A microswitch-cluster program to foster adaptive responses and head control in students with multiple disabilities: replication and validation assessment

A program relying on microswitch clusters (i.e., combinations of microswitches) and preferred stimuli was recently developed to foster adaptive responses and head control in persons with multiple disabilities. In the last version of this program, preferred stimuli (a) are scheduled for adaptive responses occurring in combination with head control (i.e., head upright) and (b) last through the scheduled time only if head control is maintained for that time. The first of the present two studies was aimed at replicating this program with three new participants with multiple disabilities adding to the three reported by Lancioni et al. [Lancioni, G. E., Singh, N. N., O'Reilly, M. F., Sigafoos, J., Didden, R., Oliva, D., et al. (2007). Fostering adaptive responses and head control in students with multiple disabilities through a microswitch-based program: Follow-up assessment and program revision. Research in Developmental Disabilities, 28, 187-196]. The second of the two studies served to carry out an expert validation of the program's effects on head control and general physical condition with the three participants of Study I as well as the three participants involved in the Lancioni et al. study mentioned above. The expert raters were 72 new physiotherapists and 72 experienced physiotherapists. The results of Study I supported previous data and indicated that the program was effective in helping the participants increase the frequency of adaptive responses in combination with head control and the length of such control. The results of Study II showed that the raters found the effects of the new program more positive than those of other intervention conditions and also considered such program a useful complement to formal motor rehabilitation programs.     

Network plasticity in cortical assemblies

To investigate distributed synaptic plasticity at the cell assembly level, we used dissociated cortical networks from embryonic rats grown on grids of 60 extracellular substrate-embedded electrodes (micro-electrode arrays). We developed a set of experimental plasticity protocols based on the pairing of tetanic bursts (20 Hz) with low-frequency stimuli (≤ 1 Hz), delivered through two separate channels of the array (i.e. associative tetanic stimulation). We tested our protocols on a large data set of 26 stable cultures, selected on the basis of both their initial level of spontaneous firing and the capability of low-frequency test stimuli to evoke spikes. Our main results are summarized as follows: (i) low-frequency stimuli produce neither short- nor long-term changes in the evoked response of the network; (ii) associative tetanic stimulation is able to induce plasticity in terms of a significant increase or decrease of the evoked activity in the whole network; (iii) the amount of change (i.e. increase or decrease of the evoked firing) strongly depends on the specific features of the applied protocols; and (iv) the potentiation induced by a specific associative protocol can last several hours. The results obtained demonstrate that large in vitro cortical assemblies display long-term network potentiation, a mechanism considered to be involved in the memory formation at cellular level. This pilot study could represent a relevant step towards understanding plastic properties at the neuronal population level.     

Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle

Aminoglycosides force read through of premature stop codon mutations and introduce new mutation-specific gene-corrective strategies in Duchenne muscular dystrophy. A chronic treatment with gentamicin (32 mg/kg/daily i.p., 8-12 weeks) was performed in exercised mdx mice with the dual aim to clarify the dependence on dystrophin of the functional, biochemical and histological alterations present in dystrophic muscle and to verify the long term efficiency of small molecule gene-corrective strategies in work-loaded dystrophic muscle. The treatment counteracted the exercise-induced impairment of in vivo forelimb strength after 6-8 weeks. We observed an increase in dystrophin expression level in all the fibers, although lower than that observed in normal fibers, and found a concomitant recovery of aquaporin-4 at sarcolemma. A significant reduction in centronucleated fibers, in the area of necrosis and in the percentage of nuclear factor-kB-positive nuclei was observed in gastrocnemious muscle of treated animals. Plasma creatine kinase was reduced by 70%. Ex vivo, gentamicin restored membrane ionic conductance in mdx diaphragm and limb muscle fibers. No effects were observed on the altered calcium homeostasis and sarcolemmal calcium permeability, detected by electrophysiological and microspectrofluorimetric approaches. Thus, the maintenance of a partial level of dystrophin is sufficient to reinforce sarcolemmal stability, reducing leakiness, inflammation and fiber damage, while correction of altered calcium homeostasis needs greater expression of dystrophin or direct interventions on the channels involved.     

