The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch predicts the response to ...thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients.
Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWIvol-DWIvol) and DWI expansion (T2(Day 90-vol)-DWI(Acute-vol)) were also assessed.
Mean age was 68+/-11, time to MRI 4.5+/-0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (P<0.001). Mismatch > or =20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (R=-0.51; P=0.009).
Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.
Elderly humans are more susceptible to bacterial infections because of declining immune status. We have investigated the effect of aging on neutrophil bactericidal responses, comparing neutrophil ...function in healthy, young (23-35 years) and elderly (>65 years) volunteers. Superoxide generation in response to fMLP was slightly increased in neutrophils from elderly donors, and serum from the elderly was able to opsonize E. coli efficiently. In contrast, phagocytic index was significantly lower in neutrophils from the elderly, compared with young donors (P<0.005). CD11a and CD11b expression was not affected by age, but CD16 was significantly reduced in neutrophils from elderly donors (P<0.0001). CD16 expression and phagocytic index were measured in the same neutrophils using FITC-labeled E. coli, PE-conjugated anti-CD16 antibody, and CD16 expression correlated with phagocytic index (r=0.83; P<0.05). In elderly patients with bacterial infection, CD16 expression remained low. We propose that reduced neutrophil CD16 expression and phagocytosis contribute to human immunesenescence.
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we ...characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.
Icequakes, microseismic earthquakes at glaciers, offer insights into the dynamics of ice sheets. For the first time in the Antarctic, we explore the use of fiber optic cables as Distributed Acoustic ...Sensors (DAS) as a new approach for monitoring basal icequakes. We present the use of DAS for studying icequakes as a case study for the application of DAS to microseismic datasets in other geological settings. Fiber was deployed on the ice surface at Rutford Ice Stream in two different configurations. We compare the performance of DAS with a conventional geophone network for: microseismic detection and location; resolving source and noise spectra; source mechanism inversion; and measuring anisotropic shear‐wave splitting parameters. Both DAS array geometries detect fewer events than the geophone array. However, DAS is superior to geophones for recording the microseism signal, suggesting the applicability of DAS for ambient noise interferometry. We also present the first full‐waveform source mechanism inversions using DAS anywhere, successfully showing the horizontal stick‐slip nature of the icequakes. In addition, we develop an approach to use a 2D DAS array geometry as an effective multi‐component sensor capable of accurately characterizing shear‐wave splitting due to the anisotropic ice fabric. Although our observations originate from a glacial environment, the methodology and implications of this work are relevant for employing DAS in other microseismic environments.
Plain Language Summary
Icequakes are like small earthquakes but are caused by the movement of ice rather than two plates sliding past one another. They allow us to investigate glacier processes. For the first time in the Antarctic, we use lasers fired down fiber optic cables to detect and analyze icequake signals. This technique is called Distributed Acoustic Sensing (DAS). These fiber optic cables were laid on the surface of Rutford Ice Stream, Antarctica, in two different shapes. We compare the performance of DAS to conventional geophones for icequake detection and location, investigating the frequency of the earthquake source, investigating the physics that generates the icequake, and the effect of the ice fabric on the travel of seismic waves through ice. For our experiment, DAS is not as good as conventional geophones for detecting icequakes. However, DAS is better than geophones for looking at the frequency of an icequake and the physics that causes an icequake. It also allows us to investigate ice fabric properties in a similar way to geophones. Although our results are for icequakes at a glacier, the methods we use and our findings are relevant for using DAS in many other environments where small earthquakes occur.
Key Points
Distributed acoustic sensing can outperform geophones for source spectra and full‐waveform source mechanism inversion
2D distributed acoustic sensing array geometries can be used as a multi‐component sensor capable of measuring shear‐wave splitting
Larger surface distributed acoustic sensing deployments and/or hybrid networks are required for accurate microseismic detection/location
Two new copper(II) complexes Cu(L
1
)
2
(NO
3
)NO
3
1
and Cu(L
2
)(H
2
O)
2
(NO
3
)
2
2
(L
1
= 2(2-pyridyl)benzimidazole and L
2
= 2-benzoylpyridine) have been prepared and characterized by ...elemental and spectral (UV–visible, FTIR and epr) techniques. Crystal structures of these complexes were determined using single crystal X-ray diffraction analysis. The low value of magnetic moments 1.75 BM for
1
and 1.73 BM for
2
and unusual X-band epr spectral pattern authenticate the antiferromagnetic behavior of complexes. The single crystal X-ray analysis reveals the development of supramolecular architectures through various non-covalent weak interactions such as CH
⋯
π
and lp
⋯
π
interactions. In order to see the stability of complexes, density functional theory (DFT) calculations were carried out. From the energy gap (ΔE) of frontier molecular orbitals (various molecular descriptors were also evaluated. In addition, superoxide dismutase SOD) activities of both complexes were also determined. The enhanced SOD activity of
1
is due to loosely bound nitrate ion.
