Myocardial MIBG scintigraphy: a useful clinical tool? : A retrospective study in 50 parkinsonian patients.

Meta-iodbenzylguanidine scintigraphy (MIBG scintigraphy) shows reduced uptake in idiopathic Parkinson's disease (IPD), idiopathic REM sleep behavior disorder (IRBD) and Lewy body dementia (LBD), but not in other parkinsonian or dementia syndromes. We retrospectively reevaluated 50 patients. Concordance rate between last clinical diagnosis and scintigraphy diagnosis was only given in two-thirds of the patients. Confounding factors were: decreasing heart/mediastinum ratio (HMR) with progressive age, higher HMR in women and possibly interference with antihypertensive medication. Standardization of the methods and precise clinical guidelines are warranted for better clinical use.

Enteral nutrition and cardiovascular failure: from myths to clinical practice.

Cardiovascular failure and low flow states may arise in very different conditions from both cardiac and noncardiac causes. Systemic hemodynamic failure inevitably alters splanchnic blood flow but in an unpredictable way. Prolonged low splanchnic blood flow causes intestinal ischemia, increased mucosal permeability, endotoxemia, and distant organ failure. Mortality associated with intestinal ischemia is high. Why would enteral nutrition (EN) be desirable in these complex patients when parenteral nutrition could easily cover energy and substrate requirements? Metabolic, immune, and practical reasons justify the use of EN. In addition, continuous enteral feeding minimizes systemic and myocardial oxygen consumption in patients with congestive heart failure. Further, early feeding in critically ill mechanically ventilated patients has been shown to reduce mortality, particularly in the sickest patients. In a series of cardiac surgery patients with compromised hemodynamics, absorption has been maintained, and 1000-1200 kcal/d could be delivered by enteral feeding. Therefore, early EN in stabilized patients should be attempted, and can be carried out safely under close clinical monitoring, looking for signs of incipient intestinal ischemia. Energy delivery and balance should be monitored, and combined feeding considered when enteral feeds cannot be advanced to target within 4-6 days.

Insulin-Like growth-factor 1 myocardial expression decreases in chronic alcohol consumption

Background Chronic alcohol ingestion may cause severe biochemical and pathophysiological derangements to skeletal muscle. Unfortunately, these alcohol-induced events may also prime skeletal muscle for worsened, delayed, or possibly incomplete repair following acute injury. As alcoholics may be at increased risk for skeletal muscle injury, our goals were to identify the effects of chronic alcohol ingestion on components of skeletal muscle regeneration. To accomplish this, age- and gender-matched C57Bl/6 mice were provided normal drinking water or water that contained 20% alcohol (v/v) for 1820 wk. Subgroups of mice were injected with a 1.2% barium chloride (BaCl2) solution into the tibialis anterior (TA) muscle to initiate degeneration and regeneration processes. Body weights and voluntary wheel running distances were recorded during the course of recovery. Muscles were harvested at 2, 7 or 14 days post-injection and assessed for markers of inflammation and oxidant stress, fiber cross-sectional areas, levels of growth and fibrotic factors, and fibrosis. Results Body weights of injured, alcohol-fed mice were reduced during the first week of recovery. These mice also ran significantly shorter distances over the two weeks following injury compared to uninjured, alcoholics. Injured TA muscles from alcohol-fed mice had increased TNFα and IL6 gene levels compared to controls 2 days after injury. Total protein oxidant stress and alterations to glutathione homeostasis were also evident at 7 and 14 days after injury. Ciliary neurotrophic factor (CNTF) induction was delayed in injured muscles from alcohol-fed mice which may explain, in part, why fiber cross-sectional area failed to normalize 14 days following injury. Gene levels of TGFβ1 were induced early following injury before normalizing in muscle from alcohol-fed mice compared to controls. However, TGFβ1 protein content was consistently elevated in injured muscle regardless of diet. Fibrosis was increased in injured, muscle from alcohol-fed mice at 7 and 14 days of recovery compared to injured controls. Conclusions Chronic alcohol ingestion appears to delay the normal regenerative response following significant skeletal muscle injury. This is evidenced by reduced cross-sectional areas of regenerated fibers, increased fibrosis, and altered temporal expression of well-described growth and fibrotic factors.

Hypoxia: unique myocardial morphology?

