bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and type of drug‐drug interactions involving antiretrovirals in patients attending a specialist outpatient clinic in Kampala, Uganda
Authors: Seden K , Merry C , Lamorde M , Byakika P , Laker E , Back D , Parkes‐Ratanshi R , Khoo S
Published: November 2012

Scale‐up of HIV services in countries such as Uganda has resulted in a rapid increase in facilities offering antiretrovirals (ARVs) and an increase in healthcare workers trained to deliver care. Consequently, evaluating medication safety is increasingly important in these settings. Data from developed countries suggest that drug‐drug interactions (DDIs) involving ARVs are common, occurring at rates of 14–58%. Few data are available from low resource settings, however a study of 996 Kenyan patients found that 33.5% were at risk of clinically significant DDIs. We evaluated the prevalence and type of ARV DDIs and the patients most at risk in an African outpatient setting. A random sample of patients taking current ARVs and accessing care at the Infectious Diseases Institute, Makerere University, Kampala was selected from the clinic database. The most recent prescription for each patient was screened for DDIs using www.hiv‐druginteractions.org. Clinical significance of DDIs was assessed by two of us using a previously developed technique evaluating: likelihood of interaction, therapeutic index of affected drug and severity of potential adverse effect. From 1000 consecutive patients 99.6% were taking≥1 co‐medication alongside their ARV regimen (mean 1.89). 24.5% had≥1 potential DDI, with a total of 335 DDIs observed. Of these, 255 DDIs were considered clinically significant, affecting 18.8% of patients. Only 0.3% of DDIs involved a contraindicated combination. There was a higher rate of potential DDIs observed in patients taking TB treatment (p=0.0047), who were WHO stage 3 or 4 (p=0.001), or patients taking ≥2 co‐medications alongside ARVs (p<0.0001) (Fishers exact test). Patient age, gender, CD4 count and weight did not affect risk for DDIs. Co‐medications commonly associated with potential DDIs were antibiotics (6.2% of 1000 patients), anthelminthics (4.6%) and antifungals (3.5%). Potential DDIs involving ARVs occur at similar rates in resource‐limited settings and developed countries. Drug combinations which most frequently cause DDIs, however, differ between settings; for example CNS and cardiovascular drugs in the UK and anti‐infectives in Kenya and Uganda. Development of tools which are relevant to particular settings are essential for recognition of DDIs. Initiatives such as incorporation of WHO essential medicines into the Liverpool DDI database and the AIDS Treatment Information Centre in Uganda are important in achieving this.
Development and validation of a LC‐MS/MS assay to quantify intracellular tenofovir‐diphosphate (TFV‐DP) and emtricitabine‐triphosphate (FTC‐TP)
Authors: Watson V , Else L , Tjia J , Khoo S , Back D
Published: November 2012

Introduction

Combination antiretroviral therapy has been associated with dramatic reductions in morbidity and mortality in HIV‐infected patients. The key to successful HIV treatment is strict adherence to the prescribed regimen. The combination of tenofovir, emtricitabine and efavirenz co‐formulated in a single tablet (Atripla) provides a ‘one tablet once a day’ regimen, making adherence easier for patients. Tenofovir and emtricitabine are converted intracellularly to active phosphate anabolites. Therefore, knowledge of intracellular pharmacokinetics should aid understanding of the virological response and toxicity of these agents. This intracellular methodology has been developed and applied to clinical trial samples.

Method

Peripheral blood mononuclear cells (PBMC) were isolated from whole blood by gradient centrifugation using ficoll. PBMC were counted and lysed (70% MeOH) giving a final cell density of 2×106 cells/ml. Lysate was centrifuged, supernatant (intracellular matrix), was spiked with drug anabolites at various concentrations to produce standard curves and quality controls (QC). Samples were extracted by protein precipitation (acetonitrile), evaporated to dryness, internal standard (IS) added, and reconstituted in 5 mM ammonuim formate. Weak anion exchange chromatography with an optimised step‐wise gradient, interfaced with a triple quadrupole mass spectrometer operated in SRM with positive ionisation mode was used for quantification.

Results

Analytes eluted within 12 minutes run‐time with adequate separation. Calibration curves were validated over the following range TFV‐DP = 0.35–10.91 ng/mL, FTC‐TP = 0.38–103.17 ng/mL (r2 values > 0.99; linear 1/x). The lower limit of quantification was < 20%, signal to noise was > 5% and carryover < 0.1%. The precision (relative standard deviation,% RSD) of the assays as determined from analysis of quality control samples was; TFV‐DP = 6.3–11% and FTC‐TP = 6–18.6%, and accuracy was TFV‐DP = 97.5–100.8%, FTC‐TP = 98–100.3%.

Conclusions

A direct, highly sensitive intracellular anabolite assay has been developed and validated which elutes analytes and IS rapidly and has been applied to patient samples from a pivotal trial the results of which are crucial in our understanding of antiretroviral drug ‘forgiveness’.
GAM analysis of the relationship between DRV PK and pharmacodynamics following DRV/r 800/100 mg qd in the phase III trials ARTEMIS and ODIN
Authors: Kakuda T , Tomaka F , Van De Casteele T , Vangeneugden T
Published: November 2012

Background

Once‐daily (qd) darunavir/ritonavir (DRV/r) 800/100mg was evaluated in two randomised and controlled Phase III trials, showing high response rates in treatment‐naïve (ARTEMIS; TMC114‐C211) and treatment‐experienced patients with no DRV resistance‐associated mutations (ODIN; TMC114‐C229). Treatment interruptions, medical co‐morbidities, drug‐drug interactions, and challenges to adherence can decrease exposures and result in suboptimal DRV coverage. Consequences of suboptimal dosing could be detrimental to patients, namely the selection of drug‐resistant HIV strains. No relevant relationship between DRV area under the plasma concentration‐time curve over 24 hours (AUC24h) or plasma trough concentrations (C0h) and efficacy or safety were observed in ARTEMIS or ODIN [1,2]. The PK/PD analysis for efficacy has been extended using a generalized additive model (GAM).

