Impact of Bariatric Surgery on Subtilisin/Kexin Type 9 (PCSK9) Gene Expression and Inflammation in the Adipose Tissue of Obese Diabetic Rats.

Bariatric surgery improves dyslipidaemia and reduces body weight, but it remains unclear how bariatric surgery modulates gene expression in fat cells to influence the proprotein convertase subtilisin/kexin type 9 (PCSK-9) and low-density lipoprotein receptor (LDLR) gene expression. The expression of the PCSK9/LDLR/tumor necrosis factor-alpha (TNFα) gene in adipose tissue was measured in two groups of Zucker Diabetic Sprague Dawley (ZDSD) rats after Roux-en-Y gastric bypass (RYGB) surgery or 'SHAM' operation. There was lower PCSK9 (p = 0.02) and higher LDLR gene expression (p = 0.02) in adipose tissue in rats after RYGB. Weight change did not correlate with PCSK9 gene expression (r = -0.5, p = 0.08) or TNFα gene expression (r = -0.4, p = 0.1). TNFα gene expression was positively correlated with PCSK9 gene expression (r = 0.7, p = 0.001) but not correlated with LDLR expression (r = -0.3, p = 0.3). Circulating triglyceride levels were lower in RYGB compared to the SHAM group (1.1 (0.8-1.4) vs. 1.5 (1.0-4.2), p = 0.038) mmol/L with no difference in cholesterol levels. LDLR gene expression was increased post-bariatric surgery with the potential to reduce the number of circulating LDL particles. PCSK9 gene expression and TNFα gene expression were positively correlated after RYGB in ZDSD rats, suggesting that the modulation of pro-inflammatory pathways in adipose tissue after RYGB may partly relate to PCSK9 and LDLR gene expression.

Bioguided isolation of potential antitumor agents from the aerial parts of cultivated cardoon (Cynara cardunculus var. altilis).

Hepatocellular carcinoma (HCC) is one of the leading causes of mortality worldwide; therefore, searching for an effective treatment for this illness is of great importance. In the present work, in vitro cytotoxic activity of the ethanol extract of the aerial parts of Cynara cardunculus L. against human liver carcinoma cells (Hep G2) was tested. Additionally, the antitumor activity of the extract was confirmed using chemically induced rat liver carcinogenesis with diethylnitrosamine (DEN). Moreover, bioguided fractionation and column chromatographic separation of the active compounds were carried out. The extract of C. cardunculus showed a promising cytotoxic activity according to the protocols of the National Cancer Institute. Bioguided chromatographic separation of the ethanol extract of C. cardunculus led to the isolation of seven secondary metabolites including two sesquiterpene lactones as the principal active components of the methylene chloride soluble fraction, grosheimin (IC50 = 7.49 µg/mL) and cynaropicrin (IC50 = 13.9 µg/mL). The compounds were characterized by different spectroscopic techniques such as EI-MS, IR and NMR. Additionally, in silico analysis of the two active compounds revealed their ability to bind with caspase-3 via hydrogen bonds interactions to initiate apoptosis of cancer cells. The results shed the light on the significance of C. cardunculus as a potential source of antitumor agents.

A New Dissection Ladder Approach for Perforator Vessels in Infant Meningomyelocele Soft Tissue Reconstruction.

BACKGROUND: Meningomyelocele reconstruction is a lifesaving procedure. A freestyle propeller perforator flap is an ideal option for moderate to large soft tissue meningomyelocele reconstruction. Previous studies that focused on the reliability of perforator flaps for meningomyelocele reconstruction recommended preserving a cuff of soft tissue around the perforators to avoid vasospasm. This method is a very conservative approach in comparison to the recently well-established principles of pedicled perforator flap dissection. In this study, we used a dissection ladder approach. In this method, the pedicle is freed by just islanding the pedicle, skeletonization of the perforator, or further dissection of the perforators beyond the muscles, based on intraoperatively monitoring of the flap. MATERIALS AND METHODS: Thirty-six infants with a mean age of 2.1 ± 1.1 months underwent surgery for dorsolumbar meningomyelocele at Assuit University Hospital for 3 years. During surgery, the freestyle perforator flap followed a dissection ladder for perforating vessels and intraoperative flap monitoring. Flap viability, seroma, hematoma, and cerebrospinal fluid leakage were evaluated. RESULTS: Nine cases required perforator skeletonization, 4 cases required dissection beyond the muscle, and 23 cases required islanding the flap on the perforators. The average operative time was 43.37 ± 7.87 minutes. Partial tip ischemia was detected in 2 cases. These cases exhibited partial dehiscence and healed by secondary intention. Complete flap loss did not occur in any cases. CONCLUSIONS: A conservative approach for perforator flap elevation in infants did not provide optimal results in all cases of thoracolumbar meningomyelocele reconstructions. Well-established principles of perforator dissection, including skeletonization and dissection beyond the muscle, are safe, prevent vasospasms, and improve flap viability.

