bluuebunny/crossref_metadata_2025 huggingface dataset:
Carfilzomib and ONX 0912 Inhibit Cell Survival and Tumor Growth of Head and Neck Cancer and Their Activities Are Enhanced by Suppression of Mcl-1 or Autophagy
Authors: Zang Yan , Thomas Sufi M. , Chan Elena T. , Kirk Christopher J. , Freilino Maria L. , DeLancey Hannah M. , Grandis Jennifer R. , Li Changyou , Johnson Daniel E.
Published: August 2012

Purpose: Carfilzomib is a selective, irreversible inhibitor of the chymotrypsin-like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC).

Experimental Design: The effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined.

Results: Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner.

Conclusions: These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy. Clin Cancer Res; 18(20); 5639–49. ©2012 AACR.
Loss of the Malignant Phenotype of Human Neuroblastoma Cells by a Catalytically Inactive Dominant-Negative hTERT Mutant
Authors: Samy Mona , Gattolliat Charles-Henry , Pendino Frédéric , Hillion Josette , Nguyen Eric , Bombard Sophie , Douc-Rasy Sétha , Bénard Jean , Ségal-Bendirdjian Evelyne
Published: August 2012

Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. Mol Cancer Ther; 11(11); 2384–93. ©2012 AACR.
Stromal Platelet-Derived Growth Factor Receptor α (PDGFRα) Provides a Therapeutic Target Independent of Tumor Cell PDGFRα Expression in Lung Cancer Xenografts
Authors: Gerber David E. , Gupta Puja , Dellinger Michael T. , Toombs Jason E. , Peyton Michael , Duignan Inga , Malaby Jennifer , Bailey Timothy , Burns Colleen , Brekken Rolf A. , Loizos Nick
Published: August 2012

In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα monoclonal antibodies (mAb) on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression. Mol Cancer Ther; 11(11); 2473–82. ©2012 AACR.
Decreased Hypoxia-Inducible Factor-1α in Gastrocnemius Muscle in Rats with Chronic Kidney Disease
Authors: Flisiński Mariusz , Brymora Andrzej , Bartłomiejczyk Irena , Wiśniewska Ewa , Gołda Ryszard , Stefańska Anna , Pączek Leszek , Manitius Jacek
Published: August 2012

Background/Aims: Hypoxia-inducible factor (HIF)-1α is responsible for increased expression of genes engaged in angiogenesis. Our previous study indicated capillary rarefaction and atrophy of glycolytic fibers, mainly in locomotor muscles of uremic animals. Perhaps these changes are secondary to disturbances of HIF-1α in skeletal muscles. Methods: Expression of HIF-1α at mRNA and protein levels, as well as mRNA of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), in gastrocnemius muscle (MG) and longissimus thoracic muscle (ML) were measured by RT-PCR and Western blot. Rats were randomized to subtotal nephrectomy (CKD5/6), uninephrectomy (CKD1/2) or sham operation (controls). Results: For CKD5/6 versus controls, mRNA levels for HIF-1α, VEGF-A, VEGFR-1 and VEGFR-2 were significantly reduced only in MG, while eNOS was significantly decreased and iNOS was significantly increased only in ML. Western blot analysis indicated significantly increased HIF-1α protein levels in MG and ML from CKD1/2 animals versus controls, whereas in the CKD5/6 group, the level of HIF-1α protein decreased significantly in MG and increased significantly in ML versus controls and CKD1/2. Conclusion: The reduced expression of HIF-1α mRNA and protein in locomotor muscle from CKD5/6 animals may be involved in the pathogenesis of uremic myopathy. Increased expression of iNOS in the postural muscles may act as a protective factor through HIF-1α stabilization.
Less Cognitive and Neurological Deficits in Schizophrenia Patients Carrying Risk Variant in ZNF804A
Authors: Van Den Bossche Maarten J.A. , Docx Lise , Morrens Manuel , Cammaerts Sophia , Strazisar Mojca , Bervoets Chris , Smolders Stefanie , Depreeuw Veerle , Lenaerts An-Sofie , De Rijk Peter , Del-Favero Jurgen , Sabbe Bernard G.C.
Published: August 2012

