bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative muscle weakness as defined by handgrip strength and postoperative outcomes: a systematic review
Authors: Sultan Pervez , Hamilton Mark A , Ackland Gareth L
Published: January 2012

Background

Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform "bedside" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.

Methods

PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.

Results

Nineteen clinical studies (17 prospective; 4 in urgent surgery) comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).

Conclusions

Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity.
Factors linked to severe thrombocytopenia during antiviral therapy in patients with chronic hepatitis c and pretreatment low platelet counts
Authors: Lin Kung-Hung , Hsu Ping-I , Yu Hsien-Chung , Lin Chun-Ku , Tsai Wei-Lun , Chen Wen-Chi , Chan Hoi-Hung , Lai Kwok-Hung
Published: January 2012

Background

Baseline low platelet count (< 150,000/μL) increases the risk of on-treatment severe thrombocytopenia (platelet count < 50,000/μL) in patients with chronic hepatitis C (CHC) undergoing antiviral therapy, which may interrupt treatment. The purpose of this study was to identify risk factors for severe thrombocytopenia during treatment for CHC in patients with baseline thrombocytopenia.

Methods

Medical records were reviewed for 125 patients with CHC treated with antiviral therapy according to the standard of care, with regular follow-up examinations. Early platelet decline was defined as platelet decrease during the first 2 weeks of therapy.

Results

Severe thrombocytopenia developed in 12.8% of patients with baseline thrombocytopenia, and predicted a higher therapeutic dropout rate. Multivariate analysis revealed baseline platelet count < 100,000/μL and rapid early platelet decline (> 30% decline in the first 2 weeks) were significantly associated with severe thrombocytopenia (P < 0.001 and 0.003, odds ratios, 179.22 and 45.74, respectively). In these patients, baseline PLT ≥ 100,000/μL and lack of rapid early platelet decline predicted absence of severe thrombocytopenia (negative predictive values were 95.1% and 96.6%, respectively). In contrast, baseline platelet count < 100,000/μL combined with rapid early platelet decline predicted severe thrombocytopenia (positive predictive value was 100%).

Conclusions

For patients with CHC on antiviral therapy, baseline platelet counts < 100,000/μL and rapid early platelet decline can identify patients at high risk of developing on-treatment severe thrombocytopenia.
Type D personality is associated with impaired psychological status and unhealthy lifestyle in Icelandic cardiac patients: A cross-sectional study
Authors: Svansdottir Erla , van den Broek Krista C , Karlsson Hrobjartur D , Gudnason Thorarinn , Denollet Johan
Published: January 2012

Background

Type D (distressed) personality has been associated with adverse cardiac prognosis and poor emotional well-being in cardiac patients, but it is still unclear what mechanisms link Type D personality with poor clinical outcomes in cardiac patients. In the present cohort of Icelandic cardiac patients, we examined potential pathways that may explain this relationship. The objectives were to examine 1) the association between Type D personality and impaired psychological status, and to explore whether this association is independent of disease severity; and 2) the association between Type D personality and an unhealthy lifestyle.

Methods

A sample of 268 Icelandic coronary angiography patients (74% males (N = 199); mean age 62.9 years (SD 10.5), range 28-85 years) completed the Type D Scale (DS14), Hospital Anxiety and Depression Scale (HADS), and Perceived Stress Scale (PSS) at hospitalization. Health-related behaviors were assessed 4 months following angiography. Clinical data were collected from medical files.

Results

Type D personality was associated with an increased risk of anxiety (OR 2.97, 95% CI:1.55-5.69), depression (OR 4.01, 95% CI:1.42-11.29), and stress (OR 5.99, 95% CI:3.08-11.63), independent of demographic variables and disease severity. Furthermore, fish consumption was lower among Type Ds, as 21% of Type Ds versus 5% of non-Type Ds consumed fish < 1 a week (p < 0.001). Type D patients were also more likely to smoke at follow-up (22% versus 10%, p = 0.024) and to use antidepressants (17% versus 9%, p = 0.049) and sleeping pills (49% versus 33%, p = 0.019) compared to non-Type Ds. Type D personality was not associated with other health-related behaviors, aside from trends towards less fruit and vegetable consumption, and more weight gain.