Reno-protective effect of mangiferin against methotrexate-induced kidney damage in male rats: PPARγ-mediated antioxidant activity.

Methotrexate (MTX) is an immunosuppressant used for the treatment of cancer and autoimmune diseases. MTX has a major adverse effect, acute kidney injury, which limits its use. Mangiferin (MF) is a natural bioactive xanthonoid used as a traditional herbal supplement to boost the immune system due to its potent anti-inflammatory and antioxidant activity. The present study evaluates the protective effect of MF against MTX-induced kidney damage. Male Wistar rats received MTX to induce nephrotoxicity or were pretreated with MF for 10 constitutive days before MTX administration. MF dose-dependently improved renal functions of MTX-treated rats and this activity was correlated with increased renal expression of PPARγ, a well-known transcriptional regulator of the immune response. Pretreating rats with PPARγ inhibitor, BADGE, reduced the reno-protective activity of MF. Furthermore, MF treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NFκB, interleukin-1ß, TNF-α, and COX-2), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (nitric oxide and iNOS) markers in the kidney. Importantly, BADGE treatment significantly reduced the anti-inflammatory and antioxidant activity of MF. Therefore, our data suggest that the reno-protective effect of MF against MTX-induced nephrotoxicity is due to inhibition of inflammation and oxidative stress in a PPAR-γ-dependent manner.

Dietary restriction and medical therapy drives PPARα-regulated improvements in early diabetic kidney disease in male rats.

The attenuation of diabetic kidney disease (DKD) by metabolic surgery is enhanced by pharmacotherapy promoting renal fatty acid oxidation (FAO). Using the Zucker Diabetic Fatty and Zucker Diabetic Sprague Dawley rat models of DKD, we conducted studies to determine if these effects could be replicated with a non-invasive bariatric mimetic intervention. Metabolic control and renal injury were compared in rats undergoing a dietary restriction plus medical therapy protocol (DMT; fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin) and ad libitum-fed controls. The global renal cortical transcriptome and urinary 1H-NMR metabolomic profiles were also compared. Kidney cell type-specific and medication-specific transcriptomic responses were explored through in silico deconvolution. Transcriptomic and metabolomic correlates of improvements in kidney structure were defined using a molecular morphometric approach. The DMT protocol led to ∼20% weight loss, normalized metabolic parameters and was associated with reductions in indices of glomerular and proximal tubular injury. The transcriptomic response to DMT was dominated by changes in fenofibrate- and peroxisome proliferator-activated receptor-α (PPARα)-governed peroxisomal and mitochondrial FAO transcripts localizing to the proximal tubule. DMT induced urinary excretion of PPARα-regulated metabolites involved in nicotinamide metabolism and reversed DKD-associated changes in the urinary excretion of tricarboxylic acid (TCA) cycle intermediates. FAO transcripts and urinary nicotinamide and TCA cycle metabolites were moderately to strongly correlated with improvements in glomerular and proximal tubular injury. Weight loss plus pharmacological PPARα agonism is a promising means of attenuating DKD.

Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats.

Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.

Ultrafast Tm-doped fiber laser system delivering 1.65-mJ, sub-100-fs pulses at a 100-kHz repetition rate.

High-energy, ultrafast, short-wavelength infrared laser sources with high average power are important tools for industrial and scientific applications. Through the coherent combination of four ultrafast thulium-doped rod-type fiber amplifiers, we demonstrate a Tm-doped chirped pulse amplification system with a compressed pulse energy of 1.65 mJ and 167 W of average output power at a repetition rate of 101 kHz. The system delivers 85 fs pulses with a peak power of 15 GW. Additionally, the system presents a high long- and short-term stability. To the best of our knowledge, this is the highest average output power short wavelength IR, mJ-class source to date. This result shows the potential of coherent beam combining techniques in the short wavelength infrared spectral region for the power scalability of these systems.

Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease.

Background: Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. Methods: The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (1H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. Results: RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Conclusions: Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.

