The prototypic phenolic group of LY255582 has been successfully replaced by carbamate and carboxamide groups. Carboxamide analog (R
=
3-CONH
2) has proved to be efficacious in in vivo studies.
The ...phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog
12 has an improved metabolism profile and proved to be efficacious in in vivo studies.
Recent observations have revealed that some Type Ia supernovae exhibit narrow, time-variable Na I D absorption features. The origin of the absorbing material is controversial, but it may suggest the ...presence of circumstellar gas in the progenitor system prior to the explosion, with significant implications for the nature of the supernova (SN) progenitors. We present the third detection of such variable absorption, based on six epochs of high-resolution spectroscopy of the Type Ia supernova SN 2007le from the Keck I Telescope and the Hobby-Eberly Telescope. The data span a time frame of approximately three months, from 5 days before maximum light to 90 days after maximum. We find that one component of the Na I D absorption lines strengthened significantly with time, indicating a total column density increase of {approx}2.5 x 10{sup 12} cm{sup -2}. The data limit the typical timescale for the variability to be more than 2 days but less than 10 days. The changes appear to be most prominent after maximum light rather than at earlier times when the ultraviolet flux from the SN peaks. As with SN 2006X, we detect no change in the Ca II H and K absorption lines over the same time period, rendering line-of-sight effects improbable and suggesting a circumstellar origin for the absorbing material. Unlike the previous two supernovae exhibiting variable absorption, SN 2007le is not highly reddened (E {sub B-V} = 0.27 mag), also pointing toward circumstellar rather than interstellar absorption. Photoionization calculations show that the data are consistent with a dense (10{sup 7} cm{sup -3}) cloud or clouds of gas located {approx}0.1 pc (3 x 10{sup 17} cm) from the explosion. These results broadly support the single-degenerate scenario previously proposed to explain the variable absorption, with mass loss from a nondegenerate companion star responsible for providing the circumstellar gas. We also present possible evidence for narrow H{alpha} emission associated with the SN, which will require deep imaging and spectroscopy at late times to confirm.
Disseminated coccidioidomycosis merits greater attention because the number of persons living and traveling in endemic areas is increasing.
Our purpose was to study the clinical and histopathologic ...findings in patients with specific cutaneous disseminated coccidioidomycosis.
In six patients with specific skin lesions of disseminated coccidioidomycosis, the diagnosis was confirmed by identification of the organism in tissue or by positive results of tissue culturing.
Clinical lesions included solitary granulomatous plaques in two patients and multiple papular, nodular, or pustular lesions in four patients, two of whom also had subcutaneous abscesses. Identifying organisms directly in tissue was possible in only 8 of 17 biopsy specimens and in five of six patients. The histopathologic features showed various degrees of three primary patterns: (1) abscess formation with necrosis, (2) epithelial hyperplasia and granuloma formation with microabscesses, and (3) vascular and perivascular proliferative and inflammatory cell reactions at times suggesting vasculitis. Tissue eosinophilia, present in all patients, was striking in two (eosinophilic abscess formation) and notable in another (vascular inflammation with eosinophilia).
Cutaneous manifestations of disseminated coccidioidomycosis may be more common and varied than usually recognized.
Study of 18 biopsy specimens in 11 patients with L-tryptophan-related eosinophiliamyalgia (fasciitis) syndrome showed hyaline sclerodermoid changes. Dermal scleroderma was found in eight of nine ...punch biopsy specimens and eight of nine excisional biopsy specimens. Fascial scleroderma was found in eight excisional biopsy specimens. One specimen obtained by excision had no fascia present. Eleven biopsy specimens showed edema of the dermis, and 13 showed dilated lymphatic structures; thus, the clinical picture of edematous sclerosis was confirmed. Mucinous fasciitis was present in five excisional biopsy specimens, in conjunction with a large number of macrophages in four. Dermal mucinosis was present in 11 biopsy specimens. Lymphocytic and macrophage inflammation was minimal in 14 biopsy specimens and pronounced in only 4. Plasma cells were present in eight cases. Eosinophils were present in substantial numbers in three biopsy specimens and only occasionally in four. Eosinophilic spongiosis was observed in one patient. Lymphocytic inflammation was noted around a single muscle spindle and around large nerve trunks in three patients. No relationship was established between these pathologic features and the duration or dose of tryptophan, prednisone treatment, or duration of symptoms. Pathologic features of the L-tryptophan syndrome consist of hyaline sclerodermoid collagen in the dermis, the septa, and the fascia. Edema, focal mucinosis, and macrophage inflammation may be features that identify this event.
Recent observations have revealed that some Type Ia supernovae exhibit narrow, time-variable Na I D absorption features. The origin of the absorbing material is controversial, but it may suggest the ...presence of circumstellar gas in the progenitor system prior to the explosion, with significant implications for the nature of the supernova progenitors. We present the third detection of such variable absorption, based on six epochs of high-resolution spectroscopy of the Type Ia supernova SN 2007le from Keck and the HET. The data span ~3 months, from 5 days before maximum light to 90 days after maximum. We find that one component of the Na D absorption lines strengthened significantly with time, indicating a total column density increase of ~2.5 x 10^12 cm^-2. The changes are most prominent after maximum light rather than at earlier times when the UV flux from the SN peaks. As with SN 2006X, we detect no change in the Ca II H&K lines over the same time period, rendering line-of-sight effects improbable and suggesting a circumstellar origin for the absorbing material. Unlike the previous two SNe exhibiting variable absorption, SN 2007le is not highly reddened (E_B-V = 0.27 mag), also pointing toward circumstellar rather than interstellar absorption. Photoionization models show that the data are consistent with a dense (10^7 cm^-3) cloud or clouds of gas located ~0.1 pc from the explosion. These results broadly support the single-degenerate scenario previously proposed to explain the variable absorption, with mass loss from a nondegenerate companion star responsible for providing the circumstellar gas. We also present tentative evidence for narrow Halpha emission associated with the SN, which will require followup observations at late times to confirm. abridged
