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Objectives The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS. Methods In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons. Results MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04). Conclusions We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition. Key Points • Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.

Background The clinical role of perfusion-weighted MRI (PWI) in head and neck squamous cell carcinoma (HNSCC) remains to be defined. The aim of this study was to provide evidence-based recommendations for the use of PWI sequence in HNSCC with regard to clinical indications and acquisition parameters. Methods Public databases were searched, and selected papers evaluated applying the Oxford criteria 2011. A questionnaire was prepared including statements on clinical indications of PWI as well as its acquisition technique and submitted to selected panelists who worked in anonymity using a modified Delphi approach. Each panelist was asked to rate each statement using a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree). Statements with scores equal or inferior to 5 assigned by at least two panelists were revised and re-submitted for the subsequent Delphi round to reach a final consensus. Results Two Delphi rounds were conducted. The final questionnaire consisted of 6 statements on clinical indications of PWI and 9 statements on the acquisition technique of PWI. Four of 19 (21%) statements obtained scores equal or inferior to 5 by two panelists, all dealing with clinical indications. The Delphi process was considered concluded as reasons entered by panelists for lower scores were mainly related to the lack of robust evidence, so that no further modifications were suggested. Conclusions Evidence-based recommendations on the use of PWI have been provided by an independent panel of experts worldwide, encouraging a standardized use of PWI across university and research centers to produce more robust evidence.

PurposeTo evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139–151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions.ResultsSUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p p p p p p ConclusionsThese preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.

The functional organization of the brain is usually presented with a back-to-front gradient of timescales, reflecting regional specialization with sensory areas (back) processing information faster than associative areas (front), which perform information integration. However, cognitive processes require not only local information processing but also coordinated activity across regions. Using magnetoencephalography recordings, we find that the functional connectivity at the edge level (between two regions) is also characterized by a back-to-front gradient of timescales following that of the regional gradient. Unexpectedly, we demonstrate a reverse front-to-back gradient when nonlocal interactions are prominent. Thus, the timescales are dynamic and can switch between back-to-front and front-to-back patterns.

Deficit schizophrenia is a subtype of schizophrenia presenting primary and enduring negative symptoms (NS). Although one of the most updated hypotheses indicates a relationship between NS and impaired motivation, only a few studies have investigated abnormalities of motivational circuits in subjects with deficit schizophrenia (DS). Our aim was to investigate structural connectivity within motivational circuits in DS. We analyzed diffusion tensor imaging (DTI) data from 46 subjects with schizophrenia (SCZ) and 35 healthy controls (HCs). SCZ were classified as DS (n = 9) and non-deficit (NDS) (n = 37) using the Schedule for Deficit Syndrome. The connectivity index (CI) and the Fractional Anisotropy (FA) of the connections between selected brain areas involved in motivational circuits were examined. DS, as compared with NDS and HCs, showed increased CI between the right amygdala and dorsal anterior insular cortex and increased FA of the pathway connecting the left nucleus accumbens with the posterior insular cortex. Our results support previous evidence of distinct neurobiological alterations underlying different clinical subtypes of schizophrenia. DS, as compared with NDS and HCs, may present an altered pruning process (consistent with the hyperconnectivity) in cerebral regions involved in updating the stimulus value to guide goal-directed behavior.

Two structurally connected brain regions are more likely to interact, with the lengths of the structural bundles, their widths, myelination, and the topology of the structural connectome influencing the timing of the interactions. We introduce anin vivoapproach for measuring functional delays across the whole brain in humans (of either sex) using magneto/electroencephalography (MEG/EEG) and integrating them with the structural bundles. The resulting topochronic map of the functional delays/velocities shows that larger bundles have faster velocities. We estimated the topochronic map in multiple sclerosis patients, who have damaged myelin sheaths, and controls, demonstrating greater delays in patients across the network and that structurally lesioned tracts were slowed down more than unaffected ones. We provide a novel framework for estimating functional transmission delaysin vivoat the single-subject and single-tract level.SIGNIFICANCE STATEMENTThis article provides a straightforward way to estimate patient-specific delays and conduction velocities in the CNS, at the individual level, in healthy and diseased subjects. To do so, it uses a principled way to merge magnetoencephalography (MEG)/electroencephalography (EEG) and tractography.

