Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study.

PURPOSE: To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. PATIENTS AND METHODS: This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. RESULTS: 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. CONCLUSION: PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

PKCε is a regulator of hypertrophic differentiation of chondrocytes in osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a common and highly debilitating degenerative disease whose complex pathogenesis and the multiplicity of the molecular processes involved, hinder its complete understanding. Protein Kinase C (PKC) novel isozyme PKCε recently proved to be an interesting molecule for further investigations as it can represent an intriguing, new actor in the acquisition of a OA phenotype by the chondrocyte. DESIGN: PKCε was modulated in primary chondrocytes from human OA patient knee cartilage samples by means of short hairpin RNA (ShRNA) and the expression of cartilage specific markers observed at mRNA and protein level. The involvement of Histone deacetylases (HDACs) signaling pathway was also investigated through the use of specific inhibitors MS-275 and Inhibitor VIII. RESULTS: PKCε loss induces up-regulation of Runt-domain transcription factor (RUNX2), Metalloproteinase 13 (MMP13) and Collagen X (COL10) as well as an enhanced calcium deposition in OA chondrocyte cultures. In parallel, PKCε knock-down also leads to SOX9 and Collagen II (COL2) down-modulation and to a lower deposition of glycosaminoglycans (GAGs) in the extracellular matrix (ECM). This novel regulatory role of PKCε over cartilage hypertrophic phenotype is exerted via an HDAC-mediated pathway, as HDAC2 and HDAC4 expression is modulated by PKCε. HDAC2 and HDAC4, in turn, are at least in part responsible for the modulation of the master transcription factors RUNX2 and SOX9, key regulators of chondrocyte phenotype. CONCLUSIONS: PKCε prevents the phenotypic progression of the OA chondrocyte, acting on cartilage specific markers through the modulation of the transcription factors SOX9 and RUNX2. The loss of PKCε enhances, in fact, the OA hypertrophic phenotype, with clear implications in the pathophysiology of the disease.

PKCε as a novel promoter of skeletal muscle differentiation and regeneration.

INTRODUCTION: Satellite cells are muscle resident stem cells and are responsible for muscle regeneration. In this study we investigate the involvement of PKCε during muscle stem cell differentiation in vitro and in vivo. Here, we describe the identification of a previously unrecognized role for the PKCε-HMGA1 signaling axis in myoblast differentiation and regeneration processes. METHODS: PKCε expression was modulated in the C2C12 cell line and primary murine satellite cells in vitro, as well as in an in vivo model of muscle regeneration. Immunohistochemistry and immunofluorescence, RT-PCR and shRNA silencing techniques were used to determine the role of PKCε and HMGA1 in myogenic differentiation. RESULTS: PKCε expression increases and subsequently re-localizes to the nucleus during skeletal muscle cell differentiation. In the nucleus, PKCε blocks Hmga1 expression to promote Myogenin and Mrf4 accumulation and myoblast formation. Following in vivo muscle injury, PKCε accumulates in regenerating, centrally-nucleated myofibers. Pharmacological inhibition of PKCε impairs the expression of two crucial markers of muscle differentiation, namely MyoD and Myogenin, during injury induced muscle regeneration. CONCLUSION: This work identifies the PKCε-HMGA1 signaling axis as a positive regulator of skeletal muscle differentiation.

Protein kinase Cɛ inhibition restores megakaryocytic differentiation of hematopoietic progenitors from primary myelofibrosis patients.

Among the three classic Philadelphia chromosome-negative myeloproliferative neoplasms, primary myelofibrosis (PMF) is the most severe in terms of disease biology, survival and quality of life. Abnormalities in the process of differentiation of PMF megakaryocytes (MKs) are a hallmark of the disease. Nevertheless, the molecular events that lead to aberrant megakaryocytopoiesis have yet to be clarified. Protein kinase Cɛ (PKCɛ) is a novel serine/threonine kinase that is overexpressed in a variety of cancers, promoting aggressive phenotype, invasiveness and drug resistance. Our previous findings on the role of PKCɛ in normal (erythroid and megakaryocytic commitment) and malignant (acute myeloid leukemia) hematopoiesis prompted us to investigate whether it could be involved in the pathogenesis of PMF MK-impaired differentiation. We demonstrate that PMF megakaryocytic cultures express higher levels of PKCɛ than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKCɛ function (by a negative regulator of PKCɛ translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKCɛ-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKCɛ directly affects the PMF neoplastic clone and represent a proof-of-concept for PKCɛ inhibition as a novel therapeutic strategy in PMF.

