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Patient-Specific MRI-Based Right Ventricle Models Using Different Zero-Load Diastole and Systole Geometries for Better Cardiac Stress and Strain Calculations and Pulmonary Valve Replacement Surgical Outcome Predictions

Thu, 02/02/2017 - 2:44pm

BACKGROUND: Accurate calculation of ventricular stress and strain is critical for cardiovascular investigations. Sarcomere shortening in active contraction leads to change of ventricular zero-stress configurations during the cardiac cycle. A new model using different zero-load diastole and systole geometries was introduced to provide more accurate cardiac stress/strain calculations with potential to predict post pulmonary valve replacement (PVR) surgical outcome.

METHODS: Cardiac magnetic resonance (CMR) data were obtained from 16 patients with repaired tetralogy of Fallot prior to and 6 months after pulmonary valve replacement (8 male, 8 female, mean age 34.5 years). Patients were divided into Group 1 (n = 8) with better post PVR outcome and Group 2 (n = 8) with worse post PVR outcome based on their change in RV ejection fraction (EF). CMR-based patient-specific computational RV/LV models using one zero-load geometry (1G model) and two zero-load geometries (diastole and systole, 2G model) were constructed and RV wall thickness, volume, circumferential and longitudinal curvatures, mechanical stress and strain were obtained for analysis. Pairwise T-test and Linear Mixed Effect (LME) model were used to determine if the differences from the 1G and 2G models were statistically significant, with the dependence of the pair-wise observations and the patient-slice clustering effects being taken into consideration. For group comparisons, continuous variables (RV volumes, WT, C- and L- curvatures, and stress and strain values) were summarized as mean +/- SD and compared between the outcome groups by using an unpaired Student t-test. Logistic regression analysis was used to identify potential morphological and mechanical predictors for post PVR surgical outcome.

RESULTS: Based on results from the 16 patients, mean begin-ejection stress and strain from the 2G model were 28% and 40% higher than that from the 1G model, respectively. Using the 2G model results, RV EF changes correlated negatively with stress (r = -0.609, P = 0.012) and with pre-PVR RV end-diastole volume (r = -0.60, P = 0.015), but did not correlate with WT, C-curvature, L-curvature, or strain. At begin-ejection, mean RV stress of Group 2 was 57.4% higher than that of Group 1 (130.1+/-60.7 vs. 82.7+/-38.8 kPa, P = 0.0042). Stress was the only parameter that showed significant differences between the two groups. The combination of circumferential curvature, RV volume and the difference between begin-ejection stress and end-ejection stress was the best predictor for post PVR outcome with an area under the ROC curve of 0.855. The begin-ejection stress was the best single predictor among the 8 individual parameters with an area under the ROC curve of 0.782.

CONCLUSION: The new 2G model may be able to provide more accurate ventricular stress and strain calculations for potential clinical applications. Combining morphological and mechanical parameters may provide better predictions for post PVR outcome.

Alcohol Consumption, Left Atrial Diameter, and Atrial Fibrillation

Thu, 02/02/2017 - 2:44pm

BACKGROUND: Alcohol consumption has been associated with atrial fibrillation (AF) in several epidemiologic studies, but the underlying mechanisms remain unknown. We sought to test the hypothesis that an atrial myopathy, manifested by echocardiographic left atrial enlargement, explains the association between chronic alcohol use and AF.

METHODS AND RESULTS: We evaluated the relationship between cumulative alcohol consumption and risk of incident AF in 5220 Offspring and Original Framingham Heart Study participants (mean age 56.3 years, 54% women) with echocardiographic left atrial size measurements. The incidence of AF was 8.4 per 1000 person-years, with 1088 incident AF cases occurring over a median 6.0 years (25th-75th percentiles 4.0-8.7 years) of follow-up. After multivariable adjustment for potential confounders, every additional 10 g of alcohol per day (just under 1 drink per day) was associated with a 0.16 mm (95% CI, 0.10-0.21 mm) larger left atrial dimension. Also in multivariable adjusted analysis, every 10 g per day of alcohol consumed was associated with a 5% higher risk of developing new-onset AF (hazard ratio, 1.05; 95% CI, 1.01-1.09). An estimated 24% (95% CI, 8-75) of the association between alcohol and AF risk was explained by left atrial enlargement.

CONCLUSIONS: Our study of a large, community-based sample identified alcohol consumption as a predictor of left atrial enlargement and subsequent incident AF. Left atrial enlargement may be an intermediate phenotype along the causal pathway linking long-term alcohol consumption to AF.