The development of prophylactic agents against the SARS-CoV-2 virus is a public health priority in the search for new surrogate markers of active virus replication. Early detection markers are needed to follow disease progression and foresee patient negativization. Subgenomic RNA transcripts (with a focus on sgN) were evaluated in oro/nasopharyngeal swabs from COVID-19-affected patients with an analysis of 315 positive samples using qPCR technology. Cut-off Cq values for sgN (Cq < 33.15) and sgE (Cq < 34.06) showed correlations to high viral loads. The specific loss of sgN in home-isolated and hospitalized COVID-19-positive patients indicated negativization of patient condition, 3–7 days from the first swab, respectively. A new detection kit for sgN, gene E, gene ORF1ab, and gene RNAse P was developed recently. In addition, in vitro studies have shown that 2’-O-methyl antisense RNA (related to the sgN sequence) can impair SARS-CoV-2 N protein synthesis, viral replication, and syncytia formation in human cells (i.e., HEK-293T cells overexpressing ACE2) upon infection with VOC Alpha (B.1.1.7)-SARS-CoV-2 variant, defining the use that this procedure might have for future therapeutic actions against SARS-CoV-2.

Objectives To stratify patients with multiple sclerosis (pwMS) based on brain MRI-derived volumetric features using unsupervised machine learning. Methods The 3-T brain MRIs of relapsing-remitting pwMS including 3D-T1w and FLAIR-T2w sequences were retrospectively collected, along with Expanded Disability Status Scale (EDSS) scores and long-term (10 ± 2 years) clinical outcomes (EDSS, cognition, and progressive course). From the MRIs, volumes of demyelinating lesions and 116 atlas-defined gray matter regions were automatically segmented and expressed as z-scores referenced to external populations. Following feature selection, baseline MRI-derived biomarkers entered the Subtype and Stage Inference (SuStaIn) algorithm, which estimates subgroups characterized by distinct patterns of biomarker evolution and stages within subgroups. The trained model was then applied to longitudinal MRIs. Stability of subtypes and stage change over time were assessed via Krippendorf’s α and multilevel linear regression models, respectively. The prognostic relevance of SuStaIn classification was assessed with ordinal/logistic regression analyses. Results We selected 425 pwMS (35.9 ± 9.9 years; F/M: 301/124), corresponding to 1129 MRI scans, along with healthy controls (N = 148; 35.9 ± 13.0 years; F/M: 77/71) and external pwMS (N = 80; 40.4 ± 11.9 years; F/M: 56/24) as reference populations. Based on 11 biomarkers surviving feature selection, two subtypes were identified, designated as “deep gray matter (DGM)-first” subtype (N = 238) and “cortex-first” subtype (N = 187) according to the atrophy pattern. Subtypes were consistent over time (α = 0.806), with significant annual stage increase (b = 0.20; p < 0.001). EDSS was associated with stage and DGM-first subtype (p ≤ 0.02). Baseline stage predicted long-term disability, transition to progressive course, and cognitive impairment (p ≤ 0.03), with the latter also associated with DGM-first subtype (p = 0.005). Conclusions Unsupervised learning modelling of brain MRI-derived volumetric features provides a biologically reliable and prognostically meaningful stratification of pwMS. Key Points • The unsupervised modelling of brain MRI-derived volumetric features can provide a single-visit stratification of multiple sclerosis patients. • The so-obtained classification tends to be consistent over time and captures disease-related brain damage progression, supporting the biological reliability of the model. • Baseline stratification predicts long-term clinical disability, cognition, and transition to secondary progressive course.

The aim of this trial was to investigate the effects of a blend of monoglycerides of short- and medium-chain fatty acids (SMCFA) on health status and growth of preweaned male calves from 16 to 72 days of age. The in vivo study was conducted as a complete randomised block design. Twenty Italian Holstein calves received starter administered ad libitum and 6 L of milk replacer/day (12% powder concentration) and were divided into treated (T) and control (C) groups. A preliminary in vitro antibiotic activity test of SMCFA was performed on several bacterial strains showing a minimum inhibiting concentration ranging from 0.8 to 12.5%. The group T received SMCFA (11 g/day) within the milk replacer while, to obtain isoenergetic liquid diets, the group C received additional 18 g/day of milk replacer powder. Body weight and morphological measurements of the calves were performed weekly. Health scores were checked daily. Faecal and blood samples were collected every two weeks for routine clinical investigations including serum concentration of non-esterified fatty acids and β-Hydroxybutyric acid. At the end of the trial calves were slaughtered and gastrointestinal tract (GIT) organs weighed. The group T reported a better health status and did not require Ab therapy. No differences in biometrical measurements, feed efficiency, blood parameters, and GIT measures were found between the two groups. At 44 days of age, group T showed higher β-Hydroxybutyric acid concentration compared to group C (p

The administration of high quality colostrum reduces preweaning morbidity, mortality and, therefore, economic losses related to replacement animals. It also stimulates and improves calf growth, increasing milk production and longevity of the future dairy cows. The aim of the present study was to evaluate the influence of breed and parity of the dam on colostrum quality, and of breed and gender of the calf, and time from calf birth to the administration of the first colostrum meal on the transfer of passive immunity to the calf by the field test of the Failure of Passive Transfer (FPT) on calf serum. A further objective was to improve the diagnostic accuracy of the field FPT test through a second laboratory phase improving the turbidity evaluation. The amount of IgG fed to calves (IgG concentration multiplied by the volume of colostrum administered) was influenced by dam parity as significant differences (P < 0.05) were detected between first- and fourth-parity cows, and between second- and fourth-parity cows. The administration of good quality colostrum (IgG > 50 mg/ml) between 5 and 9 h of life was able to reduce the risk of FPT more effectively than the administration performed within the first 4 h of life. However, further studies on larger sample size is needed to confirm the present findings. The spectrophotometric measurements confirmed the results obtained by the field turbidity test at 14% sodium sulphite dilution. It would be interesting in future to expand the dataset and validate the spectrophometric method.

