MRI findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 enterovirus D68 outbreak.

BACKGROUND AND PURPOSE: Enterovirus D68 was responsible for widespread outbreaks of respiratory illness throughout the United States in August and September 2014. During this time, several patients presented to our institution with acute flaccid paralysis and cranial nerve dysfunction. The purpose of this report is to describe the unique imaging findings of this neurologic syndrome occurring during an enterovirus D68 outbreak. MATERIALS AND METHODS: Patients meeting a specific case definition of acute flaccid paralysis and/or cranial nerve dysfunction and presenting to our institution during the study period were included. All patients underwent routine MR imaging of the brain and/or spinal cord, including multiplanar T1, T2, and contrast-enhanced T1-weighted imaging. RESULTS: Eleven patients met the inclusion criteria and underwent MR imaging of the brain and/or spinal cord. Nine patients presented with brain stem lesions, most commonly involving the pontine tegmentum, with bilateral facial nerve enhancement in 1 patient. Ten patients had longitudinally extensive spinal cord lesions; those imaged acutely demonstrated involvement of the entire central gray matter, and those imaged subacutely showed lesions restricted to the anterior horn cells. Ventral cauda equina nerve roots enhanced in 4 patients, and ventral cervical nerve roots enhanced in 3, both only in the subacute setting. CONCLUSIONS: Patients presenting with acute flaccid paralysis and/or cranial nerve dysfunction during the recent enterovirus D68 outbreak demonstrate unique imaging findings characterized by brain stem and gray matter spinal cord lesions, similar to the neuroimaging findings described in previous outbreaks of viral myelitis such as enterovirus 71 and poliomyelitis.

Peptide model of a highly conserved, N-terminal domain of apolipoprotein E is able to modulate lipoprotein binding to a member of the class A scavenger receptor family.

Apolipoprotein E plays a critical role in plasma lipoprotein clearance. Peptide models of a highly conserved, N-terminal domain of this protein have been shown to increase the binding of low density lipoprotein (LDL) to fibroblast cell surfaces independently of the low density lipoprotein receptor. Here we provide data to show that these peptides not only increase the binding of LDL, but also of high density lipoprotein, though not acetylated LDL. We also have data suggesting that this novel activity is mediated, at least in part, by a member of the scavenger receptor family, SR-AI. Furthermore, we show that this activity is also prominent in macrophages, a cell relevant to atherogenesis. In addition, this current paper provides evidence suggesting that this complex binding activity is initiated by a peptide-receptor interaction, and that our peptides are able to induce activity at physiologically relevant concentrations. This study provides evidence for a possible novel receptor interaction and further anti-atherogenic properties of apolipoprotein E and raises the possibility of a therapeutic potential of our peptide models.

Structure-function relationships in side chain lactam cross-linked peptide models of a conserved N-terminal domain of apolipoprotein E.

Bioactive peptides have multiple conformations in solution but adopt well-defined conformations at lipid surfaces and in interactions with receptors. We have used side chain lactam cross-links to stabilize secondary structures in the following peptide models of a conserved N-terminal domain of apolipoprotein E (cross-link periodicity in parentheses): I, H2N-GQTLSEQVQEELLSSQVTQELRAG-COOH (none); III, [sequence; see text] (i to i + 3); IV,[sequence; see text] (i to i + 4); IVa, [sequence, see text] (i to i + 4) (lactams above the sequence, potential salt bridges below the sequence). We previously demonstrated [Luo et al. (1994) Biochemistry 33, 12367-12377; Braddock et al. (1996) Biochemistry 35, 13975-13984] that peptide III, containing lactam cross-links between the i and i + 3 side chains, enhances specific binding of LDL via a receptor other than the LDL-receptor. Peptide III in solution consists of two short alpha helices connected by a non alpha helical segment. Here we examine the hypothesis that the domain modeled by peptide III is one antipode of a conformational switch. To model another antipode of the switch, we introduced two strategic modifications into peptide III to examine structure-function relationships in this domain: (1) the spacing of the lactam cross-links was changed (i to i + 4 in peptides IV and IVa) and (2) peptides IV and IVa contain the two alternative sequences at a site of a possible end-capping interaction in peptide III. The structure of peptide IV, determined by 2D-NMR, is alpha helical across its entire length. Despite the remarkable degree of structural order, peptide IV is biologically inactive. In contrast, peptides III and possibly IVa contain a central interruption of the alpha helix, which appears necessary for biological activity. These and other studies support the hypothesis that this domain is a conformational switch which, to the extent that it models apolipoprotein E itself, may modulate interactions between apo E and its various receptors.

Conformationally specific enhancement of receptor-mediated LDL binding and internalization by peptide models of a conserved anionic N-terminal domain of human apolipoprotein E.

In this paper, we test the hypothesis that peptide models of a highly conserved domain of apolipoprotein E (amino acids 41-60 in human apo E) modulate the binding and internalization of LDL to cell surface receptors in a conformationally specific manner. Three peptides were compared: peptide I containing the natural sequence of amino acids 41-60 of human apo E; peptide III containing side-chain lactam cross-links designed to enhance alpha-helical structure; and peptide II containing cross-links designed to prevent formation of alpha-helices. Peptide III was shown previously to consist of two short alpha-helical domains linked by a turn and to have more alpha-helical content than peptide I, while peptide II was shown to have less helical content than either peptide III or I(Luo et al., 1994). Peptide III induced a 30-fold increase in the specific binding of 125I-LDL to normal human skin fibroblasts and a 60-fold increase in the binding to fibroblasts lacking the LDL-R. This same peptide also restored the binding to normal fibroblasts of 125I-LDL from a patient with familial defective apolipoprotein B, the R3500-->Q mutation. Analysis of binding indicated an increase in the apparent number of binding sites, with little effect on the affinity of 125I-LDL for the cell surface. Heparinase treatment of the cells did not abrogate this effect, suggesting that the increased binding is not mediated by cell surface glycans. LDL internalization but not degradation was also increased by peptide III. Similar but smaller effects were also induced by peptide I. Peptide II was much less active than peptide I or III. Thus, the order of biological activity was the same as the order of alpha-helical content, i.e., peptide III > peptide I > peptide II. These results suggest a hitherto unknown biological function for a highly conserved domain of apolipoprotein E, and this bioactivity was shown by peptide models to be specific to the alpha-helical conformation.