A New Myohaptic Instrument to Assess Wrist Motion Dynamically

The pathophysiological assessment of joint properties and voluntary motion in neurological patients remains a challenge. This is typically the case in cerebellar patients, who exhibit dysmetric movements due to the dysfunction of cerebellar circuitry. Several tools have been developed, but so far most of these tools have remained confined to laboratories, with a lack of standardization. We report on a new device which combines the use of electromyographic (EMG) sensors with haptic technology for the dynamic investigation of wrist properties. The instrument is composed of a drivetrain, a haptic controller and a signal acquisition unit. Angular accuracy is 0.00611 rad, nominal torque is 6 N·m, maximal rotation velocity is 34.907 rad/sec, with a range of motion of −1.0472 to +1.0472 rad. The inertia of the motor and handgrip is 0.004 kg·m2. This is the first standardized myohaptic instrument allowing the dynamic characterization of wrist properties, including under the condition of artificial damping. We show that cerebellar patients are unable to adapt EMG activities when faced with an increase in damping while performing fast reversal movements. The instrument allows the extraction of an electrophysiological signature of a cerebellar deficit

Neurological Tremor: Sensors, Signal Processing and Emerging Applications

Neurological tremor is the most common movement disorder, affecting more than 4% of elderly people. Tremor is a non linear and non stationary phenomenon, which is increasingly recognized. The issue of selection of sensors is central in the characterization of tremor. This paper reviews the state-of-the-art instrumentation and methods of signal processing for tremor occurring in humans. We describe the advantages and disadvantages of the most commonly used sensors, as well as the emerging wearable sensors being developed to assess tremor instantaneously. We discuss the current limitations and the future applications such as the integration of tremor sensors in BCIs (brain-computer interfaces) and the need for sensor fusion approaches for wearable solutions

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Tremor: from pathogenesis to a multimodal brain-computer interface controlling functional electrical stimulation

Doctorat en Sciences médicalesinfo:eu-repo/semantics/nonPublishe

Cerebellar stimulation

Non invasive brain stimulation (NIBS), encompassing Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), is becoming more and more promising as a novel procedure to modulate cerebellar functions and as therapy for cerebellar patients. This chapter provides the elementary concept of this therapeutic approach, which is based on the modulation of the cerebellar brain inhibition (CBI), and reports a brief overview of the studies focusing on the therapeutic potentials and effectiveness of these techniques. Evidences of the effectiveness of this appealing therapeutic approach are growing, but many issues remain to be clarifi ed to include these treatments in the standard management of the cerebellar patients.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Cerebellar motor disorders

Many of the clinical manifestations of cerebellar damage were described at the turn of the nineteenth and twentieth centuries by the pioneers of the cerebellar physiopathology, including Luciani, Babinski, and Holmes. Cerebellar diseases result in lack of coordination and disturbances of accuracy of movements, causing a constellation of symptoms and motor signs which can be grouped into four categories: oculomotor disturbances, speech deficits, deficits of limb movements, and abnormalities of gait and posture. Instability of gaze and nystagmus, hypermetria/hypometria of saccades, saccadic pursuit, skew deviation (ocular misalignment), and disorders of vestibulo-ocular reflex/optokinetic responses are the main oculomotor alterations observed in cerebellar diseases. Gaze-evoked nystagmus is the most common form of nystagmus encountered in disorders of the cerebellum. Ataxic dysarthria has a typical scanning quality; it is often explosive, with a staccato rhythm and a nasal character. Ataxic speech tends to become slow with slurring, and words may be unintelligible. Cerebellar damage typically results in impairment of performance of limb movements. Ataxia of limbs includes: dysmetria, decomposition of movement, dysdiadochokinesia, cerebellar tremor, isometrAtaxia, disorders of muscle tone (both hypotonia and cerebellar fits), loss of check and rebound, abnormal handwriting, and megalographia. Tremor in cerebellar diseases is mainly composed of low frequency oscillations, usually with a kinetic component. Kinetic tremor is often associated with a concomitant postural tremor. Cerebellar patients have increased body sway and a broad-based stance due to the inability to maintain the body in a stationary position (Ataxia of stance). Similarly, gait in cerebellar patients is irregular and broad based. Successive steps are spaced in a staggering way and followed by corrections or falls. Rhythm is distorted and speed is often reduced. Walking trajectory veers erratically with difficulties in initiation, stops, or turns.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Deficits of limbs movements

This chapter provides a clinical description of the defi cits involving limbs movements in cerebellar patients. The following cerebellar signs are described: dysmetria (hypermetria and hypometria); cerebellar tremor (kinetic, postural and isometric tremor); decomposition of movements; disorders of muscle tone (hypotonia, cerebellar fi ts); dysdiadochokinesia and dysrhythmokinesia; loss of check and rebound; isometrataxia; handwriting abnormalities and megalographia. Also, an explanation of the manoeuvres and tests currently used for clinical evaluation of limb defi cits in cerebellar patients is provided.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Pharmacological treatments of tremor

SCOPUS: ch.binfo:eu-repo/semantics/publishe