Imaging Frontotemporal Lobar Degeneration

The term frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative disorders that target the frontal and temporal lobes. It accounts for approximately 10 % of pathologically confirmed dementias but has been demonstrated to be as prevalent as Alzheimer’s disease in patients below the age of 65. The 3 major clinical syndromes associated with FTLD include behavioral variant frontotemporal dementia, semantic and nonfluent variants of primary progressive aphasia. The more recently introduced term logopenic variant appears to represent an atypical form of Alzheimer’s disease in the majority of cases. The neuropathology underlying these clinical syndromes is very heterogeneous and does not correlate well with the clinical phenotype. This causes great difficulties in early and reliable diagnosis and treatment of FTLD. However, significant advances have been made in recent years via the application of magnetic resonance imaging and positron emission tomography imaging methods as biomarkers. The current review aims to provide a synopsis on the value of magnetic resonance imaging-based and molecular imaging procedures in FTLD.     

Reactive Hemophagocytic Lymphohistiocytosis After Hepatitis A Infection

Hemophagocytic lymphohistiocytosis (HLH) is a clinical condition which result in cytotoxic Tcell and antigen presenting cell overproduction and also their cytokines. Hepatitis A Virus associated HLH is very rare condition among other viruses. This condition is often difficult to diagnose, so treatment is often delayed. Here we present a case of adolescent boy with secondary virus associated HLH diagnosis with Hepatitis A infection and successfull treatment by short course of intravenous immunoglobulin and steroid.     

Engineered kinase activation reveals unique morphodynamic phenotypes and associated trafficking for Src family isoforms

The Src kinase family comprises nine homologous members whose distinct expression patterns and cellular distributions indicate that they have unique roles. These roles have not been determined because genetic manipulation has not produced clearly distinct phenotypes, and the kinases’ homology complicates generation of specific inhibitors. Through insertion of a modified FK506 binding protein (insertable FKBP12, iFKBP) into the protein kinase isoforms Fyn, Src, Lyn, and Yes, we engineered kinase analogs that can be activated within minutes in living cells (RapR analogs). Combining our RapR analogs with computational tools for quantifying and characterizing cellular dynamics, we demonstrate that Src family isoforms produce very different phenotypes, encompassing cell spreading, polarized motility, and production of long, thin cell extensions. Activation of Src and Fyn led to patterns of kinase translocation that correlated with morphological changes in temporally distinct stages. Phenotypes were dependent on N-terminal acylation, not on Src homology 3 (SH3) and Src homology 2 (SH2) domains, and correlated with movement between a perinuclear compartment, adhesions, and the plasma membrane.Since its discovery, c-Src (1) has been subject to intensive research into its cellular functions and regulation. Whereas c-Src is the best-studied protooncogene, less is known about the other, closely related Src family kinase (SFK) members. Their high degree of similarity in structure and regulation suggests that SFKs can partially compensate for each other in vivo. Indeed, knockout studies have shown that only mice deficient in all three genes (src, yes, and fyn) show embryonic lethality (2). Early studies demonstrated that disruption of Src or Fyn genes individually resulted only in subtle changes in function of a few cell types (e.g., osteoclasts for src^−/−, and T cells for fyn^−/−) (3, 4). Roche et al. provided strong evidence that Src, Yes, and Fyn substitute for each other during cell cycle progression (5). These studies suggested that there is a high degree of functional redundancy among Src family kinases.Nonetheless, emerging evidence indicates that Src and Fyn regulate distinct processes in the same cell. Down-regulation of Fyn expression enhances VEGF-stimulated migration of endothelial cells, whereas down-regulation of Src does not (6). Differences in the transforming capacity of SFKs are thought to depend on their affinity for cholesterol-enriched membrane microdomains, which is determined in part by their N-terminal lipid modifications (7, 8). Src has higher tumorigenic potential than Fyn in prostate epithelium, and this is differently affected by alterations in N-terminal palmitoylation (9). Previous studies have shown that Src localizes to perinuclear endosomal compartments and translocates to the plasma membrane upon activation (10–12), whereas Fyn localizes to the plasma membrane regardless of its activity (13, 14). Although these studies suggest that localization is important in differentiating the actions of the two kinases, they do not identify specific roles associated with particular subcellular locations.Various techniques have been applied to elucidate the differences in signaling specificity of SFKs. Kinase–substrate interactions have been examined using purified substrates (15). Mutated kinases with selectivity for radiolabeled ATP analogs have identified directly phosphorylated substrates of Src (16). These methods were restricted to cell lysates or purified proteins, and so were unable to address the role of cellular localization in substrate specificity.To dissect the unique role of different SFK isoforms (2–4, 17, 18) in living cells, we engineered regulatable analogs of Fyn, Yes, and LynA kinases using our rapamycin-regulated activation (RapR) strategy, which has been developed using Src as a prototype (19, 20). Insertable FKBP12 (iFKBP, a truncated form of FKBP) was inserted into the catalytic domain of each SFK, which abolished their kinase activity. Activity was rescued by treating cells with rapamycin in the presence of the FKBP12-rapamycin binding domain (FRB) (Fig. 1A). Molecular dynamics studies have indicated that heterodimerization of the inserted iFKBP with FRB likely reduces the conformational mobility of the kinase G loop, restoring ATP binding (3, 21).Open in a separate windowFig. 1.Design of RapR kinases. (A) Schematic representation of the approach used to regulate catalytic activity of SFKs. The insertion of iFKBP at a highly conserved site in the catalytic domain of each kinase resulted in loss of kinase activity. Catalytic activity was restored by rapamycin, which induced binding of iFKBP and coexpressed FRB. (B) Sequence alignment of SFKs shows that there is a well-defined loop where iFKBP is inserted (blue). It is linked to the G loop (red) through a β-sheet in each SFK.These analogs enabled activation of each isoform specifically, within minutes, resulting in clear phenotypic differences. Unlike genetic modifications of cell populations, there was little time for the cell to compensate for kinase activation before observation. The induced cell behaviors occurred in a succession of stages, associated with changes in the subcellular distribution of each kinase. We focused on Src and Fyn, developing quantitative tools to carefully characterize the kinetics of induced behaviors and associated localization dynamics. Our results indicated that Src’s unique ability to induce polarized movement shortly after kinase activation results from its localization in a perinuclear compartment, where it phosphorylates substrates that traffic on microtubules to the cell perimeter. Both the localization dynamics and phenotype differences between Src and Fyn were dependent on N-terminal lipid modifications, and not on SH2 and SH3 domain interactions.     

