FAD Mutations in Amyloid Precursor Protein Do Not Directly Perturb Intracellular Calcium Homeostasis

Disturbances in intracellular calcium homeostasis are likely prominent and causative factors leading to neuronal cell death in Alzheimer's disease (AD). Familial AD (FAD) is early-onset and exhibits autosomal dominant inheritance. FAD-linked mutations have been found in the genes encoding the presenilins and amyloid precursor protein (APP). Several studies have shown that mutated presenilin proteins can directly affect calcium release from intracellular stores independently of Aβ production. Although less well established, there is also evidence that APP may directly modulate intracellular calcium homeostasis. Here, we directly examined whether overexpression of FAD-linked APP mutants alters intracellular calcium dynamics. In contrast to previous studies, we found that overexpression of mutant APP has no effects on basal cytosolic calcium, ER calcium store size or agonist-induced calcium release and subsequent entry. Thus, we conclude that mutated APP associated with FAD has no direct effect on intracellular calcium homeostasis independently of Aβ production

Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis

Fas receptor is a member of the tumor necrosis factor-α family of death receptors that mediate physiologic apoptotic signaling. To investigate the molecular mechanisms regulating calcium mobilization during Fas-mediated apoptosis, we have analyzed the sequential steps leading to altered calcium homeostasis and cell death in response to activation of the Fas receptor. We show that Fas-mediated apoptosis requires endoplasmic reticulum–mediated calcium release in a mechanism dependent on phospholipase C-γ1 (PLC-γ1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. The kinetics of Ca2+ release were biphasic, demonstrating a rapid elevation caused by PLC-γ1 activation and a delayed and sustained increase caused by cytochrome c binding to IP3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-γ1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling

Neonatal Seizures.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures

Perceived stress and norepinepherine predict the effectiveness of the response to protenase inhibitor medication in HIV

BACKGROUND: In vitro evidence has suggested that increasing levels of norepinephrine (NE) can accelerate HIV replication; however, the importance in a clinical setting has not been tested. PURPOSE: The purpose of this study was to determine if perceived stress as well as the stress hormones NE and cortisol would predict the response to starting a new protease inhibitor (PI) prospectively. METHOD: Perceived stress, urinary cortisol and norepinephrine, CD4 and viral load (VL) were measured in people with HIV before starting a new PI and six months later (an average of three months after starting the new PI) in order to determine CD4 and VL response to the PI. RESULTS: Higher perceived stress significantly predicted lower effectiveness of the new PI in increasing CD4 and decreasing VL controlling for age, duration of new PI, baseline CD4/VL, sexually transmitted diseases (STDs), and gender/ethnic risk groups. Higher norepinephrine, but not cortisol, predicted worse VL response to PIs and, in fact, mediated the relationship between perceived stress and change in VL. CONCLUSION: Perceived stress and high norepinephrine levels are prospectively associated with a poorer response to starting a new PI. Assessing stress and norepinephrine levels in patients starting on antiretroviral medications might be clinically useful