Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy

Fast breath-hold cardiovascular magnetic resonance (CMR) shows excellent results for interstudy reproducibility of left ventricular (LV) volumes, ejection fraction, and mass, which are thought to be superior to results of 2-dimensional echocardiography. However, there is no direct comparison of the interstudy reproducibility of both methods in the same subjects. A total of 60 subjects (normal volunteers [n = 20], or patients with heart failure [n = 20] or LV hypertrophy [n = 20]) underwent 2 CMRs and 2 echocardiographic studies for assessment of LV volumes, function, and mass. The interstudy reproducibility coefficient of variability was superior for CMR in all groups for all parameters. Statistical significance was reached for end-systolic volume (4.4% to 9.2% vs 13.7% to 20.3%, p <0.001), ejection fraction (2.4% to 7.3% vs 8.6% to 19.4%, p <0.001), and mass (2.8% to 4.8% vs 11.6% to 15.7% p <0.001), with a trend for end-diastolic volume (2.9% to 4.9% vs 5.5% to 10.5%, p = 0.17). The superior interstudy reproducibility resulted in considerably lower calculated sample sizes (reductions of 55% to 93%) required by CMR compared with echocardiography to show clinically relevant changes in LV dimensions and function. Thus, CMR has excellent interstudy reproducibility in normal, dilated, and hypertrophic hearts, and is superior to 2-dimensional echocardiography.     

Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8(+) T-cell response

To understand the molecular basis for the rapid and robust memory T-cell responses, we examined gene expression and chromatin modification by histone H3 lysine 9 (H3K9) acetylation in resting and activated human naive and memory CD8(+) T cells. We found that, although overall gene expression patterns were similar, a number of genes are differentially expressed in either memory or naive cells in their resting and activated states. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role in selective and rapid gene expression of memory CD8(+) T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in naive cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8(+) T-cell response.     

CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8(+) T cells by using the glycoprotein (gp) 100-specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4(-/-) mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8(+) T-cell population and large numbers of CD4(+) T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4(-/-) CD8(+) T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4-mediated inhibition on CD8(+) T cells did not directly promote enhancement of their effector functions. Removal of CD4(+) T cells by crossing the pmel-1 CLTA-4(-/-) mouse onto a Rag-1(-/-) background resulted in the complete abrogation of CD8(+) T-cell activation and autoimmune manifestations. The effects of CD4(+) CLTA-4(-/-) T cells were dependent on the absence of CTLA-4 on CD8(+) T cells. These results indicated that CD8(+) CLTA-4(-/-) T-cell-mediated autoimmunity and tumor immunity required CD4(+) T cells in which the function was dysregulated by the absence of CTLA-4-mediated negative costimulation.     

Septicaemia due to Neisseria lactamica—Initial confusion with Neisseria meningitidis

Neisseria lactamica, isolated from a baby with septicaemia, was at first thought to be Neisseria meningitidis, possibly acquired in hospital. Extensive investigation of contacts was made until the O-nitrophenyl-D-galactopyranoside reaction proved positive. Distinction between the two species, easily made in this way, is important both in individual patients and in population surveys.     

