A Futile Cycle?: Tissue Homeostatic Trans-Membrane Water Co-Transport: Kinetics, Thermodynamics, Metabolic Consequences.

The phenomenon of active trans-membrane water cycling (AWC) has emerged in little over a decade. Here, we consider HO transport across cell membranes from the origins of its study. Historically, trans-membrane water transport processes were classified into: A) compensating bidirectional fluxes (""), and B) unidirectional flux ("") categories.

A Case Report of Delusions in a Patient Receiving Cabergoline Therapy for Prolactinoma: Pathophysiology and Proposed Treatment With Aripiprazole.

Cabergoline is a dopamine 2 receptor agonist used as first-line treatment of pituitary prolactinomas. Here, we describe the case of a 32-year-old woman with a pituitary prolactinoma who was treated with cabergoline for 1 year, during which time she developed delusions. We also discuss the use of aripiprazole to mitigate the psychotic symptoms, while maintaining the efficacy of cabergoline treatment.

Effect of sterile vs clean gloves for cervical checks in labor on maternal infection at term: a randomized trial.

Background: Intrapartum infection usually warrants immediate delivery and impacts 5-12% of term pregnancies, with the most commonly identified pathogenic organism being of the Ureaplasma genus. When performing cervical examinations during labor, providers in the United States commonly use sterile gloves, although there are no data currently to support that this practice reduces rates of infection. Furthermore, in nearly all other settings of Gynecologic care, aside from surgery in an operating room, nonsterile gloves are used.

Metabolic activity diffusion imaging (MADI): II. Noninvasive, high-resolution human brain mapping of sodium pump flux and cell metrics.

We introduce a new H O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (k ), mean cell volume (V), and cell number density (ρ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), k reflects the cytolemmal Na , K ATPase (NKA) homeostatic cellular metabolic rate ( MR ).

Metabolic activity diffusion imaging (MADI): I. Metabolic, cytometric modeling and simulations.

Evidence mounts that the steady-state cellular water efflux (unidirectional) first-order rate constant (k [s ]) magnitude reflects the ongoing, cellular metabolic rate of the cytolemmal Na , K -ATPase (NKA), MR (pmol [ATP consumed by NKA]/s/cell), perhaps biology's most vital enzyme. Optimal H O MR k determinations require paramagnetic contrast agents (CAs) in model systems. However, results suggest that the homeostatic metabolic k biomarker magnitude in vivo is often too large to be reached with allowable or possible CA living tissue distributions.

DCE-MRI of Brain Fluid Barriers: Water Cycling at the Human Choroid Plexus.

Metabolic deficits at brain-fluid barriers are an increasingly recognized feature of cognitive decline in older adults. At the blood-cerebrospinal fluid barrier, water is transported across the choroid plexus (CP) epithelium against large osmotic gradients via processes tightly coupled to activity of the sodium/potassium pump. Here, we quantify CP homeostatic water exchange using dynamic contrast-enhanced MRI and investigate the association of the water efflux rate constant (k) with cognitive dysfunction in older individuals.

Gray matter blood-brain barrier water exchange dynamics are reduced in progressive multiple sclerosis.

Background And Purpose: To compare transcapillary wall water exchange, a putative marker of cerebral metabolic health, in brain T white matter (WM) lesions and normal appearing white and gray matter (NAWM and NAGM, respectively) in individuals with progressive multiple sclerosis (PMS) and healthy controls (HC).

Methods: Dynamic-contrast-enhanced 7T MRI data were obtained from 19 HC and 23 PMS participants. High-resolution pharmacokinetic parametric maps representing tissue microvascular and microstructural properties were created by shutter-speed (SS) paradigm modeling to obtain estimates of blood volume fraction (v ), water molecule capillary efflux rate constant (k ), and the water capillary wall permeability surface area product (P S ≡ v *k ).

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging.

Background And Purpose: Transvascular water exchange plays a key role in the functional integrity of the blood-brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age-related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange.

Shutter-Speed DCE-MRI Analyses of Human Glioblastoma Multiforme (GBM) Data.

Background: The shutter-speed model dynamic contrast-enhanced (SSM-DCE) MRI pharmacokinetic analysis adds a metabolic dimension to DCE-MRI. This is of particular interest in cancers, since abnormal metabolic activity might happen.

