Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System.

Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-ß, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

Gender difference in the impact of coexisting diabetes mellitus on long-term clinical outcome in people with heart failure: a report from the Korean Heart Failure Registry.

AIM: Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure. METHODS: A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission. RESULTS: People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P < 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P > 0.05). CONCLUSIONS: In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.

Use of SkinFibrometer® to measure skin elasticity and its correlation with Cutometer® and DUB® Skinscanner.

BACKGROUND: Skin elasticity is an important indicator of skin aging. The aim of this study was to demonstrate that the SkinFibrometer® is appropriate for measuring skin biomechanical properties, and to correlate it with elasticity parameters measured using the Cutometer® and with dermis structural properties measured using DUB® Skinscanner. MATERIALS AND METHODS: Twenty-one individuals participated in this study. The skin of the cheek, around the eye, and the volar forearm were evaluated. To analyze correlations of elasticity parameters, the induration value against the indenter pressure of SkinFibrometer® and R, Q parameters of Cutometer® were compared. Dermal echogenicity using DUB® Skinscanner was compared with the induration value of SkinFibrometer® . RESULTS: The younger age group showed more firm and elastic skin properties compared to the older age group, and the elasticity values of the volar forearm were significantly higher than those of the cheek and around the eye region. Even though the measuring principle is different, both SkinFibrometer® and Cutometer® demonstrated the same trends of skin elasticity differences according to age and anatomical regions. There were significant correlations between the induration value of SkinFibrometer® , representing skin firmness, and R0, Q0 and R2, R5, R7, Q1, Q2 of Cutometer® , which represent skin firmness and resilience, respectively (P < .01). In addition, dermal echogenicity positively correlated with skin firmness determined by SkinFibrometer® (P < .01). CONCLUSION: We identified correlations between skin elasticity parameters evaluated by two different methods of suction and indentation, and demonstrated that the SkinFibrometer® is an objective, non-invasive evaluation tool for skin stiffness and elasticity.

Anterior Ischemic Optic Neuropathy Due to Calciphylaxis.

A 72-year-old woman experienced anterior ischemic optic neuropathy in her left eye. The funduscopic and fluorescein angiographic findings were strongly suggestive of giant cell arteritis. Temporal artery biopsy revealed extensive calcification in the vessel wall consistent with calciphylaxis. This unusual disorder should be considered in the differential diagnosis of anterior ischemic optic neuropathy, particularly the arteritic form.

Epac-Rap signaling reduces oxidative stress in the tubular epithelium.

Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2'-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2'-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate-induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2'-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2'-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.

[THE DIAGNOSTIC APPROACHES TO VERIFICATION OF STREPTOCOCCUS INFECTION IN PATIENTS WITH INFECTIOUS MONONUCLEOSIS].

The Rostovskii state medical university of Minzdrav of Russia, 344022 Rostov-on-Don, Russia The analysis is applied concerning significance of laboratory techniques of verification of streptococcus infection (bacteriological analysis, detection of anti-streptolysin O in pair serums) in 148 patients with infectious mononucleosis aged from 3 to 15 years. The content of anti-streptolysin O exceeded standard in 41 ± 4.8% of patients with concomitant in acute period and in 49.5 ± 4.9% during period of re-convalescence. This data differed from analogous indicator in patients with negative result of examination on streptococcus infection independently of period of disease (9.3 ± 2.8%). The exceeding of standard of anti-streptolysin O was detected more frequently (t ≥ 2, P ≥ 95%) in patients with isolation of Streptococcus pyogenes (56.9 ± 5.8%) than in patients with Streptococcus viridans (31.2 ± 6.5%). The concentration of anti-streptolysin 0 in patients with concomitant streptococcus infection varied within limits 200-1800 IE/ml. The minimal level of anti-streptolysin O (C = 200 IE/mI) was detected independently of type of isolated Streptococcus and period of disease. The high levels of anti-streptolysin O were observed exclusively in patients with isolation of Streptococcus pyogenes. In blood serum ofpatient with concomitant streptococcus infection (Streptococcus pyogenes + Streptococcus viridans) increasing of level of anti-streptolysin O was detected in dynamics of diseases from minimal (C = 200 IE/ ml) to moderately high (200 < C < 400 IE/mI). It is demonstrated that to identify streptococcus infection in patients with infectious mononucleosis the anamnesis data is to be considered. The complex bacteriological and serological examination ofpatients is to be implemented This is necessary for early detection ofpatients with streptococcus infection and decreasing risk of formation of streptococcus carrier state.