Background: The rs1344706 single nucleotide polymorphism in the ZNF804A gene is a common variant with strong evidence for association with schizophrenia. Recent studies show an association of rs1344706 with cognitive functioning, and there is some evidence suggesting that the risk allele may increase susceptibility for a subtype of schizophrenia with relatively spared cognition. Methods: We tested the effect of rs1344706 genotype in 89 schizophrenia patients on 3 basic cognitive domains (working memory, processing speed and attention) shown to be severely impaired in schizophrenia. Also we investigated the effect of rs1344706 on the severity of neurological soft signs, subtle impairments in motor and sensory functions highly frequent in schizophrenia patients. Neurological soft signs and cognitive deficits are central features of schizophrenia and are tightly linked with clinical, social and functional outcome. Results: Our results show an association of higher rs1344706 risk allele load with improved performance on processing speed and with fewer neurological soft signs. Conclusions: Together with other studies, our findings suggest that ZNF804A is associated with a subtype of schizophrenia with better cognitive and neurological functioning. Discovery of the specific pathways through which ZNF804A is exerting this effect may lead to better prevention, diagnosis and treatment for a specific group of schizophrenia patients.
2-Heptanone Increases the Firing Rate of the Basal Amygdala: Role of Anterior Olfactory Epithelial Organs
Authors: Contreras Carlos M. , Gutiérrez-García Ana G. , Molina-Jiménez Tania , Mendoza-López Remedios
Published: August 2012

Wistar rats subjected to physical stress release a urine alarm pheromone (2-heptanone) that produces signs of anxiety and despair in receptor rats not subjected to physical stress. However, unknown are the effects of 2-heptanone on the firing rate of the basal amygdala, a structure that participates in the expression of fear, and the participation of anterior olfactory epithelial organs, namely the septal organ and vomeronasal organ (SO-VNO). We explored the effects of 2-heptanone applied near the nostrils on single-unit extracellular recordings from the basal amygdala in a sham-operated group and rats that underwent removal of the SO-VNO. The firing rate of basal amygdala neurons in the SO-VNO removal group was significantly higher than in the sham-operated group. In both groups, recordings were classified according to the responses to 2-heptanone (i.e., increased firing rate, decreased firing rate, and no response). SO-VNO removal was associated with an increased firing rate in the three types of neurons. A similar number of neurons increased their firing rate during and after 2-heptanone stimulation in both groups, but such an increase in firing rate was longer in the group of rats subjected to SO-VNO removal. The results indicate that the SO-VNO is not essential for the effect of 2-heptanone on the firing rate of basal amygdala neurons. SO-VNO ablation did not block but rather accentuated the response of amygdala neurons to 2-heptanone.
Fractional Excretion of Uric Acid as a Predictor for Saline Responsiveness in Long-Term Kidney Transplant Patients
Authors: Choi Jong-Wook , Park Joon-Sung , Koo Tai Yeon , Lee Chang Hwa , Kang Chong Myung , Kim Gheun-Ho
Published: August 2012

Background/Aims: Subclinical hypovolemia may contribute to allograft dysfunction in long-term kidney transplant (KT) patients. In order to predict responsiveness to saline hydration, indices for tubular transport were investigated. Methods: Fifty-four clinically euvolemic long-term KT patients with recently aggravated azotemia were given intravenous hydration as follows: 0.9% saline 5 ml/kg over 1 h, followed by 0.9% saline 1 ml/kg/h over 12 h and 1 liter of 0.45% saline over the next 24 h. Serum and urine data were collected and analyzed to assess responses. Results: In all patients, saline hydration relieved azotemia, as shown by blood urea nitrogen (46.9 ± 17.2 vs. 39.3 ± 15.4 mg/dl; p < 0.01) and serum creatinine levels (2.9 ± 1.1 vs. 2.5 ± 1.1 mg/dl; p < 0.01) on day 0 versus day 2. In 38 patients, serum creatinine did not increase in the following month (70% responders). Compared with the nonresponders, the responders had a higher urine-to-plasma creatinine ratio and lower fractional excretion of sodium, uric acid and urea at admission. Multivariate logistic regression analysis revealed that responsiveness to saline hydration was independently associated with lower fractional excretion of uric acid. Conclusion: Subclinical hypovolemia should be considered in long-term KT patients with azotemia of unexplainable causes. Fractional excretion of uric acid may predict responsiveness to saline hydration.
RANKL Enhances Macrophage Paracrine Pro-Calcific Activity in High Phosphate-Treated Smooth Muscle Cells: Dependence on IL-6 and TNF-α
Authors: Deuell Kate Ann , Callegari Andrea , Giachelli Cecilia M. , Rosenfeld Michael E. , Scatena Marta
Published: August 2012