Newly detected atrial fibrillation and compliance with antithrombotic guidelines

BACKGROUND: Guidelines recommend the use of antithrombotic therapy for stroke prevention in patients with atrial fibrillation (AF), but compliance with such guidelines has not been widely studied among patients with newly detected AF. Our objective was to assess compliance with antithrombotic guidelines and to identify patient characteristics associated with warfarin use. METHODS: A population-based study of newly detected AF (patient age, 30-84 years) was conducted within a large health plan. Cardiovascular disease risk factors, comorbid conditions, medication use, and international normalized ratios were abstracted from the medical record. Patients were stratified by embolic risk according to American College of Chest Physicians (ACCP) criteria. We analyzed the proportion of patients with AF receiving warfarin or aspirin (> or =325 mg/d) during the 6 months following AF. Relative risk regression estimated the association of risk factors and patient characteristics with warfarin use. RESULTS: Overall, 73% of patients (418/572) with newly detected AF had evidence of antithrombotic use after AF onset. Among the 76% (437/572) of patients with AF at high risk for stroke, 59% (257/437) used warfarin, 28% (123/437) used aspirin, and 24% (104/437) used neither. The major predictor of warfarin use was AF classification; intermittent or sustained AF had relative risks for warfarin use of 2.8 (95% confidence interval, 2.2-3.6) and 2.9 (95% confidence interval, 2.2-3.7), respectively, compared with transitory AF. CONCLUSIONS: Three quarters of the patients with newly detected AF received antithrombotic therapy, yet many at high risk of stroke did not receive warfarin. Atrial fibrillation classification, rather than stroke risk factors, was strongly associated with warfarin use.     

Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells

Neuronal output is modulated by inhibition onto both dendrites and axons. It is unknown whether inhibitory synapses at these two cellular compartments of an individual neuron are regulated coordinately or separately during in vivo development. Because neurotransmission influences synapse maturation and circuit development, we determined how loss of inhibition affects the expression of diverse types of inhibitory receptors on the axon and dendrites of mouse retinal bipolar cells. We found that axonal GABA but not glycine receptor expression depends on neurotransmission. Importantly, axonal and dendritic GABA_A receptors comprise distinct subunit compositions that are regulated differentially by GABA release: Axonal GABA_A receptors are down-regulated but dendritic receptors are up-regulated in the absence of inhibition. The homeostatic increase in GABA_A receptors on bipolar cell dendrites is pathway-specific: Cone but not rod bipolar cell dendrites maintain an up-regulation of receptors in the transmission deficient mutants. Furthermore, the bipolar cell GABA_A receptor alterations are a consequence of impaired vesicular GABA release from amacrine but not horizontal interneurons. Thus, inhibitory neurotransmission regulates in vivo postsynaptic maturation of inhibitory synapses with contrasting modes of action specific to synapse type and location.Interneurons of the CNS control neuronal excitability through release of γ-aminobutyric acid (GABA) and glycine. How inhibition modifies neuronal output depends largely on the types of presynaptic interneurons making synapses onto a postsynaptic cell, and the location and densities of these synapses (1–3). Moreover, inhibitory receptor types with distinct transmitter affinities and kinetics present on the axon or dendrites of an individual neuron can critically shape its output (3–6). Although much is known about how different inhibitory synapses shape the spatiotemporal activity patterns of mature neurons, it is less clear what factors regulate the expression of inhibitory receptors at these synapses during development in vivo. Is the expression of distinct inhibitory receptor types within a cellular compartment (axon or dendrite) regulated coordinately or independently? Conversely, is the expression of the same receptor type at different cellular compartments of an individual neuron regulated by common or separate factors?To answer these questions, we assessed expression of inhibitory receptors on the axon and dendrites of individual glutamatergic retinal neurons in mice with genetically suppressed inhibition. We generated retina-specific knockouts of the vesicular inhibitory amino acid transporter (VIAAT), which mediates uptake of GABA or glycine into synaptic vesicles (7, 8). We perturbed inhibition because it has been found previously to influence pre- and postsynaptic maturation of GABAergic synapses (9–12). However, whether inhibitory receptor expression at the “input” and “output” compartments of an individual neuron is coordinately regulated by activity remains unknown. We focused on retinal bipolar cells (BCs) because of the rich variety of inhibitory synapses found on these neurons. Moreover, the many types of BCs enabled us to determine whether inhibitory transmission plays a uniform or diverse role in regulating inhibitory synapses across cell types that signal in parallel. We compared the postsynaptic maturation of GABA- and glycinergic synapses on cone BCs (CBCs) versus rod BCs (RBCs) that operate at different light levels. Among CBCs, we analyzed both ON and OFF BC types, which depolarize or hyperpolarize to light increments, respectively (13).