OBJECTIVE: The objective of this study was to investigate the effects of chronic and intermittent hypoxia on myocardial morphology. METHODS: Rats randomly divided into 3 groups (n = 14 per group) were exposed to room air (Fio(2) = 0.21), chronic hypoxia (Fio(2) = 0.10), and intermittent hypoxia (chronic hypoxia with 1 hour per day of room air) for 2 weeks. Weight, blood gas analysis, hematocrit, hemoglobin, red cells, and right and left ventricular pressures were measured. Hearts excised for morphologic examination were randomly divided into 2 groups (9 per group for gross morphologic measurements and 5 per group for histologic and morphometric analysis). The weight ratio of right to left ventricles plus interventricular septum, myocyte diameter, cross-sectional area, and free wall thickness in right and left ventricles were measured. RESULTS: Despite the same polycythemia, the right ventricle pressure (P <.05) and ratio of right to left ventricle pressures (P <.02) were higher after chronic hypoxia than intermittent hypoxia. The ratio of heart weight to total body weight and the ratio of right to left ventricles plus interventricular septum was higher (P <.01) in chronic and intermittent hypoxia than in normoxia. Myocyte diameter was not different between the right and left ventricles in normoxia, whereas right ventricle myocytes were larger than left ventricle myocytes in chronic hypoxia (P <.05) and intermittent hypoxia (P <.0005). There was marked dilatation of right ventricle size (P <.001) and marked reduction of left ventricle (P <.001) size in chronic and intermittent hypoxia compared with normoxia. The total ventricular area (right ventricle plus left ventricle area) remained the same in all groups. The wall thickness ratio in chronic hypoxia and intermittent hypoxia was increased (P <.001) compared with normoxia in the right ventricle but not in the left ventricle. CONCLUSIONS: Intermittent reoxygenation episodes do not induce a lesser ventricular hypertrophic response than observed with chronic hypoxia. The functional myocardial preconditioning consequence of intermittent reoxygenation is not supported by structural differences evident with the available techniques.

Quantification of Myocardial Perfusion Using 13N-ammonia PET: a Cross-Comparison Study on Analysis Software Packages - Carimas, PMOD and FlowQuant

Aim. Several software packages (SWP) and models have been released for quantification of myocardial perfusion (MP). Although they all are validated against something, the question remains how well their values agree. The present analysis focused on cross-comparison of three SWP for MP quantification of 13N-ammonia PET studies. Materials & Methods. 48 rest and stress MP 13N-ammonia PET studies of hypertrophic cardiomyopathy (HCM) patients (Sciagrà et al., 2009) were analysed with three SW packages - Carimas, PMOD, and FlowQuant - by three observers blinded to the results of each other. All SWP implement the one-tissue-compartment model (1TCM, DeGrado et al. 1996), and first two - the two-tissue-compartment model (2TCM, Hutchins et al. 1990) as well. Linear mixed model for the repeated measures was fitted to the data. Where appropriate we used Bland-Altman plots as well. The reproducibility was assessed on global, regional and segmental levels. Intraclass correlation coefficients (ICC), differences between the SWPs and between models were obtained. ICC≥0.75 indicated excellent reproducibility, 0.4≤ICC<0.75 indicated fair to good reproducibility, ICC<0.4 - poor reproducibility (Rosner, 2010). Results. When 1TCM MP values were compared, the SW agreement on global and regional levels was excellent, except for Carimas vs. PMOD at RCA: ICC=0.715 and for PMOD vs. FlowQuant at LCX:ICC=0.745 which were good. In segmental analysis in five segments: 7,12,13, 16, and 17 the agreement between all SWP was excellent; in the remaining 12 segments the agreement varied between the compared SWP. Carimas showed excellent agreement with FlowQuant in 13 segments and good in four - 1, 5, 6, 11: 0.687≤ICCs≤0.73; Carimas had excellent agreement with PMOD in 11 segments, good in five_4, 9, 10, 14, 15: 0.682≤ICCs≤0.737, and poor in segment 3: ICC=0.341. PMOD had excellent agreement with FlowQuant in eight segments and substantial-to-good in nine_1, 2, 3, 5, 6,8-11: 0.585≤ICCs≤0.738. Agreement between Carimas and PMOD for 2TCM was good at a global level: ICC=0.745, excellent at LCX (0.780) and RCA (0.774), good at LAD (0.662); agreement was excellent for ten segments, fair-to-substantial for segments 2, 3, 8, 14, 15 (0.431≤ICCs≤0.681), poor for segments 4 (0.384) and 17 (0.278). Conclusions. The three SWP used by different operators to analyse 13N-ammonia PET MP studies provide results that agree well at a global level, regional levels, and mostly well even at a segmental level. Agreement is better for 1TCM. Poor agreement at segments 4 and 17 for 2TCM needs further clarification.

Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.