PKCε is a negative regulator of PVAT-derived vessel formation.

RATIONALE: Vessel formation is a crucial event in tissue repair after injury. Thus, one assumption of innovative therapeutic approaches is the understanding of its molecular mechanisms. Notwithstanding our knowledge of the role of Protein Kinase C epsilon (PKCε) in cardio-protection and vascular restenosis, its role in vessel progenitor differentiation remains elusive. OBJECTIVE: Given the availability of PKCε pharmacological modulators already tested in clinical trials, the specific aim of this study is to unravel the role of PKCε in vessel progenitor differentiation, with implications in vascular pathology and vasculogenesis. METHODS AND RESULTS: Mouse Peri-Vascular Adipose Tissue (PVAT) was used as source of mesenchymal vessel progenitors. VEGF-induced differentiation of PVAT cells down-regulates both PKCε and p-PAK1 protein expression levels. PKCε overexpression and activation: i) reduced the expression levels of SMA and PECAM in endothelial differentiation of PVAT cells; ii) completely abrogated tubules formation in collagen gel assays; iii) increased the expression of p-PAK1. CONCLUSION: PKCε negatively interferes with vessel progenitor differentiation via interaction with PAK-1.

Monoamine oxidase A gene promoter methylation and transcriptional downregulation in an offender population with antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (ASPD) is characterised by elevated impulsive aggression and increased risk for criminal behaviour and incarceration. Deficient activity of the monoamine oxidase A (MAOA) gene is suggested to contribute to serotonergic system dysregulation strongly associated with impulsive aggression and antisocial criminality. AIMS: To elucidate the role of epigenetic processes in altered MAOA expression and serotonin regulation in a population of incarcerated offenders with ASPD compared with a healthy non-incarcerated control population. METHOD: Participants were 86 incarcerated participants with ASPD and 73 healthy controls. MAOA promoter methylation was compared between case and control groups. We explored the functional impact of MAOA promoter methylation on gene expression in vitro and blood 5-HT levels in a subset of the case group. RESULTS: Results suggest that MAOA promoter hypermethylation is associated with ASPD and may contribute to downregulation of MAOA gene expression, as indicated by functional assays in vitro, and regression analysis with whole-blood serotonin levels in offenders with ASPD. CONCLUSIONS: These results are consistent with prior literature suggesting MAOA and serotonergic dysregulation in antisocial populations. Our results offer the first evidence suggesting epigenetic mechanisms may contribute to MAOA dysregulation in antisocial offenders.

Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.

Early-onset absence epilepsy: SLC2A1 gene analysis and treatment evolution.

BACKGROUND AND PURPOSES: To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). METHODS: We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. RESULTS: Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failed withdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P = 0.008). CONCLUSIONS: We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED.

The role of PKCε-dependent signaling for cardiac differentiation.

Protein kinase Cepsilon (PKCε) exerts a well-known cardio-protective activity in ischemia-reperfusion injury and plays a pivotal role in stem cell proliferation and differentiation. Although many studies have been performed on physiological and morphological effects of PKCε mis-expression in cardiomyocytes, molecular information on the role of PKCε on early cardiac gene expression are still lacking. We addressed the molecular role of PKCε in cardiac cells using mouse cardiomyocytes and rat bone marrow mesenchymal stem cells. We show that PKCε is modulated in cardiac differentiation producing an opposite regulation of the cardiac genes NK2 transcription factor related, locus 5 (nkx2.5) and GATA binding protein 4 (gata4) both in vivo and in vitro. Phospho-extracellular regulated mitogen-activated protein kinase 1/2 (p-ERK1/2) levels increase in PKCε over-expressing cells, while pkcε siRNAs produce a decrease in p-ERK1/2. Indeed, pharmacological inhibition of ERK1/2 rescues the expression levels of both nkx2.5 and gata4, suggesting that a reinforced (mitogen-activated protein kinase) MAPK signaling is at the basis of the observed inhibition of cardiac gene expression in the PKCε over-expressing hearts. We demonstrate that PKCε is critical for cardiac cell early gene expression evidencing that this protein is a regulator that has to be fine tuned in precursor cardiac cells.

The selective neuropeptide Y Y5 agonist [cPP(1-7),NPY(19-23),Ala31,Aib32,Gln34]hPP differently modulates emotional processes and body weight in the rat.

