Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2

With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2-mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE(2)) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K(B) 2-20 nM in Schild regression analysis and 268- to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.     

Treatment and outcomes of acute coronary syndrome in the cancer population

Background:

Randomized trials have established the benefit of medical therapy and revascularization in the treatment of acute myocardial infarction (MI). Cancer and cardiovascular disease are the 2 most common diseases worldwide. In clinical practice, cancer patients are frequently afflicted with MI. The benefit of medical and/or revascularization therapy in the cancer population with MI is less well known.

Hypothesis:

Medical and revascularization therapy reduces mortality in cancer patients with MI.

Methods:

After approval by the institutional review board, we retrospectively reviewed all patients with a discharge diagnosis of acute MI who were admitted to the University of Texas MD Anderson Cancer Center between December 2000 and October 2006 and evaluated the association between cardiac treatments with survival outcomes.

Results:

A total of 456 patients with a discharge diagnosis of acute MI were identified and included in the study, of which 386 had non–ST‐segment elevation MI (NSTEMI) and 70 had ST‐segment elevation MI (STEMI). Compared with patients with NSTEMI, patients who had STEMI were more often prescribed aspirin (66% vs 43%; P = 0.004), β‐blockers (61% vs 46%; P = 0.018), and thrombolytic therapy (9% vs 0.3%; P = 0.0001). In the multivariable analysis, aspirin use was associated with a 23% decreased risk of death (hazard ratio [HR]: 0.77, 95% confidence interval [CI]: 0.60‐0.98, P = 0.033) and β‐blocker use was associated with a 36% decreased risk of death (HR: 0.64, 95% CI: 0.51–0.81, P = 0.0002). Statins (HR: 0.82, P = 0.18) and catheter‐based revascularization (HR: 0.57, P = 0.09) did not have an impact on the risk of death. Compared with patients with limited cancer, advanced cancer patients were twice as likely to die (HR: 2.12, 95 CI: 1.47–3.04, P < 0.0001). Previous chemotherapy (P = 0.005) and chest radiotherapy (P = 0.017) were associated with increased 1‐year mortality, whereas hyperlipidemia (P = 0.018) was protective.

Conclusions:

In this study of cancer patients with MI, medical therapy with aspirin and β‐blockers was associated with improved survival. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Effects of Neurofeedback Training on Inhibitory Capacities in ADHD Children: A Single-Blind,Randomized, Placebo-Controlled Study

Introduction. Studies performed during the last decades suggest that neurofeedback (NF) training can effectively reduce symptomatology in children with Attention deficit hyperactivity disorder (ADHD). Yet questions remain concerning specific effects of NF training in ADHD children, because these studies did not use a randomized, placebo-controlled approach. To address this issue, such an approach was used in the present study to measure the impact of NF training on inhibitory capacities.

Method. Nine ADHD children (with no comorbidity), aged 8 to 13 years, were randomly assigned to either an experimental group (n = 5) or a placebo group (n = 4). For both groups, training protocols comprised 40 one-hr sessions (20 meetings of 2 sessions each). Sensorimotor rhythm/Theta training was used in the experimental group. Prerecorded sessions of the first author's EEG activity were used in the placebo group. Pre- and posttraining assessments consisted of the Conner's Parent Rating Scales (CPRS–R) and neuropsychological tests. A multiple case study strategy was applied for data analysis using a Reliable Change Index when applicable.

Results. One experimental participant was a dropout, and one placebo participant had to be discontinued due to adverse effects. The latter participant accepted to undergo posttraining evaluations; hence an Intention-to-Treat analysis was performed on this participant's data. Remaining participants showed significant improvements on the CPRS–R. Improvements were measured on the Variability measure of the CPT–II consistently across the placebo group and on the Inhibition Condition of the Stroop Task for all but one placebo participant. The same trend was found for the Inhibition/Switching Condition (Stroop Task) across the experimental group (n = 4).

Conclusion. The small sample size precludes from evaluating specific neurofeedback effects. Still, the presence of placebo responses suggests that other factors, such as motivation or expectations, might contribute to the outcome of NF training in children with ADHD.     

Verbal adynamia in parkinsonian syndromes: behavioral correlates and neuroanatomical substrate

ABSTRACT

Verbal adynamia (impaired language generation, as during conversation) has not been assessed systematically in parkinsonian disorders. We addressed this in patients with Parkinson’s dementia, progressive supranuclear palsy and corticobasal degeneration. All disease groups showed impaired verbal fluency and sentence generation versus healthy age-matched controls, after adjusting for general linguistic and executive factors. Dopaminergic stimulation in the Parkinson’s group selectively improved verbal generation versus other cognitive functions. Voxel-based morphometry identified left inferior frontal and posterior superior temporal cortical correlates of verbal generation performance. Verbal adynamia warrants further evaluation as an index of language network dysfunction and dopaminergic state in parkinsonian disorders.     

Consensus Paper: Current Views on the Role of Cerebellar Interpositus Nucleus in Movement Control and Emotion

In the present paper, we examine the role of the cerebellar interpositus nucleus (IN) in motor and non-motor domains. Recent findings are considered, and we share the following conclusions: IN as part of the olivo-cortico-nuclear microcircuit is involved in providing powerful timing signals important in coordinating limb movements; IN could participate in the timing and performance of ongoing conditioned responses rather than the generation and/or initiation of such responses; IN is involved in the control of reflexive and voluntary movements in a task- and effector system-dependent fashion, including hand movements and associated upper limb adjustments, for quick effective actions; IN develops internal models for dynamic interactions of the motor system with the external environment for anticipatory control of movement; and IN plays a significant role in the modulation of autonomic and emotional functions.     

The multiple roles of major histocompatibility complex class-I-like molecules in mucosal immune function

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class-I genes: human leukocyte antigens (HLA) A, B, and C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa β₂-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed, polymorphic proteins, the human genome also encodes several nonclassical MHC class-I-like, or class Ib, genes that, in general, encode nonpolymorphic molecules involved in various specific immunological functions. Many of these genes, including CD1, the neonatal Fc receptor for IgG, HLA-G, HLA-E, the MHC class-I chainrelated gene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.