fMRI-Based Effective Connectivity in Surgical Remediable Epilepsies: A Pilot Study.

Simultaneous EEG-fMRI can contribute to identify the epileptogenic zone (EZ) in focal epilepsies. However, fMRI maps related to Interictal Epileptiform Discharges (IED) commonly show multiple regions of signal change rather than focal ones. Dynamic causal modeling (DCM) can estimate effective connectivity, i.e. the causal effects exerted by one brain region over another, based on fMRI data. Here, we employed DCM on fMRI data in 10 focal epilepsy patients with multiple IED-related regions of BOLD signal change, to test whether this approach can help the localization process of EZ. For each subject, a family of competing deterministic, plausible DCM models were constructed using IED as autonomous input at each node, one at time. The DCM findings were compared to the presurgical evaluation results and classified as: "Concordant" if the node identified by DCM matches the presumed focus, "Discordant" if the node is distant from the presumed focus, or "Inconclusive" (no statistically significant result). Furthermore, patients who subsequently underwent intracranial EEG recordings or surgery were considered as having an independent validation of DCM results. The effective connectivity focus identified using DCM was Concordant in 7 patients, Discordant in two cases and Inconclusive in one. In four of the 6 patients operated, the DCM findings were validated. Notably, the two Discordant and Invalidated results were found in patients with poor surgical outcome. Our findings provide preliminary evidence to support the applicability of DCM on fMRI data to investigate the epileptic networks in focal epilepsy and, particularly, to identify the EZ in complex cases.

Long-range phase synchronization of high-frequency oscillations in human cortex.

Inter-areal synchronization of neuronal oscillations at frequencies below ~100 Hz is a pervasive feature of neuronal activity and is thought to regulate communication in neuronal circuits. In contrast, faster activities and oscillations have been considered to be largely local-circuit-level phenomena without large-scale synchronization between brain regions. We show, using human intracerebral recordings, that 100-400 Hz high-frequency oscillations (HFOs) may be synchronized between widely distributed brain regions. HFO synchronization expresses individual frequency peaks and exhibits reliable connectivity patterns that show stable community structuring. HFO synchronization is also characterized by a laminar profile opposite to that of lower frequencies. Importantly, HFO synchronization is both transiently enhanced and suppressed in separate frequency bands during a response-inhibition task. These findings show that HFO synchronization constitutes a functionally significant form of neuronal spike-timing relationships in brain activity and thus a mesoscopic indication of neuronal communication per se.

Hexavalent vaccines in preterm infants: an update by Italian Society of Pediatric Allergy and Immunology jointly with the Italian Society of Neonatology.

Hexavalent vaccines, protecting against six diseases (diphtheria, tetanus, pertussis [DTaP], poliovirus, hepatitis B virus [HBV], and Haemophilus influenzae type b [Hib], are routinely the standard of care in Europe. The use of combined vaccines allows the reduction of number of injections and side effects, the reduction of costs, and the increase in adherence of the family to the vaccination schedule both in terms of the number of doses and timing. The safety profile, efficacy and effectiveness of hexavalent vaccines have been extensively documented in infants and children born at term, and data are accumulating in preterm infants. Hexavalent vaccines are particularly important for preterm infants, who are at increased risk for severe forms of vaccine preventable diseases. However, immunization delay has been commonly reported in this age group. All the three hexavalent vaccines currently marketed in Italy can be used in preterm infants, and recent data confirm that hexavalent vaccines have a similar or lower incidence of adverse events in preterm compared to full-term infants; this is likely due to a weaker immune system response and reduced ability to induce an inflammatory response in preterm infants. Apnoea episodes are the adverse events that can occur in the most severe preterm infants and / or with history of respiratory distress. The risk of apnoea after vaccination seems to be related to a lower gestational age and a lower birth weight, supporting the hypothesis that it represents an unspecific response of the preterm infant to different procedures. High seroprotection rates have been reported in preterm infants vaccinated with hexavalent vaccine. However, a lower gestational age seems to be associated with lower antibody titres against some vaccine antigens (e.g. HBV, Hib, poliovirus serotype 1, and pertussis), regardless of the type of hexavalent vaccine used. Waiting for large effectiveness studies, hexavalent vaccines should be administered in preterm infants according to the same schedule recommended for infants born at term, considering their chronological age and providing an adequate monitoring for cardio-respiratory events in the 48-72 h after vaccination, especially for infants at risk of recurrence of apnoea.

