Rocco Totaro - Academia.edu (original) (raw)
Papers by Rocco Totaro
Journal of Translational Medicine, 2011
Background Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured... more Background Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months. Methods RRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests. Results Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation. Conclusions Although differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.
Clinical Neuropharmacology, 2004
ABSTRACT The authors evaluated the relationships between clinical and pharmacologic parameters an... more ABSTRACT The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-β1a (IFN-β1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNβ-1a-treated patients. Finally, it would appear that the failure of IFNβ-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNβ-1a itself.
Italian Journal of Neurological Sciences, 1993
We investigated some ultrastructural aspects of platelet activity in patients with classic migrai... more We investigated some ultrastructural aspects of platelet activity in patients with classic migraine during an attack-free period. We focused on the production of malondialdehyde (MDA), the intracellular concentration of Ca++and the membrane phospholipid structure using a DPH (1,6 diphenyl-1,3,5 hexatriene) fluorescent probe. Our study comprised 20 patients with classic migraine and 5 healthy controls, from whom 10 cc samples of blood were collected in test tubes containing sodium citrate (1/9 cc). We found no significant differences in MDA production between migraineurs and controls either before or after stimulation with thrombin. The same applies to the concentration of intracellular Ca++(Ca++i). The membrane lipid composition assessed by DPH fluorescent probe was normal both in migraineurs and in controls. Our findings suggest no intrinsic activation of platelet aggregation. Nel nostro studio abbiamo indagato in soggetti con emicrania con aura, durante le fasi libere da crisi, alcuni aspetti ultrastrutturali dell' attività piastrinica. In particolare sono stati studiati la produzione di malondialdeide (MDA), la concentrazione del Ca++intracellulare e la struttura fosfolipidica di membrana con probe fluorescente DPH (1,6 Diphenyl-1,3,5 hexatriene). Sono stati inclusi 20 soggetti emicranici con aura e 5 soggetti sani, sottoposti a prelievi ematici di 10 cc in provette con Sodio citrato (1/9 cc). I nostri risultati non mostrano differenze significative per la produzione di MDA, prima e dopo stimolo con trombina, sia nei pazienti emicranici che nei controlli. Analogamente è stato riscontrato per la concentrazione del Ca++intracellulare [Ca++i]. La composizione lipidica di membrana valutata con probe fluorescente DPH, risulta normale negli emicranici e nei controlli. I dati ottenuti indicano la probabile assenza di attivazione intrinseca della aggregazione piastrinica.
Ultrasound in Medicine and Biology, 2002
This study evaluated the effects of two different rates of infusion of echo-contrast agents (ECA)... more This study evaluated the effects of two different rates of infusion of echo-contrast agents (ECA) on signal enhancement. A total of 15 patients with insufficient Doppler signal due to inadequate transtemporal acoustic bone window were examined. Signal from the middle cerebral artery was recorded during the IV infusion of Levovist (300 mg/mL). Increment of signal enhancement in dB, time to signal enhancement appearance, time to clinically useful signal enhancement appearance, and duration of clinically useful signal enhancement were assessed during two infusions at the rate of 1 and 0.66 mL/min, respectively. Increment of signal enhancement was similar at the rate of 1 and 0.66 mL/min (p = 0.4). Mean time to signal enhancement appearance and mean time to clinically useful signal enhancement appearance were not significantly different with the two rates of infusion (p = 0.9 and p = 0.3, respectively). Mean duration of clinically useful signal enhancement was significantly higher with the infusion rate of 0.66 mL/min as compared to 1 mL/min (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Levovist injected at the infusion rate of 0.66 mL/min prolonged the mean duration of signal enhancement, maintaining its effectiveness.
Ultrasound in Medicine and Biology, 1992
Transcranial Dopplersonography (TCD) is a useful noninvasive technique for the measurement of int... more Transcranial Dopplersonography (TCD) is a useful noninvasive technique for the measurement of intracranial arterial blood flow velocity. The present study evaluated the reproducibility of this method for repeated measurements of flow velocity in the anterior, middle and posterior cerebral, and basilar arteries. Thirtysix patients (23 males and 13 females) were studied. Three measurements were made by the same examiner on each patient with a time interval of 1 h between the first and the second examination, and about 24 h between the first and the third examination. The statistical evaluation for the reproducibility was performed by calculating the correlation coefficient (r). The results showed good reproducibility of TCD for all arteries both between the first and second and between the first and third measurements (r = 0.78-0.97;~ < O.OOl), but when the middle cerebral artery mean velocity is low the posterior cerebral artery reproducibility is poorest (r = 0.42-0.54).