The neuropeptide Y (NPY) has been suggested to act as a major regulator of emotional processes and body weight. The full spectrum of biological effects of this peptide is mediated by at least four classes of receptors known as the Y(1), Y(2), Y(4), and Y(5) subtypes. However, the respective contribution of each of these receptor subtypes, especially the Y(5) subtype, in emotional processes is still mostly unknown. In the present study, we investigated the effect of long term administration of a selective Y(5) agonist [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP on emotional processes and body weight using two rat models of emotional dysfunctions, the corticosterone (CORT)-induced anxiety model as well as the olfactory bulbectomized (OBX) model of depression and anxiety in Wistar and Sprague-Dawley rats, respectively. The sub-chronic administration of the Y(5) agonist reversed the high levels of locomotion, rearing and grooming in the open field test and the impaired social activity induced by OBX, while increased the percentage of entries and time in the open arm of the elevated plus maze in CORT-treated rats. Furthermore, this Y(5) agonist increased body weight in both strains of control rats. These data further demonstrate that Y(5) receptors are not only involved in the control of body weight but also mediate emotional processing under challenged conditions. Thus, the pharmacotherapeutic administration of a Y(5) agonist could be considered as a potentially novel strategy to alleviate some forms of anxiety and depression in humans.

Glut1 deficiency: when to suspect and how to diagnose?

Impaired glucose transport across the blood-brain barrier results in GLUT1 deficiency syndrome (GLUT1-DS), characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. A part from this classic phenotype, clinical conditions associated with a deficiency of GLUT1 are highly variable and several atypical variants have been described; in particular, patients with movement disorders, but without seizures, with paroxysmal exertion-induced dyskinesia, have been reported. Most patients carry heterozygous de novo mutations in the GLUT1-gene but autosomal dominant and recessive transmission has been identified. Diagnosis is based on low cerebrospinal fluid glucose, in the absence of hypoglycemia, and it is confirmed by molecular analysis of the GLUT1-gene and by glucose uptake studies and immunoreactivity in human erythrocytes. Treatment with a ketogenic diet results in marked improvement of seizures and movement disorders. This review summarizes recent advances in understanding of GLUT1-DS and highlights the diagnostic and therapeutic approach to GLUT1-DS.

Cannabinoids and emotionality: a neuroanatomical perspective.

The endocannabinoid system has recently emerged as a promising therapeutic target for the treatment of stress-related emotional disorders. A growing literature base has collectively demonstrated that facilitation of endocannabinoid signaling promotes antidepressant- and anxiolytic-like responses in preclinical animal models, while disruption of this system profoundly affects emotion, cognition, and neuroendocrine functioning. Although these findings are encouraging, the role of endocannabinoid signaling within discrete corticolimbic brain structures is considerably complex. Consequently, researchers have recently shifted focus to examining the effects of local cannabinoid manipulations on emotion from a neuroanatomical standpoint. This review provides an overview of the site-specific effects of cannabinergic compounds in preclinical tests of emotionality, as well as the alterations in endocannabinoid signaling observed in animal models of depression. Broadly speaking, these studies indicate that CB(1) receptors in the medial prefrontal cortex and ventral hippocampus appear to be responsible for the antidepressant- and anxiolytic-like phenotype elicited by systemic CB(1) receptor agonists, which parallels biochemical studies showing that endocannabinoids are downregulated in these two regions following exposure to chronic stress. Conversely, CB(1) receptor activation within distinct amygdalar nuclei yields opposing effects on emotional behavior, such that local stimulation of CB(1) receptors in the basolateral amygdala and central amygdala promoting anxiogenesis and anxiolysis, respectively. Moreover, a series of elegant studies has revealed that cannabinoid transmission in the basolateral amygdala strongly modulates the acquisition and processing of associative fear memory via interactions with the medial prefrontal cortex. Given the crucial role of this corticolimbic network in regulating emotional behavior, it is palpable that alterations in endocannabinoid signaling within any of these structures could have profound implications for the pathophysiological development of affective illnesses. Accordingly, local pharmacological augmentation of endocannabinoid signaling within discrete corticolimbic subregions may serve as a promising therapeutic strategy for the treatment of these debilitating disorders.

Investigation of the 3-D actinic flux field in mountainous terrain.

