Action word understanding and overt motor behavior

Cutaneous reflexes induced in lower leg muscles by non-noxious electrical stimulation to the foot sole are strongly modified depending on the stimulated location. Little is known, however, about the functional importance of this location-specificity. We examined modulation of cutaneous reflexes in the peroneus longus muscle during co-activation of the peroneus longus (PL), soleus, and tibialis anterior muscles in ten healthy volunteers. We successfully recorded 121 intramuscular single motor units (MU) of cutaneous reflexes in PL elicited by stimulating either fore-medial, fore-lateral, or heel regions of the plantar foot while performing plantarflexion and eversion (PF + EV), dorsiflexion and eversion (DF + EV), or isolated eversion (EV). Firing probability increased following fore-lateral stimulation during the PF + EV and EV tasks, but not during the DF + EV. Fore-medial stimulation, irrespective of the task, suppressed the reflex. Heel stimulation facilitated the reflex only during the PF + EV and DF + EV tasks. In general, cutaneous reflex magnitudes were larger during the PF + EV task than during the others, irrespective of whether the effects were facilitatory or suppressive. These results suggest that the magnitude of the reflex effects on the PL motoneurons strongly depends on activation of plantarflexors and dorsiflexors.     

Sex and ethnic differences among South Tirolean suicides: A psychological autopsy study

ObjectiveThe aim of the research is to study whether any differences exist in the rates and characteristics of suicide by ethnicity and sex in South Tirol, Italy.MethodsPsychological autopsy interviews were conducted for suicides who died between March 1997 and July 2006.Results332 individuals belonging to the three major South Tirolean ethnic groups (Germans, Italians, Ladins [Ladin is a Rhaeto-Romance language related to the Venetian and Swiss Romansh languages]) died by suicide. Around 23% of the victims had experienced suicidal behaviour among family members, and more than 31% of them had experienced trauma during their childhood. Germans were 1.37 times more at risk to commit suicide than Italians (95% CI: 1.04/1.80; z = 2.26, p < .05). 69% of the suicides had attended school for less than 8 years: Germans (OR = 4.62; 95% CI: 2.52/8.47; p < .001) and Ladins (OR = 11.24; 95% CI: 2.99/42.30; p < .001) were more likely to have lower education than Italians. There were several differences by ethnicity and sex but no sex-by-ethnicity interactions.ConclusionsThe study indicated that suicide, an alarming health and social problem in South Tirol, may require different preventive interventions for men and women and for those of different ethnicities.     

Neutralization of a unique, negatively-charged residue in the voltage sensor of KV7.2 subunits in a sporadic case of benign familial neonatal seizures

Benign Familial Neonatal Seizures (BFNS) is a rare, autosomal-dominant epilepsy of the newborn caused by mutations in K_v7.2 (KCNQ2) or K_v7.3 (KCNQ3) genes encoding for neuronal potassium (K⁺) channel subunits. In this study, we describe a sporadic case of BFNS; the affected child carried heterozygous missense mutations in both K_v7.2 (D212G) and K_v7.3 (P574S) alleles. Electrophysiological experiments revealed that the K_v7.2 D212G substitution, neutralizing a unique negatively-charged residue in the voltage sensor of K_v7.2 subunits, altered channel gating, leading to a marked destabilization of the open state, a result consistent with structural analysis of the K_v7.2 subunit, suggesting a possible pathogenetic role for BFNS of this K_v7.2 mutation. By contrast, no significant functional changes appeared to be prompted by the K_v7.3 P574S substitution. Computational modelling experiments in CA1 pyramidal cells revealed that the gating changes introduced by the K_v7.2 D212G increased cell firing frequency, thereby triggering the neuronal hyperexcitability which underlies the observed neonatal epileptic condition.     

Radio-induced low-grade glioma: report of two cases and review of the literature

With the increasing number of cancer survivors, we can observe a population that will present a higher risk of developing secondary long-term toxicities related to adjuvant chemo and radiotherapy regimens. Among these, children surviving from acute lymphoblastic leukemia (ALL) that were treated with prophylactic cranial irradiation represent a group of patients at a high risk of developing secondary brain tumors. Radiation-induced intracranial tumors have been documented since 1950, and today, more than one-hundred cases have been described. We report our experience with two young patients who were hospitalized for low grade gliomas and had a positive anamnesis for ALL and consequent radiotherapy.     

Therapy of Hodgkin's lymphoma in clinical practice: A retrospective long-term follow-up analysis