European Neurology, 2009
To evaluate incidence, case fatalities and prognosis of subarachnoid hemorrhage (SAH). Prospectiv... more To evaluate incidence, case fatalities and prognosis of subarachnoid hemorrhage (SAH). Prospective population-based registry (1994-1998) including patients with a first-ever stroke followed up to 10 years. In a 5-year period we included 118 patients (55 men and 63 women; mean age +/- SD 60.7 +/- 15.9 years) with an SAH. The crude annual incidence rate was 7.93 cases per 100,000 inhabitants (95% CI 6.46-9.63), 7.60 per 100,000 when standardized to the 2006 European population and 5.27 per 100,000 when standardized to the 2005 world population. The 7-day case-fatality rate was 16.1% (95% CI 9.5-22.7), 30-day case-fatality rate was 34.7% (95% CI 21.2-43.3), and 1-year case-fatality rate was 44.9% (95% CI 35.9-53.9). At the end of the 1-year follow-up, 53 patients (44.9%) had a good recovery [modified Rankin scale (mRS) 0-2] and 12 (10.2%) had a severe disability (mRS 3-5). The 10-year survival rate was 46.4% (95% CI 36.0-57.8). In our district, the SAH incidence rate was similar to what is reported in most European countries. Since more than half of the patients with SAH remained severely disabled or died, results from our population-based study strongly support the notion that the most appropriate treatments should be made available for all patients in comprehensive centers and the call for an urgent implementation of telemedicine in the rural areas of our district.
Stroke, 2005
Background and Purpose-Atrial fibrillation (AF) is a major risk factor for ischemic stroke and it... more Background and Purpose-Atrial fibrillation (AF) is a major risk factor for ischemic stroke and its prevalence increases steeply with age. Population-based data on its influence on stroke outcome are scarce. Methods-We evaluated the prevalence of AF and its influence on prognosis in patients with a first-ever ischemic stroke from a population-based registry. Results-The presence of AF at stroke onset and during the acute phase was confirmed by a standard electrocardiogram in 869 (24.6%) of 3530 patients with ischemic stroke. With respect to patients without the arrhythmia, those with AF were more frequently women, aged 80 years and older, with coronary heart disease and peripheral arterial disease. The presence of AF was associated with high 30-day (32.5%; 95% CI, 29.3 to 35.6) and 1-year case-fatality rates (49.5%; 95% CI, 46.2 to 52.8), with a higher stroke recurrence rate within the first year of follow-up (6.6% versus 4.4%; Pϭ0.046) and with the worst survival after an average follow-up of 45.2 months (PϽ0.0001). At the multivariate Cox regression analysis, AF was an independent predictor of 30-day and 1-year mortality. Approximately 17% of all deaths were attributable to the presence of AF. Conclusions-We found a high prevalence of AF in patients with a first-ever ischemic stroke, especially among elderly women. The overall contribution of AF to stroke mortality was relevant, suggesting that together with new strategies to prevent the development of the arrhythmia more appropriate treatments are needed, mostly in elderly women. (Stroke. 2005;36:1115-1119.)
Neuroimmunomodulation, 2005
The immunological effect of CD30 on dendritic cells (DCs) was examined in a comparative study of ... more The immunological effect of CD30 on dendritic cells (DCs) was examined in a comparative study of patients with relapsing-remitting multiple sclerosis (RRMS). The patients were divided into two groups on the basis of interferon (IFN)beta-1a treatment: IFNbeta-1a-treated patients and untreated patients. We have already shown that CD30 is a marker of cells involved in the regulation of the balance between TH1 and TH2 immune responses and so the aim of this study was to confirm this role in DCs and, consequently, to clarify the immunopathological mechanisms of MS and the causes of immunosuppressive drug failure. We studied network interactions between soluble (s) CD30 and TH1/TH2 cytokines in the supernatants of CD14+-derived immature DC (IDC) and DC cultures from treated and untreated patients. Network interactions between the sCD30 and cytokines in IDC and DC supernatants were also evaluated in relation to TH1/TH2 cytokine serum levels. Our overall results show that CD30 is expressed on IDCs and DCs, indicating an immunological role in resting and activated physiological conditions. This role would appear to be the regulation of the resting and activated physiological balance between the TH1/TH2 immune functions as abnormal increases in sCD30 levels result in impaired regulation. Further studies are undoubtedly required to clarify this situation. IFNbeta-1a treatment was found to determine a fall in sCD30 levels, leading to the restoration of the normal functional selection of IDCs from progenitor cells and the regulation of the TH1/TH2 network balance. However, IFNbeta-1a treatment may also be responsible for the in vivo suppression of CD30-mediated TH1-DC functions in immune activation. TH1-DC functions are involved in the induction of T-regulatory cells for the physiological deletion of self-aggressive cells. We conclude that CD30 is an important costimulatory molecule and marker of a regulatory subpopulation of DCs which induces and modulates immune cells involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. Elucidating the mechanisms restoring DC and T-regulatory cell function could lead to more effective therapy and strategies for the prevention and treatment of immunopathological conditions such as autoimmunity, transplant rejection, allergy and tumors.
Journal of Biomedical Optics, 2000
Spatially resolved spectroscopy (SRS) is a new near infrared spectroscopy (NIRS) method that, usi... more Spatially resolved spectroscopy (SRS) is a new near infrared spectroscopy (NIRS) method that, using the multi-distance approach, measures local cerebral cortex hemoglobin oxygen saturation [J. Matcher, P. Kirkpatrick, K. Nahid, M. Cope, and D. T. Delpy, Proc. SPIE 2389, 486-495 (1995)]. Using a conventional continuous wave NIRS photometer, cerebral venous oxygen saturation (SvO2) can be calculated from oxyhemoglobin and total hemoglobin rise induced by partial occlusion of jugular vein [C. E. Elwell, S. J. Matcher, L. Tyszczuk, J. H. Meek, and D. T. Delpy, Adv. Exp. Med. Biol. 411, 453-460 (1997)]. The aim of this study was to compare direct measurements of forehead tissue oxygenation index (TOI) with the calculated SvO2 during venous occlusion in 16 adult volunteers using a clinical two-channel SRS oximeter (NIRO-300). Measured TOI and calculated SvO2 values of either right or left forehead did not significantly differ. A good agreement between the two NIRS methods was also demonstrated. On 16 other subjects, no significant differences were found between the right and left forehead TOI values measured simultaneously, and between the TOI values measured by channel 1 or 2 on the same side. The results confirm that cerebral cortex hemoglobin oxygen saturation, measured directly by the SRS method, reflects predominantly the saturation of the intracranial venous compartment of circulation.
