Phytosterols have been used as blood cholesterol–lowering agents for the last half century. They have been shown to be effective and safe. Originally presented as a pharmaceutical formulation, ...phytosterols are now being added to an increasing variety of foodstuffs. On occasion, questions have arisen concerning their safety, but at the present time and at the current level of usage, no adverse effects have been observed.
SGLT2i directly inhibit the cardiac sodium-hydrogen exchanger-1 (NHE1) in isolated ventricular cardiomyocytes (CMs). However, other studies with SGLT2i have yielded conflicting results. This may be ...explained by methodological factors including cell isolation techniques, cell types and ambient pH. In this study, we tested whether the use of protease XIV (PXIV) may abrogate inhibition of SGLT2i on cardiac NHE1 activity in isolated rabbit CMs or rat cardiomyoblast cells (H9c2), in a pH dependent manner.
Rabbit ventricular CMs were enzymatically isolated from Langendorff-perfused hearts during a 30-min perfusion period followed by a 25-min after-dissociation period, using a collagenase mixture without or with a low dose PXIV (0.009 mg/mL) present for different periods. Empagliflozin (EMPA) inhibition on NHE activity was then assessed at pH of 7.0, 7.2 and 7.4. In addition, effects of 10 min PXIV treatment were also evaluated in H9c2 cells for EMPA and cariporide NHE inhibition.
EMPA reduced NHE activity in rabbit CMs that were not exposed to PXIV treatment or undergoing a 35-min PXIV treatment, independent of pH levels. However, when exposure time to PXIV was extended to 55 min, NHE inhibition by Empa was completely abolished at all three pH levels. In H9c2 cells, NHE inhibition by EMPA was evident in non-treated cells but lost after 10-min incubation with PXIV. NHE inhibition by cariporide was unaffected by PXIV.
The use of protease XIV in cardiac cell isolation procedures obliterates the inhibitory effects of SGLT2i on NHE1 activity in isolated cardiac cells, independent of pH.
Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is ...microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma.
A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed.
Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI- tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors.
In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.
Abstract
Background:
Common cold is one of the most prevalent conditions that family doctors encounter. One of the first symptoms to occur is nasal congestion, which can have a negative impact on ...daily life and prompts many patients to seek treatment for relief. Xylometazoline nasal spray (Otrivin*) is a topical decongestant that has been used successfully for many years and is generally recognized as an effective and safe therapy. However, most studies have investigated its clinical efficacy in healthy patients and few have included patients with common cold.
*Otrivin® is a registered trademark of Novartis AG, Basel, Switzerland.
Scope:
To review the published clinical efficacy and safety of xylometazoline alone and in combination in the management of nasal congestion in patients with common cold. Literature searches of PubMed and the Cochrane Library were conducted to obtain published open or blinded, randomized, placebo- or active-controlled studies on the use of xylometazoline hydrochloride for the symptomatic relief of nasal congestion in patients with common cold. Searches included papers published in English only, up to September 2009.
Findings:
Despite the small number of studies identified in common cold (n = 4), as per search criteria defined, intranasal xylometazoline quickly and effectively relieved nasal congestion. When used alone, xylometazoline had a clinically relevant decongestant effect that was significantly superior for up to 10 hours compared with placebo. The superior decongestant effect with xylometazoline led to high patient satisfaction with treatment. When used in combination with ipratropium bromide, nasal congestion and rhinorrhoea were treated simultaneously, leading to significantly higher patient general impression scores compared with either agent used alone. Xylometazoline was well tolerated, with generally mild to moderate nasal-related side effects (e.g. epistaxis in 3.4% of patients, and blood-tinged mucus in 10-26% of patients) that were easily resolved; the most frequently reported non-nasal AEs were headache (3.4%) and period pain (10.3%); no cases of sedation were reported. As expected, no rhinitis medicamentosa or rebound congestion was noted with short-term use (<10 days). No clinically important differences in ciliary motility and mucociliary clearance were observed. Xylometazoline does not result in sympathomimetic systemic side effects seen with oral decongestants (e.g. pseudoephedrine, phenylephrine).
Conclusions:
The few studies available in common cold suggest that intranasal xylometazoline provides fast and effective relief of nasal congestion and is well tolerated. When xylometazoline is used in combination with ipratropium, patients with common cold experience the additive benefit of nasal congestion and rhinorrhoea being treated simultaneously.
