An impairment of energy metabolism may underlie slow excitotoxic neuronal death in neurodegenerative diseases. We therefore examined the effects of intrastriatal, subacute systemic, or chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. Following intrastriatal injection 3-NP produced dose-dependent striatal lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P, calbindin) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of 3-NP produced age-dependent bilateral striatal lesions with a similar neurochemical profile. However, in contrast to the intrastriatal injections, striatal dopaminergic afferent projections were spared. Both freeze-clamp measurements and chemical shift magnetic resonance spectroscopy showed that 3-NP impairs energy metabolism in the striatum in vivo. Microdialysis showed no increase in extracellular glutamate concentrations after systemic administration of 3-NP. The lesions produced by intrastriatal injection or systemic administration of 3-NP were blocked by prior decortication. However, the NMDA antagonist MK-801 did not block the effects of intrastriatal 3-NP, consistent with a non-NMDA excitotoxic mechanism. In contrast to subacute systemic administration of 3-NP, chronic (1 month) administration produced lesions confined to the striatum in which there was relative sparing of NADPH-diaphorase interneurons, consistent with an NMDA excitotoxic process. Chronic administration showed growth-related proliferative changes in dendrites of spiny neurons similar to changes in Huntington's disease (HD). These results are consistent with in vitro studies showing that mild metabolic compromise can selectively activate NMDA receptors while more severe compromise activates both NMDA and non-NMDA receptors. Chronic administration of 3-NP over 1 month produces selective striatal lesions that replicate many of the characteristic histologic and neurochemical features of HD.
This study was undertaken to determine the modulation of uterine function by chorionic gonadotrophin (CG) in a nonhuman primate. Infusion of recombinant human CG (hCG) between days 6 and 10 post ovulation initiated the endoreplication of the uterine surface epithelium to form distinct epithelial plaques. These plaque cells stained intensely for cytokeratin and the proliferating cell nuclear antigen. The stromal fibroblasts below the epithelial plaques stained positively for ␣-smooth muscle actin (␣SMA). Expression of ␣SMA is associated with the initiation of decidualization in the baboon endometrium. Synthesis of the glandular secretory protein glycodelin, as assessed by Western blot analysis, was markedly up-regulated by hCG, and this increase was confirmed by immunocytochemistry, Northern blot analysis, and reverse transcriptase-PCR. To determine whether hCG directly modulated these uterine responses, we treated ovariectomized baboons sequentially with estradiol and progesterone to mimic the hormonal profile of the normal menstrual cycle. Infusion of hCG into the oviduct of steroidhormone-treated ovariectomized baboons induced the expression of ␣SMA in the stromal cells and glycodelin in the glandular epithelium. The epithelial plaque reaction, however, was not readily evident. These studies demonstrate a physiological effect of CG on the uterine endometrium in vivo and suggest that the primate blastocyst signal, like the blastocyst signals of other species, modulates the uterine environment prior to implantation.
We present the first results from the ongoing, intensive, multiwavelength monitoring program of the luminous Seyfert 1 galaxy Mrk 817. While this active galactic nucleus was, in part, selected for its historically unobscured nature, we discovered that the X-ray spectrum is highly absorbed, and there are new blueshifted, broad, and narrow UV absorption lines, which suggest that a dust-free, ionized obscurer located at the inner broad-line region partially covers the central source. Despite the obscuration, we measure UV and optical continuum reverberation lags consistent with a centrally illuminated Shakura–Sunyaev thin accretion disk, and measure reverberation lags associated with the optical broad-line region, as expected. However, in the first 55 days of the campaign, when the obscuration was becoming most extreme, we observe a de-coupling of the UV continuum and the UV broad emission-line variability. The correlation recovered in the next 42 days of the campaign, as Mrk 817 entered a less obscured state. The short C iv and Lyα lags suggest that the accretion disk extends beyond the UV broad-line region.