Rifle impulse noise affects middle-ear compliance in soldiers wearing protective earplugs.

OBJECTIVE: We tested middle-ear functioning in humans following intense exposure to noise. Noise generated by small caliber firearms was thought to have no effect on the middle-ear. DESIGN: A cross-over design. We measured middle-ear impedance, acoustic reflex, distortion product otoacoustic emissions (DPOAEs), and transient evoked otoacoustic emissions (TEOAEs) before and after practice rounds performed twice per day. STUDY SAMPLE: Fifty-nine soldiers equipped with earplugs undergoing regular training for a special mission. The mean noise exposure (LAeq8h) was estimated to be 106 ±1 dB SPL. RESULTS: Impedancemetry revealed a significant increase in the compliance and gradient of the tympano-ossicular chain after impulse noise exposure in the right and left ears. Acoustic reflex reactivity did not show a significant change. DPOAEs and TEOAEs were slightly decreased at 2 kHz, and showed a marked asymmetry in disfavor of the left ear. In soldiers with initial high reactivity of acoustic reflex, increased compliance was associated with a significant decrease in left TEOAEs at 1.5 and 2 kHz. CONCLUSION: Our results suggest that the use of small-caliber firearms, even while wearing earplugs, affects middle-ear function and may play a role in the early stage of auditory fatigue encompassing tinnitus.

A method for the assessment of time-varying brain shift during navigated epilepsy surgery.

PURPOSE: Image guidance is widely used in neurosurgery. Tracking systems (neuronavigators) allow registering the preoperative image space to the surgical space. The localization accuracy is influenced by technical and clinical factors, such as brain shift. This paper aims at providing quantitative measure of the time-varying brain shift during open epilepsy surgery, and at measuring the pattern of brain deformation with respect to three potentially meaningful parameters: craniotomy area, craniotomy orientation and gravity vector direction in the images reference frame. METHODS: We integrated an image-guided surgery system with 3D Slicer, an open-source package freely available in the Internet. We identified the preoperative position of several cortical features in the image space of 12 patients, inspecting both the multiplanar and the 3D reconstructions. We subsequently repeatedly tracked their position in the surgical space. Therefore, we measured the cortical shift, following its time-related changes and estimating its correlation with gravity and craniotomy normal directions. RESULTS: The mean of the median brain shift amount is 9.64 mm ([Formula: see text] mm). The brain shift amount resulted not correlated with respect to the gravity direction, the craniotomy normal, the angle between the gravity and the craniotomy normal and the craniotomy area. CONCLUSIONS: Our method, which relies on cortex surface 3D measurements, gave results, which are consistent with literature. Our measurements are useful for the neurosurgeon, since they provide a continuous monitoring of the intra-operative sinking or bulking of the brain, giving an estimate of the preoperative images validity versus time.

Multi-trajectories automatic planner for StereoElectroEncephaloGraphy (SEEG).

PURPOSE: StereoElectroEncephaloGraphy (SEEG) is done to identify the epileptogenic zone of the brain using several multi-lead electrodes whose positions in the brain are pre-operatively defined. Intracranial hemorrhages due to disruption of blood vessels can cause major complications of this procedure ([Formula: see text]1%). In order to increase the intervention safety, we developed and tested planning tools to assist neurosurgeons in choosing the best trajectory configuration. METHODS: An automated planning method was developed that maximizes the distance of the electrode from the vessels and avoids the sulci as entry points. The angle of the guiding screws is optimized to reduce positioning error. The planner was quantitatively and qualitatively compared with manually computed trajectories on 26 electrodes planned for three patients undergoing SEEG by four neurosurgeons. Quantitative comparison was performed computing for each trajectory using (a) the Euclidean distance from the closest vessel and (b) the incidence angle. RESULTS: Quantitative evaluation shows that automatic planned trajectories are safer in terms of distance from the closest vessel with respect to manually planned trajectories. Qualitative evaluation performed by four neurosurgeons showed that the automatically computed trajectories would have been preferred to manually computed ones in 30% of the cases and were judged good or acceptable in about 86% of the cases. A significant reduction in time required for planning was observed with the automated system (approximately 1/10). CONCLUSION: The automatic SEEG electrode planner satisfied the essential clinical requirements, by providing safe trajectories in an efficient timeframe.