Cerebrovascular Diseases, 1999
Transcranial Doppler is routinely used to assess the cerebrovascular reactivity, despite scarce i... more Transcranial Doppler is routinely used to assess the cerebrovascular reactivity, despite scarce information on its reproducibility. We evaluated the reproducibility of cerebrovascular reactivity measurements by this method utilizing different vasodilatory and vasoconstrictor stimuli. The cerebrovascular reactivity was measured in 45 healthy volunteers during hypercapnia induced by inhalation of a mixture of 5% CO2 and 95% O2, breath holding and rebreathing, and during hypocapnia induced by voluntary hyperventilation. Three sets of measurements were performed at times 0, 1, and 24 h to assess the within-observer short- and long-term reproducibility. The reproducibility was analyzed using the intraclass correlation coefficient. For the CO2 inhalation method, a good short-term (rI = 0.55; 95% CI = 0.39-0.68) and a good long-term (rI = 0.43; 95% CI = 0.25-0.59) reproducibility was found. For the breath-holding method a good short-term agreement was found (rI = 0.41; 95% CI = 0.22-0. 57), while the long-term reproducibility was poor (rI = 0.17; 95% CI = -0.03-0.36). Rebreathing showed a fair (rI = 0.31; 95% CI = 0.11-0. 48) short-term and a poor (rI = 0.17; 95% CI = -0.03-0.36) long-term reproducibility. For voluntary hyperventilation, the short-term reproducibility was good (rI = 0.53; 95% CI = 0.36-0.66), and the long- term reproducibility was fair (rI = 0.31; 95% CI = 0.11-0.48). In our study, CO2 inhalation and voluntary hyperventilation had the highest reproducibility and should be preferred when assessing cerebral vasoreactivity, especially in follow-up studies.
Journal of Neurology Neurosurgery and Psychiatry, 2000
Objective-To estimate the prevalence of multiple sclerosis in the L'Aquila district, central Ital... more Objective-To estimate the prevalence of multiple sclerosis in the L'Aquila district, central Italy. Methods-All available case sources were screened. Definite and probable cases of multiple sclerosis, classified according to the Poser criteria, were considered as prevalent cases. Results-On the prevalence day, 31 December 1996, 158 patients (105 women and 53 men; ratio 2:1) aVected by definite (n=131) or probable (n=27) multiple sclerosis were alive and resident in the L'Aquila district. Mean (SD) age was 38.4 (11.9) years (38.9 (11.7) years for women and 38.5 (12.3) years for men, p=0.9). The overall crude prevalence was 53.0/100 000 (95% confidence interval (95% CI)=45.4-62.0); 68.4/100 000 (95% CI=56.5-82.8) in women, and 36.7/100 000 (95% CI=28.1-48.0) in men. The prevalence was similar (55.9/100 000) when standardised to the 1996 European population. Mean (SD) age at onset of multiple sclerosis was 29.4 (9.6) years and mean (SD) duration of the disease was 9.4 (7.4) years, without any significant diVerence between sexes. Mean age at onset was significantly higher in patients with the primary progressive than in those with the relapsing-remitting course (p=0.0002, ScheVé's test). Conclusions-The prevalence found in the L'Aquila district gives support to the consideration of Italy as an area in which multiple sclerosis has been shown to have high prevalence at least in the populations that were surveyed recently. (J Neurol Neurosurg Psychiatry 2000;68:349-352)
European Neurology, 2004
Type 1A, the most common form of Charcot-Marie-Tooth (CMT1A) disease, is characterized by demyeli... more Type 1A, the most common form of Charcot-Marie-Tooth (CMT1A) disease, is characterized by demyelination of the peripheral nervous system. So far, only a few cases of the disease with concomitant brain white matter lesions have been described. We report an Italian family with CMT1A disease, consisting of the proband and 4 affected members, presenting with concomitant brain white matter lesions at magnetic resonance imaging. The association is particularly fascinating and might depend on an autoimmune mechanism, not yet clarified.
