P. B. Carrieri

Flunarizine in Prophylaxis of Childhood Migraine: A Double-Blind, Placebo-Controlled, Crossover Study

An 8-month, double-blind, placebo-controlled, crossover trial of flunarizine in the prophylaxis of migraine has been performed in 70 children. After 4 weeks of medication-free base-line observation, 35 children (group A) received flunarizine (5 mg/day) and 35 (group B) received placebo over a 12-week period. After a 4-week washout they crossed treatments for another 12 weeks. Sixty-three patients completed the trial. In both groups flunarizine significantly reduced the frequency and average duration of headache attacks. In group A efficacy was maintained after placebo crossover for the last 4 months of the study. Five subjects in group B stopped placebo because of ineffectiveness; two children in group A discontinued flunarizine treatment, one because of excessive daytime sedation and the other because therapy was ineffective. The main side effects were daytime sedation and weight gain. It is concluded that flunarizine is an effective drug for the treatment of childhood migraine. In a study of this length no serious side effects were discovered.

Regulatory T cell proliferative potential is impaired in human autoimmune disease

Human CD4+CD25highCD127−FoxP3+ regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4+ cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)–signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27kip1) and extracellular signal–related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.

Cerebrospinal fluid cytokines in AIDS dementia complex

SummaryWe evaluated cerebrospinal fluid (CSF) and serum concentrations of interleukin-1-alpha (IL-1 alpha), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) in 30 patients with AIDS dementia complex (ADC), and in 20 HIV-seronegative subjects with other neurological diseases (OND). CSF TNF alpha, IL-1-alpha and IL-6 were more frequently detectable in ADC patients than in OND subjects. These cytokines were also detectable in CSF of ADC patients with minimal symptoms. In contrast, the majority of both ADC and OND patients did not contain detectable serum levels of cytokines. Our data support the notion of intrathecal synthesis of cytokines in ADC patients and raise the possibility that activated macrophages may play a significant role in the pathogenesis of ADC.

Profile of Cerebrospinal Fluid and Serum Cytokines in Patients with Relapsing-Remitting Multiple Sclerosis. A Correlation with Clinical Activity

Levels of tumor necrosis factor (TNF)-alpha, granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-10 and transforming growth factor (TGF)-beta in cerebrospinal fluid (CSF) and serum of 29 patients with multiple sclerosis (MS) of the relapsing-remitting type and of 20 controls with other non inflammatory neurological diseases were studied. Sixteen patients were in the active phase of disease and 13 in remission. In CSF, higher IL-10 and TGF-beta concentrations were found in patients with a stable phase of MS, while in the active phase there were elevated levels of TNF-alpha and GM-CSF. These results suggest that a different cytokine pattern could be probably involved in the pathogenesis of relapsing-remitting MS.

Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants

Human regulatory T cells (Treg cells) that develop from conventional T cells (Tconv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced Treg cells (iTreg cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iTreg cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2–related suppressive activity of iTreg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of Treg cells in health and in autoimmunity.

Leptin as a metabolic link to multiple sclerosis

Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.

Markers of Activated T Lymphocytes and T Cell Receptor Gamma/ Delta+ in Patients with Multiple Sclerosis

We studied interferon-gamma (IFN-gamma), alpha-tumor necrosis factor (alpha-TNF) and granulocyte macrophage colony-stimulating factor (GM-CSF) in the cerebrospinal fluid and serum of 18 patients with multiple sclerosis (MS) and 10 subjects with other neurological diseases (OND). We also studied the cerebrospinal-fluid CD 69 expression, and T cells with T cell receptor (TcR) gamma/delta+. We found an increase of IFN-gamma (14.0 +/- 3.5 U/ml) and GM-CSF (8.0 +/- 3.4 pg/ml) levels in the cerebrospinal fluid of MS patients compared to the OND group (p < 0.005 and p < 0.01, respectively). The frequency of detectable cerebrospinal-fluid and serum alpha-TNF was similar in patients with MS and with OND. The cerebrospinal-fluid CD69 expression in lymphocytes was significantly higher in MS patients (15.0 +/- 9.9%) than in the control group (3.7 +/- 6.2%; p < 0.005). Comparable serum levels of IFN-gamma and GM-CSF were detected in patients with MS and in OND subjects. No significant difference in the incidence of TcR gamma/delta+ in the cerebrospinal fluid was found between the two groups. These results indicate an activation of T lymphocytes and macrophages in patients with MS. Our data do not suggest a role for an increased incidence of TcR gamma/delta+. However, we cannot rule out the possibility that these T cells could be present at the plaque site of MS patients.

Age-Related Risk Factors for Ischemic Stroke in Italian Men

We evaluated the age-related stroke risk factors in 164 Italian male patients with a diagnosis of first-ever ischemic stroke. Based on the age, we divided the patients into two groups: 42 patients ranging in age from 40 to 55 years, and 122 patients ranging in age from 56 to 75 years. For each case, an age-matched control without a history or symptoms indicating vascular disease was randomly selected from hospital patients. Information were obtained on the various risk factors. Univariate analysis showed that for the younger patients high systolic blood pressure, diabetes mellitus, hypertriglyceridemia, smoking and family history of ischemic stroke were significantly related to stroke. In the older patients, high diastolic blood pressure and smoking had a strong association with stroke. Multivariate analysis showed that high systolic blood pressure, hypertriglyceridemia, smoking and family history of stroke remained significantly and independently associated with stroke in patients up to the age of 55 years. Among patients 56 years or older, only high systolic and diastolic blood pressure, and smoking were significant predictors of stroke. In conclusion, the sets of factors associated with the risk of stroke among young and old male patients appear to be different.

Interleukin-6 and granulocyte macrophage-CSF in the cerebrospinal fluid from HIV infected subjects with involvement of the central nervous system.

We detected the cytokines interleukin-6 (IL-6) and granulocyte macrophage-CSF (GM-CSF) by ELISA in the CSF and serum of 30 HIV-infected patients classified as AIDS dementia complex (ADC), and 20 subjects with other neurological diseases (OND). We have found a high incidence of detectable IL-6 and GM-CSF in the CSF of ADC patients compared with OND patients. No statistical differences were observed between both groups for serum IL-6 and GM-CSF levels. These results suggest an intrathecal synthesis of these cytokines and a possible involvement in the pathogenesis of ADC.

Interleukin-10 and Interleukin-12 Modulation in Patients with Relapsing-Remitting Multiple Sclerosis on Therapy with Interferon-beta 1a: Differences in Responders and Non Responders

We examined the effects of interferon (IFN)beta-1a on interleukin (IL)-12p70 and IL-10 secretion in 27 Relapsing Remitting Multiple Sclerosis (RRMS) patients, divided in responders and non-responders. In responders, IFNbeta-1a does not change the IL-12p70 concentrations, but it leads to a remarkable increase in the IL-10 production. Besides, a high IL-10/IL-12 ratio is demonstrated during the first six months of therapy. In non-responders, there were not significant alterations in the cytokine profile. We suggest that IFNbeta-1a effect in RRMS patients could be explained by its modifying effect on cytokine pattern. Moreover, we propose a possible role of IL-10/ IL-12 ratio as a serum marker predictive of favorable clinical course.