Phosphoinositide kinase activities in synaptosomes prepared from brains of patients with Alzheimer's disease and controls

Previously, phosphatidylinositol (PI) kinase activity in cytosolic fractions repared from postmortem tissue of the cerebral cortex from patients with Alzheimer's disease (AD) appeared to be lower than that of age-matched controls [Jolles et al., J. Neurochem., 58 (1992) 2326–2329]. In the study presented here, PI and PIP (phosphatidylinositol phosphate) kinase activities were studied in synaptosomes prepared from postmortem brain tissue of AD patients and age-matched controls. Firstly, PI kinase activity in synaptosomes prepared from the frontal superior gyrus of AD brain was 30% lower than in synaptosomes prepared from postmortem tissue of control brain. PIP kinase activity was the same in AD and control synaptosomes. Secondly, the yield of synaptosomal protein (μg protein per mg tissue wet weight) was lower in preparations from AD brain than in preparations from control brain, which could be a manifestation of a loss of presynaptic terminals in the frontal cortex. These results suggest that the difference in PI kinase activity between AD and control brain tissue may originate from differences in intact neurons in view of the fact that synaptosomes can originate only from intact neurons

Behavioural and biochemical effects of acute central metabolic inhibition:Effects of acetyl-l-carnitine

In the present study we evaluated a new method to assess the behavioural and biochemical effects of a brief period of acute hypoxia in the brain. In this method, cyanide is injected into the lateral ventricles. Spatial navigation performance in a Morris task was found to be impaired 1 and 5 min after an i.c.v. injection of 5.0 μg cyanide but not after 2.5 μg cyanide. Increased rate of phosphatidic acid formation, reflecting increased phospholipase C activity, were observed after injection of 5.0 μg cyanide, indicating that energy-dependent phosphoinositide metabolism was affected. Chronic treatment with acetyl-carnitine attenuated the cyanide-induced behavioural deficit, but had no effect on energy-dependent phophoinositide metabolism. The results suggest that, in this model, acetyl-l-carnitine may act via free fatty acid metabolism, by increasing the reservoir of activated acyl groups which are involved in the reacylation of membrane phospholipids

Acute effects of acetyl-L-carnitine on sodium cyanide-induced behavioral and biochemical deficits

In the present study we investigated the effects of acute treatment with acetyl-L-carnitine (50 mg/kg, i.v. 90 min before the sodium cyanide injection) on a sodium cyanide-induced behavioral deficit in the Morris water escape task. In a first experiment the spatial discrimination performance of the rats was found to be dose-dependently impaired after an i.c.v. injection of sodium cyanide (2.5 and 5.0 mu g). Acute treatment with acetyl-L-carnitine was found to increase the behavioral deficit after sodium cyanide, these findings were replicated in a second experiment. Based on these results it can be argued that an acute administration of acetyl-L-carnitine appears to potentiate a sodium cyanide-induced behavioral deficit. An additional in vitro experiment with rat brain synaptosomes showed clear effects of administered sodium cyanide on the energy-dependent incorporation of inositol into phosphoinositides and on the ATP concentration. In vitro acetyl-L-carnitine administration had no effect on the sodium cyanide-induced energy depletion. The negative behavioral findings are in contrast with our previously found protective effect of chronic treatment with acetyl-L-carnitine (via drinking water) on the sodium cyanide-induced behavioral deficit. Since chronic acetyl-L-carnitine treatment has no effect on the phosphoinositide metabolism it was suggested that acetyl-L-carnitine may act via the formation of an ATP-independent reservoir of activated acyl groups. Thus, fatty acids as acylated derivatives can be used for reacylation processes during an acute period of energy depletion. However, we have no clear explanation for the discrepancy in behavioral results between the chronic vs acute treatment of acetyl-L-carnitine at present. Further research is needed to characterize the mechanism of action of acetyl-L-carnitine in relation to sodium cyanide. (C) 1998 Elsevier Science Ltd. All rights reserved

Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine Cmax increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations

Young adults and the 5 a day campaign: perceived benefits and barriers of eating more fruits and vegetables

Although consuming adequate amounts of fruits and vegetables reduces the risk of developing chronic diseases, it is widely recognized that young adults’ intakes are currently well below the Department of Health’s recommended five portions a day, with men consuming even less than women. One approach in the UK has been to introduce health campaigns such as the 5 A DAY programme; however, little is currently known about how well their messages are understood amongst young adults. This study examined current knowledge of the 5 A DAY message in young adults, as well as the perceived benefits and remaining barriers towards consuming more fruits and vegetables. In total, four focus groups were conducted using male (n = 22) and female (n = 18) students at the University of Reading. Content analysis revealed that while participants were aware of the 5 A DAY recommendation, there was widespread confusion regarding the detail. In addition, men were less accepting of the message than women, reporting greater disbelief and a lack of motivation to increase intake. Finally, a range of barriers was reported by participants of both genders, despite the perceived beneficial effects for health and appearance. The results illustrate a considerable gap between awareness and knowledge of the 5 A DAY message, and underscore the challenge that changing behaviour in young adults represents. As well as stepping up education- and skill-based health campaigns, more targeted gender specific interventions will be needed to achieve sustained increases in fruit and vegetable intake

Thoughts from a past AGU SPA fellows committee

Community honours, such as those bestowed by professional scientific societies like the American Geophysical Union (AGU) are an important element of both individual career advancement and contributes to the historical record of scientific progress. The process by which honours are bestowed is not widely shared amongst the community. The purpose of this article is to share the recent experiences of several members of the AGU Space Physics and Aeronomy (SPA) Fellows committee. We outline the criteria for selection, the evaluation process, difficulties encountered by the committee, and steps taken to mitigate these difficulties. Of particular note is the impact of implicit bias in the award system. Steps could be taken by the awarding scientific societies to reduce the impact of these biases, but in the meantime individual award committees can employ some of the strategies we outline in this article. By sharing our experiences, we hope to improve the process of granting awards and honours for the scientists putting together award nominations, future committee members, and the scientific societies granting these awards. &nbsp;</p

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma

Feeling Healthy? A Survey of Physical and Psychological Wellbeing of Students from Seven Universities in the UK

University students’ physical and psychological health and wellbeing are important and comprise many variables. This study assessed perceived health status in addition to a range of physical and psychological wellbeing indicators of 3,706 undergraduate students from seven universities in England, Wales and Northern Ireland. We compared differences in these variables across males and females, and across the participating universities. The data was collected in 2007–2008. A self-administered questionnaire assessed socio-demographic information (e.g., gender, age), self-reported physical and psychological health data, as well as questions on health awareness, health service use, social support, burdens and stressors and university study related questions. While females generally reported more health problems and psychological burdens, male students felt that they received/had fewer persons to depend on for social support. The comparisons of health and wellbeing variables across the different universities suggested some evidence of ‘clustering’ of the variables under study, whereby favourable situations would be exhibited by a cluster of the variables that is encountered at some universities; and conversely, the clustering of less favourable variables as exhibited at other universities. We conclude that the level of health complaints and psychological problems/burdens is relatively high and calls for increased awareness of university administrators, leaders and policy makers to the health and well-being needs of their students. The observed clustering effects also indicated the need for local (university-specific) health and wellbeing profiles as basis and guidance for relevant health promotion programmes at universities