Italian Journal of Neurological Sciences, 1993
Cerebral blood flow was measured by transcranial Dopplersonography (TCD) in 15 patients during an... more Cerebral blood flow was measured by transcranial Dopplersonography (TCD) in 15 patients during and after an attack of paroxysmal atrial fibrillation. During the attack the mean flow velocity (MFV) was reduced significantly in the middle cerebral artery (p<0.05) and nonsignificantly in the other arteries. The pulsatility index (PI) was reduced in all the arteries but not significantly. During the fibrillation phase the MFV and PI tended to decrease as the heart rate increased. None of the patients showed clinical signs of cerebral ischemia during the attacks. The absence of such signs despite the reduced cerebral blood flow in atrial fibrillation is probably due to the activation of mechanisms of autoregulation. Il flusso ematico cerebrale, valutato con Doppler Transcranico (TCD), è stato misurato in 15 pazienti durante e dopo un episodio di fibrillazione atriale parossistica. Durante l'attacco di fibrillazione la Mean Flow Velocity (MFV) è risultata ridotta in modo significativo nella cerebrale media (p<0.05), mentre si è ridotta in modo non significativo nelle altre arterie. I valori dell'indice di pulsatilità (PI) sono risultati ridotti in tutte le arterie ma non significativamente. La correlazione tra la velocità di flusso, il PI e la frequenza cardiaca durante la fase di fibrillazione ha mostrato una tendenza alla riduzione della MFV e del PI con l'aumentare della frequenza. Durante gli episodi di fibrillazione atriale nessuno dei pazienti ha manifestato segni clinici di ischemia cerebrale. I risultati indicano che, in corso di fibrillazione atriale, si verifica una riduzione di flusso cerebrale che non si accompagna a sintomi di ischemia cerebrale verosimilmente per l'attivazione dei meccanismi di autiregolazione.
Headache, 1992
SYNOPSISTranscranial Doppler sonography examination was performed on 44 patients with migraine wi... more SYNOPSISTranscranial Doppler sonography examination was performed on 44 patients with migraine with aura and 88 controls. All patients were investigated in headache-free periods and 10 of them also during a migraine attack. During the headache-free period a not significant increase of mean flow velocity in patients compared to controls was obtained. The pulsatility index (PI) mean values were also higher in patients than in controls and the differences were significant in the MCA (p<0.05). No difference between right and left side was observed. During the attack the mean flow velocity (MFV) decreased in all arteries but the decrease was significant only in MCA and ACA (p<0.05). The mean PI increased in all arteries but not significantly. These variations were observed both on the headache and contralateral side. Nevertheless, the MFV decrease in all arteries was observed in four patients only. In four patients the MFV decrease was found in the anterior arteries and the MFV increase in the posterior arteries, while in two patients the MFV increase was observed both in the anterior and posterior arteries. The correlation between the variations of MFV values during the attacks and the time interval from the onset of attacks showed that the PCA and BA flow velocities were increased in patients examined between 0.5 and 3 hours, while an increase in MCA and ACA flow velocities were observed only in patients examined after 1.5 hours.
Clinical Science, 1998
1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain ... more 1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain to the light in the near-IR region (700-1100 nm) and on the oxygen-dependent tissue absorption changes of haemoglobin.2. We evaluated the most relevant factors (reproducibility, venous return, age and sex) that might affect reliability of near-IR spectroscopy to test CO2 cerebrovascular reactivity.3.Thirty-four healthy volunteers were enrolled in the study. The protocol consisted of a 3-min baseline, a 3-min hypercapnia (5% CO2 in air) and a 2-min recovery. Transcranial Doppler sonography measurements were simultaneously performed. The CO2 reactivity test was repeated on 27 subjects after 1 h to assess reproducibility. CO2 reactivity was also evaluated at different body positions (supine, 35 degrees Trendelenburg and 35 degrees reverse Trendelenburg), and over a gradual increase of the inspired CO2.4. Changes in near-IR spectroscopy and transcranial Doppler sonography parameters were significantly correlated with variations of end-tidal CO2 (P<0.005). A significant correlation between the reactivity indexes of near-IR spectroscopy parameters and flow velocity was also found (P<0.01). A high reproducibility was also found for deoxyhaemoglobin (rI=0.76), oxyhaemoglobin (rI=0.68) and flow velocity (rI=0.60) reactivity indexes. No significant differences between the reactivity indexes of different body positions were found (P>0.05). The reactivity index of oxyhaemoglobin and deoxyhaemoglobin decreased (P<0.05) and increased (P<0.01) with age respectively.5. We found that near-IR spectroscopy is a reliable and reproducible method for the evaluation of cerebrovascular reactivity and might be considered, after appropriate validation, for the assessment of patients with cerebrovascular disease.
Cephalalgia, 1997
Alterations of intracranial vessel tone have been implicated in the pathophysiology of migraine. ... more Alterations of intracranial vessel tone have been implicated in the pathophysiology of migraine. The cerebrovascular reactivity was measured by means of transcranial Doppler in 60 migraine patients with (n = 30) or without aura (n = 30) during the headache-free interval and in 30 healthy controls. The vasomotor response was evaluated during hypercapnia induced by inhalation of a mixture of CO2 5% and O2 95% and during hypocapnia obtained after voluntary hyperventilation. To improve the power of the study in detecting possible abnormalities of cerebrovascular reactivity, two different measures were performed at 1 week intervals in migraine patients and controls. Reactivity index values during CO2 inhalation were significantly different (p = 0.01) among the three groups during the first and second measurements; in particular, lower values were found in patients suffering from migraine without aura with respect to controls (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05, Scheffé&amp;amp;amp;amp;amp;amp;amp;#39;s test). Values of reactivity index obtained following induction of hypocapnia did not differ between migraine patients and controls (all p values &amp;amp;amp;amp;amp;amp;amp;gt; 0.05). Our data suggest a reduced vasodilatory response to hypercapnia of cerebral arterioles in patients suffering from migraine without aura with respect to controls that might be related to baseline arteriolar vasodilation.
