Vestibulo-cochlear function in inflammatory neuropathies

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Marisa Blanquet, Jens A. Petersen, Antonella Palla, Dorothe Veraguth, Konrad P. Weber, Dominik Straumann, Alexander A. Tarnutzer, Hans H. Jung
ObjectiveWe aimed to quantify peripheral-vestibular deficits that may contribute to imbalanced stance/gait in patients with inflammatory neuropathies.MethodsTwenty-one patients (58±15y [mean age±1SD]; chronic-inflammatory-demyelinating-polyneuropathy=10, Guillain-Barré Syndrome=5, Anti-MAG peripheral neuropathy=2, multifocal-motor-neuropathy=4) were compared with 26 healthy controls. All subjects received video-head-impulse testing (vHIT), caloric irrigation and cervical/ocular vestibular-evoked myogenic-potentials (VEMPs). The Yardley vertigo-symptom-scale (VSS) was used to assess vertigo/dizziness. Postural stability was assessed using the functional gait-assessment (FGA). Pure-tone audiograms (n=18), otoacoustic emissions (n=12) and auditory brainstem responses were obtained (n=12).ResultsSemicircular-canal hypofunction was noted in 9/21 (43%) patients (vHIT=6; caloric irrigation=5), whereas otolith function was impaired in 12/21 (57%) (oVEMPs=8; cVEMPs=5), resulting in vestibular impairment of at least one sensor in 13/21 (62%). On average, 2.4±1.1 vestibular end organs (each side: anterior/posterior/horizontal canal, utriculus, sacculus; total=10) were affected. The VSS-scores were higher in patients (16.8±8.6 vs. 9.5±6.2, p=0.002) but did not correlate with the number of affected organs. Auditory neuropathy was found in 1/12 (8%) patients.ConclusionImpairment of one or more vestibular end organs was frequent, but usually mild, possibly contributing to imbalance of stance/gait in inflammatory neuropathies.SignificanceWhile our data does not support routine vestibular testing in inflammatory neuropathies, this may be considered in selected cases.



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Spectral and temporal electroencephalography measures reveal distinct neural networks for the acquisition, consolidation, and interlimb transfer of motor skills in healthy young adults

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): M.P. Veldman, N.M. Maurits, M.A.M. Nijland, N.E. Wolters, J.C. Mizelle, T. Hortobágyi
ObjectivePlasticity of the central nervous system likely underlies motor learning. It is however unclear, whether plasticity in cortical motor networks is motor learning stage-, activity-, or connectivity-dependent.MethodsFrom electroencephalography (EEG) data, we quantified effective connectivity by the phase slope index (PSI), neuronal activity by event-related desynchronization, and sensorimotor integration by N30 during the stages of visuomotor skill acquisition, consolidation, and interlimb transfer.ResultsAlthough N30 amplitudes and event-related desynchronization in parietal electrodes increased with skill acquisition, changes in PSI correlated most with motor performance in all stages of motor learning. Specifically, changes in PSI between the premotor, supplementary motor, and primary motor cortex (M1) electrodes correlated with skill acquisition, whereas changes in PSI between electrodes representing M1 and the parietal and primary sensory cortex (S1) correlated with skill consolidation. The magnitude of consolidated interlimb transfer correlated with PSI between bilateral M1s and between S1 and M1 in the non-practiced hemisphere.ConclusionsSpectral and temporal EEG measures but especially PSI correlated with improvements in complex motor behavior and revealed distinct neural networks in the acquisition, consolidation, and interlimb transfer of motor skills.SignificanceA complete understanding of the neuronal mechanisms underlying motor learning can contribute to optimizing rehabilitation protocols



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Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Claudio Babiloni, Giuseppe Noce, Alfredo Pennica, Paolo Onorati, Paolo Capotosto, Claudio Del Percio, Paolo Roma, Valentina Correr, Elisa Piccinni, Ginevra Toma, Andrea Soricelli, Francesco Di Campli, Laura Gianserra, Lorenzo Ciullini, Antonio Aceti, Elisabetta Teti, Loredana Sarmati, Gloria Crocetti, Raffaele Ferri, Valentina Catania, Maria Teresa Pascarelli, Massimo Andreoni, Stefano Ferracuti
ObjectiveHere we evaluated the hypothesis that resting state electroencephalographic (EEG) cortical sources correlated with cognitive functions and discriminated asymptomatic treatment-naïve HIV subjects (no AIDS).MethodsEEG, clinical, and neuropsychological data were collected in 103 treatment-naïve HIV subjects (88 males; mean age 39.8 years ± 1.1 standard error of the mean, SE). An age-matched group of 70 cognitively normal and HIV-negative (Healthy; 56 males; 39.0 years ± 2.0 SE) subjects, selected from a local university archive, was used for control purposes. LORETA freeware was used for EEG source estimation in fronto-central, temporal, and parieto-occipital regions of interest.ResultsWidespread sources of delta (< 4 Hz) and alpha (8-12 Hz) rhythms were abnormal in the treatment-naïve HIV group. Fronto-central delta source activity showed a slight but significant (p < 0.05, corrected) negative correlation with verbal and semantic test scores. So did parieto-occipital delta/alpha source ratio with memory and composite cognitive scores. These sources allowed a moderate classification accuracy between HIV and control individuals (area under the ROC curves of 70-75%).ConclusionsRegional EEG abnormalities in quiet wakefulness characterized treatment-naïve HIV subjects at the individual level.SignificanceThis EEG approach may contribute to the management of treatment-naïve HIV subjects at risk of cognitive deficits.



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Loss of maximal explosive power of lower limbs after two weeks of disuse and incomplete recovery after retraining in older adults

Abstract

Disuse-induced loss of muscle power can be detrimental in older individuals, seriously impairing functional capacity. In this study, we examined the changes in maximal explosive power (MEP) of lower limbs induced by a 14-day disuse (bed-rest, BR) and a subsequent 14-day retraining, to assess whether the impact of disuse was greater in older than in young men, and to analyse the causes of such adaptations. Sixteen older adults (Old: 55–65 years) and seven Young (18–30 years) individuals participated in this study. In a subgroup of eight Old subjects, countermeasures based on cognitive training and protein supplementation were applied. MEP was measured with an explosive ergometer, muscle mass was determined by magnetic resonance, motor control was studied by EMG, and single muscle fibres were analysed in vastus lateralis biopsy samples. MEP was ∼33% lower in Old than in Young, and remained significantly lower (−19%) when normalized by muscle volume. BR significantly affected MEP in Old (−15%), but not in Young. Retraining tended to increase MEP; however, this intervention was not sufficient to restore pre-BR values in Old. Ankle co-contraction increased after BR in Old only, and remained elevated after retraining (+30%). Significant atrophy occurred in slow fibres in Old, and in fast fibres in Young. After retraining, the recovery of muscle fibre thickness was partial. The proposed countermeasures were not sufficient to affect muscle mass and power. The greater impact of disuse and smaller retraining-induced recovery observed in Old highlight the importance of designing suitable rehabilitation protocols for older individuals.

This article is protected by copyright. All rights reserved

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Vestibulo-cochlear function in inflammatory neuropathies

Inflammatory neuropathies are a heterogeneous group of peripheral nerve disorders linked by their immune-related pathogenesis. They are caused by auto-immune inflammation within the peripheral nerves associated with destruction of myelin and/or axons (Lunn et al., 2009). Inflammatory neuropathies may be acute (e.g., Guillain-Barré Syndrome, GBS) or chronic (e.g., Chronic Inflammatory Demyelinating Neuropathy, CIDP; Multifocal Motor Neuropathy, MMN) and are closely related to neuropathies associated with paraproteinemia (Lunn et al., 2009).

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Spectral and temporal electroencephalography measures reveal distinct neural networks for the acquisition, consolidation, and interlimb transfer of motor skills in healthy young adults

Motor practice results in skill acquisition, an asymptotic process leading to quicker and more accurate movements (Willingham, 1998). Synapses that form de novo and strengthen in the offline period after motor practice make the newly acquired motor skill stable and less susceptible to interference because the skill becomes consolidated into motor memory (Brashers-Krug et al., 1996; Shadmehr and Holcomb, 1997; Dayan and Cohen, 2011). Curiously, unilateral motor practice also improves skill performance in the contralateral non-practiced limb, most likely through synaptic adaptations in the hemisphere ipsilateral to the practiced limb (Hortobagyi et al., 2011; Veldman et al., 2015; Nojima et al., 2012; Lee and Carroll, 2007).

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Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals

Human immunodeficiency virus (HIV) causes neurological, cognitive, and behavioral symptoms during the progression of the infection (Reger et al., 2002; Anthony and Bell 2008; Antinori et al., 2007). From an epidemiological point of view, subclinical neuropathy was reported in 10-40% of asymptomatic subjects with HIV and 53-100% in those with the AIDS (Chavanet et al., 1988; Gastaut et al., 1989). Also, 50-70% of subjects with HIV suffer from neurologic and the so-called HIV-associated neurocognitive disorders (HANDs) including deficits of episodic memory, attention, cognitive-motor, and executive functions such as planning and problem solving (Selnes, 2005).

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Clinical Presentation and Outcomes of Diagnostic Endoscopy in Newly Presenting Children with Gastrointestinal Symptoms.

Objectives: Paediatric endoscopy is an important diagnostic tool however there is little published data to guide clinicians in selecting patients for endoscopy. This study aimed to evaluate a single centre's experience of newly presenting children focusing on presenting symptoms, investigations and diagnostic yield. Methods: Clinical factors and endoscopic plus histological findings over a six-month period were assessed. Only first diagnostic endoscopies were included. All biopsies were reviewed in a weekly histopathology multidisciplinary team meeting with a final agreed outcome. Abnormal histology was used as the gold standard for reporting abnormality. Results: 218 endoscopies were reviewed in 164 children. 65% were histologically normal (49% of children had macroscopically and histologically normal findings). Macroscopic and histological abnormalities (respectively) were 44% and 28% of oesophagogastroduodenoscopy (OGD) patients, 25% and 25% of colonoscopy alone, and 53% and 53% of those undergoing both OGD and colonoscopy (OGD&Col). For OGD-only patients, excluding those with raised anti-tissue transglutaminase antibodies (anti-tTG), vomiting led to the highest rate of abnormal histology (22%). For colonoscopy-only and OGD&Col patients, per rectum bleeding led to the highest rates of abnormal histology (14% and 29% respectively), after excluding those with laboratory abnormalities (anaemia and raised erythrocyte sedimentation rate) suggestive of inflammatory bowel disease (IBD). Conclusions: This study showed that half of all first diagnostic endoscopies in our unit had neither macroscopic nor histological abnormalities. There was discrepancy between macroscopic abnormalities and histological findings in OGD. Prospective studies are needed to develop guidelines in appropriately predicting abnormality and selecting patients for endoscopy. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Non-cirrhotic Portal Fibrosis in a Young Girl.

No abstract available

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CFTR protein function modulation therapy is finally targeting CF-related gastrointestinal disease.

No abstract available

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Effectiveness of Implementing Initial Education Strategies to Promote Awareness and Healthy Habits in Childhood Obesity: A Quality Improvement Project

Rising incidence and prevalence of childhood obesity and related costly health consequences suggest the need for an effective training tool at the primary care level. Evidence-based studies show how a healthy diet and physical activity help reduce the incidence of obesity.

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Cardiovascular Monitoring During Video Urodynamic Studies in Persons With Spinal Cord Injury

Objective The aims of the study were to observe cardiovascular responses during video urodynamic studies and to identify correlations between autonomic dysreflexia events and video urodynamic study findings in spinal cord injuries. Design Thirty-four persons with spinal cord injury were enrolled and investigated using continuous cardiovascular monitoring during video urodynamic studies. Associations between cardiovascular responses and video study variables were analyzed. Results Bladder type–specific cardiovascular responses occurred during the study. The incidence of overactive detrusor during urodynamic study and bladder trabeculation on voiding cystourethrogram was significantly higher in autonomic dysreflexia persons with spinal cord injury (P

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Effects of Transcranial Direct Current Stimulation Plus Physical Therapy on Gait in Patients With Parkinson Disease: A Randomized Controlled Trial

Objective The aim of the study was to study the combined effects of transcranial direct current stimulation (tDCS) and physical therapy on the walking ability of patients with Parkinson disease (PD). Study Design The study used an experimental, double-blinded, randomized controlled trial. Results After intervention, group 1 (only tDCS) demonstrated a significant increase in gait speed by 0.13 to 0.14 m/sec (17.8%–19.2%) and an increase in step length by 5.9 to 6.1 cm (14.0%–14.5%), whereas group 2 (tDCS and physical therapy) revealed a significant increase in gait speed by 0.10 to 0.13 m/sec (14.9%–19.4%) and step length by 4.5 to 5.4 cm (10.6%–12.8%) and group 3 (sham tDCS and physical therapy) showed a significant increase in gait speed by 0.09 to 0.14 m/sec (13.0%–20.3%) and step length by 3.0 to 5.4 cm (6.8%–12.3%). All these results lasted for at least 8 wks after intervention. Upon comparing the parameters of gait among the three groups at every follow-up visit, no significant difference was observed. Conclusions Anodal tDCS or physical therapy could be used alone or together as a combination treatment to improve the walking speed of patients with Parkinson disease. The effects lasted for approximately 8 wks. The combination treatment was not superior to the use of tDCS or physical therapy alone.

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Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: A Case–Control Study With a Pair of Identical Twins

No abstract available

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Effects of Myofascial Release on Pressure Pain Thresholds in Patients With Neck Pain: A Single-Blind Randomized Controlled Trial

Objective This study aimed to investigate the efficacy of myofascial release therapy (MRT) for improving pressure pain thresholds (PPTs) and pain in patients with mechanical neck pain. Design Forty-one participants with neck pain were randomly allocated to either a MRT group (five sessions) or a physical therapy (PT) group (ten sessions) for 2 wks. The multimodal PT program included ultrasound therapy (US), transcutaneous electric nerve stimulation, and massage. Visual analog scale (VAS) and PPTs in suboccipital and upper trapezius muscles were measured at baseline, at the end of treatment, and at 1 month follow-up. Results At the end of treatment, significant mean differences in VAS (−0.99, 95% confidence interval [CI] = −1.82 to −0.16), in both left (0.28, 95% CI = 0.06 to 0.50) and right (0.40, 95% CI = 0.16 to 0.63) suboccipital PPTs and in the right trapezius PPT (0.38, 95% CI = 0.07 to 0.69) were observed. At 1-month follow-up, significant mean differences were found for VAS (−1.85, 95% CI = −2.76 to −0.94) and both left (0.46, 95% CI = 0.12 to 0.80) and right (0.38, 95% CI = 0.06 to 0.69) suboccipital PPTs. Conclusions This study provides evidence that MRT could be better than a multimodal PT program for short-term improvement of pain and PPTs in patients with neck pain.

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Cochrane Rehabilitation: Organization and Functioning

No abstract available

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Pre-therapy Neural State of Bilateral Motor and Premotor Cortices Predicts Therapy Gain After Subcortical Stroke: A Pilot Study

Objective The aim of the study was to examine whether neural state of spared motor and premotor cortices captured before a therapy predicts therapy-related motor gains in chronic subcortical stroke. Design Ten survivors, presenting chronic moderate upper limb impairment, underwent proton magnetic resonance spectroscopy, magnetic resonance imaging, clinical, and kinematics assessments before a 4-wk impairment-oriented training. Clinical/kinematics assessments were repeated after therapy, and motor gain was defined as positive values of clinical upper limb/elbow motion changes and negative values of trunk motion changes. Candidate predictors were N-acetylaspartate-neuronal marker, glutamate-glutamine-indicator of glutamatergic neurotransmission, and myo-inositol-glial marker, measured bilaterally within the upper limb territory in motor and premotor (premotor cortex, supplementary motor area) cortices. Traditional predictors (age, stroke length, pre-therapy upper limb clinical impairment, infarct volume) were also investigated. Results Poor motor gain was associated with lower glutamate-glutamine levels in ipsilesional primary motor cortex and premotor cortex (r = 0.77, P = 0.01 and r = 0.78, P = 0.008, respectively), lower N-acetylaspartate in ipsilesional premotor cortex (r = 0.69, P = 0.02), higher glutamate-glutamine in contralesional primary motor cortex (r = −0.68, P = 0.03), and lower glutamate-glutamine in contralesional supplementary motor area (r = 0.64, P = 0.04). These predictors outperformed myo-inositol metrics and traditional predictors (P ≈ 0.05–1.0). Conclusions Glutamatergic state of bilateral motor and premotor cortices and neuronal state of ipsilesional premotor cortex may be important for predicting motor outcome in the context of a restorative therapy.

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Interventional Spine Considerations for Dural Ectasia in a Patient With Marfan Syndrome

For patients with Marfan syndrome who present with radicular low back pain, interventional spine providers should be familiar with dural ectasia with variable diffuse thinning of the posterior wall of the lumbar spine and sacrum. Providers should carefully weigh the risks and benefits of offering elective procedures because altered anatomy may put these patients at higher risk of dural puncture. Patient selection is essential because hydrostatic pressures and/or neural tension should also be considered as potential pain generators that may not be relieved by steroid injections. Careful evaluation of recent magnetic resonance images and vigilant procedural technique is highly recommended.

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Women Physicians Are Underrepresented in Recognition Awards From the Association of Academic Physiatrists

Objective Determine representation by gender for individual recognition awards presented to physicians by the Association of Academic Physiatrists (AAP). Design Cross-sectional survey was used. Lists of individual recognition award recipients for the 27-yr history of the AAP awards (1990–2016) were analyzed. The primary outcome measures were the total numbers of men versus women physician award recipients overall and for the past decade (2007–2016). Results No awards were given to women physicians for the past 4 yrs (2013–2016) or in half of the award categories for the past decade (2007–2016). No woman received the outstanding resident/fellow award since its inception (2010–2016). There was a decrease in the proportion of awards given to women in the past decade (2007–2016, 7 of 39 awards, 17.9%) as compared with the first 17 yrs (1990–2006, 10 of 46 awards, 21.7%). Furthermore, compared with their proportional membership within the specialty, women physicians were underrepresented for the entire 27-yr history of the AAP awards (1990–2016, 17 of 85 awards, 20%). According to the Association of American Medical Colleges, the proportion of full-time female physical medicine and rehabilitation faculty members was 38% in 1992 and 41% in 2013. Conclusions Women physicians have been underrepresented by the AAP in recognition awards. Although the reasons are not clear, these findings should be further investigated.

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Increased Reliability of Quantitative Ultrasound Measures of the Supraspinatus Tendon Using Multiple Image Analysts and Analysis Runs

Quantitative ultrasound (QUS) is an inexpensive and promising tool for sensitive measurement of tendon pathology. However, few studies have reported the psychometric properties of measurements obtained using this technique for assessments of the supraspinatus tendon. The present study was undertaken to determine the variance contributed by several sources of error (participant, ultrasound operator, image analyst, analysis session) to QUS measures of the supraspinatus tendon. Transverse images of the supraspinatus tendon were captured from eleven subjects (22 shoulders) by two ultrasonographers, and each image was analyzed by two image analysts who each completed two analysis runs. Generalizability theory and intraclass correlations were used to assess the reliability of seven QUS metrics. Measures of tendon/cartilage thickness demonstrated the greatest degree of overall dependability (ϕ = 0.84), followed by echogenicity (ϕ = 0.56), variance (ϕ = 0.55), and entropy (ϕ = 0.47), suggesting that these measures of the supraspinatus tendon may be promising metrics for assessing differences in tendon health. Interrater reliability between ultrasound operators ranged from low to moderate for different QUS metrics, but using more than one image analyst and performing repeated measurement analysis runs on each image help increase reliability of QUS measures for the supraspinatus tendon.

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Mobility Functional Outcomes of Neurofibromatosis Patients: A Preliminary Report

Objective The aim of the study was to describe the mobility outcomes of neurofibromatosis (NF) patients who received acute inpatient rehabilitation. Design This is a retrospective study of 62 consecutive neurofibromatosis patients of any age who received physical medicine and rehabilitation consultations at a comprehensive cancer center. Postoperative, inpatient rehabilitation admission and discharge functional independence measures (FIM scores) of transfers and gait and length of hospital stay were obtained from 37 patients who were transferred to inpatient rehabilitation (acute rehabilitation) and 25 who had an alternative disposition (consultation only). Results Mean age was 34 yrs. Both groups had similar postoperative FIM transfer and gait scores; however, at approximately postoperative day 10, the consultation only group was discharged with median FIM of 5 (supervision level) as compared with the acute rehabilitation group FIM of 4 (P = 0.000). The acute rehabilitation group had improved mobility FIM scores from postoperative to rehabilitation admission and again from rehabilitation admission to discharge (P

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Potential Harms With Long-Term Glucocorticoid Use

No abstract available

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Cytotoxicity of Local Anesthetics in Mesenchymal Stem Cells

Cell therapy based on the trophic, mitogenic, and immunomodulatory capacity of mesenchymal stem cells is a promising treatment modality for degenerative musculoskeletal conditions. Local anesthetics have been commonly used in interventional procedures for alleviating pain, but local anesthetics may have negative impact on MSC dosing because of cytotoxicity or other biological effects. Because previous studies have not reached consensus yet on the potential complications of local anesthetics in cell therapy, we reviewed 11 studies that involve in vitro experimentation with MSCs using aminoamide-type anesthetics including lidocaine, ropivacaine, mepivacaine, bupivacaine, articaine, and prilocaine. Three studies that compare the effects of different types of local anesthetic agents showed that ropivacaine has the least detrimental effects on mesenchymal stem cell populations, whereas lidocaine seems to have the most significant effects on stem cell viability. Concentration- and time-dependent effects on cell viability were reported with bupivacaine, ropivacaine, lidocaine, and mepivacaine. We conclude that local anesthetic agents have time- and concentration-dependent detrimental effects on MSCs. However, in vivo studies will be required to understand the interactions of these agents with MSCs, because in vitro studies cannot replicate the pharmacokinetics of anesthetics in vivo or the recovery of MSCs in a more physiological environment.

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Reply to the Letter to the Editor on “Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-Control Study With a Pair of Identical Twins”

No abstract available

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Point-of-Care Ultrasonography Findings and Care Use Among Patients Undergoing Ultrasound-Guided Shoulder Injections

Objective The aims of the study were to assess the overall reduction of pain in patients undergoing ultrasound-guided shoulder injections and to characterize the preinjection point-of-care ultrasound findings and use of clinical services postinjection including the use of magnetic resonance imaging and surgeries. Design Data of 172 patients who underwent ultrasound-guided subacromial subdeltoid injection or glenohumeral joint injection were reviewed for preinjection point-of-care ultrasound findings, change in pain intensity at 2 mos from baseline, and use of care at 6 mos' postinjection. Pain intensity was measured by the numeric rating scale and a dichotomous report of global impression of significant improvement in pain. Responders were defined as those with 50% or more reduction in numeric rating scale or those with global impression of 50% or more improvement. Results There were 141 responders among the 172 patients analyzed. Full-thickness rotator cuff tears were higher in the ultrasound-guided subacromial subdeltoid injection group when compared with the glenohumeral joint injection group (P = 0.038) and abnormal bicipital tendon findings higher in the glenohumeral joint injection group (P = 0.016). There were no significant differences in specific abnormal U findings between responders versus nonresponders. Twelve patients had a shoulder magnetic resonance imaging and four patients underwent operative interventions after the injection. Conclusions Overall pain reduction after ultrasound-guided shoulder injections was favorable in the short term. There was no specific preinjection point-of-care ultrasound findings associated with clinical pain reduction after injection. Additional imaging and operative intervention after ultrasound-guided shoulder injections seemed to be relatively low.

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Presumed Acute Leukemia Presenting as Acute Spinal Cord Injury

No abstract available

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Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates

Microbial Drug Resistance , Vol. 0, No. 0.


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Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients.

Objective: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. Patients and methods: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test. Results: The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). Conclusion: This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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How many trials does it take to get a significant ERP effect? It depends

Abstract

In designing an ERP study, researchers must choose how many trials to include, balancing the desire to maximize statistical power and the need to minimize the length of the recording session. Recent studies have attempted to quantify the minimum number of trials needed to obtain reliable measures for a variety of ERP components. However, these studies have largely ignored other variables that affect statistical power in ERP studies, including sample size and effect magnitude. The goal of the present study was to determine whether and how the number of trials, number of participants, and effect magnitude interact to influence statistical power, thus providing a better guide for selecting an appropriate number of trials. We used a Monte Carlo approach to measure the probability of obtaining a statistically significant result when testing for (a) the presence of an ERP effect, (b) within-participant condition differences in an ERP effect, and (c) between-participants group differences in an ERP effect. Each of these issues was examined in the context of the error-related negativity and the lateralized readiness potential. We found that doubling the number of trials recommended by previous studies led to more than a doubling of statistical power under many conditions. Thus, when determining the number of trials that should be included in a given study, researchers must consider the sample size, the anticipated effect magnitude, and the noise level, rather than relying solely on general recommendations about the number of trials needed to obtain a "stable" ERP waveform.

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ERP correlates of processing the auditory consequences of own versus observed actions

Abstract

Research has so far focused on neural mechanisms that allow us to predict the sensory consequences of our own actions, thus also contributing to ascribing them to ourselves as agents. Less attention has been devoted to processing the sensory consequences of observed actions ascribed to another human agent. Focusing on audition, there is consistent evidence of a reduction of the auditory N1 ERP for self- versus externally generated sounds, while ERP correlates of processing sensory consequences of observed actions are mainly unexplored. In a between-groups ERP study, we compared sounds generated by self-performed (self group) or observed (observation group) button presses with externally generated sounds, which were presented either intermixed with action-generated sounds or in a separate condition. Results revealed an overall reduction of the N1 amplitude for processing action- versus externally generated sounds in both the intermixed and the separate condition, with no difference between the groups. Further analyses, however, suggested that an N1 attenuation effect relative to the intermixed condition at frontal electrode sites might exist only for the self but not for the observation group. For both groups, we found a reduction of the P2 amplitude for processing action- versus all externally generated sounds. We discuss whether the N1 and the P2 reduction can be interpreted in terms of predictive mechanisms for both action execution and observation, and to what extent these components might reflect also the feeling of (self) agency and the judgment of agency (i.e., ascribing agency either to the self or to others).

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Modulation of sympathetic vasoconstriction is critical for the effects of sleep on arterial pressure in mice

Abstract

The values of arterial pressure (AP) during sleep predict cardiovascular risk. Sleep exerts similar effects on cardiovascular control in human subjects and mice. We aimed to determine the underlying autonomic mechanisms in 12 C57Bl/6J mice with a novel technique of intraperitoneal infusion of autonomic blockers, while monitoring the electroencephalogram, electromyogram, AP, and heart period (HP, i.e. 1/heart rate). In different sessions, we administered atropine methyl nitrate, atenolol, and prazosin to block muscarinic cholinergic, β₁ adrenergic, and α₁ adrenergic receptors, respectively, and compared each drug infusion with a matched vehicle infusion. The decrease in AP from wakefulness to non-rapid-eye-movement sleep (N) was abolished by prazosin but was not significantly affected by atropine and atenolol, which, however, blunted the accompanying increase in HP to a similar extent. On passing from N to rapid-eye-movement sleep (R), the increase in AP was significantly blunted by prazosin and atenolol, whereas the accompanying decrease in HP was blunted by atropine and abolished by atenolol. Cardiac baroreflex sensitivity (cBRS, sequence technique) was dramatically decreased by atropine and slightly increased by prazosin. These data indicate that in C57Bl/6J mice, N decreases mean AP by decreasing sympathetic vasoconstriction, increases HP by balancing parasympathetic activation and sympathetic withdrawal, and increases cBRS mainly by increasing fluctuations in parasympathetic activity. R increases mean AP by increasing sympathetic vasoconstriction and cardiac sympathetic activity, which also explains, at least in part, the concomitant decrease in HP. These data represent the first comprehensive assessment of the autonomic mechanisms of cardiovascular control during sleep in mice.

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Sodium channel clusters: harmonizing the cardiac conduction orchestra

Abstract

It is now widely appreciated that proteins within biological systems are organized into macromolecular complexes and that such organization is a key determinant of their function.

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Leucocytes Mutation load Declines with Age in Carriers of the m.3243A>G Mutation. A 10-year Prospective Cohort

Abstract

Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopaty, lactoacidosis and stroke-like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy was determined by next generation sequencing covered by 100.000 X reads in 32 individuals with a median follow-up of 10.2 years. Ten-year clinical follow-up is reported on 46 individuals. The annual leucocyte mutation level declined by -0.7 (± 0.4) percentage points/year (p<0.0001), and correlated with the level of the initial sample (ρ =-0.92, p<0.0001). Eleven of 46 m.3243A>G carriers died, and clinical symptoms progressed. This longitudinal study demonstrates the decline in leucocyte m.3243A>G heteroplasmy associates with the level of the initial sample. Further, there was a high mortality among carriers.

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Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis

Publication date: Available online 20 December 2017
Source:Journal of Genetics and Genomics
Author(s): Sebastià Franch-Expósito, Clara Esteban-Jurado, Pilar Garre, Isabel Quintanilla, Saray Duran-Sanchon, Marcos Díaz-Gay, Laia Bonjoch, Miriam Cuatrecasas, Esther Samper, Jenifer Muñoz, Teresa Ocaña, Sabela Carballal, María López-Cerón, Antoni Castells




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