bluuebunny/crossref_metadata_2025 huggingface dataset:
Liposomal Antioxidants for Protection against Oxidant-Induced Damage
Authors: Suntres Zacharias E.
Published: August 2011

Reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, and hydroxyl radical, can be formed as normal products of aerobic metabolism and can be produced at elevated rates under pathophysiological conditions. Overproduction and/or insufficient removal of ROS result in significant damage to cell structure and functions.In vitrostudies showed that antioxidants, when applied directly and at relatively high concentrations to cellular systems, are effective in conferring protection against the damaging actions of ROS, but results from animal and human studies showed that several antioxidants provide only modest benefit and even possible harm. Antioxidants have yet to be rendered into reliable and safe therapies because of their poor solubility, inability to cross membrane barriers, extensive first-pass metabolism, and rapid clearance from cells. There is considerable interest towards the development of drug-delivery systems that would result in the selective delivery of antioxidants to tissues in sufficient concentrations to ameliorate oxidant-induced tissue injuries. Liposomes are biocompatible, biodegradable, and nontoxic artificial phospholipid vesicles that offer the possibility of carrying hydrophilic, hydrophobic, and amphiphilic molecules. This paper focus on the use of liposomes for the delivery of antioxidants in the prevention or treatment of pathological conditions related to oxidative stress.
Enhancement of Carboplatin-Mediated Lung Cancer Cell Killing by Simultaneous Disruption of Glutathione and Thioredoxin Metabolism
Authors: Fath Melissa A. , Ahmad Iman M. , Smith Carmen J. , Spence Jacquelyn , Spitz Douglas R.
Published: August 2011

Purpose: Cancer cells (relative to normal cells) show increased steady-state levels of hydroperoxides that are compensated by increased glucose and hydroperoxide metabolism. The current study determined whether inhibitors of glucose and hydroperoxide metabolism could induce chemoradiosensitization by enhancing oxidative stress in lung cancer cells.

Experimental Design: A549 and NCI-H292 human lung carcinoma cells were treated with 2-deoxy-d-glucose (2DG) combined with carboplatin + ionizing radiation (IR). Lung cancer cells were further sensitized with inhibitors of glutathione (GSH)- and thioredoxin (Trx)-dependent metabolism [buthionine sulfoximine (BSO) and auranofin, respectively] in vitro and in vivo.

Results: When 2DG was combined with carboplatin + IR, clonogenic cell killing was enhanced in A549 and NCI-H292 cells, and this combination was more effective than paclitaxel + carboplatin + IR. The thiol antioxidant (N-acetylcysteine, NAC) was capable of protecting cancer cells from 2DG + carboplatin -induced cell killing. Simultaneous treatment of cancer cells with BSO and auranofin, at doses that were not toxic as single agents, also enhanced lung cancer cell killing and sensitivity to 2DG + carboplatin. This treatment combination also increased oxidation of both GSH and Trx, which were inhibited by NAC. Mice treated with auranofin + BSO showed no alterations in circulating leukocytes or red blood cells. Xenograft lung tumor growth in mice was more effectively inhibited by treatment with auranofin + BSO + carboplatin than animals treated with carboplatin or auranofin + BSO alone.

Conclusions: These results show in vitro and in vivo that simultaneous inhibition of GSH and Trx metabolism can effectively inhibit lung cancer cell growth and induce chemosensitization by a mechanism that involves thiol-mediated oxidative stress. Clin Cancer Res; 17(19); 6206–17. ©2011 AACR.
mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop
Authors: Keniry Megan , Parsons Ramon
Published: August 2011

mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinase–dependent feedback activation of AKT. Cancer Discovery; 1(3); 203–4. © 2011 AACR.

Commentary on Rodrik-Outmezguine et al., p. 248.
Presence of HBV-DNA in Cord Blood Is Associated with Spontaneous Preterm Birth in Pregnant Women with HBeAg-Negative Chronic Hepatitis B Virus Infection
Authors: Elefsiniotis Ioannis S. , Papadakis Miltos , Vlachos George , Vezali Elena , Tsoumakas Konstantinos , Saroglou George , Antsaklis Aristidis
Published: August 2011

Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality. In this study the spontaneous preterm birth rates in a group of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected pregnant women without known risk factors for preterm delivery as well as the role of maternal laboratory data and hepatitis B surface antigen/HBV deoxyribonucleic acid (HBV-DNA) in cord blood in respect to preterm labour were evaluated. 138 consecutive HBeAg-negative chronic HBV-infected pregnant women were evaluated during the perinatal period. Serum HBV-DNA was determined by using the Cobas Amplicor HBV Test in both maternal and cord blood samples. 102 women were finally evaluated (36 were excluded) and 15 of them (14.7%) had spontaneous preterm birth. A significant association between spontaneous preterm birth and HBV-DNA in cord blood was observed (p = 0.007). HBV-DNA positivity in cord blood was significantly associated with maternal HBV-DNA levels (p = 0.002). The relative risk of HBV-DNA in cord blood was 6.43 times higher among women with serum HBV-DNA ≧10,000 copies/ml and lymphocyte count <1,500 compared to those with all the other combinations of both parameters (p = 0.001). In conclusion, the presence of HBV-DNA in cord blood is significantly associated with spontaneous preterm birth in chronic HBV-infected pregnant women. Women with HBV-DNA ≧10,000 copies/ml and lymphocyte count <1,500 during the perinatal period have a higher probability of HBV-DNA in their cord blood.
Effects of Vitamin Treatment or Supplements with Purported Antioxidant Properties on Skin Cancer Prevention: A Meta-Analysis of Randomized Controlled Trials
Authors: Chang Yoon Jung , Myung Seung-Kwon , Chung Sung Tae , Kim Yeol , Lee Eun-Hyun , Jeon Young-Jee , Park Chang-Hae , Seo Hong Gwan , Huh Bong Yul
Published: August 2011

Aims: To investigate the effect of vitamin treatment or supplements with purported antioxidant properties on the primary and secondary prevention of skin cancer using a meta-analysis of randomized controlled trials (RCTs). Methods: We searched PubMed, Embase and the Cochrane Library in June 2009. Among 398 articles searched, 11 articles on 10 RCTs were included in the final analysis. Results: In a fixed-effects meta-analysis of all 10 trials, vitamin treatment or supplements with purported antioxidant properties were found to have no preventive effect on skin cancer [relative risk (RR) = 0.98; 95% confidence interval (CI) = 0.94–1.03]. Similar findings were observed in a subgroup meta-analysis of 10 studies on both primary prevention trials (RR = 0.98; 95% CI = 0.93–1.03) and secondary prevention trials (RR = 0.97; 95% CI = 0.83–1.13). Further, subgroup meta-analyses revealed no preventive effect on cancer by type of antioxidant, type of cancer and the methodological quality of the studies. Conclusion: The current meta-analysis of RCTs indicated that there is no clinical evidence to support an overall primary and secondary preventive effect of vitamin treatment or supplements with purported antioxidant properties on skin cancer. The effect of vitamin supplements on skin cancer should not be overemphasized.
Cutaneous and Mucosal Aphthosis during Temsirolimus Therapy for Advanced Renal Cell Carcinoma: Review of Cutaneous and Mucosal Side Effects of mTOR Inhibitors
Authors: De Masson A. , Fouchard N. , Méry-Bossard L. , Dauendorffer J.N.
Published: August 2011

Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is a new targeted therapy used in advanced renal cell carcinoma and mantle cell lymphoma and is currently tested in several other human tumors. It induces several cutaneous and mucosal side effects, including painful, dose-limiting stomatitis. We report the unusual case of a 77-year-old man who developed severe mucosal, scrotal and perianal cutaneous aphthous-like ulcerations, 6 weeks after introduction of temsirolimus therapy for advanced-stage renal cell carcinoma. Other causes of aphthous-like ulcerations were ruled out. Topical corticosteroids remained ineffective. It led to the interruption of the treatment. Introduction of colchicine resulted in a dramatic improvement within 1 month. Reintroduction of temsirolimus with concomitant colchicine therapy was followed by a delayed recurrence of the lesions. We provide here a review of the potential cutaneous and mucosal side effects of mTOR inhibitors.
Recurrent Postural Vasovagal Syncope
Authors: Vaddadi Gautam , Guo Ling , Esler Murray , Socratous Florentia , Schlaich Markus , Chopra Reena , Eikelis Nina , Lambert Gavin , Trauer Thomas , Lambert Elisabeth
Published: August 2011

Background—

The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (>100 mm Hg) or low (70–100 mm Hg). We investigated neural circulatory control in these 2 phenotypes.

Methods and Results—

Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype (
P
=0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups (
P
=0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal,
P
=0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal,
P
=0.019), augmenting transmitter reuptake.

Conclusions—

Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.
n-3 Polyunsaturated Fatty Acids in the Prevention of Atrial Fibrillation Recurrences After Electrical Cardioversion
Authors: Nodari Savina , Triggiani Marco , Campia Umberto , Manerba Alessandra , Milesi Giuseppe , Cesana Bruno M. , Gheorghiade Mihai , Dei Cas Livio
Published: August 2011

Background—

n-3 polyunsaturated fatty acids (n-3 PUFAs) exert antiarrhythmic effects and reduce sudden cardiac death. However, their role in the prevention of atrial fibrillation remains controversial. We aimed to determine the effect of n-3 PUFAs in addition to amiodarone and a renin-angiotensin-aldosterone system inhibitor on the maintenance of sinus rhythm after direct current cardioversion in patients with persistent atrial fibrillation.

