Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression.

OBJECTIVE: Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH. DESIGN: We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined. RESULTS: Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr-/- fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice. CONCLUSIONS: MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH.

Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice--brief report.

OBJECTIVE: Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm. METHODS AND RESULTS: C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-ß antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02). CONCLUSIONS: These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.

The Relations Among Oral and Silent Reading Fluency and Comprehension in Middle School: Implications for Identification and Instruction of Students With Reading Difficulties.

The purpose of this study was to investigate the relations among oral and silent reading fluency and reading comprehension for students in Grades 6 to 8 (n = 1,421) and the use of fluency scores to identify middle school students who are at risk for failure on a high-stakes reading test. Results indicated moderate positive relations between measures of fluency and comprehension. Oral reading fluency (ORF) on passages was more strongly related to reading comprehension than ORF on word lists. A group-administered silent reading sentence verification test approximated the classification accuracy of individually administered ORF passages. The correlation between a maze task and comprehension was weaker than has been reported for elementary students. The best predictor of a high-stakes reading comprehension test was the previous year's administration of the grade-appropriate test; fluency and verbal knowledge measures accounted for only small amounts of unique variance beyond that accounted for by the previous year's administration.

Effects of Individualized and Standardized Interventions on Middle School Students With Reading Disabilities.

This study reports the effectiveness of a year-long, small-group, tertiary (Tier 3) intervention that examined 2 empirically derived but conceptually different treatments and a comparison condition. The researchers had randomly assigned all students to treatment or comparison conditions. The participants were seventh- and eighth-grade students from the previous year who received an intervention and did not meet exit criteria. The researchers assigned them to one of two treatments: standardized (n = 69) or individualized (n = 71) for 50 min a day, in group sizes of 5, for the entire school year. Comparison students received no researcher-provided intervention (n = 42). The researchers used multigroup modeling with nested comparisons to evaluate the statistical significance of Time 3 estimates. Students in both treatments outperformed the comparison students on assessments of decoding, fluency, and comprehension. Intervention type did not moderate the pattern of effects, although students in the standardized treatment had a small advantage over individualized students on word attack. This study provides a framework from which to refine further interventions for older students with reading disabilities.

Response to Intervention for Middle School Students With Reading Difficulties: Effects of a Primary and Secondary Intervention.

This study examined the effectiveness of a yearlong, researcher-provided, Tier 2 (secondary) intervention with a group of sixth-graders. The intervention emphasized word recognition, vocabulary, fluency, and comprehension, Participants scored below a proficiency level on their slate accountability test and were compared to a similar group of struggling readers receiving school-provided instruction. All students received the benefits of content area teachers who participated in researcher-provided professional development designed to integrate vocabulary and comprehension practices throughout the school day (Tier 1). Students who participated in the Tier 2 intervention showed gains on measures of decoding, fluency, and comprehension, but differences relative to students in the comparison group were small (median d = +0.16). Students who received the re searcher-provided intervention scored significantly higher than students who received comparison intervention on measures of word attack, spelling, the state accountability measure, passage comprehension, and phonemic decoding efficiency, although most often in particular subgroups.

Response to Intervention with Older Students with Reading Difficulties.

Addressing the literacy needs of secondary school students involves efforts to raise the achievement levels of all students and to address specifically the needs of struggling readers. One approach to this problem is to consider the application of a Response to Intervention (RTI) model with older students. We describe an approach to enhanced literacy instruction for middle school students that includes the essential components of any RTI model: universal screening, progress monitoring, and multi-tiered instructional service delivery. We use screening and progress-monitoring tools specifically tied to state accountability tests and a multi-tiered instructional framework that addresses the literacy needs of all middle school students, including struggling readers. Presently a large-scale, multi-site randomized trial is under way to evaluate the feasibility and effectiveness of this RTI model for middle school students.

Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease.

Reading skill components and impairments in middle school struggling readers.

This study investigated how measures of decoding, fluency, and comprehension in middle school students overlap with one another, whether the pattern of overlap differs between struggling and typical readers, and the relative frequency of different types of reading difficulties. The 1,748 sixth, seventh, and eighth grade students were oversampled for struggling readers (n = 1,025) on the basis of the state reading comprehension proficiency measure. Multigroup confirmatory factor analyses showed partial invariance among struggling and typical readers (with differential loadings for fluency and for comprehension), and strict invariance for decoding and a combined fluency/comprehension factor. Among these struggling readers, most (85 %) also had weaknesses on nationally standardized measures, particularly in comprehension; however, most of these also had difficulties in decoding or fluency. These results show that the number of students with a specific comprehension problem is lower than recent consensus reports estimate and that the relation of different reading components varies according to struggling versus proficient readers.

Reliability and Validity of Oral Reading Fluency Median and Mean Scores among Middle Grade Readers When Using Equated Texts.

We evaluated the reliability and validity of two oral reading fluency scores for one-minute equated passages: median score and mean score. These scores were calculated from measures of reading fluency administered up to five times over the school year to students in grades 6-8 (n = 1,317). Both scores were highly reliable with strong convergent validity for adequately developing and struggling middle grade readers. These results support the use of either the median or mean score for oral reading fluency assessments for middle grade readers.

Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. METHODS AND RESULTS: We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. CONCLUSIONS: Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

An Experimental Study of Scheduling and Duration of "Tier 2" First-Grade Reading Intervention.

This study compared the effects on reading outcomes of delivering supplemental, small-group intervention to first-grade students at risk for reading difficulties randomly assigned to one of three different treatment schedules: extended (4 sessions per week, 16 weeks; n = 66), concentrated (4 sessions per week, 8 weeks; n = 64), or distributed (2 sessions per week, 16 weeks; n = 62) schedules. All at-risk readers, identified through screening followed by 8 weeks of oral reading fluency (ORF) progress monitoring, received the same Tier 2 reading intervention in groups of 2 to 4 beginning in January of Grade 1. Group means were higher in word reading and ORF at the final time point relative to pretest; however, the groups did not differ significantly on any reading outcome or on rates of adequate intervention response. Of potential covariates, site, age, free lunch status, program coverage rate, and tutor were significantly related to student outcomes; however, the addition of these variables in multivariate models did not substantially change results. Rates of adequate intervention response were lower than have been reported for some first-grade interventions of longer duration.

The relative effects of group size on reading progress of older students with reading difficulties.

This study reports findings on the relative effects from a yearlong secondary intervention contrasting large-group, small-group, and school-provided interventions emphasizing word study, vocabulary development, fluency, and comprehension with seventh- and eighth-graders with reading difficulties. Findings indicate that few statistically significant results or clinically significant gains were associated with group size or intervention. Findings also indicate that a significant acceleration of reading outcomes for seventh- and eighth-graders from high-poverty schools is unlikely to result from a 50 min daily class. Instead, the findings indicate, achieving this outcome will require more comprehensive models including more extensive intervention (e.g., more time, even smaller groups), interventions that are longer in duration (multiple years), and interventions that vary in emphasis based on specific students' needs (e.g., increased focus on comprehension or word study).

Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17-dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule-1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation.