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Background: Heart failure is a highly prevalent, morbid, and costly disease with a poor long-term prognosis. Evidence-based therapies utilized over the past 2 decades hold the promise of improved outcomes, yet few contemporary studies have examined survival trends in patients with acute heart failure.

Objectives: The primary objective of this population-based study was to describe trends in short and long-term survival in patients hospitalized with acute decompensated heart failure (ADHF). A secondary objective was to examine patient characteristics associated with decreased long-term survival.

Methods and Results: We reviewed the medical records of 9,748 patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004. Patients hospitalized with ADHF were more likely to be elderly and to have been diagnosed with multiple comorbidities in 2004 compared with 1995. Over this period, survival was significantly improved in-hospital, and at 1, 2, and 5 years post-discharge. Five-year survival rates increased from 20% in 1995 to 28% in 2004. Although survival improved substantially over time, older patients and patients with chronic kidney disease, chronic obstructive pulmonary disease, anemia, low body mass index, and low blood pressures had consistently lower post-discharge survival rates than patients without these comorbidities.

Conclusion: Between 1995 and 2004, patients hospitalized with ADHF have become older and increasingly comorbid. Although there has been a significant improvement in survival among these patients, their long-term prognosis remains poor, as fewer than 1 in 3 patients hospitalized with ADHF in 2004 survived more than 5 years.

Discusses double diabetes -- the coexistence of features of both type 1 and type 2 diabetes in the same individual -- with a comprehensive discussion of the various aspects of this disorder and a focus on the search for a treatment paradigm in children and adolescents.

Chitin is the second most common polysaccharide found in nature. It is present in crustacean shells, insect exoskeletons, parasitic nematode eggs and gut linings, and in the cell wall of fungi. The deacetylated derivative of chitin, chitosan, is less common but is particularly evident in certain species of fungi, such as Cryptococcus, and the cyst wall of Entamoeba. How mammals sense and respond to these polymers is not well understood, and conflicting reports on their immunological activity have led to some controversy. Despite this, promising translational applications that exploit the unique properties of chitin and chitosan are being developed.

BACKGROUND: Although popular clinically, the psychometric properties of motivation rulers for tobacco cessation are unknown. This study examined the psychometric properties of rulers assessing importance, readiness, and confidence in tobacco cessation.

METHODS: This observational study of current smokers was conducted at 10 US emergency departments (EDs). Subjects were assessed during their ED visit (baseline) and reassessed two weeks later. We examined intercorrelations between the rulers as well as their construct and predictive validity. Hierarchical multinomial logistic regressions were used to examine the rulers' predictive ability after controlling for covariables.

RESULTS: We enrolled 375 subjects. The correlations between the three rulers ranged from 0.50 (between Important and Confidence) to 0.70 (between Readiness and Confidence); all were significant (p < 0.001). Individuals in the preparation stage displayed the highest motivation-ruler ratings (all rulers F 2, 363 >/= 43; p < 0.001). After adjusting for covariables, each of the rulers significantly improved prediction of smoking behavior change. The strength of their predictive ability was on par with that of stage of change.

CONCLUSION: Our results provide preliminary support for the psychometric soundness of the importance, readiness, and confidence rulers.

TNF-related apoptosis-inducing ligand (TRAIL) is an important component of the immune system. Although it is well acknowledged that it also has an important role in Type 1 Diabetes (T1D) development, this presumed role has not yet been clearly revealed. Streptozotocin (STZ) and Cyclophosphamide (CY) are frequently used agents for establishment or acceleration of T1D disease in experimental models, including the non-obese diabetic (NOD) mice. Although such disease models are very suitable for diabetes research, different expression patterns for various T1D-related molecules may be expected, depending on the action mechanism of the applied agent. We accelerated diabetes in female NOD mice using STZ or CY and analyzed the expression profiles of TRAIL ligand and receptors throughout disease development. TRAIL ligand expression followed a completely different pattern in STZ- versus CY-accelerated disease, displaying a prominent increase in the former, while appearing at reduced levels in the latter. Decoy receptor 1 (DcR1) expression also increased significantly in the pancreatic islets in STZ-induced disease. Specific increases observed in TRAIL ligand and DcR1 expressions may be part of a defensive strategy of the beta islets against the infiltrating leukocytes, while the immune-suppressive agent CY may partly hold down this defense, contributing further to diabetes development.

