Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.

C10Pred: A First Machine Learning Based Tool to Predict C10 Family Cysteine Peptidases Using Sequence-Derived Features.

Streptococcus pyogenes, or group A Streptococcus (GAS), a gram-positive bacterium, is implicated in a wide range of clinical manifestations and life-threatening diseases. One of the key virulence factors of GAS is streptopain, a C10 family cysteine peptidase. Since its discovery, various homologs of streptopain have been reported from other bacterial species. With the increased affordability of sequencing, a significant increase in the number of potential C10 family-like sequences in the public databases is anticipated, posing a challenge in classifying such sequences. Sequence-similarity-based tools are the methods of choice to identify such streptopain-like sequences. However, these methods depend on some level of sequence similarity between the existing C10 family and the target sequences. Therefore, in this work, we propose a novel predictor, C10Pred, for the prediction of C10 peptidases using sequence-derived optimal features. C10Pred is a support vector machine (SVM) based model which is efficient in predicting C10 enzymes with an overall accuracy of 92.7% and Matthews' correlation coefficient (MCC) value of 0.855 when tested on an independent dataset. We anticipate that C10Pred will serve as a handy tool to classify novel streptopain-like proteins belonging to the C10 family and offer essential information.

Maspin binds to cardiolipin in mitochondria and triggers apoptosis.

A central question in cell biology is how cells respond to stress signals and biochemically regulate apoptosis. One critical pathway involves the change of mitochondrial function and release of cytochrome c to initiate apoptosis. In response to apoptotic stimuli, we found that maspin-a noninhibitory member of the serine protease inhibitor superfamily-translocates from the cytosol to mitochondria and binds to cardiolipin in the inner mitochondrial membrane. Biolayer interferometry assay revealed that recombinant maspin binds cardiolipin with an apparent Kd,of ∼15.8 µM and competes with cytochrome c (apparent Kd of ∼1.31 µM) for binding to cardiolipin-enriched membranes. A hydrophobic, lysine-rich domain in maspin consists of 27 aa, is located at position 268-294, and is responsible for the interaction of this protein with cardiolipin. Depletion of cardiolipin in cells significantly prevents maspin binding to the inner mitochondrial membrane and decreases cytochrome c release and apoptosis. Alteration to maspin's cardiolipin binding domain changes its ability to bind cardiolipin, and tumor cells expressing this mutant have a low frequency of apoptosis. We propose a model of apoptosis in which maspin binds to cardiolipin, displaces cytochrome c from the membrane, and facilitates its release to the cytoplasm.-Mahajan, N., Hoover, B., Rajendram, M., Shi, H. Y., Kawasaki, K., Weibel, D. B., Zhang, M. Maspin binds to cardiolipin in mitochondria and triggers apoptosis.

Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.

Overexpression of the multiple myeloma set domain (MMSET) Wolf-Hirschhorn syndrome candidate 1 gene, which contains an orphan box H/ACA class small nucleolar RNA, ACA11, in an intron, is associated with several cancer types, including multiple myeloma (MM). ACA11 and MMSET are overexpressed cotranscriptionally as a result of the t(4;14) chromosomal translocation in a subset of patients with MM. RNA sequencing of CD138+ tumor cells from t(4;14)-positive and -negative MM patient bone marrow samples revealed an enhanced oxidative phosphorylation mRNA signature. Supporting these data, ACA11 overexpression in a t(4;14)-negative MM cell line, MM1.S, demonstrated enhanced reactive oxygen species (ROS) levels. In addition, an enhancement of cell proliferation, increased soft agar colony size, and elevated ERK1/2 phosphorylation were observed. This ACA11-driven hyperproliferative phenotype depended on increased ROS levels as exogenously added antioxidants attenuate the increased proliferation. A major transcriptional regulator of the cellular antioxidant response, nuclear factor (erythroid-derived 2)-like 2 (NRF2), shuttled to the nucleus, as expected, in response to ACA11-driven increases in ROS; however, transcriptional up-regulation of some of NRF2's antioxidant target genes was abrogated in the presence of ACA11 overexpression. These data show for the first time that ACA11 promotes proliferation through inhibition of NRF2 function resulting in sustained ROS levels driving cancer cell proliferation.-Mahajan, N., Wu, H.-J., Bennett, R. L., Troche, C., Licht, J. D., Weber, J. D., Maggi, L. B., Jr., Tomasson, M. H. Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.

Signatures of prostate-derived Ets factor (PDEF) in cancer.

