Predictive model for chaplain taxonomy patterns identified through latent class analysis among infants in a pediatric inpatient setting.

This study investigated patterns of spiritual care provided to inpatient infants and their parents, based on a taxonomy developed to describe spiritual care activities provided by chaplains. Data from 821 visits with 433 patients were included in the analyses. We applied a data-driven statistical approach, Latent Class Analysis (LCA), to identify patterns of taxonomy items that may be used for spiritual care. Three distinct patterns were identified and a predictive model was built to link a series of predictors to these patterns. Hospital length of stay and whether a visit is an initial or follow-up within an admission were significantly associated with the identified taxonomy patterns. These findings are helpful in understanding predictors and the nature of spiritual care delivery in an inpatient setting with infants. To our knowledge, this is the first application of LCA in research related to healthcare chaplaincy.

fMRI of pain processing in the brain: a within-animal comparative study of BOLD vs. CBV and noxious electrical vs. noxious mechanical stimulation in rat.

This study aims to identify fMRI signatures of nociceptive processing in whole brain of anesthetized rats during noxious electrical stimulation (NES) and noxious mechanical stimulation (NMS) of paw. Activation patterns for NES were mapped with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) fMRI, respectively, to investigate the spatially-dependent hemodynamic responses during nociception processing. A systematic evaluation of fMRI responses to varying frequencies of electrical stimulus was carried out to optimize the NES protocol. Both BOLD and CBV fMRI showed widespread activations, but with different spatial characteristics. While BOLD and CBV showed well-localized activations in ipsilateral dorsal column nucleus, contralateral primary somatosensory cortex (S1), and bilateral caudate putamen (CPu), CBV fMRI showed additional bilateral activations in the regions of pons, midbrain and thalamus compared to BOLD fMRI. CBV fMRI that offers higher sensitivity compared to BOLD was then used to compare the nociception processing during NES and NMS in the same animal. The activations in most regions were similar. In the medulla, however, NES induced a robust activation in the ipsilateral dorsal column nucleus while NMS showed no activation. This study demonstrates that (1) the hemodynamic response to nociception is spatial-dependent; (2) the widespread activations during nociception in CBV fMRI are similar to what have been observed in (14)C-2-deoxyglucose (2DG) autoradiography and PET; (3) the bilateral activations in the brain originate from the divergence of neural responses at supraspinal level; and (4) the similarity of activation patterns suggests that nociceptive processing in rats is similar during NES and NMS.

fMRI investigation of the effect of local and systemic lidocaine on noxious electrical stimulation-induced activation in spinal cord.

Spinal cord fMRI offers an excellent opportunity to quantify nociception using neuronal activation induced by painful stimuli. Measurement of the magnitude of stimulation-induced activation, and its suppression with analgesics can provide objective measures of pain and efficacy of analgesics. This study investigates the feasibility of using spinal cord fMRI in anesthetized rats as a pain assay to test the analgesic effect of locally and systemically administered lidocaine. Blood volume (BV)-weighted fMRI signal acquired after intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles was used as an indirect readout of the neuronal activity. Transcutaneous noxious electrical stimulation was used as the pain model. BV-weighted fMRI signal could be robustly quantified on a run-by-run basis, opening the possibility of measuring pharmacodynamics (PD) of the analgesics with a temporal resolution of approximately 2 min. Local administration of lidocaine was shown to ablate all stimulation-induced fMRI signals by the total blockage of peripheral nerve transmission, while the analgesic effect of systemically administered lidocaine was robustly detected after intravenous infusion of approximately 3mg/kg, which is similar to clinical dosage for human. This study establishes spinal cord fMRI as a viable assay for analgesics. With respect to the mode of action of lidocaine, this study suggests that systemic lidocaine, which is clinically used for the treatment of neuropathic pain, and believed to only block the peripheral nerve transmission of abnormal neural activity (ectopic discharge) originating from the damaged peripheral nerves, also blocks the peripheral nerve transmission of normal neural activity induced by transcutaneous noxious electrical stimulation.

Pain fMRI in rat cervical spinal cord: an echo planar imaging evaluation of sensitivity of BOLD and blood volume-weighted fMRI.

