Nociceptive and non-nociceptive sub-regions in the human secondary somatosensory cortex: an MEG study using fMRI constraints

Previous evidence from functional magnetic resonance imaging (fMRI) has shown that a painful galvanic stimulation mainly activates a posterior sub-region in the secondary somatosensory cortex (SII), whereas a non-painful sensory stimulation mainly activates an anterior sub-region of SII [Ferretti, A., Babiloni, C., Del Gratta, C., Caulo, M., Tartaro, A., Bonomo, L., Rossini, P.M., Romani, G.L., 2003. Functional topography of the secondary somatosensory cortex for non-painful and painful stimuli: an fMRI study. Neuroimage 20 (3), 1625-1638.]. The present study, combining fMRI with magnetoencephalographic (MEG) findings, assessed the working hypothesis that the activity of such a posterior SII sub-region is characterized by an amplitude and temporal evolution in line with the bilateral functional organization of nociceptive systems. Somatosensory evoked magnetic fields (SEFs) recordings after alvanic median nerve stimulation were obtained from the same sample of subjects previously examined with fMRI [Ferretti, A., Babiloni, C., Del Gratta, C., Caulo, M., Tartaro, A., Bonomo, L., Rossini, P.M., Romani, G.L., 2003. Functional topography of the secondary somatosensory cortex for non-painful and painful stimuli: an fMRI study. Neuroimage 20 (3), 1625-1638.]. Constraints for dipole source localizations obtained from MEG recordings were applied according to fMRI activations, namely, at the posterior and the anterior SII sub-regions. It was shown that, after painful stimulation, the two posterior SII sub-regions of the contralateral and ipsilateral hemispheres were characterized by dipole sources with similar amplitudes and latencies. In contrast, the activity of anterior SII sub-regions showed statistically significant differences in amplitude and latency during both non-painful and painful stimulation conditions. In the contralateral hemisphere, the source activity was greater in amplitude and shorter in latency with respect to the ipsilateral. Finally, painful stimuli evoked a response from the posterior sub-regions peaking significantly earlier than from the anterior sub-regions. These results suggested that both ipsi and contra posterior SII sub-regions process painful stimuli in parallel, while the anterior SII sub-regions might play an integrative role in the processing of somatosensory stimuli.     

Epigenetic therapy in myelodysplastic syndromes

The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies – with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life‐threatening infections, bleeding, and progression to acute myeloid leukemia (AML) – that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so‐called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting.     

Arcus Marginalis Release II Via Endoscopic Midface-Lift

Tear troughs in combination with midfacial ptosis may be early and synergistic signs of aging. Premaxillary and suborbicularis oculi fat (SOOF) descent decreases soft tissue volume covering the orbital rim, while prolapsing retroseptal fat actually underscores the resulting tear trough shadow. This volume change precedes skin redundancy. Thus, volume redistribution avoiding external skin incisions is the adequate treatment. De la Plaza’s transconjunctival lower lid blepharoplasty is a reliable tool for arcus marginalis release. For patients also requiring an endoscopic midface-lift, even the transconjunctival incision for intraorbital fat compartment realignment can be avoided by performing the release of the lower orbita septum via the buccal mucosa incision. Presented in part at the XXth anniversary meeting of the Mediterranean Society of Plastic Aesthetic Surgery, Nice France, 13–15 April 2007     

Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection

The functional impairment of HCV-specific T cell responses is believed to be an important determinant of HCV persistence, but the functional T cell defects of patients with chronic hepatitis C (CH-C) are only partially defined. CD8 responses to HLA-A2-restricted epitopes of HCV and other unrelated viruses were studied in 23 HLA-A2-positive patients both ex vivo and after in vitro culture. Degranulation capacity, intracellular perforin, and granzyme-A content and cytokine production (IFN-gamma, TNF-alpha) by HCV- and non-HCV-specific CD8 cells were tested both ex vivo and in vitro, whereas cytolytic activity was studied after 10 days' expansion in vitro. Memory maturation and role of exhaustion were assessed ex vivo by HCV-specific CD8 staining for CD127 and PD-1, and in vitro after peripheral blood mononuclear cells (PBMC) culture in the presence of anti-PD-L1 monoclonal antibodies. IFN-gamma production and cytolytic activity were expressed less efficiently by HCV-specific than by non-HCV specific CD8 cells derived from the same CH-C patients. The amount of stored granzyme-A within single cells was always lower in HCV-specific CD8 cells, which were less efficient also in the release of lytic granules and in the production of TNF-alpha. The CD8 dysfunction was associated with high PD-1 expression by most HCV-specific CD8 cells, and PD-1/PD-L1 blockade by anti-PD-L1 antibodies in vitro was able to improve the HCV-specific CD8 function. CONCLUSION: Our study characterizes CD8 defects that may be important in maintaining HCV persistence; identification of strategies to correct these defects may help to define novel approaches to treat HCV infection.     

Chemotherapy as initial treatment of locally advanced unresectable pancreatic cancer: a valid option?

INTRODUCTION: Radio-chemotherapy is the standard treatment for locally advanced unresectable pancreatic cancer (LAPC). Chemotherapy has been shown to be effective in the treatment of metastatic disease and we therefore evaluated its use as a first-line treatment for LAPC. PATIENTS AND METHODS: We carried out a retrospective analysis of all consecutive patients treated for LAPC (N=33) between July 1997 and April 2005, analysing the results of first-line chemotherapy (CT group) and radio-chemotherapy (RCT group) in this setting. RESULTS: The first-line treatment was RCT in six patients (18.3%) and CT in 26 patients (78.8%). Secondary treatment was administered to nine patients of CT group with well-controlled disease: "closure" radio-chemotherapy for seven patients (26.9%) and secondary resection for three (12%). After a median follow-up of 27 months, 23 patients died (69.7%). Overall survival was 13.8 months [95% CI: 10.1-19.4] for the whole population, 9.5 months [95% CI: 4.6-] for the RCT and 18.0 months [95% CI: 12.4-25.5] for the CT. Overall survival for the CT patients undergoing secondary surgery or "consolidation" radio-chemotherapy was 28.8 months [95% CI: 13.8-]. CONCLUSION: First-line chemotherapy is a valid option for LAPC treatment, making it possible to identify the patients who may benefit from secondary resection or radio-chemotherapy.     

Colorectal carcinogenesis. 1. Hereditary predisposition and colorectal cancer

Tumors arising sporadically represent 70-80% of colorectal cancer (CRC). The two best defined forms of inherited CRC-familial multiple polyposis (FMP) and Hereditary Non-Polyposis Colon Cancer (HNPCC) account respectively for<1% and 2-3% of CRC. These rare genetic syndromes (FMP, HNPCC, Peutz-Jeghers Syndrome) are caused by major predisposing gene mutations (APC gene, MMR gene, BMPR1A. SMAD4,...) and local environmental factors play only a minor role. In the sporadic forms of CRC, 25% have significant genetic predisposition probably related to alleles with weak penetration (APC*I1307K, TGFbR1*6Ala...) and are more strongly affected by environmental factors.     

Hepatectomy for resectable colorectal cancer metastases--indicators of prognosis, definition of resectability, techniques and outcomes

The field of surgery for liver metastases is evolving rapidly. The proportion of patients viewed as amenable to resection is increasing with surgeons becoming more aggressive and systemic therapy more effective. Surgical resection is associated with low mortality and overall 5-year survival approaching 40%. Best candidates for resection are those with stage I or II colorectal cancer, fewer than 4 hepatic lesions, no lesions larger than 5 cm in diameter, no evidence of extra-hepatic disease, CEA level less than 5 ng/mL, and a disease-free interval of at least 2 years. Perioperative chemotherapy with or without biotherapies, in-situ ablation techniques, portal vein embolization, and staged hepatectomy have extended the indications without lessening the results of liver resection for colorectal metastases.     

Pharmacological characterization and molecular determinants of the activation of transient receptor potential V2 channel orthologs by 2-aminoethoxydiphenyl borate

Despite its expression in different cell types, transient receptor potential V2 (TRPV2) is still the most cryptic members of the TRPV channel family. 2-Aminoethoxydiphenyl borate (2APB) has been shown to be a common activator of TRPV1, TRPV2, and TRPV3, but 2APB-triggered TRPV2 activation remains to be thoroughly characterized. In this study, we have developed an assay based on cell lines stably expressing mouse TRPV2 channels and intracellular calcium measurements to perform a pharmacological profiling of the channel. Phenyl borate derivatives were found to activate mouse TRPV2 with similar potencies and thus were used to screen a panel of channel blockers. Besides the classic TRP inhibitors ruthenium red (RR) and 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SKF96365), two potassium channel blockers, tetraethylammonium (TEA) and 4-aminopyridine, and an inhibitor of capacitative calcium entry, 1-(2-(trifluoromethyl) phenyl) imidazole (TRIM), were found to inhibit TRPV2 activation by 100 microM 2APB. Activation by 300 microM 2APB, however, could only be inhibited by RR and TRIM. Electrophysiological recordings demonstrated that TEA inhibition was use-dependent, suggesting that high concentrations of 2APB might induce a progressive conformational change of the channel. Comparison of TRPV2 orthologs revealed that the human channel was insensitive to 2APB. Analysis of chimeric constructs of mouse and human TRPV2 channels showed that the molecular determinants of 2APB sensitivity could be localized to the intracellular amino and carboxyl domains. Finally, using lentiviral-driven expression, we demonstrate that hTRPV2 exerts a dominant-negative effect on 2APB activation of native rodent TRPV2 channels and thus may provide an interesting tool to investigate cellular functions of TRPV2 channels.     

A critical evaluation of the concomitant use of the implantable Doppler probe and the Vacuum Assisted Closure system in free tissue transfer

Introduction of the Vacuum-Assisted Closure (V.A.C.) system has revolutionized the approach to a multitude of clinical settings. Yet, its use precludes adequate clinical monitoring of skin-grafted free flaps, thus, making a reliable monitoring system essential if broad clinical application is aspired. In a clinical study, the usefulness of the combination of the V.A.C. and implantable Doppler probe was critically evaluated in patients with microsurgical lower extremity reconstruction. We retrospectively analyzed the usefulness of the implantable Doppler probe in five consecutive patients treated in our department from January to July 2007. Inclusion criteria were lower extremity reconstruction by means of skin-grafted free tissue transfers with subsequent application of the V.A.C. device. Five consecutive patients (four males, one female) with a mean age of 37.8 years (range, 8-58 years) matched the criteria mentioned above. Of note, the two pediatric patients (8-year-old male and 12-year-old female) suffered from significant posttraumatic stress disorder necessitating concomitant psychological care by the Department of Psychiatry. All flaps healed uneventfully displaying no signs of vascular compromise. Interpretation of the Doppler signal was simple and well received by the nursing staff. The combination of V.A.C. and the implantable Doppler probe enhances patient comfort due to a reduction of the number of dressing changes while still allowing continuous free flap monitoring. Interpretation of the signal transmitted by the probe is simple and potentially reduces misinterpretations due to different levels of experience.