Methods

A univariate GAM analysis was undertaken for each trial, exploring the relationship between DRV C0h and virological response at Week 48. A quadratic spline (2 degrees of freedom) was selected, based on the Akaike information criterion value. Additionally, a linear logistic regression model was applied to model virologic response as a function of DRV C0h.

Results

In ARTEMIS, there was no relationship between DRV C0h and the observed virological response or virological response predicated in the GAM analysis, with no indication that lower values within the observed DRV C0h range are associated with lower predicted virological response (Figure A). The mean predicted virological response was 92.8% in the total population (N = 304). A 50% reduction in DRV C0h would result in a similar predicted mean virological response (93.9%). In ODIN, for values of DRV C0h up to 3000ng/mL, there was no clear relationship between DRV C0h and observed virological response. The GAM analysis showed a counter‐intuitive inverse relationship between DRV C0h and predicted virological response (Figure B). The mean predicted virological response was 80.6% in the total population (N = 252). For each trial, similar results to GAM were obtained when a linear logistic regression model was applied.

Conclusion

In patients who received 800/100mg qd DRV/r in the ARTEMIS and ODIN trials, a reduction in DRV C0h of up to 50% is not associated with a reduced virologic response at Week 48, as predicted by both the GAM and logistic regression model. DRV/r doses below 800/100mg qd should not be administered.

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Etravirine concentrations in seminal plasma in HIV‐infected patients
Authors: Tiraboschi J , Niubo J , Ferrer E , Barrera‐Castillo G , Rozas N , Maso‐Serra M , Podzamczer D
Published: November 2012

Purpose of the study

Good penetration of antiretroviral drugs to the seminal plasma may be associated with a decrease in viral replication and play an important role in the prevention of sexual transmission of HIV. We present data from a series of HIV‐infected ARV‐experienced patients receiving etravirine‐containing regimens, in whom etravirine concentrations and viral loads were determined in blood plasma and seminal plasma. The objective was to determine etravirine concentrations and HIV‐1 viral load (VL) in blood plasma (BP) and seminal plasma (SP) of HIV‐infected patients.

Methods

Ten HIV‐1 adult antiretroviral‐experienced patients receiving an etravirine‐containing regimen for at least 1 month were enrolled. Semen and blood samples were both collected around 12–24 h after the last etravirine dose, depending on once‐daily or twice‐daily dosing, respectively. HPLC/MS/MS was used to determine etravirine concentrations, and HIV‐1 VL was determined by real‐time PCR (limit of detection, VL 40 copies/mL).

Results

Ten blood and twenty semen samples were collected. Median (range) CD4 count was 502 cells/mm3 (252–817) and median (range) BP VL was<40 copies/mL (40–362). Median (range) time on etravirine was 52 weeks (12–124). Median (range) BP etravirine concentration was 452.5 ng/mL (258–751). Median (range) SP etravirine concentration was 62.9 ng/mL (31.2–166), and values were above the protein‐free IC50 range (0.39–2.4 ng/mL) in all cases. Median (range) etravirine SP:BP ratio was 0.16 (0.07–0.26). SP VL was<40 copies/mL in all patients, whereas BP VL was detectable in one patient with poor adherence to treatment.

Patient
SP (ng/ml)
BP (ng/ml)
SP VL (copies/ml)
BP VL (copies/ml)
SP:BP
Concomitant ARV

1
31.2
375
<40
<40
0.08
DRVr/TDF

2*
57.1
307
<40
<40
0.18
3TC/ABC

3*
36.9
506
<40
<40
0.07
TDF/FTC

4*
60.6
399
<40
<40
0.15
3TC/ABC

5
68.1
258
<40
<40
0.26
LPVr/TDF

6*
104
414
<40
<40
0.25
3TC/ABC

7
107
491
<40
362
0.21
DRVr/TDF/FTC

8*
65.3
592
<40
<40
0.11
TDF/FTC

9
52.2
518
<40
<40
0.1
DRVr

10
166
751
<40
<40
0.22
TDF/FTC

Median
62.9
452.5
<40
<40
0.16

Patients taking ETR once a day.

Conclusions

Total etravirine concentrations in male genital secretion are modest, reaching only 16% of the BP concentration, but nevertheless, more than 10 times above the wild type IC50 range.
Determination of rilpivirine (TMC‐278) plasma concentrations by the conventional LC‐MS method
Authors: Shibata M , Takahashi M , Kuwahara T , Nomura T , Yokomaku Y , Sugiura W
Published: November 2012

Background

Rilpivirine (TMC‐278) is a second‐generation NNRTI that is highly potent against both wild‐type and drug‐resistant HIV‐1 strains. The quantification of rilpivirine in human plasma is important to support clinical studies and determine pharmacokinetic parameters of rilpivirine. Until now there has been a methodological report for the determination of rilpivirine using LC‐MS/MS. However, the MS‐MS detector needs to be delicately set and it is expensive. To bypass these difficulties, we aimed to develop more conventional procedures for determining rilpivirine plasma concentration by LC‐MS method.

Methods

A Waters Alliance 2695 HPLC and a Micromass ZQ‐2000 MS, controlled with MassLynx version 4.0 software, were used for detection. Our method involves rapid liquid‐liquid drug extraction from plasma and use of gradient elution on a reversed‐phase C18 column. The mobile phase comprised 0.1 mM EDTA in 0.1% acetic acid (65%), acetonitrile (15%), and methanol (20%). Quantitative analysis detected rilpivirine at m/z 367, and the internal standard, at m/z 313, all in the form of ions.

