Methodological advancements in organ-specific ectopic lipid quantitative characterization: Effects of high fat diet on muscle and liver intracellular lipids.

Ectopic lipid accumulation is a hallmark of metabolic diseases, linking obesity to non-alcoholic fatty liver disease, insulin resistance and diabetes. The use of zebrafish as a model of obesity and diabetes is raising due to the conserved properties of fat metabolism between humans and zebrafish, the homologous genes regulating lipid uptake and transport, the implementation of the '3R's principle and their cost-effectiveness. To date, a method allowing the conservation of lipid droplets (LDs) and organs in zebrafish larvae to image ectopic lipids is not available. Our objectives were to develop a novel methodology to quantitatively evaluate organ-specific LDs, in skeletal muscle and liver, in response to a nutritional perturbation. We developed a novel embedding and cryosectioning protocol allowing the conservation of LDs and organs in zebrafish larvae. To establish the quantitative measures, we used a three-arm parallel nutritional intervention design. Zebrafish larvae were fed a control diet containing 14% of nutritional fat or two high fat diets (HFDs) containing 25 and 36% of dietary fats. In muscle and liver, LDs were characterized using immunofluorescence confocal microscopy. In liver, intrahepatocellular lipids were discriminated from intrasinusoid lipids. To complete liver characteristics, fibrosis was identified with Masson's Trichrome staining. Finally, to confirm the conservation and effect of HFD, molecular players of fat metabolism were evaluated by RT-qPCR. The cryosections obtained after setting up the embedding and cryopreservation method were of high quality, preserving tissue morphology and allowing the visualization of ectopic lipids. Both HFDs were obesogenic, without modifying larvae survival or development. Neutral lipid content increased with time and augmented dietary fat. Intramuscular LD volume density increased and was explained by an increase in LDs size but not in numbers. Intrahepatocellular LD volume density increased and was explained by an increased number of LDs, not by their increased size. Sinusoid area and lipid content were both increased. Hepatic fibrosis appeared with both HFDs. We observed alterations in the expression of genes associated with LD coating proteins, LD dynamics, lipogenesis, lipolysis and fatty acid oxidation. In this study, we propose a reproducible and fast method to image zebrafish larvae without losing LD quality and organ morphology. We demonstrate the impact of HFD on LD characteristics in liver and skeletal muscle accompanied by alterations of key players of fat metabolism. Our observations confirm the evolutionarily conserved mechanisms in lipid metabolism and reveal organ specific adaptations. The methodological advancements proposed in this work open the doors to study organelle adaptations in obesity and diabetes related research such as lipotoxicity, organelle contacts and specific lipid depositions

The FDA “black box” warning on antidepressant suicide risk in young adults: More harm than benefits?

The decision made in the year 2004 by the U.S. Food and Drug Administration (FDA) to require a boxed warning on antidepressants regarding the risk of suicidality in young adults still represents a matter of controversy. The FDA warning was grounded on industry-sponsored trials carried one decade ago or earlier. However, within the past decade, an increasing number of reports have questioned the actual validity of the FDA warning, especially considering a decline in the prescription of the antidepressant drugs associated with an increase in the rate of suicidal events among people with severe depression. The present report provides an overview of the FDA black box warning, also documenting two Major Depressive Disorder patients whose refusal to undergo a pharmacological antidepressant treatment possibly led to an increased risk for suicidal behaviors. The concerns raised by the FDA black box warning need to be considered in real-world clinical practice, stating the associated clinical and public health implications

Recreational Drug Misuse and Its Potential Contribution to Male Fertility Levels’ Decline: A Narrative Review

Recreational drug intake may be associated with a range of medical untoward consequences, including male infertility. However, as the related evidence is still limited, the main outcome of this review is to provide a better understanding of the existence of any association between recreational drug misuse and male fertility levels’ decline. Whilst searching the MEDLINE/PubMed, a comprehensive overview of the literature regarding male infertility and substances of abuse (e.g., phytocannabinoids, opiates/opioids, stimulants, ‘herbal highs’, psychedelics, and ‘novel psychoactive substances) was here undertaken. Due to the paucity of robust, high-quality, empirical, human studies, a narrative strategy was here preferred over a systematic approach. Relevant data are qualitatively analyzed and presented in a table. Although most available evidence is in support of a detrimental role of cannabis on human spermatogenesis, a few remaining studies failed to document any effect of this drug on seminal quality, and it is not clear to which extent this drug impacts fertility rates/time to pregnancy. The current understanding of the impact of opiate-, cocaine- and amphetamine/stimulant-misuse on human reproduction is widely unknown, and most studies dealing with this matter represent only an extrapolation of data derived from specific clinical circumstances. Although the message of ‘no smoking, no alcohol and no street drugs’ should always be offered as good health advice to all patients seeking medical help for fertility issues, robust scientific clinical evidence in support of a direct detrimental impact of recreational drugs on spermatogenesis is scant to date