Conclusion

Type D personality was associated with psychological distress and an unhealthy lifestyle in Icelandic cardiac patients. Future studies should further investigate the association between Type D personality and health-related behaviors.
A multilevel examination of gender differences in the association between features of the school environment and physical activity among a sample of grades 9 to 12 students in Ontario, Canada
Authors: Hobin Erin P , Leatherdale Scott T , Manske Steve , Dubin Joel A , Elliott Susan , Veugelers Paul
Published: January 2012

Background

Creating school environments that support student physical activity (PA) is a key recommendation of policy-makers to increase youth PA. Given males are more active than females at all ages, it has been suggested that investigating gender differences in the features of the environment that associate with PA may help to inform gender-focused PA interventions and reduce the gender disparity in PA. The purpose of this cross-sectional study was to explore gender differences in the association between factors of the school environment and students' time spent in PA.

Methods

Among a sample of 10781 female and 10973 male students in grades 9 to 12 from 76 secondary schools in Ontario, Canada, student- and school-level survey PA data were collected and supplemented with GIS-derived measures of the built environment within 1-km buffers of the 76 schools.

Results

Findings from the present study revealed significant differences in the time male and female students spent in PA as well as in some of the school- and student-level factors associated with PA. Results of the gender-specific multilevel analyses indicate schools should consider providing an alternate room for PA, especially for providing flexibility activities directed at female students. Schools should also consider offering daily physical education programming to male students in senior grades and providing PA promotion initiatives targeting obese male students.

Conclusions

Although most variation in male and female students' time spent in PA lies between students within schools, there is sufficient between-school variation to be of interest to practitioners and policy-makers. More research investigating gender differentials in environment factors associated with youth PA are warranted.
Dimensionality and predictive validity of the HAM-Nat, a test of natural sciences for medical school admission
Authors: Hissbach Johanna C , Klusmann Dietrich , Hampe Wolfgang
Published: January 2012

Background

Knowledge in natural sciences generally predicts study performance in the first two years of the medical curriculum. In order to reduce delay and dropout in the preclinical years, Hamburg Medical School decided to develop a natural science test (HAM-Nat) for student selection. In the present study, two different approaches to scale construction are presented: a unidimensional scale and a scale composed of three subject specific dimensions. Their psychometric properties and relations to academic success are compared.

Methods

334 first year medical students of the 2006 cohort responded to 52 multiple choice items from biology, physics, and chemistry. For the construction of scales we generated two random subsamples, one for development and one for validation. In the development sample, unidimensional item sets were extracted from the item pool by means of weighted least squares (WLS) factor analysis, and subsequently fitted to the Rasch model. In the validation sample, the scales were subjected to confirmatory factor analysis and, again, Rasch modelling. The outcome measure was academic success after two years.

Results

Although the correlational structure within the item set is weak, a unidimensional scale could be fitted to the Rasch model. However, psychometric properties of this scale deteriorated in the validation sample. A model with three highly correlated subject specific factors performed better. All summary scales predicted academic success with an odds ratio of about 2.0. Prediction was independent of high school grades and there was a slight tendency for prediction to be better in females than in males.

