Imaging intact human organs from the organ to the cellular scale in three dimensions is a goal of biomedical imaging. To meet this challenge, we developed hierarchical phase-contrast tomography ...(HiP-CT), an X-ray phase propagation technique using the European Synchrotron Radiation Facility (ESRF)'s Extremely Brilliant Source (EBS). The spatial coherence of the ESRF-EBS combined with our beamline equipment, sample preparation and scanning developments enabled us to perform non-destructive, three-dimensional (3D) scans with hierarchically increasing resolution at any location in whole human organs. We applied HiP-CT to image five intact human organ types: brain, lung, heart, kidney and spleen. HiP-CT provided a structural overview of each whole organ followed by multiple higher-resolution volumes of interest, capturing organotypic functional units and certain individual specialized cells within intact human organs. We demonstrate the potential applications of HiP-CT through quantification and morphometry of glomeruli in an intact human kidney and identification of regional changes in the tissue architecture in a lung from a deceased donor with coronavirus disease 2019 (COVID-19).
The initial acquisition and early development of the intestinal microbiome during infancy are important to human health across the lifespan. Mode of birth, antibiotic administration, environment of ...care, and nutrition have all been shown to play a role in the assembly of the intestinal microbiome during early life. For preterm infants, who are disproportionately at risk of inflammatory intestinal disease (i.e., necrotizing enterocolitis), a unique set of clinical factors influence the establishment of the microbiome. The purpose of this study was to establish the influence of nutritional exposures on the intestinal microbiome in a cohort of preterm infants early in life.
Principal component analysis of 199 samples from 30 preterm infants (<32 weeks) over the first 60 days following birth showed that the intestinal microbiome was influenced by postnatal time (p < 0.001, R
= 0.13), birth weight (p < 0.001, R
= 0.08), and nutrition (p < 0.001, R
= 0.21). Infants who were fed breast milk had a greater initial bacterial diversity and a more gradual acquisition of diversity compared to infants who were fed infant formula. The microbiome of infants fed breast milk were more similar regardless of birth weight (p = 0.049), in contrast to the microbiome of infants fed infant formula, which clustered differently based on birth weight (p < 0.001). By adjusting for differences in gut maturity, an ordered succession of microbial phylotypes was observed in breast milk-fed infants, which appeared to be disrupted in those fed infant formula. Supplementation with pasteurized donor human milk was partially successful in promoting a microbiome more similar to breast milk-fed infants and moderating rapid increases in bacterial diversity.
The preterm infant intestinal microbiome is influenced by postnatal time, birth weight, gestational age, and nutrition. Feeding with breast milk appears to mask the influence of birth weight, suggesting a protective effect against gut immaturity in the preterm infant. These findings suggest not only a microbial mechanism underpinning the body of evidence showing that breast milk promotes intestinal health in the preterm infant but also a dynamic interplay of host and dietary factors that facilitate the colonization of and enrichment for specific microbes during establishment of the preterm infant microbiota.
Supplemental long-chain omega-3 (n–3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA omega-3 index (O3I) concentrations, but the magnitude or variability of this effect is unclear.
The purpose ...of this study was to model the effects of supplemental EPA + DHA on the O3I.
Deidentified data from 1422 individuals from 14 published n–3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form ethyl ester (EE) compared with triglyceride (TG), and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion.
Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products.
Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.
A 31-year-old man presented systemically unwell with diabetic ketoacidosis (DKA). He was using an intermittently scanned continuous glucose monitoring (CGM) device that had been recording low or ...normal glucose readings for the 48 hours prior to admission. The sensor site had become infected, and we believe this soft tissue infection caused his CGM device to record falsely low glucose readings leading the patient to erroneously lower his insulin doses and take extra carbohydrates, precipitating DKA. CGM devices measure glucose levels in the interstitial fluid. When interstitial glucose readings do not match symptoms or expectations, a capillary blood glucose reading should be taken to correlate and impact treatment decisions. There will be an increase in patients presenting to hospital with CGM devices as the National Institute for Health and Care Excellence guidelines have recently been updated. We use this interesting clinical case to provide context for key learning points about CGM devices for the general physician.
As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs ...of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.
•The rTg4510 mouse model exhibits specific tau pathology.•This enables dissection of the unique role of tau in Alzheimer's Disease.•We applied five quantitative, non-invasive MRI techniques to the rTg4510.•We demonstrate the sensitivity of each to discriminate regions of high tau burden.•This study provides a platform for the longitudinal assessment of tau therapies.
