ABSTRACT
The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury.
Subject(s)
Brain Ischemia/prevention & control , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Nitric Oxide Donors/therapeutic use , Oximes/therapeutic use , Quinoxalines/therapeutic use , Reperfusion Injury/prevention & control , Animals , Blood-Brain Barrier/chemistry , Brain Infarction/pathology , Brain Infarction/prevention & control , Brain Ischemia/metabolism , Brain Ischemia/physiopathology , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Motor Skills/drug effects , Nitric Oxide/metabolism , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacology , Oximes/chemistry , Oximes/pharmacology , Permeability , Quinoxalines/chemistry , Quinoxalines/pharmacology , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathologyABSTRACT
OBJECTIVE: Parental relationships and maladaptive problem solving have been associated with anorexic symptomatology. This study investigates the relationship between perceived parental bonding, social problem solving and eating psychopathology. METHODS: Forty three female inpatients with anorexia nervosa and 76 student controls were assessed using the Parental Bonding Instrument, the Social Problem Solving Inventory and the Eating Disorders Examination or the Eating Disorders Examination-Questionnaire. RESULTS: The anorexic group reported significantly lower levels of parental care than the student control group and used more negative and avoidance style coping. In the anorexic group, disordered eating was significantly correlated with low maternal care and high control. Maternal bonding was found to mediate the relationship between avoidance style coping and eating pathology. CONCLUSIONS: Findings suggest a relationship between maternal bonding, the use of maladaptive problem solving techniques and eating disorder pathology in inpatients with anorexia nervosa.
Subject(s)
Anorexia Nervosa/psychology , Feeding Behavior/psychology , Object Attachment , Parent-Child Relations , Problem Solving , Social Behavior , Adaptation, Psychological , Adult , Anorexia Nervosa/diagnosis , Body Image , Female , Humans , Inpatients , Personality Inventory , Regression Analysis , Social Perception , Surveys and QuestionnairesABSTRACT
PURPOSE: Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them. PATIENTS AND METHODS: A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients' cancer diagnoses and treatments were obtained from the cancer center clinical database. RESULTS: Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and--to a lesser extent--older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role. CONCLUSION: A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.