Conclusions

A model separating biology, physics, and chemistry into different Rasch scales seems to be more suitable for item bank development than a unidimensional model, even when these scales are highly correlated and enter into a global score. When such a combination scale is used to select the upper quartile of applicants, the proportion of successful completion of the curriculum after two years is expected to rise substantially.
Plate-based transfection and culturing technique for genetic manipulation of Plasmodium falciparum
Authors: Caro Florence , Miller Mathew G , DeRisi Joseph L
Published: January 2012

Genetic manipulation of malaria parasites remains an inefficient, time-consuming and resource-intensive process. Presented here is a set of methods for 96-well plate-based transfection and culture that improve the efficiency of genetic manipulation of Plasmodium falciparum. Compared to standard protocols plate-based transfection requires 20-fold less DNA, transient transfection efficiency achieved is approximately seven-fold higher, whilst stable transfection success rate is above 90%. Furthermore the utility of this set of protocols to generate a knockout of the PfRH3 pseudogene, screened by whole-cell PCR, is demonstrated. The methods and tools presented here will facilitate genome-scale genetic manipulation of P. falciparum.
Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population
Authors: Kanaan Ziad M , Eichenberger Maurice R , Ahmad Surriya , Weller Clayton , Roberts Henry , Pan Jianmin , Rai Shesh N , Petras Robert , Weller E Brooks , Galandiuk Susan
Published: January 2012

Background

Crohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America.

Methods

Patients were diagnosed to have CD or UC using conventional radiologic, endoscopic, and/or histopathologic findings. Histological diagnosis was made by a single specialist gastrointestinal pathologist with a particular interest in IBD. Information regarding cigarette smoke exposure was obtained by administration of the Behavioral Risk Factor Surveillance System Survey (BRFSS) to all patients. Genomic DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 Single Nucleotide Polymorphisms (SNP) in NOD2, IL23r, OCTN1 genes along with IGR.

Results

Our cohort consists of 1196 patients: 435 controls, 485 CD patients, and 276 UC patients. Only patients with genotype data for at least 7 of 11 SNPs were included in our data analysis. The control groups for all 11 SNPs were in Hardy-Weinberg Equilibrium. In genotype-association SNP analysis, all NOD2 SNPs (rs5743293, rs2066844, rs2066845) and the IL23r SNP (rs11465804) showed a significant association to IBD (p < 0.03). A multiple gene-interaction analysis showed an association between NOD2 and IL23r with UC (p = 0.04). There were no associations between any OCTN1 and IGR SNPs and IBD in this cohort. A multivariable logistic regression analysis showed that female gender, "current" or "former" smoking status, family history of IBD, and NOD2 SNP minor alleles were associated with CD.

Conclusion

IBD remains to be challenging to properly diagnose, characterize, and treat. Our study proposes a combined genetic, phenotypic, and environmental approach in an attempt to better understand IBD. Previously demonstrated associations between OCTN1 and IGR and IBD were not confirmed.
Adsorption and desorption characteristics of arsenic onto ceria nanoparticles
Authors: Feng Qinzhong , Zhang Zhiyong , Ma Yuhui , He Xiao , Zhao Yuliang , Chai Zhifang
Published: January 2012

The rapid increase in the use of engineered nanoparticles [ENPs] has resulted in an increasing concern over the potential impacts of ENPs on the environmental and human health. ENPs tend to adsorb a large variety of toxic chemicals when they are emitted into the environment, which may enhance the toxicity of ENPs and/or adsorbed chemicals. The study was aimed to investigate the adsorption and desorption behaviors of arsenic on ceria NPs in aqueous solution using batch technique. Results show that the adsorption behavior of arsenic on ceria NPs was strongly dependent on pH and independent of ionic strength, indicating that the electrostatic effect on the adsorption of these elements was relatively not important compared to surface chemical reactions. The adsorption isotherms fitted very well to both the Langmuir and Freundlich models. The thermodynamic parameters (ΔH

0
, ΔS

0
, and ΔG

0
) for the adsorption of arsenic were determined at three different temperatures of 283, 303, and 323 K. The adsorption reaction was endothermic, and the process of adsorption was favored at high temperature. The desorption data showed that desorption hysteresis occurred at the initial concentration studied. High adsorption capacity of arsenic on ceria NPs suggests that the synergistic effects of ceria NPs and arsenic on the environmental systems may exist when they are released into the environment.
The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: cytokeratin 7-/20+ phenotype is more specific than CDX2 antibody
Authors: Bayrak Reyhan , Haltas Hacer , Yenidunya Sibel
Published: January 2012

