Stapes surgery in osteogenesis imperfecta: retrospective analysis of 18 operated ears.

PURPOSE: To evaluate short and long term results of stapes surgery in patients with osteogenesis imperfecta (OI), METHODS: Retrospective case series of 18 primary stapes surgeries performed on 11 hearing-impaired OI patients with evidence of stapes fixation, in a Tertiary referral center. We analysed pre-operative and post-operative hearing results at 1 month and at least 1 year RESULTS: The main operative findings were stapes fixation, thickened footplate and fragile or fractured stapes crura. No revision surgery was necessary. Hearing improvement was achieved in 94% of the cases. We obtained an air-bone gap closure to within 10 dB in 46% of the cases and to within 15 dB in 92% of the cases at 1-year follow-up. The mean hearing gain in air conduction (at 0.5, 1, 2 and 4 kHz) was 18.4 dB at 1 month and 22.4 dB at 1 year. CONCLUSION: Stapes surgery in OI gives good results with few complications in our series. A hearing gain is often obtained in spite of the sensorineural hearing loss caused by the natural progression of the disease.

Does post dural puncture headache exist in idiopathic intracranial hypertension? A pilot study.

BACKGROUND/OBJECTIVE: Occurrence of post-dural puncture headache (PDPH) after diagnostic lumbar puncture (LP) for idiopathic intracranial hypertension (IIH) may seem very unlikely in clinical practice. Nevertheless, it has been suggested by several studies, mainly in sub-group analyses. We aimed to evaluate the prevalence of PDPH in an IIH population and determine any eventual predictive factors of PDPH occurrence. METHODS: We conducted a retrospective multiple-center observational study. All newly diagnosed IIH patients who met the International Classification of Headache Disorders (ICHD-3) or the Dandy modified criteria were included from three different French hospitals. They all underwent LP following the same process with the same type of needle. We recorded PDPH occurring within five days after LP, as defined by ICHD-3 criteria. RESULTS: Seventy-four IIH patients were recruited, of whom 23 (31%) presented with PDPH. Neither classical risk factors for PDPH such as body mass index, age or gender, nor cerebrospinal fluid opening pressure, or specific IIH features were associated with occurrence of PDPH. CONCLUSION: PDPH can occur after LP in IIH patients. Clinicians should be aware of this possible event during the IIH diagnosis assessment and should not automatically reconsider IIH diagnosis. PDPH prevention using an atraumatic needle and dedicated PDPH treatment seem relevant in IIH patients.

Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 µM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4ß2 nAChR agonist RJR-2403 and was not influenced by TTX (1 µM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

Nicotine stimulation of dorsal raphe neurons: effects on laterodorsal and pedunculopontine neurons.

Previous studies showed that nicotine suppresses the ponto-geniculo-occipital (PGO) spikes of rapid eye movement (REM) sleep in cats. This effect may depend on stimulation of dorsal raphe nucleus (DRN) serotoninergic neurons that inhibit the pedunculopontine (PPT) and laterodorsal tegmental (LDT) cholinergic neurons, generators of PGO spikes. For testing this hypothesis 37 experiments were performed in rat midbrain slices. Nicotine (2 mM), administered locally into DRN, significantly increased the firing rate of 81.1% DRN neurons and serotonin release while simultaneously and significantly decreasing the firing rate of 80.8% LDT neurons and of 81.8% PPT neurons. The inhibition of LDT neurons by nicotine administered into DRN was blocked by the 5-HT1A receptor antagonist WAY-100635 (140 nM) administered into LDT. These results indicate that nicotine inhibits the activity of LDT and PPT neurons and consequently the generation of PGO spikes through stimulation of DRN serotoninergic neurons.

Design, synthesis, and modeling of novel cyclic thrombin receptor-derived peptide analogues of the Ser42-Phe-Leu-Leu-Arg46 motif sequence with fixed conformations of pharmacophoric groups: importance of a Phe/Arg/NH2 cluster for receptor activation and implications in the design of nonpeptide thrombin receptor mimetics.

The novel cyclic analogues cyclo(Phe-Leu-Leu-Arg-epsilonLys-Dap) (1) and cyclo(D-Phe-Leu-Leu-Arg-epsilonLys-Dap) (2), which differ only in the absolute conformation of Phe, have been designed and synthesized based upon the minimal peptide sequence Phe-Leu-Leu-Arg which has been found to exhibit biological activity for the thrombin receptor. Compound 1, in which all amino acids have the L-configuration, exhibited higher activity in the rat aorta relaxation and rat longitudinal muscle bioassays compared to compound 2, in which the Phe residue is in the D-configuration. This is attributed to the spatial proximity of the Phe and Arg in compound 1 which does not exist in its diastereomeric compound 2, as is depicted from a combination of NMR studies and computational analysis. Structure-activity studies (SAR) showed that the Phe and Arg side chains along with a primary amino group form an active recognition motif that is augmented by the presence of a second primary amino group in the cyclic peptide. We suggest that a comparable cyclic conformation may be responsible for the interaction of linear TRAPs with the thrombin receptor. The validity of this proposition was tested by the synthesis of four active nonpeptide thrombin receptor mimetics. Substance (S)-N-(6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (3), in which the pharmacophoric phenyl, guanidino, and amino groups were incorporated onto a piperazine template, was found to be the most active compared to the other synthesized compounds which lack the amino pharmacophoric group.

Subcutaneous administration of nicotine changes dorsal raphe serotonergic neurons discharge rate during REM sleep.