A new method for computer-assisted detection,definition and differentiation of the urinary calculi

Purpose: Urinary stones are common and can be diagnosed with computed tomography (CT) easily. In this study, we aimed to specify the opacity characteristics of various types of calcified foci that develop through the urinary system by using an image analysis program. With this method, we try to differentiate the calculi from the non-calculous opacities and also we aimed to present how to identify the characteristic features of renal and ureteral calcules. Materials and methods: We obtained the CT studies of the subjects (n?=?48, mean age?=?41 years) by using a dual source CT imaging system. We grouped the calculi detected in the dual-energy CT sections as renal (n?=?40) or ureteric (n?=?45) based on their locations. Other radio-opaque structures that were identified outside but within close proximity of the urinary tract were recorded as calculi “mimickers”. We used ImageJ program for morphological analysis. All the acquired data were analyzed statistically. Results: According to thorough morphological parameters, there were statistically significant differences in the angle and Feret angle values between calculi and mimickers (p?p?=?0.003) and kidney (p?=?0.001) stones. Conclusions: Computer-based morphologic parameters can be used simply to differentiate between calcular and noncalcular densities on CT and also between renal and ureteric stones.     

Effects of vitamin K in postmenopausal women: Mini review

Possible benefits of vitamin K on bone health, fracture risk, markers of bone formation and resorption, cardiovascular health, and cancer risk in postmenopausal women have been investigated for over three decades; yet there is no clear evidence-based universal recommendation for its use.     

Effects of vitamin E on bone remodeling in perimenopausal women: Mini review

Vitamin E is known to be the most important antioxidant in the body, protecting against the effects of toxic radicals. The main idea behind the studies on vitamin E and bone metabolism stems from the concept that oxidative stress may interfere with the bone formation activity of osteoblasts which in turn can lead to osteoporosis. This mini-review, summarizes the studies on the effects of vitamin E on bone mineral density, fracture risk, bone formation, and resorption markers in perimenopausal women. Current evidence does not the support daily use of vitamin E for protection against osteoporosis and hip fracture risk in perimenopausal women. However some benefit has been shown in some observational studies. Low vitamin E (>6.2 mg/day) intake seems to be associated with an OR of 3.0 of hip fracture in current smokers. Compared with the highest quintile of alpha-tocopherol intake, the lowest quintile of intake conferred a multivariable-adjusted HR of 1.86 for hip fracture and 1.20 for any fracture. Alpha-tocopherol supplementation may alter the alpha-tocopherol/gamma-tocopherol ratio; which in turn may be associated with decreased osteoblastic activity. Interventional studies, especially randomized controlled trials (RCT), evaluating a possible causal relationship between serum vitamin E levels and BMD and hip fracture risk in perimenopausal women are needed.