Virgilio Gallai

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Vasoactive Peptide Levels in The Plasma of Young Migraine Patients With and Without Aura Assessed Both Interictally and Ictally

We measured, by RIA methods, ictal and interictal levels of substance P (SP), calcitonin-gene related peptide (CGRP) and neurokinin A (NKA) in the plasma of 30 young migraine patients with aura (MPA) and 45 migraine patients without aura (MWA), and compared the results with those of 30 age-matched controls. There were no significant differences between the levels of these vasoactive peptides in the control group and the levels in both migraine groups studied in headache-free periods. An elevation of CGRP levels in plasma was found during attacks in MPA and, to a lesser extent, in MWA (p < 0.03 and p < 0.05, respectively). A significant increase in NKA levels was also demonstrated in the MPA and MWA groups (p < 0.02 and p < 0.04, respectively). These data suggest, although indirectly, that CGRP and NKA could be involved in the pathogenesis of migraine attacks in juvenile migraine patients.

Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids.

To demonstrate the influence of n-3 PUFA supplementation on cytokine and eicosanoid production in peripheral blood mononuclear cells (PBMCs) of MS patients (MSP), we investigated the impact of a 6-month dietary supplementation with these fatty acids on the levels of interleukin-1 beta (IL-1 beta), IL-2, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the supernatants of stimulated PBMCs and serum soluble IL-2 receptors in a group of 20 relapsing-remitting (R-R) MSP and a group of 15 age-matched control individuals (CI). The production of PGE2 and LTB4 in the stimulated PBMCs was also assessed in patient and control groups supplemented with n-3 PUFAs. In both groups, n-3 PUFA supplementation led to a significant decrease in the levels of IL-1 beta and TNF-alpha, and this reduction was more pronounced in the 3rd and 6th month of supplementation. An analogous decrease was observed in the levels of IL-2 and IFN-gamma produced by stimulated PBMCs, and in the levels of serum soluble IL-2 receptors. n-3 PUFA supplementation also appeared to significantly affect prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production in PBMCs, both in MSP and the control group. The reduced production of these proinflammatory eicosanoids, and the decrease of some cytokines with an immunohenancing effect as a consequence of n-3 PUFA supplementation, could modulate some immune functions which have been demonstrated to be altered in MSP.

Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks

Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the l-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be confirmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of five patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1α, the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the first hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (anova, statistical significance: P < 0.001; P < 0.002; P < 0.002; P < 0.003, respectively). PGE2 and 6 keto PGF1α, as well as cAMP levels also significantly increased at the first hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (anova: P < 0.002, P < 0.004, P < 0.001, respectively). Our results support early activation of the l-arginine/NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase.

Dysphagia following Stroke

Background: Dysphagia is common after stroke. We aimed to study the prognosis of dysphagia (assessed clinically) over the first 3 months after acute stroke and to determine whether specific neurovascular-anatomical sites were associated with swallowing dysfunction. Methods: We prospectively examined consecutive patients with acute first-ever stroke. The assessment of dysphagia was made using standardized clinical methods. The arterial territories involved were determined on CT/MRI. All patients were followed up for 3 months. Results: 34.7% of 406 patients had dysphagia. Dysphagia was more frequent in patients with hemorrhagic stroke (31/63 vs. 110/343; p = 0.01). In patients with ischemic stroke, the involvement of the arterial territory of the total middle cerebral artery was more frequently associated with dysphagia (28.2 vs. 2.2%; p < 0.0001). Multivariate analysis revealed that stroke mortality and disability were independently associated with dysphagia (p < 0.0001). Conclusions: The frequency of dysphagia was relatively high. Regarding anatomical-clinical correlation, the most important factor was the size rather than the location of the lesion. Dysphagia assessed clinically was a significant variable predicting death and disability at 90 days.

Plasma cytokine levels in patients with obstructive sleep apnea syndrome: a preliminary study

The levels of some pro‐ and anti‐inflammatory cytokines [interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, IL‐6, IL‐10, and transforming growth factor (TGF)‐β], were measured by enzyme‐linked immunosorbent assay (ELISA) method in the plasma of patients affected by obstructive sleep apnea syndrome (OSAS) at 22:00 hours before polysomnographic recording and immediately after the first obstructive apnea causing an SaO2 below 85%. Significantly higher levels of TNF‐α were found in OSAS patients assessed before polysomnography compared with the control group (P < 0.01). A slight but significant increase in the plasma levels of IL‐6 was also present (P < 0.05). Conversely, a significant decrease in the plasma levels of IL‐10 was evident at baseline in OSAS patients (P < 0.04). No significant difference emerged between the mean values of IL‐1α and TGF‐β between OSAS patients and controls. The present data support a prevailing activation of the Th1‐type cytokine pattern in OSAS patients, which is not associated with the severity and duration of OSAS. This can have important consequences for the outcome of OSAS patients, especially with regard to the increased risk for developing atherosclerosis and cardiovascular and cerebrovascular diseases. Immediately after the first obstructive apnea causing an SaO2 <85%, a significant variation was observed in the plasma levels of TNF‐α in OSAS patients compared with those measured before the beginning of polysomnographic recording (P < 0.001). The role played by this further increase in TNF‐α levels after the obstructive apnea in OSAS patients remains to be established in the light of the pathogenic mechanisms of this sleep disorder.

Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients

Nerve growth factor (NGF) levels were determined in the CSF of patients with chronic daily headache (CDH) and correlated with levels of sensory neuropeptides. Patients with CDH showed higher NGF levels in the CSF compared with control subjects (p < 0.0001). Higher CSF levels of substance P (SP) (p < 0.002) and calcitonin-gene–related peptide (CGRP) (p < 0.0001) were also found. There was a significant positive correlation between NGF and both SP and CGRP values. These findings suggest that NGF is involved in the long-lasting sensitization and sustained activation of the trigeminal system in CDH.

Applicability of the 1988 IHS Criteria to Headache Patients Under the Age of 18 Years Attending 21 Italian Headache Clinics

Seven hundred nineteen young patients attending 21 Italian headache care settings were evaluated by a diagnostic headache interview and a neurological examination. Headache disorders were classified according to the current 1988 criteria of the International Headache Society (IHS); 54.9% of the patients suffered from migraine, 33.9% from tension‐type headache, 1.9% from secondary headache, and 3.4% had non‐classifiable headache. A further 5.9% of the patients were not classified due to incomplete questionnaires.

Brain-derived neurotrophic factor in patients with multiple sclerosis

UNLABELLED The aim of the present research was to verify the production of BDNF by peripheral blood mononuclear cells (PBMCs), unstimulated and stimulated with phytohemagglutinin (PHA), anti-OKT3 Ab and myelin basic protein (MBP), in 35 patients affected by multiple sclerosis (MS), 20 with relapsing-remitting (R-R) MS and 15 with secondary progressive (SP) MS. Seven R-R MS patients were assessed during the attack, in the subsequent recovery phase and also 3 months after relapse. The production of BDNF by PBMCs was also evaluated in 20 age- and sex-matched control subjects. Levels of BDNF were also determined in CSF of both patient groups and 20 control subjects. RESULTS Levels of BDNF (pg/ml) in the supernatants of unstimulated and PHA-, anti-OKT3 Ab- and MBP-stimulated PBMCs in patients with R-R MS were significantly higher during relapse and in the recovery phase compared with values detected in the stable phase of the disease. Significantly lower BDNF values were found in unstimulated and stimulated PBMC supernatants of patients with SP MS compared to control subjects. This reduction was greater in patients with a 1-point increase in the EDSS score in the last 6 months compared with that in patients without a progression of the disability score. Reduction in the levels of BDNF was also confirmed in the CSF of SP MS patients compared with R-R MS patients assessed during a stable phase of the disease and control subjects. DISCUSSION On the basis of recent experimental findings, a neuroprotective effect of BDNF produced by inflammatory cells can be hypothesized during relapses in MS. This can favor remyelination. The reduced production of BDNF by PBMCs of patients with SP MS can contribute to the progression of demyelinating disease and axonal loss in this form.

Endothelin 1 in migraine and tension-type headache

We determined the plasma levels of ET1, both interictally and ictally, in 50 migraine patients, 20 with aura (MPA) and 30 without aura (MPWA), comparing them with the levels of 40 age‐matched tension‐type headache patients (20 episodic and 20 chronic) (ETTHP and CTTHP) and the levels of a group of 20 healthy control subjects (CS). No statistically significant difference was evident between the mean ET1 plasma levels of MPA and those of MPWA, assessed in headache‐free periods. The mean ET1 plasma levels of MPA and MPWA, assessed interictally, were significantly higher than those of CS. However, the values of plasma ET1 in ETTP and in CTTHP did not differ statistically from those of CS. MPA and MPWA ET1 plasma levels increased significantly within 2 h from the onset of attacks (p<0.0001) and remained significantly higher between 4 and 6 h from the onset. The ET1 plasma levels of ETTHP and CTTHP assessed during attacks did not differ statistically from those of the same patients assessed in the headache‐free periods. The increase in ET1 levels in MPA and MPWA patients when assessed ictally, suggests that this peptide is involved in the haemodynamic changes and vascular tone modifications observed during migraine attacks, particularly in the first phase of the ictal period.