Role of Interleukin 12 and Costimulators in T Cell Anergy In Vivo

The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti–CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti–CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one

Behavioral activation, inhibition and mood symptoms in early-onset bipolar disorder.

BACKGROUND: Hypomania/mania and depression are hypothesized to correspond to high and low expressions of behavioral activation system (BAS) activity, respectively, in bipolar individuals. In contrast, behavioral inhibition system (BIS) activity is hypothesized to regulate anxiety. The aim of the present study was to examine whether self-reported levels of BAS functioning in bipolar adolescents corresponded with levels of concurrent manic and depressive symptomatology. The secondary aim was to investigate whether self-reported BIS levels were associated with self-reported anxiety symptoms. METHODS: Twenty-five adolescents diagnosed with bipolar I, II or not otherwise specified were recruited from a treatment-development study. Adolescents were interviewed using the Depression and Mania Rating Scales of the Kiddie Schedule for Affective Disorders and Schizophrenia and given the Self-Report for Childhood Anxiety Related Disorders. Next, they completed the Behavioral Inhibition/Activation Scales. RESULTS: Contrary to hypotheses, adolescents with higher BAS levels exhibited less severe concurrent mania symptoms. Furthermore, levels of BAS sensitivity were not associated with concurrent levels of depression. As predicted, BIS scores correlated positively with self-reported anxiety scores. Adolescents reporting higher levels of the motor activity symptoms of mania also reported higher levels of anxiety symptoms. LIMITATIONS: The conclusions are based upon cross-sectional analyses in a small sample. CONCLUSIONS: In bipolar adolescents, mania and depression appear to be independent of self-reported behavioral activation levels. However, mood symptoms in adolescent patients are closely tied to components of anxiety, which may lead to diminished approach behaviors

Early-onset bipolar disorder: a family treatment perspective.

Mood disorder symptoms and their associated functional impairments are hypothesized to come about as the result of the conjoint, interactive influences of genetic, biological, and psychological vulnerabilities, family distress, and life stress at different points of development. We discuss a developmental psychopathology model that delineates pathways to high family conflict and mood exacerbation among early-onset bipolar patients. New data from a treatment development study indicate that adolescent bipolar patients in high expressed emotion families have more symptomatic courses of illness over 2 years than adolescents in low expressed emotion families. Chronic and episodic stressors are also correlated with lack of mood improvement while adolescents are in treatment. Family-focused treatment (FFT) given in conjunction with pharmacotherapy appears to ameliorate the course of bipolar disorder in adults. This treatment has recently been modified to address the developmental presentation of bipolar disorder among adolescents. We present data from an open trial of FFT and pharmacotherapy (N = 20) indicating that bipolar adolescents stabilize in mania, depression, and parent-rated problem behaviors over 2 years. Future research should focus on clarifying the developmental pathways to early-onset bipolar disorder and the role of protective factors and preventative psychosocial interventions in delaying the first onset of the disorder

Life stress and the course of early-onset bipolar disorder.

BACKGROUND: Studies of adult bipolar patients and adolescents with major depression indicate that life stress and mood symptoms are temporally and causally related to one another. This study examined whether levels of life stress predict levels of mood symptoms among bipolar adolescents participating in a treatment development study of family-focused psychoeducation and pharmacotherapy. METHODS: Bipolar adolescents (n=38) who reported a period of acute mood symptoms within the prior 3 months were recruited for a 1-year study of life stress. Clinician-administered evaluations were completed with adolescents and parents at 3-month intervals for up to 12 months, using the UCLA Life Stress Interview and the K-SADS Mania and Depression Rating Scales. RESULTS: Chronic stress in family, romantic and peer relationships was associated with less improvement in mood symptoms over the study year. The frequency of severe, independent life events also predicted less improvement in mood symptoms. Higher levels of chronic stress in family and romantic relationships, and higher severity of independent events, were more strongly associated with mood symptoms among older adolescents. Results were independent of adolescents' psychosocial treatment regimens. LIMITATIONS: The majority of adolescents received family-focused psychoeducational treatment and all were being treated with psychotropic medication. The influence of life stress on mood symptoms may have been attenuated by intensive intervention. CONCLUSIONS: Stress is linked to changes in mood symptoms among bipolar adolescents, although correlations between life events and symptoms vary with age. Chronic stress in family, romantic, and peer relationships are important targets for psychosocial intervention

Relationship between consultation length and rational prescribing of drugs in gorgan city, islamic Republic of Iran

Doctors with longer consultation times tend to diagnose illnesses more precisely, prescribe fewer drugs and present better health advice to their patients. The aim of this study was to measure the average consultation time of general practitioners in Gorgan, Islamic Republic of Iran and to investigate the factors affecting consultation length, especially in relation to rational prescribing of drugs. Data were collected on 620 patient consultations with 62 randomly selected general practitioners. Mean consultation length was 6.9 (SD 2.6) minutes. Patient factors that were significantly associated with a longer mean duration of consultation time were: higher number of health problems, older age and fewer items of previously used drugs. Physician factors that were significantly associated with a longer mean consultation time were: younger age, higher numbers of items prescribed and injectable drugs prescribed, frequency of interruptions and higher workload