In the present study nicotine (0.1 mg/kg, s.c.) increased discharge rate of putative dorsal raphe (DRN) serotonergic neurons of behaving rats during REM sleep (362.61%), without any significant change during waking and non-REM sleep. Since serotonergic DRN neurons gate PGO onset, these results suggest that nicotine-induced suppression of PGO spikes during REM sleep previously reported is achieved through stimulation of dorsal raphe serotonergic cells.

Nicotine, brain nicotinic receptors, and neuropsychiatric disorders.

Neuronal nicotinic acetylcholine receptors (nAChRs) represent a large family of ligand-gated cation channels with diverse structures and properties. In contrast to the muscular nAChRs, the physiological functions of neuronal nAChRs are not well defined to date. Behavioral studies indicate that brain nAChRs participate in complex functions such as attention, memory, and cognition, whereas clinical data suggest their involvement in the pathogenesis of certain neuropsychiatric disorders (Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, etc.). For the majority of these disorders, the use of nAChRs' agonists may represent either a prophylactic (especially for Alzheimer's and Parkinson's diseases) or a symptomatic treatment. The possible mechanisms underlying these beneficial effects as well as the characteristics and potential therapeutic use of new, subtype-selective nAChRs agonists are presented.

Nicotine and brain disorders.

During the last decade, brain nicotinic acetylcholine receptors were extensively characterized from electrophysiological and pharmacological points of view. These receptors play important roles in memory and cognition and participate in the pathogenesis of several brain disorders (Parkinson's and Alzheimer's diseases, Tourette's syndrome, schizophrenia, depression, attention deficit disorder). In the same diseases, clinical studies showed that nicotine had beneficial effects, both as therapeutic and prophylactic agent. This review presents recent data concerning the structure and properties of neuronal nicotinic receptors, their involvement in the pathogenesis of various brain disorders and the beneficial effects of nicotine as therapeutic agent.

Effects of nicotine and mecamylamine on rat dorsal raphe neurons.

This study investigates the hypothesis that serotonin mediates certain nicotine effects, such as mood improvement and the suppression of the ponto-geniculo-occipital spikes of rapid eye movement sleep. The influence of nicotine (10-300 microM) on the firing rate of dorsal raphe neurons and on serotonin release was therefore, studied in rat midbrain slices. Nicotine increased the firing rate, 10-90%, in 67.5% recorded neurons and decreased it, 8-100%, in the remaining 32.5%. Serotonin release increased 2-7 times after nicotine administration, regardless of firing frequency, but the absolute value of serotonin release was 3 times higher during the decreases than during the increases in firing rate. Mecamylamine (1-20 microM) transiently stimulated the dorsal raphe neurons and competitively antagonized the nicotine-induced serotonin release. The results support the working hypothesis and additionally show that mecamylamine also stimulates dorsal raphe neurons.

The determinant role of arterial hypertension in cardiac rhythm disturbances, both induced by electrical stimulation of the midbrain reticular formation in the cat.

The arrhythmogenic and hypertensive effect of electric stimulation of the midbrain reticular formation (MRF) is known. The aim of the present paper is to demonstrate that the hypertensive effect potentiates the arrhythmogenic effect. Ten semiacute experiments were carried out on curarized cats, stimulating the MRF by stereotoxically implanted electrodes. After stimulation complex cardiac rhythm disturbances developed (consisting in their order of appearance of tachycardia, bradycardia, ventricular extrasystoles and idioventricular paroxysmal tachycardia--IPT), as well as an increase in arterial pressure. IPT always appeared after the increase in arterial pressure reached almost maximum values and disappeared after pressure values fell below this threshold. During the transition period from sinusal rhythm to arrhythmia fusion contractions were observed and in the course of IPT frequent capture phenomena. In all the cases, the frequency of IPT was inferior to that of the control. The correlation coefficient between latency in the onset of IPT and latency in the peak rise in arterial pressure was = +0.840, and between the duration of arrhythmia and the duration of the rise in arterial pressure was = +0.768. In conclusion the increase in arterial pressure produced by stimulation of the MRF represents a definite correlation to the genesis of rhythm disturbances: produced by the same stimulation.

The role of the sympathetic system in producing cardiac disturbances determined by stimulation of the midbrain reticular formation in the cat.

The authors check the theory according to which cardiac rhythm disturbances developing after myocardial infarction or in the course of a long Q-T interval syndrome are due to stimulation of the autonomic nervous system which innervates the heart via the stellate ganglia, the tonus of the left sympathetic being predominant over the right sympathetic at cardiac level. Six semiacute experiments were carried out on curarized cats in which arrhythmia was produced by stereotaxic electric stimulation of the midbrain reticular formation (MRF). Stimulation of MRF after either left or right stellectomy induced the same type of rhythm disturbances as that produced before stellectomy (ventricular extrasystoles and idioventricular paroxysmal tachycardia); however, latency in the development of these rhythm disturbances significantly increased after left stellectomy. After bilateral removal of the stellate ganglia, stimulation of the MRF only induced isolated or clustered ventricular extrasystoles. The results suggest that both stellate ganglia have an almost equal determinant role in the appearance of cardiac system disturbances obtained by stimulation of the MRF, the left having a somewhat more rapid effect.

Modern technique for following up changes in the mechanical and electric parameters of the heart.

The perfected experimental model described was developed for study of the action of various drugs on the isolated frog heart, recording concomitantly variations in the volume of the heart in the course of the cardiac cycle, the electrocardiogram and cardiac output. A description is given of the original components of the apparatus developed by the authors, as well as the normal values of the parameters studied.