Cerebrovascular disease and hippocampal atrophy are differently linked to functional coupling of brain areas: an EEG coherence study in MCI subjects

The working hypothesis of paper is that the functional coupling of brain areas is combined with different neuroradiological substrates and has different clinical manifestations. 31 normal old subjects and 85 subjects with mild cognitive impairment (MCI) underwent EEG recordings and magnetic resonance imaging (MRI). Intrahemispheric and interhemispheric linear EEG coherences were computed. At first, all normal old and MCI subjects were compared. Subsequently, three subgroups of MCI were obtained based on neuroradiological substrate (subcortical cerebrovascular damage, MCI-CVD; cholinergic pathways vascular damage MCI-CHOL; and hippocampal atrophy, MCI-HIPP) and compared with a normal old sample matched for age, education and Mini-Mental State Examination score. The group of MCI subjects compared to normal old subjects shows: 1) decrease of intrahemispheric coherence in fronto-parietal regions (both right and left hemisphere); 2) increase of interhemispheric coherence on frontal regions in delta frequency; and 3) increase of interhemispheric coherence on temporal regions (from delta to alpha3 frequency bands). In the MCI subgroups, hippocampal atrophy is linked to an increase of interhemispheric coherence seen on frontal and temporal regions whereas subcortical CVD is linked to the largest decrease of coherence in fronto-parietal regions. MCI-CVD patients performed worst on Trail Making Test battery whereas MCI-HIPP patients were impaired on Rey word list delayed recall and Rey figure recall.     

Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy

The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection.We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.     

Epidemiology and pathophysiology of obesity as cause of cancer

According to World Health Organisation estimates 1.1 billion people were overweight or obese worldwide in the year 2000 with the prevalence rapidly increasing. Compelling evidence suggests that excess body weight is a risk factor for several cancer types including cancer of the colon, breast, endometrium, kidney, oesophagus, as well as possibly additional sites. According to previous meta-analyses and systematic literature reviews, an important proportion of cancer has been estimated to be attributable to excess body weight. The extrapolation of a European meta-analysis [1] to the Swiss situation broadly estimates that around 700 cancers could be prevented in the absence of overweight and obesity in this country. The data presented highlights the public health relevance of preventing excess body weight. Several interacting metabolic and hormonal pathways seem to underlie the association between being overweight and cancer with insulin-resistance playing a central role. Since evidence is mounting that excess body weight can also adversely affect cancer prognosis, obesity is a primary target for cancer control programs.     

Slow versus fast proteins in the stimulation of beta-cell response and the activation of the entero-insular axis in type 2 diabetes

BACKGROUND: We tested whether ingestion of whey protein can induce greater post-prandial amino acid (AA) levels in the plasma and a higher beta-cell response than casein ingestion in type 2 diabetes mellitus patients. METHODS: The study was designed as a double-blind, randomized, and controlled cross-over clinical trial. Twelve post-absorptive type 2 diabetic subjects who were withdrawn from their usual hypoglycemic therapy were studied. A medium calorie (approximately 6 kcal/kg BW), high protein (approximately 50% of total kcal) mixed meal, containing whey protein, casein, or a free amino acid (FREE AA) mixture matching the casein AA composition, was randomly administered on three different occasions. RESULTS: Following ingestion of whey protein, plasma concentrations of total, branched chain, and essential AA were 25-50% greater than after ingestion of casein (p < 0.0001), and were similar to those observed after the FREE AA meal. With whey protein, C-peptide, insulin, and pro-insulin concentrations were greater by 12-40% (p < 0.02 or less) than with casein, and similar to those with FREE AA. Glucagon-like polypeptide 1 (GLP-1) response tended to be lower with casein than with whey protein. Glucose-dependent insulinotropic polypeptide (GIP) response was greater with either whey protein or casein than with FREE AA. Post-prandial glucose concentrations were similar after whey protein and casein ingestion, but lower after the FREE AA meal. CONCLUSIONS: In type 2 diabetes, the ingestion of a fast-absorbable protein results in a greater post-prandial aminoacidemia and a higher beta-cell secretion than the ingestion of a 'slow' protein. Whether these changes can be maintained chronically in combination with hypoglycemic therapy, possibly also resulting in better glycemic control, remains to be established.