Intraoperative esophageal washout reduces free intraluminal tumor cells during resection of carcinomas of the esophagus and cardia.

OBJECTIVE: Intraluminally shed viable tumor cells might contribute to anastomotic recurrence in cancer of the esophagus and the cardia. The study aimed to establish a method of esophageal washout and, hence, to reduce intraluminal cancer cells before esophageal anastomosis. METHODS: Forty-eight consecutive patients with esophago-gastric resection for histologically proven cancer of the esophagus or the cardia were included in a prospective, interventional study. Before transection, the esophagus was clamped proximally to the tumor and rinsed with 1:10 diluted povidone-iodine-solution (10 × 30 ml) applied by a transorally inserted 24F-Foley catheter. The first, fifth and tenth portion of the lavage fluid were sent to cytological examination. RESULTS: Intraoperative frozen sections confirmed clear proximal resection margins of the esophagus. The cytological examination of the fluid recovered from the esophageal washout revealed malignant cells in 13/48 patients (27%). The presence of malignant cells was significantly less likely in patients with neoadjuvant treatment than in patients without neoadjuvant treatment: 2/23 (9%) vs. 11/25 (44%) (p = 0.009). Repetitive washout reduced the probability of detectable malignant cells from 13 to 8 (62%) patients after 5, and further to 4 patients (30%) after 10 washout maneuvers. CONCLUSIONS: Free malignant cells may be present in the esophageal lumen following intraoperative manipulation of cancers of the esophagus or cardia. Transoral washout of the esophagus is novel, feasible and enables reduction or even elimination of these tumor cells. The reliability of this procedure raises with increasing washout volume. Esophageal washout might be especially worthwhile in patients who do not receive neoadjuvant therapy.

Correction to: Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

In the original publication of this article [1], Fig. 10 contained two panels "C" as panel "F" was accidentally omitted. The incorrect (Fig. 1) and correct (Fig. 2) versions are published in this correction article.

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.

Exploring experimental autoimmune optic neuritis using multimodal imaging.

BACKGROUND: Neuro-axonal injury is a key contributor to non-reversible long-term disability in multiple sclerosis (MS). However, the underlying mechanisms are not yet fully understood. Visual impairment is common among MS patients, in which episodes of optic neuritis (ON) are often followed by structural retinal damage and sustained functional impairment. Alterations in the optic nerve and retina have also been described in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Thus, investigating structural anterior visual pathway damage may constitute a unique model for assessing mechanisms and temporal sequence of neurodegeneration in MS. We used a multimodal imaging approach utilizing optical coherence tomography (OCT) and diffusion tensor imaging (DTI) to explore the mechanisms and temporal dynamics of visual pathway damage in the animal model of MS. METHODS: 7 EAE-MOG35-55 and 5 healthy female C57BL/6J mice were used in this study. Ganglion cell complex (GCC) thickness was derived from an OCT volume scan centred over the optic nerve head, while the structure of the optic nerve and tracts was assessed from DTI and co-registered T2-weighted sequences performed on a 7T MRI scanner. Data was acquired at baseline, disease onset, peak of disease and recovery. Linear mixed effect models were used to account for intra-subject, inter-eye dependencies, group and time point. Correlation analyses assessed the relationship between GCC thickness and DTI parameters. Immunofluorescence staining of retina and optic nerve sections was used to assess distribution of marker proteins for microglia and neurodegeneration (nerve filaments). RESULTS: In EAE mice, a significant increase in GCC thickness was observed at disease onset (p < 0.001) followed by a decrease at recovery (p < 0.001) compared to controls. The EAE group had significant GCC thinning at recovery compared to all other time points (p < 0.001 for each). Signal increase on T2-weighted images around the optic nerves indicative of inflammation was seen in most of the EAE mice but in none of the controls. A significant decrease in axial diffusivity (AD) and increase in radial diffusivity (RD) values in EAE optic nerves (AD: p = 0.02, RD: p = 0.01) and tract (AD: p = 0.02, RD: p = 0.006) was observed compared to controls. GCC at recovery was positively correlated with AD (optic nerve: rho = 0.74, p = 0.04, optic tract: rho = 0.74, p = 0.04) and negatively correlated with RD (optic nerve: rho = -0.80, p = 0.02, optic tract: rho = -0.75, p = 0.04). Immunofluorescence analysis indicated the presence of activated microglia in the retina and optic nerves in addition to astrocytosis and axonal degeneration in the optic nerve of EAE mice. CONCLUSION: OCT detected GCC changes in EAE may resemble what is observed in MS-related acute ON: an initial phase of swelling (indicative of inflammatory edema) followed by a decrease in thickness over time (representative of neuro-axonal degeneration). In line with OCT findings, DTI of the visual pathway identifies EAE induced pathology (decreased AD, and increased RD). Immunofluorescence analysis provides support for inflammatory pathology and axonal degeneration. OCT together with DTI can detect retinal and optic nerve damage and elucidate to the temporal sequence of neurodegeneration in this rodent model of MS in vivo.