We present the first intensive continuum reverberation mapping study of the high accretion-rate Seyfert galaxy Mrk 110. The source was monitored almost daily for more than 200 days with the Swift X-ray and UV/optical telescopes, supported by ground-based observations from Las Cumbres Observatory, the Liverpool Telescope, and the Zowada Observatory, thus extending the wavelength coverage to 9100 Å. Mrk 110 was found to be significantly variable at all wavebands. Analysis of the intraband lags reveals two different behaviours, depending on the timescale. On timescales shorter than 10 days the lags, relative to the shortest UV waveband (∼1928 Å), increase with increasing wavelength up to a maximum of ∼2d lag for the longest waveband (∼9100 Å), consistent with the expectation from disc reverberation. On longer timescales, however, the g-band lags the Swift BAT hard X-rays by ∼10 days, with the z-band lagging the g-band by a similar amount, which cannot be explained in terms of simple reprocessing from the accretion disc. We interpret this result as an interplay between the emission from the accretion disc and diffuse continuum radiation from the broad line region.
Progesterone stimulates the expression of 17beta-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, E2, to an inactive form, estrone, in epithelial cells of human endometrial tissue. Various effects of progesterone on uterine epithelium have recently been shown to be mediated by stromal PRs in mice. We describe herein a critical paracrine mechanism whereby progesterone induction of 17beta-HSD type 2 enzyme activity, transcript levels, and promoter activity in human endometrial epithelial cells are mediated primarily by PR in endometrial stromal cells. Medium conditioned with progestin-pretreated human endometrial stromal cells robustly increased 17beta-HSD type 2 enzyme activity (2-fold) and mRNA levels (13.2-fold) in Ishikawa malignant endometrial epithelial cells. In contrast, direct progestin treatment of Ishikawa epithelial cells gave rise to much smaller increases in enzyme activity (1.2-fold) and mRNA levels (4-fold). These results suggest that progesterone- dependent paracrine factors arising from stromal cells are primarily responsible for the induction of epithelial 17beta-HSD type 2 expression in the endometrium. We transfected serial deletion mutants of the -1,244 bp 5'-flanking region of the 17beta-HSD type 2 gene into Ishikawa cells. No progesterone response elements could be identified upstream of the 17beta-HSD type 2 promoter. Stromal PR-dependent induction of the 17beta-HSD type 2 promoter was mediated by a critical regulatory region mapped to the -200/-100 bp sequence. Direct treatment of Ishikawa cells with progestin gave rise to a maximal increase in the activity of -200 bp/Luciferase construct only by 1.2-fold, whereas medium conditioned by progestin-pretreated endometrial stromal cells increased promoter activity up to 2.4-fold in a time- and concentration-dependent manner. The stimulatory effect of medium conditioned by progestin-pretreated stromal cells was enhanced strikingly by increasing stromal cell PR levels with the addition of estrogen. This epithelial-stromal interaction was specific for endometrial epithelial cells, since 17beta-HSD type 2 could not be induced in malignant breast epithelial cells by media conditioned with progestin-treated breast or endometrial stromal cells. In conclusion, progesterone regulates the conversion of biologically active E2 to estrone by inducing the 17beta-HSD type 2 enzyme in human endometrial epithelium primarily via PR in stromal cells, which secrete factors that induce transcription mediated primarily by the -200/-100 bp 5'-regulatory region of the 17beta-HSD type 2 promoter.
The purpose of this randomized clinical trial study was to determine the effectiveness of a 24-week, home-based, moderate-intensity, walking intervention in improving symptoms (vasomotor, uro-genital/sexual, sleep, psychological, cognitive, physical) experienced by midlife women. One hundred and seventy-three Caucasian and African American women aged 45 to 65 who were not on hormone therapy, had no major signs or symptoms of cardiovascular disease, and were sedentary in their leisure activity were randomly assigned to the moderate-intensity walking group or the nonexercise control group. The exercise prescription was walking at a frequency of 4 times a week for a duration of 20 to 30 minutes. The symptom impact inventory included the frequency, intensity, and bothersomeness of 33 symptoms collected at baseline and 24 weeks. Adherence was measured with a heart rate monitor and exercise log. Average adherence to frequency of walking was 71.6% of the expected walks. After 24 weeks, there were no differences between the walking and control group on change in symptoms. However, multiple regression revealed that frequency of adherence to walking along with change in physical symptoms and menopausal status were significant predictors of change in sleep symptoms. While walking did not improve most symptoms experienced by midlife women, frequency of walking may improve sleep.
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