DTI is increasingly being used as a measure to study tissue damage in several neurologic diseases. Our aim was to investigate the comparability of DTI measures between different MR imaging magnets ...and platforms.
Two healthy volunteers underwent DTI on five 3T MR imaging scanners (3 Trios and 2 Signas) by using a matched 33 noncollinear diffusion-direction pulse sequence. Within each subject, a total of 16 white matter (corpus callosum, periventricular, and deep white matter) and gray matter (cortical and deep gray) ROIs were drawn on a single image set and then were coregistered to the other images. Mean FA, ADC, and longitudinal and transverse diffusivities were calculated within each ROI. Concordance correlations were derived by comparing ROI DTI values among each of the 5 magnets.
Mean concordance for FA was 0.96; for both longitudinal and transverse diffusivities, it was 0.93; and for ADC, it was 0.88. Mean scan-rescan concordance was 0.96-0.97 for all DTI measures. Concordance correlations within platforms were, in general, better than those between platforms for all DTI measures (mean concordance of 0.96).
We found that a 3T magnet and high-angular-resolution pulse sequence yielded comparable DTI measurements across different MR imaging magnets and platforms. Our results indicate that FA is the most comparable measure across magnets, followed by individual diffusivities. The comparability of DTI measures between different magnets supports the feasibility of multicentered clinical trials by using DTI as an outcome measure.
Acute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic inflammation, and failure of hepatic regeneration. Its treatment is a major unmet medical need. This ...study was conducted to explore whether combining TAK-242, a Toll-like receptor-4 (TLR4) antagonist, with granulocyte-colony stimulating factor (G-CSF), could reduce inflammation whilst enhancing liver regeneration.
Two mouse models of ACLF were investigated. Chronic liver injury was induced by carbon tetrachloride; lipopolysaccharide (LPS) or galactosamine (GalN) were then administered as extrahepatic or hepatic insults, respectively. G-CSF and/or TAK-242 were administered daily. Treatment durations were 24 hours and 5 days in the LPS model and 48 hours in the GalN model.
In a mouse model of LPS-induced ACLF, treatment with G-CSF was associated with significant mortality (66% after 48 hours vs. 0% without G-CSF). Addition of TAK-242 to G-CSF abrogated mortality (0%) and significantly reduced liver cell death, macrophage infiltration and inflammation. In the GalN model, both G-CSF and TAK-242, when used individually, reduced liver injury but their combination was significantly more effective. G-CSF treatment, with or without TAK-242, was associated with activation of the pro-regenerative and anti-apoptotic STAT3 pathway. LPS-driven ACLF was characterised by p21 overexpression, which is indicative of hepatic senescence and inhibition of hepatocyte regeneration. While TAK-242 treatment mitigated the effect on senescence, G-CSF, when co-administered with TAK-242, resulted in a significant increase in markers of hepatocyte regeneration.
The combination of TAK-242 and G-CSF inhibits inflammation, promotes hepatic regeneration and prevents mortality in models of ACLF; thus, this combination could be a potential treatment option for ACLF.
Acute-on-chronic liver failure is associated with severe liver inflammation and poor short-term survival. Therefore, effective treatments are urgently needed. Herein, we have shown, using mouse models, that the combination of granulocyte-colony stimulating factor (which can promote liver regeneration) and TAK-242 (which inhibits a receptor that plays a key role in inflammation) could be effective for the treatment of acute-on-chronic liver failure.
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•We hypothesised that a TLR4 inhibitor, TAK-242, might mitigate the negative effects of G-CSF in ACLF.•G-CSF alone increases mortality and promotes inflammation in rodent models of ACLF.•The combination of TAK-242 and G-CSF inhibits inflammation, promotes hepatic regeneration and prevents mortality in models of ACLF.
Introduction
Acute kidney injury (AKI) is a common and serious complication increasing morbidity and mortality from all causes of hospital admission. We have previously shown that AKI decreases ...midazolam metabolism, a substrate of the cytochrome P450 3A (CYP3A) enzymes and our primary aim was to determine if this effect is dependent on the severity of AKI. We also present preliminary data on the functional impact of different genotypes of CYP3A.
Methods
Critically ill patients at risk of AKI and admitted to a general intensive care unit were categorised after initial resuscitation according to the RIFLE criteria for AKI. Midazolam (1mg) was administered and the serum concentration of midazolam measured at 4 h. Samples were taken for CYP3A genotyping.
Results
Seventy-three patients were assigned to categories R, I and F of the RIFLE criteria or C (controls). Midazolam concentrations (ng mL
−1
) increased significantly (
p
= 0.002) as the severity of AKI worsened control 3.1 (1.4–5.9), risk 4.7 (1.3–10.3), injury 3.9 (2.0–11.1) and failure 6.8 (2.2–113.6) and were predicted by the duration of AKI (
p
= 0.000) and γ-glutamyl transferase (p = 0.005) concentrations. Increasing BMI negatively predicted the midazolam concentration (
p
= 0.001). Preliminary data suggest this effect is diminished if the patient expresses functional CYP3A5.