Background: Vascular calcification is highly correlated with cardiovascular disease (CVD) morbidity and mortality, and it is associated with inflammation. Receptor activator of NF-ĸB ligand (RANKL) inhibition in vivo has been shown to reduce vascular calcification in a mouse model of atherosclerosis. Therefore, we tested the hypothesis that RANKL regulates smooth muscle cell (SMC) calcification by modulating macrophage production of pro-calcific cytokines. Methods: We used a bone marrow-derived macrophage (BMDM)/SMC co-culture system and examined the effects of RANKL on BMDM activation and SMC matrix calcification. Results: Treatment with RANKL alone did not stimulate SMC calcification induced by elevated phosphate. BMDMs differentiated with macrophage colony-stimulating factor and placed in co-culture with SMCs increased phosphate-induced SMC calcification. RANKL added to the BMDM/SMC co-cultures further enhanced SMC calcification. Treatment of BMDMs with RANKL resulted in increased expression of IL-6 and TNF-α. Thus, increased expression of these pro-calcific cytokines in macrophages may mediate RANKL-induced SMC calcification in a paracrine fashion. Addition of neutralizing IL-6 and TNF-α antibodies together with RANKL treatment significantly reduced the RANKL induction of SMC calcification. Conclusion: RANKL activation of pro-inflammatory and pro-calcific pathways in macrophages may contribute to vascular calcification and inflammation.
BMPR2
Mutations Influence Phenotype More Obviously in Male Patients With Pulmonary Arterial Hypertension
Authors: Liu Dong , Wu Wen-Hui , Mao Yi-Min , Yuan Ping , Zhang Rui , Ju Feng-Ling , Jing Zhi-Cheng
Published: August 2012

Background—

BMPR2
mutations predispose to idiopathic and heritable pulmonary arterial hypertension (IPAH and HPAH). The influence of
BMPR2
mutations on clinical outcome is not concordant in different ethnic groups. Although the
BMPR2
mutation spectrum and mutation rate in Chinese PAH patients has been reported previously, the influence of genotype on phenotype and whether this influence is associated with sex have not been investigated.

Methods and Results—

We analyzed data from 305 PAH patients considered as either idiopathic or heritable who underwent genetic counseling in Shanghai Pulmonary Hospital. The clinical, functional, and hemodynamic characteristics of
BMPR2
mutation carriers and noncarriers were compared. The more severe hemodynamic compromise at diagnosis in
BMPR2
mutation carriers versus noncarriers is concordant with other ethnic groups. In the Chinese PAH cohort,
BMPR2
mutations were associated with a higher risk of mortality after adjustment for age and sex (hazard ratio, 1.971; 95% confidence interval, 1.121–3.466;
P
=0.018). The overall survival difference between mutation carriers and noncarriers was more obvious in male patients, which was reflected by a higher mortality risk of male mutation carriers than that of male noncarriers after adjustment for age at diagnosis (hazard ratio, 3.702; 95% confidence interval, 1.416–9.679;
P
=0.008). In females, this trend did not reach statistical significance.

Conclusions—

BMPR2
mutations influence phenotype more obviously in male PAH patients. The pathogenesis of female PAH patients is more complicated, and the influence of
BMPR2
mutations may be modified by other unknown factors, making disparities in the prognosis between female mutation carriers and noncarriers less evident.
Diagnostic and Prognostic Performance of Myeloperoxidase Plasma Levels Compared With Sensitive Troponins in Patients Admitted With Acute Onset Chest Pain
Authors: Rudolph Volker , Keller Till , Schulz Andreas , Ojeda Francisco , Rudolph Tanja K. , Tzikas Stergios , Bickel Christoph , Meinertz Thomas , Münzel Thomas , Blankenberg Stefan , Baldus Stephan
Published: August 2012

Background—

Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP.

Methods and Results—

One thousand, eight hundred and eighteen consecutive patients (mean age, 61.4±13.5 years; 33.6% female) admitted for CP underwent determination of MPO, sTnI, and B-natriuretic peptide plasma levels at admission and 3 hours and 6 hours thereafter. A cut-off for MPO was defined in 5000 population-based subjects. Baseline MPO levels were elevated in patients with acute myocardial infarction compared with patients with noncoronary CP. For all time-points accuracy of MPO was inferior to sTNI for predicting AMI. The sensitivity of MPO to diagnose AMI at presentation was 73.5% compared with 90.7% for sTNI, and the specificity of MPO was 45.5% as opposed to 90.2%. B-natriuretic peptide levels also failed to demonstrate independent diagnostic information. Both MPO and B-natriuretic peptide were predictive for increased risk of adverse events at 30 days and 6 months, whereas their predictive value was weakened after covariate adjustment.