During three field campaigns spectral actinic flux was measured from 290-500 nm under clear sky conditions in Alpine terrain and the associated O3- and NO2-photolysis frequencies were calculated and the measurement products were then compared with 1-D- and 3-D-model calculations. To do this 3-D-radiative transfer model was adapted for actinic flux calculations in mountainous terrain and the maps of the actinic flux field at the surface, calculated with the 3-D-radiative transfer model, are given. The differences between the 3-D- and 1-D-model results for selected days during the campaigns are shown, together with the ratios of the modeled actinic flux values to the measurements. In many cases the 1-D-model overestimates actinic flux by more than the measurement uncertainty of 10%. The results of using a 3-D-model generally show significantly lower values, and can underestimate the actinic flux by up to 30%. This case study attempts to quantify the impact of snow cover in combination with topography on spectral actinic flux. The impact of snow cover on the actinic flux was ~ 25% in narrow snow covered valleys, but for snow free areas there were no significant changes due snow cover in the surrounding area and it is found that the effect snow-cover at distances over 5 km from the point of interest was below 5%. Overall the 3-D-model can calculate actinic flux to the same accuracy as the 1-D-model for single points, but gives a much more realistic view of the surface actinic flux field in mountains as topography and obstruction of the horizon are taken into account.

MRI Findings in Patients with Clinical Onset Consistent with Infantile Neuroaxonal Dystrophy (INAD), Literature Review, Clinical and MRI Follow-up.

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity. The neuroradiologic hallmark of the disease is represented by progressive cerebellar atrophy. Prior to the discovery of mutations in the PLA2G6 gene in family with INAD, the clinical diagnosis of the disease had been confirmed by the presence of spheroid bodies (SB) in a peripheral nerve biopsy. Various studies have found that some patients with mutations lacked SB and some without mutations had SB, indicating incomplete detection using either pathologic or molecular methods (7). This, together with the observation that the spectrum of clinical features associated with mutations in PLA2G6 is broader than previously described, has increased the usefulness of Magnetic Resonance (MR) in INAD diagnosis, particularly in the frequent occurrence of atypical cases, especially in the early stages of the disease. We retrospectively reviewed the MR studies of eight patients in whom clinical and imaging onset met the typical criteria for INAD. Their clinical and MR imaging (MRI) onset and follow-up were evaluated together with the neuroradiological findings reported in the literature in order to identify MRI features useful in differentiating INAD from other diseases with similar clinical onset and to discuss which of them are the most important, thus suggesting INAD diagnosis. Our contribution included the use of Proton Spectroscopy ((1)H-MR), diffusion weighted MR imaging (DWI) and diffusion tensor imaging (DTI) in the follow-up of seven of the eight patients. The literature reviewed included attempts to correlate clinical and MR data with the genotype in the group of patients carrying PLA2G6 mutations. From the limited and inhomogeneous cohort of patients included in our study, a correlation between the MR features, phenotype and genotype was not exhaustive.

The subjective feeling of burden in caregivers of elderly with dementia: how to intervene?

The aim of this study was to know how caregiver burden was influenced by caregivers' and patients' characteristics and by social support; the intention was to use these elements in order to suggest how to optimize the interventions which may reduce caregivers' subjective feeling of burden. A sample of 99 caregivers was studied using a descriptive-correlational design. Caregiver burden was assessed by using the caregiver burden inventory (CBI). The burden was due to restrictions on their personal time and to the sense of failure regarding their hopes and expectations. These results suggest that it could be useful to intervene in two ways. On one hand, improving all those interventions targeted to reduce restrictions on the personal caregivers' time, making respite care and day care units more accessible to elderly with dementia. On the other hand, giving caregivers the opportunity to benefit from interventions oriented to cope the sense of failure and the physical stress, to say, individual counseling or continued informal support.

Severe epilepsy preceding by four months the onset of scleroderma en coup de sabre.

Juvenile localized scleroderma (JLS) includes several subtypes including plaque morphea, linear scleroderma and the en coup de sabre type which affects face and head. The latter variety may involve the eye and the brain with various appearance and clinical complications.We describe the case of a 6-year-old boy who presented partial complex seizures, with status epilepticus, four months before the appearance of sclerodermatous skin lesions on the face. This case report raises important questions on the pathogenesis of JLS and, particularly, on the issue whether it is a mere autoimmune condition or a neuro-cutaneous disease.

A 1H magnetic resonance spectroscopy study in patients with obstructive sleep apnea.

