The authors searched for mitochondrial DNA (mtDNA) A3243G mutation in peripheral blood leukocytes from female migraine patients with pure matrilinear history of migraine along two or three generations. The current study was designed to exclude any male transmission of the disease. The mutation was absent in all patients. We conclude that mtDNA A3243G mutation does not contribute to the pathogenesis of pure matrilinear multigenerational migraine with or without aura.

Adult↗

PubMed2000

Stimulating effect of HIV-1 coat protein gp120 on corticotropin-releasing hormone and arginine vasopressin in the rat hypothalamus: involvement of nitric oxide.

Subjects with human immunodeficiency virus type 1 (HIV-1) infection display increased activity of the hypothalamo-pituitary-adrenal (HPA) axis, which may play a role in both HIV-related neurodegenerative processes and disease progression. It has been speculated that the HIV coat protein gp120 may be responsible for these changes, and previous experimental evidence in both transgenic and nontransgenic mice supports this view. We speculated that one of the effects of gp120 in the CNS is to act within the hypothalamus to affect both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), the principal regulators of HPA axis. We therefore administered i.p. gp120 (100 ng/rat) or vehicle to male Wistar rats and then detected Fos protein (an index of neuronal activation), CRH, and AVP immunoreactivity in the cellular compartments of the hypothalamic paraventricular nucleus (PVN). In addition, we tested the direct effect of various concentrations of gp120 on the release of CRH and AVP from rat hypothalamic explants maintained in vitro. Any modulation of gp120 effects by nitric oxide (NO) pathways was also sought by coadministering i.p. to rats or adding to the hypothalamic preparations the NO synthase inhibitor N(G)-methyl-l-arginine (l-NMMA). Gp120 induced the expression of Fos protein in both the parvo- and the magnocellular PVN, which was significantly attenuated by l-NMMA 10(-6) nM/L (P < 0.001 vs gp120 alone). Double immunochemistry showed costaining for Fos protein and CRH or AVP in the PVN following gp120; the number of double-labeled CRH and AVP cells for Fos protein was markedly reduced (P < 0.001) by coadministration of l-NMMA 10(-6) nM/L. In the in vitro studies, addition of gp120 to the hypothalamic explants in the dose range of 10 pM-1 nM resulted in a clear stimulation of both CRH and AVP release (P < 0.05-0.001 compared to control); in the presence of l-NMMA at 10-fold higher concentrations the stimulatory effect of gp120 on the release of both peptides was completely lost. It would therefore appear that gp120 activates CRH and AVP-producing neurons in the hypothalamic PVN and stimulates the release of both peptides in vitro via NO-dependent mechanisms. These findings, in line with previous evidence, further suggest that the increased activity of the HPA axis associated with HIV infection may be of central origin, due to the effects of gp120 on hypothalamic CRH and AVP release.

Animals↗

PubMed2000

Botulinum toxin treatment for functional disability induced by essential tremor.

This study aimed to improve botulinum toxin's (BTX) efficacy and to reduce its unwanted effects in the treatment of functional disability due to essential tremor (ET) of the hand. Twenty patients with disabling ET, not responding to conventional pharmacological therapy, were enrolled in this open-label study. Activities of daily living self-questionnaire (ADLS) and severity tremor scale (STS) were used to establish patients' functional disability and tremor severity. Accelerometry and surface electromyography were used to identify the arm muscles with tremorogenic activity during impaired positions. Global rating was used to measure treatment efficacy and unwanted effects. BTX type A was injected into the muscles principally responsible for impaired positions. After BTX treatment, there was a significant reduction in both severity and functional rating scales scores (ADLS and STS) and of tremor amplitude as measured with accelerometry and EMG. Adverse effects were limited to a slight third finger extension weakness in 15% of patients. BTX injections are effective and safe in reducing disability due to ET, if based on the criterion of functional selection.

Aged↗

PubMed2000

Effects of hypnosis on diffuse noxious inhibitory controls.