Results

The established LC‐MS method was validated by estimating the precision and accuracy for inter‐ and intraday analysis in the concentration range of 18–715 ng/ml. The calibration curve was linear in this range. Average accuracy ranged from 100.0 to 100.6%. Relative standard deviations of both inter‐ and intraday assays were less than 3.3%. Recovery of rilpivirine was more than 82.0%.

Conclusions

Our newly developed LC‐MS method achieves the same level of reproducibility and accuracy as the LC‐MS/MS method. Our method provides a conventional, accurate and precise way to determine rilpivirine in human plasma. This method can be used in routine clinical application for HIV‐1 infected patients, and permits management of drug interactions and toxicity for rilpivirine.
Interaction of antiretroviral medications with finasteride
Authors: Ward D
Published: November 2012

Antiretroviral medications are known inhibitors and inducers of cytochrome p450 enzymes and can affect levels of non‐HIV medications. Finasteride 1 mg (Propecia), which prevents the conversion of testosterone (T) to dihydrotestosterone (DHT) is commonly prescribed for prevention of hair loss. This medication is a substrate of p450 3A4. Its efficacy may therefore be affected by HIV medications which induce or inhibit this enzyme. Levels of DHT to prevent hair loss are not well established, but likely need to be<15–20 ng/dl, or a DHT/T ratio of<0.02. Observational analysis in a private practice, measuring DHT and T levels in patients on finasteride and various antiretrovirals 21 patients were identified. 7 patients were taking protease inhibitors and had DHT levels<12 ng/dL; DHT/T<0.20. Three of these patients decreased their finasteride dose to 1 mg every‐other‐day and still have DHT <10. 8 patients were taking potent p450 inducers (efavirenz or etravirine) and had DHT levels between >20; DHT/T>0.025. Two of these patients increased the dose of finasteride to 2 mg/day and subsequently decreased DHT to 14 and 17. Two additional patients on efavirenz, however, had DHT levels of<15 without dose adjustment. Four patients taking nevirapine, a less potent inducer of p450 had DHT levels of<15, as did one patient on raltegravir, which does not affect CYP450. Antiretrovirals that affect CYP 3A4 may interact with finasteride. While it is unlikely that this interaction is dangerous, it may affect its efficacy of the finasteride. Evaluation of DHT/T levels, and/or dose adjustment of finasteride may be appropriate in men being treated for HIV.
Potential drug‐drug interactions in HIV‐infected children on highly active antiretroviral therapy in Lagos, Nigeria
Authors: Oshikoya K , Lawal S , Oreagba I , Ezeaka C , Temiye E , Adeyemo T
Published: November 2012

Objective

Multiple therapies are common in HIV‐infected children on highly active antiretroviral therapy (HAART). These children are at risk for clinically significant drug interactions (CSDIs). While CSDIs are under‐recognized in developed countries, data are lacking for developing African countries. We aimed to investigate the prevalence of CSDIs between antiretrovirals (ARVs) and co‐prescribed drugs for children attending a large HIV clinic in Lagos, Nigeria.

Methods

We retrospectively assessed the risk for clinically significant drug interactions in children on HAART. Of the 417 patients enrolled for treatment, 80 were eligible for inclusion. We defined CSDIs as ‘major’ (capable of causing severe or permanent damage, contraindicated, avoid or not recommended by the manufacturer, or requiring dose modification) or ‘moderate’ (manufacturers advise caution, or close monitoring, or capable of causing clinical deterioration).

Results

A total of 60 (75%) patients were at risk for a CSDI resulting in major interactions in 13 (16.3%) patients and could potentially lower the plasma concentration of antiretroviral drugs in 9 (15%) patients. Major interactions most frequently involved rifampicin in 9 (11.3%) patients and artemisinin combination therapies (ACTs) in 8 (10%) patients whereas moderate interactions frequently involved ACTs (48.8%), fluconazole (36.3%), and rifampicin (11.3%). Age (p = 0.392), gender (p = 0.813), and moderate (p = 0.692) or severe (p = 0.788) malnourished state of the children were not associated with risk for CSDIs.

Conclusions

Three‐quarters of children receiving ARV drugs are at risk for CSDIs. Strategies are needed to be put in place to prevent important drug interactions and to manage unavoidable interactions.
Prevalence of HIV 2: A retrospective study from a HIV/AIDS consult
Authors: Guerreiro C , Sousa C , Santos A , Gomes R , Ferreira J , Fonseca P
Published: November 2012

The western Africa is the origin of the HIV2 infection where Guinea Bissau has been the country where the rate of infection is higher. This infection have extended to Europe through the relationship established between European countries and there African colonies in the past. At 2010, 1.295 cases of HIV 2 infection were notified in Portugal, which represents nearly 3.3% of all HIV infections. Almost 510 of these cases are classified as AIDS. Although the majority of notified cases is from African patients there is still a significant contribution of the Portuguese people in these numbers. Retrospective analysis of HIV2 infected women and men followed at Faro's Hospital HIV/AIDS consult between January 1992 and June 2012. In this sample were included every patient older than 15 years and were excluded every patient than haven't been at the consult for a period superior to 18–24 months. Deceased patients and address change were also exclusion factors. Of all 1500 patients followed in consult, 35 of them were infected with HIV2 (2.3%); 18 women and 17 men. There were 3 patients that were co‐infected with HIV1 and HIV2. Mean age were 52.9 years. 19 of the infected patients were leucodermic and 16 were melanodermic. The majority of patients (19 cases) were Portuguese. The rest of them were from Africa where Guinea Bissau were the only country represented. In opposition to the HIV1 infection, the sexual transmission is by far the more common way of being infected. There's no case of vertical transmission known in our population. At the first contact, the majority of patients appear asymptomatic (16 cases) while a minority (4 cases) manifest themselves by AIDS. There is an AIDS case that result from HIV1 and HIV2 co‐infection (only one intravenous drug user in the group). The more common treatment is the association of NRTI and PI. The HIV2 infection is characterized by a longer clinical evolution when compared to the HIV1 infection. That fact explains why the mean age of patients is higher in the first case. This study shows that there isn't a gender incidence difference between men and women. Despite what happens at a national level, at local level the HIV2 infection is more prevalent among patients born in Portugal. It's important to notice that the HIV1 and HIV2 co‐infection is rising and that leads to some questions like viral synergism with consequent rapid disease progression.
Cost‐efficacy analysis of darunavir/r monotherapy in clinical practice
Authors: Pérez Elías M , Martinez‐Colubi M , Sanz J , Gomez C , Sepulveda M , Estrada V , Moreno A , Muriel A , Dronda F , Del Palacio M , Casado J , Gómez‐Ayerbe C , Rodriguez Sagrado M , Moreno S
Published: November 2012