Within-patient fluctuation of brain volume estimates from short-term repeated MRI measurements using SIENA/FSL.

BACKGROUND: Measurements of brain volume loss (BVL) in individual patients are currently discussed controversially. One concern is the impact of short-term biological noise, like hydration status. METHODS: Three publicly available reliability MRI datasets with scan intervals of days to weeks were used. An additional cohort of 60 early relapsing multiple sclerosis (MS) patients with MRI follow-ups was analyzed to test whether after 1 year pathological BVL is detectable in a relevant fraction of MS patients. BVL was determined using SIENA/FSL. Results deviating from zero in the reliability datasets were considered as within-patient fluctuation (WPF) consisting of the intrinsic measurement error as well as the short-term biological fluctuations of brain volumes. We provide an approach to interpret BVL measurements in individual patients taking the WPF into account. RESULTS: The estimated standard deviation of BVL measurements from the pooled reliability datasets was 0.28%. For a BVL measurement of x% per year in an individual patient, the true BVL lies with an error probability of 5% in the interval x% ± (1.96 × 0.28)/(scan interval in years)%. To allow a BVL per year of at least 0.4% to be identified after 1 year, the measured BVL needs to exceed 0.94%. The median BVL per year in the MS patient cohort was 0.44%. In 11 out of 60 MS patients (18%) we found a BVL per year equal or greater than 0.94%. CONCLUSION: The estimated WPF may be helpful when interpreting BVL results on an individual patient level in diseases such as MS.

Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults.

Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages.

Effect of fentanyl on the induction dose and minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose of propofol and minimum infusion rate required to prevent movement in response to noxious stimulation (MIRNM) in dogs. STUDY DESIGN: Crossover experimental design. ANIMALS: Six healthy, adult intact male Beagle dogs, mean±standard deviation 12.6±0.4 kg. METHODS: Dogs were administered 0.9% saline (treatment P), fentanyl (5 µg kg-1) (treatment PLDF) or fentanyl (10 µg kg-1) (treatment PHDF) intravenously over 5 minutes. Five minutes later, anesthesia was induced with propofol (2 mg kg-1, followed by 1 mg kg-1 every 15 seconds to achieve intubation) and maintained for 90 minutes by constant rate infusions (CRIs) of propofol alone or with fentanyl: P, propofol (0.5 mg kg-1 minute-1); PLDF, propofol (0.35 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1); PHDF, propofol (0.3 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). Propofol CRI was increased or decreased based on the response to stimulation (50 V, 50 Hz, 10 mA), with 20 minutes between adjustments. Data were analyzed using a mixed-model anova and presented as mean±standard error. RESULTS: ropofol induction doses were 6.16±0.31, 3.67±0.21 and 3.33±0.42 mg kg-1 for P, PLDF and PHDF, respectively. Doses for PLDF and PHDF were significantly decreased from P (p<0.05) but not different between treatments. Propofol MIRNM was 0.60±0.04, 0.29±0.02 and 0.22±0.02 mg kg-1 minute-1 for P, PLDF and PHDF, respectively. MIRNM in PLDF and PHDF was significantly decreased from P. MIRNM in PLDF and PHDF were not different, but their respective percent decreases of 51±3 and 63±2% differed (p=0.035). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, caused statistically significant and clinically important decreases in the propofol induction dose and MIRNM.

Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis.

Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days -7, -6, -5, -2, -1, 0 in the nostrils of male mice. PT100 (40µg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1-14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P<0.001, N=24) was found between the volumes of BLM-induced lesions detected in vivo by MRI and the collagen content determined histologically (picrosirius staining). FAP was overexpressed in the lungs of BLM-challenged mice. Upon PT100 treatment, FAP expression was reduced. Significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs of PT100- compared to vehicle-treated mice were also revealed by qRT-PCR. The IBA-1 level determined histologically was higher in the lungs of PT100- compared to vehicle-treated mice. Taken together, these observations suggest that treatment with PT100 in this murine model of pulmonary fibrosis had an anti-fibro-proliferative effect and increased macrophage activation.

Effect of fentanyl and lidocaine on the end-tidal sevoflurane concentration preventing motor movement in dogs.

OBJECTIVE To determine effects of fentanyl, lidocaine, and a fentanyl-lidocaine combination on the minimum alveolar concentration of sevoflurane preventing motor movement (MACNM) in dogs. ANIMALS 6 adult Beagles. PROCEDURES Dogs were anesthetized with sevoflurane in oxygen 3 times (1-week intervals). Baseline MACNM (MACNM-B) was determined starting 45 minutes after induction of anesthesia. Dogs then received 1 of 3 treatments IV: fentanyl (loading dose, 15 µg/kg; constant rate infusion [CRI], 6 µg/kg/h), lidocaine (loading dose, 2 mg/kg; CRI, 6 mg/kg/h), and the fentanyl-lidocaine combination at the same doses. Determination of treatment MACNM (MACNM-T) was initiated 90 minutes after start of the CRI. Venous blood samples were collected at the time of each treatment MACNM measurement for determination of plasma concentrations of fentanyl and lidocaine. RESULTS Mean ± SEM overall MACNM-B for the 3 treatments was 2.70 ± 0.27 vol%. The MACNM decreased from MACNM-B to MACNM-T by 39%, 21%, and 55% for fentanyl, lidocaine, and the fentanyl-lidocaine combination, respectively. This decrease differed significantly among treatments. Plasma fentanyl concentration was 3.25 and 2.94 ng/mL for fentanyl and the fentanyl-lidocaine combination, respectively. Plasma lidocaine concentration was 2,570 and 2,417 ng/mL for lidocaine and the fentanyl-lidocaine combination, respectively. Plasma fentanyl and lidocaine concentrations did not differ significantly between fentanyl and the fentanyl-lidocaine combination or between lidocaine and the fentanyl-lidocaine combination. CONCLUSIONS AND CLINICAL RELEVANCE CRIs of fentanyl, lidocaine, and the fentanyl-lidocaine combination at the doses used were associated with clinically important and significant decreases in the MACNM of sevoflurane in dogs.

MRI FLAIR lesion segmentation in multiple sclerosis: Does automated segmentation hold up with manual annotation?

INTRODUCTION: Magnetic resonance imaging (MRI) has become key in the diagnosis and disease monitoring of patients with multiple sclerosis (MS). Both, T2 lesion load and Gadolinium (Gd) enhancing T1 lesions represent important endpoints in MS clinical trials by serving as a surrogate of clinical disease activity. T2- and fluid-attenuated inversion recovery (FLAIR) lesion quantification - largely due to methodological constraints - is still being performed manually or in a semi-automated fashion, although strong efforts have been made to allow automated quantitative lesion segmentation. In 2012, Schmidt and co-workers published an algorithm to be applied on FLAIR sequences. The aim of this study was to apply the Schmidt algorithm on an independent data set and compare automated segmentation to inter-rater variability of three independent, experienced raters. METHODS: MRI data of 50 patients with RRMS were randomly selected from a larger pool of MS patients attending the MS Clinic at the Brain and Mind Centre, University of Sydney, Australia. MRIs were acquired on a 3.0T GE scanner (Discovery MR750, GE Medical Systems, Milwaukee, WI) using an 8 channel head coil. We determined T2-lesion load (total lesion volume and total lesion number) using three versions of an automated segmentation algorithm (Lesion growth algorithm (LGA) based on SPM8 or SPM12 and lesion prediction algorithm (LPA) based on SPM12) as first described by Schmidt et al. (2012). Additionally, manual segmentation was performed by three independent raters. We calculated inter-rater correlation coefficients (ICC) and dice coefficients (DC) for all possible pairwise comparisons. RESULTS: We found a strong correlation between manual and automated lesion segmentation based on LGA SPM8, regarding lesion volume (ICC = 0.958 and DC = 0.60) that was not statistically different from the inter-rater correlation (ICC = 0.97 and DC = 0.66). Correlation between the two other algorithms (LGA SPM12 and LPA SPM12) and manual raters was weaker but still adequate (ICC = 0.927 and DC = 0.53 for LGA SPM12 and ICC = 0.949 and DC = 0.57 for LPA SPM12). Variability of both manual and automated segmentation was significantly higher regarding lesion numbers. CONCLUSION: Automated lesion volume quantification can be applied reliably on FLAIR data sets using the SPM based algorithm of Schmidt et al. and shows good agreement with manual segmentation.