The neurophysiological mechanisms of hypnotic analgesia are still under debate. It is known that pain occurring in one part of the body (counterstimulation) decreases pain in the rest of the body by activating the diffuse noxious inhibitory controls (DNICs). The aim of this study was to explore the effects of hypnosis on both pain perception and heterotopic nociceptive stimulation. The A forms of both the Harward Group Scale of Hypnotic Susceptibility and the Stanford Hypnotic Susceptibility Scale were administered to 50 healthy students. Twenty subjects were selected and assigned to two groups: group A, consisting of 10 subjects with high hypnotic susceptibility; and group B, consisting of 10 subjects with low hypnotic susceptibility. The subjects were then randomly assigned first to either a control session or a session of hypnotic analgesia. The nociceptive flexion reflex (RIII) was recorded from the biceps femoris muscle in response to stimulation of the sural nerve. The subjective pain threshold, the RIII reflex threshold, and the mean area with suprathreshold stimulation were determined. Heterotopic nociceptive stimulation was investigated by the cold-pressor test (CPT). During and immediately after the CPT, the subjective pain threshold, pain tolerance, and mean RIII area were determined again. The same examinations were repeated during hypnosis. Hypnosis significantly reduced the subjective pain perception and the nociceptive flexion reflex. It also increased pain tolerance and reduced pain perception and the nociceptive reflex during the CPT. These effects were found only in highly susceptible subjects. However, the DNIC's activity was less evident during hypnosis than during the CPT effects without hypnosis. Both hypnosis and DNICs were able to modify the perception of pain. It seems likely that DNICs and hypnosis use the same descending inhibitory pathways for the control of pain. The susceptibility of the subject is a critical factor in hypnotically induced analgesia.

Adult↗

PubMed2000

Functional changes of the basal ganglia circuitry in Parkinson's disease.

The basal ganglia circuitry processes the signals that flow from the cortex, allowing the correct execution of voluntary movements. In Parkinson's disease, the degeneration of dopaminergic neurons of the substantia nigra pars compacta triggers a cascade of functional changes affecting the whole basal ganglia network. The most relevant alterations affect the output nuclei of the circuit, the medial globus pallidus and substantia nigra pars reticulata, which become hyperactive. Such hyperactivity is sustained by the enhanced glutamatergic inputs that the output nuclei receive from the subthalamic nucleus. The mechanisms leading to the subthalamic disinhibition are still poorly understood. According to the current model of basal ganglia organization, the phenomenon is due to a decrease in the inhibitory control exerted over the subthalamic nucleus by the lateral globus pallidus. Recent data, however, suggest that additional if not alternative mechanisms may underlie subthalamic hyperactivity. In particular, given the reciprocal innervation of the substantia nigra pars compacta and the subthalamic nucleus, the dopaminergic deficit might influence the subthalamic activity, directly. In addition, the increased excitatory drive to the dopaminergic nigral neurons originating from the hyperactive subthalamic nucleus might sustain the progression of the degenerative process. The identification of the role of the subthalamic nucleus and, more in general, of the glutamatergic mechanisms in the pathophysiology of Parkinson's disease might lead to a new approach in the pharmacological treatment of the disease. Current therapeutic strategies rely on the use of L-DOPA and/or dopamine agonists to correct the dopaminergic deficit. Drugs capable of antagonizing the effects of glutamate might represent, in the next future, a valuable tool for the development of new symptomatic and neuroprotective strategies for therapy of Parkinson's disease.

Animals↗

PubMed2000

The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache.