The Ets proteins are a family of transcription factors characterized by an evolutionarily conserved DNA-binding domain and have diverse biological functions including tumor suppressor as well as tumor promoter functions. They are regulated via a complex and diverse number of mechanisms and control key cellular processes. Prostate-derived Ets transcription factor (PDEF), a unique member of the ETS family, is present in tissues with high epithelial content are hormone-regulated, such as prostate, breast, salivary glands, ovaries, colon, airways, and stomach tissues. PDEF (prostate-derived Ets factor) is also referred to as SPDEF (SAM pointed domain containing Ets transcription factor), PSE (mouse homolog), or hPSE (human PSE) in the literature and is the sole member of the PDEF ETS sub-family. The role of PDEF in cancer development is still not fully elucidated though. The present article focuses on the key findings about the PDEF's biological functions, interacting proteins, and its target genes. There is a strong urge to focus on the clinical studies in larger cohort, which elucidate the regulation of PDEF and its target genes, to determine the potential of PDEF as biomarker. Based on the studies discussed in the present article, one can anticipate that PDEF offers a great potential for developing therapeutics against cancer.

Tumor-suppressive maspin functions as a reactive oxygen species scavenger: importance of cysteine residues.

Maspin is a member of the serine protease inhibitor (serpin) superfamily and displays tumor-suppressing activity by controlling cell migration, proliferation, apoptosis, and adhesion. Here, we provide evidence that maspin acts as a reactive oxygen species (ROS) scavenger through oxidation of three structurally exposed cysteine thiols to sulfenic acid. Ablation of these cysteine residues in maspin resulted in a significant increase in total ROS production in mouse mammary TM40D cells. Also, cells containing a triple-cysteine mutant of maspin showed elevated ERK1/2 activity, a downstream target of ROS, and enhanced proliferation and colony formation. These findings establish a novel mechanism by which maspin utilizes its cysteine thiols to inhibit oxidative stress and cell growth.

The role of early LDL lowering to prevent the onset of atherosclerotic disease.

Coronary atherosclerosis is a chronic progressive disease that begins early in life and progresses slowly over several decades before becoming clinically manifest. The causal relationship between low-density lipoprotein cholesterol (LDL-C) and the risk of coronary atherosclerosis is well established. Multiple randomized trials have demonstrated that lowering LDL-C levels during treatment with a statin reduces the risk of major atherosclerotic coronary events. However, individuals being treated with a statin continue to experience a high residual risk of events. Here we review the evidence that lowering LDL-C levels beginning earlier in life, and therefore earlier in the atherosclerotic disease process, can prevent or substantially delay the development of atherosclerosis and thereby substantially improve the clinical benefit of therapies that lower LDL-C levels. We focus on providing a critical appraisal of the naturally randomized evidence that is emerging from recently conducted genetic association studies.

Levels of interleukin-18 and endothelin-1 in children with Henoch-Schönlein purpura: a study from northern India.

Henoch-Schönlein purpura (HSP) is an acute systemic vasculitis with unknown etiology, although several studies have found HSP to be related to cytokines such as tumor necrosis factor α, interleukin (IL)-1, and adhesion molecules. In the present study we determined the levels of cytokines such as IL-18 and endothelin-1 (ET-1) in children with HSP. Subjects were divided into three groups (group 1, 20 subjects with HSP; group 2, 10 subjects belonging to group 1 during their follow-up 4 to 6 months later; and group 3, 16 controls who were healthy siblings of the subjects). IL-18 and ET-1 levels were determined using enzyme immunoassay and expressed as mean ± standard deviation. We observed higher IL-18 levels in children with HSP (767.6 ± 145.1 pg/mL) than in controls (614.6 ± 66.54 pg/mL, p > 0.05), but IL-18 levels were found to be significantly lower in subjects with HSP in remission (502.7 ± 60.81 pg/mL) than in those who were in an active phase (1,050 ± 244.5 pg/mL, p < 0.05, n = 10). ET-1 levels were found to be significantly higher in subjects with HSP (1.93 ± 0.19 pg/mL) than in controls (1.10 ± 0.13 pg/mL, p < 0.05), although no significant difference was observed in ET-1 levels between subjects in group 1 (1.88 ± 0.30 pg/mL) and group 2 (1.91 ± 0.120, p > 0.05, n = 10). A positive correlation was observed between IL-18 and ET-1 levels in subjects with HSP (correlation coefficient [r] = 0.5254, p < 0.01). These results suggest that levels of IL-18 and ET-1 are worth monitoring during the clinical course of the disease, but caution must be exercised in extrapolating data based on small study samples.

Inhibition of C-reactive protein induced expression of matrix metalloproteinases by atorvastatin in THP-1 cells.

