These data provide further support for the involvement of genetic variation in TPH2 in the etiology of BPI.
This study investigated for the first time in the psychiatric literature the effect of parental age on age-of-onset (AO) in bipolar I disorder (BPI) in relation to proband sex and family history (FH) for major psychoses in a sample of 564 BPI probands. All probands, 72.68% of their first-degree and 12.13% of their second-degree relatives were directly interviewed. The FH-method was used for all unavailable relatives. The diagnoses were made according to DSM-IV(TR) . The impact of parental age on proband early/late AO was evaluated through logistic regression with the cut-off for early AO determined through commingling analysis. We found evidence for a significant influence of increasing paternal age, and especially age ≥ 35 years, on AO of BPI disorder in the total sample (OR = 0.54, CI: 0.35-0.80), in the female subsample (OR = 0.44, CI: 0.25-0.78), in the sporadic subsample (OR = 0.64, CI: 0.38-0.95), and in the subsample with FH of recurrent unipolar major depression (Mdd-RUP) (OR = 0.55, CI: 0.34-0.87). No significant effect of paternal age on disease AO was found in patients with FH of bipolar (BP), schizoaffective disorders (SA), or schizophrenia (SCZ), nor in males. Mean age was significantly higher in fathers of sporadic cases and of cases with FH of Mdd-RUP than in fathers of cases with FH of BP/SA/SCZ (P = 0.011). Maternal age had no significant effect either in the total sample or in subsamples defined by proband sex or FH. In conclusion, in our sample increasing paternal age lowered the onset of BPI selectively, the effect being related to the female sex and FH-type.
The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is being used in clinical trials for its potential in the treatment of hematopoietic insufficiency due to various causes. Involvement of leukotrienes in the effects of GM-CSF is suggested by analytical and pharmacologic evidence obtained in vitro. However, until now no data in support of a role of leukotrienes in GM-CSF action in vivo have been presented. In the present investigation this question was approached by measurement of endogenous cysteinyl leukotriene formation in patients treated with the cytokine for cytopenia induced by cytostatic drugs or for refractory anemia with excess of blasts (RAEB). Endogenous cysteinyl leukotriene formation was assessed by determination of urinary leukotriene metabolites using combined high- performance liquid chromatography and radioimmunoassay analysis. After GM-CSF administration a distinct increase in urinary cysteinyl leukotrienes was found in the cytopenic and the RAEB patients that ranged from 2.3- to 57-fold and 2.4- to 333-fold, respectively. In the cytopenic patients the increase in leukotriene production was correlated to an expansion of peripheral blood leukocytes; RAEB patients responded to GM-CSF with enhanced leukotriene biosynthesis even if the peripheral leukocytes decreased, possibly due to an abnormal number and/or irritability of leukotriene-producing cells. The increase in endogenous leukotriene production during therapy with GM- CSF may indicate that leukotrienes play a role in GM-CSF action in vivo.
Age of onset (AO) has been proposed as a promising criterion by which to select homogeneous subgroups for the genetic analysis of bipolar disorder. This is the first study to investigate the effect of the interaction between gender and family history (FH)-type on AO in bipolar disorder. In accordance with the literature, no difference in AO was observed between females and males in our sample of 264 Romanian bipolar I probands. Cox regression, however, showed a strong influence of FH-type on AO (P = 0.006). This was due to a significant variation in AO according to the type of FH in females (P = 0.002) but not in males (P = 0.64). Female bipolar disorder patients with a negative FH (FH(-)) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.001) or a FH of recurrent unipolar major depression only (P = 0.04). Females with FH(-) had a later AO than males with FH(-) (P = 0.03). No sex difference was observed for AO in the group with a FH of recurrent unipolar depression. In the group with a FH of bipolar and/or schizoaffective disorder, females had an earlier AO than males (P = 0.01). A trend for support was observed in an independent sample of 217 German bipolar I patients for an influence of FH-type on AO in females (P = 0.09) but not in males (P = 0.15). Female bipolar disorder patients with FH(-) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.04) or a FH of recurrent unipolar major depression only (P = 0.05). Females with FH(-) had a later AO than males with FH(-) (P = 0.05). Other comparisons were statistically not significant, which may be due to limited sample size. Our findings emphasize that the interaction between gender and FH-type is a source of heterogeneity for AO in bipolar disorder.
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