Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1cM of major candidate genes, namely APOB (LOD =2.1), LDLR (LOD =1.9) and APOE (LOD =1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate. © 2005 Nature Publishing Group. All rights reserved

Dual targeting of ptp1b and aldose reductase with marine drug phosphoeleganin: A promising strategy for treatment of type 2 diabetes

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands

Orexin-A/Hypocretin-1 Controls the VTA-NAc Mesolimbic Pathway via Endocannabinoid-Mediated Disinhibition of Dopaminergic Neurons in Obese Mice

Disinhibition of orexin-A/hypocretin-1 (OX-A) release occurs to several output areas of the lateral hypothalamus (LH) in the brain of leptin knockout obese ob/ob mice. In this study, we have investigated whether a similar increase of OX-A release occurs to the ventral tegmental area (VTA), an orexinergic LH output area with functional effects on dopaminergic signaling at the mesolimbic circuit. By confocal and correlative light and electron microscopy (CLEM) morphological studies coupled to molecular, biochemical, and pharmacological approaches, we investigated OX-A-mediated dopaminergic signaling at the LH-VTA-nucleus accumbens (NAc) pathway in obese ob/ob mice compared to wild-type (wt) lean littermates. We found an elevation of OX-A trafficking and release to the VTA of ob/ob mice and consequent orexin receptor-1 (OX1R)-mediated over-activation of dopaminergic (DA) neurons via phospholipase C (PLC)/diacylglycerol lipase (DAGL-α)-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). In fact, by retrograde signaling to cannabinoid receptor type 1 (CB1R) at inhibitory inputs to DA neurons, 2-AG inhibited GABA release thus inducing an increase in DA concentration in the VTA and NAc of ob/ob mice. This effect was prevented by the OX1R antagonist SB-334867 (30 mg/Kg, i.p.), or the CB1R antagonist AM251 (10 mg/Kg, i.p.) and mimicked by OX-A injection (40 μg/Kg, i.p.) in wt lean mice. Enhanced DA signaling to the NAc in ob/ob mice, or in OX-A-injected wt mice, was accompanied by β-arrestin2-mediated desensitization of dopamine D2 receptor (D2R) in a manner prevented by SB-334867 or the D2R antagonist L741 (1.5 mg/Kg, i.p.). These results further support the role of OX-A signaling in the control of neuroadaptive responses, such as compulsive reward-seeking behavior or binge-like consumption of high palatable food, and suggest that aberrant OX-A trafficking to the DA neurons in the VTA of ob/ob mice influences the D2R response at NAc, a main target area of the mesolimbic pathway, via 2-AG/CB1-mediated retrograde signaling

The FHP01 DDX3X helicase inhibitor exerts potent anti-tumor activity in vivo in breast cancer pre-clinical models

Inhibition of DDX3X expression or activity reduces proliferation in cells from various tumor tissues, in particular in breast cancer, and its expression often correlates to tumor aggressiveness. This makes DDX3X a prominent candidate for the design of drugs for novel personalized therapeutic strategies. Starting from an in silico drug discovery approach, a group of molecules has been selected by molecular docking at the RNA binding site of DDX3X. Here, the most promising among them, FHP01, was evaluated in breast cancer preclinical models. Specifically, FHP01 exhibited very effective antiproliferative and killing activity against different breast cancer cell types, among which those from triple-negative breast cancer (TNBC). Interestingly, FHP01 also inhibited WNT signaling, a key tumorigenic pathway already correlated to DDX3X functions in breast cancer model cell lines. Ultimately, FHP01 also caused a significant reduction, in vivo, in the growth of MDA MB 231- derived TNBC xenograft models. Importantly, FHP01 showed good bioavailability and no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. Overall, our data suggest that the use of FHP01 and its related compounds may represent a novel therapeutic approach with high potential against breast cancer, including the triple-negative subtype usually correlated to the most unfavorable outcomes because of the lack of available targeted therapies

Artificial Intelligence in Surgery, Surgical Subspecialties, and Related Disciplines