Purpose of the study

To evaluate the economic impact of a swiching strategy to DRV/r mx in clinical practice using Spanish prices.

Methods

Multicenter retrospective study of four tertiary hospitals in Spain. The analysis includes 147 patients switching to DRV/r mx mainly due to toxicity or simplification from March 2009 to June 2011. The Spanish costs (ex‐factory price+VAT) per patient with HIV RNA<50 copies/ml were calculated, accounting for additional/ switch antiretroviral taken after initial treatment failure and management of adverse events. Cost of adverse events were based on a Spanish publication [1] (updated by the inflation rate until april 2012) The horizon of the analysis was of 48 weeks.

Summary of results

Baseline characteristics were: women (30.6%), median age (49 yr), IDU (45%), AIDS stage (32%), HCV coinfected (48%, 40% with advanced fibrosis), length of HIV‐RNA<1.7 before DRV/rtv mtx 67.6. Most frequent reasons for switching to DRVr mx were toxicity (62.6%) and simplification (23.8%). If a hospital with 600 patients in ART treatment, switched from 10% to 20% of its patients to DRV/r mx, there is a potential to save up to 448,000€/year.

Conclusions

Switching to DRV/r mx is a cost‐effective strategy that allows more patients to be treated for a fixed budget. Higher cost saving is expected when toxicity is the reason for switching.

Baseline HAART
DRV/r Monotherapy
Difference

Mean cost per patient (ARV)
8.471€
5.773€ ‐
2.698€

Mean cost per patient (AEs)
70€
5€ ‐
65€

Total Mean cost per patient*
8.541€
5.778€ ‐
2.762€

Number treated for 1,000,000
117
173
56

% HIV RNA<50 copies/ml (OTT)
93,10%
93,10%
0,00%

Cost per success
9.174€
6.207€ ‐
2.967€

Number of success
109
161
52

ICER (Incremental Cost Efficacy Ratio)

Dominated

Includes ARV and AEs treatment costs.

48 Weeks Cost‐Efficacy analysis: Simplification strategy to DRV/r monotherapy

% of patients that Switches to DRV/r monotherapy

10%
15%
20%

Number of patients in ARV treatment
600
600
600

Number of patients in DRV/r Monotherapy
60
90
120

Before Switch: 1 year cost
512.441€
768.662€
1.024.883€

After Switch: 1 year cost
346.698€
520.048€
693.397€

Total Cost Saving
165.743€
248.614€
331.486€

Hospital Budget Impact Analysis: assuming that 10%–20% of 600 patients in ARV treatment simplifies to DRV/r monotherapy
Cost‐efficacy of European AIDS Clinical Society‐recommended initial antiretroviral regimens for treatment of HIV infection in Portugal
Authors: Aldir I , Doroana M , Oliveira J , Serrão R , Vera J , Aragão F , Lázaro P , Blasco A
Published: November 2012

Purpose of the study

Guidelines are based on clinical trial data as well as expert opinion and do not reflect economic considerations. Cost‐efficacy analysis of recommended regimens allows for a ranking which takes into account both clinical and economic considerations. The aim of the present analysis was thus complement the information provided by the EACS (v6) guidelines regarding recommended initial treatment for HIV‐1 infection.

Methods

The methodology used was that described in Blasco et al. 2011 [1], but applied to Portugal in terms of (i) resource prices, (ii) resource utilization upon ART initiation, regimen switch and treatment of adverse events, and (iii) subsequent regimen selection according to the initial regimen and the reason for switch. Regarding costs, the payer (National Healthcare Service) perspective was considered taking into account only differential direct costs. The time horizon was 48 weeks.

Summary of results

In this analysis, efficacy ranged from 66% with ABC/3TC+LPV/r to 86% for TDF/FTC+RAL. TDF/FTC+NVP was the least expensive regimen both in terms of the 48 weeks’ cost of the initial regimen and in terms of the total 48 weeks’ costs (i.e., including sequential therapy and other direct medical costs) (7,592€). Nonetheless, once cost and efficacy are considered simultaneously, TDF/FTC+NVP ranks third (11,419€), ABC/3TC+EFV ranks second (11,073€) and TDF/FTC+EFV (also available, in a single tablet regimen) ranks first (10,888€) indicating that this is the regimen yielding the lowest cost per suppressed patient. Among regimens containing boosted protease inhibitors, TDF/FTC+DRV/r was the regimen with the lowest cost/efficacy ratio (13,020€) and TDF/FTC+ATV/r had the highest ratio (15,102€).

