Quantitative measurement of blood flow in paediatric brain tumours. A comparative study of dynamic susceptibility contrast and multi-timepoint arterial spin-labelled MRI

OBJECTIVE: Arterial spin-labelling (ASL) MRI uses intrinsic blood water to quantify the cerebral blood flow (CBF), removing the need for the injection of a gadolinium-based contrast agent used for conventional perfusion imaging such as dynamic susceptibility contrast (DSC). Owing to the non-invasive nature of the technique, ASL is an attractive option for use in paediatric patients. This work compared DSC and multi-timepoint ASL measures of CBF in paediatric brain tumours. METHODS: Patients (n = 23; 20 low-grade tumours and 3 high-grade tumours) had DSC and multi-timepoint ASL with and without vascular crushers (VC). VC removes the contribution from larger vessel blood flow. Mean perfusion metrics were extracted from control and T(1)-enhanced tumour regions of interest (ROIs): arterial arrival time (AAT) and CBF from the ASL images with and without VC, relative cerebral blood flow (rCBF), relative cerebral blood volume, delay time (DT) and mean transit time (MTT) from the DSC images. RESULTS: Significant correlations existed for: AAT and DT (r = 0.77, p = 0.0002) and CBF and rCBF (r = 0.56, p = 0.02) in control ROIs for ASL-noVC. No significant correlations existed between DSC and ASL measures in the tumour region. Significant differences between control and tumour ROI were found for MTT (p < 0.001) and rCBF (p < 0.005) measures. CONCLUSION: Significant correlations between ASL-noVC and DSC measures in the normal brain suggest that DSC is most sensitive to macrovascular blood flow. The absence of significant correlations within the tumour ROI suggests that ASL is sensitive to different physiological mechanisms compared with DSC measures. ADVANCES IN KNOWLEDGE: ASL provides information which is comparable with that of DSC in healthy tissues, but appears to reflect a different physiology in tumour tissues

Post-operative pediatric cerebellar mutism syndrome and its association with hypertrophic olivary degeneration

Background: The dentato-thalamo-cortical (DTC) pathway is recognized as the anatomical substrate for postoperative pediatric cerebellar mutism (POPCMS), a well-recognized complication affecting up to 31% of children undergoing posterior fossa brain tumour resection. The proximal structures of the DTC pathway also form a segment of the Guillain and Mollaret triangle, a neural network which when disrupted causes hypertrophic olivary degeneration (HOD) of the inferior olivary nucleus (ION). We hypothesize that there is an association between the occurrence of POPCMS and HOD and aim to evaluate this on MR imaging using qualitative and quantitative analysis of the ION in children with and without POPCMS. Methods: In this retrospective study we qualitatively analysed the follow up MR imaging in 48 children who underwent posterior fossa tumour resection for presence of HOD. Quantitative analysis of the ION was possible in 28 children and was performed using semi-automated segmentation followed by feature extraction and feature selection techniques and relevance of the features to POPCMS were evaluated. The diagnosis of POPCMS was made independently based on clinical and nursing assessment notes. Results: There was significant association between POPCMS and bilateral HOD (P=0.002) but not unilateral HOD. Quantitative analysis showed that hyperintensity in the left ION was the most relevant feature in children with POPCMS. Conclusions: Bilateral HOD can serve as a reliable radiological indicator in establishing the diagnosis of POPCMS particularly in equivocal cases. The strong association of signal change due to HOD in the left ION suggests that injury to the right proximal efferent cerebellar pathway plays an important role in the causation of POPCMS. Keywords: Cerebellar mutism syndrome (CMS); hypertrophic olivary degeneration; posterior fossa syndrome (PFS); postoperative pediatric cerebellar mutism syndrom

Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine

BACKGROUND: There has been some evidence to suggest that the addition of chloroquine (CQ) or quinine (QN) to 8-aminoquinoline (8-AQ) treatment regimens may increase the therapeutic efficacy of the 8-AQ and simultaneously mitigate against its haemolytic toxicity. However, both CQ and QN are considered effective, although perhaps moderate inhibitors of CYP2D6, an enzyme now regarded as necessary for primaquine (PQ) pharmacologic activity. An understanding of the influence of CQ and QN on the metabolism of PQ may shed light on the potential mechanisms of the beneficial interaction. METHODS: Differential metabolism of PQ enantiomers by recombinant human CYP2D6, monoamine oxidase A (MAO), and cryopreserved human hepatocytes in the presence/absence of CQ and QN. RESULTS: Both CQ and QN significantly inhibited the activity of CYP2D6. PQ depletion by MAO and human hepatocytes was not affected significantly by the presence of CQ and QN. CYP2D6-mediated hydroxylation was largely suppressed by both CQ and QN. The formation of the primary deaminated metabolites, including carboxyprimaquine (CPQ) and cyclized side chain derivative from the aldehyde (m/z 241), was not sensitive to the presence of CQ and QN. However, the appearance of the glucuronides of CPQ and PQ alcohol were significantly suppressed. CQ and QN also inhibited the appearance of the m/z 257 metabolite with a similar pattern, suggesting that it may be derived from the CPQ conjugate. The apparent quinone-imine of CPQ (m/z 289) was only partially suppressed by both QN and CQ, but with a differential pattern of inhibition for the two drugs. The m/z 274 (quinone-imine of a ring-hydroxylated PQ metabolite) and m/z 422 (an apparent glucose conjugate of PQ) metabolites in hepatocytes were strongly suppressed by both QN and CQ, perhaps a reflection of the 2D6 inhibition by these drugs. The formation of the carbamoyl glucuronide of PQ (m/z 480) was not affected by CQ/QN. CONCLUSION: The metabolite-specific interactions in the current studies seem at variance with earlier reports of the dependence of PQ on CYP2D6 metabolism, and enhanced PQ anti-malarial activity/reduced toxicity in the presence of CQ/QN. These results suggest a complex picture in which CQ/QN may shift metabolite pathway balances towards a profile that retains efficacy, while reducing the formation or availability of toxic metabolites to erythrocytes. Alternatively, these drugs may alter transport or distribution of PQ metabolites in a fashion that reduces toxicity while maintaining efficacy against the parasite

Formation primaquine-5, 6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics Short precorneal residence time and poor transocular membrane permeability are the major challenges associated with topical ocular drug delivery. In the present research, the efficiency of the electrolyte-triggered sol-to-gel-forming system of natamycin (NT) transfersomes was investigated for enhanced and prolonged ophthalmic delivery. Transfersomes were optimized by varying the molar ratios of phospholipid, sorbitan monostearate (Span) and tocopheryl polyethylene glycol succinate (TPGS). NT transfersome formulations (FNs) prepared with a 1:1 molar ratio of phospholipid-to-Span and low levels of TPGS showed optimal morphometric properties, and were thus selected to fabricate the in situ gelling system. Gellan gum-based (0.3% w/v) FN-loaded formulations (FNGs) immediately formed an in situ gel in the simulated tear fluid, with considerable viscoelastic characteristics. In vitro cytotoxicity in corneal epithelial cells and corneal histology studies demonstrated the ocular safety and cytocom-patibility of these optimized formulations. Transcorneal permeability of NT from these formulations was significantly higher than in the control suspension. Moreover, the ocular disposition studies of NT, from the FNs and FNGs, in New Zealand male albino rabbits demonstrated the superiority of the electrolyte-sensitive FNGs in terms of NT delivery to the ocular tissues