[ESOPHAGITIS, CAUSED BY HERPES SIMPLEX VIRUS: CASE REPORT].

The clinical observation of the patient at the age of 56 years, with lesions of the esophagus by the herpes simplex virus has been presented. The patient complained of odynophagia and dysphagia. Treatment with proton pump inhibitors in outpatient stage was not effective. On endoscopic examination revealed multiple ulcers in all parts of the esophagus. Herpes simplex virus has been detected in biopsy specimens of esophageal mucosa by the PCR method. Treatment with acyclovir led to rapid and complete clinical recovery. Analysis of the literature allowed making the conclusion about the importance and actuality this demonstration.

[Apoptogenic activity of microbes-associants during Epstein-Barr virus infection].

AIM: Study apoptogenic activity of-microbes-associants during Epstein-Barr virus infection (EBVI) on the model of mice peritoneal macrophages in vitro. MATERIALS AND METHODS: Evaluation of apoptosis induced by bacteria isolated from EBVI patients was carried out by characteristic morphological changes of macrophages in smears stained by May-Grunwald with additional staining by Romanowsky-Giemsa. RESULTS: All the EBVI microbes-associants were established to have apoptogenic activity, however, the highest pathogenic potential was noted in Streptococcus pyogenes. CONCLUSION: The presence of apoptogenic activity in bacterial microflora accompanying EBVI against immune system cells could serve as means of their survival and be the pathogenetic basis for prolonged persistence in the organism.

Human cortical spheroids with a high diversity of innately developing brain cell types.

BACKGROUND: Three-dimensional (3D) human brain spheroids are instrumental to study central nervous system (CNS) development and (dys)function. Yet, in current brain spheroid models the limited variety of cell types hampers an integrated exploration of CNS (disease) mechanisms. METHODS: Here we report a 5-month culture protocol that reproducibly generates H9 embryonic stem cell-derived human cortical spheroids (hCSs) with a large cell-type variety. RESULTS: We established the presence of not only neuroectoderm-derived neural progenitor populations, mature excitatory and inhibitory neurons, astrocytes and oligodendrocyte (precursor) cells, but also mesoderm-derived microglia and endothelial cell populations in the hCSs via RNA-sequencing, qPCR, immunocytochemistry and transmission electron microscopy. Transcriptomic analysis revealed resemblance between the 5-months-old hCSs and dorsal frontal rather than inferior regions of human fetal brains of 19-26 weeks of gestational age. Pro-inflammatory stimulation of the generated hCSs induced a neuroinflammatory response, offering a proof-of-principle of the applicability of the spheroids. CONCLUSIONS: Our protocol provides a 3D human brain cell model containing a wide variety of innately developing neuroectoderm- as well as mesoderm-derived cell types, furnishing a versatile platform for comprehensive examination of intercellular CNS communication and neurological disease mechanisms.

Birth mode is associated with development of atopic dermatitis in infancy and early childhood.

Background: Birth by caesarean section (CS) is associated with development of allergic diseases, but its role in the development of atopic dermatitis (AD) is less convincing. Objective: Our primary aim was to determine if birth mode was associated with AD in 3-year-olds and secondarily to determine if birth mode was associated with early onset and/or persistent AD in the first 3 years of life. Methods: We included 2129 mother-child pairs from the Scandinavian population-based prospective PreventADALL cohort with information on birth mode including vaginal birth, either traditional (81.3%) or in water (4.0%), and CS before (6.3%) and after (8.5%) onset of labor. We defined early onset AD as eczema at 3 months and AD diagnosis by 3 years of age. Persistent AD was defined as eczema both in the first year and at 3 years of age, together with an AD diagnosis by 3 years of age. Results: AD was diagnosed at 3, 6, 12, 24, and/or 36 months in 531 children (25%). Compared to vaginal delivery, CS was overall associated with increased odds of AD by 3 years of age, with adjusted odds ratio (95% confidence interval) of 1.33 (1.02-1.74), and higher odds of early onset AD (1.63, 1.06-2.48). The highest odds for early onset AD were observed in infants born by CS after onset of labor (1.83, 1.09-3.07). Birth mode was not associated with persistent AD. Conclusion: CS was associated with increased odds of AD by 3 years of age, particularly in infants presenting with eczema at 3 months of age.

MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome.

BACKGROUND: The aim of this study was to compare gene copy number (GCN) and protein expression of MET and to evaluate their prognostic roles in gastric carcinomas. METHODS: MET protein expression and gene amplification (GA) status were determined by immunohistochemistry (IHC) and silver in-situ hybridisation (SISH), respectively, in a large series of gastric carcinoma. RESULTS: Protein overexpression was observed in 104 of 438 cases, with IHC 2+ in 94 and IHC 3+ in 10, and high polysomy of chromosome 7 and GA were found in 61 and 13 of 381, respectively. Direct comparison revealed a significant correlation between high level of protein expression and increased GCN. All cases with GA showed protein overexpression. Furthermore, all with IHC 3+ showed GA except 1, even which could be categorised as GA according to the ASCO/CAP guideline for human epidermal growth factor receptor 2 assessment. IHC 3+ and GA were significantly associated with poor prognosis. CONCLUSION: MET IHC reflects well on GA, and therefore, it could be a primary screening test for patient selection for anti-MET therapy if GA is a major determinant of drug responsiveness. Also, the prognostic role of MET indicates that anti-MET therapy is a very promising modality in adjuvant treatment for gastric cancer.

Molecular Signature of Neuroinflammation Induced in Cytokine-Stimulated Human Cortical Spheroids.

Crucial in the pathogenesis of neurodegenerative diseases is the process of neuroinflammation that is often linked to the pro-inflammatory cytokines Tumor necrosis factor alpha (TNFα) and Interleukin-1beta (IL-1ß). Human cortical spheroids (hCSs) constitute a valuable tool to study the molecular mechanisms underlying neurological diseases in a complex three-dimensional context. We recently designed a protocol to generate hCSs comprising all major brain cell types. Here we stimulate these hCSs for three time periods with TNFα and with IL-1ß. Transcriptomic analysis reveals that the main process induced in the TNFα- as well as in the IL-1ß-stimulated hCSs is neuroinflammation. Central in the neuroinflammatory response are endothelial cells, microglia and astrocytes, and dysregulated genes encoding cytokines, chemokines and their receptors, and downstream NFκB- and STAT-pathway components. Furthermore, we observe sets of neuroinflammation-related genes that are specifically modulated in the TNFα-stimulated and in the IL-1ß-stimulated hCSs. Together, our results help to molecularly understand human neuroinflammation and thus a key mechanism of neurodegeneration.

Physical activity in pregnancy: a Norwegian-Swedish mother-child birth cohort study.