Anti-Gal is the most abundant antibody in humans, constituting 1% of immunoglobulins. Anti-Gal binds specifically alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R). Immunogenicity of autologous tumor associated antigens (TAA) is greatly increased by manipulating tumor cells to express alpha-gal epitopes and bind anti-Gal. Glycolipids with alphagal epitopes (alpha-gal glycolipids) injected into tumors insert into the tumor cell membrane. Anti-Gal binding to the multiple alpha-gal epitopes de novo presented on the tumor cells results in targeting of these cells to APC via the interaction between the Fc portion of the bound anti-Gal and Fcgamma; receptors on APC. The APC process and present immunogenic TAA peptides and thus, effectively activate tumor specific CD4+ helper T cells and CD8+ cytotoxic T cells which destroy tumor cells in micrometastases. The induced immune response is potent enough to overcome immunosuppression by Treg cells. A phase I clinical trial indicated that alpha-gal glycolipid treatment has no adverse effects. In addition to achieving destruction of micrometastases in cancer patients with advance disease, alpha-gal glycolipid treatment may be effective as neo-adjuvant immunotherapy. Injection of alpha-gal glycolipids into primary tumors few weeks prior to resection can induce a protective immune response capable of destroying micrometastases expressing autologous TAA, long after primary tumor resection.

CD4 T cells that acquire cytotoxic phenotype and function have been repeatedly identified in humans, mice, and other species in response to many diverse pathogens. Since CD4 cytotoxic T cells are able to recognize antigenic determinants unique from those recognized by the parallel CD8 cytotoxic T cells, they can potentially contribute additional immune surveillance and direct effector function by lysing infected or malignant cells. Here, we briefly review much of what is known about the generation of cytotoxic CD4 T cells and describe our current understanding of their role in antiviral immunity. Furthering our understanding of the many roles of CD4 T cells during an anti-viral response is important for developing effective vaccine strategies that promote long-lasting protective immunity.

Emergency departments and hospitals are being urged to implement onsite interventions to promote smoking cessation, yet little is known about the theoretical underpinnings of behavior change after a healthcare visit.

This observational pilot study evaluated three factors that may predict smoking cessation after an acute health emergency: perceived illness severity, event-related emotions, and causal attribution. Fifty smokers who presented to a hospital because of suspected cardiac symptoms were interviewed, either in the emergency department (ED) or, for those who were admitted, on the cardiac inpatient units. Their data were analyzed using both qualitative and quantitative methodologies to capture the individual, first-hand experience and to evaluate trends over the illness chronology. Reported perceptions of the event during semistructured interview varied widely and related to the individual's intentions regarding smoking cessation. No significant differences were found between those interviewed in the ED versus the inpatient unit. Although the typical profile was characterized by a peak in perceived illness severity and negative emotions at the time the patient presented in the ED, considerable pattern variation occurred.

Our results suggest that future studies of event-related perceptions and emotional reactions should consider using multi-item and multidimensional assessment methods rated serially over the event chronology.

The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs) or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death-a fundamental form of innate immunity-is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals.

BACKGROUND: Ultrasound measurement of dynamic changes in inferior vena cava (IVC) diameter can be used to assess intravascular volume status in critically ill patients, but published studies vary in accuracy as well as recommended diagnostic cutoffs. Part of this variability may be related to movements of the vessel relative to the transducer during the respiratory cycle which results in unintended comparison of different points of the IVC at end expiration and inspiration, possibly introducing error related to variations in normal anatomy. The objective of this study was to quantify both craniocaudal and mediolateral movements of the IVC as well as the vessel's axis of collapse during respirophasic ultrasound imaging.

METHODS: Patients were enrolled from a single urban academic emergency department with ultrasound examinations performed by sonographers experienced in IVC ultrasound. The IVC was imaged from the level of the diaphragm along its entire course to its bifurcation with diameter measurements and respiratory collapse measured at a single point inferior to the confluence of the hepatic veins. While imaging the vessel in its long axis, movement in a craniocaudal direction during respiration was measured by tracking the movement of a fixed point across the field of view. Likewise, imaging the short axis of the IVC allowed for measurement of mediolateral displacement as well as the vessel's angle of collapse relative to vertical.

RESULTS: Seventy patients were enrolled over a 6-month period. The average diameter of the IVC was 13.8 mm (95% CI 8.41 to 19.2 mm), with a mean respiratory collapse of 34.8% (95% CI 19.5% to 50.2%). Movement of the vessel relative to the transducer occurred in both mediolateral and craniocaudal directions. Movement was greater in the craniocaudal direction at 21.7 mm compared to the mediolateral movement at 3.9 mm (p < 0.001). Angle of collapse assessed in the transverse plane averaged 115 degrees (95% CI 112 degrees to 118 degrees ).

CONCLUSIONS: Movement of the IVC occurs in both mediolateral and craniocaudal directions during respirophasic ultrasound imaging. Further, collapse of the vessel occurs not at true vertical (90 degrees ) but 25 degrees off this axis. Technical approach to IVC assessment needs to be tailored to account for these factors.