Conclusions

Viral suppression is a relevant efficacy outcome not only due to individual benefits but also from a public health perspective. In this analysis, TDF/FTC+EFV was the initial ART regimen with the lowest cost per suppressed patient at 48 weeks.
Budget impact analysis of introducing the new single‐tablet regimen rilpivirine/emtricitabine/tenofovir for the treatment of HIV in Portugal
Authors: Gouveia M , Costa J , Teófilo E , Borges M
Published: November 2012

Purpose of the study

Rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) is a new single‐tablet regimen (STR) approved for the initial treatment of HIV‐1 infection. The aim of this study was to estimate the impact on the State Budget of this new STR introduction in the Portuguese Health System (PHS) using secondary data from official statistics and observational studies.

Methods

The analysis considers a time frame of three years, does not include mortality, assumes a constant flow of new patients, and deals only with antiretroviral therapy (ART) costs. Values are not discounted. The stock and flow data of total HIV‐1 patients comes from official statistics from the National Committee for HIV/AIDS. The model starts with recent historical data on the percentage of different ART drugs used for the treatment of naïve patients. Estimates from an observational study also provide 1) the probability that a patient in a given regimen switches to another therapy and 2) the probability distribution for the new therapy choices given that the patient has switched. The penetration of the new STR is also linked with the prevalence of adverse effects of other ART, in particular teratogenic effects, central nervous systems effects and possible interactions with methadone. The distribution of patients according to ART drug, together with price information, allow us to estimate average costs of treatment per year and per patient for each class of ART. Estimates of patients’ numbers for the second and third years assume the same inflow as in the first year, a given annual percentage of non‐switchers from RPV/FTC/TDF and additional flows from patients switching to non‐nucleoside reverse transcriptase inhibitors from other third‐agent classes.

Summary of results

The model predicts a flow of 245 new naïve patients on RPV/FTC/TDF per year, with 209 and 194 of these patients staying with RPV/FTC/TDF in the second and third years, respectively. Given that the average cost of treatment is lower in the scenarios with RPV/FTC/TDF (because the percentage of patients on the more expensive PI class are lower), the overall budget impact consists in savings of about €2.3 million.

Conclusions

The introduction of the new STR RPV/FTC/TDF in the PHS will lead to cost savings in the resources spent on the anti‐retroviral therapy of HIV‐1.
Proteolytic Fingerprinting of Complex Biological Samples Using Combinatorial Libraries of Fluorogenic Probes
Authors: Jambunathan Kalyani , Watson Douglas S. , Kodukula Krishna , Galande Amit K.
Published: November 2012

Proteases have garnered interest as candidate biomarkers and therapeutic targets for many human diseases. A key challenge is the identification and characterization of disease‐relevant proteases in the complex milieu of biological fluids such as serum, plasma, and bronchoalveolar lavage, in which a multitude of hydrolases act in concert. This unit describes a protocol to map the global proteolytic substrate specificities of complex biological samples using a concise combinatorial library of internally quenched fluorogenic peptide probes (IQFPs). This substrate profiling approach provides a global and quantitative comparison of protease specificities between different biological samples. Such a comparative analysis can lead to the identification of disease‐specific ‘fingerprints' of proteolytic activities with potential utility in diagnosis and therapy. Curr. Protoc. Protein Sci. 70:21.22.1‐21.22.14. © 2012 by John Wiley & Sons, Inc.
Functional Stem Cell Integration Assessed by Organotypic Slice Cultures
Authors: Herlenius Eric , Thonabulsombat Charoensri , Forsberg David , Jäderstad Johan , Jäderstad Linda Maria , Björk Lars , Olivius Petri
Published: November 2012

Re‐formation or preservation of functional, electrically active neural networks has been proffered as one of the goals of stem cell‐mediated neural therapeutics. A primary issue for a cell therapy approach is the formation of functional contacts between the implanted cells and the host tissue. Therefore, it is of fundamental interest to establish protocols that allow us to delineate a detailed time course of grafted stem cell survival, migration, differentiation, integration, and functional interaction with the host. One option for in vitro studies is to examine the integration of exogenous stem cells into an existing active neuronal network in ex vivo organotypic cultures. Organotypic cultures leave the structural integrity essentially intact while still allowing the microenvironment to be carefully controlled. This allows detailed studies over time of cellular responses and cell‐cell interactions, which are not readily performed in vivo. This unit describes procedures for using organotypic slice cultures as ex vivo model systems for studying neural stem cell and embryonic stem cell engraftment and communication with CNS host tissue. Curr. Protoc. Stem Cell Biol. 23:2D.13.1‐2D.13.26. © 2012 by John Wiley & Sons, Inc.
High Temperature Oxidation of Ni–Fe–Cr–Al Porous Metal
Authors: Choi Sung‐Hwan , Oh Jae‐Sung , Yun Jung‐Yeul , Kong Young‐Min , Kim Byoung‐Kee , Lee Kee‐Ahn
Published: November 2012

This study investigated the high temperature oxidation of Ni–Fe–Cr–Al porous metal. Two types of open porous metals with pore sizes of 30 and 40 PPI were used. For 24‐h, the isothermal oxidation TGA tests were conducted at three different temperatures of 900, 1000, and 1100 °C. The oxidation resistance of porous metal decreased with decreasing pore size. Porous metals mainly created oxides such as Al2O3, Cr2O3, NiAl2O4, and NiCr2O4. The porous metal represented increasingly faster dwindling of Al and Cr content and easy progress to internal oxidation, comparing to the oxidation of bulk metal.
Enhanced adhesion of polypyrrole/PW12O hybrid coatings on polyester fabrics
Authors: Molina J. , Oliveira F.R. , Souto A. P. , Esteves M. F. , Bonastre J. , Cases F.
Published: November 2012