BACKGROUND: Physical activity during pregnancy is important for maternal and offspring health. Optimal conditions during pregnancy may help reduce the burden of noncommunicable diseases. National and international guidelines recommend at least 150 minutes of physical activity of at least moderate intensity per week. To optimize physical activity in pregnant women, it is important to identify factors associated with higher levels of physical activity. OBJECTIVE: This study aimed to explore types and levels of physical activity in midpregnancy in Norway and Sweden and to identify factors associated with higher levels of physical activity. MATERIALS AND METHODS: From the population-based mother-child cohort Preventing Atopic Dermatitis and Allergies in Children study recruiting 2697 women in Norway and Sweden from 2014 to 2016, we included 2349 women who answered an electronic questionnaire at enrollment in midpregnancy. Women were asked about regular physical activity in the last 2 weeks of pregnancy and afterward for types and levels of physical activity in pregnancy and before pregnancy and socioeconomic status, lifestyle, and maternal health. Logistic regression analyses were used to identify factors associated with higher levels of physical activity in pregnancy, defined as >30 minutes per session of ≥2 times per week of moderate- or high-intensity brisk walking, strength training, jogging, and bicycling. RESULTS: No regular physical activity during the last 2 weeks before answering the questionnaire at midpregnancy was reported by 689 women (29%). In this study, 1787 women (76%) reported weekly strolling during pregnancy. Regular physical activity at least twice weekly in the first half of pregnancy was reported as brisk walking by 839 women (36%), bicycling by 361 women (15%), strength training by 322 women (14%), and other activities by <10% of women. Among the 1430 women with regular moderate- or high-intensity physical activity, the estimated median duration per week was 120 minutes. Higher physical activity levels were achieved in 553 women (23.5%) by brisk walking, 287 women (12.2%) by strength training, 263 women (11.2%) by bicycling, and 114 women (4.9%) by jogging. Higher physical activity levels were positively associated with regular physical activity before pregnancy, dog ownership, and atopic dermatitis and negatively associated with higher body mass index, study location in Østfold, previous pregnancy or pregnancies, non-Nordic origin, suburban living, and sick leave. CONCLUSION: At midpregnancy, 29% of women were inactive, and less than 50% of women had at least 2 hours of moderate-intensity physical activity weekly. Awareness of physical activity in pregnancy should be discussed at pregnancy follow-up visits, particularly among women with higher body mass index, sick leave, previous pregnancy or pregnancies, and non-Nordic origin.

Prognosis of surgical hernia repair in cirrhotic patients with refractory ascites.

BACKGROUND: Abdominal wall hernias are common in patients with ascites. Elective surgical repair is recommended for the treatment of abdominal wall hernias. However, surgical hernia repair in cirrhotic patients with refractory ascites is controversial. In this study, we aimed to evaluate the outcomes of elective surgical hernia repair in patients with liver cirrhosis with and without refractory ascites. METHOD: From January 2005 to June 2018, we retrospectively reviewed the records of consecutive patients with liver cirrhosis who underwent a surgical hernia repair. RESULTS: This study included 107 patients; 31 patients (29.0%) had refractory ascites. Preoperatively, cirrhotic patients with refractory ascites had a higher median model for end-stage liver disease (MELD) score (13.0 vs 11.0, P = 0.001) than those without refractory ascites. The 30-day mortality rate (3.2% vs 0%, P = 0.64) and the risk of recurrence (hazard ratio 0.410; 95% CI 0.050-3.220; P = 0.39) did not differ significantly between cirrhotic patients with refractory ascites and cirrhotic patients without refractory ascites. Among cirrhotic patients with refractory ascites, albumin (P = 0.23), bilirubin (P = 0.37), creatinine (P = 0.97), and sodium levels (P = 0.35) did not change significantly after surgery. CONCLUSION: In advanced liver cirrhosis patients with refractory ascites, hernias can be safely treated with elective surgical repair. Mortality rate within 30 days did not differ by the presence or absence of refractory ascites. Elective hernia repair might be beneficial for treatment of abdominal wall hernia in cirrhotic patients with refractory ascites.

BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.

BACKGROUND: Epithelial ovarian cancer is one of the most lethal malignancies, and has a high recurrence rate. Thus, prognostic markers for recurrence are crucial for the care of ovarian cancer. As ovarian cancers frequently exhibit chromosome instability, we aimed at assessing the prognostic significance of two key mitotic kinases, BubR1 and Aurora A. METHODS: We analysed paraffin-embedded tissue sections from 160 ovarian cancer patients whose clinical outcomes had been tracked after first-line treatment. RESULTS: The median recurrence-free survival in patients with a positive and negative expression of BubR1 was 27 and 83 months, respectively (P<0.001). A positive BubR1 expression was also associated with advanced stage, serous histology and high grade. In contrast, Aurora A immunostaining did not correlate with any of the clinical parameters analysed. CONCLUSION: BubR1, but not Aurora A, is a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer.

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.