Optical Coherence Tomography and Magnetic Resonance Imaging in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases.

Effects of magnesium sulfate and propofol on the minimum alveolar concentration preventing motor movement in sevoflurane-anesthetized dogs.

OBJECTIVE To evaluate the effect of MgSO4, alone and in combination with propofol, on the minimum alveolar concentration preventing motor movement (MACNM) in sevoflurane-anesthetized dogs. ANIMALS 6 healthy purpose-bred adult male Beagles (least squares mean ± SEM body weight, 12.0 ± 1.1 kg). PROCEDURES Dogs were anesthetized 3 times at weekly intervals. The MACNM was measured 45 minutes after induction of anesthesia (baseline; MACNM-B) and was determined each time by use of a noxious electrical stimulus. Treatments were administered as a loading dose and constant rate infusion (CRI) as follows: treatment 1, MgSO4 loading dose of 45 mg/kg and CRI of 15 mg/kg/h; treatment 2, propofol loading dose of 4 mg/kg and CRI of 9 mg/kg/h; and treatment 3, MgSO4 and propofol combination (same doses used previously for each drug). A mixed-model ANOVA and Tukey-Kramer tests were used to determine effects of each treatment on the percentage decrease from MACNM-B. Data were reported as least squares mean ± SEM values. RESULTS Decrease from MACNM-B was 3.4 ± 3.1%, 48.3 ± 3.1%, and 50.3 ± 3.1%, for treatments 1, 2, and 3, respectively. The decrease for treatments 2 and 3 was significantly different from that for treatment 1; however, no significant difference existed between results for treatments 2 and 3. CONCLUSIONS AND CLINICAL RELEVANCE MgSO4 did not affect MACNM, nor did it potentiate the effects of propofol on MACNM. Administration of MgSO4 in this study appeared to provide no clinical advantage as an anesthetic adjuvant.

Effect of ketamine on the minimum infusion rate of propofol needed to prevent motor movement in dogs.

OBJECTIVE: To determine the minimum infusion rate (MIR) of propofol required to prevent movement in response to a noxious stimulus in dogs anesthetized with propofol alone or propofol in combination with a constant rate infusion (CRI) of ketamine. ANIMALS: 6 male Beagles. PROCEDURES: Dogs were anesthetized on 3 occasions, at weekly intervals, with propofol alone (loading dose, 6 mg/kg; initial CRI, 0.45 mg/kg/min), propofol (loading dose, 5 mg/kg; initial CRI, 0.35 mg/kg/min) and a low dose of ketamine (loading dose, 2 mg/kg; CRI, 0.025 mg/kg/min), or propofol (loading dose, 4 mg/kg; initial CRI, 0.3 mg/kg/min) and a high dose of ketamine (loading dose, 3 mg/kg; CRI, 0.05 mg/kg/min). After 60 minutes, the propofol MIR required to prevent movement in response to a noxious electrical stimulus was determined in duplicate. RESULTS: Least squares mean ± SEM propofol MIRs required to prevent movement in response to the noxious stimulus were 0.76 ± 0.1 mg/kg/min, 0.60 ± 0.1 mg/kg/min, and 0.41 ± 0.1 mg/kg/min when dogs were anesthetized with propofol alone, propofol and low-dose ketamine, and propofol and high-dose ketamine, respectively. There were significant decreases in the propofol MIR required to prevent movement in response to the noxious stimulus when dogs were anesthetized with propofol and low-dose ketamine (27 ± 10%) or with propofol and high-dose ketamine (30 ± 10%). CONCLUSIONS AND CLINICAL RELEVANCE: Ketamine, at the doses studied, significantly decreased the propofol MIR required to prevent movement in response to a noxious stimulus in dogs.

The anesthetic interaction of propofol and sevoflurane on the minimum alveolar concentration preventing motor movement (MACNM) in dogs.

