Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior

Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice.     

Prospective, randomized trial comparing blood and oxygenated crystalloid cardioplegia in reoperative coronary artery bypass grafting

OBJECTIVES: Reoperative coronary artery bypass grafting presents unique challenges for myocardial preservation. The purpose of this study was to compare oxygenated blood cardioplegia with oxygenated crystalloid cardioplegia during reoperative coronary artery bypass grafting using transesophageal echocardiography to assess regional wall motion of the left ventricle before and after cardiopulmonary bypass. METHODS: Sixty-one patients undergoing reoperative coronary artery bypass grafting were prospectively randomized to receive oxygenated blood cardioplegia or oxygenated crystalloid cardioplegia delivered with a combined antegrade-retrograde technique. Transgastric short axis views of the left ventricle were made with transesophageal echocardiography during the operation before cardiopulmonary bypass and immediately after cardiopulmonary bypass. Regional wall motion was graded by a blinded observer, and before cardiopulmonary bypass scores were compared with after cardiopulmonary bypass scores. RESULTS: No significant differences were found in the change in regional wall motion score from before cardiopulmonary bypass to after cardiopulmonary bypass between the blood and crystalloid cardioplegia groups. CONCLUSIONS: This study found blood and crystalloid cardioplegia to be equally efficacious for myocardial preservation during reoperative coronary artery bypass grafting.     

Effects of fibinolysis on neurite growth from dorsal root ganglia cultured in two- and three-dimensional fibrin gels

The mechanism of neurite penetration of three-dimensional fibrin matrices was investigated by culturing embryonic chick dorsal root ganglia (DRGs) within fibrin gels, upon fibrin gels, and upon laminin. The length of neurites within three-dimensional matrices of fibrin was decreased in a concentration-dependent manner by agents that inhibited plasmin, e.g. aprotinin, or that inhibited plasminogen activation, e.g., epsilon-aminocaproic acid (EACA), or plasminogen antiserum. In contrast, such agents increased the length of neurites growing out from DRGs cultured upon two-dimensional substrates of fibrin and had no effect on the length of neurites growing out from DRGs cultured upon laminin. Visualization of neurites within three-dimensional fibrin matrices demonstrated that the distance between fibrin strands was much smaller than the diameter of neurites. All these data were consistent with the hypothesis that fibrinolysis localized to the region of the neurite tip is an important mechanism for neurite penetration of a physical barrier of fibrin strands arranged in a three-dimensional matrix.     

A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice

OBJECTIVE: Platelet factor 4 (PF-4) is a critical alpha chemokine in inflammation and injury responses, with multiple effects upon cellular activities. Discrete peptide sequences of the PF-4 molecule have been shown to retain biological activity. Our aim was to examine the influence of the PF-4 derived octapeptide (CT-112; TTSQVRPR) on type II collagen induced arthritis in mice, to determine if this peptide exhibited antiinflammatory properties. METHODS: DBA/1 mice were treated with CT-112 from either the time of immunization with type II collagen or from the initial onset of arthritis. RESULTS: CT-112 both prevented the development of arthritis in mice treated prophylactically and reduced progression of disease in animals treated therapeutically, and was active when delivered by either subcutaneous injection or oral gavage. No marked immunosuppressive effects were observed during CT-112 treatment, with only moderate decrease in antibody levels and mitogen responses. A significant reduction of the circulating levels of IL-1 was a consistent finding in mice treated therapeutically with CT-112. CONCLUSION: These data suggest PF-4 derived octapeptide exerts antiinflammatory effects of experimental arthritis in mice.     

Oxygen mass transfer calculations in large arteries

Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Local blockade of glutamatergic transmission in these pathways can alleviate parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effects. These side-effects, including ataxia and dissociative anaesthesia, are particularly problematic when N-methyl-D-aspartate (NMDA) antagonists are used. In an attempt to overcome these problems we have attempted to manipulate excitatory amino acid (EAA)-mediated neurotransmission indirectly by targeting the NMDA receptor associated modulatory sites. We review evidence which demonstrates that antagonists for both the NMDA associated glycine and polyamine sites can reverse parkinsonian symptoms when injected intra-cerebrally in both MPTP-treated and bilateral 6-OHDA lesioned marmosets without eliciting unwanted side-effects. We further review preliminary data which suggest that ifenprodil, a polyamine site antagonist, has striking anti-parkinsonian actions in the marmoset. Potential mechanisms of action underlying these effects are discussed in terms of NMDA receptor subtypes and the neuroanatomical locus of action. The anti-parkinsonian efficacy of intra-striatally administered EAA antagonists leads us to question the view of dopamine acting in the striatum as a simple neuromodulator.     

Development of a risk profile for intentions to use alcohol among fifth and sixth graders

OBJECTIVE: The relationship between intentions to use alcohol and risk factors was examined among fifth and sixth graders. METHOD: Subjects completed a questionnaire that assessed intentions to use alcohol and eight risk factors. Risk factors included peer and parental use and attitudes toward use, sensation seeking, tolerance of deviance, rejection of parental authority, and family cohesion. RESULTS: Multivariate analyses showed that the risk factors were able to discriminate between those who intended to use alcohol and those who did not. Family factors showed stronger relationships to intentions among fifth graders, and peer factors were more strongly related to intentions among sixth graders. CONCLUSIONS: Risk factors can be used to target preadolescents who may be at risk for early alcohol use, and programs that attempt to prevent early initiation of alcohol use among adolescents can be designed.