Quantifying the CDK inhibitor VMY-1-103\u27s activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI.

The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma

Parasympathetic Activity and Blood Catecholamine Responses Following a Single Partial-Body Cryostimulation and a Whole-Body Cryostimulation

The aim of this study was to compare the effects of a single whole-body cryostimulation (WBC) and a partial-body cryostimulation (PBC) (i.e., not exposing the head to cold) on indices of parasympathetic activity and blood catecholamines. Two groups of 15 participants were assigned either to a 3-min WBC or PBC session, while 10 participants constituted a control group (CON) not receiving any cryostimulation. Changes in thermal, physiological and subjective variables were recorded before and during the 20-min after each cryostimulation. According to a qualitative statistical analysis, an almost certain decrease in skin temperature was reported for all body regions immediately after the WBC (mean decrease±90% CL, -13.7±0.7°C) and PBC (-8.3±0.3°C), which persisted up to 20-min after the session. The tympanic temperature almost certainly decreased only after the WBC session (-0.32±0.04°C). Systolic and diastolic blood pressures were very likely increased after the WBC session, whereas these changes were trivial in the other groups. In addition, heart rate almost certainly decreased after PBC (-10.9%) and WBC (-15.2%) sessions, in a likely greater proportion for WBC compared to PBC. Resting vagal-related heart rate variability indices (the root-mean square difference of successive normal R-R intervals, RMSSD, and high frequency band, HF) were very likely increased after PBC (RMSSD: +54.4%, HF: +138%) and WBC (RMSSD: +85.2%, HF: +632%) sessions without any marked difference between groups. Plasma norepinephrine concentrations were likely to very likely increased after PBC (+57.4%) and WBC (+76.2%), respectively. Finally, cold and comfort sensations were almost certainly altered after WBC and PBC, sensation of discomfort being likely more pronounced after WBC than PBC. Both acute cryostimulation techniques effectively stimulated the autonomic nervous system (ANS), with a predominance of parasympathetic tone activation. The results of this study also suggest that a whole-body cold exposure induced a larger stimulation of the ANS compared to partial-body cold exposure

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation

Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor

Structural Brain Defects.

Up to 14% of patients with congenital metabolic disease may show structural brain abnormalities from perturbation of cell proliferation, migration, and/or organization. Most inborn errors of metabolism have a postnatal onset. Abnormalities from genetic disease processes have a prenatal onset. Energy impairment, substrate insufficiency, cell membrane receptor and cell signaling abnormalities, and toxic byproduct accumulation are associations between genetic disorders and structural brain anomalies. Collective imaging patterns of brain abnormalities can provide clues to the underlying etiology. We review selected metabolic diseases associated with brain malformations and highlight characteristic clinical and imaging manifestations that help narrow the differential diagnosis

Reduced Subarachnoid Fluid Diffusion in Enlarged Subarachnoid Spaces of Infancy.

Background and purposeEnlargement of the subarachnoid spaces in infancy (ESSI) is a common cause of macrocephaly without proven explanation. We have observed subarachnoid diffusion to be decreased in these patients. We aim to quantify the diffusivity of ventricular and subarachnoid cerebrospinal fluid in ESSI patients, to determine if diffusion characteristics deviate from normocephalic infants, and to propose a unique mechanism for ESSI.Materials and methods227 consecutive brain magnetic resonance exams from different macrocephalic children were retrospectively reviewed after institutional review board waiver. Patients with noncommunicating hydrocephalus, substantial ventriculomegaly, atrophy, structural bone and/parenchymal abnormalities, abnormal brain signal, hemorrhages, meningitis, and normal imaging were excluded. A total of 53 exams from macrocephalic patients and 21 normocephalic subjects were analyzed. Mean quantitative apparent diffusion coefficient (ADC) values were obtained from the ventricular frontal horn and frontal subarachnoid spaces. The subarachnoid:ventricular ADC ratios were compared using a Mann–Whitney U-test.ResultsThe mean age was 13 +/−8 months (macrocephalic cohort) and 13 +/− 6 months (normocephalic cohort). The subarachnoid fluid mean ADC was 2.50+/−0.26 × 10−3 mm2/s in the macrocephalic group and 2.84+/−0.29 × 10−3 mm2/s in the normocephalic group. The ventricular fluid mean ADC was 2.97+/−0.37 × 10−3mm2/s and 2.74 +/−0.32 × 10−6 mm2/s, respectively. The mean quantitative ADC ratios in the macrocephalic group were 0.85, significantly smaller than the normocephalic group (1) ( z = −6.3; p = 0).ConclusionSubarachnoid space fluid diffusivity is reduced in patients with enlarged subarachnoid spaces of infancy. We propose insufficient frontotemporal capillary protein resorption to be the initiating factor in ESSI, leading to unbalanced osmotic/hydrostatic pressures, and secondary congestion.</jats:sec

Urea cycle defects and hyperammonemia: Effects on functional imaging

The urea-cycle disorders (UCDs) are a group of congenital enzyme and carrier deficiencies predisposing to hyperammonemia (HA). HA causes changes in the central nervous system (CNS) including alterations of neurotransmitter function, cell volume, and energy deprivation ultimately leading to cerebral edema. Neuropathological findings of UCDs primarily reflect changes in astrocyte morphology. Neurological features accompanying acute HA include changes in behavior and consciousness in the short term, and potential for impairments in memory and executive function as long-term effects. Plasma measures of ammonia and glutamine, although useful for clinical monitoring, prove poor markers of CNS function. Multimodal neuroimaging has potential to investigate impact on cognitive function by interrogating neural networks, connectivity and biochemistry. As neuroimaging methods become increasingly sophisticated, they will play a critical role in clinical monitoring and treatment of metabolic disease. We describe our findings in UCDs; with focus on Ornithine Transcarbamylase deficiency (OTCD) the only X linked UCD