Pharmacokinetic and clinical considerations for monitoring asparaginase activity levels during pegaspargase therapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111166/1/pbc25426.pd

Bundle Theory of Improper Spin Transformations

{\it We first give a geometrical description of the action of the parity operator ($\hat{P}$) on non relativistic spin ${{1}\over{2}}$ Pauli spinors in terms of bundle theory. The relevant bundle, $SU(2)\odot \Z_2\to O(3)$, is a non trivial extension of the universal covering group $SU(2)\to SO(3)$. $\hat{P}$ is the non relativistic limit of the corresponding Dirac matrix operator ${\cal P}=i\gamma_0$ and obeys $\hat{P}^2=-1$. Then, from the direct product of O(3) by $\Z_2$, naturally induced by the structure of the galilean group, we identify, in its double cover, the time reversal operator ($\hat{T}$) acting on spinors, and its product with $\hat{P}$. Both, $\hat{P}$ and $\hat{T}$, generate the group $\Z_4 \times \Z_2$. As in the case of parity, $\hat{T}$ is the non relativistic limit of the corresponding Dirac matrix operator ${\cal T}=\gamma^3 \gamma^1$, and obeys $\hat{T}^2=-1$.}Comment: 8 pages, Plaintex; titled changed, minor text modifications, one reference complete

KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

Dorsal root ganglion (DRG) neurons process pain signaling through specialized nociceptors located in their peripheral endings. It has long been established low voltage-activated (LVA) CaV3.2 calcium channels control neuronal excitability during sensory perception in these neurons. Silencing CaV3.2 activity with antisense RNA or genetic ablation results in anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. CaV3.2 channels are regulated by many proteins (Weiss and Zamponi, 2017), including KLHL1, a neuronal actin-binding protein that stabilizes channel activity by recycling it back to the plasma membrane through the recycling endosome. We explored whether manipulation of KLHL1 levels and thereby function as a CaV3.2 modifier can modulate DRG excitability and mechanical pain transmission or sensitivity to pain. We first assessed the mechanical sensitivity threshold and DRG properties in the KLHL1 KO mouse model. KO DRG neurons exhibited smaller T-type current density compared to WT without significant changes in voltage dependence, as expected in the absence of its modulator. Western blot analysis confirmed CaV3.2 but not CaV3.1, CaV3.3, CaV2.1, or CaV2.2 protein levels were significantly decreased; and reduced neuron excitability and decreased pain sensitivity were also found in the KLHL1 KO model. Analogously, transient down-regulation of KLHL1 levels in WT mice with viral delivery of anti-KLHL1 shRNA also resulted in decreased pain sensitivity. These two experimental approaches confirm KLHL1 as a physiological modulator of excitability and pain sensitivity, providing a novel target to control peripheral pain.Fil: Martínez Hernández, Elizabeth. Loyola University Chicago; Estados UnidosFil: Zeglin, Alissa. Loyola University Chicago; Estados UnidosFil: Almazan, Erik. Loyola University Chicago; Estados UnidosFil: Perissinotti, Paula Patricia. Loyola University Chicago; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: He, Yungui. University of Minnesota; Estados UnidosFil: Koob, Michael. University of Minnesota; Estados UnidosFil: Martin, Jody L.. Loyola University Chicago; Estados UnidosFil: Piedras-Rentería, Erika S.. Loyola University Chicago; Estados Unido

Differential effects of sleep on brain structure and metabolism at the preclinical stages of AD

INTRODUCTION: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. METHODS: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. RESULTS: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. DISCUSSION: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep–wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD

Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer's continuum

PURPOSE: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. METHODS: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages). RESULTS: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. CONCLUSIONS: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes

Electron spin resonance kinetic studies of malonyl radical self-decay and oxidation reactions by cerium(IV) and bromate in acid aqueous media. The role of free radicals in the Belousov-Zhabotinskii oscillator

Kinetics of selected reactions involving malonyl radicals (M), generated by Ce(IV) oxidation of malonic acid in acid aqueous media, have been studied by steady-state electron spin resonance under stopped-flow conditions. Rate constants for second-order radical self-decay, k_2(M+M) = 3.2 x 10^9, oxidation by bromate, k_4(M+BrO_3^-) = 6.7 x 10^3, and an upper limit for its oxidation by Ce(IV), k_3(M+Ce(Iv)) ≤ 1.2 x 10^5 M^(-1) s^(+1), have been obtained at 298 K. Some of the consequences of the present results on the mechanism of the Belousov-Zhabotinskii oscillator are examined