Melatonin reduces nitric oxide synthase activity in rat hypothalamus

Abstract: In this report, rat hypothalamic nitric oxide synthase (NOS) activity is shown to be partially inhibited by physiological concentrations of the pineal hormone melatonin. In vitro studies demonstrate that 1 nM melatonin, which approximates the physiological concentration of the hormone at night, significantly inhibited NOS activity. In vivo studies show that administering melatonin or collecting the hypothalamus from animals at night, when endogenous melatonin levels are elevated, results in a significant decrease of NOS activity. Results also show that calmodulin may be involved in this process since its presence in the incubation medium prevents the inhibitory effect of melatonin on NOS activity.     

Novel Mutations in the Amyloid Precursor Protein Gene within Moroccan Patients with Alzheimer's Disease

In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition.     

Correction to: Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva

Clinical Rheumatology - One of the author’s name on this article was incorrectly spelled as “Renata Borcciadi”. The correct spelling is “Renata Bocciardi” and is now...     

Fungicidal Mechanisms of Cathelicidins LL-37 and CATH-2 Revealed by Live-Cell Imaging

Antifungal mechanisms of action of two cathelicidins, chicken CATH-2 and human LL-37, were studied and compared with the mode of action of the salivary peptide histatin 5 (Hst5). Candida albicans was used as a model organism for fungal pathogens. Analysis by live-cell imaging showed that the peptides kill C. albicans rapidly. CATH-2 is the most active peptide and kills C. albicans within 5 min. Both cathelicidins induce cell membrane permeabilization and simultaneous vacuolar expansion. Minimal fungicidal concentrations (MFC) are in the same order of magnitude for all three peptides, but the mechanisms of antifungal activity are very different. The activity of cathelicidins is independent of the energy status of the fungal cell, unlike Hst5 activity. Live-cell imaging using fluorescently labeled peptides showed that both CATH-2 and LL-37 quickly localize to the C. albicans cell membrane, while Hst5 was mainly directed to the fungal vacuole. Small amounts of cathelicidins internalize at sub-MFCs, suggesting that intracellular activities of the peptide could contribute to the antifungal activity. Analysis by flow cytometry indicated that CATH-2 significantly decreases C. albicans cell size. Finally, electron microscopy showed that CATH-2 affects the integrity of the cell membrane and nuclear envelope. It is concluded that the general mechanisms of action of both cathelicidins are partially similar (but very different from that of Hst5). CATH-2 has unique features and possesses antifungal potential superior to that of LL-37.     

Syncopes gélastiques récurrentes

Introduction

Laughter-induced syncope or gelastic syncope is a rare and unrecognized phenomenon. We report an additional case.

Case report

We report a 65-year-old man with no personal past medical history, particularly diabetes or heart disease, was admitted to investigate recent four episodes of loss of consciousness exclusively induced by laugh. The first episode had occurred 8 months earlier after reading a funny story. There were no other symptoms and physical examination, particularly neurological and cardiac was normal. All paraclinical investigations were also unremarkable: laboratory tests (glucose, thyroid function test and blood cobalamin level), cardiac and neurological investigations (electrocardiographic monitoring, echocardiography, electroencephalography and brain MRI). Treatment with propanolol prevented subsequent attacks.

Conclusion

Sustained laugh is accompanied by repetitive bursts of forced expiration, equivalent to short repetition of Valsalva maneuvers. Laughter-induced syncope is thought to be a subtype of the vagal mediated syncopal attacks. Differential diagnosis should rule out especially gelastic atonic seizures and cataplexy. Propanolol is an effective therapy to prevent recurrence.     

Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

Chronic nicotine exposure (CNE) alters synaptic transmission in the ventral tegmental area (VTA) in a manner that enhances dopaminergic signaling and promotes nicotine use. The present experiments identify a correlation between enhanced production of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and diminished release of the inhibitory neurotransmitter GABA in the VTA following CNE. To study the functional role of on-demand 2-AG signaling in GABAergic synapses, we used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by diacylglycerol lipase (DAGL). The potency and selectivity of these inhibitors were established in rats in vitro (rat brain proteome), ex vivo (brain slices), and in vivo (intracerebroventricular administration) using activity-based protein profiling and targeted metabolomics analyses. Inhibition of DAGL (2-AG biosynthesis) rescues nicotine-induced VTA GABA signaling following CNE. Conversely, enhancement of 2-AG signaling in naïve rats by inhibiting 2-AG degradation recapitulates the loss of nicotine-induced GABA signaling evident following CNE. DAGL inhibition reduces nicotine self-administration without disrupting operant responding for a nondrug reinforcer or motor activity. Collectively, these findings provide a detailed characterization of selective inhibitors of rat brain DAGL and demonstrate that excessive 2-AG signaling contributes to a loss of inhibitory GABAergic constraint of VTA excitability following CNE.The mesocorticolimbic dopamine (DA) system provides a critical link between the brain regions that process cognitive information and those controlling motor behavior. Precise control of these ventral tegmental area (VTA) projections facilitates seeking rewarding stimuli, retreating from aversive stimuli, constraint of motivational state, and behavioral flexibility necessary for survival. GABAergic signaling provides robust inhibition that gates VTA DA cell excitability (1, 2), and loss of this inhibition leads to pathological dysregulation of mesocorticolimbic circuitry (3, 4).Endocannabinoids (eCBs) regulate DAergic activity through retrograde signaling from DA cell bodies onto presynaptic cannabinoid type 1 (CB₁) receptors expressed on both inhibitory and excitatory inputs. Although both 2-arachidonoylglycerol (2-AG) and anandamide (AEA) function as endogenous CB₁ agonists in the brain (5–7), these lipids exhibit distinct pharmacological profiles in vivo (8, 9) and mediate differential behavioral effects (10, 11). Endocannabinoids are produced and degraded on-demand, and the primary enzymes responsible for eCB degradation have been well-characterized using selective pharmacological tools that inactivate monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) (11–13). However, a complete evaluation of the influence of eCB signaling in the brain has been hampered by the lack of appropriate corresponding tools for selectively inactivating on-demand eCB biosynthesis.Substantial evidence implicates eCB signaling in the etiology of nicotine addiction, and recent work demonstrates that chronic nicotine exposure (CNE) selectively enhances nicotine-induced increases in VTA 2-AG formation (14). The present study investigated the possible contribution of this effect to aberrant VTA DA cell excitation present following CNE (15). We find that sensitized nicotine-induced 2-AG release (14) strongly correlates with a loss of nicotine-induced GABA release, which may contribute to impaired inhibitory constraint of VTA DA cell excitation following CNE. To test this hypothesis, we characterized a series of selective inhibitors of 2-AG biosynthesis by diacylglycerol lipase α and β (DAGLα and DAGLβ; hereafter referred to as DAGL) (16–18) and 2-AG degradation by α/β-hydrolase domain 6 (ABHD6) and MAGL (11, 12, 19), and used these compounds to investigate the functional impact of enhanced 2-AG recruitment on GABAergic signaling at VTA synapses and nicotine self-administration.     

Brain tumor revealed by atrial sinus block

Bradycardia is rare in children and may be asymptomatic or cause fatigue or discomfort leading to syncope. It may be a warning sign of underlying pathology. A check-up for a cardiac or extra-cardiac organic cause should be performed. We report the case of an 8-year-old child admitted to the emergency room for bradycardia with a sino-atrial block that caused syncope. The assessment has objectified a brain tumor. We will discuss the different mechanisms that can explain the occurrence of bradycardia during a brain tumor, and the specificities of the management.