The objective of this study was to determine the effects of propofol on the minimum alveolar concentration of sevoflurane needed to prevent motor movement (MAC(NM)) in dogs subjected to a noxious stimulus using randomized crossover design. Six, healthy, adult beagles (9.2 ± 1.3 kg) were used. Dogs were anesthetized with sevoflurane on 3 occasions, at weekly intervals, and baseline MAC(NM) (MAC(NM-B)) was determined on each occasion. Propofol treatments were administered as loading dose (LD) and constant rate infusion (CRI) as follows: Treatment 1 (T1) was 2 mg/kg body weight (BW) and 4.5 mg/kg BW per hour; T2 was 4 mg/kg BW and 9 mg/kg BW per hour; T3 was 8 mg/kg BW and 18 mg/kg BW per hour, respectively. Treatment MAC(NM) (MAC(NM-T)) determination was initiated 60 min after the start of the CRI. Two venous blood samples were collected and combined at each MAC(NM-T) determination for measurement of blood propofol concentration using high-performance liquid chromatography method (HPLC). Data were analyzed using a mixed-model ANOVA and are presented as least square means (LSM) ± standard error of means (SEM). Propofol infusions in the range of 4.5 to 18 mg/kg BW per hour resulted in mean blood concentrations between 1.3 and 4.4 µg/mL, and decreased (P < 0.05) sevoflurane MAC(NM) in a concentration-dependent manner. The percentage decrease in MAC(NM) was 20.5%, 43.0%, and 68.3%, with corresponding blood propofol concentrations of 1.3 ± 0.3 µg/mL, 2.5 ± 0.3 µg/mL, and 4.4 ± 0.3 µg/mL, for T1, T2, and T3, respectively. Venous blood propofol concentrations were strongly correlated (r = 0.855, P < 0.0001) with the decrease in MAC(NM). In dogs, propofol decreased the sevoflurane MAC(NM) in a concentration-dependent manner.

L'objectif de la présente étude était de déterminer les effets du propofol sur la concentration alvéolaire minimale de sevoflurane requise pour empêcher les mouvements moteurs (MACNM) chez des chiens soumis à un stimulus délétère en utilisant un modèle expérimental croisé aléatoire. Six chiens Beagle adultes et en santé (9,2 ± 1,3 kg) ont été utilisés. Les chiens étaient anesthésiés avec du sevoflurane à trois occasions, à une semaine d'intervalle, et la valeur de base de MACNM (MACNM-B) déterminée à chaque occasion. Les traitements de propofol furent administrés à une dose d'attaque (LD) et un taux d'infusion constant (CRI) comme suit: Traitement 1 (T1) était de 2 mg/kg de poids corporel (BW) et 4,5 mg/kg BW par heure; T2 était de 4 mg/kg BW et 9 mg/kg BW par heure; T3 était de 8 mg/kg BW et 18 mg/kg BW par heure, respectivement. La détermination de la MACNM du traitement (MACNM-T) fut initiée 60 min après le début du CRI. Deux échantillons de sang veineux furent prélevés et combinés à chaque mesure de MACNM-T pour mesurer la concentration sanguine de propofol par une méthode de chromatographie à haute performance en phase liquide (HPLC). Les données furent analysées par un modèle mixte d'ANOVA et sont présentées sous forme du moindre carré (LSM) ± écart-type (SEM).Les infusions de propofol variant entre 4,5 à 18 mg/kg BW par heure ont résulté en des concentrations sanguines moyennes entre 1,3 et 4,4 µg/mL, et diminuèrent (P < 0,05) la MACNM de sevoflurane d'une manière dépendante de la concentration. Le pourcentage de diminution de MACNM était de 20,5 %, 43,0 % et 68,3 %, avec des concentrations sanguines de propofol correspondantes de 1,3 ± 0,3 µg/mL, 2,5 ± 0,3 µg/mL, et 4,4 ± 0,3 µg/mL, pour T1, T2 et T3, respectivement. Les concentrations veineuses en propofol étaient fortement corrélées (r = 0,855, P < 0,0001) avec la diminution de MACNM. Chez les chiens, le propofol a diminué la MACNM du sevoflurane de manière dépendante de la concentration.(Traduit par Docteur Serge Messier).

Adriamycin-induced nephropathy in rats: functional and cellular effects characterized by MRI.

