Tag Archives: elastase

br Discussion Previous literature demonstrated six reports of tick adherence

Previous literature demonstrated six reports of tick adherence to the conjunctiva. Four of the six reports were secondary to Amblyomma americanum, one was secondary to Otobius megninii, and the last was of unknown species. The species unique to each report occurred in areas where the ticks are commonly found; for example, the four reports of A. americanum occurred in Arkansas, Texas, and Alabama. Our patient was camping in the Adirondacks, a portion of the Northeastern United States where the I. scapularis is more prevalent. Despite the limited number of reported cases, there appears to be no predilection for gender, age, or ocular location of tick attachment. In any case of suspected tick penetration to the ocular surface, immediate ophthalmologic consultation and prompt removal via the method mentioned above is recommended in order to minimize the localized inflammatory reaction and potential for infection transmission. Additionally, attention should be paid to the IDSA guidelines on when to initiate prophylaxis for any tick-borne diseases endemic to the region where the patient was affected.

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Eastern equine encephalitis (EEE) is an arboviral infection transmitted by mosquitos that is rarely symptomatic in humans, unless there is central nervous system involvement progressing to coma and death. The life elastase of EEE virus in North America involves enzootic transmission among songbirds and mosquitos, followed by transmission to horses and man (dead-end hosts). The incubation period in humans typically ranges from 4 to 10 days. The virus multiplies in the blood, then it passes to the nasal mucosa and to the brain.
Most patients have abrupt onset of high fever, chills, nausea, myalgias, and intense headache with neck stiffness. Encephalitis ensues in 1–2 days, results in altered mental status and possibly impaired vision, and progresses to coma and/or death. Feemster and Haymaker (1958) included impaired vision as a possible sequel to eastern equine encephalitis. In another form of arboviral infection that may result in encephalitis, Rift Valley fever, ocular manifestations are well-described. The Zika virus has been recently shown to cause pathological changes in the retina and the optic nerve in the majority of affected infants. However, no published ophthalmological observations in patients with EEE have been documented. We describe the first report of ophthalmic histopathological findings in a human case of EEE, which parallel the changes in the brain.

Case report

We are unaware of any published ophthalmological observations in EEE patients, although Feemster and Haymaker included impaired vision as a possible sequel to EEE. One review stated that horses affected with EEE often have visual problems resulting in partial blindness. In the guinea pig, the EEE virus was shown to produce an insignificant, non-specific reaction in the posterior chamber, with a few occasional leukocytes in the vitreous and retina, and rare necrotic ganglion cells. There was complete absence of overt necrosis or a focal reaction similar to that found in the brain. By contrast, in Rift Valley fever, another form of arboviral infection that may result in encephalitis, ocular manifestations are well-described in patients including exudative lesions of the macula and paramacular region that are frequently associated with hemorrhage, edema, and less often with vasculitis, retinitis, and vascular occlusion. A related arbovirus of recent importance, the Zika virus, has been associated with an epidemic of microcephaly in the western world. The ophthalmologic findings present in 85% of infants examined were focal pigmentary clumping, well circumscribed chorioretinal atrophy surrounded by hyperpigmentation, optic nerve hypoplasia and severe disc cupping, and possibly bilateral iris colobomas and lens subluxation.

We have previously demonstrated that

We have previously demonstrated that p30II interacts with TIP60 and enhances c-MYC-dependent transcriptional activation and oncogenic potential (Awasthi et al., 2005). However, the molecular mechanism(s) by which p30II cooperates with c-MYC remains to be fully elucidated. Herein, we have shown that p30II is recruited to c-MYC/TIP60/p300 transcriptional complexes on E-box enhancer elements within the endogenous cyclin D2 promoter in HTLV-1-transformed HuT-102 T-lymphocytes using dual-ChIPs (Fig. 1H). p30II induces acetylation of the c-MYC oncoprotein in transfected 293 cells (Fig. 4C); and c-MYC is also strongly acetylated in the HTLV-1-infected T-cell-lines HuT-102 and MJG11 (Fig. 4D). In the Awasthi et al. (2005) study, we demonstrated that amino elastase residues 99–154 of p30II interact with the TIP60 acetyltransferase, which functions as a transcriptional cofactor and has been shown to acetylate the c-MYC protein (Patel et al., 2004; Frank et al., 2003). The specific sites of TIP60-mediated acetylation within c-MYC are yet to be identified (Patel et al., 2004). Furthermore, we found that the acetylation-defective Lys→Arg substitution mutants of c-MYC (R5 and K323R/K417R) are impaired for oncogenic cellular transformation/foci formation with p30II in cotransfected c-myc HO15.19 fibroblasts (Fig. 2A−C).
We did not observe discernable differences in cellular apoptosis induced by wildtype c-MYC or the acetylation-defective c-MYC mutants K323/R/K417R or R5 in the presence of p30II in cotransfected c-myc HO15.19 fibroblasts (Fig. 5A and B). As Datta et al. (2007) have reported that p30II expression inhibits apoptosis induced by genotoxic stress in Camptothecin-treated primary T-lymphocytes transduced with an HTLV-1 ACH proviral clone, we next tested whether c-MYC-acetylation plays a role in the ability of p30II to protect against cell-death induced by DNA-damage-inducing agents. Interestingly, p30II significantly inhibited c-MYC-dependent apoptosis caused by prolonged exposure to BrdU, which induces single-strand DNA breaks (Fig. 5C–F; Ackland et al., 1988). Neither of the acetylation-defective c-MYC mutants resulted in increased apoptosis in BrdU-treated cells (Fig. 5C–F). This could be attributed to an inability of these mutants to restore normal cell-cycle functions and genomic replication in transfected c-myc HO15.19 fibroblasts, as compared to wildtype c-MYC. We also observed that p30II results in an increased number of multinucleate cells in the presence of the genotoxic chemical, etoposide (Fig. 6A and B). These findings collectively agree with our previous results (Awasthi et al., 2005) and those in Datta et al. (2007), as well as the report by Baydoun et al. (2011) that p30II promotes error-prone nonhomologous-end-joining DNA-repair.
Doueiri et al. (2012) have reported a list of proteins detected in the interactomes of S-tagged HTLV-1 p30II and related HTLV-2 p28II proteins, based upon S-tag affinity purification and mass spectrometric/proteomic analyses. Noticeably, however, these studies failed to detect interactions between p30II and TIP60, c-MYC, or other known p30II-binding partners including p300/CBP, CREB, PU.1, and large ribosomal subunit protein L18a (Awasthi et al., 2005; Michael et al., 2006; Zhang et al., 2000, 2001; Ghorbel et al., 2006; Datta et al., 2006; Doueiri et al., 2012). Using the I-TASSER computational protein-folding and structure prediction algorithm (University of Michigan, 〈http://zhanglab.ccmb.med.umich.edu/I-TASSER/〉), we determined that the TIP60-binding domain (aa residues 99–154; Awasthi et al., 2005) of the S-tagged p30II protein is predicted to be misfolded and likely inaccessible, compared to the wildtype p30II protein elastase structure (Supplementary Fig. S1). Thus, albeit intriguing, the significance of the interacting factors identified through this proteomic screen remains to be determined until the biological functionality (e.g., inhibition of Tax-dependent transactivation, cooperation with oncoproteins, or nuclear sequestration of tax/rex mRNA) of the S-tagged p30II protein has been demonstrated (Doueiri et al., 2012).