The high prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward an innovative diagnostic framework

BACKGROUND: Young adults with early-onset major depressive disorder (MDD) may be at high risk of progression to bipolar disorder. Although hypomanic symptoms are common in young people with depression, many do not reach the strict DSM-IV and ICD-10 criteria for hypomania. We used an emerging innovative framework for bipolar spectrum to evaluate this question. METHODS: Consecutive referrals to a psychiatric outpatient clinic at a university health service were assessed for recurrent episodes of depression. DSM-IV diagnoses were based on a SCID-1 interview. We used two approaches to delineate bipolar spectrum. The first focused on bipolar spectrum disorder (BSD, as defined by Ghaemi et al. [Can. J. Psychiatry 47 (2002) 125]), and the second on a symptoms perspective based on MDD with a history of hypomanic symptoms, using a 15-point hypomanic symptoms checklist with a cut-off > or =8 or more symptoms (modified from J. Affect. Disord. 73 (2003) 39 and J. Affect. Disord. 73 (2003) 73). Data were also obtained on family history of affective disorder, course and number of episodes of depression, symptom severity, psychosocial functioning, suicidality and deliberate self-harm, and drug and alcohol use. RESULTS: High rates of bipolar and bipolar spectrum disorder were identified. Under DSM-IV, 14 subjects (16.1%) had bipolar affective disorder and 73 subjects (83.9%) had recurrent MDD. Depending on the method used to diagnose bipolar spectrum, between 47.1% and 77.0% of the total cohort could be so diagnosed. Hypomanic symptom counts, irrespective of duration, yielded the highest estimates for bipolar spectrum. High rates of pharmacological hypomania were also identified: 12 subjects (16.4%) with recurrent MDD group reported this, and all could be diagnosed with bipolar spectrum. LIMITATIONS: The reliability of using the 15-point hypomanic scale for the diagnostic assignments was not tested. All subjects were recruited from a university health service and, given the affluence of their parents, findings may not generalise to other populations. Most importantly, because bipolar family history and pharmacological hypomania were part of the diagnostic criteria of the BSD group, they could not be used as external validators for Ghaemi's BSD construct. CONCLUSIONS: Bipolar disorders emerge as extremely common in this cohort of young adults with recurrent depression. Antidepressant-induced hypomania and high scores on a hypomanic symptoms checklist help to identify patients who are likely to have a bipolar spectrum illness, but who do not meet DSM-IV criteria for bipolar disorder. This is a preliminary study, and further evidence from external validating strategies are needed to verify the bipolar status of these patients in a larger and unselected cohort representing a broader socio-economic demographic profile.     

Cystathionine beta-lyase is important for virulence of Salmonella enterica serovar Typhimurium

The biosynthesis of methionine in bacteria requires the mobilization of sulfur from Cys by the formation and degradation of cystathionine. Cystathionine beta-lyase, encoded by metC in bacteria and STR3 in Schizosaccharomyces pombe, catalyzes the breakdown of cystathionine to homocysteine, the penultimate step in methionine biosynthesis. This enzyme has been suggested to be the target for pyridinamine antimicrobial agents. We have demonstrated, by using purified enzymes from bacteria and yeast, that cystathionine beta-lyase is not the likely target of these agents. Nonetheless, an insertional inactivation of metC in Salmonella enterica serovar Typhimurium resulted in the attenuation of virulence in a mouse model of systemic infection. This result confirms a previous chemical validation of the Met biosynthetic pathway as a target for the development of antibacterial agents and demonstrates that cystathionine beta-lyase is important for bacterial virulence.     

Pneumocystis carinii f. sp. hominis is not infectious for SCID mice

The infectious power of Pneumocystis carinii f. sp. hominis was explored by inoculating SCID mice intranasally with either P. carinii f. sp. hominis or P. carinii f. sp. muris isolates. Only mice inoculated with mouse parasites developed Pneumocystis pneumonia, as assessed by microscopy and PCR. These results suggest that humans do not contract pneumocystosis from animals.     

Evidence for involvement of a tumor suppressor gene on 1p in malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue malignancies. The genetic basis of these tumors is still poorly understood. Cytogenetic analyses predominantly revealed complex karyotypes, precluding the identification of recurrent chromosomal changes. We report loss of 1p material in a near-diploid karyotype with few or no additional structural chromosome changes in two sporadic cases of MPNST, indicating an important role of 1p loss in MPNST development. In one of these two tumors, a distal 1p deletion (1p31.2 approximately pter) was detected suggesting involvement of a tumor suppressor gene located within this distal region of 1p. Further evidence for recurrent 1p loss in MPNST was obtained by interphase fluorescence in situ hybridization, which showed loss of 1p material in 3 out of 13 tumors. These findings together with data from the literature suggest that loss of a tumor suppressor gene located within distal 1p is implicated in the pathogenesis of MPNST.     

