Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome

Background: There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. Methodology/Principal Findings: We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). Conclusions/Significance: These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for th

Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

BACKGROUND:Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING:Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. SIGNIFICANCE:Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis

Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS).

BACKGROUND: Delayed gastric emptying (DGE) is one of the most common complications after pancreatic resection. In the literature, the reported incidence of DGE after pancreatic surgery varies considerably between different surgical centers, primarily because an internationally accepted consensus definition of DGE is not available. Several surgical centers use a different definition of DGE. Hence, a valid comparison of different study reports and operative techniques is not possible. METHODS: After a literature review on DGE after pancreatic resection, the International Study Group of Pancreatic Surgery (ISGPS) developed an objective and generally applicable definition with grades of DGE based primarily on severity and clinical impact. RESULTS: DGE represents the inability to return to a standard diet by the end of the first postoperative week and includes prolonged nasogastric intubation of the patient. Three different grades (A, B, and C) were defined based on the impact on the clinical course and on postoperative management. CONCLUSION: The proposed definition, which includes a clinical grading of DGE, should allow objective and accurate comparison of the results of future clinical trials and will facilitate the objective evaluation of novel interventions and surgical modalities in the field of pancreatic surgery

Fundamentals of tooth preparation

This chapter will emphasise the need to:Consider extra-coronal restorations that require minimal preparation (veneers, onlays and {\textthreequarters} crowns) instead of always prescribing crownsPlan your tooth preparation keeping in mind the space requirements and marginal configurations recommended for different restorations and materialsOptimise resistance and retention, particularly in tooth preparations for zirconia restorations and restorations cemented with conventional cementsChoose an appropriate preparation margin and marginal position to optimise gingival health and aestheticsAdopt a systematic approach for preparing teeth, evaluating the quality of the preparation and determining if adequate, but not excessive, tooth reduction has been achievedEnsure proper planning before tooth preparation and use a check list to develop an efficient work-flo