The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the ...previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.
The use of ultrasound has developed over the last 50 years into an indispensable first-line test for the cardiac evaluation of symptomatic patients. The technologic miniaturization and improvement in ...transducer technology, as well as the implementation of educational curriculum changes in residency training programs and specialty practice, have facilitated the integration of focused cardiac ultrasound into practice by specialties such as emergency medicine. In the emergency department, focused cardiac ultrasound has become a fundamental tool to expedite the diagnostic evaluation of the patient at the bedside and to initiate emergent treatment and triage decisions by the emergency physician.
Abstract The field of tissue engineering continues to expand and mature, and several products are now in clinical use, with numerous other preclinical and clinical studies underway. However, specific ...challenges still remain in the repair or regeneration of tissues that serve a predominantly biomechanical function. Furthermore, it is now clear that mechanobiological interactions between cells and scaffolds can critically influence cell behavior, even in tissues and organs that do not serve an overt biomechanical role. Over the past decade, the field of “functional tissue engineering” has grown as a subfield of tissue engineering to address the challenges and questions on the role of biomechanics and mechanobiology in tissue engineering. Originally posed as a set of principles and guidelines for engineering of load-bearing tissues, functional tissue engineering has grown to encompass several related areas that have proven to have important implications for tissue repair and regeneration. These topics include measurement and modeling of the in vivo biomechanical environment; quantitative analysis of the mechanical properties of native tissues, scaffolds, and repair tissues; development of rationale criteria for the design and assessment of engineered tissues; investigation of the effects biomechanical factors on native and repair tissues, in vivo and in vitro ; and development and application of computational models of tissue growth and remodeling. Here we further expand this paradigm and provide examples of the numerous advances in the field over the past decade. Consideration of these principles in the design process will hopefully improve the safety, efficacy, and overall success of engineered tissue replacements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Summary: zCall is a variant caller specifically designed for calling rare single-nucleotide polymorphisms from array-based technology. This caller is implemented as a post-processing step ...after a default calling algorithm has been applied. The algorithm uses the intensity profile of the common allele homozygote cluster to define the location of the other two genotype clusters. We demonstrate improved detection of rare alleles when applying zCall to samples that have both Illumina Infinium HumanExome BeadChip and exome sequencing data available.
Availability: http://atguweb.mgh.harvard.edu/apps/zcall.
Contact: bneale@broadinstitute.org
Supplementary Information: Supplementary data are available at Bioinformatics online.
Among the known genetic risk factors for Parkinson disease, mutations in GBA1, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed ...attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of α-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced α-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease.
Because GBA1 mutations are the most common genetic risk factor for Parkinson disease, dopaminergic neurons were generated from iPSC lines derived from patients with Gaucher disease with and without parkinsonism. These cells exhibit deficient enzymatic activity, reduced lysosomal glucocerebrosidase levels, and storage of glucosylceramide and glucosylsphingosine. Lines generated from the patients with parkinsonism demonstrated elevated levels of α-synuclein. To reverse the observed phenotype, the neurons were treated with a novel noninhibitory glucocerebrosidase chaperone, which successfully restored glucocerebrosidase activity and protein levels and reduced glycolipid storage. In addition, the small-molecule chaperone reduced α-synuclein levels in dopaminergic neurons, indicating that chaperoning glucocerebrosidase to the lysosome may provide a novel therapeutic strategy for both Parkinson disease and neuronopathic forms of Gaucher disease.
The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the ...previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.
To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA).
This 12-week, multicenter, ...double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies.
Women (n = 631; ospemifene n = 316, placebo n = 315) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed.
Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.
Objectives This study aimed to determine the success, complications, and survival of patients after balloon aortic valvuloplasty (BAV). Background The introduction of transcatheter aortic valve ...implantation (TAVI) BAV has led to a revival in the treatment of patients with severe aortic stenosis. Methods A cohort of 262 patients with severe aortic stenosis underwent 301 BAV procedures. Of these, 39 (14.8%) patients had ≥2 BAV procedures. Clinical, hemodynamic, and follow-up mortality data were collected. Results The cohort mean age was 81.7 ± 9.8 years, and the mean Society of Thoracic Surgeons and logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 13.3 ± 6.7 and 45.6 ± 21.6, respectively. BAV was performed as a bridge to TAVI or to surgical aortic valve replacement in 28 patients (10.6%) and for symptom relief in 234 (89.4%). The mean aortic valve area (AVA) increased from 0.58 ± 0.3 cm2 to 0.96 ± 0.3 cm2 (p < 0.001). Of these, 111 (45.0%) had final AVA >1 cm2 , and in 195 patients (79%), AVA increased by >40%. De novo BAV resulted in a higher mean increase in AVA 0.41 ± 0.24 cm2 versus 0.28 ± 0.24 cm2 in redo BAV (p = 0.003). Serious adverse events occurred in 47 patients (15.6%), intraprocedural death in 5 (1.6%), stroke in 6 (1.99%), coronary occlusion in 2 (0.66%), severe aortic regurgitation in 4 (1.3%), resuscitation/cardioversion in 5 (1.6%), tamponade in 1 (0.33%), and permanent pacemaker in 3 (0.99%). A vascular complication occurred in 21 patients (6.9%); 34 (11.3%) had a post-procedure rise in creatinine >50%; and 3 (0.99%) required hemodialysis. During median follow-up of 181 days, the mortality rate was 50% (n = 131). The mortality rate in the group with final AVA >1 cm2 was significantly lower than in the group with final AVA of <1 cm2 (36.4% vs. 57.9%, p < 0.001). Final AVA was associated with lower mortality (hazard ratio: 0.46, p = 0.03). BAV as a bridge to TAVI or surgical aortic valve replacement had a better outcome compared with BAV alone: mortality rate 7 (25%) versus 124 (52.9%), respectively (p < 0.0001). Conclusions Long-term survival is poor after BAV alone. BAV as a bridge to percutaneous or surgical aortic valve replacement is feasible, safe, and associated with better outcome than BAV alone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential ...electrophysiological properties and distributions of Na
V
1.2 and Na
V
1.6 channels lead to distinct contributions to AP initiation and propagation. While Na
V
1.6 at the distal AIS promotes AP initiation and forward propagation, Na
V
1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the small ubiquitin-like modifier (SUMO) pathway modulates Na
+
channels at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect Na
V
1.6, these effects were attributed to SUMOylation of Na
V
1.2. Moreover, SUMO effects were absent in a mouse engineered to express Na
V
1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of Na
V
1.2 exclusively controls I
NaP
generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.
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