Conclusions—

The data demonstrate that MPO and B-natriuretic peptide fail to provide incremental information for patients with acute onset CP when added to sensitive troponin. However, there is a potential value for both biomarkers as prognostic markers.
Spongious Hypertrophic Cardiomyopathy in Patients With Mutations in the Four-and-a-Half LIM Domain 1 Gene
Authors: Binder Josepha S. , Weidemann Frank , Schoser Benedikt , Niemann Markus , Machann Wolfram , Beer Meinrad , Plank Gernot , Schmidt Albrecht , Bisping Egbert , Poparic Ivana , Lafer Ingrid , Stojakovic Tatjana , Quasthoff Stefan , Vincent John B. , Rienmueller Rainer , Speicher Michael R. , Berghold Andrea , Pieske Burkert , Windpassinger Christian
Published: August 2012

Background—

X-linked myopathy with postural muscle atrophy is a novel X-linked myopathy caused by mutations in the four-and-a-half LIM domain 1 gene (FHL1). Cardiac involvement was suspected in initial publications. We now systematically analyzed the association of the
FHL1
genotype with the cardiac phenotype to establish a potential cardiac involvement in the disease.

Methods and Results—

Seventeen male patients and 23 female mutation carriers were compared with healthy controls. Every patient underwent a comprehensive clinical and cardiovascular workup. ECG abnormalities occurred frequently in affected males and were less frequent in heterozygous females. Both male and female mutation carriers had increased myocardial mass (affected males=115.1±25.3 g/m
2
; heterozygous females=95.1±19.6 g/m
2
; controls=89.0±15.6 g/m
2
and 72.6±12.6 g/m
2
; respectively) with increased wall thickness (typically midventricular and apical segments) mainly in affected males. Longitudinal systolic function was reduced in affected males (radial systolic strain: affected males=24.6±11.8%; male controls=43.2±14.8%;
P
=0.002). Diastolic dysfunction occurred in both affected males and heterozygous females. Cardiac MRI revealed a morphological hallmark of X-linked myopathy with postural muscle atrophy; a characteristic spongious structure and replacement fibrosis indicated by late enhancement could be detected in most affected males. X-linked myopathy with postural muscle atrophy was associated with reduced exercise capacity in affected males but not in heterozygous female mutation carriers.

Conclusions—

X-linked myopathy with postural muscle atrophy patients consistently showed electrical, functional, and characteristic morphological cardiac abnormalities that translate into reduced exercise capacity. Reduced systolic and diastolic function is associated with a novel type of spongious hypertrophic cardiomyopathy. An unexpected finding was that some cardiac abnormalities were also present in heterozygous female mutation carriers.
Pooled DNA Resequencing of 68 Myocardial Infarction Candidate Genes in French Canadians
Authors: Beaudoin Mélissa , Lo Ken Sin , N’Diaye Amidou , Rivas Manuel A. , Dubé Marie-Pierre , Laplante Nathalie , Phillips Michael S. , Rioux John D. , Tardif Jean-Claude , Lettre Guillaume
Published: August 2012

Background—

Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg,
PCSK9
), the role of low-frequency genetic variation (minor allele frequency [MAF]) ≈0.1%−5% on MI/coronary artery disease predisposition has not been extensively investigated.

Methods and Results—

We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF≥1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French-Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians.

Conclusions—

We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size.
Exome Sequencing Identifies 2 Rare Variants for Low High-Density Lipoprotein Cholesterol in an Extended Family
Authors: Reddy M.V. Prasad Linga , Iatan Iulia , Weissglas-Volkov Daphna , Nikkola Elina , Haas Blake E. , Juvonen Miina , Ruel Isabelle , Sinsheimer Janet S. , Genest Jacques , Pajukanta Päivi
Published: August 2012

Background—

Exome sequencing is a recently implemented method to discover rare mutations for Mendelian disorders. Less is known about its feasibility to identify genes for complex traits. We used exome sequencing to search for rare variants responsible for a complex trait, low levels of serum high-density lipoprotein cholesterol (HDL-C).

Methods and Results—

We conducted exome sequencing in a large French-Canadian family with 75 subjects available for study, of which 27 had HDL-C values less than the fifth age-sex-specific population percentile. We captured ≈50 Mb of exonic and transcribed sequences of 3 closely related family members with HDL-C levels less than the fifth age-sex percentile and sequenced the captured DNA. Approximately 82 000 variants were detected in each individual, of which 41 rare nonsynonymous variants were shared by the sequenced affected individuals after filtering steps. Two rare nonsynonymous variants in the ATP-binding cassette, subfamily A (ABC1), member 1 (ABCA1), and lipoprotein lipase genes predicted to be damaging were investigated for cosegregation with the low HDL-C trait in the entire extended family. The carriers of either variant had low HDL-C levels, and the individuals carrying both variants had the lowest HDL-C values. Interestingly, the ABCA1 variant exhibited a sex effect which was first functionally identified, and, subsequently, statistically demonstrated using additional French-Canadian families with ABCA1 mutations.

Conclusions—

This complex combination of 2 rare variants causing low HDL-C in the extended family would not have been identified using traditional linkage analysis, emphasizing the need for exome sequencing of complex lipid traits in unexplained familial cases.
National Survey of Hospital Strategies to Reduce Heart Failure Readmissions
Authors: Kociol Robb D. , Peterson Eric D. , Hammill Bradley G. , Flynn Kathryn E. , Heidenreich Paul A. , Piña Ileana L. , Lytle Barbara L. , Albert Nancy M. , Curtis Lesley H. , Fonarow Gregg C. , Hernandez Adrian F.
Published: August 2012

Background—

Reducing 30-day heart failure readmission rates is a national priority. Yet, little is known about how hospitals address the problem and whether hospital-based processes of care are associated with reductions in readmission rates.

Methods and Results—

We surveyed 100 randomly selected hospitals participating in the Get With the Guidelines-Heart Failure quality improvement program regarding common processes of care aimed at reducing readmissions. We grouped processes into 3 domains (ie, inpatient care, discharge and transitional care, and general quality improvement) and scored hospitals on the basis of survey responses using processes selected a priori. We used linear regression to examine associations between these domain scores and 30-day risk-standardized readmission rates. Of the 100 participating sites, 28% were academic centers and 64% were community hospitals. The median readmission rate among participating sites (24.0%; 95% CI, 22.6%–25.7%) was comparable with the national average (24.6%; 23.5–25.9). Sites varied substantially in care processes used for inpatient care, education, discharge process, care transitions, and quality improvement. Overall, neither inpatient care nor general quality improvement domains were associated with 30-day readmission rates. Hospitals in the lowest readmission rate quartile had modestly higher discharge and transitional care domain scores (
P
=0.03).

Conclusions—

A variety of strategies are used by hospitals in an attempt to improve 30-day readmission rates for patients hospitalized with heart failure. Although more complete discharge and transitional care processes may be modestly associated with lower 30-day readmission rates, most current strategies are not associated with lower readmission rates.
Lost in Transgenesis
Authors: Davis Jennifer , Maillet Marjorie , Miano Joseph M. , Molkentin Jeffery D.
Published: August 2012

The advent of modern mouse genetics has benefited many fields of diseased-based research over the past 20 years, none perhaps more profoundly than cardiac biology. Indeed, the heart is now arguably one of the easiest tissues to genetically manipulate, given the availability of an ever-growing tool chest of molecular reagents/promoters and “facilitator” mouse lines. It is now possible to modify the expression of essentially any gene or partial gene product in the mouse heart at any time, either gain or loss of function. This review is designed as a handbook for the nonmouse geneticist and/or junior investigator to permit the successful manipulation of any gene or RNA product in the heart, while avoiding artifacts. In the present review, guidelines, pitfalls, and limitations are presented so that rigorous and appropriate examination of cardiac genotype-phenotype relationships can be performed. This review uses examples from the field to illustrate the vast spectrum of experimental and design details that must be considered when using genetically modified mouse models to study cardiac biology.
Stem Cell Factor Gene Transfer Promotes Cardiac Repair After Myocardial Infarction via In Situ Recruitment and Expansion of c-kit
+
Cells
Authors: Yaniz-Galende Elisa , Chen Jiqiu , Chemaly Elie , Liang Lifan , Hulot Jean-Sebastien , McCollum LaTronya , Arias Teresa , Fuster Valentin , Zsebo Krisztina M. , Hajjar Roger J.
Published: August 2012

Rationale:

There is growing evidence that the myocardium responds to injury by recruiting c-kit
+
cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit
+
cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested.

Objective:

To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit
+
progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved.

Methods and Results:

Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit
+
progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction.

