Urinary 6-hydroxy-melatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome

The precise etiology of the restless legs syndrome (RLS) is unknown. Sensory and motor symptoms of RLS worsen during evening/night, coincident with the physiological peak of pineal melatonin excretion. Decreased melatonin levels have been reported in insomnia, which is an associated feature of RLS. Melatonin substitution improved insomnia. A potential association between the idiopathic RLS (iRLS) and alterations in melatonin excretion was therefore explored. Daytime (7:00-22:00 hr) and night-time (22:00-7:00 hr) urinary excretion of 6-OH-melatonin-sulfate (aMLTs) was measured in 15 patients with iRLS and 11 controls by a radioimmunoassay. There was no significant difference between daytime and night-time urinary aMLTs excretion in iRLS as compared with controls (daytime: 6.14 +/- 5.20 ng versus 5.02 +/- 5.11 ng, NS; night-time: 21.07 +/- 17.05 ng versus 22.92 +/- 16.52 ng, NS). Our data do not provide evidence for a decrease of cumulative melatonin production in iRLS. Insomnia in RLS does not seem to be correlated with a deficit of melatonin.     

Detection of biliary origin of acute pancreatitis

Fifty consecutive patients with acute pancreatitis were assessed with respect to a biliary origin of the disease. Endoscopie retrograde cholangiopancreaticography, surgery, and autopsy were used to define biliary pancreatitis. Ultrasound, computed tomography, and several laboratory tests (SGOT, SGPT, alkaline phosphatase, and bilirubin) were analyzed for their ability to detect a biliary origin of the disease. Ultrasound and computed tomography could not reliably make the diagnosis in the 10 patients found to have biliary disease. Receiver-operator-characteristic curves revealed that none of the laboratory tests assessed had sufficient sensitivity and specificity to determine the diagnosis, although all tests showed higher mean values in biliary pancreatitis. SGPT gave the best discrimination (positive predictive value 53%, negative predictive value 94%, cut off 40 Units/liter). Therefore, initial ERCP is suggested for a reliable diagnosis of biliary origin of acute pancreatitis.     

Recombinant human alpha fetoprotein synergistically potentiates the anti-cancer effects of 1′-S-1′-acetoxychavicol acetate when used as a complex against human tumours harbouring AFP-receptors

Purpose

Previous in vitro and in vivo studies have reported that 1′-S-1′-acetoxychavicol acetate (ACA) isolated from rhizomes of the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) induces apoptosis-mediated cell death in tumour cells via dysregulation of the NF-κB pathway. However there were some clinical development drawbacks such as poor in vivo solubility, depreciation of biological activity upon exposure to an aqueous environment and non-specific targeting of tumour cells. In the present study, all the problems above were addressed using the novel drug complex formulation involving recombinant human alpha fetoprotein (rhAFP) and ACA.

Experimental Design

To study the synergistic effect of both agents on human cancer xenografts, athymic nude (Nu/Nu) mice were used and treated with various combination regimes intraperitoneally. Serum levels of tumour markers for carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) were assessed using sandwich ELISA. IHC and Western blotting were also conducted on in vivo tumour biopsies to investigate the involvement of NF-κB regulated genes and inflammatory biomarkers. Quantification and correlation between drug efficacies and AFP-receptors were done using IF-IC and Pearson''s correlation analysis.

Results

Mice exposed to combined treatments displayed higher reductions in tumour volume compared to stand alone agents, consistent with in vitro cytotoxicity assays. Milder signs of systemic toxicity, such as loss in body weight and inflammation of vital organs were also demonstrated compared to stand alone treatments. Tumour marker levels were consistent within all rhAFP/ACA treatment groups where levels of CEA and PSA were initially elevated upon commencement of treatment, and consecutively reduced corresponding to a decrease in tumour bulk volume. Both IHC and Western blotting results indicated that the combined action of rhAFP/ACA was not only able to down-regulate NF-κB activation, but also reduce the expression of NF-κB regulated genes and inflammatory biomarkers. The efficacy of rhAFP/ACA complex was also found to be weakly negatively correlated to the level of surface AFP-receptors between tumour types.

Conclusions

This drug complex formulation shows great therapeutic potential against AFP-receptor positive tumours, and serves as a basis to overcome insoluble and non-specific anti-neoplastic molecules.     

APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls

Background

The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC).

Methods

Cross-sectional study. HC from the Alzheimer’s Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β_1–42 (Aβ_1–42), total-tau (t-tau) and phospho-tau (p-tau_181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses.

Results

APOE4 carriers had lower CSF Aβ_1–42 and higher CSF p-tau_181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers.

Conclusions

The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.     

Consensus document on the overlap phenotype COPD-asthma in COPD

IntroductionAlthough asthma and COPD are different pathologies, many patients share characteristics from both entities. These cases can have different evolutions and responses to treatment. Nevertheless, the evidence available is limited, and it is necessary to evaluate whether they represent a differential phenotype and provide recommendations about diagnosis and treatment, in addition to identifying possible gaps in our understanding of asthma and COPD.MethodsA nation-wide consensus of experts in COPD in two stages: (1) during an initial meeting, the topics to be dealt with were established and a first draft of statement was elaborated with a structured “brainstorming” method; (2) consensus was reached with two rounds of e-mails, using a Likert-type scale.ResultsConsensus was reached about the existence of a differential clinical phenotype known as “Overlap Phenotype COPD–Asthma”, whose diagnosis is made when 2 major criteria and 2 minor criteria are met. The major criteria include very positive bronchodilator test (increase in FEV₁ ≥15% and ≥400 ml), eosinophilia in sputum and personal history of asthma. Minor criteria include high total IgE, personal history of atopy and positive bronchodilator test (increase in FEV₁ ≥12% and ≥200 ml) on two or more occasions. The early use of individually adjusted inhaled corticosteroids is recommended, and caution must be taken with their abrupt withdrawal. Meanwhile, in severe cases the use of triple therapy should be evaluated. Finally, there is an obvious lack of specific studies about the natural history and the treatment of these patients.ConclusionsIt is necessary to expand our knowledge about this phenotype in order to establish adequate guidelines and recommendations for its diagnosis and treatment.