Methods and Results—

We conducted a randomized, double-blind, placebo-controlled, parallel-arm trial in patients with persistent atrial fibrillation, with at least 1 relapse after cardioversion, and treated with amiodarone and a renin-angiotensin-aldosterone system inhibitor. Participants were assigned to placebo or n-3 PUFAs 2 g/d and then underwent direct current cardioversion 4 weeks later. The primary end point was the probability of maintenance of sinus rhythm at 1 year after cardioversion. Of 254 screened patients, 199 were found to be eligible and randomized. At the 1-year follow up, the probability of maintenance of sinus rhythm was significantly higher in the n-3 PUFAs–treated patients compared with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively;
P
=0.0001).

Conclusions—

In patients with persistent atrial fibrillation on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after direct current cardioversion. Our data suggest that n-3 PUFAs may exert beneficial effects in the prevention of atrial fibrillation recurrence. Further studies are needed to confirm and expand our findings.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01198275.
Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness
Authors: Falcão-Pires Inês , Hamdani Nazha , Borbély Attila , Gavina Cristina , Schalkwijk Casper G. , van der Velden Jolanda , van Heerebeek Loek , Stienen Ger J.M. , Niessen Hans W.M. , Leite-Moreira Adelino F. , Paulus Walter J.
Published: August 2011

Background—

Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.

Methods and Results—

Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F
passive
). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM;
P
=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%;
P
<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm
2
versus AS-DM, 31.4±6.1 score per 1 mm
2
;
P
=0.03), and higher F
passive
(AS, 3.5±1.7 kN/m
2
versus AS-DM, 5.1±0.7 kN/m
2
;
P
=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F
passive
and normalization of F
passive
after in vitro treatment with protein kinase A.

Conclusions—

Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F
passive
, which was related to hypophosphorylation of the N2B titin isoform.
Still Looking: Self-Love, Ethics, and Seeing Jewish
Authors: Levitt Laura
Published: August 2011

The photographs of Larry Sultan and Cindy Sherman, considered in the context of American Jewish identification, make a case for self-love as a part of seeing and performing Jewish.
Influences of carbon fillers on electrical conductivity and crystallinity of polyethylene terephthalate
Authors: Xin Fei , Li Lin , Chan Siew Hwa , Zhao Jianhong
Published: August 2011

Three forms of carbon, i.e., carbon nanotubes (CNT), conductive carbon black (CCB), and graphite (G), were added to polyethylene terephthalate (PET) to prepare several types of composites, namely, CNT/PET, CCB/PET, G/PET, CNT/CCB/PET, and CNT/G/PET composites, using melt compounding, followed by injection molding. These composites were characterized using field emission scanning electron microscopy, differential scanning calorimetry, and electrical conductivity measurements. It was found that the addition of these conductive fillers could result in the electrically conductive composites directly but the conductivities were dependent on many factors including filler type, content, dispersion state in the matrix, complementary effect of two fillers (i.e., dual fillers), and post melt annealing. Among those carbon/PET composites studied, the highest conductivity that could be reached was 1.2 S/cm, which was 17 orders of magnitude higher than that of the matrix PET. The melt annealing process was found to remarkably enhance the electrical conductivity of carbon/PET composites. CNT, CCB, and G, all could act as nucleating agents but the crystallinity of PET decreased with increasing the filler content in the composites. All types of fillers caused shifting of the crystallization temperature to higher temperatures. The mechanisms for the effects of carbon fillers on electrical conductivity and cystallinity of PET have been proposed and discussed.
Families, Secrets and Memories
Authors: Smart Carol
Published: August 2011

In this article I argue that the telling of family secrets is tied into the workings of family memories and that the stories that people tell cannot be regarded as simple factual accounts. Rather they are amongst the kinds of stories that are part of the constitution of ‘the family’. Secrets, it might be assumed, are buried and forgotten but it is equally likely in families that secrets can be kept alive by innuendo, palpable silences, and rumour. I argue that it is important to understand the sociological significance of family secrets, not because they reveal a simple ‘truth’ about family life, but because these secrets are a route into understanding the complex relationship between power, the personal, the cultural and the social. This entanglement of secrets, memories and family practices is explored through written accounts of family secrets found in the Mass Observation Project. The study of family secrets throws additional light on the everyday workings of families and the ways in which family stories are managed.
Culture of Honor and Violence Against the Self
Authors: Osterman Lindsey L. , Brown Ryan P.
Published: August 2011