Journal of Translational Medicine, 2011
Background Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured... more Background Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months. Methods RRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests. Results Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation. Conclusions Although differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.
Clinical Neuropharmacology, 2004
ABSTRACT The authors evaluated the relationships between clinical and pharmacologic parameters an... more ABSTRACT The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-β1a (IFN-β1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNβ-1a-treated patients. Finally, it would appear that the failure of IFNβ-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNβ-1a itself.
Italian Journal of Neurological Sciences, 1993
We investigated some ultrastructural aspects of platelet activity in patients with classic migrai... more We investigated some ultrastructural aspects of platelet activity in patients with classic migraine during an attack-free period. We focused on the production of malondialdehyde (MDA), the intracellular concentration of Ca++and the membrane phospholipid structure using a DPH (1,6 diphenyl-1,3,5 hexatriene) fluorescent probe. Our study comprised 20 patients with classic migraine and 5 healthy controls, from whom 10 cc samples of blood were collected in test tubes containing sodium citrate (1/9 cc). We found no significant differences in MDA production between migraineurs and controls either before or after stimulation with thrombin. The same applies to the concentration of intracellular Ca++(Ca++i). The membrane lipid composition assessed by DPH fluorescent probe was normal both in migraineurs and in controls. Our findings suggest no intrinsic activation of platelet aggregation. Nel nostro studio abbiamo indagato in soggetti con emicrania con aura, durante le fasi libere da crisi, alcuni aspetti ultrastrutturali dell' attività piastrinica. In particolare sono stati studiati la produzione di malondialdeide (MDA), la concentrazione del Ca++intracellulare e la struttura fosfolipidica di membrana con probe fluorescente DPH (1,6 Diphenyl-1,3,5 hexatriene). Sono stati inclusi 20 soggetti emicranici con aura e 5 soggetti sani, sottoposti a prelievi ematici di 10 cc in provette con Sodio citrato (1/9 cc). I nostri risultati non mostrano differenze significative per la produzione di MDA, prima e dopo stimolo con trombina, sia nei pazienti emicranici che nei controlli. Analogamente è stato riscontrato per la concentrazione del Ca++intracellulare [Ca++i]. La composizione lipidica di membrana valutata con probe fluorescente DPH, risulta normale negli emicranici e nei controlli. I dati ottenuti indicano la probabile assenza di attivazione intrinseca della aggregazione piastrinica.
Ultrasound in Medicine and Biology, 2002
This study evaluated the effects of two different rates of infusion of echo-contrast agents (ECA)... more This study evaluated the effects of two different rates of infusion of echo-contrast agents (ECA) on signal enhancement. A total of 15 patients with insufficient Doppler signal due to inadequate transtemporal acoustic bone window were examined. Signal from the middle cerebral artery was recorded during the IV infusion of Levovist (300 mg/mL). Increment of signal enhancement in dB, time to signal enhancement appearance, time to clinically useful signal enhancement appearance, and duration of clinically useful signal enhancement were assessed during two infusions at the rate of 1 and 0.66 mL/min, respectively. Increment of signal enhancement was similar at the rate of 1 and 0.66 mL/min (p = 0.4). Mean time to signal enhancement appearance and mean time to clinically useful signal enhancement appearance were not significantly different with the two rates of infusion (p = 0.9 and p = 0.3, respectively). Mean duration of clinically useful signal enhancement was significantly higher with the infusion rate of 0.66 mL/min as compared to 1 mL/min (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Levovist injected at the infusion rate of 0.66 mL/min prolonged the mean duration of signal enhancement, maintaining its effectiveness.
Ultrasound in Medicine and Biology, 1992
Transcranial Dopplersonography (TCD) is a useful noninvasive technique for the measurement of int... more Transcranial Dopplersonography (TCD) is a useful noninvasive technique for the measurement of intracranial arterial blood flow velocity. The present study evaluated the reproducibility of this method for repeated measurements of flow velocity in the anterior, middle and posterior cerebral, and basilar arteries. Thirtysix patients (23 males and 13 females) were studied. Three measurements were made by the same examiner on each patient with a time interval of 1 h between the first and the second examination, and about 24 h between the first and the third examination. The statistical evaluation for the reproducibility was performed by calculating the correlation coefficient (r). The results showed good reproducibility of TCD for all arteries both between the first and second and between the first and third measurements (r = 0.78-0.97;~ < O.OOl), but when the middle cerebral artery mean velocity is low the posterior cerebral artery reproducibility is poorest (r = 0.42-0.54).
European Neurology, 2009
To evaluate incidence, case fatalities and prognosis of subarachnoid hemorrhage (SAH). Prospectiv... more To evaluate incidence, case fatalities and prognosis of subarachnoid hemorrhage (SAH). Prospective population-based registry (1994-1998) including patients with a first-ever stroke followed up to 10 years. In a 5-year period we included 118 patients (55 men and 63 women; mean age +/- SD 60.7 +/- 15.9 years) with an SAH. The crude annual incidence rate was 7.93 cases per 100,000 inhabitants (95% CI 6.46-9.63), 7.60 per 100,000 when standardized to the 2006 European population and 5.27 per 100,000 when standardized to the 2005 world population. The 7-day case-fatality rate was 16.1% (95% CI 9.5-22.7), 30-day case-fatality rate was 34.7% (95% CI 21.2-43.3), and 1-year case-fatality rate was 44.9% (95% CI 35.9-53.9). At the end of the 1-year follow-up, 53 patients (44.9%) had a good recovery [modified Rankin scale (mRS) 0-2] and 12 (10.2%) had a severe disability (mRS 3-5). The 10-year survival rate was 46.4% (95% CI 36.0-57.8). In our district, the SAH incidence rate was similar to what is reported in most European countries. Since more than half of the patients with SAH remained severely disabled or died, results from our population-based study strongly support the notion that the most appropriate treatments should be made available for all patients in comprehensive centers and the call for an urgent implementation of telemedicine in the rural areas of our district.