Artificial intelligence (AI) and machine learning (ML) algorithms show promise in revolutionizing many aspects of surgical care. ML algorithms may be used to improve radiologic diagnosis of disease and predict peri-, intra-, and postoperative complications in patients based on their vital signs and other clinical characteristics. Computer vision may improve laparoscopic and minimally invasive surgical education by identifying and tracking the surgeon’s movements and providing real-time performance feedback. Eventually, AI and ML may be used to perform operative interventions that were not previously possible (nanosurgery or endoluminal surgery) with the utilization of fully autonomous surgical robots. Overall, AI will impact every surgical subspecialty, and surgeons must be prepared to facilitate the use of this technology to optimize patient care. This chapter will review the applications of AI across different surgical disciplines, the risks and limitations associated with AI and ML, and the role surgeons will play in implementing this technology into their practice

EUS-guided tissue acquisition in chronic pancreatitis: Differential diagnosis between pancreatic cancer and pseudotumoral masses using EUS-FNA or core biopsy

none14Background and Objective: EUS-FNA sensitivity for malignancy in parenchymal masses of patients with concurrent chronic pancreatitis (CP) has been reported to be unsatisfactory. The aim of the present study was to directly compare the diagnostic accuracy of EUS-FNA and EUS-fine-needle biopsy (FNB) in differentiating between inflammatory masses and malignancies in the setting of CP. Methods: We performed a retrospective analysis of prospective, multicentric databases of all patients with pancreatic masses and clinico-radiological-endosonographic features of CP who underwent EUS-FNA or FNB. Results: Among 1124 patients with CP, 210 patients (60% males, mean age: 62.7 years) with CP and pancreatic masses met the inclusion criteria and were enrolled. In the FNA group (110 patients), a correct diagnosis was obtained in all but 18 cases (diagnostic accuracy 83.6%, sensitivity 69.5%, specificity 100%, positive predictive value [PPV] 100%, and negative predictive value [NPV] 73.9%); by contrast, among 100 patients undergoing FNB, a correct diagnosis was obtained in all but seven cases (diagnostic accuracy 93%, sensitivity 86.8%, specificity 100%, PPV 100%, and NPV 87%) (P = 0.03, 0.03, 1, 1, and 0.07, respectively). At binary logistic regression, focal pancreatitis (odds of event occurrence [OR]: 4.9; P < 0.001), higher Ca19-9 (OR: 2.3;P= 0.02), and FNB (OR: 2.5; P < 0.01) were the only independent factors associated with a correct diagnosis. Conclusion: EUS-FNB is effective in the differential diagnosis between pseudotumoral masses and solid neoplasms in CP, showing higher diagnostic accuracy and sensitivity than EUS-FNA. EUS-FNB should be considered the preferred diagnostic technique for diagnosing cancer in the setting of CP.openGrassia R.; Imperatore N.; Capone P.; Cereatti F.; Forti E.; Antonini F.; Tanzi G.P.; Martinotti M.; Buffoli F.; Mutignani M.; MacArri G.; Manes G.; Vecchi M.; Nucci G.Grassia, R.; Imperatore, N.; Capone, P.; Cereatti, F.; Forti, E.; Antonini, F.; Tanzi, G. P.; Martinotti, M.; Buffoli, F.; Mutignani, M.; Macarri, G.; Manes, G.; Vecchi, M.; Nucci, G

Abdominal Adiposity Is Associated With Elevated C-Reactive Protein Independent of BMI in Healthy Nonobese People

Objective: There is debate over the most appropriate adiposity markers of obesityassociated health risks. We evaluated the relationship between fat distribution and highsensitivity C-reactive protein (hs-CRP), independent of total adiposity. Research design and methods : We studied 350 people with abdominal adiposity (waist-to-hip ratio (WHR) ≥0.9 in male and ≥0.85 in female subjects) and 199 control subjects (WHR< 0.9 in male and <0.85 in female subjects) matched for BMI and age. We measured hs-CRP and major cardiovascular risk factors. Results Participants with abdominal adiposity had BMI similar to that in control subjects (24.8 ±2.5 vs. 24.7 ±2.2 kg/m2, respectively), but significantly higher waist circumference (96.4 6.±0 vs. 83.3 ±6.7 cm; p < 0.01) and WHR (1.07 ± 0.08 vs. 0.85 ±0.05; p<0.001). Compared with the control subjects, participants with abdominal adiposity had an adverse cardiovascular risk factor profile, significantly higher hs-CRP (1.96 ±2.60 vs. 1.53 ± 1.74 mg/dl; p< 0.01), and a twofold prevalence of elevated CRP values (≥3 mg/dl). Conclusions In non obese people, moderate abdominal adiposity is associated with markers of subclinical inflammation independent of BMI

