Chronic consumption of a high‐fat diet rich in corn oil activates intrinsic cell death pathway and induces several ultrastructural changes in the atria of healthy and type 1 diabetic rat

This study investigates the effect of chronic consumption of a high‐fat diet rich in corn oil (CO‐HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)‐induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO‐HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO‐HFD. CO‐HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase‐3, and ANF and decreased levels of Bcl‐2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO‐HFD. In conclusion, chronic consumption of CO‐HFD by T1DM‐induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria‐mediated cell death.     

Transport kinetics of cisplatin in the perfused human placental lobule in vitro

Objective.?Platinum-containing drugs are used extensively in the treatment of various malignancies in humans. Data are scarce on the maternal–fetal transport characteristics in humans of one such widely used drug, cisplatin, and this prompted us to study its transport characteristics in the human placenta in vitro.

Methods.?Placentae from normal pregnancies were collected after delivery. Cisplatin, along with antipyrine as an internal reference marker, was injected as a single bolus (100 μL) into the maternal arterial circulation of isolated perfused placental lobules and perfusate samples collected from both maternal and fetal circulations over a period of 5 minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution, was used as the perfusate. The concentration of cisplatin in various samples was determined by atomic absorption spectrophotometry, while antipyrine concentration was quantified by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using appropriate parameters.

Results.?The differential transport rate of cisplatin for 10, 25, 50, 75, and 90% efflux fractions in fetal venous effluent averaged 0.49 ± 0.02, 1.23 ± 0.03, 2.41 ± 0.04, 3.67 ± 0.03, and 4.48 ± 0.07 minutes in 12 perfusions, while corresponding rates for antipyrine, for above mentioned efflux fractions averaged 0.51 ± 0.01, 1.26 ± 0.05, 2.52 ± 0.01, 3.78 ± 0.01, and 4.52 ± 0.01 minutes, respectively. Cisplatin transport rates averaged 0.97, 0.97, 0.96, 0.97, and 0.99 times the antipyrine reference value. Analysis of variance (ANOVA) did not show any significant difference (p > 0.05) between the control and study group data. The transport fraction (TF) of cisplatin, expressed as a fraction of the drug appearing in the fetal vein during a study period of 5 minutes, averaged 9.00 ± 0.52% of bolus dose, while antipyrine TF averaged 68.6 ± 2.01% of injected bolus dose, representing 13.10% of reference marker value. The Student's t-test showed cisplatin and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, absorption rate, and elimination rate of study and reference substances also varied significantly (p < 0.05).

Conclusions.?We report for the first time that cisplatin transport is negligible in the human placenta at term. It is reasonable to assume that the risk for the neonate from cisplatin use in pregnancy is minimal when it is used in emergency clinical situations.     

Triggering of erythrocyte cell membrane scrambling by ursolic acid

Ursolic acid (1), a triterpenoid with pleotropic effects including inhibition of tumor growth, is well known to trigger apoptosis of nucleated cells. The effect is at least partially due to altered gene expression and mitochondrial dysfunction. Erythrocytes lack nuclei and mitochondria but, similar to nucleated cells, may undergo suicidal cell death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), ceramide formation and/or ATP depletion. The present study has investigated whether or not 1 induces eryptosis. [Ca2+]i was estimated from Fluo-3 fluorescence, cell volume from forward scatter, phospholipid scrambling from annexin V binding, hemolysis from hemoglobin release, and cytosolic ATP concentration ([ATP]i) utilizing a luciferase assay and ceramide-utilizing fluorescent antibodies in FACS analysis. As a result, exposure of erythrocytes for 48 h to 1 (≥5 μM) did not significantly modify [ATP]i, but significantly increased [Ca2+]i, stimulated ceramide formation, decreased forward scatter, triggered annexin V binding, and elicited hemolysis. At 5 μM, 1 stimulated phospholipid scrambling in 10% and hemolysis in 2% of treated erythrocytes. Annexin V binding was blunted in the nominal absence of Ca2+. In conclusion, the food component ursolic acid stimulates suicidal death of erythrocytes, i.e., cells devoid of nuclei and mitochondria.     

Association of body mass index, sagittal abdominal diameter and waist-hip ratio with cardiometabolic risk factors and adipocytokines in arab children and adolescents

ABSTRACT: OBJECTIVE: Sagittal abdominal diameter (SAD) is a novel anthropometric measure hypothesized to be a surrogate measure of visceral abdominal obesity in adults. This study aims to determine whether SAD is superior to other anthropometric measures such as body mass index (BMI) and waist to hip ratio (WHR) in terms of association to cardiometabolic risk and circulating adipocytokine concentrations in a cohort of Saudi children and adolescents. METHODS: A total of 948 (495 boys and 453 girls) apparently healthy children with varying BMI, aged 10-17 years, were included in this cross sectional study. Fasting glucose, lipid profile, leptin, adiponectin, resistin, insulin, TNF-alpha and aPAI-1 were measured in serum and HOMA-IR was calculated. MetS components were defined according to the International Diabetes Federation (IDF) criteria. RESULTS: BMI was superior to SAD as well as WHR, and had the highest number of significant associations to MetS components and adipocytokines even after adjustment for age and gender, including blood pressure, lipids, glucose and leptin. CONCLUSION: In conclusion, while SAD is significantly associated with components of MetS among children and adolescents, it is not superior to BMI. The use of SAD therefore may not be practical for use in the pediatric clinical setting. Follow-up studies are needed to determine whether SAD has clinical significance in terms of harder outcomes such as predicting diabetes mellitus or cardiovascular diseases.     