BACKGROUND AND PURPOSE: Repeated episodes of hypoxia, hypercapnia and transient blood pressure elevation in obstructive sleep apnea syndrome (OSAS) may damage neutral structures and induce cerebral metabolic impairment. This study aimed to determine the impact of OSAS on cerebral metabolites measured by (1)H magnetic resonance spectroscopy ((1)H -MRS). METHODS: Twenty OSAS patients underwent standard overnight polysomnography and (1)H-MRS separately. Proton volumes of interest (VOIs) were placed in frontal and midtemporal regions bilaterally. RESULTS: Significantly lower values of the N-acetylaspartate (NAA)/creatine (Cr) ratio were found in frontal regions (P < 0.004) compared with 20 age-matched control subjects. A significant increase in the myo-inositol (Ins)/Cr ratio was evident bilaterally in temporal and frontal regions (P < 0.00002 and P < 0.04). Choline (Cho)/Cr ratio values were also significantly greater in temporal regions (P < 0.00001). A significant negative correlation (r = -0.51, P < 0.03) was found between the apnea-hypopnea index (AHI) and NAA/Cr ratio in the frontal regions of OSAS patients. CONCLUSIONS: Reduction in the NAA/Cr ratio in frontal regions of OSAS patients could be related to neural loss. Increase in the Cho/Cr ratio in temporal regions and Ins/Cr ratio in both frontal and temporal regions could be interpreted as evidence of membrane breakdown and reactive gliosis, respectively, consequent to repeated episodes of hypoxia in OSAS.

The ABC-Pyramid Atmospheric Research Observatory in Himalaya for aerosol, ozone and halocarbon measurements.

In this work we present the new ABC-Pyramid Atmospheric Research Observatory (Nepal, 27.95 N, 86.82 E) located in the Himalayas, specifically in the Khumbu valley at 5079 m a.s.l. This measurement station has been set-up with the aim of investigating natural and human-induced environmental changes at different scales (local, regional and global). After an accurate instrumental set-up at ISAC-CNR in Bologna (Italy) in autumn 2005, the ABC-Pyramid Observatory for aerosol (physical, chemical and optical properties) and trace gas measurements (ozone and climate altering halocarbons) was installed in the high Khumbu valley in February 2006. Since March 2006, continuous measurements of aerosol particles (optical and physical properties), ozone (O3) and meteorological parameters as well as weekly samplings of particulate matter (for chemical analyses) and grab air samples for the determination of 27 halocarbons, have been carried out. These measurements provide data on the typical atmospheric composition of the Himalayan area between India and China and make investigations of the principal differences and similarities between the monsoon and pre-monsoon seasons possible. The study is carried out within the framework of the Ev-K2-CNR "SHARE-Asia" (Stations at High Altitude for Research on the Environment in Asia) and UNEP-"ABC" (Atmospheric Brown Clouds) projects. With the name of "Nepal Climate Observatory-Pyramid" the station is now part of the Observatory program of the ABC project.

Specifically designed physical exercise programs improve children's motor abilities.

Physical activity in schools is declining in many countries and inactivity in childhood has become a recognized risk factor. Data from a program of professionally guided physical exercise in primary school children were collected before and after the academic year of training. Four thousand five hundred children (6-10 years) were enrolled, and conditional and coordinative motor abilities (speed, trunk flexibility, long jumping, somersault, Harre circuit test) were measured. Anthropometric measurements were focused on body mass index (BMI), weight and height. Females never showed a significant variation of BMI, whereas males in the first and fourth grades showed significant differences. On the contrary, when considering the motor abilities studied, all the comparisons were highly significant. At the end of training, both males and females did better than at the beginning, and males were constantly faster than females. Our data, generated on a large number of children, show that professionally guided programs of physical education in the primary school lead to significant progresses in the development of conditional and coordinative abilities, without altering BMI values, thus not interfering with the balanced progression of body weight and height.

Neuroendocrine regulation and tumor immunity.

The morphogenetic events leading to the transendothelial passage of lymphoid and tumoral cells are analyzed in light of a very recent and global theory of intercellular communication designated as the Triune Information Network (TIN). The TIN system is based on the assumption that cell-cell interactions primarily occur through cell surface informations or topobiological procesess, whose mechanisms rely upon expression of adhesion molecules, and are regulated by an array of locally-borne (autocrine/paracrine signals and autonomic inputs) and distantly-borne (endocrine secretions) messages. The final aim of the TIN is to control homeostatic functions crucial for the organism survival, like morphogenesis. Knowledge of the TIN signals involved in lymphoid and tumoral cell intravasation might offer a new perspetive to study the mechanisms of tumor immunity. Recognition of tumor target cells by immune cytotoxic effectors, in fact, can be considered a notable case of TIN-mediated cell to cell interaction. In particular, Natural Killer (NK) cells play a role in the cell-mediated control of tumor growth and metastatic spreading. Cell targeting and killing are dependent on the different NK cell receptors and on the efficacy of NK cells after cytokine and monoclonal antibody administration in cancer therapy. Since efficacy of NK cell-based immunotheraphy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell based immunotherapy.