BACKGROUND: Recent data suggest that beta-blockers can be beneficial in subgroups of patients with chronic heart failure (CHF). For metoprolol and carvedilol, an increase in ejection fraction has been shown and favorable effects on the myocardial remodeling process have been reported in some studies. We examined the effects of bisoprolol fumarate on exercise capacity and left ventricular volume with magnetic resonance imaging (MRI) and applied a novel high-resolution MRI tagging technique to determine myocardial rotation and relaxation velocity. METHODS: Twenty-eight patients (mean age, 57 +/- 11 years; mean ejection fraction, 26 +/- 6%) were randomized to bisoprolol fumarate (n = 13) or to placebo therapy (n = 15). The dosage of the drugs was titrated to match that of the the Cardiac Insufficiency Bisoprolol Study protocol. Hemodynamic and gas exchange responses to exercise, MRI measurements of left ventricular end-systolic and end-diastolic volumes and ejection fraction, and left ventricular rotation and relaxation velocities were measured before the administration of the drug and 6 and 12 months later. RESULTS: After 1 year, heart rate was reduced in the bisoprolol fumarate group both at rest (81 +/- 12 before therapy versus 61 +/- 11 after therapy; P <.01) and peak exercise (144 +/- 20 before therapy versus 127 +/- 17 after therapy; P <.01), which indicated a reduction in sympathetic drive. No differences were observed in heart rate responses in the placebo group. No differences were observed within or between groups in peak oxygen uptake, although work rate achieved was higher (117.9 +/- 36 watts versus 146.1 +/- 33 watts; P <.05) and exercise time tended to be higher (9.1 +/- 1.7 minutes versus 11.4 +/- 2.8 minutes; P =.06) in the bisoprolol fumarate group. A trend for a reduction in left ventricular end-diastolic volume (-54 mL) and left ventricular end-systolic volume (-62 mL) in the bisoprolol fumarate group occurred after 1 year. Ejection fraction was higher in the bisoprolol fumarate group (25.0 +/- 7 versus 36.2 +/- 9%; P <.05), and the placebo group remained unchanged. Most changes in volume and ejection fraction occurred during the latter 6 months of treatment. With myocardial tagging, insignificant reductions in left ventricular rotation velocity were observed in both groups, whereas relaxation velocity was reduced only after bisoprolol fumarate therapy (by 39%; P <.05). CONCLUSION: One year of bisoprolol fumarate therapy resulted in an improvement in exercise capacity, showed trends for reductions in end-diastolic and end-systolic volumes, increased ejection fraction, and significantly reduced relaxation velocity. Although these results generally confirm the beneficial effects of beta-blockade in patients with chronic heart failure, they show differential effects on systolic and diastolic function.

Long-term monitoring of post-stroke plasticity after transient cerebral ischemia in mice using in vivo and ex vivo diffusion tensor MRI.

WE USED A MURINE MODEL OF TRANSIENT FOCAL CEREBRAL ISCHEMIA TO STUDY: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus.Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.

Mechanisms underlying functional recovery after in vivo focal cerebral ischemia : from preconditioning to diffusion MRI

