Headache in epilepsy: prevalence and clinical features.

BACKGROUND: Headache and epilepsy are two relatively common neurological disorders and their relationship is still a matter of debate. Our aim was to estimate the prevalence and clinical features of inter-ictal (inter-IH) and peri-ictal headache (peri-IH) in patients with epilepsy. METHODS: All patients aged ≥ 17 years referring to our tertiary Epilepsy Centre were consecutively recruited from March to May 2011 and from March to July 2012. They underwent a semi-structured interview including the International Classification Headache Disorders (ICHD-II) criteria to diagnose the lifetime occurrence of headache.χ(2)-test, t-test and Mann-Whitney test were used to compare clinical variables in patients with and without inter-IH and peri-IH. RESULTS: Out of 388 enrolled patients 48.5 % had inter-IH: migraine in 26.3 %, tension-type headache (TTH) in 19.1 %, other primary headaches in 3.1 %. Peri-IH was observed in 23.7 %: pre-ictally in 6.7 %, ictally in 0.8 % and post-ictally in 19.1 %. Comparing patients with inter-ictal migraine (102), inter-ictal TTH (74) and without inter-IH (200), we found that pre-ictal headache (pre-IH) was significantly represented only in migraineurs (OR 3.54, 95 % CI 1.88-6.66, P < 0.001). Post-ictal headache (post-IH) was significantly associated with both migraineurs (OR 2.60, 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR 2.05, 95 % CI 1.41-2.98, P < 0.001). Moreover, post-IH was significantly associated with antiepileptic polytherapy (P < 0.001), high seizure frequency (P = 0.002) and tonic-clonic seizures (P = 0.043). CONCLUSIONS: Migraine was the most represented type of headache in patients with epilepsy. Migraineurs are more prone to develop pre-IH, while patients with any inter-IH (migraine or TTH) are predisposed to manifest a post-IH after seizures.

Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Association between restless legs syndrome and hypertension: a preliminary population-based study in South Tyrol, Italy.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a sleep-related movement disorder characterized by an irresistible urge to move the legs accompanied by paresthesia and/or dysesthesia that begins or worsens in the evening and night and that is partially or totally relieved by movement. Many studies have investigated the association between RLS and cardiovascular risk factors, particularly hypertension, leading to conflicting results. The aim of this study was to assess the association between RLS and hypertension considering also other cardiovascular risk factors that could act as confounders. METHODS: In all, 1709 participants of an on-going adult population-based study performed in South Tyrol, northern Italy, were enrolled. RLS was assessed through face-to-face interviews according to current International Restless Legs Syndrome Study Group diagnostic criteria. The presence of hypertension was self-reported and determined by questionnaires administered by trained study nurses. RESULTS: The association between RLS and hypertension was not significant after adjustment for age, sex, diabetes mellitus, history of myocardial infarction, raised blood lipids and body mass index (odds ratio 1.24, 95% CI 0.85-1.80, P = 0.271). CONCLUSION: Despite the small sample size of this study, RLS and hypertension were not associated in our adult population after adjustment for possible confounding factors. The presence of other cardiovascular risk factors could play a role as a confounder of this association.

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy.

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Nociception and autonomic nervous system.

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain may also be experienced in absence of noxious stimuli and together with temperature and other bodily feelings constitute the interoception redefined as the sense of the physiological condition of the entire body, not just the viscera. The main characteristic of these feelings is the affective aspect. Emotion, motivation, and consequent behavior connected with these feelings characterize their homeostatic role. This implies an interaction between neural structures involved in pain sensation and autonomic control. The aim of this review is to focus on pain perception, mainly on pain matrix structures' connections with the autonomic nervous system.

Migraine: risk factor and comorbidity.

The burden of migraine strongly increases considering its linkage with other psychiatric, neurological, cardiovascular and cerebrovascular diseases. Migraine is positively associated with many disorders: some are confirmed by several studies whereas others remain uncertain or controversial. The association with some disorders is not simply due to concomitance but it implies a linkage in terms of causality. Highlighting these relationships is important to improve treatment strategies, broaden our knowledge of the pathophysiology and understand if migraine is per se a modifiable risk factor for some disorders.

Migraine and sleep disorders.

The burden of migraine strongly increases, considering its linkage with sleep disorders. Migraine is positively associated with many sleep-complaint disorders; some are confirmed by several studies, such as restless leg syndrome, whereas others still remain uncertain or controversial, e.g. narcolepsy. Many studies have investigated the association between headache and other sleep disturbances such as daytime sleepiness, insomnia, snoring and/or apnea, but only a few have focused on migraine. Highlighting the comorbidity between migraine and sleep disorders is important to improve treatment strategies and to extend the knowledge of migraine pathophysiology.

Migraine and cardiovascular diseases.

Migraine has complex relationships with cerebrovascular and cardiovascular disorders but also with cardiac anomalies. Patients affected by migraine with aura have an increased prevalence of right-to-left shunt due to patent foramen ovale or pulmonary arteriovenous malformations. The association between ischemic heart disease, cardiovascular mortality and migraine remains unsettled. The debate focuses on a physiopathological link between migraine and cardiovascular diseases or a higher prevalence of risk factors in migraineurs.

SPARTACUS: underdiagnosis of chronic daily headache in primary care.

Despite the burden of chronic daily headache (CDH), general practitioners' (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs' knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

The E LiBANS project: Thermal and epithermal neutron sources based on a medical Linac.

The E_LIBANS project (INFN) aims at producing neutron facilities for interdisciplinary irradiation purposes among which pre-clinical research for BNCT. After the successful setting-up of the thermal neutron source based on a medical LINAC, a similar apparatus for epithermal neutrons has been developed. Both structures are based on an Elekta 18 MV coupled with a photoconverter-moderator system which deploys the (γ,n) reaction to convert the X-rays into neutrons. This communication describes the two neutron sources and the results obtained in their characterization.

The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues.

Ryanodine receptors (RyRs) are intracellular calcium release channels that participate in controlling cytosolic calcium levels. At variance with the probably ubiquitous inositol 1,4,5-trisphosphate-operated calcium channels (1,4,5-trisphosphate receptors), RyRs have been mainly regarded as the calcium release channels controlling skeletal and cardiac muscle contraction. Increasing evidence has recently suggested that RyRs may be more widely expressed, but this has never been extensively examined. Therefore, we cloned three cDNAs corresponding to murine RyR homologues to carry a comprehensive analysis of their expression in murine tissues. Here, we report that the three genes are expressed in almost all tissues analyzed, where tissue-specific patterns of expression were observed. In the uterus and vas deferens, expression of RyR3 was localized to the smooth muscle component of these organs. In the testis, expression of RyR1 and RyR3 was detected in germ cells. RyR mRNAs were also detected in in vitro-cultured cell lines. RyR1, RyR2, and RyR3 mRNA were detected in the cerebrum and in the cerebellum. In situ analysis revealed a cell type-specific pattern of expression in the different regions of the central nervous system. The differential expression of the three ryanodine receptor genes in the central nervous system was also confirmed using specific antibodies against the respective proteins. This widespread pattern of expression suggests that RyRs may participate in the regulation of intracellular calcium homeostasis in a range of cells wider than previously recognized.

Expression of a ryanodine receptor-Ca2+ channel that is regulated by TGF-beta.

Ryanodine receptors (RyRs) are intracellular channels that release calcium ions from the sarcoplasmic reticulum (SR) in response to either plasma membrane depolarization (in skeletal muscle) or increases in the concentration of intracellular free Ca2+ (in the heart). A gene (beta 4) encoding a ryanodine receptor (similar to, but distinct from, the muscle RyRs) was identified. The beta 4 gene was expressed in all tissues investigated, with the exception of heart. Treatment of mink lung epithelial cells (Mv1Lu) with transforming growth factor beta (TGF-beta) induced expression of the beta 4 gene together with the release of Ca2+ in response to ryanodine (but not in response to caffeine, the other drug active on muscle RyRs). This ryanodine receptor may be important in the regulation of intracellular Ca2+ homeostasis.

Identification and quantitation of vitamins K1 and K3 in cosmetic products for facial skin protection.

A simple and rapid analytical method was developed for the determination of vitamins K1 and K3 in facial anti-rash creams. The procedure is based on an ultrasonic extraction of the cosmetic sample with dimethylacetamide, in the presence of an internal standard, followed by HPLC separation. HPLC was performed using a C18 column and spectrophotometric detection at 333 nm. A linear gradient elution was carried out starting with 50% acetonitrile-methanol (75:25 v/v) and water up to 100% acetonitrile-methanol for 5 min. Linearity was established over the concentration range from 0.2 to 1.0 mg/ml for vitamin K1 and from 0.02 to 0.1 mg/ml for vitamin K3, with LOD values of 100 ng and 20 ng injected, respectively. The accuracy was verified by spiking experiments on model cosmetic samples. The proposed method has been successfully applied for the analysis of commercial samples of creams.

MEASUREMENTS OF THE PARASITIC NEUTRON DOSE AT ORGANS FROM MEDICAL LINACS AT DIFFERENT ENERGIES BY USING BUBBLE DETECTORS.

Conventional linear accelerators (LINACs) for radiotherapy produce fast secondary neutrons due to photonuclear processes. The neutron presence is considered as an extra undesired dose during the radiotherapy treatment, which could cause secondary radio-induced tumors and malfunctions to cardiological implantable devices. It is thus important to measure the neutron dose contribution to patients during radiotherapy, not only at high-energy LINACs, but also at lower energies, near the giant dipole resonance reaction threshold. In this work, the full body neutron dose equivalent has been measured during single-field radiotherapy sessions carried out at different LINAC energies (15, 10 and 6 MV) by using a tissue equivalent (for neutrons) anthropomorphic phantom together with bubble dosemeters. Results have shown that some neutron photoproduction is still present also at lower energies. As a consequence, emitted photoneutrons cannot be ignored and represent a risk contribution for patients undergoing radiotherapy.

DEVELOPING RADIATION RESISTANT THERMAL NEUTRON DETECTORS FOR THE E_LIBANS PROJECT: PRELIMINARY RESULTS.

Radiation-resistant, gamma-insensitive, active thermal neutron detectors were developed to monitor the thermal neutron cavity of the E_LIBANS project. Silicon and silicon carbide semiconductors, plus vented air ion chambers, were chosen for this purpose. This communication describes the performance of these detectors, owing on the results of dedicated measurement campaigns.

INTENSE THERMAL NEUTRON FIELDS FROM A MEDICAL-TYPE LINAC: THE E_LIBANS PROJECT.

The e_LiBANS project aims at producing intense thermal neutron fields for diverse interdisciplinary irradiation purposes. It makes use of a reconditioned medical electron LINAC, recently installed at the Physics Department and INFN in Torino, coupled to a dedicated photo-converter, developed within this collaboration, that uses (γ,n) reaction within high Z targets. Produced neutrons are then moderated to thermal energies and concentrated in an irradiation volume. To measure and to characterize in real time the intense field inside the cavity new thermal neutron detectors were designed with high radiation resistance, low noise and very high neutron-to-photon discrimination capability. This article offers an overview of the e_LiBANS project and describes the results of the benchmark experiment.

Inhibitory control is not lateralized in Parkinson's patients.

Parkinson's disease (PD) is often characterized by asymmetrical symptoms, which are more prominent on the side of the body contralateral to the most extensively affected brain hemisphere. Therefore, lateralized PD presents an opportunity to examine the effects of asymmetric subcortical dopamine deficiencies on cognitive functioning. As it has been hypothesized that inhibitory control relies upon a right-lateralized pathway, we tested whether left-dominant PD (LPD) patients suffered from a more severe deficit in this key executive function than right-dominant PD patients (RPD). To this end, via a countermanding task, we assessed both proactive and reactive inhibition in 20 LPD and 20 RPD patients, and in 20 age-matched healthy subjects. As expected, we found that PD patients were significantly more impaired in both forms of inhibitory control than healthy subjects. However, there were no differences either in reactive or proactive inhibition between LPD and RPD patients. All in all, these data support the idea that brain regions affected by PD play a fundamental role in subserving inhibitory function, but do not sustain the hypothesis according to which this executive function is predominantly or solely computed by the brain regions of the right hemisphere.

PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma.

High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results. However, the expression of PARP enzymes in human neuroblastoma and the biological consequences of their inhibition remained largely unexplored. Here, we show that high PARP1 and PARP2 expression is significantly associated with high-risk neuroblastoma cases and poor survival, highlighting its previously unrecognized prognostic value for human neuroblastoma. In vitro, PARP1 and 2 are abundant in MYCN amplified and MYCN-overexpressing cells. In this context, PARP inhibitors with high 'PARP trapping' potency, such as olaparib or talazoparib, yield DNA damage and cell death preceded by intense signs of replication stress. Notwithstanding the activation of a CHK1-CDC25A replication stress response, PARP-inhibited MYCN amplified and overexpressing cells fail to sustain a prolonged checkpoint and progress through mitosis in the presence of damaged DNA, eventually undergoing mitotic catastrophe. CHK1-targeted inhibition of the replication stress checkpoint exacerbated this phenotype. These data highlight a novel route for cell death induction by PARP inhibitors and support their introduction, together with CHK1 inhibitors, in therapeutic approaches for neuroblastomas with high MYC(N) activity.

BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models.

BACKGROUND: Breast cancer is an extremely complex disease, characterized by a progressive multistep process caused by interactions of both genetic and non-genetic factors. A combination of BRCA1 and BRCA2 gene mutations appears responsible for about 20%-30% of the cases with breast cancer familial history. The prevalence of BRCA1/2 pathogenic mutations largely varies within different populations; in particular, the rate of mutations in Italian breast and/or ovarian cancer families is rather controversial and ranges from 8% to 37%. PATIENTS AND METHODS: Of the 152 breast/ovarian cancer families counseled in our centre, 99 were selected for BRCA1/2 mutation screening according to our minimal criteria. The entire coding sequences and each intron/exon boundary of BRCA1/2 genes were screened by direct sequencing (PTT limited to BRCA1 exon 11). For each proband, the a priori probability of carrying a pathogenic BRCA1/2 germline mutation was calculated by means of different mutation prediction models (BRCApro, IC and Myriad Table) in order to evaluate their performances. RESULTS: Our analysis resulted in the identification of 25 and 52 variants in the BRCA1 and BRCA2 genes, respectively. Seventeen of them represent novel variants, including four deleterious truncating mutations in the BRCA2 gene (472insA, E33X, C1630X and IVS6+1G>C). Twenty-seven of the 99 probands harbored BRCA1 (n = 15) and BRCA2 (n = 12) pathogenic germline mutations, indicating an overall detection rate of 27.3% and increasing by more than 15% the spectrum of mutations in the Italian population. Furthermore, we found the lowest detection rate (19.4%) in pure hereditary breast cancer family subset. All of the prediction models showed praises and faults, with the IC software being extremely sensitive but poorly specific, compared to BRCApro. In particular all models accumulated most false-negative prediction in the HBC subset. Interestingly preliminary results of a study addressing the presence of genomic rearrangements in HBC probands with BRCApro or IC prediction scores >/=95%, provided evidence for additional mutations undetectable with our conventional screening for point mutations. CONCLUSIONS: Altogether our results suggest that HBC families, the largest pool in our series, represent an heterogeneous group where the apparently faulty performances of the prediction models might be at least partially explained by the presence of additional kinds of BRCA1/2 alteration (such as genomic rearrangements) or by mutations on different breast cancer related genes.

HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and affect retinoic acid responsiveness.

HMGI-C and HMGI(Y) are architectural DNA-binding proteins that participate in the conformational regulation of active chromatin. Their pattern of expression in embryonal and adult tissues, the analysis of the "pygmy" phenotype induced by the inactivation of the HMGI-C gene, and their frequent qualitative or quantitative alteration in experimental and human tumors indicate their pivotal role in the control of cell growth, differentiation, and tumorigenesis in several tissues representative of the epithelial, mesenchymal, and hematopoietic lineages. In contrast, very little information is available on their expression and function in neural cells. Here, we investigated the expression of the HMGI(Y) and HMGI-C genes in neuroblastoma (NB), a tumor arising from an alteration of the normal differentiation of neural crest-derived cells and in embryonal and adult adrenal tissue. Although HMGI(Y) is constitutively expressed in the embryonal and adult adrenal gland and in all of the NB cell lines and ex vivo tumors examined, its regulation appears to be associated to growth inhibition and differentiation because we observed that HMGI(Y) expression is reduced by retinoic acid (RA) in several NB cell lines that are induced to differentiate into postmitotic neurons, whereas it is up-regulated by RA in cells that fail to differentiate. Furthermore, the decrease of HMGI(Y) expression observed in RA-induced growth arrest and differentiation is abrogated in cells that have been made insensitive to this drug by NMYC overexpression. In contrast, HMGI-C expression is down-regulated during the development of the adrenal gland, completely absent in the adult individual, and only detectable in a subset of ex vivo NB tumors and in RA-resistant NB cell lines. We provide evidence of a causal link between HMGI-C expression and resistance to the growth arrest induced by RA in NB cell lines because exogenous HMGI-C expression in HMGI-C-negative and RA-sensitive cells is sufficient to convert them into RA-resistant cells. Therefore, we suggest that HMGI-C and HMGI(Y) may participate in growth- and differentiation-related tumor progression events of neuroectodermal derivatives.