The activities of presenilin 1 (PS1) and 2 modulate the proteolytic processing of amyloid precursor proteins to produce Abeta1-42, and mutations in these proteins are associated with an accelerated ...rate of Abeta deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Abeta deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Abeta deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of beta-amyloid is not proportional to the level of transgene expression.
BACKGROUND: Estrogens directly dilate arteries, and this acute relaxation of vascular smooth muscle (VSM) may contribute to the cardioprotective effect of this important hormone. However, the ...mechanism by which estrogens relax VSM is not clear. METHODS AND RESULTS: Based on observations in isolated smooth muscle cells, we hypothesized that 17beta-estradiol (E(2)) causes dilation through receptor-mediated activation of K(+) channels in VSM cells. To test this hypothesis, E(2)-relaxation was studied in arteries from male Sprague-Dawley rats. We observed that the estrogen receptor antagonist, tamoxifen (3 µmol) attenuated E(2) relaxation, suggesting that at least a portion of the relaxation depends on activation of E(2) receptors. The nitric oxide synthase inhibitor, Nomega-nitro-larginine (100 µmol) did not affect E(2) relaxation in either denuded or endothelium-intact arterial strips. Furthermore, inhibition of guanylyl cyclase with LY83583 (10 µmol) had no effect on the relaxation, suggesting that nitric oxide does not contribute to this relaxation. Vascular segments contracted with 90 mmol KCl to disrupt the K(+) gradient had a similar E(2) relaxation does not require K(+)-channel activation. Finally, E(2) pretreatment inhibited contraction of arterial segments depleted of intracellular calcium but in the presence of extracellular calcium. However, E(2) did not affect contraction of strips in calcium-free solution. CONCLUSIONS: These final experiments suggest that E(2) inhibits Ca(2+) influx but not intracellular calcium release. Together, these studies establish that E(2) causes receptor-mediated relaxation of peripheral resistance arteries through inhibition of calcium entry independent of nitric oxide production, guanylyl cyclase stimulation, and K(+)-channel activation.
Abstract Cord blood transplantation (CBT) is a known risk factor for human herpesvirus-6 (HHV-6) infection. We analyzed the nature of HHV-6 infections in 125 double-unit CBT recipients (median age, ...42 years) transplanted for hematologic malignancies with calcineurin inhibitor/mycophenolate mofetil prophylaxis and no antithymocyte globulin. One hundred seventeen patients (94%) reactivated HHV-6 by quantitative plasma PCR (median peak, 7600 copies/mL; range, 100 to 160,000) at a median of 20 days (range, 10 to 59) after transplantation. HHV-6 encephalitis occurred in 2 patients (1.6%), of whom 1 died and 1 recovered with therapy. No association was found between high-level HHV-6 viremia (≥10,000 or ≥25,000 copies/mL) and age, diagnosis, conditioning intensity, or dominant unit characteristics or between high-level viremia and transplant outcomes (engraftment, cytomegalovirus reactivation, day 100 grades II to IV acute graft-versus-host disease, day 100 transplant-related mortality, or 1-year disease-free survival). HHV-6 therapy delayed the onset of cytomegalovirus reactivation. Interestingly, HHV-6 resolution was observed in untreated patients, and resolution of viremia correlated with absolute lymphocyte count recovery. We observed a low incidence of encephalitis and no association with CBT outcomes. Our data suggest therapy in uncomplicated viremia may not be warranted. However, further investigation of the risk-to-benefit of HHV-6 viremia treatment and standardization of PCR testing is required.
The training of local clinicians is the best way to raise the standard of medical knowledge in developing countries. This requires transferring skills, techniques and resources.
Grid technology opens ...new perspectives for preparation and follow-up of medical missions in developing countries as well as support to local medical centers in terms of teleconsulting, telediagnosis and patient follow-up. Indeed, grids allow to hide the complexity of handling distributed data in such a way that physicians will be able to access patient data while ignoring where these data are stored.
To meet requirements of a development project of the French NPO Chain of Hope in China, we propose to deploy a grid-based federation of databases. FIRST RESULTS AND CONCLUSIONS: A first protocol was established for describing the patients' pathologies and their pre- and post-surgery states through a web interface in a language-independent way. This protocol was evaluated by French and Chinese clinicians during medical missions in the fall of 2003. The first sets of medical patients recorded in the databases will be used to evaluate grid implementation of services.