Cultures of honor facilitate certain forms of interpersonal violence. The authors suggest that these cultures might also promote values and expectations that could heighten suicide risk, such as strict gender-role standards and hypersensitivity to reputational threats, which could lead people living in such cultures to consider death as an option when failure occurs or reputation is threatened sufficiently. Study 1 shows that, controlling for a host of statewide covariates, honor states in the United States have significantly higher male and female suicide rates than do nonhonor states, particularly in nonmetropolitan areas among Whites. Study 2 shows that statewide levels of antidepressant prescriptions (an indicator of mental health resource utilization) are lower in honor states, whereas levels of major depression are higher, and statewide levels of depression are associated with suicide rates only among honor states. Finally, Study 3 shows that individual endorsement of honor ideology is positively associated with depression.
On the migration of smooth particle hydrodynamic formulation in Cartesian coordinates to the axisymmetric formulation
Authors: Lee M , Cho Y J
Published: August 2011

The smooth particle hydrodynamic (SPH) method has been extended for application to large deformation problems such as high velocity impacts by including the effect of material strength. This paper presents a simple modification of the kernel function that allows the SPH formulation in Cartesian coordinates to be migrated into an axisymmetric formulation. The proposed procedure is first applied to analyse transient deformations of a cylindrical rod impacting a rigid wall (Taylor impact test). A good agreement with published experimental data for the deformed shape is obtained. A sensitivity study of the key parameters required in the SPH formulation is conducted to provide better insight into the SPH modelling approach. Impacts between two bodies at high speed have also been simulated using an axisymmetric SPH code.
The Development of Writing Proficiency as a Function of Grade Level: A Linguistic Analysis
Authors: Crossley Scott A. , Weston Jennifer L. , McLain Sullivan Susan T. , McNamara Danielle S.
Published: August 2011

In this study, a corpus of essays stratified by level (9th grade, 11th grade, and college freshman) are analyzed computationally to discriminate differences between the linguistic features produced in essays by adolescents and young adults. The automated tool Coh-Metrix is used to examine to what degree essays written at various grade levels can be distinguished from one another using a number of linguistic features related to lexical sophistication (i.e., word frequency, word concreteness), syntactic complexity (i.e., the number of modifiers per noun phrase), and cohesion (i.e., word overlap, incidence of connectives). The analysis demonstrates that high school and college writers develop linguistic strategies as a function of grade level. Primarily, these writers produce more sophisticated words and more complex sentence structure as grade level increases. In contrast, these writers produce fewer cohesive features in text as a function of grade level. This analysis supports the notion that linguistic development occurs in the later stages of writing development and that this development is primarily related to producing texts that are less cohesive and more elaborate.
The Pharmacists' Role in Improving Guideline Compliance for Thyroid Function Testing in Patients With Heart Failure
Authors: Ziman Melanie E. , Bui Hien T. , Smith Craig S. , Tsukiji Lori A. , Asmatey Veda M. , Chu Steven B. , Miano John S.
Published: August 2011

This single-center retrospective pilot program’s objective was to utilize outpatient pharmacists to improve laboratory test adherence in chronic heart failure (CHF) patients overdue for thyroid function testing, thereby demonstrating the value of the outpatient pharmacist and justifying possible clinical role expansion. Thyroid disorders may contribute to CHF development, progression, and exacerbation. Testing is the standard of care in CHF patients per American Heart Association’s 2009 Guidelines. Delinquency was defined as labs not conducted within 1 year in patients with euthyroid history, within 6 months in patients with thyroid dysfunction, abnormal labs at any time without follow-up, or lab absence after thyroid medication initiation, adjustment, or discontinuation. Targeted 80 nonpregnant adult CHF patients with delinquent thyroid function tests were counseled to get thyroid labs at point of sale, via telephone, e-mail, or letter. In collaboration with physicians, pharmacists ordered thyroid-stimulating hormone (TSH) and free T4 (FT4) labs. For patients with abnormal laboratory results, pharmacists coordinated drug therapy and follow-up labs. Data were collected from November 1, 2009 to March 30, 2010. Seventy-two patients (90%) previously delinquent for thyroid function testing received relevant thyroid labs. Ten patients (12.5%) with abnormal thyroid function tests not on prior drug therapy received treatment.
Relative timing of the Storegga submarine slide, methane release, and climate change during the 8.2 ka cold event
Authors: Dawson A. , Bondevik S. , Teller J.T.
Published: August 2011

This paper highlights the similarity in the timing between the 8.2 ka cold event across the North Atlantic region and one of the world’s largest underwater slides, the Storegga submarine landslide that took place on the continental slope west of Norway. We argue on the basis of a reinterpretation of the age of tsunami deposits that date the slide, as well as published ages of sediment directly resting upon the slide surface, that the slide occurred between 8100 and 8200 cal. yr, near the end of the 8.2 ka cold event. Because sediment exposed at the base of the slide contained less methane-gas-hydrate c. 8200 years ago than exists today and because Greenland ice cores do not show an increase in methane at the time of the slide, it is argued here that the slide did not release significant volumes of methane to the atmosphere and did not contribute to any change in temperature during or after the 8.2 ka cold event.
Stuck on a Plateau?
Authors: Cordner Gary , Cordner AnnMarie
Published: August 2011