Risk and protective factors for suicidal behavior in abused African American women

This study examined risk and protective factors that differentiate low-income, abused African American women (N = 200) who attempted suicide from those who had never made a suicide attempt. Results from multivariate analyses revealed that numerous and/or severe negative life events, a history of child maltreatment, high levels of psychological distress and depression, hopelessness about the future, and alcohol and drug problems were factors associated with attempter status. Protective factors associated with nonattempter status included hopefulness, self-efficacy, coping skills, social support, and effectiveness in obtaining material resources. Culturally competent intervention approaches for abused women should target increasing their protective factors and reducing their risk factors to decrease the likelihood that these women engage in suicidal behavior.     

Single nucleotide variation analysis in 65 candidate genes for CNS disorders in a representative sample of the European population

The detailed investigation of variation in functionally important regions of the human genome is expected to promote understanding of genetically complex diseases. We resequenced 65 candidate genes for CNS disorders in an average of 85 European individuals. The minor allele frequency (MAF), an indicator of weak purifying selection, was lowest in radical amino acid alterations, whereas similar MAF was observed for synonymous variants and conservative amino acid alterations. In noncoding sequences, variants located in CpG islands tended to have a lower MAF than those outside CpG islands. The transition/transversion ratio was increased among both synonymous and conservative variants compared with noncoding variants. Conversely, the transition/transversion ratio was lowest among radical amino acid alterations. Furthermore, among nonsynonymous variants, transversions displayed lower MAF than did transitions. This suggests that transversions are associated with functionally important amino acid alterations. By comparing our data with public SNP databases, we found that variants with lower allele frequency are underrepresented in these databases. Therefore, radical variants obtain distinctively lower database coverage. However, those variants appear to be under weak purifying selection and thus could play a role in the etiology of genetically complex diseases.     

Quantification of HIV-1 p24 by a highly improved ELISA: an alternative to HIV-1 RNA based treatment monitoring in patients from Abidjan, C?te d'Ivoire.

BACKGROUND: Quantification of HIV-1 RNA remains difficult to implement in Africa. Simple and inexpensive tests for antiretroviral treatment (ART) monitoring are needed. OBJECTIVE: To evaluate an HIV-1 p24 ELISA, which combines efficient virus disruption, heat-denaturation and signal amplification, in a West African setting. STUDY DESIGN: Eighty-six HIV-1 infected patients from Abidjan, C?te d'Ivoire, were tested for p24, HIV-1 RNA, and CD4+ count at baseline, and twice within 8 months after ART initiation. RESULTS: All patients responded to ART with a minimal HIV-1 RNA drop of 0.5 log(10) at first follow-up. Forty-one (47.7%) then rebounded >0.5 log(10) or persisted above 1000 copies/mL by week 24. The predicted baseline concentration of p24 corresponding to 100,000 copies/mL of HIV-1 RNA, above which ART is recommended, was 4546 fg/mL (95% confidence interval 3148-6566). A prediction model of virologic failure, occurring after an initial response to ART, correctly classified 84% of patients using baseline p24, p24 change on therapy, and achievement of undetectable p24 as explanatory variables. The model and further bootstrap evaluation suggested a good ability to discriminate between sustained or failing virologic response to ART. CONCLUSION: HIV-1 p24 and RNA based-ART monitoring in a low-resource country dominated by HIV-1 CRF02 AG appeared comparable.     

Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects,increased cancer susceptibility,and male and female sterility

Exonuclease 1 (Exo1) is a 5'-3' exonuclease that interacts with MutS and MutL homologs and has been implicated in the excision step of DNA mismatch repair. To investigate the role of Exo1 in mammalian mismatch repair and assess its importance for tumorigenesis and meiosis, we generated an Exo1 mutant mouse line. Analysis of Exo1(-/-) cells for mismatch repair activity in vitro showed that Exo1 is required for the repair of base:base and single-base insertion/deletion mismatches in both 5' and 3' nick-directed repair. The repair defect in Exo1(-/-) cells also caused elevated microsatellite instability at a mononucleotide repeat marker and a significant increase in mutation rate at the Hprt locus. Exo1(-/-) animals displayed reduced survival and increased susceptibility to the development of lymphomas. In addition, Exo1(-/-) male and female mice were sterile because of a meiotic defect. Meiosis in Exo1(-/-) animals proceeded through prophase I; however, the chromosomes exhibited dynamic loss of chiasmata during metaphase I, resulting in meiotic failure and apoptosis. Our results show that mammalian Exo1 functions in mutation avoidance and is essential for male and female meiosis.