Cognitive decline in thrombotic thrombocytopenic purpura survivors: The role of white matter health as assessed by MRI.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities.

Simultaneous measurements of myocardial glucose metabolism and extracellular volumes with hybrid PET/MRI using concurrent injections of Gd-DTPA and [18F]FDG.

BACKGROUND: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV. METHODS: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min-1·kg-1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection. RESULTS: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout. CONCLUSIONS: The suppression of myocardial uptake of [18F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV.

Tracking the progress of inflammation with PET/MRI in a canine model of myocardial infarction.

BACKGROUND: Following myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction. METHODS: Eight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18F-FDG using a hybrid PET/MRI scanner. RESULTS: There was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40. CONCLUSIONS: The significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct.

Same day comparison of PET/CT and PET/MR in patients with cardiac sarcoidosis.

BACKGROUND: Inflammatory cardiac disorders, in particular, sarcoidosis, play an important role in left ventricular dysfunction, conduction abnormalities, and arrhythmias. In this study, we compared the imaging characteristics and diagnostic information obtained when patients were imaged sequentially with PET/CT and then with hybrid PET/MRI on the same day following a single 18F-FDG injection. METHODS: Ten patients with known or suspected sarcoidosis underwent imaging in sequence of (a) 99mTc-MIBI, (b) 18F-FDG with PET/CT, and (c) 18F-FDG with 3T PET/MRI. Images were compared quantitatively by determination of SUVmax and SUV on a voxel by voxel basis, and qualitatively by two experienced observers. RESULTS: When both platforms were compared quantitatively, similar data for the evaluation of enhanced 18F-FDG uptake were obtained. Qualitatively, there were (1) several instances of normal perfusion with delayed enhancement and/or focal 18F-FDG uptake, (2) comparable enhanced 18F-FDG uptake on PET/CT vs. PET/MRI, and (3) diversity in disease patterns with delayed enhancement only, increased 18F-FDG uptake only, or both. CONCLUSION: In this limited patient study, PET/CT and PET/MR provided similar diagnostic data for 18F-FDG uptake, and the concurrent acquisition of MR images provided further insight into the disease process.

Hybrid PET/MR imaging in myocardial inflammation post-myocardial infarction.

Hybrid PET/MR imaging is an emerging imaging modality combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in the same system. Since the introduction of clinical PET/MRI in 2011, it has had some impact (e.g., imaging the components of inflammation in myocardial infarction), but its role could be much greater. Many opportunities remain unexplored and will be highlighted in this review. The inflammatory process post-myocardial infarction has many facets at a cellular level which may affect the outcome of the patient, specifically the effects on adverse left ventricular remodeling, and ultimately prognosis. The goal of inflammation imaging is to track the process non-invasively and quantitatively to determine the best therapeutic options for intervention and to monitor those therapies. While PET and MRI, acquired separately, can image aspects of inflammation, hybrid PET/MRI has the potential to advance imaging of myocardial inflammation. This review contains a description of hybrid PET/MRI, its application to inflammation imaging in myocardial infarction and the challenges, constraints, and opportunities in designing data collection protocols. Finally, this review explores opportunities in PET/MRI: improved registration, partial volume correction, machine learning, new approaches in the development of PET and MRI pulse sequences, and the use of novel injection strategies.

Rigid-body motion correction in hybrid PET/MRI using spherical navigator echoes.

Integrated positron emission tomography and magnetic resonance imaging (PET/MRI) is an imaging technology that provides complementary anatomical and functional information for medical diagnostics. Both PET and MRI are highly susceptible to motion artifacts due, in part, to long acquisition times. The simultaneous acquisition of the two modalities presents the opportunity to use MRI navigator techniques for motion correction of both PET and MRI data. For this task, we propose spherical navigator echoes (SNAVs)-3D k-space navigators that can accurately and rapidly measure rigid body motion in all six degrees of freedom. SNAVs were incorporated into turbo FLASH (tfl)-a product fast gradient echo sequence-to create the tfl-SNAV pulse sequence. Acquiring in vivo brain images from a healthy volunteer with both sequences first compared the tfl-SNAV and product tfl sequences. It was observed that incorporation of the SNAVs into the image sequence did not have any detrimental impact on the image quality. The SNAV motion correction technique was evaluated using an anthropomorphic brain phantom. Following a stationary reference image where the tfl-SNAV sequence was acquired along with simultaneous list-mode PET, three identical PET/MRI scans were performed where the phantom was moved several times throughout each acquisition. This motion-up to 11° and 14 mm-resulted in motion artifacts in both PET and MR images. Following SNAV motion correction of the MRI and PET list-mode data, artifact reduction was achieved for both the PET and MR images in all three motion trials. The corrected images have improved image quality and are quantitatively more similar to the ground truth reference images.