Stroke, 2005
Background and Purpose-Atrial fibrillation (AF) is a major risk factor for ischemic stroke and it... more Background and Purpose-Atrial fibrillation (AF) is a major risk factor for ischemic stroke and its prevalence increases steeply with age. Population-based data on its influence on stroke outcome are scarce. Methods-We evaluated the prevalence of AF and its influence on prognosis in patients with a first-ever ischemic stroke from a population-based registry. Results-The presence of AF at stroke onset and during the acute phase was confirmed by a standard electrocardiogram in 869 (24.6%) of 3530 patients with ischemic stroke. With respect to patients without the arrhythmia, those with AF were more frequently women, aged 80 years and older, with coronary heart disease and peripheral arterial disease. The presence of AF was associated with high 30-day (32.5%; 95% CI, 29.3 to 35.6) and 1-year case-fatality rates (49.5%; 95% CI, 46.2 to 52.8), with a higher stroke recurrence rate within the first year of follow-up (6.6% versus 4.4%; Pϭ0.046) and with the worst survival after an average follow-up of 45.2 months (PϽ0.0001). At the multivariate Cox regression analysis, AF was an independent predictor of 30-day and 1-year mortality. Approximately 17% of all deaths were attributable to the presence of AF. Conclusions-We found a high prevalence of AF in patients with a first-ever ischemic stroke, especially among elderly women. The overall contribution of AF to stroke mortality was relevant, suggesting that together with new strategies to prevent the development of the arrhythmia more appropriate treatments are needed, mostly in elderly women. (Stroke. 2005;36:1115-1119.)
Neuroimmunomodulation, 2005
The immunological effect of CD30 on dendritic cells (DCs) was examined in a comparative study of ... more The immunological effect of CD30 on dendritic cells (DCs) was examined in a comparative study of patients with relapsing-remitting multiple sclerosis (RRMS). The patients were divided into two groups on the basis of interferon (IFN)beta-1a treatment: IFNbeta-1a-treated patients and untreated patients. We have already shown that CD30 is a marker of cells involved in the regulation of the balance between TH1 and TH2 immune responses and so the aim of this study was to confirm this role in DCs and, consequently, to clarify the immunopathological mechanisms of MS and the causes of immunosuppressive drug failure. We studied network interactions between soluble (s) CD30 and TH1/TH2 cytokines in the supernatants of CD14+-derived immature DC (IDC) and DC cultures from treated and untreated patients. Network interactions between the sCD30 and cytokines in IDC and DC supernatants were also evaluated in relation to TH1/TH2 cytokine serum levels. Our overall results show that CD30 is expressed on IDCs and DCs, indicating an immunological role in resting and activated physiological conditions. This role would appear to be the regulation of the resting and activated physiological balance between the TH1/TH2 immune functions as abnormal increases in sCD30 levels result in impaired regulation. Further studies are undoubtedly required to clarify this situation. IFNbeta-1a treatment was found to determine a fall in sCD30 levels, leading to the restoration of the normal functional selection of IDCs from progenitor cells and the regulation of the TH1/TH2 network balance. However, IFNbeta-1a treatment may also be responsible for the in vivo suppression of CD30-mediated TH1-DC functions in immune activation. TH1-DC functions are involved in the induction of T-regulatory cells for the physiological deletion of self-aggressive cells. We conclude that CD30 is an important costimulatory molecule and marker of a regulatory subpopulation of DCs which induces and modulates immune cells involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. Elucidating the mechanisms restoring DC and T-regulatory cell function could lead to more effective therapy and strategies for the prevention and treatment of immunopathological conditions such as autoimmunity, transplant rejection, allergy and tumors.
Journal of Biomedical Optics, 2000
Spatially resolved spectroscopy (SRS) is a new near infrared spectroscopy (NIRS) method that, usi... more Spatially resolved spectroscopy (SRS) is a new near infrared spectroscopy (NIRS) method that, using the multi-distance approach, measures local cerebral cortex hemoglobin oxygen saturation [J. Matcher, P. Kirkpatrick, K. Nahid, M. Cope, and D. T. Delpy, Proc. SPIE 2389, 486-495 (1995)]. Using a conventional continuous wave NIRS photometer, cerebral venous oxygen saturation (SvO2) can be calculated from oxyhemoglobin and total hemoglobin rise induced by partial occlusion of jugular vein [C. E. Elwell, S. J. Matcher, L. Tyszczuk, J. H. Meek, and D. T. Delpy, Adv. Exp. Med. Biol. 411, 453-460 (1997)]. The aim of this study was to compare direct measurements of forehead tissue oxygenation index (TOI) with the calculated SvO2 during venous occlusion in 16 adult volunteers using a clinical two-channel SRS oximeter (NIRO-300). Measured TOI and calculated SvO2 values of either right or left forehead did not significantly differ. A good agreement between the two NIRS methods was also demonstrated. On 16 other subjects, no significant differences were found between the right and left forehead TOI values measured simultaneously, and between the TOI values measured by channel 1 or 2 on the same side. The results confirm that cerebral cortex hemoglobin oxygen saturation, measured directly by the SRS method, reflects predominantly the saturation of the intracranial venous compartment of circulation.