Macular infarction in thrombotic thrombocytopenic purpura

Purpose: To report a patient with transient acute generalized thrombotic thrombocytopenic purpura (TTP) who suffered severe permanent visual loss due to retinal vascular occlusions in both eyes. Methods: Case report. Results: Severe permanent visual loss occurred in a patient with acute transient TTP. Extensive soft exudates were seen at the fundus of both eyes. Fluorescein angiography demonstrated multiple retinal vascular occlusions associated with capillary nonperfusion. Conclusions: Severe and permanent visual loss due to retinal vascular occlusions demonstrated by fluorescein angiography occurred in a patient with transient thrombotic thrombocytopenic purpura.     

Portrayal of organ donation and transplantation on American primetime television

Recently, both living and deceased organ donation rates have hit a plateau, despite increases in need for viable organs. One approach to improve donation rate is public education and policy; thus, it is necessary to understand the information the public is receiving regarding organ donation. We hypothesized that primetime medical dramas portray organ donation and transplantation in a negative manner. We compiled data on all primetime medical drama episodes with transplant themes from November 2008 through June 2010 and assessed depictions of organ donors and transplant candidates. Positive and negative thematic elements surrounding the process and individuals involved were also identified. One hundred and fifty-five million and 145 million households watched episodes containing any negative message and any positive message, respectively. Episodes containing only negative messages had over twice the household viewership per episode compared to episodes containing only positive messages (8.4 million vs. 4.1 million, p = 0.01). Widespread exposure to these representations may reinforce public misconceptions of transplantation. The transplant community should consider the popularity of medical dramas as an opportunity to impact the perception of organ donation and transplantation for millions of Americans.     

Plasma metalloproteinase-12 and tissue inhibitor of metalloproteinase-1 levels and presence, severity, and outcome of coronary artery disease

Several matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the development and outcome of coronary artery disease (CAD). We investigated whether MMP-12 and TIMP-1 levels were associated with risk, severity, and outcome of CAD. Plasma MMP-12 and TIMP-1 levels are measured in 50 and 44 patients with CAD, respectively, by enzyme-linked immunosorbent assay. Of all patients, 16 were taking statins. Patients who were not on statins were classified into 3 groups according to number of >50% stenotic vessels. Compared with 29 volunteers without CAD, patients without statins (n = 34) had higher MMP-12 concentrations (1.71 vs 1.08 ng/ml, p = 0.021). MMP-12 levels were significantly lower in patients with than in those without statin treatment (0.99 vs 1.71 ng/ml, p = 0.008). There was no association between MMP-12 levels and number of >50% stenotic vessels. MMP-12 concentrations were not associated with outcome of CAD. However, plasma TIMP-1 levels were associated with restenosis independently of number of stenotic vessels and age (p = 0.035) but not with risk or severity of CAD. In conclusion, plasma MMP-12 concentration was associated with the presence of CAD. Statin therapy decreases plasma MMP-12 levels in patients with CAD. Increased TIMP-1 levels may prevent restenosis after angioplasty.     

Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma

The current study focuses on the development and evaluation of nano lipidic carriers (NLCs) for codelivery of sorafenib (SRF) and ganoderic acid (GA) therapy in order to treat hepatocellular carcinoma (HCC). The dual drug-loaded NLCs were prepared by hot microemulsion technique, where SRF and GA as the drugs, Precirol ATO5, Capmul PG8 as the lipids, while Solutol HS15 and ethanol was used as surfactant and cosolvents. The optimized drug-loaded NLCs were extensively characterized through in vitro and in vivo studies. The optimized formulation had particle size 29.28 nm, entrapment efficiency 93.1%, and loading capacity 14.21%. In vitro drug release studies revealed>64% of the drug was released in the first 6 h. The enzymatic stability analysis revealed stable nature of NLCs in various gastric pH, while accelerated stability analysis at 25^◦C/60% RH indicated the insignificant effect of studied condition on particle size, entrapment efficiency, and loading capacity of NLCs. The cytotoxicity performed on HepG2 cells indicated higher cytotoxicity of SRF and GA-loaded NLCs as compared to the free drugs (p < 0.05). Furthermore, the optimized formulation suppressed the development of hepatic nodules in the Wistar rats and significantly reduced the levels of hepatic enzymes and nonhepatic elements against DEN intoxication. The SRF and GA-loaded NLCs also showed a significant effect in suppressing the tumor growth and inflammatory cytokines in the experimental study. Further, histopathology study of rats treated SRF and GA-loaded NLCs and DEN showed absence of necrosis, apoptosis, and disorganized hepatic parenchyma, etc. over other treated groups of rats. Overall, the dual drug-loaded NLCs outperformed over the plain drugs in terms of chemoprotection, implying superior therapeutic action and most significantly eliminating the hepatic toxicity induced by DEN in Wistar rat model.