Negative BOLD effect on somato-motor inhibitory processing: An fMRI study

Inhibiting inappropriate behavior and thoughts in the current context is an essential ability for humans, but the neural mechanisms for response inhibitory processing are a matter of continuous debate. The aim of this event-related functional magnetic resonance imaging (fMRI) study was to evaluate the negative blood oxygen level dependent (BOLD) effect on inhibitory processing during go/no-go paradigms. Fifteen subjects performed two different types of somatosensory go/no-go paradigm: (1) button press and (2) count. Go and no-go stimuli were presented with an even probability. We observed a common negative activation during Movement No-go and Count No-go trials in the right SFG, corresponding to BA 8. These findings suggest that the right SFG region was responsible for the negative BOLD effect on inhibitory processing, which was independent of the required response mode. We hypothesized several possible explanations for the deactivation of the SFG during no-go trials.     

Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage

Recent evidences suggest a significant role of Plasmacytoid dendritic cells (PDC) role in the pathogenesis of lupus erythematosus (LE) via production of type I IFN. Taking advantage on the availability of multiple reagents (CD123, BDCA2, and CD2ap) specifically recognizing PDC on fixed tissues, we investigated the occurrence of PDC in a cohort of 74 LE patients. The large majority of LE biopsies (67/74; 90.5%) showed cutaneous infiltration of PDC. PDC were more frequently observed (96.4 vs 72.2) and numerous in cutaneous LE compared to systemic LE (SLE) and correlated with the density of the inflammatory infiltrate (r=0.40; p<0.001). PDC reduction in SLE might be related to a broader tissue distribution of this cellular population, as indicated by their occurrence in kidneys in 11 out of 24 (45.8%) cases studied. The distribution of cutaneous PDC showed two distinct patterns. More commonly, PDC were observed within perivascular inflammatory nodules in the dermis, associated with CD208+ mature DC and T-bet+ cells [D-PDC]. A second component was observed along the dermal-epithelial junction [J-PDC], in association with cytotoxic T-cells in areas of severe epithelial damage. Notably, chemerin reactivity was observed in 64% of LE biopsies on endothelial cells and in the granular layer keratinocytes. Cutaneous PDC in LE strongly produced type I IFN, as indicated by the diffuse MxA expression, and the cytotoxic molecule granzyme B.This study confirms cutaneous PDC infiltration as hallmark of LE. The topographical segregation in D-PDC and J-PDC suggests a novel view of the role of these cells in skin autoimmunity.     

Structural characterization and cell response evaluation of electrospun PCL membranes: micrometric versus submicrometric fibers

Electrospinning is a valuable technique to fabricate fibrous scaffolds for tissue engineering. The typical nonwoven architecture allows cell adhesion and proliferation, and supports diffusion of nutrients and waste products. Poly(epsilon-caprolactone) (PCL) electrospun membranes were produced starting from 14% w/v solutions in (a) mixture 1:1 tetrahydrofuran and N,N-dimethylformamide and (b) chloroform. Matrices made up of randomly arranged uniform fibers free of beads were obtained. The average fiber diameters were (a) 0.8 +/- 0.2 microm and (b) 3.6 +/- 0.8 microm. PCL matrices showed the following tensile mechanical properties: tensile modulus (a) 5.0 +/- 0.7 MPa (b) 6.4 +/- 0.2 MPa, yield stress (a) 0.55 +/- 0.06 MPa (b) 0.43 +/- 0.02 MPa, and ultimate tensile stress (a) 1.7 +/- 0.2 MPa and (b) 0.8 +/- 0.1 MPa. The ultimate strain ranged between 300% and 400%. Cytotoxicity of electrospun membranes was continuously evaluated by means of electric cell-substrate impedance sensing technique using human umbilical vein endothelial cells (HUVEC). PCL matrices resulted free of toxic amounts of contaminants and/or process by-products. In vitro studies performed by culturing HUVEC on micrometric and submicrometric fibrous mats showed that both structures supported cell adhesion and spreading. However, cells cultured on the micrometric network showed higher vitality and improved interaction with the polymeric fibers, suggesting an increased ability to promote cell colonization.     

