Structural basis for the recognition and cleavage of histone H3 by cathepsin L

Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate–cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L–histone H3 interaction and the first structural description of cathepsin L in complex with a substrate

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian Consensus Conference on Pain in Neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

A comparison between extensive and intensive rehabilitation: FIM measurements as indicators of appropriateness and efficiency

Background: In Italy, post-acute inpatient rehabilitation is available in both 'intensive' and 'extensive-geriatric' rehabilitation facilities (IF and EF, respectively). Three vs 1 hour/daily of formal rehabilitation (including rehabilitation nursing) should be administered in either setting, respectively. For any given case, no formal criteria of patient allocation are available. Methods. Patients discharged from either a 50-bed IF (n=251, 6-month time span) or a 50-bed EF (n=142, 12-month time span) located in northern Italy were compared. The FIM(TM)-Functional Independence Measure Scale and data set was adopted. The FIM rates patients' independence in the domains of self-care, sphincter control, mobility, locomotion, communication and social cognition. On a 18-item 7-level scale, total scores may range from 18 to 126, and are higher the greater patient's independence. Results. The prevalence of neurological impairments was 41% and 27% in the IF and EF, respectively, of either unit. Orthopaedic impairments were 56% and 61%, respectively. Mean age was 64 (IF) vs 80 yrs. (EF). Mortality during stay was 0.8 vs 8% in IF vs, EF, respectively. Mean admission and discharge scores were 80 and 106 in the IF, vs 64 and 80 in the EF. Median length of stay was 32 (IF) vs 85 (EF) days. Ninety-one per cent of IF patients were discharged home, vs 70% of the EF patients. A greater FIM score at admission predicted a lower mortality. Conclusions. The lower performances of the EF are consistent with the patients being older, more clinically unstable, more dependent at admission, and presumably unsuitable for more than 1 hour daily of rehabilitation procedures. These differences in the case-mix seem to be consistent with the specific mission of either facility. In either type of facility, the FIM(TM) appears to be a valid help for formal decisions on appropriateness of admission, for the assessment of the burden of care, and for the measurement of effectiveness of the treatment