Cerebrovascular Diseases, 1999
Transcranial Doppler is routinely used to assess the cerebrovascular reactivity, despite scarce i... more Transcranial Doppler is routinely used to assess the cerebrovascular reactivity, despite scarce information on its reproducibility. We evaluated the reproducibility of cerebrovascular reactivity measurements by this method utilizing different vasodilatory and vasoconstrictor stimuli. The cerebrovascular reactivity was measured in 45 healthy volunteers during hypercapnia induced by inhalation of a mixture of 5% CO2 and 95% O2, breath holding and rebreathing, and during hypocapnia induced by voluntary hyperventilation. Three sets of measurements were performed at times 0, 1, and 24 h to assess the within-observer short- and long-term reproducibility. The reproducibility was analyzed using the intraclass correlation coefficient. For the CO2 inhalation method, a good short-term (rI = 0.55; 95% CI = 0.39-0.68) and a good long-term (rI = 0.43; 95% CI = 0.25-0.59) reproducibility was found. For the breath-holding method a good short-term agreement was found (rI = 0.41; 95% CI = 0.22-0. 57), while the long-term reproducibility was poor (rI = 0.17; 95% CI = -0.03-0.36). Rebreathing showed a fair (rI = 0.31; 95% CI = 0.11-0. 48) short-term and a poor (rI = 0.17; 95% CI = -0.03-0.36) long-term reproducibility. For voluntary hyperventilation, the short-term reproducibility was good (rI = 0.53; 95% CI = 0.36-0.66), and the long- term reproducibility was fair (rI = 0.31; 95% CI = 0.11-0.48). In our study, CO2 inhalation and voluntary hyperventilation had the highest reproducibility and should be preferred when assessing cerebral vasoreactivity, especially in follow-up studies.
Journal of Neurology Neurosurgery and Psychiatry, 2000
Objective-To estimate the prevalence of multiple sclerosis in the L'Aquila district, central Ital... more Objective-To estimate the prevalence of multiple sclerosis in the L'Aquila district, central Italy. Methods-All available case sources were screened. Definite and probable cases of multiple sclerosis, classified according to the Poser criteria, were considered as prevalent cases. Results-On the prevalence day, 31 December 1996, 158 patients (105 women and 53 men; ratio 2:1) aVected by definite (n=131) or probable (n=27) multiple sclerosis were alive and resident in the L'Aquila district. Mean (SD) age was 38.4 (11.9) years (38.9 (11.7) years for women and 38.5 (12.3) years for men, p=0.9). The overall crude prevalence was 53.0/100 000 (95% confidence interval (95% CI)=45.4-62.0); 68.4/100 000 (95% CI=56.5-82.8) in women, and 36.7/100 000 (95% CI=28.1-48.0) in men. The prevalence was similar (55.9/100 000) when standardised to the 1996 European population. Mean (SD) age at onset of multiple sclerosis was 29.4 (9.6) years and mean (SD) duration of the disease was 9.4 (7.4) years, without any significant diVerence between sexes. Mean age at onset was significantly higher in patients with the primary progressive than in those with the relapsing-remitting course (p=0.0002, ScheVé's test). Conclusions-The prevalence found in the L'Aquila district gives support to the consideration of Italy as an area in which multiple sclerosis has been shown to have high prevalence at least in the populations that were surveyed recently. (J Neurol Neurosurg Psychiatry 2000;68:349-352)
European Neurology, 2004
Type 1A, the most common form of Charcot-Marie-Tooth (CMT1A) disease, is characterized by demyeli... more Type 1A, the most common form of Charcot-Marie-Tooth (CMT1A) disease, is characterized by demyelination of the peripheral nervous system. So far, only a few cases of the disease with concomitant brain white matter lesions have been described. We report an Italian family with CMT1A disease, consisting of the proband and 4 affected members, presenting with concomitant brain white matter lesions at magnetic resonance imaging. The association is particularly fascinating and might depend on an autoimmune mechanism, not yet clarified.