Dental Calculus Stimulates Interleukin-1beta Secretion by Activating NLRP3 Inflammasome in Human and Mouse Phagocytes

Thu, 02/02/2017 - 2:44pm

Dental calculus is a mineralized deposit associated with periodontitis. The bacterial components contained in dental calculus can be recognized by host immune sensors, such as Toll-like receptors (TLRs), and induce transcription of proinflammatory cytokines, such as IL-1beta. Studies have shown that cellular uptake of crystalline particles may trigger NLRP3 inflammasome activation, leading to the cleavage of the IL-1beta precursor to its mature form. Phagocytosis of dental calculus in the periodontal pocket may therefore lead to the secretion of IL-1beta, promoting inflammatory responses in periodontal tissues. However, the capacity of dental calculus to induce IL-1beta secretion in human phagocytes has not been explored. To study this, we stimulated human polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) with dental calculus collected from periodontitis patients, and measured IL-1beta secretion by ELISA. We found that calculus induced IL-1beta secretion in both human PMNs and PBMCs. Calculus also induced IL-1beta in macrophages from wild-type mice, but not in macrophages from NLRP3- and ASC-deficient mice, indicating the involvement of NLRP3 and ASC. IL-1beta induction was inhibited by polymyxin B, suggesting that LPS is one of the components of calculus that induces pro-IL-1beta transcription. To analyze the effect of the inorganic structure, we baked calculus at 250 degrees C for 1 h. This baked calculus failed to induce pro-IL-1beta transcription. However, it did induce IL-1beta secretion in lipid A-primed cells, indicating that the crystalline structure of calculus induces inflammasome activation. Furthermore, hydroxyapatite crystals, a component of dental calculus, induced IL-1beta in mouse macrophages, and baked calculus induced IL-1beta in lipid A-primed human PMNs and PBMCs. These results indicate that dental calculus stimulates IL-1beta secretion via NLRP3 inflammasome in human and mouse phagocytes, and that the crystalline structure has a partial role in the activation of NLRP3 inflammasome.

Regulation of X-linked gene expression during early mouse development by Rlim

Thu, 02/02/2017 - 2:44pm

Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist. Our results reveal crucial roles of Rlim for the maintenance of high Xist RNA levels, Xist clouds and X-silencing in female embryos at blastocyst stages, while initial Xist expression appears Rlim-independent. We find further that X/A upregulation is initiated in early male and female preimplantation embryos.

Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

Thu, 02/02/2017 - 2:44pm

The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.

IMPORTANCE: Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.

Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance

Thu, 02/02/2017 - 2:44pm

OBJECTIVE: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis.

METHOD: White and brown adipocyte-deficient (Hig2fl/fl x Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl x Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process.

RESULTS: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl x Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes.

CONCLUSIONS: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 degrees C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.

Common Statistical Pitfalls in Basic Science Research

Thu, 02/02/2017 - 2:44pm

In this review, we focused on common sources of confusion and errors in the analysis and interpretation of basic science studies. The issues addressed are seen repeatedly in the authors' editorial experience, and we hope this article will serve as a guide for those who may submit their basic science studies to journals that publish both clinical and basic science research. We have discussed issues related to sample size and power, study design, data analysis, and presentation of results. We then illustrated these issues using a set of examples from basic science research studies.

Relationship between Massachusetts Youth Screening Instrument-second version and psychiatric disorders in youths in welfare and juvenile justice institutions in Switzerland

Thu, 02/02/2017 - 2:44pm

BACKGROUND: There is growing evidence that it is important to have well-standardized procedures for identifying the mental health needs of youths in welfare and juvenile justice institutions. One of the most widely used tools for mental health screening in the juvenile justice system is the Massachusetts Youth Screening Instrument-second version (MAYSI-2). To contribute to the body of research examining the utility of the MAYSI-2 as a mental health screening tool; the first objective of the current study was to examine the relationship between the MAYSI-2 and the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL) in a sample of Swiss youths in welfare and juvenile justice institutions using a cross-sectional design. Secondly, as the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample and consequently differences between the language regions were analyzed as well. The third objective was to examine gender differences in this relationship.

METHODS: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions in Switzerland. The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). Binomial logistic regression analysis was used to predict (cluster of) psychiatric disorders from MAYSI-2 scales.