Version abregée L'ischémie cérébrale est la troisième cause de mort dans les pays développés, et la maladie responsable des plus sérieux handicaps neurologiques. La compréhension des bases moléculaires et anatomiques de la récupération fonctionnelle après l'ischémie cérébrale est donc extrêmement importante et représente un domaine d'intérêt crucial pour la recherche fondamentale et clinique. Durant les deux dernières décennies, les chercheurs ont tenté de combattre les effets nocifs de l'ischémie cérébrale à l'aide de substances exogènes qui, bien que testées avec succès dans le domaine expérimental, ont montré un effet contradictoire dans l'application clinique. Une approche différente mais complémentaire est de stimuler des mécanismes intrinsèques de neuroprotection en utilisant le «modèle de préconditionnement» : une brève insulte protège contre des épisodes d'ischémie plus sévères à travers la stimulation de voies de signalisation endogènes qui augmentent la résistance à l'ischémie. Cette approche peut offrir des éléments importants pour clarifier les mécanismes endogènes de neuroprotection et fournir de nouvelles stratégies pour rendre les neurones et la glie plus résistants à l'attaque ischémique cérébrale. Dans un premier temps, nous avons donc étudié les mécanismes de neuroprotection intrinsèques stimulés par la thrombine, un neuroprotecteur «préconditionnant» dont on a montré, à l'aide de modèles expérimentaux in vitro et in vivo, qu'il réduit la mort neuronale. En appliquant une technique de microchirurgie pour induire une ischémie cérébrale transitoire chez la souris, nous avons montré que la thrombine peut stimuler les voies de signalisation intracellulaire médiées par MAPK et JNK par une approche moléculaire et l'analyse in vivo d'un inhibiteur spécifique de JNK (L JNK) .Nous avons également étudié l'impact de la thrombine sur la récupération fonctionnelle après une attaque et avons pu démontrer que ces mécanismes moléculaires peuvent améliorer la récupération motrice. La deuxième partie de cette étude des mécanismes de récupération après ischémie cérébrale est basée sur l'investigation des bases anatomiques de la plasticité des connections cérébrales, soit dans le modèle animal d'ischémie transitoire, soit chez l'homme. Selon des résultats précédemment publiés par divers groupes ,nous savons que des mécanismes de plasticité aboutissant à des degrés divers de récupération fonctionnelle sont mis enjeu après une lésion ischémique. Le résultat de cette réorganisation est une nouvelle architecture fonctionnelle et structurelle, qui varie individuellement selon l'anatomie de la lésion, l'âge du sujet et la chronicité de la lésion. Le succès de toute intervention thérapeutique dépendra donc de son interaction avec la nouvelle architecture anatomique. Pour cette raison, nous avons appliqué deux techniques de diffusion en résonance magnétique qui permettent de détecter les changements de microstructure cérébrale et de connexions anatomiques suite à une attaque : IRM par tenseur de diffusion (DT-IR1V) et IRM par spectre de diffusion (DSIRM). Grâce à la DT-IRM hautement sophistiquée, nous avons pu effectuer une étude de follow-up à long terme chez des souris ayant subi une ischémie cérébrale transitoire, qui a mis en évidence que les changements microstructurels dans l'infarctus ainsi que la modification des voies anatomiques sont corrélés à la récupération fonctionnelle. De plus, nous avons observé une réorganisation axonale dans des aires où l'on détecte une augmentation d'expression d'une protéine de plasticité exprimée dans le cône de croissance des axones (GAP-43). En appliquant la même technique, nous avons également effectué deux études, rétrospective et prospective, qui ont montré comment des paramètres obtenus avec DT-IRM peuvent monitorer la rapidité de récupération et mettre en évidence un changement structurel dans les voies impliquées dans les manifestations cliniques. Dans la dernière partie de ce travail, nous avons décrit la manière dont la DS-IRM peut être appliquée dans le domaine expérimental et clinique pour étudier la plasticité cérébrale après ischémie. Abstract Ischemic stroke is the third leading cause of death in developed countries and the disease responsible for the most serious long-term neurological disability. Understanding molecular and anatomical basis of stroke recovery is, therefore, extremely important and represents a major field of interest for basic and clinical research. Over the past 2 decades, much attention has focused on counteracting noxious effect of the ischemic insult with exogenous substances (oxygen radical scavengers, AMPA and NMDA receptor antagonists, MMP inhibitors etc) which were successfully tested in the experimental field -but which turned out to have controversial effects in clinical trials. A different but complementary approach to address ischemia pathophysiology and treatment options is to stimulate and investigate intrinsic mechanisms of neuroprotection using the "preconditioning effect": applying a brief insult protects against subsequent prolonged and detrimental ischemic episodes, by up-regulating powerful endogenous pathways that increase resistance to injury. We believe that this approach might offer an important insight into the molecular mechanisms responsible for endogenous neuroprotection. In addition, results from preconditioning model experiment may provide new strategies for making brain cells "naturally" more resistant to ischemic injury and accelerate their rate of functional recovery. In the first part of this work, we investigated down-stream mechanisms of neuroprotection induced by thrombin, a well known neuroprotectant which has been demonstrated to reduce stroke-induced cell death in vitro and in vivo experimental models. Using microsurgery to induce transient brain ischemia in mice, we showed that thrombin can stimulate both MAPK and JNK intracellular pathways through a molecular biology approach and an in vivo analysis of a specific kinase inhibitor (L JNK1). We also studied thrombin's impact on functional recovery demonstrating that these molecular mechanisms could enhance post-stroke motor outcome. The second part of this study is based on investigating the anatomical basis underlying connectivity remodeling, leading to functional improvement after stroke. To do this, we used both a mouse model of experimental ischemia and human subjects with stroke. It is known from previous data published in literature, that the brain adapts to damage in a way that attempts to preserve motor function. The result of this reorganization is a new functional and structural architecture, which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new architecture. For this reason, we applied diffusion magnetic resonance techniques able to detect micro-structural and connectivity changes following an ischemic lesion: diffusion tensor MRI (DT-MRI) and diffusion spectrum MRI (DS-MRI). Using DT-MRI, we performed along-term follow up study of stroke mice which showed how diffusion changes in the stroke region and fiber tract remodeling is correlating with stroke recovery. In addition, axonal reorganization is shown in areas of increased plasticity related protein expression (GAP 43, growth axonal cone related protein). Applying the same technique, we then performed a retrospective and a prospective study in humans demonstrating how specific DTI parameters could help to monitor the speed of recovery and show longitudinal changes in damaged tracts involved in clinical symptoms. Finally, in the last part of this study we showed how DS-MRI could be applied both to experimental and human stroke and which perspectives it can open to further investigate post stroke plasticity.