Objective measure of pain is valuable in drug discovery research and development of analgesics. Spinal cord is an important relay of the pain pathway, and fMRI offers an excellent opportunity to quantify pain using activation in the spinal cord induced by painful stimuli. fMRI literature of cervical spinal cord with regard to the spatial extent, in both longitudinal and cross-sectional directions, of neuronal activation induced by noxious stimulation is ambiguous. This study investigates the feasibility of developing a robust pain assay using fMRI in the cervical spinal cord in alpha-chloralose anesthetized rats subjected to transcutaneous noxious electrical stimulation of the forepaw. Blood oxygenation level dependent (BOLD) and blood volume (BV)-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively. BOLD data were acquired by gradient-echo (GE) and spin-echo (SE) echo planar imaging (EPI), while BV-weighted fMRI data were acquired only by GE EPI. Cervical spinal cord activity was robustly detected by all three fMRI techniques. The sensitivity of the fMRI signal was highest in GE BV-weighted fMRI followed in order by GE BOLD, and SE BOLD, respectively. Spatially, the fMRI signal extended approximately 9 mm in the longitudinal direction, covering C(4)-C(8) segments, coinciding with the synapse location of afferent terminals from the stimulated site. In the cross-sectional direction, the signal change is localized predominantly to the ipsilateral dorsal region. This study demonstrates that cervical spinal cord fMRI can be performed reliably in anesthetized rats offering it as a potential tool for analgesic drug development.

BOLD and blood volume-weighted fMRI of rat lumbar spinal cord during non-noxious and noxious electrical hindpaw stimulation.

Spinal cord fMRI is a useful tool for studying spinal mechanisms of pain, hence for analgesic drug development. Its technical feasibility in both humans and rats has been demonstrated. This study investigates the reproducibility, robustness, and spatial accuracy of fMRI of lumbar spinal cord activation due to transcutaneous noxious and non-noxious electrical stimulation of the hindpaw in alpha-chloralose-anesthetized rats. Blood oxygenation level-dependent (BOLD) and blood volume-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively, using a gradient echo (GE) echo planar imaging (EPI) technique at 4.7 T. Neuronal activation in the spinal cord induced by noxious stimulation to the hindpaw (2 ms wide, 5 mA amplitude, known to activate C-fibers) can be robustly detected by both fMRI techniques with excellent reproducibility and peaked at the stimulus frequency of 40 Hz. However, both fMRI techniques were not sensitive to neuronal activation in spinal cord induced by non-noxious stimulation (0.3 ms, 1.5 mA, known only to activate A-fibers). Spatially, the fMRI signal extended approximately 5 mm in the longitudinal direction, covering L(3)-L(5) segments. In the cross-sectional direction, the highest signal change of blood volume-weighted fMRI was in the middle of the ipsilateral dorsal horn, which roughly corresponds to laminae V and VI, while the highest signal change of BOLD fMRI was in the ipsilateral dorsal surface. This study demonstrates that spinal cord fMRI can be performed in anesthetized rats reliably and reproducibly offering it as a potential tool for analgesic drug discovery.

Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability.

Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.

Differential effects of sodium nitroprusside and hydralazine in a rat model of topical FeCl3-induced carotid artery thrombosis.

INTRODUCTION: In the rat model of topical ferric chloride-induced carotid artery thrombosis, a transient blood flow velocity (VEL) increase is observed immediately following ferric chloride application. The immediacy of the response suggested vasoconstriction, as thrombotic narrowing of the vessel lumen was hypothesized to be too slow to account for the rapidity of the response. METHODS: To explore this phenomenon, the effects of two mechanistically distinct vasodilators, sodium nitroprusside (SNP) and hydralazine (HYD), on velocity increase, ex vivo platelet aggregation and thrombosis, were assessed in the rat ferric chloride-induced thrombosis model. RESULTS: Sodium nitroprusside (10, 30 and 50 microg/kg/min i.v.) and hydralazine (0.1, 0.3 and 1.0 mg/kg/min i.v.) reduced the mean arterial pressure with the higher dose regimens eliciting equivalent hypotensive effects. Both sodium nitroprusside and hydralazine blunted the initial velocity increase, but only sodium nitroprusside significantly reduced the incidence of thrombotic occlusion. No differences in ex vivo platelet aggregation responses to adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were observed between the sodium nitroprusside and hydralazine treatment groups. However, platelet aggregation response to thrombin was significantly reduced in the 50 microg/kg/min i.v. sodium nitroprusside compared to the 1.0 mg/kg/min i.v. hydralazine and vehicle groups. CONCLUSIONS: Inhibition of the initial velocity increase by two mechanistically distinct vasodilators, and the dissociation between this velocity change and antithrombotic efficacy, support the hypothesis that the early velocity increase results from a change in vascular tone rather than due to enhanced platelet activation and thrombus formation. Inhibition of thrombin-induced platelet activation may contribute to the antithrombotic actions of sodium nitroprusside in this preparation.

Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.