RESULTS: The regression analyses revealed that the MAYSI-2 scales generally related well to their corresponding homotypic (cluster of) psychiatric disorders. For example, the alcohol/drug use scale identified the presence of any substance use disorder and the suicide ideation scale identified youths reporting suicide ideation or suicide attempts. Several MAYSI-2 scales were also related to heterotypic (cluster of) psychiatric disorders. For example, the MAYSI-2 scale alcohol/drug use, was positively related to any disruptive disorder. Furthermore, the results revealed gender differences in the relationship between the MAYSI-2 and K-SADS-PL (e.g., in the boys' subsample no MAYSI-2 scale was significantly related to any affective disorder; whereas, in the girls' subsample the MAYSI-2 scales depressed-anxious and somatic complaints were significantly related to any affective disorder).

CONCLUSIONS: Overall, The MAYSI-2 seems to serve well as a first-stage screen to identify service needs for youths in welfare and juvenile justice institutions in Switzerland. Its effectiveness to identify the presence of (cluster of) psychiatric disorders differs between genders.

Diagnostic Prevalence of Ankylosing Spondylitis Using Computerized Health Care Data, 1996 to 2009: Underrecognition in a US Health Care Setting

Thu, 02/02/2017 - 2:44pm

INTRODUCTION: Few studies have assessed the prevalence and features of axial spondyloarthritis (axSpA) and ankylosing spondylitis in diverse, population-based, community settings.

OBJECTIVES: We used computerized diagnoses to estimate the prevalence of axSpA and ankylosing spondylitis in Kaiser Permanente Northern California (KPNC).

METHODS: We identified persons aged 18 years or older with 1 or more International Classification of Diseases, Ninth Revision (ICD-9) diagnosis Code 720.X (ankylosing spondylitis and other inflammatory spondylopathies) in clinical encounter data from 1996 through 2009 to estimate the prevalence of axSpA and ankylosing spondylitis. We reviewed medical records to confirm the diagnosis in a random sample and estimated the positive predictive value of computerized data to identify confirmed cases using various case definitions.

RESULTS: In the computerized data, 5568 adults had diagnostic codes indicating axSpA. On the basis of our case-finding approach using a single physician diagnosis code for ICD-9 720.X, the point prevalence of these conditions, standardized to the 2000 US Census, was 2.26 per 1000 persons for axSpA and 1.07 per 1000 for ankylosing spondylitis. Less than half of suspected cases saw a rheumatologist. The most specific algorithm for confirmed ankylosing spondylitis required 2 or more computerized diagnoses assigned by a rheumatologist, with 67% sensitivity (95% confidence interval, 64%-69%) and 81% positive predictive value (95% confidence interval, 79%-83%).

CONCLUSIONS: Observed prevalence in the KPNC population, compared with national estimates for axSpA and ankylosing spondylitis, suggests there is substantial underrecognition of these conditions in routine clinical practice. However, use of computerized data is able to identify true cases of ankylosing spondylitis, facilitating population-based research.

Autophagy Activation by Transcription Factor EB (TFEB) in Striatum of HDQ175/Q7 Mice

Thu, 02/02/2017 - 2:44pm

BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy.

OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels.

METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9. The levels of exogenous TFEB were analyzed using qPCR and Western blot. Proteins involved in autophagy, levels of huntingtin, and striatal-enriched proteins were examined using biochemical and/or immunohistochemical methods.

RESULTS: In HD mice expressing TFEB-HA, HA immunoreactivity distributed throughout the striatum in neuronal cell bodies and processes and preferentially in neuronal nuclei and overlapped with a loss of DARPP32 immunoreactivity. TFEB-HA mRNA and protein were detected in striatal lysates. There were increased levels of proteins involved with autophagosome/lysosome activity including LAMP-2A, LC3II, and cathepsin D and reduced levels of mutant HTT and the striatal enriched proteins DARPP32 and PDE10A. Compared to WT mice, HDQ175/Q7 mice had elevated levels of the ER stress protein GRP78/BiP and with TFEB-HA expression, increased levels of the astrocyte marker GFAP and pro-caspase 3.

CONCLUSION: These results suggest that TFEB expression in the striatum of HDQ175/Q7 mice stimulates autophagy and lysosome activity, and lowers mHTT, but may also increase a neuronal stress response.

Listening for Grace

Thu, 02/02/2017 - 2:44pm

Narrative essay which under the title "That's Our Saving Grace" was the Family Medicine Education Consortium (FMEC) Annual Prose Contest Winner for 2015.