Treatment of Hodgkin's lymphoma (HL) is perceived to be relatively straightforward. Consequently, patients are not usually referred to hemato-oncologically specialized centres and are treated locally instead. Comprehensive findings beyond prospective controlled trials are therefore lacking. Clinical data of 209 patients who had received a HL diagnosis were collected. A total of 7 patients received radiotherapy (RT) alone (3%), 75 (35%) were treated with a combination of chemotherapy (CT) and RT and 127 patients received CT alone [mainly doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)]. Complete response (CR) following first-line treatment was achieved in 178 patients (85%) and in 195 (93%) after salvage treatment. Favorable disease (p=0.000359), limited-stage disease (p=0.0003), involvement of lymph nodes above the diaphragm (p=0.05) and absence of mediastinal bulky tumor involvement positively affected the CR rate following first-line treatment. Out of the 195 patients that achieved CR, 31 relapsed. Male gender (p=0.043) and age over 45 years (p=0.047) were significantly associated with an increased incidence of relapse. Age at diagnosis was the key factor affecting long-term outcome. The event-free survival (EFS) projected at 120 months was 80 and 57% for patients younger and older than 45 years, respectively (p=0.022). The overall survival (OS) projected at 120 months was 92 and 38% for patients younger and older than 45 years, respectively (p=0.00561). A second neoplasia was diagnosed in 8 patients. The development of a tumor in 4 cases (breast, lung and thyroid cancer) was likely RT-related. Only 1 patient not receiving RT developed acute myeloid leukemia. The EFS and OS of the 141 early-stage patients treated with CT + RT (n=62) or with CT alone (n=79) were not statistically different.     

Stressed to death: targeting endoplasmic reticulum stress response induced apoptosis in gliomas

Glial tumors are the main primary adult brain tumor. Even with the most advanced treatments, which include stereotactic microscope aided surgical resection, internal and external radiation therapy and local and systemic chemotherapy, median survival time for patients diagnosed with these malignancies is about 12 months. We explore here the possibility that the endoplasmic reticulum stress response (ERSR) could be a possible target to develop chemotherapeutic agents to induce toxicity in glioma cells. ERSR has the dual capacity of activating repair and/or cytotoxic mechanisms. ERSR is triggered by the accumulation of unfolded proteins in the ER. The presence of unfolded proteins in the ER regulates, via a complex biochemical cascade, the upregulation of molecular chaperones, inhibition of protein synthesis, and an increase of proteasome mediated unfolded protein degradation. ERSR in particular conditions can also contribute to cell death via activation of programmed cell death. Apoptosis activation during ERSR is usually caused by the activation of one or a combination of three biochemical cascades. Induction of these pathways ultimately leads to caspase 3 activation culminating in apoptosis. Glioma cells are in a condition of constant low grade ERSR, which possibly contributes to their resistance to treatment protocols. It is conceivable that small molecules that interact with this phenomenon ultimately could be used to modulate the system to activate apoptosis and cause gliotoxicity. We will discuss here ERSR biochemically relevant features to death mechanisms and already identified small molecules that by modulating ERSR are able to activate glioma cell death.     

Tobacco smoking, alcohol drinking, and the risk of different histological types of nasopharyngeal cancer in a low-risk population

Nasopharyngeal carcinoma (NPC) is rare in western Countries. Tobacco smoking is a well-recognised risk factor, whereas the role of alcohol drinking is still in debate. We conducted a hospital-based case-control study in Italy on 150, histologically-confirmed, NPC cases of Caucasian ethnicity, aged 18-76years, including 118 undifferentiated NPCs and 22 differentiated squamous-cell NPC. Controls were 450 Caucasian cancer-free patients admitted to general hospitals for acute conditions. Cases and controls were matched according to sex, age, and place of residence. Logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) while adjusting for known confounders. No significant association emerged between tobacco smoking and all NPCs (OR for current vs. never smokers=1.52; 95% CI: 0.89-2.60). Conversely, for differentiated NPC only, statistically significant elevated OR were associated with increasing smoking intensity (OR for ?15cigarettes/day=5.40; 95% CI: 1.34-21.76) and duration of the habit (OR for ?32years=4.48; 95% CI: 1.11-18.04). Although alcohol drinking was not, per se, significantly associated to NPC risk, the combination of tobacco smoking and alcohol drinking accounted for 57% of differentiated NPCs, whereas it accounted for only 14% of undifferentiated carcinomas. Our findings suggest that, in western populations, NPC includes two separate entities: the differentiated NPC, associated with tobacco smoking like other cancers of head and neck, and the undifferentiated NPC, upon which tobacco smoking has little or no influence.     

Intensity-modulated radiotherapy (IMRT)/Tomotherapy following neoadjuvant chemotherapy in stage IIB-IVA/B undifferentiated nasopharyngeal carcinomas (UCNT): a mono-institutional experience

To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3–64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a–2b and T3–T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach.     

Notch signaling in lung cancer

Lung cancer is the leading cause of cancer-related deaths in the Western world. The lungs can be affected by a number of histologically diverse malignancies. Nonetheless, the vast majority of lung cancers are classified as non-small-cell lung cancer (NSCLC). Despite extensive research on different therapeutic regimens, the overall 5-year survival of patients diagnosed with NSCLC (all stages) is a dismal 15%. Although strongly correlated with tobacco smoke, there is an increasing NSCLC morbidity in individuals who have never smoked. The pattern of genetic lesions found in NSCLC derived from smokers and never-smokers appears to be different. This fact led to the hypothesis that different, still unidentified carcinogens are responsible for lung cancer onset in never-smokers. All the aforementioned considerations compel the scientific community to find novel therapeutic targets to fight such a deadly disease. In recent years critical pathways governing embryonic development have been increasingly linked to cancer. Here we will focus on the role of Notch signaling in lung cancer. Notch receptors' activity can be blocked through the use of different strategies, thus representing a promising alternative/complement to the arsenal of therapeutic strategies currently used to treat lung cancer.