Polyester fabrics have been treated with plasma to increase polypyrrole/PW12O403‐ (hybrid material) adhesion to its surface. With the plasma treatment, the roughness of the fibers increases as it has been observed by means of atomic force microscopy (AFM). Polar functional groups are also created on the surface of polyester fabrics as X‐ray photoelectron spectroscopy (XPS) measurements have shown. These polar groups contribute to the adhesion of polypyrrole to the fibers. Coatings obtained on plasma treated fabrics were more resistant to washing and rubbing fastness tests. The use of an inorganic counter ion (PW12O) that contains an element with a high atomic number (W) helps to locate zones where the coating is missed; this is achieved by means of micrographs obtained by backscattered electrons (BSE). The electrical resistance of the fabrics was also measured by electrochemical impedance spectroscopy (EIS), obtaining also better results with the plasma treated fabrics. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Synthesis and chemical properties of electrochromic π‐conjugated polyphenylenes with pendant viologen‐TCNQ salts
Authors: Yamaguchi Isao , Makishi Shingo
Published: November 2012

Polyphenylene (PP) with NH2 side groups, namely, PFluNH2, was synthesized by the Pd‐catalyzed reaction of 2,5‐dibromoaniline with 9,9‐dihexylfluorene‐2,7‐diboronic acid bis(1,3‐propanediol) ester. The reaction of PFluNH2 with 1‐hexyl‐1′‐(2,4‐dinitrophenyl)‐4,4′‐bipyridinium diiodide (SaltBPy(I−)) eliminated 2,4‐dinitroaniline to yield PPs with viologen (1,1′‐disubstituted 4,4′‐bipyridinium dications), PFluBPy(I−). The reaction of PFluBPy(I−) with Li+TCNQ− resulted in anion exchange between Cl− and TCNQ−, and yielded PFluBPy(TCNQ−). The reaction of PFluBPy(TCNQ−) with the neutral TCNQ0 resulted in an interaction between TCNQ− and TCNQ0, and yielded PFluBPy(TCNQ−‐TCNQ0). Cyclic voltammetry measurements suggested that an electrochemical reduction of the viologen moiety and oxidation of the polymer backbone within PFluBPy(TCNQ−) and PFluBPy(TCNQ−‐TCNQ0). Furthermore, this reaction was accompanied by electrochromism. The electric conductivities (σ) of the pellets molded from PFluBPy(TCNQ−) to PFluBPy(TCNQ−‐TCNQ0) were 2.7 × 10−4 and 4.2 × 10−4 Scm−1, respectively; these σ values were higher than that observed for PFluNH2 (σ < 10−8 Scm−1) due to the self‐doping in the polymers. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Selective hydrolysis of lignocelluloses from corn stalk in an ionic liquid
Authors: Yin Wei‐ping , Li Xin , Ren Yun‐lai , Zhao Shuang , Wang Jian‐ji
Published: November 2012

In this work, a selective two‐stage hydrolysis of lignocelluloses from corn stalk was developed through pH adjustment in 1‐n‐butyl‐3‐methylimidazolium chloride ([C4mim]Cl). In the first stage, the lignin–hemicelluloses matrix of corn stalk was disrupted and hydrolyzed in the ionic liquid at pH 4.5 and 90°C to obtain xylose with 23.1% yield. In the second stage, cellulose‐rich materials in solid residues were further hydrolyzed in the ionic liquid at pH 2–3 and 90°C to produce glucose with 26.9% yield, and pure lignin was also obtained. Structures of the hydrolysates were identified by 13C NMR and IR spectrum analysis, and the ionic liquid was recycled throughout the process. It is expected that the information provided here would be useful for the development of new methods to selectively produce monosaccharides from catalytic hydrolysis processes of biomass. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Coagulase‐negative staphylococci as reservoirs of genes facilitating MRSA infection
Authors: Otto Michael
Published: November 2012

Recent research has suggested that Staphylococcus epidermidis is a reservoir of genes that, after horizontal transfer, facilitate the potential of Staphylococcus aureus to colonize, survive during infection, or resist antibiotic treatment, traits that are notably manifest in methicillin‐resistant S. aureus (MRSA). S. aureus is a dangerous human pathogen and notorious for acquiring antibiotic resistance. MRSA in particular is one of the most frequent causes of morbidity and death in hospitalized patients. S. aureus is an extremely versatile pathogen with a multitude of mechanisms to cause disease and circumvent immune defenses. In contrast, most other staphylococci, such as S. epidermidis, are commonly benign commensals and only occasionally cause disease. Recent findings highlight the key importance of efforts to better understand how genes of staphylococci other than S. aureus contribute to survival in the human host, how they are transferred to S. aureus, and why this exchange appears to be uni‐directional.
A circuit‐based gatekeeper for adult neural stem cell proliferation
Authors: Moss Jonathan , Toni Nicolas
Published: November 2012

Newborn neurons are generated in the adult hippocampus from a pool of self‐renewing stem cells located in the subgranular zone (SGZ) of the dentate gyrus. Their activation, proliferation, and maturation depend on a host of environmental and cellular factors but, until recently, the contribution of local neuronal circuitry to this process was relatively unknown. In their recent publication, Song and colleagues have uncovered a novel circuit‐based mechanism by which release of the neurotransmitter, γ‐aminobutyric acid (GABA), from parvalbumin‐expressing (PV) interneurons, can hold radial glia‐like (RGL) stem cells of the adult SGZ in a quiescent state. This tonic GABAergic signal, dependent upon the activation of γ2 subunit‐containing GABAA receptors of RGL stem cells, can thus prevent their proliferation and subsequent maturation or return them to quiescence if previously activated. PV interneurons are thus capable of suppressing neurogenesis during periods of high network activity and facilitating neurogenesis when network activity is low.
Highly Selective Synthesis of Phenol from Benzene over a Vanadium‐Doped Graphitic Carbon Nitride Catalyst
Authors: Ding Guodong , Wang Weitao , Jiang Tao , Han Buxing , Fan Honglei , Yang Guanying
Published: November 2012

