACJ injuries. Stress application helped to distinguish between partial and complete coracoclavicular ligament tears in two cases. Insufficiency of the ACJ ligaments was present in all acute and chronic ACJ injuries. Stress application in chronic ACJ ligaments revealed isolated insufficiency of the conoid ligament in three cases and of the trapezoid ligament in one case. Combined insufficiency was present in two cases.

Conclusion:

Stress MRI facilitates simultaneous acquisition of morphologic and functional information of the ACJ stabilizers. In acute ACJ injuries it helps to distinguish between partial and complete ligament tears. In chronic ACJ injuries it provides functional information of the ligament regrinds. J. Magn. Reson. Imaging 2013;37:1486–1492. © 2012 Wiley Periodicals, Inc.
Targeted biopsy based on ADC map in the detection and localization of prostate cancer: A feasibility study
Authors: Watanabe Yuji , Nagayama Masako , Araki Tohru , Terai Akito , Okumura Akira , Amoh Yoshiki , Ishimori Takayoshi , Nakashita Satoru , Dodo Yoshihiro
Published: November 2012

Purpose:

To investigate the feasibility of targeted biopsy based on an apparent diffusion coefficient (ADC) map in the detection and localization of prostate cancer.

Materials and Methods:

This study included 288 consecutive patients with high or increasing serum prostate‐specific antigen (PSA) levels who underwent prostatic magnetic resonance imaging (MRI) examination with an ADC map. Four core‐targeted biopsies of low ADC lesions were performed under transrectal‐ultrasound guidance with reference to ADC map. The positive predictive values (PPVs) of low ADC lesions were calculated and compared for the peripheral zone (PZ), transition zone (TZ), and anterior portion, respectively. Comparisons of ADC values and sizes between malignant and nonmalignant lesions were also performed.

Results:

A total of 313 low ADC lesions were detected in 195 patients and sampled by targeted biopsies. The PPVs were 55.3% (95% confidence interval [CI]: 50–61) in total, 61.0% (95% CI: 53–69) for PZ, 50.6% (95% CI: 43–58) for TZ, and 90.9% (95% CI: 81–100) for the anterior portion. The most common nonmalignant pathology of low ADC lesions was hyperplasia, followed by chronic prostatitis. There were significant differences in ADC values and sizes between malignant and nonmalignant low ADC lesions.

Conclusion:

Targeted biopsies could be capable of detecting cancers well wherever they may be in the prostate, although the PPVs varied depending on the location of low ADC lesions. J. Magn. Reson. Imaging 2013;37:1168–1177. © 2012 Wiley Periodicals, Inc.
A comparative assessment of monthly mean wind speed products over the global ocean
Authors: Kent Elizabeth C. , Fangohr Susanne , Berry David I.
Published: November 2012

The accurate estimation of marine wind speed is important for climate and air–sea interaction applications. There are many datasets of monthly mean wind speeds available based either on in situ measurements, satellite retrievals, atmospheric reanalysis assimilating both in situ and satellite data and blended datasets combining some or all of these other data sources. Twelve different monthly mean wind speed datasets are compared for the period from 1987 to 2009. The results suggest that we cannot presently be confident that the mean wind speed over the ocean is known to the accuracy required for the calculation of air–sea heat fluxes. Comparisons are complicated by different representations of wind speed being presented in different datasets. The in situ and reanalysis datasets present stability‐dependent, earth‐relative, wind speeds adjusted to a reference level of 10 m. The satellite and blended datasets present neutral equivalent, surface‐relative, speeds adjusted to a reference level of 10 m. Differences between these estimates depend on atmospheric stability and ocean currents and can be greater than the required accuracy target. The adjustment for stability is itself uncertain but it is shown that these uncertainties are likely to be smaller than biases caused when the effects of stability are neglected. Further differences among the datasets are identified. Biases are caused by unidentified rain in Ku‐band scatterometer‐derived wind speeds and by atmospheric effects on passive microwave wind retrievals. When satellite observations affected by rain are removed a fair‐weather bias remains. Some datasets are biased low in coastal regions by the effects of lower wind speeds over land in atmospheric models affecting wind speeds near the coast. All these uncertainties combine to give a wide range of estimates of monthly mean wind speed for the chosen datasets with uncertainty in mean values, spatial patterns and changes over time.