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Background and purpose: For many years deep brain stimulation (DBS) devices relied only on voltage-controlled stimulation (CV), but recently current-controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant-current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant-voltage with constant-current DBS devices, in order to verify the clinical efficacy and safety of this procedure. Methods: Nineteen patients with Parkinson's disease or dystonic syndrome underwent DBS IPG CV/CC replacement. Clinical features and therapy satisfaction were assessed before surgery, 1 week after and 3 and 6 months after replacement. Programming settings and impedances were recorded before removing the CV device and when the CC IPGs were switched on. Results: The clinical outcome of CC stimulation was similar to that obtained with CV devices and remained stable at 3 and 6 months of follow-up. Impedance values recorded for CV and CC IPGs were similar. Ninety-five percent of patients and physicians were satisfied with mixed implants. No adverse events occurred after IPG replacement. Conclusion: Replacing CV with CC IPGs is a safe and effective procedure. Longer follow-up is necessary to better clarify the impact of CC stimulation on clinical outcome after chronic stimulation in CV mode. [ABSTRACT FROM AUTHOR]

Melanoma-associated peptides recognized by cytolytic T lymphocytes (CTL) in the context of several histocompatibility leukocyte antigens (HLA) are required for the development of specific immunotherapies. Using a transient transfection assay into COS-7 cells, we identified the gp100/pMel17 melanosomal protein as the shared antigen recognized by three independent CD8+ CTL clones in HLA-A*6801-restricted fashion. This finding was confirmed by the correlation between lack of gp100/pMel17 protein in a number of HLA-A*6801-positive melanomas and their resistance to lysis/cytokine production by the specific effectors. The gp100/pMel17 antigenic epitope was identified based on recognition of subfragments and on a computer-based prediction algorithm. Among a panel of gp100/pMel17-derived synthetic peptides only the 10-mer HTMEVTVYHR (gp100/pMel17182-191 ) induced tumor necrosis factor (TNF) release by CTL clones when pulsed on suitable target cells whereas both the 10-mer and the shorter 9-mer gp100/pMel17183-191 sensitized the same antigen-pulsed cells to lysis. In conclusion, the identification of the HTMEVTVYHR peptide will extend to HLA-A*6801 melanoma patients the possibility to exploit gp100/pMel17 melanosomal protein for experimental and clinical studies. [ABSTRACT FROM AUTHOR]

Gangliosides have been shown to modulate autoimmune phenomena in experimental diabetes. The effects of a pancreatic ganglioside preparation or of a commercial brain ganglioside mixture on the insulitis and blood glucose levels in the low-dose streptozotocin mouse model of diabetes have been investigated. Fifty-five C57BL/6J male mice were grouped as follows: Group 1 (n = 20) was injected intraperitoneally with repeated low doses of streptozotocin; Group 2 (n = 10) received streptozotocin as above but was also injected with a pancreatic ganglioside preparation equivalent to 2 µg sialic acid 2 h before each streptozotocin dose; Group 3 (n = 15) received streptozotocin and brain-derived gangliosides in the same dose as that of pancreatic gangliosides; Group 4 (n = 10) consisted of normal animals. Half of the mice were killed on day 12 and the others on day 24 from the beginning of treatment. On day 12, among the streptozotocin-injected animals only those treated with pancreatic gangliosides remained normoglycaemic, whereas on day 24 all streptozotocin mice were hyperglycaemic. Such a result paralleled that data pertaining to insulitis scores. In conclusion, pancreatic gangliosides have a short-term protective role on the development of diabetes in the low-dose streptozotocin model, an effect therefore linked to tissue-related differences in the glycosphingolipid composition. [ABSTRACT FROM AUTHOR]

We report here the molecular characterization of the T-cell receptor (TCR) expressed by a human HLA-A2 specific cytotoxic T-cell clone named CTL 49. Flow cytometry analysis with a panel of anti-TCR antibodies revealed an OKT3+, WT31+, A13+, BB3-, TCR &δ-, δ TCS1-, TCR γ/δ 1-, OKT4-, and OKT8+ phenotype, suggesting that, in CTL 49, the V δ 1-encoded A13 epitope could be included in its α β TCR. Northern blot analysis confirmed the presence of C α, C β and V δ 1 specific transcripts while no hybridization signal was detected by a C δ specific probe. Polymerase chain reaction (PCR) amplification of the first strand cDNA from CTL 49 with TCR-specific primers and sequence analysis revealed that V δ 1 region is productively rearranged to J α and to C α regions. This α chain pairs with a β chain composed of V β 13.2/D β/J β 2.3/C β 2 leading to the expression of a functional TCR complex. These results, in addition to providing further evidence for the sharing of V δ 1 by α/β and γ/δ TCR, indicate that an α/β T-cell receptor which includes the V δ 1 variable region can be involved in alloreactive recognition. [ABSTRACT FROM AUTHOR]