The role of CRP as a mediator in atherosclerosis and inflammation is being investigated worldwide. In the present study, the effect of CRP on matrix metalloproteinases (MMP)-1, 2, 9, and their tissue inhibitor (TIMP-1) gene expression in THP-1 monocytic cell line was investigated. Specific mitogen activated protein (MAP) kinase (ERK, p38, and JNK) inhibitors were used to elucidate the signaling pathways involved. Effect of atorvastatin was determined in the presence of CRP on the expression of genes. Time and dose-dependent experiments were performed in the presence of CRP. The results showed that the treatment of THP-1 cells with 100 microg of CRP/ml/10(6) cells for 24 h enhanced the expression of MMPs and TIMP-1 genes significantly. CRP upregulated the expression of these genes via FcgammaRII and utilized ERK signaling pathway to transduce signals. Atorvastatin was able to significantly attenuate CRP-induced MMPs expression and augmented TIMP-1 gene expression significantly. In conclusion, CRP is not only a risk marker for vascular events, but also directly involved in the mechanisms leading to remodeling and destabilization of atherosclerotic plaque. Also, atorvastatin serves as potential therapeutic modality to curb these harmful events.

Error-corrected sequencing strategies enable comprehensive detection of leukemic mutations relevant for diagnosis and minimal residual disease monitoring.

BACKGROUND: Pediatric leukemias have a diverse genomic landscape associated with complex structural variants, including gene fusions, insertions and deletions, and single nucleotide variants. Routine karyotype and fluorescence in situ hybridization (FISH) techniques lack sensitivity for smaller genomic alternations. Next-generation sequencing (NGS) assays are being increasingly utilized for assessment of these various lesions. However, standard NGS lacks quantitative sensitivity for minimal residual disease (MRD) surveillance due to an inherently high error rate. METHODS: Primary bone marrow samples from pediatric leukemia (n = 32) and adult leukemia subjects (n = 5), cell line MV4-11, and an umbilical cord sample were utilized for this study. Samples were sequenced using molecular barcoding with targeted DNA and RNA library enrichment techniques based on anchored multiplexed PCR (AMP®) technology, amplicon based error-corrected sequencing (ECS) or a human cancer transcriptome assay. Computational analyses were performed to quantitatively assess limit of detection (LOD) for various DNA and RNA lesions, which could be systematically used for MRD assays. RESULTS: Matched leukemia patient samples were analyzed at three time points; diagnosis, end of induction (EOI), and relapse. Similar to flow cytometry for ALL MRD, the LOD for point mutations by these sequencing strategies was ≥0.001. For DNA structural variants, FLT3 internal tandem duplication (ITD) positive cell line and patient samples showed a LOD of ≥0.001 in addition to previously unknown copy number losses in leukemia genes. ECS in RNA identified multiple novel gene fusions, including a SPANT-ABL gene fusion in an ALL patient, which could have been used to alter therapy. Collectively, ECS for RNA demonstrated a quantitative and complex landscape of RNA molecules with 12% of the molecules representing gene fusions, 12% exon duplications, 8% exon deletions, and 68% with retained introns. Droplet digital PCR validation of ECS-RNA confirmed results to single mRNA molecule quantities. CONCLUSIONS: Collectively, these assays enable a highly sensitive, comprehensive, and simultaneous analysis of various clonal leukemic mutations, which can be tracked across disease states (diagnosis, EOI, and relapse) with a high degree of sensitivity. The approaches and results presented here highlight the ability to use NGS for MRD tracking.

Strong concordance between RNA structural and single nucleotide variants identified via next generation sequencing techniques in primary pediatric leukemia and patient-derived xenograft samples.

Acute leukemia represents the most common pediatric malignancy comprising diverse subtypes with varying prognosis and treatment outcomes. New and targeted treatment options are warranted for this disease. Patient-derived xenograft (PDX) models are increasingly being used for preclinical testing of novel treatment modalities. A novel approach involving targeted error-corrected RNA sequencing using ArcherDX HemeV2 kit was employed to compare 25 primary pediatric acute leukemia samples and their corresponding PDX samples. A comparison of the primary samples and PDX samples revealed a high concordance between single nucleotide variants and gene fusions whereas other complex structural variants were not as consistent. The presence of gene fusions representing the major driver mutations at similar allelic frequencies in PDX samples compared to primary samples and over multiple passages confirms the utility of PDX models for preclinical drug testing. Characterization and tracking of these novel cryptic fusions and exonal variants in PDX models is critical in assessing response to potential new therapies.

Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation.

Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

Correlation among soluble markers and severity of disease in non-diabetic subjects with pre-mature coronary artery disease.

