Characterization of visual manifestations and identification of risk factors for permanent vision loss in patients with giant cell arteritis

Clinical Rheumatology - Permanent vision loss (PVL) is a feared complication and a leading cause of morbidity in giant cell arteritis (GCA). The objective of this study is to describe visual...     

Muscle system of Diplodiscus subclavatus (Trematoda: Paramphistomida) cercariae,pre-ovigerous,and ovigerous adults

The musculature of cercariae, pre-ovigerous, and ovigerous adults of Diplodiscus subclavatus was studied by means of TRITC-conjugated phalloidin staining of filamentous actin and confocal scanning laser microscopy. The body wall appears to include four muscle layers as follows: circular, outer longitudinal, diagonal, and inner longitudinal. Two layers of longitudinal muscle fibers are arranged in different modes due to the secondary transformed paramphistomid body construction. The organization of the acetabulum turned out to be more complex than ever described, with a radial layer, two layers of circular, two layers of meridional, an additional starry layer of muscle fibers, as well as a few separate muscle layers of the accessory sucker. Within the pharynx, I found a group of alar muscle fibers, never described before for any paramphistomids, and some morphological features which were not considered to be characteristic for D. subclavatus (namely—the middle semicircular layer and the transverse muscle fibers in the pre-sphincteric space). No significant reorganizations of the somatic musculature occur throughout the development from the cercaria to the ovigerous adult worm, so the metamorphosis goes in the manner of completion. The cercarial tail includes a layer of circular muscle fibers and a longitudinal muscle layer beneath. The latter consists of two medial longitudinal bundles of smooth muscle fibers and two lateral longitudinal bands of obliquely striated muscle fibers which are partially divided in halves.     

Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation

BACKGROUND Arachidyl amido cholanoic acid(Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1(SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis(NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control.AIM To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet(0.1 MCD)] after treatment with Aramchol.METHODS Isolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with ~(13)C-uniformly labeled glucose. For the in vivo part of the study, male C57 BL/6 J mice were randomly fed a control or 0.1 MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.RESULTS Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid(FA) synthesis and oxidation [PACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation(NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid(TCA) cycle(MDH2, SUCLA2, and SUCLG2), and ribosome(P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with ~(13)C uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1 MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5 P/Xyl5 P.CONCLUSION Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation.     

Hypnotic enhancement of creative drawing

A hypnotically based intervention to enhance creativity in drawing was evaluated in a controlled study. Participants were randomly assigned to either a hypnotic treatment or a nonhypnotic (task-motivational) control treatment. Subjects drew a standard still-life tableau twice. The first drawing involved no special instructions and provided a baseline measure of creativity in drawing. The second drawing was completed after the creativity-enhancement procedure. The drawings were rated blindly on several dimensions of artistic creativity. Hypnotizability, absorption, and debriefing measures were also administered. Results indicated that the hypnotic procedure had significantly greater effects on creativity in drawing. However, there were no significant main effects or interactions involving hypnotizability or absorption. Hypnotic and task-motivational groups did not differ on debriefing measures regarding their experience.     

The Gut Microbiome: Human Health and Inflammatory Skin Diseases

The human microbiome is a rich environment consisting of bacteria, fungi and other commensal microorganisms of the gut, mucosa and skin. The functional role of the gut microbiome includes facilitation in metabolism of macronutrients, maturation of the immune system, and production of pro- or anti-inflammatory signaling molecules and peptides. The identification of these resident organisms has brought about a new understanding of disease processes. Nevertheless, more questions remain regarding the interactions within the microbiome, its interactions with the host, and its contributions to the pathophysiology of disease. The purpose of this review is to examine the existing medical literature to highlight the role of the gut microbiome in human health, also paying attention to its role in several inflammatory skin diseases, namely atopic dermatitis, psoriasis, and rosacea.     

CAR T cells for brain tumors: Lessons learned and road ahead

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.     

