The antiatherogenic effect of allicin: possible mode of action.

OBJECTIVE: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. METHODS AND RESULTS: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. CONCLUSIONS: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.     

Hypothyroidism and levothyroxine therapy following bariatric surgery: a systematic review,meta-analysis,network meta-analysis,and meta-regression

BackgroundMany health benefits of bariatric surgery are known and well-studied, but there is scarce data on the benefits of bariatric surgery on the thyroid function.ObjectiveWe aimed to make a meta-analysis regarding the impact of bariatric surgery on thyroid-stimulating hormone (TSH) levels, levothyroxine dose, and the status of subclinical hypothyroidism.SettingSystematic review and meta-analysis.MethodsPubMed, EMBASE, and Cochrane Library were searched up to December 2020 for relevant clinical studies. Random-effects model was used to pool results. Network meta-analysis was performed, incorporating direct and indirect comparisons among different types of bariatric surgery. Meta-regression analysis was performed to evaluate the impact of moderator variables on TSH levels and required levothyroxine dose after surgery. We followed the PRISMA guidelines for data selection and extraction. PROSPERO registry number: CRD42018105739.ResultsA total of 28 studies involving 1284 patients were included. There was a statistically significant decrease in TSH levels after bariatric surgery (mean difference = ?1.66 mU/L, 95%CI [?2.29, ?1.03], P < .0001). In meta-regression analysis, we found that the following moderator variables: length of follow-up, mean age, baseline TSH, and preoperative thyroid function, could explain 1%, 43%, 68%, and 88% of the between-study variance, respectively. Furthermore, subclinical hypothyroidism was completely resolved in 87% of patients following bariatric surgery. In addition, there was a statistically significant decrease of levothyroxine dose in frank hypothyroid patients following bariatric surgery (mean difference = ?13.20 mcg/d, 95%CI [?19.69, ?6.71]). In network meta-analysis, we found that discontinuing or decreasing levothyroxine dose was significant following Roux-en-Y gastric bypass, 1 anastomosis gastric bypass, and sleeve gastrectomy, (OR = 31.02, 95%CI [10.34, 93.08]), (OR = 41.73, 95%CI [2.04, 854.69]), (OR = 104.03, 95%CI [35.79, 302.38]), respectively.ConclusionsBased on our meta-analysis, bariatric surgery is associated with the resolution of subclinical hypothyroidism, a decrease in TSH levels, and a decrease in levothyroxine dose.     

Amelioration of Child Depression Through Behavioral Parent Training: A Preliminary Study

Child depression is an impairing condition for which tested treatments have shown relatively modest mean effects. One possible explanation is that the treatments have generally adopted an individual child focus, without addressing the dysfunctional parent–child interactions that often accompany child depression. The present study provides preliminary evidence bearing on this hypothesis, using data from a treatment outcome study in which clinically referred children with a depression diagnosis could receive individual cognitive behavioral therapy (CBT) focusing on the depression or behavioral parent training (BPT) focusing on comorbid conduct problems. Among children in the study who met criteria for Diagnostic and Statistical Manual of Mental Disorders (4th ed.) depressive disorders, we identified two groups, matched on gender and age: 15 who received only CBT focused on child depression and 15 who received only BPT focused on child conduct problems. Children were 7 to 13, 20 of whom were male, and race included Caucasian (17), Latino (5), African American (2), and multirace (6). Measures assessed depressive diagnoses and symptoms, as well as parenting stress. Analyses focused on whether BPT alone might lead to reduced depression, and if so how that reduction would compare to the depression reduction achieved through CBT that focused on depression. Both groups showed significant reductions from pre- to post-treatment in depressive diagnoses and depression symptoms, and there were no BPT versus CBT group differences at post-treatment. BPT that focuses on child conduct problems, with no emphasis on depression treatment, may produce significant depression reduction in comorbid children who meet criteria for depressive disorders.     

Providing more through less: current methods of retraction in SIMIS and NOTES cholecystectomy

Background

As the field of minimally invasive surgery continues to develop, surgeons are confronted with the challenge of performing conventional laparoscopic surgeries through fewer incisions while maintaining the same degree of safety and surgical efficiency. Most of these methods involve elimination of the ports previously designated for retraction. As a result, minimally invasive surgeons have been forced to develop minimally invasive and ingenious methods for providing adequate retraction for these procedures. Herein we present our experience using endoloops and internal retractors to provide retraction during Single Incision Minimally Invasive Surgery (SIMIS) and Natural Orifice Transluminal Endoscopic Surgery (NOTES) cholecystectomy. We also present a review of the alternative retraction methods currently being employed for these surgeries.

Methods

SIMIS was performed on 20 patients and NOTES was performed on 5 patients at our institution. Endoloops or internal retractors were used to provide retraction for all SIMIS procedures. Internal retractors provided retraction for all NOTES procedures.