PHYTOCHEMICALS OF CHRISTIA VESPERTILIONIS LEAF EXTRACT: ANTIOXIDANT, ANTIDIABETIC AND TOXICITY CAPABILITIES

Phytochemicals of Christia vespertilionis plant is known for medicinal properties and used to treat various health problems. The present study revealed medicinal properties of the leaf extract of Christia vespertilionis plant as its total phenolic content derived is screened for their antioxidant, antidiabetic and toxicity properties by Folin-Ciocalteu method, DPPH assay with butylated hydroxytoluene standard, α-amylase inhibition assay with metformin standard, brine shrimp lethality bioassay respectively

Magnetic properties of strained multiferroic CoCr2O4\mathrm{CoC}{\mathrm{r}}_{2}{\mathrm{O}}_{4}: A soft x-ray study

Using resonant soft x-ray techniques we follow the magnetic behavior of a strained epitaxial film of CoCr2O4, a type-II multiferroic. The film is [110] oriented, such that both the ferroelectric and ferromagnetic moments can coexist in-plane. X-ray magnetic circular dichroism (XMCD) is used in scattering and in transmission modes to probe the magnetization of Co and Cr separately. The transmission measurements utilized x-ray excited optical luminescence from the substrate. Resonant soft x-ray diffraction (RXD) was used to study the magnetic order of the low temperature phase. The XMCD signals of Co and Cr appear at the same ordering temperature TC≈90K, and are always opposite in sign. The coercive field of the Co and of Cr moments is the same, and is approximately two orders of magnitude higher than in bulk. Through sum rules analysis an enlarged Co2+ orbital moment (mL) is found, which can explain this hardening. The RXD signal of the (q q 0) reflection appears below TS, the same ordering temperature as the conical magnetic structure in bulk, indicating that this phase remains multiferroic under strain. To describe the azimuthal dependence of this reflection, a slight modification is required to the spin model proposed by the conventional Lyons-Kaplan-Dwight-Menyuk theory for magnetic spinels

Enantioselective metabolism of primaquine by human CYP2D6

BACKGROUND: Primaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers. METHODS: Stable isotope (13)C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites. RESULTS: The rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 μM in 120 min) compared to (−)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated V(max) (μmol/min/mg) were 0.75, 0.98 and 0.42, with K(m) (μM) of 24.2, 33.1 and 21.6 for (±)-primaquine, (+)-primaquine and (−)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH-PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+)-primaquine in a ratio of 4:1 compared to (−)-primaquine. The racemic (±)-primaquine showed a pattern similar to the (−)-primaquine; 2-OH-PQ accounted for about 15–17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (−)-primaquine (5:1), accounting for 22% of the total (−)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (−)-primaquine) was identified and accounted for 18–20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers. CONCLUSION: The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers

Magnetic properties of strained multiferroic CoCr2O4: a soft X-ray study

Using resonant soft X-ray techniques we follow the magnetic behavior of a strained epitaxial film of CoCr2O4, a type-II multiferroic. The film is [110]-oriented, such that both the ferroelectric and ferromagnetic moments can coexist in plane. X-ray magnetic circular dichroism (XMCD) is used in scattering and in transmission modes to probe the magnetization of Co and Cr separately. The transmission measurements utilized X-ray excited optical luminescence from the substrate. Resonant soft X-ray diffraction (RSXD) was used to study the magnetic order of the low temperature phase. The XMCD signals of Co and Cr appear at the same ordering temperature Tc~90K, and are always opposite in sign. The coercive field of the Co and of Cr moments is the same, and is approximately two orders of magnitude higher than in bulk. Through sum rules analysis an enlarged Co2+ orbital moment (m_L) is found, which can explain this hardening. The RSXD signal of the (q q 0) reflection appears below Ts, the same ordering temperature as the conical magnetic structure in bulk, indicating that this phase remains multiferroic under strain. To describe the azimuthal dependence of this reflection, a slight modification is required to the spin model proposed by the conventional Lyons-Kaplan-Dwight-Menyuk theory for magnetic spinels. Lastly, a slight increase in reflected intensity is observed below Ts=27K when measuring at the Cr edge (but not at the Co edge).Comment: 28 pages, 15 figure