Neoadjuvant Chemoradiation Herapy for Soft Tissue Sarcomas of the Extremities

INTRODUCTION AND OBJECTIVE

Neoadjuvant and adjuvant therapies for soft tissue sarcomas of the extremities are still controversial. The aim of this study was to analyze the results of a protocol of neoadjuvant chemoradiation therapy for extremity sarcomas.

METHODS

A retrospective analysis was carried out in a consecutive series of 49 adult patients with advanced extremity soft tissue sarcomas that could not be resected with adequate margins during the primary resection. All patients were treated with a protocol of preoperative radiation therapy at a total dose of 30 Gy, concomitant with doxorubicin (60 mg/m²) chemotherapy. The main endpoints assessed were local recurrence-free survival, metastasis-free survival and overall survival. The median follow-up time was 32.1 months.

RESULTS

The five-year local recurrence-free survival, metastasis-free survival and overall survival rates were 81.5%, 46.7% and 58.3%, respectively. For high-grade tumors, the five-year metastasis-free and overall survival rates were only 36.3% and 41.2%, respectively. Severe wound complications were observed in 41.8% of the patients who underwent surgery. These complications precluded adjuvant chemotherapy in 73.7% (14/19) of the patients eligible to receive it.

CONCLUSIONS

In this study, neoadjuvant chemoradiation therapy was associated with a good local control rate, but the distant relapse-free rate and overall survival rate were still poor. The high rate of wound complications modified the planning of adjuvant treatment in most patients.     

Ethanol enhances GABAB-mediated inhibitory postsynaptic transmission on rat midbrain dopaminergic neurons by facilitating GIRK currents

It is largely accepted that an activation of the dopaminergic system underlies the recreational and convivial effects of ethanol. However, the mechanisms of action of this drug on the dopaminergic neurons are not fully understood yet. In the present study, we have used intracellular electrophysiological techniques (current and single-electrode voltage-clamp) to investigate the actions of ethanol on the γ-aminobutyric acid (GABA)_B-mediated inhibitory postsynaptic potentials (IPSPs) in rat midbrain dopaminergic neurons. Ethanol (10–200 m m ) augmented, in a concentration-dependent and reversible manner, the amplitude of the GABA_B–IPSP. In addition, the GABA_B agonist baclofen generated G-protein-gated inward rectifying K⁺ channels (GIRK)-related membrane hyperpolarizations/outward currents that were potentiated by ethanol. The potentiating effect of ethanol persisted in tetrodotoxin (TTX)-treated neurons, suggesting a postsynaptic site of action. These effects of ethanol were not changed by manipulating adenyl cyclase, protein kinases and phospholipase C activity, or by chelating intracellular Ca²⁺ with EGTA. Interestingly, the outward current caused by the intracytoplasmatic diffusion of the irreversible G-protein activator GTPγS was transiently enhanced by ethanol. Our observations suggest that the action of ethanol occurs on activated GIRK channels downstream of the GABA_B receptors. These enhancing effects of ethanol on GABA_B-induced synaptic responses could modulate alcohol intake and the altered mental and motor performance of individuals in an acute intoxicative phase.     

Extending the duration of first-line chemotherapy in metastatic breast cancer: a perspective review

The treatment of metastatic breast cancer is mainly palliative, but optimal management might result in survival improvement as well. For this reason, many trials have attempted to optimize the therapeutic approach in this disease setting. Among the possible options, chemotherapy represents the backbone of the treatment and survival improvements that have been shown by the use of modern chemotherapeutic agents. Whereas the type of chemotherapy is generally dictated by patient characteristics and those of their disease, substantial controversy still remains on how long chemotherapy should be administered after disease control is achieved. In this review, we have analysed all available evidence on the duration of first-line chemotherapy in advanced breast cancer.     

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.