Conclusions:

Stem cell factor gene transfer induces c-kit
+
stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction.
Principal Component Analysis of Smoothed Tetrachoric Correlation Matrices as a Measure of Dimensionality
Authors: Debelak Rudolf , Tran Ulrich S.
Published: August 2012

The application of principal component analysis and parallel analysis to smoothed tetrachoric correlation matrices was investigated in a simulation study. To evaluate the effect of several smoothing algorithms, 360 different types of data sets were simulated. Under each simulated condition, two item sets, each fitting a unidimensional two-parameter logistic model, were combined with each other. The simulations differed in the size of the simulated item sets, the size of the person samples, the distribution of the difficulty and discrimination parameters, and the correlation between the person parameters. In general, the application of a smoothing algorithm led to an improved performance in the assessment of dimensionality, but minor differences between the three investigated smoothing algorithms were found. Procedures to apply two of the three investigated smoothing algorithms via R software packages are presented.
Saturated Versus Just Identified Models
Authors: Raykov Tenko , Marcoulides George A. , Patelis Thanos
Published: August 2012

Two concepts of particular relevance for educational and psychological measurement research using the popular structural equation modeling methodology are revisited—saturated model and (just) identified model. The distinction is emphasized between a saturated model on the one hand and an identified model on the other. It is shown that a saturated model need not be identified (and thus need not be just identified). Within that context, it is stressed that for a given set of observed variables there may be more than a single saturated model. To avoid possible confusion, a proposal is made to use the concept of “the saturated model” as referring only to the model with unconstrained variances, covariances, and means for a given set of manifest measures and to make references to “a saturated model” whenever any of the possible set of saturated models for these observed variables is meant.
Occupational Plans, Beliefs about Educational Requirements, and Patterns of College Entry
Authors: Morgan Stephen L. , Leenman Theodore S. , Todd Jennifer J. , Weeden Kim A.
Published: August 2012

In this article, a measure of students’ beliefs is constructed from three sources of information on 12,509 high school seniors from the Education Longitudinal Study (2002 to 2006). First, verbatim responses to questions on occupational plans, drawn from restricted-access data records, are coded into 1,220 categories to capture detailed information (specific job titles), extended information (the listing of multiple jobs), and contradictory information (the listing of multiple jobs with divergent characteristics). Second, the educational requirements of detailed jobs, as specified in the U.S. Department of Labor’s Occupational Information Network database, are matched to all jobs that students list within their verbatim occupational plans. Third, student perceptions of the educational requirements of their planned jobs, which were revealed in response to a follow-up question posed immediately after they provided their verbatim occupational plans, are used to identify students with puzzling beliefs about their educational and occupational trajectories. The authors then show that (1) students who are categorized as having uncertain and/or inaccurate beliefs about the educational requirements of their expected jobs have lower rates of college entry than those with certain and accurate beliefs, and (2) among entrants, these same students have lower rates of immediate college enrollment and lower attendance at four-year colleges.
The Rule of Law and the Enforcement of the Law
Authors: Goldín Liliana , Dowdall Courtney
Published: August 2012

Research with hundreds of mostly indigenous Maya workers in the export processing plants (maquilas) of highland Guatemala has revealed a disconnect between working conditions in the factories, perceived rights, national and international labor laws, and law enforcement. Because of this disjunction, efforts to address the plight of workers must engage the complex conditions of the current labor regimes. Maquilas operate in contexts that are virtually exempt from regulation and conflate national and global orders, precluding a clear perspective on issues of rights and legal claims. In the new geographies of power, workers in transnational factories fall into the interstices between state and nonstate spaces and lose their rights and entitlements in the process.

Investigaciones en torno a cientos de trabajadores, en su mayor parte indígenas mayas, en las maquilas del altiplano guatemalteco revelan profundas discrepancias entre las condiciones laborales en las fábricas, los derechos presuntamente establecidos, una gama de leyes nacionales e internacionales a las cuales se suscribe Guatemala, y los sistemas de tutela y aplicación de la ley. Dadas estas divergencias, cualquier esfuerzo por atender las condiciones de los trabajadores tiene que tomar en cuenta el complejo entorno de los actuales regímenes laborales. Las maquilas operan en contextos prácticamente exentos de regulación y entremezclan el orden nacional y global, impidiendo una visión clara sobre los derechos y reclamos legales. En las nuevas geografías de poder, los trabajadores de las fábricas transnacionales desaparecen en los intersticios entre el espacio estatal y espacios no estatales, dando lugar a una pérdida de derechos y situaciones vagas dentro del marco de la ley.
The People, Not the Movement
Authors: Frajman Eduardo
Published: August 2012

The social mobilization against the Central American Free Trade Agreement (CAFTA) in Costa Rica between 2002 and 2007 was the strongest of any nation associated with the treaty. The popular opposition was able to delay for years and nearly stop its ratification. It did so by amassing support from the public at large and, in preparation for a national referendum, adopting a strategy of complete decentralization and horizontal, voluntary work at the grassroots level. This strategy ultimately led to a loss of the battle against the agreement, but it avoided costly clashes over leadership and forced the Costa Rican government to become more open and transparent vis-à-vis the popular organizations and the public.