Real-time MR imaging of myocardial regional function using strain-encoding (SENC) with tissue through-plane motion tracking.

PURPOSE: To implement real-time myocardial strain-encoding (SENC) imaging in combination with tracking the tissue displacement in the through-plane direction. MATERIALS AND METHODS: SENC imaging was combined with the slice-following technique by implementing three-dimensional (3D) selective excitation. Certain adjustments were implemented to reduce scan time to one heartbeat. A total of 10 volunteers and five pigs were scanned on a 3T MRI scanner. Spatial modulation of magnetization (SPAMM)-tagged images were acquired on planes orthogonal to the SENC planes for comparison. Myocardial infarction (MI) was induced in two pigs and the resulting SENC images were compared to standard delayed-enhancement (DE) images. RESULTS: The strain values computed from SENC imaging with slice-following showed significant difference from those acquired without slice-following, especially during systole (P < 0.01). The strain curves computed from the SENC images with and without slice-following were similar to those computed from the orthogonal SPAMM images, with and without, respectively, tracking the tag line displacement in the strain direction. The resulting SENC images showed good agreement with the DE images in identifying MI in infarcted pigs. CONCLUSION: Correction of through-plane motion in real-time cardiac functional imaging is feasible using slice-following. The strain measurements are more accurate than conventional SENC measurements in humans and animals, as validated with conventional MRI tagging.

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB(2) knockout mice and were not prevented by CB(1/2) antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB(1/2) receptors.

Quantification of Myocardial Blood Flow in Absolute Terms Using (82)Rb PET Imaging: The RUBY-10 Study.

OBJECTIVES: The purpose of this study was to compare myocardial blood flow (MBF) and myocardial flow reserve (MFR) estimates from rubidium-82 positron emission tomography ((82)Rb PET) data using 10 software packages (SPs) based on 8 tracer kinetic models. BACKGROUND: It is unknown how MBF and MFR values from existing SPs agree for (82)Rb PET. METHODS: Rest and stress (82)Rb PET scans of 48 patients with suspected or known coronary artery disease were analyzed in 10 centers. Each center used 1 of 10 SPs to analyze global and regional MBF using the different kinetic models implemented. Values were considered to agree if they simultaneously had an intraclass correlation coefficient >0.75 and a difference <20% of the median across all programs. RESULTS: The most common model evaluated was the Ottawa Heart Institute 1-tissue compartment model (OHI-1-TCM). MBF values from 7 of 8 SPs implementing this model agreed best. Values from 2 other models (alternative 1-TCM and Axially distributed) also agreed well, with occasional differences. The MBF results from other models (e.g., 2-TCM and retention) were less in agreement with values from OHI-1-TCM. CONCLUSIONS: SPs using the most common kinetic model-OHI-1-TCM-provided consistent results in measuring global and regional MBF values, suggesting that they may be used interchangeably to process data acquired with a common imaging protocol.

Clinical relevance of L-carnitine-supplemented total parenteral nutrition in postoperative trauma. Metabolic effects of continuous or acute carnitine administration with special reference to fat oxidation and nitrogen utilization.

Carnitine-free total parenteral nutrition (TPN) is claimed to result in a carnitine deficiency with subsequent impairment of fat oxidation. The present study was designed to evaluate the possible benefit of carnitine supplementation on postoperative fat and nitrogen utilization. Sixteen patients undergoing total esophagectomy were evenly randomized and received TPN without or with L-carnitine supplementation (74 mumol.kg-1.d-1) during 11 postoperative days. On day 11, a 4-h infusion of L-carnitine (125 mumol/kg) was performed in both groups. The effect of supplementation was evaluated by indirect calorimetry, N balance, and repeated measurements of plasma lipids and ketone bodies. Irrespective of continuous or acute supplementation, respiratory quotient and fat oxidation were similarly maintained throughout the study in both groups whereas N balance appeared to be more favorable without carnitine. We conclude that carnitine-supplemented TPN does not improve fat oxidation or promote N utilization in the postoperative phase.