This article explores reasons why the level of employment of women police in the United States is relatively low and no longer seems to be increasing. Surveys were administered to all women officers and all police chiefs in a three-county area of Pennsylvania where the proportion of women police is lower than the national average. The chiefs and women officers largely agreed about the impact of many components of the hiring process. Women officers perceived more shortcomings in recruitment practices than did the chiefs, though, and put much more emphasis on the male-dominated cultures of police academies and police organizations as obstacles to both recruitment and retention of women officers.
The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy
Authors: Javle M. , Curtin N. J.
Published: August 2011

The modulation of DNA repair pathways for therapeutic benefit in cancer has now become a reality with the development of poly (ADP-ribose) polymerase inhibitors (PARPi). PARP is involved in single-strand DNA breaks, which in the presence of defective homologous recombination repair lead to double-strand DNA breaks, the most lethal form of DNA damage. These agents therefore may be the drugs of choice for BRCA mutant breast and ovarian cancers. PARPi result in synergistic antitumor effects when combined with cisplatin, temozolomide, topoisomerase inhibitors and ionizing radiation. The indications for PARPi lie beyond BRCA mutations and may include genomic and functional defects in DNA repair and damage response pathways. Several PARPi are in the clinical development phase at this time and, given the recent failure of a phase III clinical trial of iniparib in triple-negative breast cancer, the identification of structural and functional differences between these inhibitors becomes critical. Acquired resistance to PARPi is being noted and represents an important limitation in this field. A concise review of the literature in this field is presented.
Quality of life assessment as a predictor of survival in non-small cell lung cancer
Authors: Braun Donald P , Gupta Digant , Staren Edgar D
Published: August 2011

Background

There are conflicting and inconsistent results in the literature on the prognostic role of quality of life (QoL) in cancer. We investigated whether QoL at admission could predict survival in lung cancer patients.

Methods

The study population consisted of 1194 non-small cell lung cancer patients treated at our institution between Jan 2001 and Dec 2008. QoL was evaluated using EORTC-QLQ-C30 prior to initiation of treatment. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression evaluated the prognostic significance of QoL.

Results

Mean age at presentation was 58.3 years. There were 605 newly diagnosed and 589 previously treated patients; 601 males and 593 females. Stage of disease at diagnosis was I, 100; II, 63; III, 348; IV, 656; and 27 indeterminate. Upon multivariate analyses, global QoL as well as physical function predicted patient survival in the entire study population. Every 10-point increase in physical function was associated with a 10% increase in survival (95% CI = 6% to 14%, p < 0.001). Similarly, every 10-point increase in global QoL was associated with a 9% increase in survival (95% CI = 6% to 11%, p < 0.001). Furthermore, physical function, nausea/vomiting, insomnia, and diarrhea (p < 0.05 for all) in newly diagnosed patients, but only physical function (p < 0.001) in previously treated patients were predictive of survival.

Conclusions

Baseline global QoL and physical function provide useful prognostic information in non-small cell lung cancer patients.
Barriers to antiretroviral therapy adherence in rural Mozambique
Authors: Groh Kate , Audet Carolyn M , Baptista Alberto , Sidat Mohsin , Vergara Alfredo , Vermund Sten H , Moon Troy D
Published: August 2011

Background

HIV is treated as a chronic disease, but high lost-to-follow-up rates and poor adherence to medication result in higher mortality, morbidity, and viral mutation. Within 18 clinical sites in rural Zambézia Province, Mozambique, patient adherence to antiretroviral therapy has been sub-optimal.

Methods

To better understand barriers to adherence, we conducted 18 community and clinic focus groups in six rural districts. We interviewed 76 women and 88 men, of whom 124 were community participants (CP; 60 women, 64 men) and 40 were health care workers (HCW; 16 women, 24 men) who provide care for those living with HIV.

Results

While there was some consensus, both CP and HCW provided complementary insights. CP focus groups noted a lack of confidentiality and poor treatment by hospital staff (42% CP vs. 0% HCW), doubt as to the benefits of antiretroviral therapy (75% CP vs. 0% HCW), and sharing medications with family members (66% CP vs. 0%HCW). Men expressed a greater concern about poor treatment by HCW than women (83% men vs. 0% women). Health care workers blamed patient preference for traditional medicine (42% CP vs. 100% HCW) and the side effects of medication for poor adherence (8% CP vs. 83% CHW).