Background/Objective

Metastatic adenocarcinoma from an unknown primary site is a common clinical problem. Determining the cytokeratin (CK) 7/CK20 pattern of tumors is one of the most helpful procedures for this purpose since the CK7-/CK20+ pattern is typical of colorectal adenocarcinomas. CDX2, a critical nuclear transcription factor for intestinal development, is expressed in intestinal epithelium and adenocarcinomas. In the present study, we compared the sensitivity and specificity of CDX2 expression and the CK7-/CK20+ phenotype in differentiating colorectal adenocarcinomas from pancreatic and gastric adenocarcinomas.

Methods

CK7/CK20 staining pattern and CDX2 expression were evaluated in 118 cases of colorectal, 59 cases of gastric, and 32 cases of pancreatic adenocarcinomas. The sensitivity, specificity, and positive and negative predictive values of the CK7-/CK20+ phenotype and of CDX2 expression were analyzed.

Results

The CK7-/CK20+ immunophenotype was expressed by 75 of 118 (64%) colorectal and 3 of 59 (5%) gastric tumors and was not observed in any pancreatic adenocarcinomas. The CK7+/CK20+ immunophenotype was expressed in 24/118 (20%) of colon, 28/59 (48%) of gastric and 7/32 (22%) of pancreatic adenocarcinomas. The CK7+/CK20- expression pattern was observed in only 2% (2 of 118) of colorectal carcinomas. CDX2 was expressed in 114 of 118 (97%) colorectal, 36 of 59 (61%) gastric, and 5 of 32(16%) pancreatic adenocarcinomas. There was no significant association between CDX2 expression and tumor differentiation in colorectal carcinomas. In gastric carcinomas, CDX2 expression was more common in intestinal type tumors than in diffuse type carcinomas. The CK7-/CK20+ phenotype showed a specificity of 96.7% in predicting colorectal adenocarcinomas, which was superior to that of CDX2 expression. CDX2 expression at both cut-off levels (> 5% and > 50%) had a higher sensitivity (96.6% and 78%) than the CK phenotype.

Conclusions

Both the CK7-/CK20+ phenotype and expression of the antibody CDX2 are highly specific and sensitive markers of colorectal origin. CDX2 expression should be a useful adjunct for the diagnosis of intestinal adenocarcinomas, particularly when better established markers such as CK7 and CK20 yield equivocal results. The CK7-/CK20+ phenotype is superior in its specificity and positive predictive value and might be preferred.

Virtual slides

The virtual slide(s) for this article can be found here:

http://www.diagnosticpathology.diagnomx.eu/vs/4851011866354821
Towards real-time metabolic profiling of a biopsy specimen during a surgical operation by 1H high resolution magic angle spinning nuclear magnetic resonance: a case report
Authors: Piotto Martial , Moussallieh François-Marie , Neuville Agnès , Bellocq Jean-Pierre , Elbayed Karim , Namer Izzie Jacques
Published: January 2012

Introduction

Providing information on cancerous tissue samples during a surgical operation can help surgeons delineate the limits of a tumoral invasion more reliably. Here, we describe the use of metabolic profiling of a colon biopsy specimen by high resolution magic angle spinning nuclear magnetic resonance spectroscopy to evaluate tumoral invasion during a simulated surgical operation.

Case presentation

Biopsy specimens (n = 9) originating from the excised right colon of a 66-year-old Caucasian women with an adenocarcinoma were automatically analyzed using a previously built statistical model.