Subannual growth increments in bivalves provide insight into past seasonal seawater conditions at high temporal resolution. The Antarctic scallop
Adamussium colbecki
(Smith 1902) accretes putatively ...fortnightly surficial growth lines (striae) and interstrial growth increments have the potential to archive sea ice variations. Cycles of paired groups of wide and narrow striae are sometimes used to determine ontogenetic age in these scallops, but previous quantitative work describing strial grouping and formation is limited to a few months of juvenile growth. Here, we analyze striae patterns in
A. colbecki
collected from two sites on western McMurdo Sound, Antarctica that differ by sea ice duration: Explorers Cove with multi-annual sea ice and Bay of Sails with annual sea ice. At both sites, visual analysis of striae groups and cycles (using the methods of previous authors) and wavelet analysis of interstrial increments suggest that striae groups are too variable to age
A. colbecki
. Only ~ 40% of striae groups and cycles conformed to expectations from annual cycles of fortnightly growth increments (~ 26 striae per cycle). Moreover, only one scallop from each study site displayed consistent periodicity at ~ 26 striae throughout juvenile growth in wavelet analysis. Though striae grouping was inconsistent, analysis of concurrent growth of juvenile scallops from Explorers Cove suggested strong environmental control on interstrial increment size and thus that strial increments are suitable for further analysis as sea ice proxies. Finally, the multi-annual sea ice site had smaller interstrial growth increments and less valve wear than the annual sea ice site, indicating overall slower growth and possibly lower metabolic activity.
Key points
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The extracellular concentration of the neurotransmitter γ‐aminobutyric acid (GABA) is critical in determining GABAA receptor‐mediated tonic conductance in the hippocampus.
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Two GABA ...transporters (GAT‐1 and GAT‐3) are present in the CA3 and dentate gyrus of the hippocampus. The expression of GAT‐3 is confined to astrocytes and its role in the regulation of GABAergic neurotransmission is unclear.
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Using microdialysis and specific GAT uptake inhibitors we show that not only GAT‐1 but also GAT‐3 contributes to the regulation of hippocampal extracellular concentrations of GABA in rats under in vivo conditions.
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We further found that changes in extracellular concentrations of GABA resulting from both GAT‐1 and GAT‐3 inhibition precipitate supra‐additive changes in tonic conductance in dentate granule cells in vitro.
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These results help us to understand the mechanisms underlying the regulation of GABAergic tonic conductance in the hippocampus and can help to develop improved therapeutic strategies for neurological and psychiatric disorders.
Tonic γ‐aminobutyric acid (GABA)A receptor‐mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (eGABA) is critical in determining tonic conductances, knowledge on how eGABA is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal eGABA using in vivo microdialysis in freely moving rats. Here we show that GAT‐1, which is predominantly presynaptically located, is the major GABA transporter under baseline, quiescent conditions. Furthermore, a significant contribution of GAT‐3 in regulating eGABA was revealed by administration of the GAT‐3 inhibitor SNAP‐5114 during simultaneous blockade of GAT‐1 by NNC‐711. Thus, the GABA transporting activity of GAT‐3 (the expression of which is confined to astrocytes) is apparent under conditions in which GAT‐1 is blocked. However, sustained neuronal activation by K+‐induced depolarization caused a profound spillover of GABA into the extrasynaptic space and this increase in eGABA was significantly potentiated by sole blockade of GAT‐3 (i.e. even when uptake of GAT‐1 is intact). Furthermore, experiments using tetrodotoxin to block action potentials revealed that GAT‐3 regulates extrasynaptic GABA levels from action potential‐independent sources when GAT‐1 is blocked. Importantly, changes in eGABA resulting from both GAT‐1 and GAT‐3 inhibition directly precipitate changes in tonic conductances in dentate granule cells as measured by whole‐cell patch‐clamp recording. Thus, astrocytic GAT‐3 contributes to the regulation of eGABA in the hippocampus in vivo and may play an important role in controlling the excitability of hippocampal cells when network activity is increased.