PURPOSE: To assess with magnetic resonance imaging (MRI) adriamycin-induced nephropathy in living rats, an established model for proteinuric renal disease was used. MATERIALS AND METHODS: Functional information of contrast agent clearance was obtained with dynamic contrast-enhanced (DCE) imaging following intravenous Gd-DOTA administration. Perfusion data were obtained with a bolus tracking technique comprising intravenous injection of superparamagnetic iron oxide (SPIO) nanoparticles. Cellular information was derived from anatomical images acquired 24 hours after SPIO. Treatment with the transforming growth factor-ß123 (TGF-ß1,2,3 ) antibody, 1D11, started 1 week after adriamycin. Histology was performed at week 6 post-adriamycin. RESULTS: Tracer washout rates derived by DCE-MRI decreased by 65.5% with respect to baseline at week 6 post-adriamycin. The impaired kidney function agreed with glomerulopathy, nephropathy and fibrosis revealed histologically (picrosirius collagen staining in adriamycin-treated rats increased by 125.8% [P = 0.005] with respect to controls). Perfusion was reduced by 16.1%. Images acquired 24 hours after SPIO presented contrast changes that correlated inversely with the histologically determined iron content (R = -0.74, P = 2.6 × 10(-4) ). In adriamycin-challenged animals, iron was found in macrophages and in sclerotic tubuli, only in areas where macrophages were present. Treatment with 1D11 did not improve the adriamycin-induced renal injury. CONCLUSION: MRI provides longitudinal functional and cellular (macrophage infiltration) information that correlates with nephropathy development in adriamycin-challenged rats.

Hyaluronidase modulates bleomycin-induced lung injury detected noninvasively in small rodents by radial proton MRI.

PURPOSE: To assess whether hyaluronic acid, a building block of proteoglycans and extracellular matrix with hydrophilic characteristics, might contribute to magnetic resonance imaging (MRI)-detected proton signals elicited by bleomycin in the lung. To this end, hyaluronidase, which degrades hyaluronic acid, was administered to bleomycin-challenged animals. MATERIALS AND METHODS: Fibrosis was induced by oropharyngeal aspiration (OA) of bleomycin. Mice received bleomycin once daily (0.1 mg/kg) on 6 consecutive days, while rats were given a single dose (2 or 4 mg/kg). Hyaluronidase, budesonide, and the respective vehicles were also administered via OA. Animals were examined using a radial ultrashort echo time sequence. Histology of picrosirius reflecting collagen and tissue gene analysis were performed postmortem. RESULTS: In mice, hyaluronidase induced an increase of high intensity signals by 34 ± 12 µL (means ± SD, P = 0.007), consistent with the ability of the degradation products of hyaluronic acid to provoke acute inflammation. Budesonide was able to resolve hyaluronidase-induced signals or to prevent their formation. Combined administration of budesonide and hyaluronidase to bleomycin-treated rats resulted in an overall decrease (-17.1 ± 7%, P = 0.02) of the MRI-detected bleomycin-induced signals. Moreover, the relative gene expression of hyaluronidase was reduced (-61.8 ± 10.2%, P < 0.001) in fibrotic lungs. CONCLUSION: The present data indicate that hyaluronic acid contributes to the bleomycin-induced responses detected by MRI in the lung.

The interaction of nitrous oxide and fentanyl on the minimum alveolar concentration of sevoflurane blocking motor movement (MACNM) in dogs.

The study objective was to determine the effects of 70% nitrous oxide (N2O) and fentanyl on the end-tidal concentration of sevoflurane necessary to prevent movement (MACNM) in response to noxious stimulation in dogs. Six healthy, adult, intact male, mixed-breed dogs were used on 3 occasions in a randomized crossover design. After induction of anesthesia with sevoflurane, each of the following treatments was randomly administered: fentanyl loading dose (Ld) of 15 µg/kg and infusion of 6 µg/kg per hour [treatment 1 (T1)], 70% N2O (T2), or fentanyl (Ld of 15 µg/kg and infusion of 6 µg/kg per hour) combined with 70% N2O (T3). Each dog received each of the 3 treatments once during the 3-week period. Determination of MACNM was initiated 90 min after the start of each treatment. The values were compared using the baseline MACNM, which had been determined in a previous study on the same group of dogs. Data were analyzed using a mixed-model analysis of variance (ANOVA) and Tukey-Kramer tests, and expressed as least squares mean ± SEM. The baseline MACNM decreased by 36.6 ± 4.0%, 15.0 ± 4.0%, and 46.0 ± 4.0% for T1, T2, and T3, respectively (P < 0.05), and differed (P < 0.05) among treatments. Mean fentanyl plasma concentrations did not differ (P ≥ 0.05) between T1 (3.70 ± 0.56 ng/mL) and T3 (3.50 ± 0.56 ng/mL). The combination of fentanyl and N2O resulted in a greater sevoflurane MACNM sparing effect than either treatment alone.

