The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate expression of eotaxin-3, an eosinophil chemoattractant, in eosinophilic diseases suggest therapeutic potential for PPIs in CRSwNP. Objective We assessed the effect of type-2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in CRS. Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro with exploration of underlying mechanisms. Methods Type-2 mediator levels in nasal tissues and secretions were measured by multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2Bs with or without PPIs was assessed by using ELISA, Western blot, real-time PCR, and intracellular pH (pHi) imaging. Results Nasal tissues and secretions from CRSwNP patients had increased IL-13, eotaxin-2 and eotaxin-3 levels, and these were positively correlated with tissue ECP and radiographic scores in CRS (P<.05). IL-13-stimulation of HNECs and BEAS-2Bs dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P<.05). CRS patients taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P<.05). Using pHi imaging and by altering extracellular [K+], we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the non-gastric H,K-ATPase [ngH,K-ATPase]) significantly attenuated IL-13-induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13-induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13-induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the ngH,K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, may be of therapeutic value in CRSwNP by reducing epithelial production of eotaxin-3.

No abstract

Current evidence supporting TIVA is limited to a handful of inconsistently controlled and reported studies. Standardized grading of visibility scores and preoperative characteristics would better establish the role of TIVA in endoscopic sinus surgery.

In two experiments on normals we presented CV nonsense syllables both dichotically and monotically, with onsets of the syllables separated by 0, 15, 30, 60, and 90 msec (first experiment) and 0, 90, 180, 250, and 500 msec (second experiment). We found that when one of the CV's trailed the other by 30–60 msec, the trailing CV became more intelligible than when it was given simultaneously; the leading syllable's intelligibility dropped from its “simultaneous” level when leading by 15 and 30 msec. The leading message was more intelligible between 15 and 250 msec when the two channels were mixed monotically. In the dichotic simultaneous conditon, voiceless consonants were more intelligible than voiced, especially in voiced-voiceless pairs. When the voiced CV trailed the voiceless CV, the former became almost as intelligible as its voiceless counterpart. A left hemisphere “speech processor” was postulated, with suppression of information from ipsilateral sources during contralateral stimulation. The postulated “speech processor” may be involved in acoustic-signal-vocal-tract control functions.