The administration of nitroderivatives in cluster headache (CH) sufferers is the most reproducible experimental paradigm to induce spontaneous-like pain attacks. Previous uncontrolled studies have reported that the local use of anaesthetic agents in the area of the sphenopalatine fossa is able to extinguish nitroglycerin (NTG)-induced pain in CH. The present study, carried out according to a double-blind placebo-controlled design, included 15 CH patients, six with episodic CH (mean +/- SD age of 36.8+/-5.6 years), and nine with chronic CH (37.8+/-10.4 years). Patients had undergone a standard NTG test (0.9 mg sublingually), during which the intensity of pain was scored using a visuoanalogic scale (VAS, range 0-10). Nine patients (two with the episodic form, seven with the chronic form) experienced a typical, spontaneous-like attack on the usual side, occurring in all cases within 45 min. In these patients, the test was repeated with an interval of 2 days, and once pain intensity reached 5 on the VAS, a 10% solution of cocaine hydrochloride (1 ml, mean amount per application 40-50 mg), or 10% lidocaine (1 ml), or saline was applied using a cotton swab in the area corresponding to the sphenopalatine fossa, under anterior rhinoscopy. This was done in both the symptomatic and the non-symptomatic side, for 5 min. Treatments were always performed randomly, in separate sessions. All patients responded promptly to both anaesthetic agents, with complete cessation of induced pain occurring after 31.3+/-13.1 min for cocaine and 37.0+/-7.8 min for lidocaine (M+/-SD). In the case of saline application, pain severity increased thereafter, and extinction of the provoked attacks occurred with a latency of 59.3+/-12.3 min (P<0.01 and P<0.01 vs. cocaine and lidocaine, respectively, Mann-Whitney U-test). While further suggesting that the sphenopalatine ganglion participates in the mechanisms of pain, these findings indicate that the local administration of the anaesthetic agents cocaine and lidocaine is effective on NTG-induced CH attacks, and may be used in the symptomatic treatment of this disorder.

Administration, Intranasal↗

PubMed2000

Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache.

The nociceptive flexion reflex (NFR) of the lower limbs (RIII reflex) was examined bilaterally in 54 cluster headache (CH) patients suffering from episodic CH (ECH) and chronic CH (CCH). Fifteen ECH patients were examined in both remission and active phases. The RIII reflex threshold (Tr) and the threshold of pain sensation (Tp) were significantly reduced on the symptomatic side in patients with episodic CH during the bout. During the active phase of episodic CH an inverse correlation was found between the severity of CH (ratio: number of cluster periods/years of illness duration) and the Tp, which may suggest a role for secondary central sensitization in pain pathways. The lower Tr and Tp on the symptomatic side is in keeping with previous observations exploring pain mechanisms using different methods (i.e. corneal reflex, pain pressure threshold). On the whole, these data tie in with the view of an impairment of the pain control system, which parallels the periodicity of the disorder in the episodic form.

Adult↗

PubMed2000

Effect of nitric oxide donors on the central nervous system--nitroglycerin studies in the rat.

The demonstration that nitrovasodilators act as nitric oxide (NO) donors has favored a resurgence of interest in this class of compounds. The demonstration of the different biological effects of NO in various districts, including the central nervous system, suggests a possible role for these substances besides their well-known cardiovascular activity. Among the various nitrovasodilators commercially available, nitroglycerin represents a well known substance to headache experts because of its capability to provoke spontaneous-like migraine attacks in headache-free migrainous subjects. Basic research has recently demonstrated that nitroglycerin activates a variegate set of brain nuclei following systemic administration via the intervention of selected neurotransmitters and neuromediators, with a specific time-pattern in different brain areas. Increasing evidence suggests that nitroglycerin-induced neuronal activation is mediated by multiple mechanisms that include direct neuronal and vascular action of nitroglycerin-derived and endogenously-synthesized NO, as well as indirect effects related to nitroglycerin-induced changes in cardiovascular and trigeminovascular systems. The study of the neurovascular effects of nitroglycerin in the rat provides relevant information for a better understanding of the pathophysiology of migraine attacks and of their triggers.

Animals↗

PubMed2000

Headache in the Diagnosis-Related Groups (DRG) era: management and appropriateness of admission.