Design and preparation of efficient and economical catalysts for direct hydroxylation of benzene to phenol is an important topic. In this work, a series of metal‐doped graphitic carbon nitride catalyst (Cu‐, Fe‐, V‐, Co‐, and Ni‐g‐C3N4) were successfully synthesized by using urea as the precursor through a facile and efficient method. The catalysts were characterized systematically using N2 adsorption–desorption, FTIR, thermogravimetric analysis, powder X‐ray diffraction, and X‐ray photoelectron spectroscopy techniques. It was found that the vanadium‐doped graphitic carbon nitride catalyst V‐g‐C3N4 was the most efficient catalyst for the direct synthesis of phenol from benzene with hydrogen peroxide as the oxidant and it could be recycled at least 4 times. The influence of reaction conditions such as the solvent, reaction temperature, reaction time, and the amounts of catalyst and hydrogen peroxide were investigated. Under optimized conditions, 18.2 % yield of phenol was obtained with the selectivity to phenol as high as 100 %.
ChemInform Abstract: Asymmetric Epoxidation Using Iminium Salt Organocatalysts Featuring Dynamically Controlled Atropoisomerism.
Authors: Page Philip C. Bulman , et al. et al.
Published: November 2012

The new iminium salts (I) and (II) are efficient catalysts for the asymmetric epoxidation of various alkenes including unfunctionalized ones.
Synthesis and Properties of Room‐Temperature Choline Carboxylate Zwitterionic Ionic Liquids as Potential Electrolytes
Authors: Rocha Ângelo , Carvalho Tânia , Vidinha Pedro , Lourenço Nuno M. T.
Published: November 2012

Choline carboxylate zwitterions were prepared by two different synthetic routes through esterification of choline salts with a range of anhydrides. Their conjugation with lithium bis(trifluoromethylsulfonyl)imide resulted in the formation of stable room‐temperature ionic liquids. In view of their use as potential electrolytes the physicochemical characterization of these attractive ionic liquids was performed. These compounds presented a glass transition temperature between −43 and −34 °C, good thermal stability up to 224 °C, densities above 1.44 g cm−3 at 25 °C, and viscosities between 3.56 and 12.27 Pa s at 25 °C. In terms of conductivity the most promising ionic liquid showed an excellent conductivity between 8.66×10−5 S cm−1 at 25 °C and 1.80×10−3 S cm−1 at 90 °C. These zwitterionic ionic liquids maintained a liquid state, and no dissociation was observed even after six months of storage at room temperature.
Synthesis of Fe3O4‐Au Nanocomposites with Enhanced Peroxidase‐Like Activity
Authors: Sun Haiyan , Jiao Xiuling , Han Yanyang , Jiang Zhen , Chen Dairong
Published: November 2012

Sphere‐like Fe3O4 aggregates were solvothermally prepared with ethylene glycol, sodium acetate and FeCl3·6H2O as raw materials. The sphere‐like Fe3O4 aggregates provided heterogeneous growth sites for Au nanoparticles. These were obtained by reduction of HAuCl4 by sodium citrate under mild reaction conditions and the Fe3O4‐Au nanocomposites were subsequently formed. The peroxidase‐like activity of nanocomposites was studied with H2O2 and 3,3′,5,5′‐tetramethylbenzidine as substrates. Fe3O4‐Au nanocomposites exhibited better catalytic activity than pure Fe3O4 aggregates, mainly resulting from the special electronic structure at the interfaces between the sphere‐like Fe3O4 aggregates and the gold nanoparticles.
Total Syntheses and Biological Evaluation of 3‐O‐Methylfunicone and Its Derivatives Prepared by TMPZnCl·LiCl‐Mediated Halogenation and Carbonylative Stille Cross‐Coupling
Authors: Ehrlich Michael , Carell Thomas
Published: November 2012

The total syntheses of the natural product 3‐O‐methylfunicone (1), a member of the funicone class of compounds, and its derivatives is reported. The key reactions in the construction of the biaryl ketone core are a regioselective TMPZnCl·LiCl halogenation and a carbonylative Stille cross‐coupling reaction. In addition, the inhibitory activities of the funicones against Y‐family DNA polymerase κ (pol κ) and polymerase η (pol η) were determined. We found that 1 and 12 exhibit inhibitory activity against pol η and 1 also against pol κ.
Electrochemical Biosensors for Cancer Biomarker Detection
Authors: Li Jianping , Li Shuhuai , Yang Catherine F.
Published: November 2012

Cancer is still one of the leading causes of death in the world. There are over 200 types of cancers currently known according to the National Cancer Institute. However, early diagnosis continues to be an important integral part of cancer treatment even though many advances in therapeutics have been made in the past decade. Quick diagnosis and early prevention are critical for the control of the disease status. Biomarkers are commonly indicative of a particular disease process and the cancer biomarkers are also widely used in oncology to help detecting the presence of various carcinomas. The detection of cancer biomarkers plays an important role in clinical diagnoses and evaluation of treatment for patients. Many immunoassay methods are developed for detection of cancer biomarkers. As the detection devices are normally viewed with high sensitivity, simple preparation and rapid response, electrochemical biosensors are increasingly used for the detection of cancer markers. This review describes the status, the latest research and trends of electrochemical sensors in the quantitation of cancer markers in recent years. In particular, the strategy to improve the sensitivities of the electrochemical biosensors by the aid of enzymatic amplification, nanoparticle amplification, ultilization of magnetic microspheres etc. is described herein. At last, we discuss some special features and limitations associated with the described systems that summarize the application and the development prospects of electrochemical immunoassay technology.
Where fast weathering creates thin regolith and slow weathering creates thick regolith
Authors: Bazilevskaya Ekaterina , Lebedeva Marina , Pavich Milan , Rother Gernot , Parkinson Dilworth Y. , Cole David , Brantley Susan L.
Published: November 2012