Rat Imaging and In Vivo Stability Studies using [11C]-Dimethyl-Diphenyl Ammonium,a Candidate Agent for PET-Myocardial Perfusion Imaging

BackgroundPET myocardial perfusion imaging (MPI) holds several advantages over SPECT for diagnosing coronary artery disease. The short half-lives of prevailing PET-MPI agents hamper wider clinical application of PET in nuclear cardiology; prompting the development of novel PET-MPI agents. We have previously reported on the potential of radiolabeled ammonium salts, and particularly on that of [¹¹C]dimethyl-diphenyl-ammonium ([¹¹C]DMDPA), for cardiac PET imaging. This study was designed to improve the radiosynthesis and increase the yield of [¹¹C]DMDPA, characterize more meticulously the kinetics of radioactivity distribution after its injection via micro-PET/CT studies, and further explore its potential for PET-MPI.MethodsThe radiosynthetic procedure of [¹¹C]DMDPA was improved with respect to the previously reported one. The kinetics of radioactivity distribution following injection of [¹¹C]DMDPA were investigated in juvenile and young adult male SD rats using microPET/CT, and compared to those of [¹³N]NH₃. Furthermore, the metabolic fate of [¹¹C]DMDPA in vivo was examined after its injection into rats.ResultsFollowing a radiosynthesis time of 25–27 min, 11.9 ± 1.1 GBq of [¹¹C]DMDPA was obtained, with a 43.7% ± 4.3% radiochemical yield (n = 7). Time activity curves calculated after administration of [¹¹C]DMDPA indicated rapid, high and sustained radioactivity uptake in hearts of both juvenile and young adult rats, having a two-fold higher cardiac radioactivity uptake compared to [¹³N]NH₃. Accordingly, at all time points after injection to both juvenile and young adult rats, image quality of the left ventricle was higher with [¹¹C]DMDPA compared to [¹³N]NH₃. In vivo stability studies of [¹¹C]DMDPA indicate that no radioactive metabolites could be detected in plasma, liver and urine samples of rats up to 20 min after injection, suggesting that [¹¹C]DMDPA is metabolically stable in vivo.ConclusionsThis study further illustrates that [¹¹C]DMDPA holds, at least in part, essential qualities required from a PET-MPI probe. Owing to the improved radiosynthetic procedure reported herein, [¹¹C]DMDPA can be produced in sufficient amounts for clinical use.     

Genetic variability of wild-type measles viruses, circulating in the Russian Federation during the implementation of the National Measles Elimination Program, 2003–2007

Genetic characterization of wild-type measles viruses (MVs) is an important component of laboratory surveillance of measles. In this study, a phylogenetic analysis was performed of the nucleoprotein gene sequences of 228 MVs isolated in the Russian Federation between 2003 and 2007. Five genotypes, D4, D5, D6, D8, and H1, were detected. From 1999 through the first 6 months of 2003, the most prevalent genotype in the European part of Russia was D4. All genotype D4-type viruses were closely related to each other (with overall sequence diversity of ≤0.9%), suggesting the presence of a single endemic MV strain. After 2003, viruses with closely related sequences within genotype D6 (≤0.9% sequence diversity) were prevalent. During this time, there was a low level of indigenous transmission of genotype D6, and genotype D6 viruses were imported from neighbouring countries, which led to the identification of two lineages of genotype D6, i.e. D6a and D6b. Lineage D6a was closely related to viruses isolated in Turkey, Kazakhstan, and Uzbekistan, whereas lineage D6b was linked to a large outbreak in Ukraine in 2005–2006. Genotypes H1, D5 and D8 were associated with sporadic cases and clusters of transmission linked to importations. Enhanced vaccination interrupted the transmission of the previous endemic lineage D4 in 2003 and of lineage D6a in 2005, although an accumulation of susceptible individuals in the population allowed for prolonged circulation of lineage D6b. These data on MV genotype distribution, in conjunction with the epidemiological data for measles, show considerable progress in measles control and suggest that regional elimination is possible.