Building nursing and midwifery leadership capacity in the Pacific.

AIM: The Australian Award Fellowship Program aimed to strengthen nursing and midwifery leadership and capacity in developing countries in the Pacific. BACKGROUND: It is necessary to build an optimal global health workforce, and leadership and mentorship are central to this need. This is especially important in small island states such as the Pacific who have limited capacity and resources. INTRODUCTION: This health system strengthening program addressed quality improvement in education, through the mentorship of potential nursing and midwifery leaders in the South Pacific Region. METHODS: Program participants between 2013 and 2015 were interviewed. Data were audio-taped, transcribed and analysed thematically using an inductive process. RESULTS: Thirty-four nurses and midwives from 12 countries participated. There were four main themes arising from the data which were: having a country-wide objective, learning how to be a leader, negotiating barriers and having effective mentorship. DISCUSSION: Our study showed that participants deemed their mentorship from country leaders highly valuable in relation to completing their projects, networking and role modelling. Similar projects are described. LIMITATIONS: The limitation of this study was its small size. There is a need to continue to build the momentum of the program and Fellows in each country in order to build regional networks. CONCLUSIONS AND IMPLICATIONS FOR NURSING AND MIDWIFERY: The Program has provided beneficial leadership education and mentorship for nurses and midwives from Pacific countries. It has provided a platform to develop quality improvement projects in line with national priorities. IMPLICATIONS FOR HEALTH POLICY: Global aid programs and the recipients of the program would benefit from comparable health strengthening approaches to nursing and midwifery in similar developing countries.

MR-compatibility of a high-resolution small animal PET insert operating inside a 7 T MRI.

A full-ring PET insert consisting of 16 PET detector modules was designed and constructed to fit within the 114 mm diameter gradient bore of a Bruker 7 T MRI. The individual detector modules contain two silicon photomultiplier (SiPM) arrays, dual-layer offset LYSO crystal arrays, and high-definition multimedia interface (HDMI) cables for both signal and power transmission. Several different RF shielding configurations were assessed prior to construction of a fully assembled PET insert using a combination of carbon fibre and copper foil for RF shielding. MR-compatibility measurements included field mapping of the static magnetic field (B 0) and the time-varying excitation field (B 1) as well as acquisitions with multiple pulse sequences: spin echo (SE), rapid imaging with refocused echoes (RARE), fast low angle shot (FLASH) gradient echo, and echo planar imaging (EPI). B 0 field maps revealed a small degradation in the mean homogeneity (+0.1 ppm) when the PET insert was installed and operating. No significant change was observed in the B 1 field maps or the image homogeneity of various MR images, with a 9% decrease in the signal-to-noise ratio (SNR) observed only in EPI images acquired with the PET insert installed and operating. PET detector flood histograms, photopeak amplitudes, and energy resolutions were unchanged in individual PET detector modules when acquired during MRI operation. There was a small baseline shift on the PET detector signals due to the switching amplifiers used to power MRI gradient pulses. This baseline shift was observable when measured with an oscilloscope and varied as a function of the gradient duty cycle, but had no noticeable effect on the performance of the PET detector modules. Compact front-end electronics and effective RF shielding led to minimal cross-interference between the PET and MRI systems. Both PET detector and MRI performance was excellent, whether operating as a standalone system or a hybrid PET/MRI.

Evidence for the involvement of calbindin D28k in the presenilin 1 model of Alzheimer's disease.

