Longitudinal changes in corneal cell and nerve fiber morphology 2 in young patients with type 1 diabetes with and without diabetic 3 retinopathy: a 2-year follow-up study

LBL

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI)

Baseline Characteristics and Disease Phenotype In Inflammatory Bowel Disease Results of A Paediatric IBD Cohort.

BACKGROUND AND AIMS Predicting short-term relapses and long-term prognosis is of outmost importance in paediatric inflammatory bowel disease. Our aim was to investigate the short-term disease outcome and medication during the first year in a paediatric incident cohort from Hungary. In addition, association laboratory markers and disease activity indices with short-term disease outcome and medication were analysed. METHODS From January 1, 2008 to December 31, 2010 demographic data and clinical characteristics of newly diagnosed paediatric inflammatory bowel disease patients younger than 18 years of age were prospectively recorded. RESULTS A total of 420 patients were identified [Crohn's disease: 266; ulcerative colitis 124]. Initially, 48% (124/256) of Crohn's disease patients had moderate to severe disease (PCDAI>31), and this rate decreased to 2.1% at one-year follow-up. Proportion of ulcerative colitis patients with moderate to severe disease (PUCAI>35) at diagnosis declined from 57.5% (69/120) to 6.8% at one-year follow-up. Terminal ileal involvement correlated with higher initial CRP (p = 0.021) and initial PCDAI (p = 0.026). In ulcerative colitis, elevated CRP (p = 0.002) was associated with disease extension. CRP and PCDAI at diagnosis were associated with the need for immunomodulators at one year in children with Crohn's disease. Initial CRP was also associated with the need for immunomodulators in patients with ulcerative colitis at one-year follow-up. CONCLUSIONS At diagnosis half of the patients with inflammatory bowel disease had moderate to severe disease and this rate decreased to less than 10% after one year. Initial CRP and PCDAI were related to the need for aggressive therapy in Crohn's disease

Nanotubes connecting B lymphocytes: High impact of differentiation-dependent lipid composition on their growth and mechanics

Nanotubes (NTs) are thin, long membranous structures forming novel, yet poorly known communication pathways between various cell types. Key mechanisms controlling their growth still remained poorly understood. Since NT-forming capacity of immature and mature B cells was found largely different, we investigated how lipid composition and molecular order of the membrane affect NT-formation. Screening B cell lines with various differentiation stages revealed that NT-growth linearly correlates with membrane ganglioside levels, while it shows maximum as a function of cholesterol level. NT-growth of B lymphocytes is promoted by raftophilic phosphatidylcholine and sphingomyelin species, various glycosphingolipids, and docosahexaenoic acid-containing inner leaflet lipids, through supporting membrane curvature, as demonstrated by comparative lipidomic analysis of mature versus immature B cell membranes. Targeted modification of membrane cholesterol and sphingolipid levels altered NT-forming capacity confirming these findings, and also highlighted that the actual lipid raft number may control NT-growth via defining the number of membrane-F-actin coupling sites. Atomic force microscopic mechano-manipulation experiments further proved that mechanical properties (elasticity or bending stiffness) of B cell NTs also depend on the actual membrane lipid composition. Data presented here highlight importance of the lipid side in controlling intercellular, nanotubular, regulatory communications in the immune system

EZH2 is a sensitive marker of malignancy in salivary gland tumors

BACKGROUND: The immunohistochemical detection of Enhancer of zeste homologue 2 (EZH2) proved to be a useful tool to recognize the malignant nature of tumors in a wide variety of neoplasms. The histological diagnostics of salivary gland tumors is a challenging task, and a reliable marker of malignancy would be extremely helpful. METHODS: EZH2 expression was investigated in 54 malignant and 40 benign salivary gland tumors of various histological types by standard immunohistochemistry. RESULTS: The majority (n = 52) of the malignant tumors stained positively, while all the investigated benign tumors were negative for EZH2. CONCLUSIONS: EZH2 expression in salivary gland tumors, similarly to the tumors of other organs is not characteristic for any tumor type, but is a solid marker of the malignant nature of the tumors

Reduced Estradiol-Induced Vasodilation and Poly-(ADP-Ribose) Polymerase (PARP) Activity in the Aortas of Rats with Experimental Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hyperandrogenism and insulin resistance, both of which have been connected to atherosclerosis. Indeed, an increased risk of clinical manifestations of arterial vascular diseases has been described in PCOS. On the other hand endothelial dysfunction can be detected early on, before atherosclerosis develops. Thus we assumed that vascular dysfunction is also related directly to the hormonal imbalance rather than to its metabolic consequences. To detect early functional changes, we applied a novel rodent model of PCOS: rats were either sham operated or hyperandrogenism was achieved by implanting subcutaneous pellets of dihydrotestosterone (DHT). After ten weeks, myograph measurements were performed on isolated aortic rings. Previously we described an increased contractility to norepinephrine (NE). Here we found a reduced immediate relaxation to estradiol treatment in pre-contracted aortic rings from hyperandrogenic rats. Although the administration of vitamin D3 along with DHT reduced responsiveness to NE, it did not restore relaxation to estradiol. Poly-(ADP-ribose) polymerase (PARP) activity was assessed by poly-ADP-ribose immunostaining. Increased PAR staining in ovaries and circulating leukocytes from DHT rats showed enhanced DNA damage, which was reduced by concomitant vitamin D3 treatment. Surprisingly, PAR staining was reduced in both the endothelium and vascular smooth muscle cells of the aorta rings from hyperandrogenic rats. Thus in the early phase of PCOS, vascular tone is already shifted towards vasoconstriction, characterized by reduced vasorelaxation and vascular dysfunction is concomitant with altered PARP activity. Based on our findings, PARP inhibitors might have a future perspective in restoring metabolic disorders in PCOS

Recurrent Scedosporium apiospermum mycetoma successfully treated by surgical excision and terbinafine treatment: a case report and review of the literature

Background: Scedosporium apiospermum is an emerging opportunistic filamentous fungus, which is notorious for its high levels of antifungal ‑resistance. It is able to cause localized cutaneous or subcutaneous infections in both immu‑ nocompromised and immunocompetent persons, pulmonary infections in patients with predisposing pulmonary diseases and invasive mycoses in immunocompromised patients. Subcutaneous infections caused by this fungus frequently show chronic mycetomatous manifestation. Case report: We report the case of a 70 ‑year ‑old immunocompromised man, who developed a fungal mycetoma‑ tous infection on his right leg. There was no history of trauma; the aetiological agent was identified by microscopic examination and ITS sequencing. This is the second reported case of S. apiospermum subcutaneous infections in Hungary, which was successfully treated by surgical excision and terbinafine treatment. After 7 months, the patient remained asymptomatic. Considering the antifungal susceptibility and increasing incidence of the fungus, Sce - dosporium related subcutaneous infections reported in the past quarter of century in European countries were also reviewed. Conclusions: Corticosteroid treatment represents a serious risk factor of S. apiospermum infections, especially if the patient get in touch with manure ‑enriched or polluted soil or water. Such infections have emerged several times in European countries in the past decades. The presented data suggest that besides the commonly applied voricona‑ zole, terbinafine may be an alternative for the therapy of mycetomatous Scedosporium infections