Weathering disaggregates rock into regolith – the fractured or granular earth material that sustains life on the continental land surface. Here, we investigate what controls the depth of regolith formed on ridges of two rock compositions with similar initial porosities in Virginia (USA). A priori, we predicted that the regolith on diabase would be thicker than on granite because the dominant mineral (feldspar) in the diabase weathers faster than its granitic counterpart. However, weathering advanced 20× deeper into the granite than the diabase. The 20 × ‐thicker regolith is attributed mainly to connected micron‐sized pores, microfractures formed around oxidizing biotite at 20 m depth, and the lower iron (Fe) content in the felsic rock. Such porosity allows pervasive advection and deep oxidation in the granite. These observations may explain why regolith worldwide is thicker on felsic compared to mafic rock under similar conditions. To understand regolith formation will require better understanding of such deep oxidation reactions and how they impact fluid flow during weathering. Copyright © 2012 John Wiley & Sons, Ltd.
Chiral Proline‐Based P,O and P,N Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation
Authors: Rageot Denise , Pfaltz Andreas
Published: November 2012

Two new classes of proline‐based P,O and P,N ligands were prepared and applied in the iridium‐catalyzed asymmetric hydrogenation of alkenes. Both types of ligands induced high enantioselectivities in the hydrogenation of trisubstituted CC bonds. Iridium complexes derived from P,O ligands bearing sterically demanding amide or urea groups at the pyrrolidine N‐atom proved to be especially efficient catalysts for the conjugate reduction of α,β‐unsaturated esters and ketones, whereas analogous P,N ligands led to better results with dialkyl‐phenyl‐substituted alkenes and an allylic alcohol as substrates.
Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums
Authors: Lam Yu‐hong , Houk Kendall N. , Cossy Janine , Gomez Pardo Domingo , Cochi Anne
Published: November 2012

The origin of the variation in the regioselectivity of the nucleophilic ring opening of a series of bicyclic aziridinium ions derived from N‐alkylprolinols was investigated by quantum‐chemical computations (M06‐2X/6‐31+G(d,p)‐SMD). These aziridiniums differ only in the degree and the configurations of F‐substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic gauche effect influences the conformation of the adjoining five‐membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring opening.
Ultrasonic‐electrodeposition of Flower‐like Graphene Nanosheets in Ionic Liquid and Its Sensing for Ascorbic Acid
Authors: Sheng Qinglin , He Yaping , Zhang Dawei , Zheng Jianbin
Published: November 2012

Choline chloride–based ionic liquid Ethaline were employed as the supporting electrolyte, graphene (GE) nanosheet was prepared with ultrasonic wave assisted electrodeposition for the first time. Scanning electron microscope results indicated that flower‐like GE nanosheets were obtained at the electrode surface. Energy dispersive X–ray spectroscopy, Fourier transform infrared spectra and Raman spectra were used to characterize the composition of the flower‐like GE nanosheets. Electrochemical methods showed that the flower‐like GE nanosheets based sensor exhibited high electrocatalytic activity for ascorbic acid (AA) oxidation and can be potentially used for the sensitive amperometric sensing of AA. Amperometric experiments showed that the sensor displayed broad linearity from 0.25 μM to 2.0 mM with a relative low detection limit of 0.1 μM (S/N = 3).
Selective catalytic reduction of NOx with NH3 over iron–cerium mixed oxide catalyst: catalytic performance and characterization
Authors: Zhibo Xiong , Chunmei Lu , Dongxu Guo , Xinli Zhang , Kuihua Han
Published: November 2012

BACKGROUND

Selective catalytic reduction (SCR) of NO with NH3 has been proved to reduce nitric oxides in exhaust flue gas from coal‐fired power plants. The commercial V2O5 ‐WO3 (MoO3)/TiO2 catalyst has the disadvantages of high reaction temperature (573–673 K), high conversion of SO2 to SO3 and toxicity of vanadium pent‐oxide to the environment and human health. Therefore, it is of some urgency to develop SCR catalyst, which works effectively in medium and low temperature ranges. In this study, a series of cerium–iron mixed oxide catalyst were prepared through a co‐precipitation method and showed strong low‐temperature SCR activity.

RESULTS

The SCR activity over iron oxide was improved significantly by adding a small amount of cerium, especially the low‐temperature activity. Cerium sharply increased the BET surface area and the pore volume of iron oxide, and also enhanced its oxidation activity of NO to NO2. The NOx conversion was improved when partial NO2 was introduced into the flue gas. Iron oxide in catalyst was amorphous phase after adding a small amount of cerium.

CONCLUSION

The SCR activity over iron oxide was improved by substituting partial Fe with Ce, and the optimized conditions for SCR with iron–cerium mixed oxide catalyst were validated in this study.© 2012 Society of Chemical Industry
A New Insight Into the Mechanism of the Ring‐Opening Polymerization of Trimethylene Carbonate Catalyzed by Methanesulfonic Acid
Authors: Campos João M. , Ribeiro Maria R. , Ribeiro Maria F. , Deffieux Alain , Peruch Frédéric
Published: November 2012

The ring‐opening polymerization (ROP) of trimethylene carbonate (TMC) initiated by a monoalcohol and catalyzed by CH3SO3H is investigated, in an effort to reveal extra features of the known activated monomer/active chain‐end (AM/ACE) combined mechanism. Size‐exclusion chromatography (SEC) profiles obtained with high‐molar‐mass samples show a poly(trimethylene carbonate) (PTMC) fraction generated by AM/ACE with a molar mass that is exactly twice that of the PTMC fraction coming from pure AM. Conversely, PTMC prepared with a diol is perfectly unimodal and keeps its molar mass dispersity below 1.1. This suggests that the side AM/ACE mechanism may be a bidirectional AM mechanism, and that PTMC with a narrow unimodal molar‐mass distribution can be obtained easily from a diol regardless of this side propagation.