Conclusions

Metabolic profiling results were in full agreement with those of a histopathological analysis. The time-response of the technique is sufficiently fast for it to be used effectively during a real operation (17 min/sample). Metabolic profiling has the potential to become a method to rapidly characterize cancerous biopsies in the operation theater.
Expression of 14-3-3 protein isoforms in mouse oocytes, eggs and ovarian follicular development
Authors: De Santanu , Marcinkiewicz Jennifer L , Vijayaraghavan Srinivasan , Kline Douglas
Published: January 2012

Background

The 14-3-3 (YWHA) proteins are a highly conserved, ubiquitously expressed family of proteins. Seven mammalian isoforms of 14-3-3 are known (β, γ, ε, ζ, η, τ and, σ). These proteins associate with many intracellular proteins involved in a variety of cellular processes including regulation of the cell cycle, metabolism and protein trafficking. We are particularly interested in the role of 14-3-3 in meiosis in mammalian eggs and the role 14-3-3 proteins may play in ovarian function. Therefore, we examined the expression of 14-3-3 proteins in mouse oocyte and egg extracts by Western blotting after polyacrylamide gel electrophoresis, viewed fixed cells by indirect immunofluorescence, and examined mouse ovarian cells by immunohistochemical staining to study the expression of the different 14-3-3 isoforms.

Results

We have determined that all of the mammalian 14-3-3 isoforms are expressed in mouse eggs and ovarian follicular cells including oocytes. Immunofluorescence confocal microscopy of isolated oocytes and eggs confirmed the presence of all of the isoforms with characteristic differences in some of their intracellular localizations. For example, some isoforms (β, ε, γ, and ζ) are expressed more prominently in peripheral cytoplasm compared to the germinal vesicles in oocytes, but are uniformly dispersed within eggs. On the other hand, 14-3-3η is diffusely dispersed in the oocyte, but attains a uniform punctate distribution in the egg with marked accumulation in the region of the meiotic spindle apparatus. Immunohistochemical staining detected all isoforms within ovarian follicles, with some similarities as well as notable differences in relative amounts, localizations and patterns of expression in multiple cell types at various stages of follicular development.

Conclusions

We found that mouse oocytes, eggs and follicular cells within the ovary express all seven isoforms of the 14-3-3 protein. Examination of the differential expression of these 14-3-3 isoforms in female germ cells and ovarian follicles provides the foundation for further investigating 14-3-3 isoform-specific interactions with key proteins involved in ovarian development, meiosis and oocyte maturation. This will lead to a better understanding of the individual functional roles of the 14-3-3 protein isoforms in mammalian oogenesis and female reproductive development.
Improving global influenza surveillance: trends of A(H5N1) virus in Africa and Asia
Authors: Escorcia Magdalena , Attene-Ramos Matias S , Estrada Marco Juarez , Nava Gerardo M
Published: January 2012

Background

Highly pathogenic avian influenza A(H5N1) viruses are an important health problem in many Asian and African countries. The current increase in human cases demonstrates that influenza A(H5N1) is still a significant global pandemic threat. Many health organizations have recognized the need for new strategies to improve influenza global surveillance. Specifically, the World Health Organization through the global technical consultation for influenza surveillance have called for a detailed picture of the current limitations, especially at the nation level, to evaluate, standardize and strength reporting systems. The main goal of our study is to demonstrate the value of genetic surveillance as part of a strategic surveillance plan. As a proof of concept, we evaluated the current situation of influenza A(H5N1) in Asian and Africa.

Results

Our analysis revealed a power-law distribution in the number of sequences of A(H5N1) viruses analyzed and/or reported to influenza surveillance networks. The majority of the Asian and African countries at great risk of A(H5N1) infections have very few (approximately three orders of magnitude) sequenced A(H5N1) viruses (e.g. hemagglutinin genes). This suggests that countries under pandemic alert for avian influenza A(H5N1) have very limited participation (e.g. data generation, genetic analysis and data share) in avian influenza A(H5N1) surveillance. More important, this study demonstrates the usefulness of influenza genetic surveillance to detect emerging pandemic threat viruses.

