Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial

Aim

The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep.

Methods

In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day⁻¹ vs. placebo during 12 months. The primary endpoint quality of life parameter ‘vitality’ was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations.

Results

Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group.

Conclusions

The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6–12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.     

Note Free Flavonoid Aglycones from Inula montana

Inula montana L. (Asteraceae) is sometimes used in folk medicine in France in place of Arnica montana L. (and improperly called “Arnica”). A preliminary study on the flavonoid chemistry of Inula montana showed the occurrence of four major flavonoid aglycones: luteolin (5,7,3',4'-hydroxyflavone), hispidulin (5,7,4'-hydroxy-6-methoxyflavone), nepetin (5,7,3'-hydroxy-6-methoxyflavone) and cirsimaritin (5,4'-hydroxy-6,7-dimethoxyflavone). This species contains less free flavonoid aglycones (only 5 compounds detected) than Arnica montana (nearly 20 free aglycones isolated and identified).     

Adolescent Substance-Use Assessment: Methodological Issues in the Use of the Adolescent Drug Abuse Diagnosis (ADAD)

THis article has been retracted.     

The radiology of gangliogliomas and ganglioneuromas of the central nervous system

Summary Plain film changes, pneumographic and angiographic features of four cases of gangliogliomas of the central nervous system are reported. The confusing pathology and nomenclature is discussed. Radiologic features include bone changes consistent with slow growth, absence of tumor vascularity and frequent involvement of the temporal lobe in the younger age group.

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Die Röntgendiagnostik der Gangliogliome und Ganglioneurome des Zentralnervensystems

Zusammenfassung Die Befunde der Nativ-Diagnostik, der Pneumographie und der Angiographie in 4 Fällen von Gangliogliomen des Zentralnervensystems werden geschildert. Auch ist die unterschiedliche Pathologie und Nomenklatur beschrieben. Langsames Wachstum der Geschwulst, Fehlen einer pathologischen Tumor-Vaskularisierung und der häufige Sitz im Temporallappen im jugendlichen Alter sind ein besonderes Merkmal dieser Geschwulst.

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Radiologie des ganglio-gliomes et des ganglio-neuromes du systeme nerveux central

Résumé Les auteurs raportent les modifications visibles sur les radiographies simples et les caractérististiques pneumographiques et angiographiques dans quatre cas de ganglioglisme du système nerveux central. Ils discutent la pathologie confuse et la nomenclature. Les caractéristiques radiologiques comprennent des altérations osseuses en rapport avec un développment lent, avec l'absence de vascularisation tumorale et l'envahissement fréquent du lobe temporal chez les malades les plus jeunes.

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Presented at the Fifty-fifth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, Illinois, November 30th-December 5th, 1969.

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This work was supported by USPHS Grants 1F11NB 2045, 2F11NB1755 and 05290-09.     

Neoadjuvant Sorafenib Treatment of Clear Cell Renal Cell Carcinoma and Release of Circulating Tumor Fragments

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding. PATIENTS AND METHODS: Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group. RESULTS: Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters. CONCLUSIONS: These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.Abbreviations: ccRCC, clear cell renal cell carcinoma; VEGF, vascular endothelial growth factor     

Effect of Polyphenols Intake on Obesity-Induced Maternal Programming

Excess caloric intake and body fat accumulation lead to obesity, a complex chronic disease that represents a significant public health problem due to the health-related risk factors. There is growing evidence showing that maternal obesity can program the offspring, which influences neonatal phenotype and predispose offspring to metabolic disorders such as obesity. This increased risk may also be epigenetically transmitted across generations. Thus, there is an imperative need to find effective reprogramming approaches in order to resume normal fetal development. Polyphenols are bioactive compounds found in vegetables and fruits that exert its anti-obesity effect through its powerful anti-oxidant and anti-inflammatory activities. Polyphenol supplementation has been proven to counteract the prejudicial effects of maternal obesity programming on progeny. Indeed, some polyphenols can cross the placenta and protect the fetal predisposition against obesity. The present review summarizes the effects of dietary polyphenols on obesity-induced maternal reprogramming as an offspring anti-obesity approach.     

Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child’s general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child’s general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.     

Reliable analysis of phenylalanine and tyrosine in a minimal volume of blood

ObjectivesPhenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to a defect in phenylalanine hydroxylase (PAH). Treatment principle is to reduce phenylalanine concentration sufficiently to prevent neuropathological effects. Dietary management is performed and the effect of treatment is monitored by regular analysis of phenylalanine and tyrosine. The aim of the study was to develop a rapid method to routinely measure both metabolites in minimal bloodspot volume (1.5 mm Ø, corresponding with a volume of 1.3 μL blood).MethodWhole blood was spiked with phenylalanine and tyrosine at 24 different concentrations. Dried blood spots (DBS) were prepared, after which punches of 1.5 mm Ø and 6 mm Ø (corresponding with a volume of 12.4 μL) were taken. Additionally, punches of both sizes were prepared from DBS of PKU-patients (n = 77). All samples were analyzed by tandem mass-spectrometry and results between both punches were compared.ResultsA good correlation between concentrations of phenylalanine and tyrosine in 1.5 and 6 mm punches was found (r² = 0.9917 and r² = 0.9892, respectively). Analysis of phenylalanine and tyrosine in punches of PKU-patients (n = 77) showed similar results and fitted within the procentual range of the between run variation.ConclusionWe developed an accurate and rapid method to analyze phenylalanine and tyrosine concentrations in a 1.5 mm Ø bloodspot punch with an estimated whole blood volume of 1.3 μL. This technical improvement does not only result in a 10 fold reduction in required patients' material, but also in a 30–60 min time saving in sample preparation.     

Conservation of DNA photolyase genes in group II nucleopolyhedroviruses infecting plusiine insects

DNA photolyase genes (phr) encode photoreactive enzymes, which are involved in the repair of UV-damaged DNA. Cyclobutane pyrimidine dimer (CPD) specific photolyase genes are present in nucleopolyhedroviruses isolated from Chrysodeixis chalcites (ChchNPV) and Trichoplusia ni (TnSNPV), insects belonging to the Plusiinae (Noctuidae). To better understand the occurrence and evolution of these genes in baculoviruses, we investigated their possible conservation in other group II NPVs, which infect plusiine insects. A PCR based strategy using degenerate phr-specific primers was designed to detect and analyze possible photolyase genes. Six additional Plusiinae-infecting NPVs were analyzed and all, except Thysanoplusia oricalcea NPV A28-1, which is a group I NPV, contained one or more phr-like sequences. Phylogenetic analysis revealed that all photolyase genes of the tested Plusiinae-infecting baculoviruses group in a single clade, separated into three subgroups. The phylogeny of the polyhedrin sequences of these viruses confirmed that the analyzed viruses also formed a single clade in group II NPVs. We hypothesize that all plusiine group II NPVs contain one or more photolyase genes and that these have a common ancestor.