Melatonin promotes sorafenib‐induced apoptosis through synergistic activation of JNK/c‐jun pathway in human hepatocellular carcinoma

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro‐apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose‐dependent growth inhibition of HuH‐7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co‐treatment of HuH‐7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib‐induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase‐3 and the JNK/c‐jun pathway. Inhibition of JNK/c‐jun pathway with its inhibitor SP600125 reversed the phosphorylation of c‐jun and the activation of caspase‐3 induced by co‐treatment of HuH‐7 cells with melatonin and sorafenib in a dose‐dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.     

Antidepressant use and risk of central nervous system metastasis

Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, were found to increase central nervous system (CNS) metastasis in mice. Our study investigated in humans whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. We identified 189 cases of CNS metastasis amongst breast cancer, melanoma, and non-Hodgkin lymphoma subjects who were diagnosed with CNS metastasis or infiltration between January 1, 2005 and September 30, 2013 and 756 controls (patients without CNS metastasis or infiltration). Using logistic regression, we estimated the relative odds of CNS metastasis associated with antidepressant use adjusting for relevant covariates. The prevalence of antidepressants was 28.6?% in cases and 27.5?% in controls, whereas SSRIs were used in 16.9?% of cases and 17.3?% of controls. Among all patients, antidepressants were not associated with CNS metastasis or infiltration. No consistent patterns of association were observed in the analyses of other cancer subsets or exposure measures, with the possible exception of an increased risk of CNS metastasis associated with ‘any SSRI use’ among breast cancer patients (OR?=?1.73, 95?% CI?=?0.75, 4.04). We did not observe clear patterns of association, which may be due in part to the small sample size in many of our analyses.     

Two cases of polymorphic ventricular tachycardia induced by the administration of verapamil against paroxysmal supraventricular tachycardia

Verapamil is widely used for the termination of paroxysmal supraventricular tachycardia (PSVT) with little proarrhythmic effect. We describe two cases of PSVT that changed to non-sustained polymorphic ventricular tachycardia after administration of verapamil. Electrophysiological study revealed atrioventricular nodal reentrant tachycardia in the first case, and atrioventricular reentrant tachycardia due to a concealed left lateral accessory pathway in the second case. Catecholamine-induced automaticity was one of the possible mechanisms of VT in the first case, but the mechanism is unknown in the second case.     

"Occult" renal insufficiency due to evaluating renal function using only serum creatinine

Timely referral to nephrologists depends on identification of renal failure. Most primary care physicians and specialists rely on serum creatinine as the standard test for determination of renal function. Creatinine clearance requires 24 hours urine collection with many pitfalls and wrong results. We compare serum creatinine and the Cockcroft-Gault (C-G) equation as measure of glomerular filtration rate (GFR). The study included 1,053 outpatients with serum creatinine lower than 2.5 mg/dl referred to our nephrological laboratory for serum creatinine and GFR determination using the C-G formula. Patients were grouped into two groups: normal renal function (serum creatinine < 1.3 mg/dl) and "incipient" abnormal renal function (serum creatinine 1.3-2.5 mg/dl). In the group of females with normal creatinine 22% (60-70 y), 35% (70-80 y) and 57% (> 80 y) had GFR values below 50 ml/min. In the group of males 11.3% (70-80 y) and 33.3% (> 80 y) also had GFR reduction in spite of normal serum creatinine. A severe renal insufficiency with creatinine clearance lower than 30 ml/min was observed in the group with "incipient" renal failure based on serum creatinine: 22.7%, 40% and 82.9% for females and 6%, 22.7% and 57% for male (60-70 y; 70-80 y; and > 80 y respectively). In order to improve management and prevention of renal failure appropriate measurements of renal function other than serum creatinine should be emphasize.     

A Low Pulse Food Intake May Contribute to the Poor Nutritional Status and Low Dietary Intakes of Adolescent Girls in Rural Southern Ethiopia

Poor nutrition in adolescent girls poses critical health risks on future pregnancy and birth outcomes especially in developing countries. Our purpose was to assess nutritional status and dietary intake of rural adolescent girls and determine pulse and food intake patterns associated with poor nutritional status. A cross-sectional community-based study was conducted in a traditional pulse growing region of southern Ethiopia on 188 girls between 15 to 19 years of age, with 70% being from food insecure families. Prevalence of stunting (30.9%) and underweight (13.3%) were associated with low food and nutrient intake. Diets were cereal-based, with both animal source foods and pulses rarely consumed. Improving dietary intakes of female adolescents with nutrient dense foods would ensure better health for themselves and for the next generation.