Despite epidemiological evidence that tea consumption is associated with the reduced risk of coronary heart disease, experimental studies designed to show that tea affects oxidative stress or blood ...cholesterol concentration have been unsuccessful. We assessed the effects of black tea consumption on lipid and lipoprotein concentrations in mildly hypercholesterolemic adults. Tea and other beverages were included in a carefully controlled weight-maintaining diet. Five servings/d of tea were compared with a placebo beverage in a blinded randomized crossover study (7 men and 8 women, consuming a controlled diet for 3 wk/treatment). The caffeine-free placebo was prepared to match the tea in color and taste. In a third period, caffeine was added to the placebo in an amount equal to that in the tea. Five servings/d of tea reduced total cholesterol 6.5%, LDL cholesterol 11.1%, apolipoprotein B 5% and lipoprotein(a) 16.4% compared with the placebo with added caffeine. Compared with the placebo without added caffeine, total cholesterol was reduced 3.8% and LDL cholesterol was reduced 7.5% whereas apolipoprotein B, Lp(a), HDL cholesterol, apolipoprotein A-I and triglycerides were unchanged. Plasma oxidized LDL, F2-isoprostanes, urinary 8-hydroxy-2′-deoxyguanosine, ex vivo ferric ion reducing capacity and thiobarbituric acid reactive substances in LDL were not affected by tea consumption compared with either placebo. Thus, inclusion of tea in a diet moderately low in fat reduces total and LDL cholesterol by significant amounts and may, therefore, reduce the risk of coronary heart disease. Tea consumption did not affect antioxidant status in this study.
A linear theory on temporal instability of megahertz Faraday waves for monodisperse microdroplet ejection based on mass conservation and linearized Navier-Stokes equations is presented using the most ...recently observed micrometer- sized droplet ejection from a millimeter-sized spherical water ball as a specific example. The theory is verified in the experiments utilizing silicon-based multiple-Fourier horn ultrasonic nozzles at megahertz frequency to facilitate temporal instability of the Faraday waves. Specifically, the linear theory not only correctly predicted the Faraday wave frequency and onset threshold of Faraday instability, the effect of viscosity, the dynamics of droplet ejection, but also established the first theoretical formula for the size of the ejected droplets, namely, the droplet diameter equals four-tenths of the Faraday wavelength involved. The high rate of increase in Faraday wave amplitude at megahertz drive frequency subsequent to onset threshold, together with enhanced excitation displacement on the nozzle end face, facilitated by the megahertz multiple Fourier horns in resonance, led to high-rate ejection of micrometer- sized monodisperse droplets (>10 7 droplets/s) at low electrical drive power (<;1 W) with short initiation time (<;0.05 s). This is in stark contrast to the Rayleigh-Plateau instability of a liquid jet, which ejects one droplet at a time. The measured diameters of the droplets ranging from 2.2 to 4.6 μm at 2 to 1 MHz drive frequency fall within the optimum particle size range for pulmonary drug delivery.
An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its ...potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery.
Protein-tyrosine phosphatase-α (PTPα) activates Src family kinases (SFKs) to promote the integrin-stimulated early autophosphorylation of focal adhesion kinase (FAK). We report here that integrin ...stimulation induces tyrosine phosphorylation of PTPα. PTPα was dephosphorylated upon fibroblast detachment from the substratum and rephosphorylated when cells were plated on the integrin ligand fibronectin. α PTP phosphorylation occurred at Tyr789 and required SFKs (Src or Fyn/Yes), FAK, and an intact cytoskeleton. It also required active PTPα or constitutively active Src. These observations indicate that PTPα activates SFKs and that the subsequently activated SFK·FAK tyrosine kinase complex in turn phosphorylates PTPα. Reintroduction of wild-type PTPα or unphosphorylatable PTPα(Y789F) (but not inactive PTPα) into PTPα-null fibroblasts restored defective integrin-induced SFK activation, FAK phosphorylation, and paxillin phosphorylation. PTPα(Y789F) and inactive PTPα could not rescue delayed actin stress fiber assembly and focal adhesion formation or defective cell migration. This study distinguishes two roles of PTPα in integrin signaling: an early role as an activator of SFKs and FAK with no requirement for PTPα phosphorylation and a later downstream role in cytoskeleton-associated events for which PTPα phosphorylation at Tyr789 is essential.
BoxCARS and pump-probe geometries are common implementations of two-dimensional infrared (2D IR) spectroscopy. BoxCARS is background-free, generally offering greater signal-to-noise ratio, which ...enables measuring weak vibrational echo signals. Pulse shapers have been implemented in the pump-probe geometry to accelerate data collection and suppress scatter and other unwanted signals by precise control of the pump-pulse delay and carrier phase. Here, we introduce a 2D-IR optical setup in the BoxCARS geometry that implements a pulse shaper for rapid acquisition of background-free 2D IR spectra. We show a signal-to-noise improvement using this new fast-scan BoxCARS setup versus the pump-probe geometry within the same configuration.
This Letter reports the first observation and theoretical analysis of a new phenomenon: one large spherical water drop ejecting simultaneously a very large number of monodisperse microdroplets. An ...ultrasonic nozzle with multiple-Fourier horns in resonance enables controlled excitation of megahertz Faraday waves on the free water surface. The temporal instability of such waves leads to the ejection of 3.5-4.4 μm monodisperse droplets at a high rate (>4.0×10(7) droplets/sec). This is in stark contrast to the Rayleigh-Plateau instability, which ejects one droplet at a time.
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