Pathological hallmarks of Alzheimer's disease include memory deficits, accumulation of amyloid beta (Abeta) plaques, the appearance of neurofibrillary tangles, and dysregulation of calcium homeostasis, which has been linked to mutations in the presenilin gene that code for presenilin (PS) proteins. PSs are a family of multi-pass transmembrane proteins where normal presenilins (PS1 and PS2) are highly localized in the endoplasmic reticulum (ER). Several past studies have explored alterations in long-term potentiation (LTP), a proposed molecular correlate of memory, and in behavioral tests of spatial memory in a variety of PS1 models. These reports suggest that calcium plays a role in these alterations, but mechanistic explanations for changes in LTP and in behavioral tests of memory are still lacking. To test the hypothesis that calcium-related mechanisms, such as changes in calcium buffering, are associated with alterations in LTP and memory, we utilized in vitro experimental paradigms of LTP in hippocampal slices obtained from the PS1-M146V transgenic mouse model of Alzheimer's disease (AD). We also used the in vivo Morris water maze (MWM), a test for hippocampal dependent spatial memory. In addition, we used cellular assays to explore molecular mechanisms. We confirm that PS1 mutations (M146V) enhance LTP. We also find increases in some parameters of the MWM, and alterations in other parameters, such as path length indicating impairment in cognitive functioning in PS1-M146V mice. In addition, these findings are observed in association with increased calbindin D28K expression in the CA1 hippocampus of PS1-M146V mice.

[Preparation of a compatibility chart for intravenous drug therapy in neonatal and pediatric intensive care units]. / Erstellung einer Kompatibilitätstabelle für die intravenöse Pharmakotherapie auf neonatologischen und pädiatrischen Intensivstationen.

BACKGROUND: Modern neonatal and pediatric intensive care includes a sophisticated pharmacotherapy with numerous drugs, mainly administered intravenously. Often, despite the use of multi-lumen central venous lines, more peripheral venous accesses are required. To reduce the necessity of numerous venous lines on one hand and on the other hand to avoid complications from incompatibilities of the administered drugs, we compiled a compatibility chart, encompassing more substances than covered in previously available charts. METHODS: Information on compatibility of commonly prescribed drugs was collected by analysis of manufacturers' information, medical and pharmaceutical handbooks, and a literature research. RESULTS: Available data on compatibility of 78 drugs were displayed in a two-dimensional chart. Beside the pH of each drug, compatibility of drug combinations was encoded for simultaneous infusion. Special emphasis was on security of the therapy. CONCLUSION: The compatibility chart gives quick reference for Data on compatibility of intravenously administered drugs in neonatal and pediatric intensive care.

Transport kinetics of iron chelators and their chelates in Caco-2 cells.

PURPOSE: Caco-2 monolayers were used to contrast the bidirectional transport of iron chelators and their chelates and to estimate fundamental kinetics associated with their intestinal absorption. METHODS: Bidirectional transport was studied at 37 degrees C and pH 7.4 using 500-microM concentrations. Monolayer integrity was tested via transepithelial electrical resistance and sodium fluorescein permeability. Apical and basolateral analysis provided mass balance evidence. Apparent permeability coefficient (P(app)) served to rank and compare molecules and estimate in vivo bioavailability. Model-dependent rate constants defined cellular influx and efflux. RESULTS: 1) P(app) ranked in decreasing order for chelators from directional transport studies were CP363 > deferiprone> ICL670 > CP502 > deferoxamine (DFO). 2) Fe(CP502)(3), Fe(ICL670)(2), and FeDFO were not measurable in receiving chambers, whereas Fe(deferiprone)(3) and Fe(CP363)(3) were detected in both directions. 3) CP363 was transported significantly faster from the basolateral to the apical direction than the converse. 4) Mass balance of donor and receiver chambers gave approximately 100% recovery in all cases. 5) Kinetic analysis supports the view that the Caco-2 chelator efflux constants are generally greater than their influx constants. CONCLUSIONS: Caco-2 cells are useful in screening iron chelators and chelates and estimating bioavailabilities. Structure and distribution coefficients partially predict passive transport through Caco-2 monolayers.

A comparative clarithromycin bioavailability study: determination of clarithromycin and 14-(R)-hydroxyclarithromycin under fasting and fed conditions.

