Robotic-assisted rehabilitation for balance in stroke patients (ROAR-S): effects of cognitive, motor and functional outcomes.

OBJECTIVE: Due to the aging population, the incidence of stroke is steadily increasing. In patients with stroke outcomes, sensory, motor and cognitive problems limit the performance of activities of daily living. The development of new technologies in rehabilitation is improving the quality and efficiency of functional recovery. Hunova robotic platform (Movendo Technology, srl, Genoa, Italy) is a robotic device for functional assessment and rehabilitation of balance. The purpose of this study is to evaluate the effects of rehabilitation with Hunova on cognitive function and balance in older adults with stroke. PATIENTS AND METHODS: This is a randomized, controlled, single-blind study. Twenty-four older adults with stroke outcomes were randomized into the Hunova group (HuG), which performed a specific rehabilitation program for balance using Hunova for 12 sessions in addition to conventional rehabilitation, and the control group (CoG), which performed only conventional rehabilitation. All patients underwent a clinical cognitive, balance, quality of life and fatigue assessment, and an instrumental balance assessment with Hunova at the beginning and end of treatment. RESULTS: Statistical analysis showed significant improvements in most clinical scales in both groups. Comparing the groups, HuG showed greater improvements in executive functions, speed of information processing, attention and discrimination of multiple stimuli, static and dynamic balance and autonomy in daily activities, standing postural sway, and trunk control in static and dynamic conditions. CONCLUSIONS: Data analysis showed that elderly with stroke who underwent balance technology treatment with Hunova in combination with conventional treatment had a greater improvement in cognitive functions, balance and reduced risk of falling.

Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Management of fulminating ulcerative colitis in childhood with chimeric anti-CD25 antibody.

Fulminating acute ulcerative colitis (UC) is a potentially life threatening medical emergency. Up to 30% of individuals respond poorly to corticosteroids alone and second line medical or surgical therapies are indicated. We describe the successful use of chimeric anti-CD25 therapy in 4 such children poorly responsive to combined therapy with intravenous steroids and calcineurin inhibitors with a pretreatment predictive risk of colectomy of 85-100%. Clinical disease activity scores normalized within 72 hours of anti-CD25 administration and colonic histology provided evidence of mucosal healing within 10-14 days. None required emergency colectomy. Anti-CD25 is efficacious in fulminating UC and randomized placebo controlled trials appear indicated.

Inhibition of p38 mitogen activated protein kinase controls airway inflammation in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) airways are characterised by chronic inflammation, increased interleukin (IL)-8 secretion, and neutrophil activation which are considered the principal factors of morbidity and mortality in CF patients. Optimising management of this chronic inflammatory response is therefore a key issue of basic and clinical CF research. Several reports have addressed ways to manage CF airways inflammation, and an attractive therapeutic strategy may be the inhibition of the p38-mitogen activated protein kinase (p38-MAP-k) pathway. METHODS: A new ex vivo model was used to study the mucosal inflammatory response to environmental airways stimuli. Nasal biopsy tissues from CF patients and controls were cultured ex vivo for 20 minutes, 4 hours, and 24 hours in the presence of lipopolysaccharide (LPS) from Pseudomonas aeruginosa (PA) with and without the p38-MAP-k inhibitor SB203580. Quantitative mRNA assessment, immunohistochemistry, and Western blots were used to detect the expression and modulation of inflammatory markers. RESULTS: PA-LPS challenge induced a time dependent mucosal inflammation indicated by rapid epithelial activation, IL-8 release, COX-2 upregulation, and neutrophil migration to the upper mucosal layers. Some of these LPS induced changes (IL-8 release and neutrophil migration) were specific to CF tissues. SB203580 significantly controlled all LPS induced mucosal changes in CF tissues. CONCLUSION: These findings provide a rationale and proof of principle for the potential use of p38-MAP-k inhibitors to control inflammation in patients with CF.

IL-15 drives the specific migration of CD94+ and TCR-gammadelta+ intraepithelial lymphocytes in organ cultures of treated celiac patients.

OBJECTIVES: Celiac disease (CD) is an under-diagnosed but extremely frequent disease, triggered by the ingestion of gliadin. The pathogenic mechanisms of CD are still poorly understood, but intraepithelial lymphocytes are considered to have a key role. We intended to define the subsets of T lymphocytes migrating upon gliadin challenge in organ cultures of treated celiac patients and establish the type of factor(s) driving such an infiltration. METHODS: Duodenum biopsies from 10 treated celiacs and 7 controls were cultured in vitro with/without gliadin digest (1 mg/ml) or interleukin (IL)-15 (10 ng/ml). In 7 treated celiacs IL-7, IL-4, and IL-2 were similarly tested. Intraepithelial CD3, CD8, TCR-gammadelta, and CD94 were detected by immunohistochemistry and numbered per mm epithelium. RESULTS: IL-15 but not IL-7, IL-4, or IL-2 induced intraepithelial increase of CD3+ and CD8+ cells in celiac and control intestine (p < 0.001 vs cultures with medium). IL-15 induced increases in the number of intraepithelial TCR- gammadelta+ and CD94+ cells only in celiacs (p < 0.001). IL-7 was also effective in increasing intraepithelial TCR-gammadelta+ (but not CD94+) cells in celiac biopsies (p < 0.001). Gliadin induced intraepithelial migration of CD3+, CD8+ (p < 0.001), and CD94+ (p < 0.05) cells in celiacs, but not in controls. CONCLUSIONS: The results we describe in this report indicate that IL-15 might have a key role in modulating and driving intraepithelial infiltration and ultimately in the pathogenesis of CD.

FAS engagement drives apoptosis of enterocytes of coeliac patients.

BACKGROUND: Villus atrophy is the most distinctive sign of untreated coeliac disease (CD) and epithelial apoptosis is considered to be involved in this stage of the coeliac lesion. The extent of villus atrophy is, however, not homogeneous and patients with patchy or mild lesions have been described. AIMS: To address: (a) the degree of "patchiness" in untreated CD patients; and (b) to clarify if apoptosis, and eventually which trigger drives it, causes epithelial damage. PATIENTS: Twenty of 40 untreated, 14 treated coeliac patients, and 15 controls received five or more multiple duodenal biopsies; the remaining 20 untreated CD patients had no more than three biopsies. METHODS: All biopsies were analysed to monitor the presence of a "flat" mucosa. Biopsies of 14 untreated, 10 treated coeliacs, and seven controls were cultured with or without gliadin. DNA fragmentation was studied by terminal deoxynucleotidyl transferase (TdT) mediated dUTP digoxigenin nick end labelling (TUNEL), and FAS and Ki67 expression by immunohistochemistry. Antiendomysium antibodies (EMA) were surveyed in biopsy culture supernatants. RESULTS: A pattern of patchy duodenal lesions was observed in all untreated CD patients biopsied up to five times. High enterocyte FAS expression, and a high number of TUNEL+ and Ki67+ enterocytes were detected in areas with villus atrophy but not in those with a normal morphology (p<0.001). Conversely, EMA in culture supernatants and signs of immunological activation were present in all untreated CD biopsies. In vitro gliadin challenge increased the number of TUNEL+ and Ki67+ enterocytes (p<0.001 v cultures with medium alone) only in "flat" biopsies. Neutralising anti-FAS monoclonal antibodies were found to control gliadin induced enterocyte apoptosis (p>0.01) while agonist anti-FAS monoclonal antibody increased it (p<0.001). CONCLUSIONS: Patchy lesions are observed in untreated CD mucosa and epithelial FAS engagement is a key trigger in driving villus atrophy in CD.