Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma

Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue‐isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13‐hydroxyoctadecadienoic acid (13‐HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue‐isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13‐HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [³H]‐thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho‐activation of ERK 1/2, AKT, GSK3β and NF‐kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian‐based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.     

Severity Scales for Use in Primary Health Care to Assess Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a physical and cognitive disabling illness, characterized by severe fatigue and a range of physiological symptoms, that primarily affects women. The immense variation in clinical presentation suggests differences in severity based on symptomology and physical and cognitive functional capacities. In this article, we examine a number of severity scales used in assessing severity of patients with CFS/ME and the clinical aspects of CFS/ME severity subgroups. The use of severity scales may be important in CFS/ME because it permits the establishment of subgroups that may improve accuracy in both clinical and research settings.     

Risk factors for early return visits to the emergency department in patients with urinary tract infection

Background

Optimal management of urinary tract infections (UTIs) in the emergency department (ED) is challenging due to high patient turnover, decreased continuity of care, and treatment decisions made in the absence of microbiologic data. We sought to identify risk factors for return visits in ED patients treated for UTI.

pdFVIII/VWF may be an alternative treatment for old medical patient with acquired haemophilia A and systemic vascular disease?

Acquired Haemophilia is a severe, rare and potentially life-threatening bleeding that affects both males and females with an incidence of 1.5 cases/million/year. Mucocutaneous haemorrhages or haematomas are the typical expression of this disease as a consequence of a decrease in FVIII activity and the presence of a FVIII inhibitor, which differs from congenital haemophilia. We report a case of a 71 year-old-man who presented with spontaneous haematomas and severe anaemia and suffered from vascular disease. At admission, all haemostatic and laboratory data were diagnostic for idiopathic AHA. Treatment with by-passing agents such as rFVIIa was contraindicated because of the risk of thromboembolic events. Despite the fact that administration of FVIII concentrates in AHA is recommended only in patients with an inhibitor titre < 5.0 BU, the physicians decided to use pdFVIII/vWF with corticosteroids in this patient. One month later, the FVIII was within the normal range and the inhibitors had disappeared. In our case, pdFVIII/vWF resulted in a safe and effective alternative for the treatment of acquired haemophilia A in a patient at high thromboembolic risk.