Graphical Abstract
Two new copper(II) complexes Cu(L
1
)
2
(NO
3
)NO
3
and Cu(L
2
)(H
2
O)
2
(NO
3
)
2
(L
1
= 2(2-pyridyl)benzimidazole and L
2
= 2-benzoylpyridine) have been prepared and characterized by elemental, spectral, and single crystal diffraction techniques
In present study, with an hydrazido-based ligand and Cu, Ni metal(II) salts, three new mononuclear and one binuclear end-to-end thiocynate bridged complexes have been synthesized and characterized by ...various physico-chemical techniques.
Display omitted
•Three new mononuclear and one binuclear end-to-end thiocynato bridged complexes have been synthesized and characterized by various physico-chemical techniques.•New complexes were fully structurally characterized using single crystal X-ray diffraction.•The classical image of an O-H⋯π interaction is a T shape with interacting hydrogen atoms approximately directly over the centre of the aromatic ring πc.•The inhibitory effect of the complexes were tested on a cell population with IMR 32 (neuroblastoma), MCF 7 (breast cancer), HepG2 (hepatocellular carcinoma), L132 (lung cells) cell lines by MTT assay.•Antioxidant super oxide dismutase activity measurements show that the complexes behave as superoxide dismutase mimics.
With an hydrazido-based ligand, C14H13N2O and Cu, Ni metal(II) salts, three new mononuclear Ni(HL)(NO3)(H2O)NO3,C14H15N5NiO8, 1, Cu(HL)(H2O)22NO3, C14H17CuN5O4, 2, Ni(HL)22ClO4, C28H30Cl2N6NiO12, 3 and one binuclear end-to-end thiocynate bridged Cu2(μ-SCN)2(L)2, C30H24Cu2N8O2S2, 4 complexes have been synthesized and characterized by physico-chemical techniques. All of the complexes were structurally characterized using single crystal X-ray diffraction. Complexes 1 and 2 have a penta-coordinated environment around the metal(II) centre, whereas complex 3 has a distorted hexa-coordinated geometry. In complex 4 two symmetry related, adjacent copper(II) coordination moieties are joined end-to-end in an unprecedented manner forming a thiocynate bridged, yielding a dicopper entity. The presence of two “symmetric” thiocynate bridges with Cu-SCN and Cu-NCS distances of 2.832 Å and 1.925 Å, respectively, results in a Cu⋯Cu distance of 5.503 Å. Binuclear complex, 4 exhibits a weak antiferromagnetic interaction between adjacent copper(II) centres. These copper(II) mononuclear and binuclear complexes have also been studied by X-band EPR spectroscopy. The crystal packing of these new complexes is stabilized by H-bonding, weak intermolecular interactions, CH⋯π and π⋯π interactions. Electrochemical data (CV and DPV) for the complexes shows MII → MI reduction activity. Electronic spectroscopy and computational features are examined by quantum chemical studies. The inhibitory effect of the complexes were tested on a cell population with IMR 32 (neuroblastoma), MCF 7 (breast cancer), HepG2 (hepatocellular carcinoma), L132 (lung cells) cell lines by MTT assay. Complex 3 showed a prominent cytotoxicity against the all cell lines. Expression levels of the Bax (pro-apoptotic) and Bcl2 (anti-apoptotic) genes were also studied, wherein the genes of interest showed a moderate down regulation after treatment with complexes 1 and 3. Finally, antioxidant superoxide dismutase activity measurements show that the complexes behave as superoxide dismutase mimics.