To assess the efficacy of bupropion SR on smoking abstinence using a "slips allowed" analysis.
Retrospective analysis, which did not consider brief episodic "slips" as a return to regular smoking, of ...data from a multicenter, randomized, doubleblind, placebo-controlled relapse prevention study.
Using a slips-allowed analysis, median time to relapse on bupropion SR was 65 weeks versus 30 weeks on placebo. This is compared to 32 and 20 weeks, respectively, using a traditional analysis not allowing for slips.
Bupropion SR is efficacious for the prevention of smoking relapse. A slips-allowed analysis may provide a more clinically relevant assessment of efficacy.
We report the discovery of KELT-12b, a highly inflated Jupiter-mass planet
transiting a mildly evolved host star. We identified the initial transit signal
in the KELT-North survey data and ...established the planetary nature of the
companion through precise follow-up photometry, high-resolution spectroscopy,
precise radial velocity measurements, and high-resolution adaptive optics
imaging. Our preferred best-fit model indicates that the $V = 10.64$ host, TYC
2619-1057-1, has $T_{\rm eff} = 6278 \pm 51$ K, $\log{g_\star} =
3.89^{+0.054}_{-0.051}$, and Fe/H = $0.19^{+0.083}_{-0.085}$, with an
inferred mass $M_{\star} = 1.59^{+0.071}_{-0.091} M_\odot$ and radius $R_\star
= 2.37 \pm 0.18 R_\odot$. The planetary companion has $M_{\rm P} = 0.95 \pm
0.14 M_{\rm J}$, $R_{\rm P} = 1.79^{+0.18}_{-0.17} R_{\rm J}$, $\log{g_{\rm P}}
= 2.87^{+0.097}_{-0.098}$, and density $\rho_{\rm P} = 0.21^{+0.075}_{-0.054}$
g cm$^{-3}$, making it one of the most inflated giant planets known. The time
of inferior conjunction in ${\rm BJD_{TDB}}$ is $2457088.692055 \pm 0.0009$ and
the period is $P = 5.0316144 \pm 0.0000306$ days. Despite the relatively large
separation of $\sim0.07$ AU implied by its $\sim 5.03$-day orbital period,
KELT-12b receives significant flux of $2.93^{+0.33}_{-0.30} \times 10^9$ erg
s$^{-1}$ cm$^{-2}$ from its host. We compare the radii and insolations of
transiting gas-giant planets around hot ($T_{\rm eff} \geq 6250$ K) and cool
stars, noting that the observed paucity of known transiting giants around hot
stars with low insolation is likely due to selection effects. We underscore the
significance of long-term ground-based monitoring of hot stars and space-based
targeting of hot stars with the Transiting Exoplanet Survey Satellite (TESS) to
search for inflated giants in longer-period orbits.
To determine whether relationships exist between elevated laser flare photometry values and common abnormalities and complications associated with uveitis.
We retrospectively studied all patients ...with uveitis on whom laser flare photometry measurements ("flare") were obtained (N = 111) at 2 academic medical centers. The first laser flare photometry values obtained for each patient were compared with the presence or absence of the following abnormalities or complications associated with uveitis: keratic precipitates, posterior synechiae, cataract, macular edema, optic disc edema, and glaucoma. In bilateral cases, the eye with the higher flare was used in primary analyses.
Flare was significantly higher in patients with posterior synechiae (P<.001) and in those with macular edema (P =.02) than in patients with uveitis who did not have these complications. Flare was significantly higher in patients with prior cataract surgery or cataract at the study visit than in those without cataracts (P =.001). There was no significant difference in flare between patients with and without keratic precipitates, optic disc edema, or glaucoma. No relationships were found between abnormalities or complications and the level of inflammatory cells or flare as determined by clinical assessment. We also identified an inverse relationship between flare and visual acuity that was not completely explained by the presence of complications in a stepwise regression model.
Although causal relationships were not established, associations between flare and some complications of uveitis suggest that aqueous humor protein may be an important factor in the development of these problems. Consequently, laser flare photometry could play a role in predicting outcomes or monitoring therapy for patients with uveitis.
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