La movilización social costarricense contra el CAFTA entre 2002 y 2007 fue la más contundente en cualquier país asociado al tratado. La oposición popular logró detener el proyecto por varios años y casi evita su ratificación. Su éxito se basó en el apoyo general del público y, en preparación para un referendo nacional, la adopción de una estrategia descentralizada y horizontal fundamentada en el voluntariado de grupos de base. Esta estrategia finalmente resultó en la pérdida de la batalla contra el tratado, pero evitó costosas desavenencias en torno al liderazgo y obligó al gobierno costarricense a abrirse y dar cuentas más transparentes a las organizaciones populares y el público en general.
Greening Urban Renewal
Authors: Bryson Jeremy
Published: August 2012

This article uses a case study of Spokane, Washington’s preparations for Expo ’74 to examine the environmental dimensions of urban renewal. Scholars often think of urban renewal as a planning project influenced by distinct racial exclusion, economic development, and urban design strategies. However, this article shows how environmental strategies—particularly the rise of urban environmentalism and the production of urban green space—had on urban renewal processes. As Spokane’s downtown elites planned for the environmentally themed World’s Fair, they used environmental strategies not only to promote the fair and the city but also to displace low-income residents and transform the downtown riverfront landscape. Understanding how the environment has been used by powerful groups as a tool of social power not only yields insights into the history of urban renewal in the 1960s and early 1970s but also highlights potential pitfalls in contemporary urban sustainability planning.
Hormone, Relationships of Parathyroid Gamma Counts, and Adenoma Mass in Minimally Invasive Parathyroidectomy
Authors: Stack Brendan C. , Moore Evan R. , Belcher Ryan H. , Spencer Horace J. , Bodenner Donald L.
Published: August 2012

Objective

To better understand relationships of parathyroid hormone (PTH) production, adenoma gamma counts, and adenoma mass in patients undergoing minimally radioguided invasive parathyroidectomy for primary hyperparathyroidism from single‐gland disease.

Study Design

A prospective review of 104 patients operated on by a single surgeon.

Setting

University tertiary hospital.

Subjects

Adults who have primary hyperparathyroidism due to a single gland.

Results

There were 23 men and 81 women with an average age of 63 years. The mean (SD) adenoma mass was 0.78 (0.69) g (median, 0.57 g). The mean (SD) percent of background for the adenoma was 120.2 (90.5). Preoperative PTH and percent of background gamma count of the adenoma showed a likely correlation with a Spearman ρ value of 0.2039 and a P value of. 037. There were significant correlations between both percent of background of the adenoma and adenoma mass (Spearman ρ = 0.4991 and P <. 0001). Preoperative PTH and adenoma mass also showed a significant positive correlation (Spearman ρ = 0.308 and P =. 002).

Conclusion

There exist correlations between gland mass, radioactivity, and PTH level. Adenoma radiation counts do not appear to be a proxy for changes in PTH levels measured during surgery as has been reported. Intraoperative PTH has been shown by others not to be necessary when doing radioguided parathyroid surgery if the Norman rule is observed. However, a radioguided technique and intraoperative PTH can provide complementary information in making an assessment of completion of parathyroid procedures.
Immediate Reconstruction with Autologous Cartilage after Removal of Infected Alloplast in Revision Rhinoplasty
Authors: Won Tae‐Bin , Jin Hong Ryul
Published: August 2012

Objective

To assess the feasibility of immediate reconstruction with autologous cartilage after removal of infected alloplast in revision rhinoplasty.

Study Design

Case series with chart review.

Setting

Academic university hospital.

Subjects and Methods

Patients who met the following inclusion criteria were the subjects of the present study: (1) revision rhinoplasty, (2) alloplastic implant‐related infection, (3) immediate reconstruction with autologous cartilage at the time of implant removal, and (4) follow‐up of more than 12 months. Data analysis included number of previous operations; type of alloplastic implant used; culture results; reconstruction method; complications, including reinfection and graft resorption; and aesthetic results.

Results

The 21 patients who met the inclusion criteria included 8 women and 13 men with a mean age of 37 years. Associated alloplast included silicone (10 cases), expanded polytetrafluoroethylene (9 cases), and Medpor (2 cases). With a mean follow‐up of 35 months, infection occurred in 1 patient that subsided with antibiotics. No major clinical absorption was encountered. Revision was performed in 1 patient with costal cartilage warping. No revision was required for infection or graft absorption.