Marine-Derived Phosphoeleganin and Its Semisynthetic Derivative Decrease IL6 Levels and Improve Insulin Signaling in Human Hepatocellular Carcinoma Cells

Marine natural products constitute a great source of potential new antidiabetic drugs. The aim of this study was to evaluate the role of phosphoeleganin (PE), a polyketide purified from the Mediterranean ascidian Sidnyum elegans, and its derivatives PE/2 and PE/3 on insulin sensitivity in human hepatocellular carcinoma (HepG2) cells. In our experiments, insulin stimulates the phosphorylation of its receptor (INSR) and AKT by 1.5- and 3.5-fold, respectively, whereas in the presence of PE, PE/2, and PE/3, the insulin induced INSR phosphorylation is increased by 2.1-, 2-, and 1.5-fold and AKT phosphorylation by 7.1-, 6.0-, and 5.1-fold, respectively. Interestingly, PE and PE/2 have an additive effect on insulin-mediated reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression. Finally, PE and PE/2, but not PE/3, decrease interleukin 6 (IL6) secretion and expression before and after palmitic acid incubation, while in the presence of high glucose (HG), only PE reduces IL6. Levels of other cytokines are not significantly affected by PE and its derivates. All these data suggest that PE and its synthetic-derived compound, PE/2, significantly decrease IL6 and improve hepatic insulin signaling. As IL6 impairs insulin action, it could be hypothesized that PE and PE/2, by inhibiting IL6, may improve the hepatic insulin pathway

Medical expenditures associated with diabetes among youth with medicaid coverage

Background: Information on diabetes-related excess medical expenditures for youth is important to understand the magnitude of financial burden and to plan the health care resources needed for managing diabetes. However, diabetes-related excess medical expenditures for youth covered by Medicaid program have not been investigated recently. Objective: To estimate excess diabetes-related medical expenditures among youth aged below 20 years enrolled in Medicaid programs in the United States. Methods: We analyzed data from 2008 to 2012 MarketScan multistate Medicaid database for 6502 youths with diagnosed diabetes and 6502 propensity score matched youths without diabetes, enrolled in fee-for-service payment plans. We stratified analysis by Medicaid eligibility criteria (poverty or disability). We used 2-part regression models to estimate diabetes-related excess medical expenditures, adjusted for age, sex, race/ethnicity, year of claims, depression status, asthma status, and interaction terms. Results: For poverty-based Medicaid enrollees, estimated annual diabetes-related total medical expenditure was $9046 per person [$3681 (no diabetes) vs. $12,727 (diabetes); P<0001], of which 41.7$9944 per person ($14,149 vs.$24,093; P<0001), of which 41.5% was accounted for by prescription drugs, 31.3% by inpatient, and 27.3% by outpatient care. Conclusions: The per capita annual diabetes-related medical expenditures in youth covered by publicly financed Medicaid programs are substantial, which is larger among those with disabilities than without disabilities. Identifying cost-effective ways of managing diabetes in this vulnerable segment of the youth population is needed

Chestnut shell tannins: effects on intestinal inflammation and dysbiosis in zebrafish

The aim of the present study was to test the possible ameliorative efficacy of phytochemicals such as tannins on intestinal inflammation and dysbiosis. The effect of a chestnut shell (Castanea sativa) extract (CSE) rich in polyphenols, mainly represented by tannins, on k-carrageenan-induced intestinal inflammation in adult zebrafish (Danio rerio) was tested in a feeding trial. Intestinal inflammation was induced by 0.1% k-carrageenan added to the diet for 10 days. CSE was administered for10 days after k-carrageenan induced inflammation. The intestinal morphology and histopathology, cytokine expression, and microbiota were analyzed. The k-carrageenan treatment led to gut lumen expansion, reduction of intestinal folds, and increase of the goblet cells number, accompanied by the upregulation of pro-inflammatory factors (TNFα, COX2) and alteration in the number and ratio of taxonomic groups of bacteria. CSE counteracted the inflammatory status enhancing the growth of health helpful bacteria (Enterobacteriaceae and Pseudomonas), decreasing the pro-inflammatory factors, and activating the anti-inflammatory cytokine IL-10. In conclusion, CSE acted as a prebiotic on zebrafish gut microbiota, sustaining the use of tannins as food additives to ameliorate the intestinal inflammation. Our results may be relevant for both aquaculture and medical clinic field