Studies are lacking in literature, which demonstrate the cumulative impact of certain soluble markers in predicting the severity of CAD. Serum hsCRP, MMP-9, TIMP-1 and sRAGE levels were measured in non-diabetic 100 angiographically proven CAD patients (Group I) and 40 non-diabetic subjects with coronary risk factors and without any lesions (Group II). Increased levels of serum hsCRP, MMP-9, TIMP-1 and decreased levels of sRAGE were observed in Group I as compared to Group II. Gensini score, a measure for severity of CAD was found to be positively correlated with serum hsCRP, MMP-9, TIMP-1 and negatively with sRAGE. Multivariate analysis revealed serum MMP-9, hsCRP, sRAGE and family history as predictors of severity of CAD with a cumulative sensitivity and specificity of 92% and 82%, respectively. Cumulative impact of these soluble markers, in addition to the established markers will contribute to improve the predictive value for the assessment of disease severity.

The snoRNA target of t(4;14) in multiple myeloma regulates ribosome biogenesis.

The orphan small nucleolar RNA (snoRNA) ACA11 is overexpressed as a result of the t(4;14) chromosomal translocation in multiple myeloma (MM), increases reactive oxygen species, and drives cell proliferation. Like other snoRNAs, ACA11 is predominantly localized to a sub-nuclear organelle, the nucleolus. We hypothesized that increased ACA11 expression would increase ribosome biogenesis and protein synthesis. We found that ACA11 overexpression in MM cells increased nucleolar area and number as well as silver-binding nucleolar organizing regions (AgNORs). Supporting these data, samples from t(4;14)-positive patients had higher AgNORs scores than t(4;14)-negative samples. ACA11 also upregulated ribosome production, pre-47S rRNA synthesis, and protein synthesis in a ROS-dependent manner. Lastly, ACA11 overexpression enhanced the response to proteasome inhibitor in MM cells, while no effect was found in response to high doses of melphalan. Together, these data demonstrate that ACA11 stimulates ribosome biogenesis and influences responses to chemotherapy. ACA11 may be a useful target to individualize the treatment for t(4;14)-positive myeloma patients.

Clinical Characteristics, Complications, and Treatment Practices in Patients With RHD: 6-Year Results From HP-RHD Registry.

BACKGROUND: Despite the high prevalence of rheumatic heart disease (RHD) in developing countries such as India, data on characteristics, complications, and treatment practices are lacking. The HP-RHD (Himachal Pradesh Rheumatic Heart Disease) registry aimed at reporting these parameters in patients with RHD from a northern state of India. METHODS: A total of 2,005 consecutive patients of RHD were enrolled over a period of 6 years (2011 to 2016) in the present study. The clinical characteristics, complications, and treatment practices were systematically recorded. RESULTS: The mean age for patients with RHD was 40.3 ± 14.3 (range 5 to 83 years). RHD predominantly affected females (72.3%) and population from rural background (92%). Multivalvular involvement was frequent (43.2%), mitral valve was the commonest affected valve (83.3%). The majority of the patients had moderate-to-severe valvular dysfunction (69.3%). Mitral and tricuspid valve involvement was more frequent in female subjects compared with more frequent aortic valve involvement in male subjects (p < 0.001). The major adverse cardiovascular events were recorded in 23.4% patients at the time of registry and comprised mainly advanced heart failure (15.6%), peripheral embolism (4.1%), and stroke (3.9%). The independent risk determinants of major adverse cardiovascular events (were advanced age (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 1.00-1.02), severe mitral stenosis (OR: 1.73; 95% CI: 1.34-2.20), severe tricuspid regurgitation (OR: 2.11; 95% CI: 1.48-3.02), presence of pulmonary artery hypertension (OR: 1.33; 95% CI: 1.04-1.69), and atrial fibrillation (OR: 1.64; 95% CI: 1.28-2.11). Evidence-based use of oral anticoagulant therapy was documented in 77.7% of high-risk patients. Only 28.5% of study population was receiving secondary prophylaxis. CONCLUSIONS: Complications in patients with RHD increase with age and worsening valvular dysfunction. Programs focused on early detection and evidence-based management will assist in improving outcomes.

Post-traumatic superolateral dislocation of condyle: A case series of 18 condyles with review of literature and a proposed classification.