Headache is an extremely common disorder which has a marked impact on the utilisation of healthcare resources and constitutes a considerable socio-economic burden. The related costs, both direct and indirect, are especially high in developed countries, since headache predominantly affects an economically-active section of the population. The Diagnosis-Related Groups (DRG) system, a method for reimbursing healthcare structures for patient admissions, was introduced in Italy in 1995. The aim of the system was to control public health expenditure and to promote better distribution of financial resources. Here, we report the results of the application of the DRG system to headache patients admitted to the Department of Neurology of the University of Pavia in 1996 and 1998. The financial analysis revealed high fixed costs (hospital running costs per days of hospitalisation); by contrast, the impact of the variable costs (those relating to the direct management of the individual patient, i.e. examinations, therapeutic interventions etc.) was low. It was found that reducing the number of days of hospitalisation increases the hospital's income and reduces the mean loss incurred in each DRG. It is therefore suggested that a complete approach to the management of headache must include educational programmes for patients and general practitioners, and that access to headache centres and to hospital care should be restricted to cases of acute, severe headache, or recurrent, chronic headache with/without drug abuse or dependence.

Costs and Cost Analysis↗

PubMed1999

Reciprocal circuits involved in nitroglycerin-induced neuronal activation of autonomic regions and pain pathways: a double immunolabeling and tract-tracing study.

This study uses tract-tracing protocols to determine the circuitry of specific nuclei involved in nitroglycerin-induced activation. Combined retrograde and anterograde tracers were injected into nuclei which consistently demonstrate robust Fos expression following our systemic nitroglycerin injection paradigm. The nuclei, which conform to these criteria, that we have evaluated in this study are the locus coeruleus, parabrachial nucleus and paraventricular nucleus of the hypothalamus. Dual Fos/tracer immunocytochemistry in treated animals documented the existence of a subset of autonomic nuclei which are activated by nitroglycerin injection and have reciprocal connections. From the nature of this rich interconnection we suggest that nitroglycerin activates autonomic responses involved in cardiovascular pressor mechanisms. Nuclei which show strong Fos labeling following nitroglycerin administration, but not traced in this study, include the nucleus trigeminalis caudalis and the ventrolateral column of the periaqueductal gray, both of which mediate nociceptive modalities. These data confirm and expand on our previous findings and demonstrate that nitroglycerin activates a complex set of structures that are functionally and structurally interconnected to articulate an integrated response.

Animals↗

PubMed1999

Determination of hydroxyl free radical formation in human platelets using high-performance liquid chromatography with electrochemical detection.

The formation of the hydroxyl free radical (HFR) can be quantified indirectly, by measuring two products of the hydroxylation of salicylic acid, 2,3-dihydroxybenzoate (2,3-DHB) and 2,5-dihydroxybenzoate (2,5-DHB). In this study, we used reversed-phase high-performance liquid chromatography with electrochemical (coulometric) detection to measure 2,3-and 2,5-DHB levels in human platelets. The limits of detection of the method were 10 and 5 fmol on column for 2,3-DHB and 2,5-DHB, respectively. We tested the technique by measuring increases in dihydroxybenzoate levels after exposure of platelets to experimentally induced oxidative stress. Then, we measured platelet levels of 2,3- and 2,5-DHB in patients with Parkinson's disease, under therapy with L-DOPA, and in normal subjects. We also measured platelet concentrations of L-DOPA and its major metabolite, 3-O-methyldopa (3-OMD). Parkinsonian patients showed increased levels of both 2,3- and 2,5-DHB. Platelet levels of 2,3-DHB were positively correlated with platelet levels of L-DOPA and 3-OMD. The technique we describe proved simple and extremely sensitive and may represent a useful tool for the study of oxidative stress in humans.

Adult↗

PubMed1999

Vasomotor response to CO2 and L-Arginine in patients with severe internal carotid artery stenosis; pre- and post-surgical evaluation with transcranial Doppler.