We studied the population dynamics and parasite load of the foraminifer Cibicides antarcticus on its host the Antarctic scallop Adamussium colbecki from three localities differing by sea ice cover ...within western McMurdo Sound, Ross Sea, Antarctica: Explorers Cove, Bay of Sails and Herbertson Glacier. We also estimated CaCO3 biomass and annual production for both species. Cibicides populations varied by locality, valve type, and depth. Explorers Cove with multiannual sea ice had larger populations than the two annual sea ice localities, likely related to differences in nutrients. Populations were higher on Adamussium top valves, a surface that is elevated above the sediment. Depth did not affect Cibicides distributions except at Bay of Sails. Cibicides parasite load (the number of complete boreholes in Adamussium valves) varied by locality between 2% and 50%. For most localities the parasite load was < 20%, contrary to a previous report that ~50% of Cibicides were parasitic. The highest and lowest parasite load occurred at annual sea ice localities, suggesting that sea ice condition is not important. Rather, the number of adults that are parasitic could account for these differences. Cibicides bioerosion traces were categorized into four ontogenetic stages, ranging from newly attached recruits to parasitic adults. These traces provide an excellent proxy for population structure, revealing that Explorers Cove had a younger population than Bay of Sails. Both species are important producers of CaCO3. Cibicides CaCO3 biomass averaged 47-73 kg ha(-1) and Adamussium averaged 4987-6806 kg ha(-1) by locality. Annual production rates were much higher. Moreover, Cibicides represents 1.0-2.3% of the total host-parasite CaCO3 biomass. Despite living in the coldest waters on Earth, these species can contribute a substantial amount of CaCO3 to the Ross Sea and need to be incorporated into food webs, ecosystem models, and carbonate budgets for Antarctica.
The initial area under the gadolinium curve (IAUGC) is often used in addition to or as an alternative to parameters derived from pharmacokinetic modelling of T1-weighted dynamic contrast-enhanced ...(DCE) MRI data in the assessment of response to treatment of cancer. However, the physiological meaning of the IAUGC has not been rigorously defined with respect to model-based parameters. Here, simulations of DCE-MRI data were used to investigate the relationship between IAUGC and the parameters K(trans) (transfer constant), v(e) (fractional extravascular extracellular volume) and v(p) (fractional plasma volume), using two vascular input functions. It is shown that IAUGC is a mixed parameter that can display correlation with K(trans), v(e) and v(p) and ultimately has an intractable relationship with all three. Furthermore, it is demonstrated that the range over which IAUGC is taken and the nature of the vascular input function do not significantly affect this relationship.
To collect the information necessary to design the methods and outcome variables for a larger trial of scheduled deep brain stimulation (DBS) for Tourette syndrome.
We performed a small National ...Institutes of Health-sponsored clinical trials planning study of the safety and preliminary efficacy of implanted DBS in the bilateral centromedian thalamic region. The study used a cranially contained constant-current device and a scheduled, rather than the classic continuous, DBS paradigm. Baseline vs 6-month outcomes were collected and analyzed. In addition, we compared acute scheduled vs acute continuous vs off DBS.
A university movement disorders center.
Five patients with implanted DBS.
A 50% improvement in the Yale Global Tic Severity Scale (YGTSS) total score. RESULTS Participating subjects had a mean age of 34.4 (range, 28-39) years and a mean disease duration of 28.8 years. No significant adverse events or hardware-related issues occurred. Baseline vs 6-month data revealed that reductions in the YGTSS total score did not achieve the prestudy criterion of a 50% improvement in the YGTSS total score on scheduled stimulation settings. However, statistically significant improvements were observed in the YGTSS total score (mean SD change, -17.8 9.4; P=.01), impairment score (-11.3 5.0; P=.007), and motor score (-2.8 2.2; P=.045); the Modified Rush Tic Rating Scale Score total score (-5.8 2.9; P=.01); and the phonic tic severity score (-2.2 2.6; P=.04). Continuous, off, and scheduled stimulation conditions were assessed blindly in an acute experiment at 6 months after implantation. The scores in all 3 conditions showed a trend for improvement. Trends for improvement also occurred with continuous and scheduled conditions performing better than the off condition. Tic suppression was commonly seen at ventral (deep) contacts, and programming settings resulting in tic suppression were commonly associated with a subjective feeling of calmness.
This study provides safety and proof of concept that a scheduled DBS approach could improve motor and vocal tics in Tourette syndrome. Refinements in neurostimulator battery life, outcome measure selection, and flexibility in programming settings can be used to enhance outcomes in a future larger study. Scheduled stimulation holds promise as a potential first step for shifting movement and neuropsychiatric disorders toward more responsive neuromodulation approaches.
clinicaltrials.gov Identifier: NCT01329198.
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