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

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

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

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

Usefulness and limitations of comprehensive characterization of mRNA splicing profiles in the definition of the clinical relevance of BRCA1/2 variants of uncertain significance

Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses

Clinical-cytological-grading and phenotyping in patients with chronic rhinosinusitis with nasal polyps: The relevance in clinical practice

Chronic rhinosinusitis (CRS) includes two main phenotypes: without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP). CRSwNP may be associated with comorbidity, mainly concerning asthma, aspirin intolerance, and allergy. CRSwNP patients may also be evaluated by clinical-cytological grading (CCG). The current study investigated the prevalence and characteristics of the different CCG and phenotypes in CRSwNP outpatients examined in clinical practice. This retrospective cross-sectional study enrolled 791 consecutive CRSwNP outpatients (424 males, mean age 48.8 years). In the total population, asthma was a common comorbidity (30.8%) as well as aspirin intolerance (24.8%), and allergy (50.8%). As concerns CCG-grading, 210 (26.5%) outpatients had low-grade, 366 (46.3%) medium, and 215 (27.2%) high. As regards cytological phenotypes, 87 (11%) had neutrophilic type, 371 (46.3%) eosinophilic, 112 (14.2%) mast cell, and 221 (27.9%) mixed. High-grade CCG was significantly associated with more frequent asthma, aspirin intolerance, allergy, recurrent surgery, and mixed cytological phenotype. Low-grade CCG was characterized by fewer comorbidities and operations, and neutrophilic phenotype. Therefore, the present study confirmed that CCG is a useful tool in the management of outpatients with CRSwNP. CRSwNP is frequently associated with asthma, aspirin intolerance, and allergy comorbidity. High-grade CCG is frequently characterized by a mixed cytological phenotype, thus, by more severe progress. These real-world outcomes underline that CRSwNP deserves adequate attention for careful management and optimal identification of the best-tailored therapy; CCG and cytological phenotyping could be fruitful tools in clinical practice. Asthma and aspirin intolerance should be adequately investigated in all CRS patients

Aldose Reductase Genotypes and Cardiorenal Complications: An 8-year prospective analysis of 1,074 type 2 diabetic patients

OBJECTIVE—We report the independent risk association of type 2 diabetic nephropathy with the z−2 allele of the 5′-(CA)n microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design

Heritability of Proliferative Diabetic Retinopathy

OBJECTIVE—Diabetic nephropathy clusters in families, suggesting that genetic factors play a role in its pathogenesis. We investigated whether similar clustering exists for proliferative retinopathy in families with two or more siblings with type 1 diabetes