OBJECTIVE: To report the first comprehensive analysis of clarithromycin (CLA) and 14-(R)-hydroxyclarithromcin (14R) bioequivalence metrics under both fasting and fed conditions when using a validated analytical method. METHODS AND MATERIALS: In separate, single dose bioequivalence studies, fasting (n = 40) and fed (n = 18) non-smoking subjects entered a 2-treatment, 2-period, 2-sequence, crossover trial to assess the comparative bioavailability of a 500 mg generic clarithromycin tablet (IVAX Pharmaceuticals, NJ, USA) relative to the reference product (Biaxin Filmtab, Abbott Laboratories, IL, USA). The validated assay employed an HPLC coupled to a triple stage quadrupole mass spectrometer. RESULTS: The analytics permitted plasma samples to be measured for both analytes with high precision and a lower limit ofquantitation (LLOQ) of 11 ng/ml. In both fasting and fed studies, and for both analytes, the IVAX product met the common mean geometric ratio and 90% confidence limits in order to be declared bioequivalent with Biaxin Filmtab. Furthermore, the intra-subject variabilities for the comparative AUC metrics in both studies and for both analytes were < or = 21% and < or = 26% for Cmax. CONCLUSIONS: The fasting and fed results present definitive evidence that 500 mg IVAX clarithromycin and Biaxin Filmtab are bioequivalent under both fasting and fed conditions, whether based on CLA or 14R. Furthermore, at a 500 mg dose, clarithromycin is not a highly variable drug.

L-arginine transport in the human coronary and peripheral circulation.

BACKGROUND: Nitric oxide synthase (NOS) uses arginine for the production of nitric oxide (NO). High intracellular concentrations of arginine suggest that NOS activity should be independent of plasma arginine supply. However, under certain conditions, increased plasma arginine concentrations appear to be associated with increased NOS activity. The purpose of this study was to explore arginine transport within the human coronary and peripheral circulation METHODS AND RESULTS: Mass-labeled 15N2-arginine was infused to steady state before cardiac catheterization in 31 patients. After diagnostic angiography, a catheter was placed in the coronary sinus. The transcardiac concentration gradient (aorta-coronary sinus) of 15N2-arginine was used as a measure of arginine transport at baseline and during infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA). No gradient was detected at rest. During the infusion of acetylcholine, a significant gradient was detected (2.5+/-1.2 micromol/L, P=0.01) corresponding to a fractional extraction of 11.7+/-7.5%. This is consistent with in vitro studies that suggest that stimulation of NOS induces arginine transport. During the infusion of L-NMMA, the concentration of 15N2-arginine increased in the coronary sinus, producing a gradient of -3.9+/-1.3 micromol/L (P=0.0002), corresponding to a fractional production of 20.5+/-5.0%. This is consistent with in vitro studies that suggest that L-NMMA induces the efflux of arginine from the cell to the extracellular space via transporter-mediated transstimulation. CONCLUSIONS: The use of steady-state 15N2-arginine to examine transorgan L-arginine gradients represents a novel tool for the study of L-arginine transport and the mechanisms of endothelial and NOS dysfunction.

Effect of PSC 833, a potent inhibitor of P-glycoprotein, on the growth of astrocytoma cells in vitro.

Malignant astrocytomas have been found to express P-glycoprotein (Pgp, mdr1 gene product). It was hypothesized that in addition to conferring multidrug resistance, Pgp is intimately associated with the development of astrocytomas. Accordingly, we studied the effect of PSC 833 (PSC, Novartis), a potent inhibitor of Pgp, on the growth of Pgp-expressing astrocytoma cells. The results showed that in all the cell lines tested, PSC (10-60 microM) inhibited the growth as well as induced cell death. Cells exposed to PSC exhibited DNA ladder characteristic of apoptosis. PSC-induced cell death could be reversed by Z-VAD-fmk, a general caspase inhibitor, indicating that PSC-induced cell death was characteristic of caspase-mediated apoptosis. These results suggest a novel therapeutic strategy in the treatment of malignant astrocytomas by inhibitors of Pgp.

High-performance liquid chromatographic assays for a second-generation novel oral iron chelator (APCP363) and their application to pharmacokinetic studies in rats.

Sensitive and specific HPLC assays for APCP363 in biological matrices (rat plasma, urine and feces) were developed. The recovery of APCP363 ranged from 81.2 to 99.9% in plasma, from 82.1 to 92.8% in urine, and from 65 to 68% in feces. Standard deviations were below 10% for all analyses. The limits of quantitation were 0.1, 10 and 30 microg/ml in plasma, urine and feces, respectively. The HPLC assays, which are the first reports for APCP363 analysis in biological matrices, have been successfully applied to preliminary pharmacokinetic studies in rats. The stool assay is the first non-radiolabeled method for hydroxypyridinones in feces.