L'objectif de la présente étude était de déterminer les effets de l'oxyde nitreux (N2O) à 70 % et du fentanyl sur la concentration de sevoflurane en fin d'expiration nécessaire pour empêcher le mouvement (MACNM) en réponse à une stimulation désagréable chez des chiens. Six chiens mâles intacts adultes en santé de race croisée furent utilisés en 3 occasions dans des études croisées aléatoires. Après induction de l'anesthésie avec du sevoflurane, chacun des traitements suivants fut administré de manière aléatoire : dose d'induction de fentanyl (Ld) de 15 µg/kg et infusion de 6 µg/kg par heure [traitement 1 (T1)], 70 % N2O (T2), ou fentalyl (Ld de 15 µg/kg et infusion de 6 µg/kg par heure) combiné avec 70 % N2O (T3). Chaque chien a reçu chacun des trois traitements une fois durant la période d'essai de 3 semaines. La détermination du MACNM fut débutée 90 min après le début de chaque traitement. Les valeurs furent comparées en utilisant la valeur de base de MACNM, qui avait été déterminée dans une étude antérieure avec le même groupe de chiens. Les données furent analysées en utilisant un modèle mixte d'analyse de variance (ANOVA) et un test de Tukey-Kramer, et présentées comme la moyenne des moindres carrés ± écart-type. La valeur de base de MACNM diminua de 36,6 ± 4,0 %, 15,0 ± 4,0 %, et 46,0 ± 4,0 % respectivement pour T1, T2 et T3 (P < 0,05), et différait (P < 0,05) entre les traitements. Les concentrations plasmatiques moyennes ne différaient pas (P ≥ 0,05) entre T1 (3,70 ± 0,56 ng/mL) et T3 (3,50 ± 0,56 ng/mL). La combinaison de fentanyl et de N2O a produit un plus grand effet réducteur sur le MACNM de sevoflurane que chaque traitement individuel.(Traduit par Docteur Serge Messier).

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230.

Idiopathic pulmonary fibrosis is a progressive and lethal disease, characterized by loss of lung elasticity and alveolar surface area, secondary to alveolar epithelial cell injury, reactive inflammation, proliferation of fibroblasts, and deposition of extracellular matrix. The effects of oropharyngeal aspiration of bleomycin in Sprague-Dawley rats and C57BL/6 mice, as well as of intratracheal administration of ovalbumin to actively sensitized Brown Norway rats on total lung volume as assessed noninvasively by magnetic resonance imaging (MRI) were investigated here. Lung injury and volume were quantified by using nongated or respiratory-gated MRI acquisitions [ultrashort echo time (UTE) or gradient-echo techniques]. Lung function of bleomycin-challenged rats was examined additionally using a flexiVent system. Postmortem analyses included histology of collagen and hydroxyproline assays. Bleomycin induced an increase of MRI-assessed total lung volume, lung dry and wet weights, and hydroxyproline content as well as collagen amount. In bleomycin-treated rats, gated MRI showed an increased volume of the lung in the inspiratory and expiratory phases of the respiratory cycle and a temporary decrease of tidal volume. Decreased dynamic lung compliance was found in bleomycin-challenged rats. Bleomycin-induced increase of MRI-detected lung volume was consistent with tissue deposition during fibrotic processes resulting in decreased lung elasticity, whereas influences by edema or emphysema could be excluded. In ovalbumin-challenged rats, total lung volume quantified by MRI remained unchanged. The somatostatin analog, SOM230, was shown to have therapeutic effects on established bleomycin-induced fibrosis in rats. This work suggests MRI-detected total lung volume as readout for tissue-deposition in small rodent bleomycin models of pulmonary fibrosis.