Italian Journal of Neurological Sciences, 1993
Cerebral blood flow was measured by transcranial Dopplersonography (TCD) in 15 patients during an... more Cerebral blood flow was measured by transcranial Dopplersonography (TCD) in 15 patients during and after an attack of paroxysmal atrial fibrillation. During the attack the mean flow velocity (MFV) was reduced significantly in the middle cerebral artery (p<0.05) and nonsignificantly in the other arteries. The pulsatility index (PI) was reduced in all the arteries but not significantly. During the fibrillation phase the MFV and PI tended to decrease as the heart rate increased. None of the patients showed clinical signs of cerebral ischemia during the attacks. The absence of such signs despite the reduced cerebral blood flow in atrial fibrillation is probably due to the activation of mechanisms of autoregulation. Il flusso ematico cerebrale, valutato con Doppler Transcranico (TCD), è stato misurato in 15 pazienti durante e dopo un episodio di fibrillazione atriale parossistica. Durante l'attacco di fibrillazione la Mean Flow Velocity (MFV) è risultata ridotta in modo significativo nella cerebrale media (p<0.05), mentre si è ridotta in modo non significativo nelle altre arterie. I valori dell'indice di pulsatilità (PI) sono risultati ridotti in tutte le arterie ma non significativamente. La correlazione tra la velocità di flusso, il PI e la frequenza cardiaca durante la fase di fibrillazione ha mostrato una tendenza alla riduzione della MFV e del PI con l'aumentare della frequenza. Durante gli episodi di fibrillazione atriale nessuno dei pazienti ha manifestato segni clinici di ischemia cerebrale. I risultati indicano che, in corso di fibrillazione atriale, si verifica una riduzione di flusso cerebrale che non si accompagna a sintomi di ischemia cerebrale verosimilmente per l'attivazione dei meccanismi di autiregolazione.
Headache, 1992
SYNOPSISTranscranial Doppler sonography examination was performed on 44 patients with migraine wi... more SYNOPSISTranscranial Doppler sonography examination was performed on 44 patients with migraine with aura and 88 controls. All patients were investigated in headache-free periods and 10 of them also during a migraine attack. During the headache-free period a not significant increase of mean flow velocity in patients compared to controls was obtained. The pulsatility index (PI) mean values were also higher in patients than in controls and the differences were significant in the MCA (p<0.05). No difference between right and left side was observed. During the attack the mean flow velocity (MFV) decreased in all arteries but the decrease was significant only in MCA and ACA (p<0.05). The mean PI increased in all arteries but not significantly. These variations were observed both on the headache and contralateral side. Nevertheless, the MFV decrease in all arteries was observed in four patients only. In four patients the MFV decrease was found in the anterior arteries and the MFV increase in the posterior arteries, while in two patients the MFV increase was observed both in the anterior and posterior arteries. The correlation between the variations of MFV values during the attacks and the time interval from the onset of attacks showed that the PCA and BA flow velocities were increased in patients examined between 0.5 and 3 hours, while an increase in MCA and ACA flow velocities were observed only in patients examined after 1.5 hours.
Clinical Science, 1998
1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain ... more 1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain to the light in the near-IR region (700-1100 nm) and on the oxygen-dependent tissue absorption changes of haemoglobin.2. We evaluated the most relevant factors (reproducibility, venous return, age and sex) that might affect reliability of near-IR spectroscopy to test CO2 cerebrovascular reactivity.3.Thirty-four healthy volunteers were enrolled in the study. The protocol consisted of a 3-min baseline, a 3-min hypercapnia (5% CO2 in air) and a 2-min recovery. Transcranial Doppler sonography measurements were simultaneously performed. The CO2 reactivity test was repeated on 27 subjects after 1 h to assess reproducibility. CO2 reactivity was also evaluated at different body positions (supine, 35 degrees Trendelenburg and 35 degrees reverse Trendelenburg), and over a gradual increase of the inspired CO2.4. Changes in near-IR spectroscopy and transcranial Doppler sonography parameters were significantly correlated with variations of end-tidal CO2 (P<0.005). A significant correlation between the reactivity indexes of near-IR spectroscopy parameters and flow velocity was also found (P<0.01). A high reproducibility was also found for deoxyhaemoglobin (rI=0.76), oxyhaemoglobin (rI=0.68) and flow velocity (rI=0.60) reactivity indexes. No significant differences between the reactivity indexes of different body positions were found (P>0.05). The reactivity index of oxyhaemoglobin and deoxyhaemoglobin decreased (P<0.05) and increased (P<0.01) with age respectively.5. We found that near-IR spectroscopy is a reliable and reproducible method for the evaluation of cerebrovascular reactivity and might be considered, after appropriate validation, for the assessment of patients with cerebrovascular disease.
Cephalalgia, 1997
Alterations of intracranial vessel tone have been implicated in the pathophysiology of migraine. ... more Alterations of intracranial vessel tone have been implicated in the pathophysiology of migraine. The cerebrovascular reactivity was measured by means of transcranial Doppler in 60 migraine patients with (n = 30) or without aura (n = 30) during the headache-free interval and in 30 healthy controls. The vasomotor response was evaluated during hypercapnia induced by inhalation of a mixture of CO2 5% and O2 95% and during hypocapnia obtained after voluntary hyperventilation. To improve the power of the study in detecting possible abnormalities of cerebrovascular reactivity, two different measures were performed at 1 week intervals in migraine patients and controls. Reactivity index values during CO2 inhalation were significantly different (p = 0.01) among the three groups during the first and second measurements; in particular, lower values were found in patients suffering from migraine without aura with respect to controls (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05, Scheffé&amp;amp;amp;amp;amp;amp;amp;#39;s test). Values of reactivity index obtained following induction of hypocapnia did not differ between migraine patients and controls (all p values &amp;amp;amp;amp;amp;amp;amp;gt; 0.05). Our data suggest a reduced vasodilatory response to hypercapnia of cerebral arterioles in patients suffering from migraine without aura with respect to controls that might be related to baseline arteriolar vasodilation.