Conclusions

Perspectives of CP and HCW likely reflect differing sociocultural and educational backgrounds. Health care workers must understand community perspectives on causes of suboptimal adherence as a first step toward effective intervention.
Genotypic and functional properties of early infant HIV-1 envelopes
Authors: Kishko Michael , Somasundaran Mohan , Brewster Frank , Sullivan John L , Clapham Paul R , Luzuriaga Katherine
Published: August 2011

Background

Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-lengthenvelope(env) clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies.

Results

Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal inenvlength, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC50≥ 100 μg/ml) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied.

Conclusions

This study provides extensive characterization of the genotypic and functional properties of HIV-1envshortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternalenvvariants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.
A meta-review of evidence on heart failure disease management programs: the challenges of describing and synthesizing evidence on complex interventions
Authors: Savard Lori A , Thompson David R , Clark Alexander M
Published: August 2011

Background

Despite favourable results from past meta-analyses, some recent large trials have not found Heart Failure (HF) disease management programs to be beneficial. To explore reasons for this, we evaluated evidence from existing meta-analyses.

Methods

Systematic review incorporating meta-review was used. We selected meta-analyses of randomized controlled trials published after 1995 in English that examined the effects of HF disease management programs on key outcomes. Databases searched: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR), DARE, NHS EED, NHS HTA, Ageline, AMED, Scopus, Web of Science and CINAHL; cited references, experts and existing reviews were also searched.

Results

15 meta-analyses were identified containing a mean of 18.5 randomized trials of HF interventions +/- 10.1 (range: 6 to 36). Overall quality of the meta-analyses was very mixed (Mean AMSTAR Score = 6.4 +/- 1.9; range 2-9). Reporting inadequacies were widespread around populations, intervention components, settings and characteristics, comparison, and comparator groups. Heterogeneity (statistical, clinical, and methodological) was not taken into account sufficiently when drawing conclusions from pooled analyses.

Conclusions

Meta-analyses of heart failure disease management programs have promising findings but often fail to report key characteristics of populations, interventions, and comparisons. Existing reviews are of mixed quality and do not adequately take account of program complexity and heterogeneity.
Giant endobronchial hamartoma resected by fiberoptic bronchoscopy electrosurgical snaring
Authors: Mondello Baldassare , Lentini Salvatore , Buda Carmelo , Monaco Francesco , Familiari Dario , Sibilio Michele , La Rocca Annunziata , Barresi Pietro , Cavallari Vittorio , Monaco Maurizio , Barone Mario
Published: August 2011

Less than 1% of lung neoplasms are represented by benign tumors. Among these, hamartomas are the most common with an incidence between 0.025% and 0.32%. In relation to the localization, hamartomas are divided into intraparenchymal and endobronchial.

Clinical manifestation of an endobronchial hamartoma (EH) results from tracheobronchial obstruction or bleeding. Usually, EH localizes in large diameter bronchus. Endoscopic removal is usually recommended. Bronchotomy or parenchimal resection through thoracotomy should be reserved only for cases where the hamatoma cannot be approached through endoscopy, or when irreversible lung functional impairment occurred after prolonged airflow obstruction. Generally, when endoscopic approach is used, this is through rigid bronchoscopy, laser photocoagulation or mechanical resection. Here we present a giant EH occasionally diagnosed and treated by fiberoptic bronchoscopy electrosurgical snaring.
Fluxomers: a new approach for 13C metabolic flux analysis
Authors: Srour Orr , Young Jamey D , Eldar Yonina C
Published: August 2011

Background

The ability to perform quantitative studies using isotope tracers and metabolic flux analysis (MFA) is critical for detecting pathway bottlenecks and elucidating network regulation in biological systems, especially those that have been engineered to alter their native metabolic capacities. Mathematically, MFA models are traditionally formulated using separate state variables for reaction fluxes and isotopomer abundances. Analysis of isotope labeling experiments using this set of variables results in a non-convex optimization problem that suffers from both implementation complexity and convergence problems.

Results

This article addresses the mathematical and computational formulation of 13C MFA models using a new set of variables referred to as fluxomers. These composite variables combine both fluxes and isotopomer abundances, which results in a simply-posed formulation and an improved error model that is insensitive to isotopomer measurement normalization. A powerful fluxomer iterative algorithm (FIA) is developed and applied to solve the MFA optimization problem. For moderate-sized networks, the algorithm is shown to outperform the commonly used 13CFLUX cumomer-based algorithm and the more recently introduced OpenFLUX software that relies upon an elementary metabolite unit (EMU) network decomposition, both in terms of convergence time and output variability.