Results

Successful cholecystectomy was accomplished in all cases. One SIMIS surgery required conversion to standard laparoscopy due to complex anatomy. There were no intraoperative complications. Although adequate retraction was accomplished in all cases, the internal retractors were found to provide superior and more versatile retraction compared to that of endoloops.

Conclusion

Adequate retraction greatly simplifies SIMIS and NOTES surgery. Endograb internal retractors were easy to use and were found to provide optimal retraction and exposure during these procedures without complications.     

Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.     

Gender effect on vascular responsiveness after bariatric surgery

Obesity, particularly abdominal obesity, is associated with increased risks of arterial hypertension, diabetes mellitus, hyperlipidemia, sleep apnea, coronary artery disease, stroke and mortality. Weight loss surgery is the most effective treatment for morbid obesity, mainly because medical and dietary treatments have been proven insufficient in the long run. Our primary end point was to study the gender effect on vascular responsiveness (endothelial function and the ankle brachial index [ABI]) 3 months post bariatric surgery. Our secondary end points were to study the effect of gender on antropometric parameters (BMI, waist circumference) and chronic diseases (diabetes mellitus type II, arterial hypertension) 3 months following bariatric surgery, and to find independent variables that may affect and predict the post-operative clinical outcome. Methods: In this prospective study, patients were evaluated one day before surgery and 3 months afterwards. Ankle brachial index was measured while the patient was supine after 15 minutes rest and measurement of the systolic blood pressure in all four extremities was done. The brachial artery method was used to measure endothelial function expressed as flow mediated diameter percent change (FMD %). FMD% more than 10% is considered a normal response. Results: Compared with diabetic females, diabetic males had a higher postoperative BMI (men with diabetes mellitus did not lose weight as much as diabetic women) (β=-0.299; P=0.04), while women with diabetes mellitus had a more significant reduction in BMI postoperatively (β=+0.287; P=0.04). Following bariatric surgery, 12 of the 21 patients with diabetes mellitus type II did not need any medications for diabetes (kept HbA1c% less than 6.5%). All other diabetic patients improved their diabetes mellitus status. Women significantly improved their ABI (average increase of 0.07, p=0.04) and their endothelial function (FMD% change was improved from -3.5±9.0% to 14.8±8.1%, an improvement of 18.3%, p<0.001). Systolic blood pressure was decreased significantly (by 6.6 mmHg, p=0.04). Men improved their endothelial function (FMD% change was improved from -1.3±10.1% to 11.7±6.2%, p<0.001), but no significant change was observed in systolic blood pressure (p=0.29) nor in ABI (P=0.8). A linear regression analysis found that a higher baseline FMD% significantly predicted a higher postoperative FMD% (β=0.294, P=0.03). In obese males, the higher the baseline BMI the worse the post operative endothelial function (β=-0.921, Pd<0.001) and the same adverse effect was documented for hypertensive men (β=-0.380, P=0.05). For females, the higher the baseline FMD% the higher the postoperative FMD% (β=+0.397; P=0.01) [a favorable outcome]. Discussion: Our study has demonstrated a possible mechanistic insight into gender effects observed in epidemiological studies through improvement in vascular response in females undergoing this operation including a better reduction in systolic blood pressure and a better weight reduction in diabetic women with improvement in ABI; unlike males, who did not improve their ABI and did not decrease systolic blood pressure, and the finding that obese diabetic males and obese hypertensive males did the worst.     

Combining individual cognitive behaviour therapy and caregiver-child sessions for childhood depression: an open trial

The objective was to obtain preliminary evidence on the feasibility and efficacy of combining individual cognitive behavior therapy (CBT) with complimentary caregiver-child sessions for depressed youths. Fifteen children participated in an open clinical trial. Treatment included 16 CBT sessions combined with seven caregiver/caregiver-child sessions over 12 weeks. Data were collected at pre-, mid-, and post-treatment and at one- and six-month follow-ups. Significant decreases in depressive symptoms were apparent, with the majority showing clinically meaningful improvement. Benchmarked against the literature, the combination equaled or outperformed CBT in other studies and was superior to control conditions. Mother and teacher reports of child functioning significantly improved, providing social validation of the effects. Mothers reported improved caregiver-child relationships and less parenting stress. Children did not report acute improvements in relations with their caregivers. However, when a father participated, improved father-child relations were reported in the follow-up period. Younger age and lower pretreatment severity predicted greater symptom change. The positive treatment effects provide support for the combined intervention and suggest a further research focus on the effects of caregiver involvement in the treatment of depressed youths.     

Novel prodrugs of tegafur that display improved anticancer activity and antiangiogenic properties

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.