Objectives: Peripheral neuropathy (PN) is a significant concern and potential cause of withdrawal in patients with Parkinson's disease (PD) treated with Levodopa/Carbidopa Intestinal Gel (LCIG) infusion. Vitamin B deficiency and/or hyperhomocysteinemia levodopa-related are considered possible causative factors. In this study, we evaluated PN incidence in LCIG-PD patients treated since the beginning of infusion with vitamins B supplementation., Materials & Methods: In this prospective open-label pilot study, 30 consecutive patients with PD on LCIG infusion were evaluated with clinical, neurophysiological, and biochemical assessments for a mean follow-up of 42.4 months (range 24-72). All evaluations were repeated every 6 months., Results: At baseline, 21 of 30 presented no signs or symptoms of PN, and 9 of 30 had pre-existing chronic PN. In whole population, a progressive worsening in nerve conduction studies of sural sensory and peroneal motor nerves was observed during the long-term follow-up. 4 of 21 patients, with normal clinical, electrophysiological assessment at baseline, developed distal symmetrical axonal polyneuropathy that remained asymptomatic during the long-term follow-up. Patients with pre-existing PN (9 of 30) showed a mild worsening of electrophysiological features during the period of observation. In none PN was cause of discontinuation of LCIG therapy. No incident cases of acute-subacute PN were documented. No correlation was found with age, sex, Levodopa dosage, duration of levodopa exposure, and homocysteine plasma levels., Conclusion: In this consecutive series of 30 patients with PD on LCIG infusion, with early and continuous vitamins B integration, we observed a low rate (19%) of new onset peripheral polyneuropathy that remained stable after long-term follow-up. Larger studies, controlled, with blinded evaluation, are needed to confirm these findings., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Advanced glycation end-products (AGEs) are irreversible compounds which, by abnormally accumulating over proteins as a consequence of diabetic hyperglycaemia, can damage tissues and thus contribute to the pathogenesis of diabetic complications. This study was performed to evaluate whether restoration of euglycaemia by islet transplantation modifies AGE accumulation in central and peripheral nervous tissue proteins and, as a comparison, in proteins from a non-nervous tissue. Two groups of streptozotocin diabetic inbred Lewis rats with 4 (T1) or 8 (T2) months disease duration were grafted into the liver via the portal vein with 1200-1500 islets freshly isolated from normal Lewis rats. Transplanted rats, age-matched control and diabetic rats studied in parallel, were followed for a further 4-month period. At study conclusion, glycaemia, glycated haemoglobin and body weight were measured in all animals, and an oral glucose tolerance test (OGTT) performed in transplanted rats. AGE levels in cerebral cortex, spinal cord, sciatic nerve proteins and tail tendon collagen were measured by enzyme-linked immunosorbent assay (ELISA). Transplanted animal OGTTs were within normal limits, as were glycaemia and glycated haemoglobin. Diabetic animal AGEs were significantly higher than those of control animals. Protein AGE values were reduced in many transplanted animals compared to diabetic animals, reaching statistical significance in spinal cord (P < 0.05), sciatic nerve (P < 0.02) and tail tendon collagen (P < 0.05) of T1 animals. Thus, return to euglycaemia following islet transplantation after 4 months of diabetes with poor metabolic control reduces AGE accumulation rate in the protein fractions of the mixed and purely peripheral nervous tissues (spinal cord and sciatic nerve, respectively). However, after a double duration of bad metabolic control, a statistically significant AGE reduction has not been achieved in any of the tissues, suggesting the importance of an early therapeutic intervention to prevent the possibly pathological accumulation of AGEs in nervous and other proteins.

The ability of recombinant interleukin 2 (rIL2) activated lymphocytes (LAK) to purge BM samples contaminated by tumour cells was evaluated. Human BM mononuclear cells were contaminated with 10% of the lymphoma line CA46 and then cultured in liquid medium containing 1000 U/ml of rIL2 and/or LAK autologous to the used BM. At the end of coculture the growth of residual tumour cells and of CFU-GM were evaluated by clonogenic assay. No tumour cell growth was observed in 5/5 independent experiments after 18 h of coculture with LAK. No significant inhibition of CFU-GM growth was also noted. Subsequently, the effect of LAK on BM obtained from four leukaemic patients and contaminated with 20-50% of their own AML and ALL cells was studied using MAb as a tool for identifying leukaemic cells. LAK eliminated 24-78% of contaminating cryopreserved uncultured autologous leukaemic cells. In five cases the BM was contaminated by a low (2%) amount of ALL cells. In these patients the monoclonal heavy chain rearrangement typical of ALL was no longer visible after coculture with LAK. Evidence for selective tumour cytotoxicity by LAK was confirmed by using autologous BM cells as hot and cold targets in a 51Cr release assay. Finally, successful haematologic reconstitution of lethally irradiated BALB/c mice was obtained using syngeneic BM cocultured with LAK. These results support the investigational use of rIL2 and LAK in the treatment of human leukaemia.