Outcomes of a Swallowable Intragastric Balloon (Elipse™) on 96 Overweight and Obese Patients.

BACKGROUND: The traditional gastric balloons have been used for several years to reduce weight in overweight and obese patients, but the need for sedation and upper endoscopy leading to several limitations. The current series is the first study that evaluates the safety and effectiveness of the swallowable gastric (Elipse™) balloon in our population on the national level. METHODS: Ninety-six patients (mean BMI was 33.6 ± 4.3 kg/m2) participated in this study. All patients swallowed one Elipse™ balloon intended to remain in the stomach for 4 months, self-empty, and then pass. Each balloon was filled with 550 mL of filling fluid. Anti-emetics and anti-spasmodic drugs were prescribed for 2-3 days after insertion; proton pump inhibitor was prescribed twice daily 1 week before the procedure and continued until the end of residence time (16-20 weeks). RESULTS: In the current series, at end of the procedure (after 4 months), the overall mean weight loss (WL) was 11.2 ± 5.1 kg, mean waist circumference reduction was 10.9 ± 2.1 cm, and a mean BMI reduction was 4.9 ± 2.0 kg/m2. The percentage of total body weight loss (TBWL%) was 12.1 ± 5.2%. The Elipse™ therapy reported improvements in the metabolic parameters investigated. CONCLUSION: This swallowable gastric balloon (Elipse™) can be safely and successfully swallowed, filled, imaged, and passed with accepted weight loss and clinical improvement in factors related to the metabolic syndrome.

Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat.

The present study designed to investigate the protective effect of curcumin nanoparticles (CUR-NPs) on the cardiotoxicity induced by doxorubicin. Rats were divided into four groups; control, rats treated daily with CUR-NPs (50 mg/kg) for 14 days, rats treated with an acute dose of doxorubicin (20 mg/kg) and rats treated daily with CUR-NPs for 14 days injected with doxorubicin on the 10th day. After electrocardiogram (ECG) recording from rats at different groups, rat decapitation was carried out and the heart of each rat was excised out to measure the oxidative stress parameters; lipid peroxidation (MDA), nitric oxide (NO) and reduced glutathione (GSH) and the activities of Na,K,ATPase and acetylcholinesterase (AchE). In addition, the levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were determined in the cardiac tissues. Lactate dehydrogenase (LDH) activity was measured in the serum. The ECG recordings indicated that daily pretreatment with CUR- NPs has prevented the tachycardia (i.e. increase in heart rate) and ameliorated the changes in ST wave and QRS complex induced by doxorubicin. In addition, CUR-NPs prevented doxorubicin induced significant increase in MDA, NO, DA, AchE and LDH and doxorubicin induced significant decrease in GSH, NE, 5-HT and Na,K,ATPase. According to the present findings, it could be concluded that CUR-NPs have a protective effect against cardiotoxicity induced by doxorubicin. This may shed more light on the importance of CUR-NPs pretreatment before the application of doxorubicin therapy.

A Randomized Comparison Between Staple-Line Oversewing Versus No Reinforcement During Laparoscopic Vertical Sleeve Gastrectomy.

BACKGROUND: Varieties of intraoperative methods such as oversewing of staple lines or other reinforcement products are used for preventing the laparoscopic vertical sleeve gastrectomy (LSG) complications. The aim of this study is to evaluate the complication rates of the gastric stapling alone versus stapling with oversewing invagination of the staple line in the LSG. METHODS: This is a single-center randomized study, Patients were randomized to two groups, 200 patients underwent LSG without reinforcement of the staple line and 200 patients underwent LSG with oversewing of the staple line. All patients were followed up for 1 year. The data collected prospectively for statistical analysis included demographics, BMI, preoperative comorbidities, operative time, complications, and hospital stay. RESULTS: The overall mean operative age was 33.7 ± 9.4 years and mean BMI was 42.4 ± 4.3 kg/m2. Patient baseline characteristics (age, gender, weight, and BMI) and comorbidities were generally a nonsignificant different between the treatment arms. Surgical time was shorter in patients of the nonreinforced group (44.3 ± vs 51.3 ± 4.3 min; p < 0.01) with lower %EWL (73 ± 13.8 vs 80.7 ± 13.6%, p < 0.01). One patient in the nonreinforced group was complicated by gastric leak. The staple-line bleeding rate was significantly lower in patients underwent oversewing of the staple line during LSG (p < 0.05). CONCLUSION: Oversewing of the staple line during LSG is a nonexpansive and easy method to decrease the incidence and severity of the postoperative bleeding. However, it is time-consuming and should be performed by experienced surgeons to avoid the complications which may occur secondary to the seroserotomy suturing.