Antinociceptive and selected physiological effects of morphine and xylazine on tiletamine-zolazepam anesthesia in llamas.

OBJECTIVE: Evaluate antinociception, anesthesia, and recovery in llamas given tiletamine-zolazepam (TZ) with either morphine, xylazine, morphine and xylazine, or saline. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: Six healthy, adult intact male llamas. METHODS: Llamas were given each of four treatments intramuscularly with a 1-week washout: TZ (2 mg kg(-1) ) combined with either morphine (0.5 mg kg(-1) ; M), xylazine (0.15 mg kg(-1) ; X), morphine (0.5 mg kg(-1) ) and xylazine (0.15mg kg(-1) ) (MX), or saline (C). Llamas breathed room air during the experiment. Characteristics of anesthesia, recovery, and selected cardiopulmonary variables were recorded. Antinociception was assessed by clamping a claw at 5-minute intervals. Data were analyzed using a mixed-model anova and Tukey-Kramer test, and are expressed as least squares mean ± SEM. Significance was set at p < 0.05. RESULTS: No llama in the control group demonstrated antinociception. Antinociception was longest with treatment MX, followed by treatments X and M, respectively. Heart rates in llamas given treatments X and MX were significantly lower than with other treatments. The respiratory rate in llamas given treatment C was greater (p < 0.05) than for all other treatments, however, the respiratory rate was not significantly different among treatments X, M and MX. The PaO2 for llamas given MX remained <60 mmHg throughout the 20 minute period of blood gas analysis. Mean arterial blood pressure in llamas in treatment MX was less than for treatments M or C. CONCLUSION AND CLINICAL RELEVANCE: The combination of morphine (0.5 mg kg(-1) ) and xylazine (0.15 mg kg(-1) ) increased the duration of antinociception compared with xylazine alone, in TZ-anesthetized llamas. Treatments X, M and MX were associated with hypoxemia (PaO2 < 60 mmHg).

The effect of nitrous oxide on the minimum alveolar concentration (MAC) and MAC derivatives of isoflurane in dogs.

This study investigated the effects of 70% nitrous oxide (N2O) on the minimum alveolar concentration (MAC) of isoflurane (ISO) that prevents purposeful movement, the MAC of ISO at which there is no motor movement (MACNM), and the MAC of ISO at which autonomic responses are blocked (MACBAR) in dogs. Six adult, healthy, mixed-breed, intact male dogs were anesthetized with ISO delivered via mask. Baseline MAC, MACNM, and MACBAR of ISO were determined for each dog using a supra-maximal electrical stimulus (50 V, 50 Hz, 10 ms). Nitrous oxide (70%) was then administered and MAC and its derivatives (N2O-MAC, N2O-MACNM, and N2O-MACBAR) were determined using the same methodology. The values for baseline MAC, MACNM, and MACBAR were 1.39 ± 0.14, 1.59 ± 0.10, and 1.72 ± 0.16, respectively. The addition of 70% N2O decreased MAC, MACNM, and MACBAR by 32%, 15%, and 25%, respectively.

Cette étude avait comme objectif d'évaluer chez des chiens les effets de 70 % d'oxyde nitreux (N2O) sur la concentration alvéolaire minimum (MAC) d'isoflurane (ISO) qui empêche les mouvements volontaires, la MAC d'ISO à laquelle il n'y a pas de mouvement moteur (MACNM), et la MAC d'ISO à laquelle les réponses autonomes sont bloquées (MACBAR).Six chiens mâles intacts adultes de race mélangée ont été anesthésiés avec de l'ISO administré via un masque. Les valeurs de base de MAC, MACNM et de MACBAR d'ISO ont été déterminées pour chaque chien à l'aide d'un stimulus électrique supra-maximal (50 V, 50 Hz, 10 ms). De l'oxyde nitreux (70 %) fut ensuite administré et la MAC et ses dérivées (N2O-MAC, N2O-MACNM et N2O-MACBAR) déterminées à l'aide de la même méthodologie. Les valeurs des données de base de MAC, MACNM et MACBAR étaient respectivement 1,39 ± 0,14, 1,59 ± 0,10 et 1,72 ± 0,16. L'ajout de 70 % de N2O a entrainé des diminutions de MAC, MACNM et MACBAR de 32 %, 15 % et 25 %, respectivement.(Traduit par Docteur Serge Messier).