Neutrophils are well known to rapidly migrate to foci of infection, where they exert microbicidal functions. We sought to determine whether neutrophils responding to in vivo infection with the ...protozoan pathogen Toxoplasma gondii were capable of IL-12 production as suggested by recent in vitro studies. Intraperitoneal infection induced a neutrophil influx by 4 h, accompanied by ex vivo IL-12 p40 and p70 release. Approximately 85% of the neutrophils displayed intracellular stores of IL-12, as determined by flow cytometry and confocal fluorescence microscopy. Neutrophils from IFN-gamma knockout mice also expressed IL-12, ruling out an IFN-gamma-priming requirement. Neither infected nor uninfected peritoneal macrophages displayed intracellular IL-12, but these cells were strongly IL-10(+). Infection per se was unnecessary for IL-12 production because peritoneal and peripheral blood neutrophils from uninfected animals contained IL-12(+) populations. Expression of the granulocyte maturation marker Gr-1 (Ly-6G) was correlated with IL-12 production. Mice depleted of their granulocytes by mAb administration at the time of infection had decreased serum levels of IL-12 p40. These results suggest a model in which neutrophils with prestored IL-12 are rapidly mobilized to an infection site where they are triggered by the parasite to release cytokine. Our findings place neutrophils prominently in the cascade of early events leading to IL-12-dependent immunity to T. gondii.
A tetranuclear complex with an open-cubane like structure was synthesized from 2-methoxy-6-(pyridin-2-yl-hydrazonomethyl)-phenol and characterized using micro-analytical and spectroscopic ...techniques, and single-crystal X-ray diffraction analysis.
A tetranuclear complex with an open-cubane-like core structure was synthesized from 2-methoxy-6-(pyridin-2-yl-hydrazonomethyl)phenol (
HL
), namely,
cyclo
-tetrakis(μ-2-methoxy-6-{2-(pyridin-2-yl)hydrazin-1-ylidenemethyl}phenolato)tetranickel(II) tetrakis(perchlorate) acetonitrile monosolvate dihydrate, Ni
4
(C
13
H
12
N
3
O
2
)
4
(ClO
4
)
4
·C
2
H
3
N·2H
2
O, and characterized using micro-analytical and spectroscopic techniques. The crystal-structure determination reveals the formation of a distorted Ni
4
O
4
cubane-like core architecture encapsulated by four hydrazone Schiff base (
HL
) molecules. A open-cube tetranuclear architecture is created in which nickel(II) ions of the NiN
2
O
3
unit are connected by μ
2
-O anions of the phenolate moiety of
HL
. In this complex, each Ni centre has a slightly distorted square-pyramidal coordination environment. The supramolecular architectures are stabilized
via
the presence of various intermolecular hydrogen bonds and (aryl–aryl, aryl–chelate and chelate–chelate) stacking interactions.
More than half of patients with TIA/minor stroke have ischemic lesions on early DWI, which represent irreversibly damaged tissue. The presence and volume of DWI lesions predict early deterioration in ...this population. We aimed to study the rate and implications of DWI reversal in patients with TIA/minor stroke.
Patients with TIA/minor stroke were prospectively enrolled and imaged within 24 hours of onset. Patients were followed for 3 months with repeat MR imaging either at day 30 or 90. Baseline DWI/PWI and follow-up FLAIR final infarct volumes were measured.
Of 418 patients included, 55.5% had DWI and 37% had PWI (time-to-peak of the impulse response ≥2 seconds' delay) lesions at baseline. The median time from symptom onset to baseline and follow-up imaging was 13.4 (interquartile range, 12.7) and 78.73 hours (interquartile range, 60.2), respectively. DWI reversal occurred in 5.7% of patients. The median DWI lesion volume was significantly smaller in those with reversal (0.26 mL, interquartile range = 0.58 mL) compared with those without (1.29 mL, interquartile range = 3.6 mL, P = .002); 72.7% of DWI reversal occurred in cortically based lesions. Concurrent tissue hypoperfusion (time-to-peak of the impulse response ≥2 seconds) was seen in 36.4% of those with DWI reversal versus 62.4% without (P = .08). DWI reversal occurred in 3.3% of patients with penumbral patterns (time-to-peak of the impulse response ≥6 seconds - DWI) > 0 and in 6.8% of those without penumbral patterns (P = .3). The severity of hypoperfusion, defined as greater prolongation of time-to-peak of the impulse response (≥2, ≥4, ≥6, ≥8 seconds), did not affect the likelihood of DWI reversal (linear trend, P = .147). No patient with DWI reversal had an mRS score of ≥2 at 90 days versus 18.2% of those without reversal (P = .02).
DWI reversal is uncommon in patients with TIA/minor stroke and is more likely to occur in those with smaller baseline lesions. DWI reversal should not have a significant effect on the accuracy of penumbra definition.
Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional ...cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data.
Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization.
Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes(-1) versus 14.3 ± 4.8 minutes(-1), P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes(-1), P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes(-1), P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes(-1), P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes(-1) versus 14.8 ± 3.4 minutes(-1), P = .38) or vary with mean arterial pressure (r = -0.08, -0.10, 0.05).
Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage.
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