Submitted 2020-07-03 | Accepted 2020-08-08 | Available 2020-12-01 https://doi.org/10.15414/afz.2020.23.mi-fpap.197-204 The first three months of life is the most critical period for the young calf, and nutrition plays an essential role for a successful weaning program. The effects of starter feed physical form have been widely investigated in the last decades, but results are variable and often inconsistent. We compared the impact of texturized and pelleted starters on growth performances during the artificial pre-weaning period on replacement female dairy calves. A total of 16 calves were divided in two independent groups, fed with pelleted or texturized starter and monitored from 2 to 44 days of life. Morphometric traits as well as health status, growth performances, feed intake and efficiency were recorded weekly. An interesting significance (p=0.013) was found for the weight increment, that starting from 5 th week showed higher values in animals fed with texturized rather than pelleted feedstuff, although no differences were obtained for the feed efficiency. Despite the lack of significant differences, the trends observed for weight increment and health status, suggest some advantages in the use of texturized feedstuff during the pre-weaning period. Keywords: calves pre-weaning nutrition, texturized feed, growth performances References Bach, A. et al. (2007) Effects of physical form of a starter for dairy replacement calves on feed intake and performance. Journal of Dairy Science. 90, 3028–3033. doi:https://doi.org/10.3168/jds.2006-761 Baldwin, R. L. VI et al. (2004) Rumen development, intestinal growth and hepatic metabolism in the pre- and post-weaning ruminant. Journal of Dairy Science. 87(E Suppl.): E55–E65. doi: https://doi.org/10.3168/jds.S0022-0302(04)70061-2 Boulton, A. C. et al. 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A. et al. (2011) Invited Review: Effects of milk ration on solid feed intake, weaning and performance in dairy heifers. Journal of Dairy Science. 94, 1071–1081. doi: https://doi.org/10.3168/jds.2010-3733 Khan et al. (2016) Invited review: Transitioning from milk to solid feed in dairy heifers. Journal of Dairy Science. 9, 885–902. doi: https://doi.org/10.3168/jds.2015-9975 Larson, L. L. et al. (1977) Guidelines toward more uniformity in measuring and reporting calf experimental data. Journal of Dairy Science. 60, 989–991. Lassiter, C.A. et al. (1955) The nutritional merits of pelleting calf starters. Journal of Dairy Science. 38, 1242-1245. Mirzaei, M. et al. (2016) Interactions between the physical form of starter (mashed versus textured) and corn silage provision on performance, rumen fermentation, and structural growth of Holstein calves. Journal of Animal Science. 94(2):678-686. doi: https://doi.org/10.2527/jas.2015-9670 Newman P.E. and Savage E.S. 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International audience; Brain activity during rest displays complex, rapidly evolving patterns in space and time. Structural connections comprising the human connectome are hypothesized to impose constraints on the dynamics of this activity. Here, we use magnetoencephalography (MEG) to quantify the extent to which fast neural dynamics in the human brain are constrained by structural connections inferred from diffusion MRI tractography. We characterize the spatio-temporal unfolding of whole-brain activity at the millisecond scale from source-reconstructed MEG data, estimating the probability that any two brain regions will significantly deviate from baseline activity in consecutive time epochs. We find that the structural connectome relates to, and likely affects, the rapid spreading of neuronal avalanches, evidenced by a significant association between these transition probabilities and structural connectivity strengths (r=0.37, p

Long-chain polyphosphates inhibit SARS-CoV-2 infection by targeting a host receptor and a viral RNA polymerase., Polyphosphates versus SARS-CoV-2 Long-chain, inorganic polyphosphates (polyPs), which are found in many cells in the blood, have cytoprotective and antiviral activities, particularly against HIV-1 infection. Ferrucci et al. tested the effects of polyPs of various lengths on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Molecular docking and binding analyses showed that polyPs bound to the host receptor ACE2, which facilitates viral entry, and a viral RNA polymerase required for replication. Both proteins underwent proteasomal degradation in cells incubated with polyP120, the optimal species tested, resulting in inhibition of SARS-CoV-2 replication and a reduced inflammatory response. Given that polyPs have low toxicity, these results suggest that their potential therapeutic use should be further explored., Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO43−) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano– LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2–infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.