Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.     

Effects of Anesthetic Agents on Focal Adhesion Kinase (pp125FAK) Tyrosine Phosphorylation in Rat Hippocampal Slices

Background: Tyrosine protein kinase proteins exert a prominent control on signaling pathways and may couple rapid events, such as action potential and neurotransmitter release, to long-lasting changes in synaptic strength and survival. Whether anesthetics modulate tyrosine kinase activity remains unknown. The aim of the current study was therefore to examine the effects of intravenous and volatile anesthetics on the phosphorylation of focal adhesion kinase (pp125FAK), a functionally important nonreceptor tyrosine kinase, in the rat hippocampus.

Methods: Phosphorylation of pp125FAK was examined in hippocampal slices by immunoblotting with both antiphosphotyrosine and specific anti-pp125FAK antibodies. Experiments were performed in the absence (control) or presence of various concentrations of pharmacologic or anesthetic agents or both.

Results: Clinically relevant concentrations of thiopental, propofol, etomidate, isoflurane, sevoflurane, and desflurane induced a concentration-related increase in tyrosine phosphorylation. In contrast, ketamine (up to 100 [mu]m) and the nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane, 25 [mu]m) did not significantly affect pp125FAK phosphorylation. The anesthetic-induced increase in pp125FAK phosphorylation was blocked by GF 109203X, RO 318220, and chelerythrin (100 [mu]m), three structurally distinct inhibitors of protein kinase C and U 73122 (50 [mu]m), an inhibitor of phospholipase C. The propofol- and isoflurane-induced increase in pp125FAK phosphorylation was reversible and showed nonadditivity of effects with phorbol 12-myristate 13-acetate (an activator of protein kinase C, 0.1 [mu]m). In contrast, ketamine (up to 100 [mu]m), MK801 (10 [mu]m, an N-methyl-d-aspartate receptor antagonist), bicuculline (10 [mu]m, a [gamma]-aminobutyric acid type A receptor antagonist), and dantrolene (30 [mu]m, an inhibitor of the ryanodine receptor) were ineffective in blocking anesthetic-induced activation of tyrosine phosphorylation.     

Extracorporeal Photopheresis for the Treatment of Cutaneous T-Cell Lymphoma

Journal of Cutaneous Medicine and Surgery -     

Interactions Between Cytomegalovirus, Human Herpesvirus-6, and the Recurrence of Hepatitis C After Liver Transplantation

Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver-transplant recipients with serial viral load testing for CMV and HHV-6. Infection and viral load were correlated with the development of biopsy-proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV-6 infection were not associated with HCV recurrence. Peak CMV and HHV-6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post-transplant and peak HHV-6 or CMV viral loads. In a subgroup analysis, HHV-6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score > or = 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV-6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV-6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence.     

Evaluation of the epidermal refractive index measured by optical coherence tomography

BACKGROUND/AIMS: It has recently been proposed that the refractive index (RI) measured by means of optical coherence tomography (OCT) may be a valid measure for hydration of skin. In this pilot study, using OCT in vivo, we aimed to investigate the interday variability of RI measurements and acute changes of RI following the application of a moisturizer. METHODS: Twenty healthy Caucasian volunteers were investigated on their forearms using a commercially available OCT system (SkinDex 300, ISIS optronics GmbH, Mannheim, Germany) fitted with an integrated algorithm for the evaluation of the RI. The interday repeatability of the OCT method was determined performing symmetrical measurements on both forearms on day 1, 5, 9, and 13. In order to investigate the acute effect of a moisturizer on RI, OCT assessments were performed before and 10 min after the application of an aqueous lotion with a lipophilic phase. As a control, the contralateral site was investigated in the same way, except for the use of distilled water instead of the lotion. RESULTS: Assessments of interday variability revealed insignificant (P>0.05) variances between the four measurement times as expressed in very small repeatability coefficients (right arm: 0.039; left arm 0.053) and small coefficients of variance (right arm: 1.02%; left arm: 1.38%). With regard to the RIs measured over time, we could not observe significant (P>0.05) differences between the two symmetrical anatomic sites (mean+/-SD of RI: 1.3893+/-0.0142 (right arm); 1.3875+/-0.0192 (left arm)). The acute effect of the moisturizer was indicated by a significant decrease of the RI 5 min after the application of the lotion (1.399+/-0.01 vs. 1.387+/-0.02; difference between means: 0.012; P=0.033; 95% confidence interval: 0.001-0.0023). However the control site treated with distilled water did not show significant differences between the two measurement times (1.387+/-0.013 vs. 1.391+/-0.023; difference between means: -0.004; P=0.57; 95% confidence interval: -0.019-0.011). CONCLUSIONS: In this pilot study, we have demonstrated that RI evaluation via OCT is a promising technique that may be used for the assessment of skin hydration in vivo. However, the direct comparison of OCT with standard methods, ideally such as nuclear magnetic resonance spectroscopy, is necessary.