Human endothelin-1 clearance kinetics revealed by a radiotracer technique.

Levels of endothelin-1 (ET-1) are elevated in many disease states, although its total body kinetics of elimination are poorly understood. Therefore, it remains uncertain whether the presence of elevated levels of ET-1 in the setting of disease are secondary to changes in production or clearance or some combination thereof. Using a 125I-labeled ET-1 infusion technique, the volume of distribution and kinetics of clearance of endothelin were described in five normal volunteers. Heart rate, blood pressure, right atrial pressure, and arterial blood samples for the counting of 125I and the measurement of ET-1 were obtained at multiple time points before and up to 45 h after the start of the infusion. The radiotracer infusion had no effect on heart rate, blood pressure, right atrial pressure, or endogenous ET-1 levels. ET-1 clearance was best described by a three-compartment model, which revealed that ET-1 has a much longer terminal half-life and volume of distribution than was previously reported. This suggests extensive uptake of ET-1 in various organ systems and slow clearance. These new findings have important implications for the understanding of the pathophysiology of ET-1 in disease states as well as for the understanding and development of ET-1 receptor blockers and endothelin-converting enzyme inhibitors.

The synergy of health promotion practice/research/education.

Many nurses are concerned about the lack of connection among nursing practice, research and education. However, the assumption that nursing practice, research, and education represent separate domains or activities that need to be linked, may well contravene the relational synergy they share. This paper describes a project that sought to illustrate, and further explore, the synergistic, iterative relationship of health promoting practice/research/education. The project revealed how this synergy lives out within the daily practice of frontline practitioners and how the researched knowledge practitioners bring forth through their practice can transform care.

Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks.

PURPOSE: 9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function. Schedule dependency was noted, with the greatest activity seen in the setting of greater than 24 hours exposure to lactone (L) concentrations > or = 10 nmol/L. In this phase I study, 9-AC was given by a continuous intravenous infusion over 24 hours once weekly times four every 5 weeks. PATIENTS AND METHODS: Twenty patients, of whom 16 had fluorouracil-refractory colorectal cancer (CRC), entered the study. Dose levels were 0.7 mg/m2 (n = 4), 1.4 mg/m2 (n = 3), 1.9 mg/m2 (n = 6), and 1.65 mg/m2 (n = 7). Detailed pharmacokinetic (PK) measurements of 9-AC L and carboxylate (C) were performed on day 1 of cycles 1 and 2. RESULTS: At 1.9 mg/m2, dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.65 mg/m2, one of seven patients had grade 4 neutropenia. Nonhematologic toxicity was modest, with diarrhea > or = grade 3 in two patients and lethargy > or = grade 3 in eight. PK/pharmacodynamic (PD) analyses showed marked interpatient variability. Steady-state concentrations (Css) of 9-AC L > or = 10 nmol/L (3.6 microg/L) were seen in five of seven patients at 1.65 mg/m2 and five of six patients at 1.9 mg/m2. Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R2 = .47), but not platelets. CONCLUSION: The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infusion weekly for 4 of every 5 weeks is 1.65 mg/m2.

Does thiopentone delay recovery in children premedicated with midazolam?

This prospective, randomized trial of paediatric surgical outpatients, premedicated with oral midazolam, was designed to determine if an intravenous thiopentone induction of anaesthesia prolongs postoperative recovery compared to an inhalation induction with halothane. One hundred children, one to ten years of age, undergoing ENT surgical procedures of 30-60 min duration received midazolam 0.5 mg.kg-1 with atropine 0.03 mg.kg-1 and were randomized to either halothane (Group 1, n = 50) or a thiopentone induction (Group 2, n = 50) technique, followed by a standardized anaesthetic-protocol. Time to extubation was significantly greater in the thiopentone group (8.8 +/- 4 min vs 7.1 +/- 3 min, P < 0.05). Patients receiving thiopentone were also more sedated than the halothane group on arrival in the PARR (3.9 +/- 1.5, 3.3 +/- 1.7, respectively P < 0.05), but the differences disappeared after 30 min. Children premedicated with oral midazolam who receive an intravenous thiopentone induction have a slightly prolonged emergence from anesthesia compared to children induced with halothane.