Identification of a cis-acting factor modulating the transcription of FUM1, a key fumonisin-biosynthetic gene in the fungal maize pathogen Fusarium verticillioides.

Fumonisins, toxic secondary metabolites produced by some Fusarium spp. and Aspergillus niger, have strong agro-economic and health impacts. The genes needed for their biosynthesis, named FUM, are clustered and co-expressed in fumonisin producers. In eukaryotes, coordination of transcription can be attained through shared transcription factors, whose specificity relies on the recognition of cis-regulatory elements on target promoters. A bioinformatic analysis on FUM promoters in the maize pathogens Fusarium verticillioides and Aspergillus niger identified a degenerated, over-represented motif potentially involved in the cis-regulation of FUM genes, and of fumonisin biosynthesis. The same motif was not found in various FUM homologues of fungi that do not produce fumonisins. Comparison of the transcriptional strength of the intact FUM1 promoter with a synthetic version, where the motif had been mutated, was carried out in vivo and in planta for F. verticillioides. The results showed that the motif is important for efficient transcription of the FUM1 gene.

Transcription of genes in the biosynthetic pathway for fumonisin mycotoxins is epigenetically and differentially regulated in the fungal maize pathogen Fusarium verticillioides.

When the fungal pathogen Gibberella moniliformis (anamorph, Fusarium verticillioides) colonizes maize and maize-based products, it produces class B fumonisin (FB) mycotoxins, which are a significant threat to human and animal health. FB biosynthetic enzymes and accessory proteins are encoded by a set of clustered and cotranscribed genes collectively named FUM, whose molecular regulation is beginning to be unraveled by researchers. FB accumulation correlates with the amount of transcripts from the key FUM genes, FUM1, FUM21, and FUM8. In fungi in general, gene expression is often partially controlled at the chromatin level in secondary metabolism; when this is the case, the deacetylation and acetylation (and other posttranslational modifications) of histones are usually crucial in the regulation of transcription. To assess whether epigenetic factors regulate the FB pathway, we monitored FB production and FUM1, FUM21, and FUM8 expression in the presence of a histone deacetylase inhibitor and verified by chromatin immunoprecipitation the relative degree of histone acetylation in the promoter regions of FUM1, FUM21, and FUM8 under FB-inducing and noninducing conditions. Moreover, we generated transgenic F. verticillioides strains expressing GFP under the control of the FUM1 promoter to determine whether its strength under FB-inducing and noninducing conditions was influenced by its location in the genome. Our results indicate a clear and differential role for chromatin remodeling in the regulation of FUM genes. This epigenetic regulation can be attained through the modulation of histone acetylation at the level of the promoter regions of the key biosynthetic genes FUM1 and FUM21, but less so for FUM8.

Role of micronucleus test in predicting breast cancer susceptibility: a systematic review and meta-analysis.

BACKGROUND: The cytokinesis-block micronucleus test (MNT), as a marker of chromosomal mutagen sensitivity, was applied in a number of studies enrolling breast cancer (BC) patients and subjects with known or putative genetic predisposition to BC. The large majority of them involve the evaluation of induced micronuclei (MN) frequency in peripheral lymphocytes, after the in vitro challenge with ionising radiations. METHODS: The aim of the present systematic review and meta-analysis is to investigate the role of MN assay in the identification of individuals at increased risk of BC and its potential use as prescreening test in women with a family history (FH) of BC. RESULTS: Twelve studies were included in the meta-analysis, covering a time interval 1998-2007, and including 752 cases and 593 controls. Among the cases, 629 are cancer patients and 123 are cancer-free subjects, including 32 first-degree relatives of the susceptible subjects and 91 BRCA1/2 mutation carriers. Our meta-analysis reveals a significant increase of baseline MN frequency related to cancer status, but the association with FH of BC and specifically with BRCA mutations is not clear. A larger difference in MN frequency between cases and controls was observed after in vitro challenge, but response to radiation exposure doesn't appear to better discriminate cancer-susceptible subjects. CONCLUSION: Our study suggests the presence of some bias affecting many of these studies, reinforcing the suggestion that a more rigorous study design is needed in this area.