Purpose: To develop a DCE-MRI SSM analysis framework for glioblastoma multiforme (GBM) cases considering the heterogeneous tissue found in GBM.

NMR shutter-speed elucidates apparent population inversion of H O signals due to active transmembrane water cycling.

Purpose: The desire to quantitatively discriminate the extra- and intracellular tissue H O MR signals has gone hand-in-hand with the continual, historic increase in MRI instrument magnetic field strength [B ]. However, recent studies have indicated extremely valuable, novel metabolic information can be readily accessible at ultra-low B . The two signals can be distinguished, and the homeostatic activity of the cell membrane sodium/potassium pump (Na ,K ,ATPase) detected.

Brain active transmembrane water cycling measured by MR is associated with neuronal activity.

Purpose: fMRI is widely used to study brain activity. Unfortunately, conventional fMRI methods assess neuronal activity only indirectly, through hemodynamic coupling. Here, we show that active, steady-state transmembrane water cycling (AWC) could serve as a basis for a potential fMRI mechanism for direct neuronal activity detection.

Using HO MR to measure and map sodium pump activity in vivo.

The cell plasma membrane Na,K-ATPase [NKA] is one of biology's most [if not the most] significant enzymes. By actively transporting Na out [and K in], it maintains the vital trans-membrane ion concentration gradients and the membrane potential. The forward NKA reaction is shown in the Graphical Abstract [which is elaborated in the text].

Fast, Na /K pump driven, steady-state transcytolemmal water exchange in neuronal tissue: A study of rat brain cortical cultures.

Purpose: Water homeostasis and transport play important roles in brain function (e.g., ion homeostasis, neuronal excitability, cell volume regulation, etc.

Human whole blood H O transverse relaxation with gadolinium-based contrast reagents: Magnetic susceptibility and transmembrane water exchange.

Purpose: To characterize transverse relaxation in oxygenated whole blood with extracellular gadolinium-based contrast reagents by experiment and simulation.

Methods: Experimental measurements of transverse H O relaxation from oxygenated whole human blood and plasma were made at 1.5 and 3.

Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling.

Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics.

Toward 20 T magnetic resonance for human brain studies: opportunities for discovery and neuroscience rationale.

An initiative to design and build magnetic resonance imaging (MRI) and spectroscopy (MRS) instruments at 14 T and beyond to 20 T has been underway since 2012. This initiative has been supported by 22 interested participants from the USA and Europe, of which 15 are authors of this review. Advances in high temperature superconductor materials, advances in cryocooling engineering, prospects for non-persistent mode stable magnets, and experiences gained from large-bore, high-field magnet engineering for the nuclear fusion endeavors support the feasibility of a human brain MRI and MRS system with 1 ppm homogeneity over at least a 16-cm diameter volume and a bore size of 68 cm.

Early Prediction and Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy Using Quantitative DCE-MRI.

The purpose is to compare quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) metrics with imaging tumor size for early prediction of breast cancer response to neoadjuvant chemotherapy (NACT) and evaluation of residual cancer burden (RCB). Twenty-eight patients with 29 primary breast tumors underwent DCE-MRI exams before, after one cycle of, at midpoint of, and after NACT. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines.

Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma.

Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents.

Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging.

Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ(b)) and blood volume fraction (v(b); capillary density-volume product (ρ(†)V)) in a high-resolution (1)H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k(po) (τ(b)(-1)), averages 3.2 and 2.

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter-speed pharmacokinetic analysis of dynamic-contrast-enhanced (DCE)-MRI data allows evaluation of equilibrium inter-compartmental water interchange kinetics. The process measured here - transcytolemmal water exchange - is characterized by the mean intracellular water molecule lifetime (τi). The τi biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE-MRI.

Human whole-blood (1)H2O longitudinal relaxation with normal and high-relaxivity contrast reagents: influence of trans-cell-membrane water exchange.

Purpose: Accurate characterization of contrast reagent (CR) longitudinal relaxivity in whole blood is required to predict arterial signal intensity in contrast-enhanced MR angiography (CE-MRA). This study measured the longitudinal relaxation rate constants (R1 ) over a concentration range for non-protein-binding and protein-binding CRs in ex vivo whole blood and plasma at 1.5 and 3.