BACKGROUND AND AIM: Carotid artery disease may cause both thromboembolism and cerebral blood flow disturbances, particularly in subjects with impaired hemodynamic compensatory mechanisms. The aim of this study was to evaluate by transcranial Doppler (TCD) the hemodynamic changes induced by CO2 and L-Arginine stimulation in a selected population with severe unilateral carotid stenosis (70-80%), before and after carotid endarterectomy, in order to determine the effect of surgery in the vascular hemodynamics of these patients. METHODS: We studied 20 subjects (mean age 66.4 years) consecutively admitted to our institute with ischemia and unilateral severe internal carotid artery stenosis (70-80%) detected by Color Doppler. All patients underwent arterial digital subtraction angiography to confirm the ultrasonographic evaluation. TCD was performed bilaterally; blood flow velocity was monitored during CO2 and L-Arginine stimulation both in basal conditions and three months after surgery. RESULTS: After endarterectomy, mean velocity increased in response to both stimuli with a trend toward statistical significance. A significantly lower reactivity to L-Arginine on the stenotic side was found in the pre-operative phase: this asymmetrical reactivity was no longer observable after carotid endarterectomy. CONCLUSIONS: We found a statistically significant difference in L-Arginine reactivity in the stenotic side of patients with severe unilateral internal carotid stenosis. This is probably related to an alteration of the endothelium function due to the carotid pathology, since the abnormalities disappeared three months after endarterectomy.

Aged↗

PubMed1999

Different effect of high doses of naloxone on spinal reflexes in normal subjects and chronic paraplegic patients.

There is still controversy over the effects of naloxone on spinal reflexes in view of the fact that both facilitatory and inhibitory activities have been observed. Dosage, supraspinal influences and interactions with different opiate receptors may account for the different findings. We investigated the effect of placebo (saline) and high doses of naloxone (1.66 mg/kg) on the monosynaptic (H reflex) and nociceptive polysynaptic reflex (RIII reflex) in five normal subjects and three chronic paraplegic subjects. Following the administration of naloxone, there were no changes in the RIII reflex threshold in either group. By contrast, there was a marked facilitation of the H reflex amplitude in the normal subjects, but not in the spinal cord-injured subjects after treatment with naloxone. Saline induced no changes in the RIII reflex threshold or the H reflex amplitude in either of the two groups. Our data suggest that under normal conditions the opiatergic modulation of the nociceptive reflex is not functionally active whereas the tonic inhibitory modulation of the monosynaptic reflex is mediated by descending pathways.

Adult↗

PubMed1999

Importance of bioavailable calcium drinking water for the maintenance of bone mass in post-menopausal women.

The aim of this research was to establish the importance of calcium intake through mineral water on vertebral bone density in women. To this purpose, we examined 255 women divided into two groups: those regularly drinking a high calcium content mineral water (group A; no.=175) and those using different type of water with a lower calcium content (group B; no.=80). Their dietary daily calcium intake was determined by means of a validated questionnaire (N.I.H. Consensus statement) and vertebral bone density was measured by Dual-Energy X-ray absorptiometry (Unigamma-plus ACN densitometer). Women in group A ingested a significantly higher quantity of calcium in water than women in group B (mean difference 258 mg; 95% confidence limits: 147-370 mg). The average bone density values were slightly but significantly higher in group A as compared to group B (mean+/-SD: 1.044+0,15 vs 1.002+0,14; p=0.03). In addition to age, BMI and menopausal status, calcium intake was a significant predictor of spinal BMD. These 4 variables explained about 35% of the spinal BMD variance. When the analysis was repeated separately for pre- and post-menopausal subjects, calcium remained a significant predictor in post-menopausal women (t=2.28; p=0.02), but not in premenopausal women. These results underline the importance of a lifelong daily calcium intake, resulting by the regular drinking of high bioavailable calcium water, in order to maintain bone mass after the menopause, in comparison to the use of a lower content calcium water.

Absorptiometry, Photon↗