Conclusions

Our study reveals that some countries suffering from human cases of avian influenza have limited participation (e.g. genetic surveillance or data share) with global surveillance networks. Also, we demonstrate that the implementation of genetic surveillance programs could increase and strengthen worldwide epidemic and pandemic preparedness. We hope that this work promotes new discussions between policy makers and health surveillance organizations to improve current methodologies and regulations.
TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism
Authors: De Larichaudy Joffrey , Zufferli Alessandra , Serra Filippo , Isidori Andrea M , Naro Fabio , Dessalle Kevin , Desgeorges Marine , Piraud Monique , Cheillan David , Vidal Hubert , Lefai Etienne , Némoz Georges
Published: January 2012

Background

Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention.

Results

We addressed this question both in vitro using differentiated myotubes treated with TNF-α, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-α was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-α, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy.

Conclusions

Ceramide accumulation induced by TNF-α or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations.
The distribution pattern of critically short telomeres in human osteoarthritic knees
Authors: Harbo Maria , Bendix Laila , Bay-Jensen Anne-Christine , Graakjaer Jesper , Søe Kent , Andersen Thomas L , Kjaersgaard-Andersen Per , Koelvraa Steen , Delaisse Jean-Marie
Published: January 2012

Introduction

Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence.

Methods

Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF).

Results

The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length.

Conclusions

These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.
Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup
Authors: Lorente Leonardo , Iceta Ruth , Martín María M , López-Gallardo Esther , Solé-Violán Jordi , Blanquer José , Labarta Lorenzo , Díaz César , Jiménez Alejandro , Montoya Julio , Ruiz-Pesini Eduardo
Published: January 2012

Introduction

We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival.

Methods

A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints.

Results

Patients with the JT mtDNA haplogroup (n = 15) showed higher COXq/CSa ratio at day 4 (P = 0.04) and day 8 (P = 0.02) than those with other haplogroups (n = 81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio = 0.18; 95% confidence interval = 0.04 to 0.94; P = 0.04) and COXq/CSa ratio (odds ratio = 0.53; 95% confidence interval = 0.30 to 0.93; P = 0.03) were associated with 1-month survival after controlling for age and lactic acid levels.

Conclusions

The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups.
Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients With Small-Cell Lung Cancer
Authors: Hou Jian-Mei , Krebs Matthew G. , Lancashire Lee , Sloane Robert , Backen Alison , Swain Rajeeb K. , Priest Lynsey J.C. , Greystoke Alastair , Zhou Cong , Morris Karen , Ward Tim , Blackhall Fiona H. , Dive Caroline
Published: January 2012

Purpose

Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and “virtual” biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment.

Patients and Methods

Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined.

Results

CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM.

Conclusion

Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.
Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group
Authors: Dubsky Peter C. , Jakesz Raimund , Mlineritsch Brigitte , Pöstlberger Sabine , Samonigg Hellmut , Kwasny Werner , Tausch Christoph , Stöger Herbert , Haider Karin , Fitzal Florian , Singer Christian F. , Stierer Michael , Sevelda Paul , Luschin-Ebengreuth Gero , Taucher Susanne , Rudas Margaretha , Bartsch Rupert , Steger Günther G. , Greil Richard , Filipcic Lidija , Gnant Michael
Published: January 2012

Purpose

Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor–positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients.

Patients and Methods

Endocrine receptor–positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated.

Results

Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment.

Conclusion

Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.
Design Issues in Randomized Phase II/III Trials
Authors: Korn Edward L. , Freidlin Boris , Abrams Jeffrey S. , Halabi Susan
Published: January 2012

Phase II trials are used to show sufficient preliminary activity of a new treatment (in single-arm designs or randomized screening designs) or to select among treatments with demonstrated activity (in randomized selection designs). The treatments prioritized in a phase II trial are then tested definitively against a control treatment in a randomized phase III trial. Randomized phase II/III trials use an adaptive trial design that combines these two types of trials in one, with potential gains in time and reduced numbers of patients required to be treated. Two key considerations in designing a phase II/III trial are whether to suspend accrual while the phase II data mature and the choice of phase II target treatment effect. We discuss these phase II/III design parameters, give examples of phase II/III trials, and provide recommendations concerning efficient phase II/III trial designs.
Improving Wait Time for Chemotherapy in an Outpatient Clinic at a Comprehensive Cancer Center
Authors: Kallen Michael A. , Terrell James A. , Lewis-Patterson Paula , Hwang Jessica P.
Published: January 2012

Excessive appointment delay time has been identified as a primary source of overall patient appointment dissatisfaction among the general medical patient population as well as oncology patients.
US Food and Drug Administration Regulation of Medical Devices and Radiation Oncology: Can Reform Improve Safety?
Authors: Hattangadi Jona A. , O'Reilly James T. , Recht Abram
Published: January 2012

A review of the issues involved in medical device regulation in radiation oncology, including a general review of federal medical device regulation and explanations of the legal and regulatory framework.
Revisions to the 2009 American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards: Expanding the Scope to Include Inpatient Settings
Authors: Jacobson Joseph O. , Polovich Martha , Gilmore Terry R. , Schulmeister Lisa , Esper Peg , LeFebvre Kristine B. , Neuss Michael N.
Published: January 2012

The ASCO/ONS Chemotherapy Administration Safety Standards were reviewed to address interim changes in practice and make needed modifications. The most significant change is to extend their scope to the inpatient setting.
Physiological Responses to Acute Psychological Stress Are Reduced by the PPARγ Agonist Rosiglitazone
Authors: Ryan Karen K. , Grayson Bernadette E. , Jones Kenneth R. , Schneider Alexander L. , Woods Stephen C. , Seeley Randy J. , Herman James P. , Ulrich-Lai Yvonne M.
Published: January 2012

Physiological reactions to psychological stress are positively associated with several important chronic conditions including cardiovascular and neurodegenerative diseases and are linked to increased mortality. As such, the identification of cellular and molecular pathways that act to reduce stress responding may represent important targets for therapeutic intervention. Here we report that acute treatment with the peroxisome-proliferator activated receptor-γ (PPARγ) agonist rosiglitazone (RSG) blunts systemic responses to acute psychological stress in rats. Rats that had previously received oral RSG for 5 d exhibited a 40% reduction in the initial heart rate response to an acute restraint stress, compared with vehicle-treated controls, suggesting that increased PPARγ signaling blunts the acute autonomic response to stress. Rats previously treated with RSG likewise had a blunted hormonal response to this stressor, exhibiting a 30% reduction in peak corticosterone levels compared with controls. Moreover, stress-induced expression of c-Fos, a marker of early neuronal activation, was similarly reduced in the paraventricular hypothalamus, a key site for brain stress integration, facilitating both autonomic and hypothalamic-pituitary-adrenocortical responses to stress. Taken as a whole, these data suggest that PPARγ stimulation potently inhibits physiological responses to psychological stress, prescribing a novel role for PPARγ signaling in the regulation of brain stress integration.
Minireview: Epigenetics of Obesity and Diabetes in Humans
Authors: Slomko Howard , Heo Hye J. , Einstein Francine H.
Published: January 2012

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.
Brown Fat Lipoatrophy and Increased Visceral Adiposity through a Concerted Adipocytokines Overexpression Induces Vascular Insulin Resistance and Dysfunction
Authors: Gómez-Hernández Almudena , Otero Yolanda F. , de las Heras Natalia , Escribano Óscar , Cachofeiro Victoria , Lahera Vicente , Benito Manuel
Published: January 2012

