Chronic migraine long-term regular treatment with onabotulinumtoxinA: a retrospective real-life observational study up to 4 years of therapy

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Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle

Altered multisensory temporal integration in obesity

Eating is a multisensory behavior. The act of placing food in the mouth provides us with a variety of sensory information, including gustatory, olfactory, somatosensory, visual, and auditory. Evidence suggests altered eating behavior in obesity. Nonetheless, multisensory integration in obesity has been scantily investigated so far. Starting from this gap in the literature, we seek to provide the first comprehensive investigation of multisensory integration in obesity. Twenty male obese participants and twenty male healthy-weight participants took part in the study aimed at describing the multisensory temporal binding window (TBW). The TBW is defined as the range of stimulus onset asynchrony in which multiple sensory inputs have a high probability of being integrated. To investigate possible multisensory temporal processing deficits in obesity, we investigated performance in two multisensory audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Results showed a wider TBW in obese participants as compared to healthy-weight controls. This holds true for both the simultaneity judgment and the temporal order judgment tasks. An explanatory hypothesis would regard the effect of metabolic alterations and low-grade inflammatory state, clinically observed in obesity, on the temporal organization of brain ongoing activity, which one of the neural mechanisms enabling multisensory integration

Dose-related effects of alcohol on cognitive functioning

We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test(TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties.Mathew J. Dry, Nicholas R. Burns, Ted Nettelbeck, Aaron L. Farquharson and Jason M. Whit

Loss of large-diameter spindle afferent fibres is not detrimental to the control of body sway during upright stance: evidence from neuropathy

Fifteen patients with Charcot-Marie-Tooth type 1A (CMT1A) disease and 46 normal controls were studied. In the patients, leg muscle strength, touch-pressure, vibration and joint position sense were reduced; lower limb tendon reflexes were absent in 12 or markedly decreased. Motor and sensory conduction velocity (CV) of leg nerves was either reduced or not measurable. The Neurological Disability Score and the Neuropathy Score were obtained from clinical and electrophysiological examination, respectively. Tilt of a supporting platform elicited short- (SLR) and medium-latency (MLR) responses to stretch in the foot muscle flexor digitorum brevis (FDB) in controls. In the patients, the former response was absent and the latter delayed. These findings are in keeping with the known loss of large-diameter myelinated fibres, with relative sparing of the smaller fibres. The MLR delay was fully accounted for by the slowed CV of the motor fibres. The MLR afferent time was similar to that in normal subjects. Body sway area (SA) during quiet stance was recorded with eyes open or closed, and with feet apart or together. Under all postural and visual conditions, SA was within normal range in the less severely affected patients, but was moderately increased in the patients with a more severe neuropathy score. Across all patients, no correlation was found between SA and muscle force, motor CV, touch pressure, vibration and joint position sense, considered either separately or as an aggregate. We suggest that: (1) functional integrity of the largest afferent fibres is not necessary for appropriate equilibrium control during quiet stance and (2) any unsteadiness is related to additional functional alterations in smaller fibres, most likely group II spindle afferent fibres

Loss of large diameter spindle afferent fibres is not detrimental to the control of body sway during upright stance: evidence from neuropathy.

Fifteen patients with Charcot-Marie-Tooth type 1A (CMT1A) disease and 46 normal controls were studied. In the patients, leg muscle strength, touch-pressure, vibration and joint position sense were reduced; lower limb tendon reflexes were absent in 12 or markedly decreased. Motor and sensory conduction velocity (CV) of leg nerves was either reduced or not measurable. The Neurological Disability Score and the Neuropathy Score were obtained from clinical and electrophysiological examination, respectively. Tilt of a supporting platform elicited short- (SLR) and medium-latency (MLR) responses to stretch in the foot muscle flexor digitorum brevis (FDB) in controls. In the patients, the former response was absent and the latter delayed. These findings are in keeping with the known loss of largediameter myelinated fibres, with relative sparing of the smaller fibres. The MLR delay was fully accounted for by the slowed CV of the motor fibres. The MLR afferent time was similar to that in normal subjects. Body sway area (SA) during quiet stance was recorded with eyes open or closed, and with feet apart or together. Under all postural and visual conditions, SA was within normal range in the less severely affected patients, but was moderately increased in the patients with a more severe neuropathy score. Across all patients, no correlation was found between SA and muscle force, motor CV, touch pressure, vibration and joint position sense, considered either separately or as an aggregate. We suggest that: (1) functional integrity of the largest afferent fibres is not necessary for appropriate equilibrium control during quiet stance and (2) any unsteadiness is related to additional functional alterations in smaller fibres, most likely group II spindle afferent fibres