Morbidity and mortality associated with obesity.

Obesity and its repercussions constitute an important source of morbidity, impaired quality of life and its complications can have a major bearing on life expectancy. The present article summarizes the most important co-morbidities of obesity and their prevalence. Furthermore, it describes classification and grading systems that can be used to assess the individual and combined impact of co-morbid conditions on mortality risk. The literature was screened for assessment tools that can be deployed in the quantification of morbidity and mortality risk in individual patients. Thirteen specific domains have been identified that account for morbidity and mortality in obesity. Cardiovascular disease (CVD) and cancer account for the greatest mortality risk associated with obesity. The King's Criteria and Edmonton Obesity Staging System (EOSS) were identified as useful tools for the detection and monitoring of individual patient mortality risk in obesity care. The stark facts on the complications of obesity should be capitalized on to improve patient management and knowledge and referred to in the wider dissemination of public health messages aimed at improving primary prevention.

Outcomes of One Anastomosis Gastric Bypass in 472 Diabetic Patients.

BACKGROUND: The positive impact of Roux-en-Y gastric bypass (RYGB) on metabolic syndrome and glycemic control has been proven in obese patients. One anastomosis gastric bypass (OAGB) is a simple, effective and easy to learn procedure. OAGB provides encouraging results for the treatment of diabetes obese patients, but does it have the ability to be an alternative procedure to RYGB in the treatment of these patients? The aim of this study is to evaluate the outcomes of OAGB on diabetic obese patients at the bariatric centre of our university hospital. By extension, we evaluated the possibility of BMI and the preoperative antidiabetic medication usage to be predictive factors for postoperative diabetes resolution. METHODS: This is a retrospective single-centre study of 472 diabetic patients who underwent OAGB from November 2009 to December 2015. All patients were followed-up for at least 1 year, and up to 3 years, where available. Weight, HbA1c, and anti-diabetic medications were recorded at baseline, 3, 6, 12, 24 and 36 months. RESULTS: A total of 472 patients have been followed-up for 1 year and 361 for 3 years. The mean BMI decreased from 46.8 ± 7.2 to 29.5 ± 2.8 kg/m2 and HbA1c from 9.6 ± 1.3 to 5.7 ± 1.5% at the 12-month follow-up. At the 3-year follow-up, the mean BMI was 32.1 ± 3.3 and HbA1c mean was 5.8 ± 0.9%. Diabetes remission was achieved by 84.1% of patients. CONCLUSIONS: OAGB can be an excellent alternative to RYGB for the treatment of diabetes and obesity. Pre-operative medications may be used to predict postoperative diabetes remission, but not BMI.

Outcomes of Omega Loop Gastric Bypass, 6-Years Experience of 1520 Cases.

BACKGROUND: Omega loop gastric bypass (OLGB) has been viewed with skepticism after the failure of the "old Mason loop." During the past 15 years, a growing number of authors worldwide approved that OLGB is a safe and effective procedure, which appears clearly from the operative outcome and long-term follow-up of consecutive cohort studies of patients who underwent OLGB. The aim of this study is to evaluate the outcomes of OLGB at the bariatric center of our university hospital between 2009 and 2015. METHODS: The data of 1520 patients who underwent OLGB from November 2009 to December 2015 at our center were reviewed. Mean age was 37.15 years, mean preoperative BMI was 46.8 ± 6.6 kg/m2, mean preoperative weight was 127.4 ± 25.3 kg, and 62.7% were women. Diabetes mellitus (DM) affected 683 (44.9%) of the 1520 patients, whereas 773 of the 1520 patients (50.9%) presented with hypertension. The mean operative time was 35 min. RESULTS: The 1-year postoperative BMI mean decreased to 29.6 ± 3.1 kg/m2, and at the 3-year follow-up, it was 27.5 ± 3.4 kg/m2. The mean of weight decreased to 81.3 ± 16.7 kg and to 78.9 ± 16.9 kg at the 1-year and the 3-year follow-up, respectively. Mortality rate was 0.1%. Overall complications were 9.3%; 0.8% required reoperations. Early complications were encountered in 50 patients (3.3%), and the late complications rate was (6.1%). CONCLUSIONS: In this study, greater excess weight loss was observed with OLGB which appeared to be a short, simple, low-risk, effective, and durable bariatric procedure.