In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF-α, leptin, and plasminogen activator inhibitor 1) and nuclear factor-κB binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-α antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-α antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-κB-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-α antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers.
Activation of Southern White Rhinoceros (Ceratotherium simum simum) Estrogen Receptors by Phytoestrogens: Potential Role in the Reproductive Failure of Captive-Born Females?
Authors: Tubbs Christopher , Hartig Phillip , Cardon Mary , Varga Nicole , Milnes Matthew
Published: January 2012

The captive southern white rhinoceros (SWR; Ceratotherium simum simum) population serves as an important genetic reservoir critical to the conservation of this vulnerable species. Unfortunately, captive populations are declining due to the poor reproductive success of captive-born females. Captive female SWR exhibit reproductive problems suggested to result from continual ovarian follicular activity and prolonged exposure to endogenous estrogen. However, we investigated the potential role of exogenous dietary phytoestrogens in the reproductive failure of SWR by cloning and characterizing in vitro phytoestrogen binding and activation of recombinant SWR estrogen receptors (ESR). We compared those characteristics with recombinant greater one-horned rhinoceros (GOHR; Rhinoceros unicornis) ESR, a species that receives similar captive diets yet reproduces relatively well. Our results indicate that phytoestrogens bind rhino ESR in a manner similar to other vertebrate species, but there are no differences found in phytoestrogen binding affinity of SWR ESR compared with GOHR ESR. However, species-specific differences in ESR activation by phytoestrogens were detected. The phytoestrogen coumestrol stimulated greater maximal activation of SWR ESR1 than GOHR ESR1. SWR ESR2 were also more sensitive to phytoestrogens and were activated to a greater extent by both coumestrol and daidzein. The concentrations in which significant differences in ESR activation occurred (10−7 to 10−5m) are consistent with circulating concentrations measured in other vertebrate species. Taken together, these findings suggest that phytoestrogens potentially pose a risk to the reproductive health of captive SWR. However, additional studies are needed to further clarify the physiological role of dietary phytoestrogens in the reduced fertility of this species.
Myoblast fusion: lessons from flies and mice
Authors: Abmayr Susan M. , Pavlath Grace K.
Published: January 2012

The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or myofibrils, within a large volume of cytoplasm. Principles learned from the study of myoblast fusion not only enhance our understanding of myogenesis, but also contribute to our perspectives on membrane fusion and cell-cell fusion in a wide array of model organisms and experimental systems. Recent studies have advanced our views of the cell biological processes and crucial proteins that drive myoblast fusion. Here, we provide an overview of myoblast fusion in three model systems that have contributed much to our understanding of these events: the Drosophila embryo; developing and regenerating mouse muscle; and cultured rodent muscle cells.
La-motif–dependent mRNA association with Slf1 promotes copper detoxification in yeast
Authors: Schenk Luca , Meinel Dominik M. , Strässer Katja , Gerber André P.
Published: January 2012

The La-motif (LAM) is an ancient and ubiquitous RNA-binding domain defining a superfamily of proteins, which comprises the genuine La proteins and La-related proteins (LARPs). In contrast to La, which binds and stabilizes pre-tRNAs and other RNA polymerase III transcripts, data on function and RNA targets of the LARPs have remained scarce. We have undertaken a global approach to elucidate the previously suggested role of the yeast LARP Slf1p in copper homeostasis. By applying RNA-binding protein immunopurification-microarray (RIP-Chip) analysis, we show that Slf1p and its paralog Sro9p copurify with overlapping sets of hundreds of functionally related mRNAs, including many transcripts coding for ribosomal proteins and histones. Interestingly, among these potential RNA targets were also mRNAs coding for proteins critical for protection of cells against elevated copper concentrations. Mutations introduced in the conserved aromatic patch of the LAM in Slf1p drastically impaired both association with its targets and Slf1-mediated protection of cells against toxic copper concentrations. Furthermore, we show that Slf1p stabilizes copper-related mRNA targets in a LAM-dependent manner. These results provide the first evidence for post-transcriptional regulation of factors/pathways implicated in copper homeostasis by a cytoplasmic RBP.