Gene therapy approaches for the treatment of retinal disorders

Thu, 02/02/2017 - 2:44pm

There is an impelling need to develop effective therapeutic strategies for patients with retinal disorders. Gleaning from the large quantity of information gathered over the past two decades on the mechanisms governing degeneration of the retina, it is now possible to devise innovative therapies based on retinal gene transfer. Different gene-based approaches are under active investigation. They include strategies to correct the specific genetic defect in inherited retinal diseases, strategies to delay the onset of blindness independently of the disease-causing mutations, and strategies to reactivate residual cells at late stages of the diseases. In this review, we discuss the status of application of these technologies, outlining the future therapeutic potential for many forms of retinal blinding diseases.

ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics

Thu, 02/02/2017 - 2:43pm

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.

Preserving Patient Privacy When Sharing Same-Disease Data

Thu, 02/02/2017 - 2:43pm

Medical and health data are often collected for studying a specific disease. For such same-disease microdata, a privacy disclosure occurs as long as an individual is known to be in the microdata. Individuals in same-disease microdata are thus subject to higher disclosure risk than those in microdata with different diseases. This important problem has been overlooked in data-privacy research and practice, and no prior study has addressed this problem. In this study, we analyze the disclosure risk for the individuals in same-disease microdata and propose a new metric that is appropriate for measuring disclosure risk in this situation. An efficient algorithm is designed and implemented for anonymizing same-disease data to minimize the disclosure risk while keeping data utility as good as possible. An experimental study was conducted on real patient and population data. Experimental results show that traditional reidentification risk measures underestimate the actual disclosure risk for the individuals in same-disease microdata and demonstrate that the proposed approach is very effective in reducing the actual risk for same-disease data. This study suggests that privacy protection policy and practice for sharing medical and health data should consider not only the individuals' identifying attributes but also the health and disease information contained in the data. It is recommended that data-sharing entities employ a statistical approach, instead of the HIPAA's Safe Harbor policy, when sharing same-disease microdata.

Distinct surveillance pathway for immunopathology during acute infection via autophagy and SR-BI

Thu, 02/02/2017 - 2:43pm

The mechanisms protecting from immunopathology during acute bacterial infections are incompletely known. We found that in response to apoptotic immune cells and live or dead Listeria monocytogenes scavenger receptor BI (SR-BI), an anti-atherogenic lipid exchange mediator, activated internalization mechanisms with characteristics of macropinocytosis and, assisted by Golgi fragmentation, initiated autophagic responses. This was supported by scavenger receptor-induced local increases in membrane cholesterol concentrations which generated lipid domains particularly in cell extensions and the Golgi. SR-BI was a key driver of beclin-1-dependent autophagy during acute bacterial infection of the liver and spleen. Autophagy regulated tissue infiltration of neutrophils, suppressed accumulation of Ly6C+ (inflammatory) macrophages, and prevented hepatocyte necrosis in the core of infectious foci. Perifocal levels of Ly6C+ macrophages and Ly6C- macrophages were unaffected, indicating predominant regulation of the focus core. SR-BI-triggered autophagy promoted co-elimination of apoptotic immune cells and dead bacteria but barely influenced bacterial sequestration and survival or inflammasome activation, thus exclusively counteracting damage inflicted by immune responses. Hence, SR-BI- and autophagy promote a surveillance pathway that partially responds to products of antimicrobial defenses and selectively prevents immunity-induced damage during acute infection. Our findings suggest that control of infection-associated immunopathology can be based on a unified defense operation.

The Zn-finger domain of MdmX suppresses cancer progression by promoting genome stability in p53-mutant cells

Thu, 02/02/2017 - 2:43pm

The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.

A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119

Thu, 02/02/2017 - 2:43pm

The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate.

Clinical Topic Review 2013 - Behavioral Health Screening Among MassHealth Children and Adolescents

Wed, 02/01/2017 - 9:28am

Results from the 2013 evaluation suggest that the Children’s Behavioral Health Initiative had a large impact on formal behavioral health screening and treatment utilization among children and adolescents enrolled in MassHealth.

Clinical Topic Review: Behavioral Health Screening for Children with Well Visits

Wed, 02/01/2017 - 9:28am

The first Clinical Topic Review was conducted in order to better understand how behavioral health screenings were occurring for children and adolescents during well visits prior to the implementation of a requirement that primary care providers perform behavioral health screening using a standardized behavioral health screening tool during every well child visit.