Conclusion

Immediate reconstruction using autologous cartilage in revision rhinoplasty needing removal of an infected alloplast has shown a favorable outcome with minimal complications.
Nine-Year Risk of Depression Diagnosis Increases With Increasing Self-Reported Concussions in Retired Professional Football Players
Authors: Kerr Zachary Y. , Marshall Stephen W. , Harding Herndon P. , Guskiewicz Kevin M.
Published: August 2012

Background:

Concussions may accelerate the progression to long-term mental health outcomes such as depression in athletes.

Purpose:

To prospectively determine the effects of recurrent concussions on the clinical diagnosis of depression in a group of retired football players.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

Members of the National Football League Retired Players Association responded to a baseline General Health Survey (GHS) in 2001. They also completed a follow-up survey in 2010. Both surveys asked about demographic information, number of concussions sustained during their professional football career, physical/mental health, and prevalence of diagnosed medical conditions. A physical component summary (Short Form 36 Measurement Model for Functional Assessment of Health and Well-Being [SF-36 PCS]) was calculated from responses for physical health. The main exposure, the history of concussions during the professional playing career (self-report recalled in 2010), was stratified into 5 categories: 0 (referent), 1 to 2, 3 to 4, 5 to 9, and 10+ concussions. The main outcome was a clinical diagnosis of depression between the baseline and follow-up GHS. Classic tabular methods computed crude risk ratios. Binomial regression with a Poisson residual and robust variance estimation to stabilize the fitting algorithm estimated adjusted risk ratios. χ2 analyses identified associations and trends between concussion history and the 9-year risk of a depression diagnosis.

Results:

Of the 1044 respondents with complete data from the baseline and follow-up GHS, 106 (10.2%) reported being clinically diagnosed as depressed between the baseline and follow-up GHS. Approximately 65% of all respondents self-reported sustaining at least 1 concussion during their professional careers. The 9-year risk of a depression diagnosis increased with an increasing number of self-reported concussions, ranging from 3.0% in the “no concussions” group to 26.8% in the “10+” group (linear trend: P < .001). A strong dose-response relationship was observed even after controlling for confounders (years retired from professional football and 2001 SF-36 PCS). Retired athletes with a depression diagnosis also had a lower SF-36 PCS before diagnosis. The association between concussions and depression was independent of the relationship between decreased physical health and depression.

Conclusion:

Professional football players self-reporting concussions are at greater risk for having depressive episodes later in life compared with those retired players self-reporting no concussions.
Clinical and Radiological Outcomes 5 Years After Matrix-Induced Autologous Chondrocyte Implantation in Patients With Symptomatic, Traumatic Chondral Defects
Authors: Marlovits Stefan , Aldrian Silke , Wondrasch Barbara , Zak Lukas , Albrecht Christian , Welsch Goetz , Trattnig Siegfried
Published: August 2012

Background:

To date, few studies have been published reporting the 5-year follow-up of clinical and radiological outcomes for chondral defects treated with matrix-induced autologous chondrocyte implantation (MACI).

Hypothesis:

A significant improvement in clinical and radiological outcomes after treatment of symptomatic, traumatic chondral defects of the knee with the MACI implant will be maintained up to 5 years after surgery.

Study Design:

Case series; Level of evidence, 4.

Methods:

A prospective evaluation of the MACI procedure was performed in 21 patients with chondral defects of the knee. After the MACI procedure, patients were clinically assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS), the Tegner-Lysholm score, the International Knee Documentation Committee (IKDC) Subjective Knee Form, and the modified Cincinnati score at years 1, 2, and 5. The quality of repair tissue was assessed by magnetic resonance imaging using the magnetic resonance observation of cartilage repair tissue (MOCART) score at months 3 and 6 and years 1, 2, and 5.

Results:

Significant improvements ( P < .05) were observed for all 5 KOOS subcategories at year 1 and were maintained through year 5 in 90.5% of patients (19/21). Treatment failure occurred in only 9.5% of patients (2/21). Significant improvements ( P < .05) from baseline to year 5 were also observed for the IKDC score (30.1 to 74.3), the modified Cincinnati score (38.1 to 79.6), and the Tegner-Lysholm activity score (1.8 to 4.3). Similarly, the MOCART score significantly improved ( P < .001) from baseline to year 5 (52.9 to 75.8). After 5 years, complete filling (83%) and integration (82%) of the graft were seen in the majority of patients. Signs of subchondral bone edema were still present in 47% of patients at 5 years. No product-specific adverse events were reported over the 5-year follow-up period.

Conclusion:

Patients treated with a MACI implant demonstrated significant clinical improvement and good quality repair tissue 5 years after surgery. The MACI procedure was shown to be a safe and effective treatment for symptomatic, traumatic chondral knee defects in this study.