Conclusion
Increasing severity and duration of AKI are associated with decreased midazolam elimination. We propose that this is caused by impaired CYP3A activity secondary to AKI. The exact mechanism remains to be elucidated. This may have important implications for our drug treatment of critically ill patients.
A statistical and quantitative perspective on the incipient slip localization behavior of the HfNbTaTiZr refractory high entropy alloy is presented, after monotonic tensile testing at room ...temperature. High-resolution digital image correlation (HR-DIC) data collected in the scanning electron microscope (SEM) is coupled with electron back-scattered diffraction (EBSD) over millimeter-scale fields of view containing over a hundred crystal orientations. Two populations of grains are identified with respect to their slip localization: a vast majority of the grains exhibit a high density of apparently straight slip bands of low intensity, while the remaining grains show few but very intense and wavy slip bands at the mesoscopic scale. The slip localization behavior is strongly correlated to the crystal orientation with respect to the loading direction. This behavior is discussed with regard to dislocation glide and cross-slip processes.
Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3′ untranslated region of the
DMPK gene on chromosome 19 (dystrophia myotonica type 1 DM1), or an untranslated CCTG ...tetranucleotide repeat expansion in intron 1 of the
ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 DM2). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a
trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions.
Abstract Aim Cardiovascular autonomic neuropathy (CAN) and pulsatile stress are considered to be independent cardiovascular risk factors. This study compared haemodynamic changes during an active ...orthostatic test in adult patients with type 1 diabetes (T1DM), using low versus high RR E/I ratios as a marker of CAN. Methods A total of 20 T1DM patients with low RR E/I ratios were compared with 20 T1DM patients with normal RR E/I ratios, matched for gender (1/1 ratio), age (mean: 46 years) and diabetes duration (22–26 years); 40 matched healthy subjects served as controls. All subjects were evaluated by continuous monitoring of arterial blood pressure (Finapres® ) and heart rate using a standardized posture test (1-min standing, 1-min squatting, 1-min standing), thus allowing calculation of baroreflex gain. Results Compared with controls, T1DM patients showed lower RR E/I ratios, reduced baroreflex gains, higher pulsatile stress (pulse pressure × heart rate), greater squatting-induced pulse pressure rises, orthostatic hypotension and reduced reflex tachycardia. Compared with T1DM patients with preserved RR E/I ratios, T1DM patients with low RR E/I ratios showed reduced post-standing reflex tachycardia and baroreflex gain, and delayed blood pressure recovery, but no markers of increased pulsatile stress. Interestingly, decreased baroreflex gain was significantly associated with both pulsatile stress and microalbuminuria. Conclusion The use of RR E/I ratios to separate T1DM patients allows the detection of other CAN markers during an orthostatic posture test, but with no significant differences in pulsatile stress or microalbuminuria. In this context, squatting-derived baroreflex gain appears to be more informative.
The axons of the dentate gyrus granule cells, the so-called mossy fibers, innervate their inhibitory interneuron and pyramidal neuron targets via both anatomically and functionally specialized ...synapses. Mossy fiber synapses onto inhibitory interneurons were comprised of either calcium-permeable (CP) or calcium-impermeable (CI) AMPA receptors, whereas only calcium-impermeable AMPA receptors existed at CA3 principal neuron synapses. In response to brief trains of high-frequency stimuli (20 Hz), pyramidal neuron synapses invariably demonstrated short-term facilitation, whereas interneuron EPSCs demonstrated either short-term facilitation or depression. Facilitation at all CI AMPA synapses was voltage independent, whereas EPSCs at CP AMPA synapses showed greater facilitation at -20 than at -80 mV, consistent with a role for the postsynaptic unblock of polyamines. At pyramidal cell synapses, mossy fiber EPSCs possessed marked frequency-dependent facilitation (commencing at stimulation frequencies >0.1 Hz), whereas EPSCs at either type of interneuron synapse showed only moderate frequency-dependent facilitation or underwent depression. Presynaptic metabotropic glutamate receptors (mGluRs) decreased transmission at all three synapse types in a frequency-dependent manner. However, after block of presynaptic mGluRs, transmission at interneuron synapses still did not match the dynamic range of EPSCs at pyramidal neuron synapses. High-frequency stimulation of mossy fibers induced long-term potentiation (LTP), long-term depression (LTD), or no change at pyramidal neuron synapses, interneuron CP AMPA synapses, and CI AMPA synapses, respectively. Induction of LTP or LTD altered the short-term plasticity of transmission onto both pyramidal cells and interneuron CP AMPA synapses by a mechanism consistent with changes in release probability. These data reveal differential mechanisms of transmission at three classes of mossy fiber synapse made onto distinct targets.
Background: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in ...parathyroid tumorigenesis. Methods: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. Results:HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. “Two-hits” (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. Conclusions: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
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