Immunological modifications induced from products used during the perioperative period.

Anesthetics and other products used during the perioperative period may influence immune function not only merely by reducing the HPA-axis stress response but also by directly modulating innate and adaptive immune responses. Most of the literature on the immune effects of anesthetics has been derived from in vitro or animal studies, due to the number of confounding variables in real life surgical settings. These immunosuppressive effects might not normally have clinical consequences for an immune-competent patient, but may act as important modifiers in postoperative morbidity and mortality. Furthermore, some inhibitory effects on neutrophil functions may provide a therapeutically beneficial effect under specific surgical clinical conditions, such as ischemia-reperfusion injury.

Perioperative allergy: clinical manifestations.

Adverse drug reactions or side effects are usually expected, dose dependent, and occur at therapeutic doses. Anaphylactic and anaphylactoid reactions are unexpected and dose independent and can occur at the first exposure to drugs used during anesthesia. Perioperative anaphylaxis is a severe and rapid clinical condition that can be lethal even in previously healthy patients. The initial diagnosis of anaphylaxis is presumptive. A precise identification of the drug responsible for the adverse reaction is more difficult to establish in the case of anaphylactoid reaction because the adverse reaction could result from additive side effects of different drugs injected simultaneously. The timing of the reaction in relation to events, e.g. induction, start of surgery, administration of other drugs, i.v. fluids, is essential for the diagnosis. Generally, reactions are predominant in the induction and recovery phases, and manifested mainly as cutaneous symptoms. Reactions to drugs coincide with the phases when they are administered. Reactions to antibiotics are more frequent in the induction phase, to neuromuscular agents in the initiation and maintenance phases and to non-steroidal anti-inflammatory agents in the recovery phase. The differential diagnosis of any adverse reaction during or following anesthesia should include the possibility of anaphylaxis.

Perioperative period: immunological modifications.

Surgical stress induces complex modifications in the hemodynamic, metabolic, neuro-hormonal and immune response of the individual. The magnitude of these alterations depends on preoperative events leading to surgery, the severity of surgical trauma, and also on post-operative/post-traumatic complications (multiple hit hypothesis). As in other conditions of tissue damage, surgery trauma is followed by an immune-inflammatory response, initiated at the site of injury by the innate immune system, followed by a compensatory anti-inflammatory (or immunosuppressive) response (CARS), involving mainly cells of the adaptive immune system, which predispose the host to septic complications. The up-regulated inflammatory response, together with a profound impairment of macrophage and cell-mediated immunity, appear to be the cause for patients' increased susceptibility in developing subsequent sepsis after major surgery.

Perioperative allergy: therapy.

Perioperative allergic reactions manifest in various ways. The majority of systemic reactions occur during anesthesia within minutes of intravenous induction; however, agents which are administered via other routes may cause reactions after more than 15 minutes. Anaphylaxis during anesthesia may present in many different ways and the signs and symptoms, which do not vary from those of anaphylactic reactions in general, may be masked by hypovolemia, light, deep anesthesia or extensive regional blockade. Recommendations for treatment are based on available evidence in the literature. A treatment algorithm is suggested, with emphasis on the incremental titration of adrenaline and fluid therapy as first-line treatment. Increased focus on this subject will hopefully lead to prompt diagnosis and rapid, correct treatment.

Clinical modifications induced by drugs during the perioperative period.

Total intravenous anesthesia (TIVA) can be defined as a technique in which general anesthesia is induced and maintained using only intravenous agents. TIVA has become more popular in recent times because of the pharmacokinetic and pharmacodynamic properties of propofol, the availability of short acting synthetic opioids, and the development of delivery systems. Significant differences in anatomy and physiology in adults and children and special needs of younger patients have important consequences on many aspects of anesthesia. Airway and respiratory complications are the most common causes of morbidity during general anesthesia in children. Knowledge of the functional anatomy of airways in children forms the basis in the understanding of the pathological conditions that may occur.