BACKGROUND: Hispanics are the fasting growing population in the U.S. and disproportionately suffer from chronic diseases such as hypertension and diabetes. Little is known about the complex interplay between acculturation and chronic disease prevalence in the growing and increasingly diverse Hispanic population. We explored the association between diabetes and hypertension prevalence among distinct U.S. Hispanic subgroups by country of origin and by degree of acculturation.

METHODS: We examined the adult participants in the 2001, 2003, 2005, and 2007 California Health Interview Survey (CHIS). Using weighted logistic regression stratified by nativity, we measured the association between country of origin and self-reported hypertension and diabetes adjusting for participants' demographics, insurance status, socio-economic status and degree of acculturation measured by citizenship, English language proficiency and the number of years of residence in the U.S.

RESULTS: There were 33,633 self-identified Hispanics (foreign-born: 19,988; U.S.-born: 13,645). After multivariable adjustment, we found significant heterogeneity in self-reported hypertension and diabetes prevalence among Hispanic subgroups. Increasing years of U.S. residence was associated with increased disease prevalence. Among all foreign-born subgroups, only Mexicans reported lower odds of hypertension after adjustment for socioeconomic and acculturation factors. Both U.S.-born and foreign-born Mexicans had higher rates of diabetes as compared to non-Hispanic whites.

CONCLUSIONS: We found significant heterogeneity among Hispanics in self-reported rates of hypertension and diabetes by acculturation and country of origin. Our findings highlight the importance of disaggregation of Hispanics by country of origin and acculturation factors whenever possible.

BACKGROUND: Tobacco smoking remains the leading cause of preventable death in America, claiming 450,000 lives annually. Chronic Obstructive Pulmonary Disease, caused by smoking in the vast majority of cases, became the third leading cause of death in the U.S. in 2008. The burden of asthma, often exacerbated by tobacco exposure, has widespread clinical and public health impact. Despite this considerable harm, we know relatively little about the natural history of lung disease and respiratory impairment in adults, especially after smoking cessation.

METHODS/DESIGN: Our paper describes the design and rationale for using the 2004 Federal Bureau of Prisons tobacco ban to obtain insights into the natural history of respiratory diseases in adult men and women of different races/ethnicities who are imprisoned in federal medical facilities. We have developed a longitudinal study of new prison arrivals, with data to be collected from each participant over the course of several years, through the use of standardized questionnaires, medical chart reviews, lung function tests, six-minute walk tests, and stored serum for the analysis of present and future biomarkers. Our endpoints include illness exacerbations, medication and health services utilization, lung function, serum biomarkers, and participants' experience with their health and nicotine addiction.

DISCUSSION: We believe the proposed longitudinal study will make a substantial contribution to the understanding and treatment of respiratory disease and tobacco addiction.

BACKGROUND: Small RNAs have proven to be essential regulatory molecules encoded within eukaryotic genomes. These short RNAs participate in a diverse array of cellular processes including gene regulation, chromatin dynamics and genome defense. The tammar wallaby, a marsupial mammal, is a powerful comparative model for studying the evolution of regulatory networks. As part of the genome sequencing initiative for the tammar, we have explored the evolution of each of the major classes of mammalian small RNAs in an Australian marsupial for the first time, including the first genome-scale analysis of the newest class of small RNAs, centromere repeat associated short interacting RNAs (crasiRNAs).

RESULTS: Using next generation sequencing, we have characterized the major classes of small RNAs, micro (mi) RNAs, piwi interacting (pi) RNAs, and the centromere repeat associated short interacting (crasi) RNAs in the tammar. We examined each of these small RNA classes with respect to the newly assembled tammar wallaby genome for gene and repeat features, salient features that define their canonical sequences, and the constitution of both highly conserved and species-specific members. Using a combination of miRNA hairpin predictions and co-mapping with miRBase entries, we identified a highly conserved cluster of miRNA genes on the X chromosome in the tammar and a total of 94 other predicted miRNA producing genes. Mapping all miRNAs to the tammar genome and comparing target genes among tammar, mouse and human, we identified 163 conserved target genes. An additional nine genes were identified in tammar that do not have an orthologous miRNA target in human and likely represent novel miRNA-regulated genes in the tammar. A survey of the tammar gonadal piRNAs shows that these small RNAs are enriched in retroelements and carry members from both marsupial and tammar-specific repeat classes. Lastly, this study includes the first in-depth analyses of the newly discovered crasiRNAs. These small RNAs are derived largely from centromere-enriched retroelements, including a novel SINE.

