Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after microinjection of phentolamine into the same sites. No significant effects on behaviour and ECoG activity were evoked after intraventricular injection or microinfusion into the locus coeruleus of prazosin or methoxamine.     

Trans-ACPD induces a slow post-stimulus inward tail current (IADP) in guinea-pig olfactory cortex neurones in vitro.

The metabotropic glutamate receptor agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) produced a slow, persistent excitation of guinea-pig olfactory cortical neurones in vitro, and the appearance of a prominent post-stimulus after depolarization. The corresponding slow inward tail current (IADP) revealed under voltage clamp was insensitive to tetrodotoxin (or atropine) but was blocked by Cd2+ or tetrabutylammonium. The IADP properties resembled those of the slow inward tail current induced by muscarinic agonists in these neurones, suggesting a common intracellular transduction mechanism.     

Sex influences clinical phenotype in frontotemporal dementia

Neurological Sciences - Frontotemporal dementia (FTD) encompasses a wide spectrum of genetic, clinical, and histological findings. Sex is emerging as a potential biological variable influencing FTD...     

Involvement of the skull base and vault in chronic idiopathic hyperphosphatasia

Chronic idiopathic hyperphosphatasia (CIH) is a rare generalised skeletal dysplasia in childhood. The clinical, radiographic and cerebral MR findings in a 5-year-old girl with the severe infantile form of CIH are reported. In spite of cranial enlargement, the intracranial space and the skull base were markedly reduced, the whole brain was compressed and a Chiari I malformation was present. Normal flow in the dural venous sinuses was documented. The patient showed no detectable cranial nerve involvement or hydrocephalus. Cranial MR in this patient enabled us to confirm that CIH involves the skull base and vault. Received: 19 December 1997 Accepted: 17 April 1998     

Pinealectomy inhibits interleukin-2 production and natural killer activity in mice

Four--five-week-old C57BL/6 mice were surgically pinealectomized. At different time intervals after surgery their spleens were removed and assayed for interleukin-2 (IL-2) production and natural killer (NK) cell activity. Non-operated and sham-operated mice were used as controls. The present results indicate that pinealectomy significantly reduced IL-2 production and NK cell activity, in comparison to sham-operated mice. These effects seem to be related to the lack of melatonin. In fact the subcutaneous injection of this hormone (50 or 100 mg/kg at 5 p.m.) in pinealectomized mice was able to restore IL-2 production and NK cell activity. However, chronic treatment with melatonin (10, 20 and 50 mg/kg for 9 consecutive days) failed to reverse the impairment of the immune responses.     

Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects

GR79236 is a highly potent and selective adenosine A1 receptor agonist that has analgesic and anti-inflammatory actions in humans and animals. In animal models it inhibits trigeminal nerve firing and calcitonin gene-related peptide release which play a pivotal role in migraine pathophysiology. Thus GR79236 may have therapeutic potential in migraine. Although there are no validated human models of migraine, the trigeminal nociceptive pathways may be studied with a novel electrode to elicit nociception-specific blink reflex responses. Twelve healthy female volunteers were randomized in a double-blind, placebo-controlled, cross-over trial to investigate the effect of GR79236 on trigeminal nociceptive pathways, as measured by the blink reflex. A secondary objective was to compare the use of two types of electrode, the standard (SE) and nociception-specific electrodes (NE), to investigate human trigeminal pharmacology. Blink reflexes were elicited with SE and NE before and 30 min after GR79236 (10 microg/kg i.v.) or placebo. The median area under the curve of repeated sweeps of the R2 component of the blink reflex was analysed using analysis of covariance with baseline as covariate. Using NE, GR79236 produced a non-significant reduction of the ipsilateral R2 compared with placebo (P = 0.097) and a significant reduction contralaterally (P = 0.008). No significant changes were observed using SE. There were no significant adverse events. The results suggest that NE is more sensitive than SE to detect pharmacological effects in the trigeminal nociceptive system. Furthermore, the adenosine A1 receptor agonist GR79236 inhibits trigeminal nociception in humans. These results support a possible therapeutic role for GR79236 in primary headache disorders.     

Ers1 links HP1 to RNAi

Pericentromeric heterochromatin formation is mediated by repressive histone H3 lysine 9 methylation (H3K9Me) and its recognition by HP1 proteins. Intriguingly, in many organisms, RNAi is coupled to this process through poorly understood mechanisms. In Schizosaccharomyces pombe, the H3-K9 methyltransferase Clr4 and the heterochromatin protein 1 (HP1) ortholog Swi6 are critical for RNAi, whereas RNAi stimulates H3K9Me. In addition to the endoribonuclease Dcr1, RNAi in S. pombe requires two interacting protein complexes, the RITS complex, which contains an Argonaute subunit, and the RDRC complex, which contains an RNA-dependent RNA polymerase subunit. We previously identified Ers1 (essential for RNAi-dependent silencing) as an orphan protein that genetically acts in the RNAi pathway. Using recombinant proteins, we show here that Ers1 directly and specifically interacts with HP1/Swi6. Two-hybrid assays indicate that Ers1 also directly interacts with several RNAi factors. Consistent with these interactions, Ers1 associates in vivo with the RITS complex, the RDRC complex, and Dcr1, and it promotes interactions between these factors. Ers1, like Swi6, is also required for RNAi complexes to associate with pericentromeric noncoding RNAs. Overexpression of Ers1 results in a dominant-negative phenotype that can be specifically suppressed by increasing levels of the RDRC subunit Hrr1 or of Dcr1, further supporting a functional role for Ers1 in promoting the assembly of the RNAi machinery. Through the interactions described here, Ers1 may promote RNAi by tethering the corresponding enzyme complexes to HP1-coated chromatin, thereby placing them in proximity to the nascent noncoding RNA substrate.     

Long-term neurological manifestations of COVID-19: prevalence and predictive factors

Neurological Sciences - Clinical investigations have argued for long-term neurological manifestations in both hospitalised and non-hospitalised COVID-19 patients. It is unclear whether long-term...     

Laparoscopic surgery of diaphragmatic diseases in children: our experience with five cases.

AIMS: In paediatric surgery the laparoscopic approach can be used to repair diaphragmatic anomalies originating from the abdomen or containing abdominal viscera. Candidates for laparoscopic correction are children with mild symptoms and good respiratory and haemodynamic conditions. The authors present their experience with 5 patients treated successfully for different types of diaphragmatic lesions. PATIENTS AND METHODS: Five children were treated laparoscopically since 1998. Two true Morgagni-Larrey hernias, one recurrent left Bochdalek hernia, one diaphragmatic dysontogenetic cyst and one huge congenital sliding and rolling hiatal hernia. All the herniated viscera were repositioned in the abdomen and the defects--including the diaphragmatic hole at the level of the dysontogenetic cyst--were directly sutured without the use of a mesh. RESULTS: All patients are healthy without signs of recurrence observed at chest X-ray after a follow-up of 3 months to 1 year. DISCUSSION: Under specific conditions the laparoscopic approach can be an effective and more advantageous alternative to laparotomy for diaphragmatic congenital diseases in a paediatric population.