Prevention of allergic reactions in anesthetized patients.

Hypersensitivity reactions during perioperative period are increasing and may be potentially life-threatening. Therefore, major emphasis is given to prevention. We perform a review to examine which measures should be taken to prevent reactions to products used in elective and emergency surgery. Any patient with a history of previous anaphylaxis or severe reaction during anaesthesia should be referred to allergist for detection of the offending compound. However, the identification of the triggering agent is not always feasible because of the low accuracy of diagnostic tests. In these cases and when emergency surgery is required, it should be considered to replace all drugs administered before the onset of the reaction with alternatives. Furthermore, any cross-reacting agent and latex, especially in patients belonging to populations at-risk for latex allergy should be avoided. In susceptible patients, premedication with antihistamines and corticosteroids might reduce the severity of reaction to drugs or contrast material while it is unclear whether pre-treatment decreases incidence of anaphylactic reactions. There is no evidence that premedication prevents allergic reactions to latex. Overall, physicians should not rely on the efficacy of premedication.

Perioperative latex allergy.

The prevalence of latex allergy varies greatly depending on the population studied and the methods used to detect sensitization. Subjects considered to be at high risk for latex allergy are rubber industry workers, children with spina bifida and urological abnormalities, children undergoing multiple surgical procedures and with urinary catheterization, health care workers and people with food allergy (latex fruit syndrome). In this paper we report a review of latex proteins, the symptoms of latex allergy, diagnosis and management in subjects with latex allergy.

Perioperative allergy: uncommon agents.

Anesthesia may often be considered as a high-risk procedure and anaphylaxis remains a major cause of concern for anesthetists who routinely administer many potentially allergenic agents. Neuromuscular blocking agents, latex and antibiotics are the substances involved in most of the reported reactions. Besides these three agents, a wide variety of substances may cause an anaphylactic reaction during anesthesia. Basically all the administered drugs or substances may be potential causes of anaphylaxis. Among them, those reported the most in literature include hypnotics, opioids, local anesthetics, colloids, dye, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Iodinated Contrast Media (ICM), antiseptics, aprotinin, ethylene oxyde and formaldehyde, and protamine and heparins. No premedication can effectively prevent an allergic reaction and a systematic preoperative screening is not justified for all patients; nevertheless, an allergy specialist should evaluate those patients with a history of anesthesia-related allergy. Patients must be fully informed of investigation results, and advised to provide a detailed report prior to future anesthesia.

Risk factors for postoperative depression in 150 subjects treated for drug-resistant focal epilepsy.

OBJECTIVE: The primary goal was to identify risk factors for post-surgical depression in subjects operated on for drug-resistant epilepsy. Secondary goals were to confirm the high rate of depression in subjects suffering from epilepsy (prior to surgery) and to look for first post-surgical depressive episode. METHODS: Case series study of 150 subjects surgically treated for partial epilepsy (side of surgery: 72 right, 78 left; site of surgery: 97 Unilobar Temporal, 17 Unilobar Frontal, 14 Posterior, 22 Multilobar). All subjects routinely had three psychiatric evaluations: before surgery (baseline) and at 6 and 12 months after surgery. Psychiatric diagnoses were made according to DSM-IV-TR criteria. Bivariate (Fisher exact test and Kruskal-Wallis rank sum test) and multivariate (logistic regression model fitting) analyses were performed. RESULTS: Thirty-three (22%) subjects had post-surgical depressive episodes, 31 of them in the first 6 months. Fourteen out of 33 experienced depression for the first time. Post-surgical depressive episodes are not associated with gender, outcome on seizures, side/site of surgical resection, histological diagnosis, psychiatric diagnoses other than depression. Depressive episodes before surgery and older age at surgery time are risk factors for post-surgical depression (p= 0.0001 and 0.01, respectively, at logistic regression analysis). No protective factors were identified. CONCLUSIONS: Our data show that lifetime depressive episodes and older age at surgery time are risk factors for postsurgery depression. Moreover, a prospective study could be useful in order to assess whether depression is really a consequence of surgery.