The Endocannabinoid System: A Putative Role in Neurodegenerative Diseases

BACKGROUND: Following the characterization of the chemical structure of D9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, researchers have moved on with scientific valuable explorations. OBJECTIVES: The aim of this review is to highlight the role of endocannabinoid system in neurodegenerative diseases. MATERIALS AND METHODS: The article is a critical analysis of the most recent data currently present in scientific literature on the subject; a qualitative synthesis of only the most significant articles has been performed. RESULTS: In central nervous system, endocannabinoids show a neuromodulatory function, often of retrograde type. This way, they play an important role in synaptic plasticity and in cognitive, motor, sensory and affective processes. In addition, in some acute or chronic pathologies of central nervous system, such as neurodegenerative and neuroinflammatory diseases, endocannabinoids can perform a pro-homeostatic and neuroprotective function, through the activation of CB1 and CB2 receptors. Scientific evidence shows that an hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s, Parkinson’s and Alzheimer’s diseases. CONCLUSIONS: The important role played by endocannabinoid system promises interesting developments, in particular to evaluate the effectiveness of new drugs in both psychiatry and neurology

Evidence that chronic hypoxia causes reversible impairment on male fertility

Aim: To evaluate the effect of chronic hypoxia on human spermatogenic parameters and their recovery time. Methods: Seminological parameters of six male healthy mountain trekkers were evaluated in normoxia at sea level. After 26 days exposure to altitude (ranging from 2 000 m to 5 600 m, Karakorum Expedition) the same parameters were again evaluated after returning to sea level. These parameters were once again evaluated after 1 month and then again after 6 months. Results: Sperm count was found to be lower immediately after returning to sea level (P = 0.0004) and again after a month (P = 0.0008). Normal levels were reached after 6 months. Spermatic motility (%) shows no reduction immediately after returning to sea level (P = 0.0583), whereas after 1 month this reduction was significant (P = 0.0066). After 6 months there was a recovery to pre-hypoxic exposure values. Abnormal or immature spermatozoa (%) increased immediately after returning to sea level (P = 0.0067) and then again after 1 month (P = 0.0004). After 6 months there was a complete recovery to initial values. The total number of motile sperm in the ejaculate was found to be lower immediately after returning to sea level (P = 0.0024) and then again after 1 month (P = 0.0021). After 6 months there was a recovery to pre-hypoxic exposure values. Conclusion: Chronic hypoxia induces a state of oligospermia and the normalization of such seminological parameters at the restoration of previous normoxic conditions after 6 months indicate the influence of oxygen supply in physiological mechanisms of spermatogenesis and male fertility. (Asian J Androl 2008 Jul; 10: 602–606

A comprehensive overview on Kratom

Kratom (Mitragyna speciosa Korth) is a tropical tree, indigenous to South East Asia. Historically, the plant is locally used as a stimulant, a remedy in traditional medicine and in social context. Imported to Western countries, Kratom is classified as a novel psychoactive substance (NPS). A systematic review of the literature on Mitragyna speciosa and its main constituents was carried by our international multidisciplinary group. Results were qualitatively analysed in three main areas of interest: in-vitro and preclinical data on pharmacology and behavioral effects, laboratoristic techniques for identification/characterization, epidemiological/toxicological reports on humans. At present, there is no systematic data on the prevalence of Kratom use in all the native countries, but it seems to be considerable. In South-East Asia, Kratom, even if banned, might be still considered a better option than other illicit drugs, an alternative opioid treatment, a “natural” remedy with no real social stigma attached to its consumption. In parallel, this ethno-drug seems to be popular in Western countries, largely unregulated, easily available on the Internet. Kratom pharmacology appears to be complex, with many alkaloids involved. The subjective effects in humans are very peculiar and seem to be dose-dependent, ranging from psycho-stimulant to sedative-narcotic. Available data on Kratom suggest caution: this psychoactive plant could exhibit a serious harmful potential. Kratom use seems to be associated with drug dependency, development of withdrawal symptoms, craving, serious adverse effects and life-threatening effects in a multidrug-intoxicating scenario. On the other hand, its anxyiolitic, antidepressant and analgesic properties deserve to be further studied

PO-0857: GTV-based prescription and Monte Carlo treatment planning in Cyberknife treatments for lung lesions

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Celecoxib Adjunctive Treatment to Antipsychotics in Schizophrenia: A Review of Randomized Clinical Add-On Trials

Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons