The ruminal level of trans-10 fatty acids of dairy cows is linked to the composition of bacterial community

The ruminal level of trans-10 fatty acids of dairy cows is linked to the composition of bacterial communit

The human semicircular canal model of galvanic vestibular stimulation

A vector summation model of the action of galvanic stimuli on the semicircular canals has been shown to explain empirical balance and perceptual responses to binaural-bipolar stimuli. However, published data suggest binaural-monopolar stimuli evoke responses that are in the reverse direction of the model prediction. Here, we confirm this by measuring balance responses to binaural-monopolar stimulation as movements of the upper trunk. One explanation for the discrepancy is that the galvanic stimulus might evoke an oppositely directed balance response from the otolith organs that sums with and overrides the semicircular canal response. We tested this hypothesis by measuring sway responses across the full range of head pitch. The results showed some modulation of sway with pitch such that the maximal response occurred with the head in the primary position. However, the effect fell a long way short of that required to reverse the canal sway response. This indicates that the model is incomplete. Here, we examine alterations to the model that could explain both the bipolar and monopolar-evoked behavioural responses. An explanation was sought by remodelling the canal response with more recent data on the orientation of the individual canals. This improved matters but did not reverse the model prediction. However, the model response could be reversed by either rotating the entire labyrinth in the skull or by altering the gains of the individual canals. The most parsimonious solution was to use the more recent canal orientation data coupled with a small increase in posterior canal gain

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist

Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

INTRODUCTION: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. METHODS: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. RESULTS: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. CONCLUSION: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment

Top-down and bottom-up modulation in processing bimodal face/voice stimuli

<p>Abstract</p> <p>Background</p> <p>Processing of multimodal information is a critical capacity of the human brain, with classic studies showing bimodal stimulation either facilitating or interfering in perceptual processing. Comparing activity to congruent and incongruent bimodal stimuli can reveal sensory dominance in particular cognitive tasks.</p> <p>Results</p> <p>We investigated audiovisual interactions driven by stimulus properties (bottom-up influences) or by task (top-down influences) on congruent and incongruent simultaneously presented faces and voices while ERPs were recorded. Subjects performed gender categorisation, directing attention either to faces or to voices and also judged whether the face/voice stimuli were congruent in terms of gender. Behaviourally, the unattended modality affected processing in the attended modality: the disruption was greater for attended voices. ERPs revealed top-down modulations of early brain processing (30-100 ms) over unisensory cortices. No effects were found on N170 or VPP, but from 180-230 ms larger right frontal activity was seen for incongruent than congruent stimuli.</p> <p>Conclusions</p> <p>Our data demonstrates that in a gender categorisation task the processing of faces dominate over the processing of voices. Brain activity showed different modulation by top-down and bottom-up information. Top-down influences modulated early brain activity whereas bottom-up interactions occurred relatively late.</p

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies.

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease

Early detection of hTTR cardiac amyloidosis with bone DPD scintigraphy in a patient with a rare transthyretin mutation

International audienc

Sarcoïdose médullaire mimant une myélopathie cervico-arthrosique : mauvais pronostic après chirurgie

International audienceIntroductionCervical spinal sarcoidosis can mimic compressive cervical myelopathy leading to potentially harmful surgical procedures before the diagnosis can be made.MethodsRetrospective description of 3 patients and review of the literature.ResultsTwenty-seven patients (16 men/11 women), median age 58 years [range 29–74] were described. Neurosurgical procedures consisted of laminectomy (n = 10), laminoplasty (n = 15) and anterior discectomy (n = 2). Immediately after surgery, 17 patients (63%) worsened or remained disabled. Among the 10 patients who improved, 9 worsened secondarily. The analysis of preoperative MRI showed T2 hypersignal lesions and contrast enhancement in all patients. Neurological symptoms were inaugural in 25/27 patients, and systemic involvement of the sarcoidosis was found after surgery in 15/27 patients. After surgery, all patients received corticosteroids, along with immunosuppressive therapy in 8 cases/27. After a follow-up of 24 [16–72] months; 13 patients were stabilized or worsened, 7 were partially improved. Three died of other cause. Only 5 recovered without sequelae.ConclusionIn patients with compressive cervical myelopathy, leptomeningeal contrast enhancement, a T2-weighted hypersignal exceeding the compression level on MRI, and the presence of extraneurological symptoms should point to inflammatory disease. These rare manifestations may be the first symptoms of sarcoidosis and should be recognized to avoid harmful surgical procedures and to provide appropriate medical treatment.IntroductionLes sarcoïdoses médullaires cervicales peuvent ressembler à des myélopathies cervico-arthrosiques compressives, pouvant conduire à des interventions chirurgicales délétères avant le rétablissement du diagnostic.MéthodesDescription rétrospective de trois patients et revue de la littérature.RésultatsVingt-sept patients (16 hommes/11 femmes), d’âge médian 58 ans [étendue : 29–74] ont été décrits. Les procédures neurochirurgicales consistaient en : laminectomie (n = 10), laminoplastie (n = 15) et discectomie antérieure (n = 2). Immédiatement après la chirurgie, l’état de 17 patients (63 %) s’aggravait ou demeurait stable. Parmi les 10 patients dont l’état s’améliorait, celui de 9 empirait secondairement. L’analyse de l’IRM préopératoire montrait des lésions en hypersignal T2 et une prise de contraste chez tous les patients. L’atteinte neurologique était inaugurale pour 25 des 27 patients. Quinze avaient une atteinte systémique. Après la chirurgie, tous les patients recevaient des corticoïdes, associés à un immunosuppresseur dans 8 cas/27. Après un suivi de 24 [16–72] mois, 15 patients étaient stabilisés ou aggravés, 7 étaient améliorés, mais gardaient un handicap fonctionnel. Trois décédaient d’une autre cause. Seuls cinq avaient récupéré sans séquelles.ConclusionDevant un tableau de myélopathie cervico-arthrosique, des atypies telles qu’une prise de contraste leptoméningée, un hypersignal T2 en IRM dépassant le site de compression et la présence de signes extraneurologiques doivent faire rechercher une maladie inflammatoire neurologique. Ces présentations rares peuvent être inaugurales de la sarcoïdose et doivent être reconnues afin d’éviter des interventions chirurgicales néfastes et proposer un traitement médical adapté