CONCLUSIONS: This study encompasses the first analyses of the major classes of small RNAs for the newly completed tammar genome, validates preliminary annotations using deep sequencing and computational approaches, and provides a foundation for future work on tammar-specific as well as conserved, but previously unknown small RNA progenitors and targets identified herein. The characterization of new miRNA target genes and a unique profile for crasiRNAs has allowed for insight into multiple RNA mediated processes in the tammar, including gene regulation, species incompatibilities, centromere and chromosome function.

BACKGROUND: One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets.

METHODS: After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment.

RESULTS: We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow researchers access to the methods and example microarray data described in this manuscript, and the ability to analyze their own gene list by using our unique consolidation methods.

CONCLUSIONS: By combining several pathway systems, implementing different, but complementary pathway consolidation methods, and providing a user-friendly web-accessible tool, we have enabled users the ability to extract functional explanations of their genome wide experiments.

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.

METHODS: This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen(R), dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment.

RESULTS: Nine subjects were enrolled, and seven (2 women and 5 men, age range 55-64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment.

CONCLUSIONS: Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

BACKGROUND: Adherences to treatments that require a behavioral action often rely on self-reported recall, yet it is vital to determine whether real time self reporting of adherence using a simple logbook accurately captures adherence. The purpose of this study was to determine whether real time self-reported adherence is an accurate measurement of device usage during a clinical trial by comparing it to electronic recording.

METHODS: Using data collected from older adult men and women (N=135, mean age 82.3 yrs; range 66 to 98 yrs) participating in a clinical trial evaluating a vibrating platform for the treatment of osteoporosis, daily adherence to platform treatment was monitored using both self-reported written logs and electronically recorded radio-frequency identification card usage, enabling a direct comparison of the two methods over one year. Agreement between methods was also evaluated after stratification by age, gender, time in study, and cognition status.

RESULTS: The two methods were in high agreement (overall intraclass correlation coefficient = 0.96). The agreement between the two methods did not differ between age groups, sex, time in study and cognitive function.

CONCLUSIONS: Using a log book to report adherence to a daily intervention requiring a behavioral action in older adults is an accurate and simple approach to use in clinical trials, as evidenced by the high degree of concordance with an electronic monitor.

BACKGROUND: Obesity remains a major public health challenge, demanding cost-effective and scalable weight management programs. Delivering key treatment components via mobile technology offers a potential way to reduce expensive in-person contact, thereby lowering the cost and burden of intensive weight loss programs. The ENGAGED study is a theory-guided, randomized controlled trial designed to examine the feasibility and efficacy of an abbreviated smartphone-supported weight loss program.

METHODS/DESIGN: Ninety-six obese adults (BMI 30-39.9 kg/m2) will be randomized to one of three treatment conditions: (1) standard behavioral weight loss (STND), (2) technology-supported behavioral weight loss (TECH); or (3) self-guided behavioral weight loss (SELF). All groups will aim to achieve a 7% weight loss goal by reducing calorie and fat intake and progressively increasing moderate intensity physical activity to 175 minutes/week. STND and TECH will attend 8 group sessions and receive regular coaching calls during the first 6 months of the intervention; SELF will receive the Group Lifestyle Balance Program DVD's and will not receive coaching calls. During months 1-6, TECH will use a specially designed smartphone application to monitor dietary intake, body weight, and objectively measured physical activity (obtained from a Blue-tooth enabled accelerometer). STND and SELF will self-monitor on paper diaries. Linear mixed modeling will be used to examine group differences on weight loss at months 3, 6, and 12. Self-monitoring adherence and diet and activity goal attainment will be tested as mediators.

DISCUSSION: ENGAGED is an innovative weight loss intervention that integrates theory with emerging mobile technologies. We hypothesize that TECH, as compared to STND and SELF, will result in greater weight loss by virtue of improved behavioral adherence and goal achievement. TRIAL REGISTRATION: NCT01051713.

BACKGROUND: Cytokines regulated by the inflammasome pathway have been extensively implicated in various age-related immune pathologies. We set out to elucidate the contribution of the nod-like receptor protein 3 (NLRP3) inflammasome pathway to the previously described deficiencies in IL-1beta production by macrophages from aged mice. We examined the production of pro-IL-1beta and its conversion into IL-1beta as two separate steps and compared these cytokine responses in bone marrow derived macrophages from young (6-8 weeks) and aged (18-24 months) C57BL/6 mice.

FINDINGS: Relative to macrophages from young mice, macrophages from aged mice produced less pro-IL-1beta after TLR4 stimulation with LPS. However upon activation of the NLRP3 inflammasome with ATP, macrophages from young and aged mice were able to efficiently convert and secrete intracellular pro-cytokines as functional cytokines.

CONCLUSIONS: Lower levels of IL-1beta production are a result of slower and lower overall production of pro-IL-1beta in macrophages from aged mice.