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Background. Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. Although more than 40 genes have been reported to cause DCM, the role of genetic testing in clinical practice is not well defined. Mutations in the troponin T (TNNT2) gene represent an important subset of known disease-causing mutations associated with DCM. Therefore, the aim of the present study was to determine the genetic variations inTNNT2and the associations of those variations with DCM in Chinese patients.Methods. An approximately 4 kb fragment of theTNNT2gene was isolated from 103 DCM patients and 192 healthy controls and was analyzed by DNA sequence analysis for genetic variations.Results. A total of 6TNNT2mutations were identified in 99 patients, including a G321T missense mutation (Leu84Phe) and 5 novel intronic mutations. Alleles of two novel SNPs (c.192+353C>A, OR=0.095, 95% CI:0.013–0.714,P=0.022; c.192+463G>A, OR=0.090, 95% CI:0.012–0.675,P=0.019) and SNP rs3729843 (OR=1.889, 95% CI:1.252–2.852;P=0.002) were significantly correlated with DCM.Conclusions. These results suggest that the missense mutation (Leu84Phe) and two novel SNPs (c.192+353C>A, c.192+463G>A) inTNNT2gene might be associated with DCM in the Chinese population.

AbstractBackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data.ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011.ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Key PointsWe identified CRBN-binding proteins and confirmed recent work implicating the Ikaros transcription factors as important members. Low IZKF1 levels predict lack of IMiD responsiveness and shorter OS; IZKF1 expression is a potential predictive biomarker for clinic application.

Abstract B7-H3 is a B7 family molecule with T cell costimulatory function in vitro. The in vivo role of B7-H3 in the stimulation of tumor immunity is unclear. We report here that expression of B7-H3 by transfection of the mouse P815 tumor line enhances its immunogenicity, leading to the regression of tumors and amplification of a tumor-specific CD8+ CTL response in syngeneic mice. Tumor cells engineered to express B7-H3 elicit a rapid clonal expansion of P1A tumor Ag-specific CD8+ CTL in lymphoid organs in vivo and acquire the ability to directly stimulate T cell growth, division, and development of cytolytic activity in vitro. Our results thus establish a role for B7-H3 in the costimulation of T cell immune responses in vivo.

Purpose The purposes of this study were to determine the frequency of acute and subacute complications (within 6 months) of arthroscopic knee procedures in patients aged 17 years or younger and to determine associated risk factors. Methods We identified all patients aged 17 years or younger who underwent arthroscopic knee procedures at our institution from 1997 to 2009. Patient demographic and surgical data were collected from the medical and surgical records, with specific focus on intraoperative and postoperative complications. Results During the study period, 1,002 knee arthroscopies were reviewed. The overall complication rate was 14.7%. Major complications occurred in 21 surgeries (2.1%) and included the following: septic arthritis (n = 3, 0.3%), wound complication requiring operative revision (n = 9, 0.9%), arthrofibrosis requiring manipulation (n = 4, 0.4%), other unplanned subsequent surgery (n = 4, 0.4%), and death (n = 1, 0.1%). Surgeries with an anesthesia time of 265 minutes or greater ( P = .026), operative time of 220 minutes or greater ( P = .013), or tourniquet time of 114 minutes or greater ( P < .001) and surgeries with 3 or more Current Procedural Terminology codes ( P = .003) had a statistically significant increase in risk of major complications. The incidence of minor complications was 12.6%, which included persistent effusion/hemarthrosis requiring arthrocentesis (n = 59, 5.9%) and superficial wound infection (n = 18, 1.8%). Conclusions Major complications after knee arthroscopy in children and adolescents are rare, but minor complications are more common. If possible, surgeons should avoid prolonged anesthesia, surgery, and tourniquet times. The pediatric patient's medical and family history should be reviewed to identify important risk factors. Level of Evidence Level IV, therapeutic case series.

Key Points Eosinophils recruited to the airways in response to A fumigatus sensitization and challenge degranulate in response to virus infection. Activated eosinophils are antiviral and promote survival from an otherwise lethal respiratory virus infection.

Summary The transcription factor forkhead box N4 (Foxn4) is a key regulator in a variety of biological processes during development. In particular, Foxn4 plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina. Although the functions of Foxn4 have been well established, the transcriptional regulation of Foxn4 expression during progenitor cell differentiation remains unclear. Here, we report that an evolutionarily conserved 129 bp noncoding DNA fragment (Foxn4CR4.2 or CR4.2), located ∼26 kb upstream of Foxn4 transcription start site, functions as a cis-element for Foxn4 regulation. CR4.2 directs gene expression in Foxn4-positive cells, primarily in progenitors, differentiating horizontal and amacrine cells. We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor. Deletion of the Meis1 binding motif or knockdown of Meis1 expression abolishes the gene regulatory activity of CR4.2. In addition, knockdown of Meis1 expression diminishes the endogenous Foxn4 expression and affects cell lineage development. Together, we demonstrate that CR4.2 and its interacting Meis1 transcription factor play important roles in regulating Foxn4 expression during early retinogenesis. These findings provide new insights into molecular mechanisms that govern gene regulation in retinal progenitors and specific cell lineage development.

We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis. Hearts from TgRR mice had elevated left ventricular systolic function compared with wild-type (WT) mice, both in vivo and in vitro, without signs of hypertrophy or altered diastolic function. Isolated cardiomyocytes from TgRR mice had enhanced contraction and relaxation, with no change in Ca 2+ transients, suggesting targeted improvement of myofilament function. TgRR hearts had normal ATP and only slightly decreased phosphocreatine levels by 31 P NMR spectroscopy, and they maintained rate responsiveness to dobutamine challenge. These data demonstrate long-term (at least 5-mo) elevation of cardiac [dATP] results in sustained elevation of basal left ventricular performance, with maintained β-adrenergic responsiveness and energetic reserves. Combined with results from previous studies, we conclude that this occurs primarily via enhanced myofilament activation and contraction, with similar or faster ability to relax. The data are sufficiently compelling to consider elevated cardiac [dATP] as a therapeutic option to treat systolic dysfunction.

Eleven fresh-frozen cadaver foot specimens were tested to define changes in tarsal alignment associated with flatfoot, or pes planus, a common clinical problem. The three-dimensional position of four bones (talus, calcaneus, navicular, and first metatarsal) relative to the fixed tibia was determined with a magnetic tracking system in the intact foot and flatfoot conditions. In the flatfoot, the average metatarsal-to-talar position difference was 11.7° ± 4.4° in abduction ( P < 0.0001), 10.4° ± 3.6° in dorsiflexion ( P < 0.0001), and 10.9° ± 6.0° in eversion ( P < 0.0001) compared with the intact foot. The average calcaneal-to-talar position difference was 2.2° ± 2.6° in abduction ( P = 0.0171) and 2.7° ± 2.0° in eversion ( P = 0.0012) compared with the intact foot. The average navicular-to-talar position difference was 13.6° ± 5.0° in abduction ( P < 0.0001), 10.5° ± 6.6° in dorsiflexion ( P = 0.0004), and 8.1° ± 3.8° in eversion ( P < 0.0001) compared with normal. The average talar-to-tibial position difference was −8.2° ± 3.2° in dorsiflexion ( P < 0.001) compared with the intact foot. The average arch height difference was 6.0 ± 2.7 mm ( P < 0.0001) less than the normal condition. The deformity associated with flatfoot is complex and occurs in multiple joints and in all three planes. An understanding of the normal and pathologic (flatfoot) conditions is necessary to surgically restore appropriate alignment and function in hindfoot reconstruction operations.