Conclusions

Substantial improvements in convergence time and statistical quality of results can be achieved by applying fluxomer variables and the FIA algorithm to compute best-fit solutions to MFA models. We expect that the fluxomer formulation will provide a more suitable basis for future algorithms that analyze very large scale networks and design optimal isotope labeling experiments.
A modified surgical technique in the management of eyelid burns: a case series
Authors: Liu Haiying , Wang Kun , Wang Qigang , Sun Shudong , Ji Youxin
Published: August 2011

Introduction

Contractures, ectropion and scarring, the most common sequelae of skin grafts after eyelid burn injuries, can result in corneal exposure, corneal ulceration and even blindness. Split-thickness or full-thickness skin grafts are commonly used for the treatment of acute eyelid burns. Plasma exudation and infection are common early complications of eyelid burns, which decrease the success rate of grafts.

Case presentation

We present the cases of eight patients, two Chinese women and six Chinese men. The first Chinese woman was 36 years old, with 70% body surface area second or third degree flame burn injuries involving her eyelids on both sides. The other Chinese woman was 28 years old, with sulfuric acid burns on her face and third degree burn on her eyelids. The six Chinese men were aged 21, 31, 38, 42, 44, and 55 years, respectively. The 38-year-old patient was transferred from the ER with 80% body surface area second or third degree flame burn injuries and third degree burn injuries to his eyelids. The other five men were all patients with flame burn injuries, with 7% to 10% body surface area third degree burns and eyelids involved. All patients were treated with a modified surgical procedure consisting of separation and loosening of the musculus orbicularis oculi between tarsal plate and septum orbital, followed by grafting a large full-thickness skin graft in three days after burn injury. The use of our modified surgical procedure resulted in 100% successful eyelid grafting on first attempt, and all our patients were in good condition at six-month follow-up.

Conclusions

This new surgical technique is highly successful in treating eyelid burn injuries, especially flame burn injuries of the eyelid.
CCR5Δ32 variant and cardiovascular disease in patients with rheumatoid arthritis: a cohort study
Authors: Rodríguez-Rodríguez Luis , González-Juanatey Carlos , García-Bermúdez Mercedes , Vázquez-Rodríguez Tomas R , Miranda-Filloy Jose A , Fernández-Gutiérrez Benjamin , Llorca Javier , Martin Javier , González-Gay Miguel A
Published: August 2011

Introduction

The aim of our study was to analyze the influence of the CCR5Δ32 polymorphism in the risk of cardiovascular (CV) events and subclinical atherosclerosis among patients with rheumatoid arthritis (RA).

Methods

A total of 645 patients fulfilling the American Rheumatism Association 1987 revised classification criteria for RA were studied. Patients were genotyped for the CCR5 rs333 polymorphism using predesigned TaqMan assays. Also, HLA DRB1 genotyping was performed using molecular-based methods. Carotid intima-media thickness, flow-mediated endothelium-dependent dilatation (FMD) and endothelium-independent vasodilatation, which were used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients with no clinical CV disease.

Results

A lower frequency of carriers of the CCR5Δ32 allele among patients with CV events (3.4% versus 11.3%, P = 0.025, odds ratio 0.28, 95% confidence interval (95% CI) 0.06 to 0.89) was observed. However, after adjusting for gender, age at time of RA diagnosis, and the presence of shared epitope, rheumatoid factor and classic CV risk factors in the Cox regression analysis, this reduction of CV events in CCR5Δ32 allele carriers was slightly outside the range of significance (P = 0.097; hazard ratio 0.37 (95% CI 0.12 to 1.19)). Carriers of the CCR5Δ32 deletion also showed higher FMD values than the remaining patients (CCR5/CCR5Δ32 patients: 7.03% ± 6.61% versus CCR5/CCR5 patients: 5.51% ± 4.66%). This difference was statistically significant when analysis of covariance was performed (P = 0.024).

Conclusions

Our results show a potential influence of the CCR5Δ32 deletion on the risk of CV disease among patients with RA. This may be due to a protective effect of this allelic variant against the development of vascular endothelial dysfunction.
The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery
Authors: Shahin Jason , deVarennes Benoit , Tse Chun Wing , Amarica Dan-Alexandru , Dial Sandra
Published: August 2011

Introduction

Acute haemodynamic complications are common after cardiac surgery and optimal perioperative use of inotropic agents, typically guided by haemodynamic variables, remains controversial. The aim of this study was to examine the relationship of inotrope use to hospital mortality and renal dysfunction.

Material and methods

A retrospective cohort study of 1,326 cardiac surgery patients was carried out at two university-affiliated ICUs. Multivariable logistic regression analysis and propensity matching were performed to evaluate whether inotrope exposure was independently associated with mortality and renal dysfunction.

Results

Patients exposed to inotropes had a higher mortality rate than those not exposed. After adjusting for differences in Parsonnet score, left ventricular ejection fraction, perioperative intraaortic balloon pump use, bypass time, reoperation and cardiac index, inotrope exposure appeared to be independently associated with increased hospital mortality (adjusted odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.2 to 4.5) and renal dysfunction (adjusted OR 2.7, 95% CI 1.5 to 4.6). A propensity score-matched analysis similarly demonstrated that death and renal dysfunction were significantly more likely to occur in patients exposed to inotropes (P = 0.01).

Conclusions

Postoperative inotrope exposure was independently associated with worse outcomes in this cohort study. Further research is needed to better elucidate the appropriate use of inotropes in cardiac surgery.
The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue
Authors: Roberts Lee D , Murray Andrew J , Menassa David , Ashmore Tom , Nicholls Andrew W , Griffin Julian L
Published: August 2011

Background

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor δ (PPARδ) play central roles in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. While the role of PPARγ in regulating insulin sensitivity has been well defined, research into PPARδ has been limited until recently due to a scarcity of selective PPARδ agonists.

Results

The metabolic effects of PPARγ and PPARδ activation have been examined in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using 1H nuclear magnetic resonance spectroscopy and mass spectrometry metabolomics to understand the receptors' contrasting roles. These steady state measurements were supplemented with 13C-stable isotope substrate labeling to assess fluxes, in addition to respirometry and transcriptomic microarray analysis. The metabolic effects of the receptors were readily distinguished, with PPARγ activation characterized by increased fat storage, synthesis and elongation, while PPARδ activation caused increased fatty acid β-oxidation, tricarboxylic acid cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased fatty acid desaturation were common pathways for the agonists.

Conclusions

PPARγ and PPARδ restore insulin sensitivity through varying mechanisms. PPARδ activation increases total oxidative metabolism in white adipose tissue, a tissue not traditionally thought of as oxidative. However, the increased metabolism of branch chain amino acids may provide a mechanism for muscle atrophy, which has been linked to activation of this nuclear receptor. PPARδ has a role as an anti-obesity target and as an anti-diabetic, and hence may target both the cause and consequences of dyslipidemia.
TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes
Authors: Swiecki Melissa , McCartney Stephen A , Wang Yaming , Colonna Marco
Published: August 2011

IFN-I are pleiotropic cytokines that impact innate and adaptive immune responses. In this article, we discuss TLR7/9 versus TLR3/MDA5 signaling in antiviral responses and diabetes. pDCs are thought to have a critical role in antiviral defense because of their ability to rapidly secrete large amounts of IFN-I through TLR7/9 signaling. A recent study demonstrates that although pDCs are a source of IFN-I in vivo, their overall contribution to viral containment is limited and time-dependent, such that additional cellular sources of IFN-I are required to fully control viral infections. dsRNA sensors, such as TLR3 and MDA5, provide another important trigger for antiviral IFN-I responses, which can be exploited to enhance immune responses to vaccines. In the absence of infection, IFN-I production by pDCs or from signaling through dsRNA sensors has been implicated in the pathogenesis of autoimmune diseases such as diabetes. However, recent data demonstrate that IFN-I production via TLR3 and MDA5 is critical to counter diabetes caused by a virus with preferential tropism for pancreatic β-cells. This highlights the complexity of the host antiviral response and how multiple cellular and molecular components balance protective versus pathological responses.
Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes
Authors: Zhang Ying , Ma Cheng J , Wang Jia M , Ji Xiao J , Wu Xiao Y , Moorman Jonathan P , Yao Zhi Q
Published: August 2011

Tim-3 and PD-1 are powerful immunoinhibitory molecules involved in immune tolerance, autoimmune responses, and antitumor or antiviral immune evasion. A current model for Tim-3 regulation during immune responses suggests a divergent function, such that Tim-3 acts synergistically with TLR signaling pathways in innate immune cells to promote inflammation, yet the same molecule terminates Th1 immunity in adaptive immune cells. To better understand how Tim-3 might be functioning in innate immune responses, we examined the kinetics of Tim-3 expression in human CD14+ M/MФ in relation to expression of IL-12, a key cytokine in the transition of innate to adaptive immunity. Here, we show that Tim-3 is constitutively expressed on unstimulated peripheral blood CD14+ monocytes but decreases rapidly upon TLR stimulation. Conversely, IL-12 expression is low in these cells but increases rapidly in CD14+ M/MФ in correlation with the decrease in Tim-3. Blocking Tim-3 signaling or silencing Tim-3 expression led to a significant increase in TLR-mediated IL-12 production, as well as a decrease in activation-induced up-regulation of the immunoinhibitor, PD-1; TNF-α production was not altered significantly, but IL-10 production was increased. These results suggest that Tim-3 has a role as a regulator of pro- and anti-inflammatory innate immune responses.