To prospectively compare tumor volume, relative cerebral blood volume (rCBV), and apparent diffusion coefficient (ADC) and short-term changes of these parameters as predictors of time to malignant ...transformation and time to death in patients with low-grade gliomas (LGGs).
Patients gave written informed consent for this institutional ethics committee-approved study. Patients with histologically proved LGGs underwent conventional, perfusion-weighted, and diffusion-weighted magnetic resonance (MR) imaging at study entry and at 6 months. At both time points, tumor volume, maximum rCBV, and ADC histogram measures were calculated. Patient follow-up consisted of MR imaging every 6 months and clinical examinations. To investigate the association between MR imaging variables and time to progression and time to death, a Cox regression curve was applied at study entry and at 6 months. The models were corrected for age, sex, and histologic findings.
Thirty-four patients (22 men, 12 women; mean age, 42 years) with histologically proved LGGs (eight oligodendrogliomas, 20 astrocytomas, and six oligoastrocytomas) were followed up clinically and radiologically for a median of 2.6 years (range, 0.4-5.5 years). Tumor growth over the course of 6 months was the best predictor of time to transformation, independent of rCBV, diffusion histogram parameters, age, sex, and histologic findings. When only single-time-point measurements were compared, tumor volume helped predict outcome best and was the only independent predictor of time to death (P < .02).
Six-month tumor growth helps predict outcome in patients with LGG better than parameters derived from perfusion- or diffusion-weighed MR imaging. Tumor growth can readily be calculated from volume measurements on images acquired with standard MR imaging protocols and may well prove most useful among various MR imaging findings in clinical practice.
Objectives
Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF ...and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine.
Methods
HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively).
Results
Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8–37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7–1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3–7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90.
Conclusions
Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP.
Background We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on 11 Ccarfentanil ...binding with positron emission tomography (PET). Methods Twelve healthy male volunteers underwent 11 Ccarfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a “high” dose, .5 mg/kg, or a sub-pharmacological “ultra-low” dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in 11 Ccarfentanil binding from baseline to post-amphetamine scans (ΔBPND ) after the “high” and “ultra-low” amphetamine doses were assessed in 10 regions of interest. Results 11 Ccarfentanil binding was reduced after the “high” but not the “ultra-low” amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. Conclusions Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and 11 Ccarfentanil PET is a practical and robust method to probe the opioid system in the living human brain.
OBJECTIVE:To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 ...integrin antibody natalizumab in patients with multiple sclerosis (MS).
METHODS:We evaluated CD45CD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10).
RESULTS:Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and nonmobilizer subgroups. Nonmobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile.
CONCLUSIONS:The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatmentʼs mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.
Alzheimer's disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention.
We aimed ...to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia.
We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40-59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI images taken at baseline and 2-year follow-up.
FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up.
CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis.
Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala ...grey‐matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed‐based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala‐SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala‐SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala‐SN/VTA RSFC and accelerated age‐related grey‐matter atrophy through potentially distinct mechanisms.
Alcohol‐dependent patients in long‐term abstinence expressed higher levels of amygdala‐SN/VTA resting state functional connectivity and lower levels of amygdala grey‐matter volumes than age‐matched healthy controls. Magnitude of amygdala‐SN/VTA functional connectivity was correlated with duration of cumulative alcohol exposure but not with amygdala grey‐matter volumes. These findings suggest distinct processes at play influencing structural and functional properties of amygdala in alcohol dependence.
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•Bombina orientalis comprises four genetically distinct populations.•Populations diverged during the Miocene.•Two populations come into secondary contact on the Korean Peninsula.•The ...insular Jeju population originated from a single dispersal event.•Rice cultivation may have contributed to population increase in the Pleistocene.
The Oriental fire-bellied toad (Bombina orientalis) is a commonly used study organism, but knowledge of its evolutionary history is incomplete. We analyze sequence data from four genetic markers (mtDNA genes encoding cytochrome c oxidase subunit I, cytochrome b, and 12S–16S rRNA; nuDNA gene encoding recombination activating gene 2) from 188 individuals across its range in Northeast Asia to elucidate phylogeographic patterns and to identify the historic events that shaped its evolutionary history. Although morphologically similar across its range, B. orientalis exhibits phylogeographic structure, which we infer was shaped by geologic, climatic, and anthropogenic events. Phylogenetic and divergence-dating analyses recover four genetically distinct groups of B. orientalis: Lineage 1—Shandong Province and Beijing (China); Lineage 2—Bukhan Mountain (Korea); Lineage 3—Russia, Northeast China, and northern South Korea; and Lineage 4—South Korea. Lineage 2 was previously unknown. Additionally, we discover an area of secondary contact on the Korean Peninsula, and infer a single dispersal event as the origin of the insular Jeju population. Skyline plots estimate different population histories for the four lineages: Lineages 1 and 2 experienced population decreases, Lineage 3 remained stable, while Lineage 4 experienced a sharp increase during the Holocene. The timing of the population expansion of Lineage 4 coincides with the advent of rice cultivation, which may have facilitated the increase in population size by providing additional breeding habitat.