AIM: The aim is to review the English literature for post-traumatic superolateral dislocation of mandibular condyle (SDMC),discuss their dynamics and clinical management and to propose to modify the existing classification of SDMC. PATIENTS AND METHODS: A literature search was carried at Pubmed, Sciencedirect, Google and references from reported articles were crosschecked to look for the cases of SDMC from 1969 to 2015 in English language. Also, we have reviewed 11 of our patients with total of 18 superolateral dislocated intact or sagittal split condyles ,who visited our unit in the previous two years. RESULTS: In our retrospective analysis 58 cases of SDMC were found in the literature, of which 38 had intact mandibular condyles and 20 had sagittal split. Early and intact SDMC were successfully managed conservatively with closed reduction, whereas old cases and largely fractured condyles necessitated open reduction. Additionally, we observed an unusual dislocation associated with fracture of contralateral posterior mandible(angle) in our series which did not gratify the existing classification. CONCLUSION: Alteration of the existing classification was required to accommodate the unusual type of dislocation.

Gender differences in the management of acute coronary syndrome patients: One year results from HPIAR (HP-India ACS Registry).

INTRODUCTION: Data from high-income countries suggest that women receive less intensive diagnostic and therapeutic management than men for acute coronary syndrome (ACS). There is a paucity of such data in the Indian population, which is 69% rural and prior studies focused mostly on urban populations. The objective of the present study was to identify the gender based differences in ACS management, if any, in a predominantly rural population. METHODS: Data from 35 hospitals across Himachal Pradesh covering >90% of state population were collected for one year (July 2015-June 2016). A total of 2118 ACS subjects met inclusion criteria and baseline characteristics, in-hospital treatments and mortality rates were analyzed. RESULTS: Women constituted less than one-third of ACS population. Women were older compared to men and were more likely to present with NSTEMI/UA. Misinterpretation of initial symptoms and late presentation were also common in women. Fewer women received optimal guideline based treatment and PCI (0.9% vs 4.2%, p<0.01). Compare to men, women more often had Killip class >1 (27.3% vs 20.4%, p<0.01) and higher in-hospital mortality (8.5% vs 5.6%, p=0.009). On multivariate analysis the association between female gender and mortality was attenuated (adjusted odds ratio [OR]=1.36 [0.77-2.38]). CONCLUSION: The present study from India, is the first of its kind to evaluate the gender based differences among ACS patients, in a predominantly rural population. Our analysis demonstrates a significant gender based difference between symptom awareness and delay in presentation, management and in-hospital outcome. Further studies are warranted across other parts of country to investigate this gender disparity.

Usefulness of the Mitral Regurgitation Severity Index to Assess the Severity of Chronic Mitral Regurgitation.

Existing metrics for grading mitral regurgitation (MR) are limited and fraught with high interobserver variability. We developed and evaluated a Doppler-based, semiquantitative novel index (Mitral Regurgitation Severity Index [MRSI]) of MR severity. In a total of 125 patients (70 in the derivation cohort and 55 in the validation cohort), MRSI was calculated as a ratio of time velocity integral of mitral inflow (continuous-wave Doppler-TVI MV) to the time velocity integral of the left ventricle outflow (pulse-wave Doppler-TVI LVOT). Inter-rater agreement for MRSI and predictive ability of the MRSI were then assessed. In the derivation cohort, MRSI differed significantly between patients with severe MR (2.6 ± 0.51) and mild-moderate (nonsevere) MR (1.4 ± 0.18) and a cutoff of ≥1.8 was associated with optimal diagnostic accuracy. In the validation cohort, MRSI exhibited excellent agreement between a level II and a level III reader with a mean difference of -0.14 (95% confidence limit of agreement: -0.80 to 0.53), correlation coefficient of 0.88 (p <0.001), and 16% CV; and using the cut point of 1.8, it exhibited good inter-rater reproducibility with a kappa coefficient of 0.72 (p <0.001). In conclusion, MRSI appears to be a simple, quantitative, practical, color-independent metric to differentiate severe MR from nonsevere MR.

Role of C-C chemokines in Takayasu's arteritis disease.

BACKGROUND: Takayasu's arteritis (TA) is a chronic obliterative inflammatory disease. Inflammatory cell infiltration and destruction of the vessel wall in TA strongly suggest that cell mediated immunological mechanisms play an important role in the pathogenesis of this disease. Therefore, in the present study our aim was to focus on the role of chemokines and adhesion molecules in patients with Takayasu's disease. METHODS: Twenty-one patients with clinically defined TA and 21 healthy control volunteers were recruited by using the standard criteria. Patients with TA were divided into those with clear-cut clinically active or inactive disease based on vasculitis activity score. RESULTS: MCP-1 and hRANTES were significantly increased in patients with TA as compared to controls. MCP-1 and hRANTES values were reliably able to distinguish between patients with active disease vs. subjects in remission. sVCAM-1 levels remained unaltered between patients and controls. CONCLUSIONS: C-C chemokines can be used as reliable markers/diagnostic tools in determining the activity of Takayasu's arteritis.