ABSTRACT
BACKGROUND: The autonomic nervous system attenuates inflammation through activation of the α7 nicotinic acetylcholine receptor (α7nAChR), a pathway termed the cholinergic anti-inflammatory reflex. Interestingly, α7nAChR is expressed on immune cells and platelets, both of which play a crucial role in the development of atherosclerosis. OBJECTIVE: To investigate the role of hematopoietic α7nAChR in inflammation and platelet function in atherosclerotic ldlr(-/-) mice and to identify its consequences for atherosclerotic lesion development. METHODS: Bone marrow from α7nAChR(-/-) mice or wild-type littermates was transplanted into irradiated ldlr(-/-) mice. After a recovery period of 8 weeks, the mice were fed an atherogenic Western-type diet for 7 weeks. RESULTS: Hematopoietic α7nAChR deficiency clearly increased the number of leukocytes in the peritoneum (2.6-fold, P < 0.001), blood (2.9-fold; P < 0.01), mesenteric lymph nodes (2.0-fold; P < 0.001) and spleen (2.2-fold; P < 0.01), indicative of an increased inflammatory status. Additionally, expression of inflammatory mediators was increased in peritoneal leukocytes (TNFα, 1.6-fold, P < 0.01; CRP, 1.8-fold, P < 0.01) as well as in the spleen (TNFα, 1.6-fold, P < 0.01). The lack of α7nAChR on platelets from these mice increased the expression of active integrin αIIb ß3 upon stimulation by ADP (1.9-fold, P < 0.01), indicating increased activation status, while incubation of human platelets with an α7nAChR agonist decreased aggregation (-35%, P < 0.05). Despite the large effects of hematopoietic α7nAChR deficiency on inflammatory status and platelet function, it did not affect atherosclerosis development or composition of lesions. CONCLUSIONS: Hematopoietic α7nAChR is important for attenuation of inflammatory responses and maintaining normal platelet reactivity, but loss of hematopoietic α7nAChR does not aggravate development of atherosclerosis.
Subject(s)
Aortic Diseases/etiology , Atherosclerosis/etiology , Blood Platelets/metabolism , Hematopoietic Stem Cells/metabolism , Inflammation/etiology , Platelet Activating Factor , alpha7 Nicotinic Acetylcholine Receptor/deficiency , Animals , Aorta/metabolism , Aorta/pathology , Aortic Diseases/blood , Aortic Diseases/genetics , Aortic Diseases/pathology , Atherosclerosis/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Bone Marrow Transplantation , Diet, Western , Disease Models, Animal , Female , Genotype , Hematopoietic Stem Cell Transplantation , Inflammation/blood , Inflammation/genetics , Inflammation Mediators/blood , Leukocytes/metabolism , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Plaque, Atherosclerotic , Receptors, LDL/deficiency , Receptors, LDL/genetics , Time Factors , alpha7 Nicotinic Acetylcholine Receptor/geneticsABSTRACT
OBJECTIVE: To determine continuities of mental health problems of children across a 24-year follow-up period. METHOD: In 1983, parent ratings of emotional and behavioral problems were collected with the Child Behavior Checklist (CBCL) in a general population sample of 2076 children. Twenty-four years later, 1365 participants completed Adult Self-Reports (ASR) to assess emotional and behavioral problems. RESULTS: Of the participants who were classified as deviant in childhood, 22.2% were also classified as deviant in adulthood. Both homotypic and heterotypic continuity was found. Childhood aggressive, delinquent, and anxious/depressed problems were associated with most adult psychopathology. Attention problems did not predict later problems independently. CONCLUSION: Even though assessed with parent-reports in childhood and analogous self-reports in adulthood, and over a large period of 24 years, continuity of psychopathology was found from childhood into adulthood. Anxious/depressed problems, delinquent behavior and aggressive behavior in childhood are core predictors for adult psychopathology.
Subject(s)
Aggression , Conduct Disorder/epidemiology , Conduct Disorder/psychology , Juvenile Delinquency/psychology , Juvenile Delinquency/statistics & numerical data , Mental Disorders/epidemiology , Mental Disorders/psychology , Social Behavior , Adolescent , Adult , Child , Child, Preschool , Conduct Disorder/diagnosis , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/psychology , Female , Follow-Up Studies , Humans , Male , Mental Disorders/diagnosis , Severity of Illness Index , Surveys and Questionnaires , Young AdultABSTRACT
The in vitro initiation of DNA replication was studied in permeable mammalian cells by a newly developed procedure. Pairs of monolayer cultures, one synchronized in G1 and the other in S phase, were incubated in a sandwich with assay solution, containing Triton X-100 for permeabilization and [3H]TTP as a tracer. After 1.5 h DNA synthesis was shown to be induced in 36 to 81% of the G1 nuclei. The inducing capacity of the S phase cultures was diminished by at least 50% after a 10 min exposure to 60 degrees C prior to incubation. The suitability application of this in vitro system for testing components that might effect the initiation of DNA replication is shown in an assay with G1 cultures where the addition of up to 1 mM Ap4A led to an increase of DNA synthesizing cells from 4 to 15%.