Abstract
Myelin-sensitive MRI such as magnetization transfer imaging has been widely used in multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings ...is, however, not well established. Here, we systematically review magnetization transfer brain imaging findings in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetization transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including ‘magnetization transfer’ and ‘brain’ for systematic review, according to a pre-defined protocol. Only studies that used human in vivo quantitative magnetization transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Additional data from relapsing-remitting multiple sclerosis subjects acquired in other studies comprising mixed disease subtypes were included in meta-analyses.
Data including sample size, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesized. Where possible, effect sizes were calculated for meta-analyses to determine magnetization transfer (i) differences between patients and healthy controls; (ii) longitudinal change and (iii) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met inclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined the magnetization transfer ratio in white matter, but magnetization transfer metrics, brain regions examined and results were heterogeneous. The analysis demonstrated a risk of bias due to selective reporting and small sample sizes. The pooled random-effects meta-analysis across all brain compartments revealed magnetization transfer ratio was 1.17 per cent units (95% CI −1.42 to −0.91) lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: −8.99, P < 0.001, 46 studies). Linear mixed-model analysis did not show a significant longitudinal change in magnetization transfer ratio across all brain regions β = 0.12 (−0.56 to 0.80), t-value = 0.35, P = 0.724, 14 studies or normal-appearing white matter alone β = 0.037 (−0.14 to 0.22), t-value = 0.41, P = 0.68, eight studies. There was a significant negative association between the magnetization transfer ratio and clinical disability, as assessed by the Expanded Disability Status Scale r = −0.32 (95% CI −0.46 to −0.17); z-value = −4.33, P < 0.001, 13 studies. Evidence suggests that magnetization transfer imaging metrics are sensitive to pathological brain changes in relapsing-remitting multiple sclerosis, although effect sizes were small in comparison to inter-study variability. Recommendations include: better harmonized magnetization transfer acquisition protocols with detailed methodological reporting standards; larger, well-phenotyped cohorts, including healthy controls; and, further exploration of techniques such as magnetization transfer saturation or inhomogeneous magnetization transfer ratio.
York et al. systematically reviewed 86 studies of magnetization transfer brain imaging in relapsing-remitting multiple sclerosis. Meta-analyses showed that magnetization transfer was reduced in patients compared with controls, but results were heterogeneous, longitudinal change subtle and associations with clinical disability weak. Better harmonized study acquisition protocols in larger, well-phenotyped cohorts are warranted.
Graphical Abstract
Graphical Abstract
Age of onset in multiple sclerosis (MS) exerts an influence on the course of disease. This study examined whether global and regional brain volumes differed between "younger" and "older" onset MS ...subjects who were matched for short disease duration, mean 1.9 years and burden as measured by the MS Severity Score and relapses. 21 younger-onset MS subjects (age 30.4 ± 3.2 years) were compared with 17 older-onset (age 48.7 ± 3.3 years) as well as age-matched controls (
= 31, 31.9 ± 3.5 years and
= 21, 47.3 ± 4.0 years). All subjects underwent 3D volumetric T1 and T2-FLAIR imaging. White matter (WM) and grey matter (GM) lesions were outlined manually. Lesions were filled prior to tissue and structural segmentation to reduce classification errors. Volume loss versus control was predominantly in the subcortical GM, at > 13% loss. Younger and older-onset MS subjects had similar, strong excess loss in the putamen, thalamus, and nucleus accumbens. No excess loss was detected in the amygdala or pallidum. The hippocampus and caudate showed significant excess loss in the younger group (
< 0.001) and a strong trend in the older-onset group. These results provide a potential imaging correlate of published neuropsychological studies that reported the association of younger age at disease onset with impaired cognitive performance, including decreased working memory.
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