Phosphoproteomic analysis reveals Akt isoform-specific regulation of cytoskeleton proteins in human temporal lobe epilepsy with hippocampal sclerosis.

Akt is one of the most important downstream effectors of phosphatidylinositol 3-kinase/mTOR pathway. Hyperactivation and expression of this pathway are seen in a variety of neurological disorders including human temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Nevertheless, the expression and activation profiles of the Akt isoforms, Akt1, Akt2, and Akt3 and their functional roles in human TLE-HS have not been studied. We examined the protein expression and activation (phosphorylation) patterns of Akt and its isoforms in human hippocampal tissue from TLE and non-TLE patients. A phosphoproteomic approach followed by interactome analysis of each Akt isoform was used to understand protein-protein interactions and their role in TLE-HS pathology. Our results demonstrated activation of the Akt/mTOR pathway as well as activation of Akt downstream substrates like GSK3ß, mTOR, and S6 in TLE-HS samples. Akt1 isoform levels were significantly increased in the TLE-HS samples as compared to the non-TLE samples. Most importantly, different isoforms were activated in different TLE-HS samples, Akt2 was activated in three samples, Akt2 and Akt1 were simultaneously activated in one sample and Akt3 was activated in two samples. Our phosphoproteomic screen across six TLE-HS samples identified 183 proteins phosphorylated by Akt isoforms, 29 of these proteins belong to cytoskeletal modification. Also, we were able to identify proteins of several other classes involved in glycolysis, neuronal development, protein folding and excitatory amino acid transport functions as Akt substrates. Taken together, our data offer clues to understand the role of Akt and its isoforms in underlying the pathology of TLE-HS and further, modulation of Akt/mTOR pathway using Akt isoforms specific inhibitors may offer a new therapeutic window for treatment of human TLE-HS.

Handling objects with very wet skin reduce variability during precision grip task.

Several extrinsic factors affect precision grip task variability. Presence of moisture in glabrous skin can regulate the impact of extrinsic factors. Consequently, wetness may influence the precision grip task variability per se by regulating its force, rate and time parameters. This study aims to examine the influence of age, coefficient of skin friction (CF) and object weight (extrinsic factors) on precision grip task variability in dry skin condition (DSC) and very wet skin conditions (VWSC). Eighty healthy subjects performed precision grip task with four different weights (1.3N, 1.4N, 1.5N, and 1.7N) sequentially in DSC and VWSC. Simple and multiple linear regression analysis were performed to estimate the independent and combined effect of extrinsic factors on precision grip parameters. Our results show that the extent of variability caused by the extrinsic factors on precision grip task significantly reduced when objects were held with VWSC than DSC. Wetting of the skin also decreased standard deviation and coefficient of variation of friction. The frictional range of individuals was widespread in DSC (0.62-3.42) while VWSC brought it to a closer range (0.77-1.64). Our findings suggest that wetness of skin reduces precision grip task variability, and further knowledge on this may help in designing precision grip as a quantitative screening tool for patients with hand dysfunction.

Quantitative Assessment of Hand Dysfunction in Patients with Early Parkinson's Disease and Focal Hand Dystonia.

OBJECTIVE: Motor impairments related to hand function are common symptoms in patients with movement disorders, such as Parkinson's disease (PD) and focal hand dystonia (FHD). However, hand dysfunction has not been quantitatively assessed as a clinical tool for screening patient groups from healthy controls (HCs). The aim of our study was 1) to quantitatively assess hand dysfunction in patients with PD and FHD and its usefulness as a screening tool 2) to grade disease severity in PD and FHD based on hand dysfunction. METHODS: The current case-control study included HCs (n = 50) and patients with known history of PD (n = 25) or FHD (n = 16). Hand function was assessed by a precision grip task while participants lifted objects of 1.3 N and 1.7 N under dry skin conditions, followed by very wet skin conditions (VWSCs). Receiver operating characteristic and summative scoring analyses were performed. RESULTS: In PD, the combination of loading phase duration and lifting phase duration at quantitative cutoffs of 0.36 and 0.74 seconds identified 21/25 patients as diseased and 49/50 subjects as HCs with 1.7 N under VWSCs. In PD, 5/21 was graded as "mild" and 16/21 as "moderate cases." In FHD, slip force at a cutoff of 1.2 N identified 13/16 patients as diseased and 41/50 subjects as HC with 1.7 N under VWSCs, but disease severity could not be graded. CONCLUSION: Our results demonstrate the use of precision grip task as an important clinical tool in assessment of hand dysfunction in movement disorder patients. Use of quantitative cutoffs may improve diagnostic accuracy and serve as a valuable adjunct to existing clinical assessment methods.

Carotid endarterectomies: who are the candidates at risk?

ABSTRACT OF REVIEWED ARTICLE: Predictors of clamp-induced electroencephalographic changes during carotid endarterectomies.Simon MV, Chiappa KH, Kilbride RD, Rordorf GA, Cambria RP, et al.J Clin Neurophysiol 2012t;29:462-467. OBJECTIVE: Electroencephalograms detect clamp-induced cerebral ischemia during carotid endarterectomy, and thus impact management and minimize the risk of perioperative stroke. We hypothesized that age, preoperative neurologic symptoms, ≥70% contralateral carotid, and bilateral vertebral stenosis increase the probability of clamp-induced electroencephalogram changes, whereas ≥70% unilateral carotid stenosis does not. METHODS: This is an observational cohort study of 299 patients who underwent carotid endarterectomy with electroencephalogram monitoring at a single large urban academic medical center in 2009. Univariate and multivariate logistic regression analyses were used. RESULTS: Seventy percent or greater ipsilateral carotid stenosis decreases the odds of clamp-induced neurophysiologic dysfunction (odds ratio = 0.43, 95% confidence interval [0.18-0.99], P = 0.04) after adjustment for symptomatic status, degree contralateral carotid or vertebral stenosis, and age. Preoperative neurologic symptoms, ≥70% contralateral carotid stenosis, and bilateral extracranial vertebral stenosis independently increase these odds (odds ratio 2.62, 95% confidence interval [1.32-5.18], P = 0.005; odds ratio 2.84, 95% confidence interval [1.27-6.34], P = 0.01; and odds ratio 3.58, 95% confidence interval [1.02-12.53], P = 0.04, respectively), after adjustment for the other factors. Age ≥70 years has no significant impact. CONCLUSIONS: Preoperative neurologic symptoms, ≥70% contralateral carotid, and bilateral vertebral stenosis increase the probability of clamp-induced ischemia as detected by intraoperative electroencephalogram, whereas ≥70% ipsilateral carotid stenosis decreases it.