Familiality of temperament in bipolar disorder: support for a genetic spectrum

BACKGROUND: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls. METHODS: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. RESULTS: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. LIMITATIONS: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. CONCLUSIONS: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.     

Requests for euthanasia or physician-assisted suicide from older persons who do not have a severe disease: an interview study

OBJECTIVE: To determine how often requests are made for euthanasia and physician-assisted suicide (EAS) in the absence of severe disease and how such requests are dealt with in medical practice in The Netherlands. METHOD: Retrospective interview study. Participants: 125 general practitioners (GPs), 77 nursing home physicians (NHPs), and 208 clinical specialists. RESULTS: In The Netherlands, each year approximately 400 people request EAS, because they are 'weary of life'. Thirty per cent of all physicians have at some time received an explicit request for EAS in the absence of severe disease; 3% of all physicians had granted a request for EAS in such a case. Most requests for EAS to GPs in the absence of severe disease (n = 29) were made by single people aged 80 years and over. While their problems were most frequently of a social nature, 79% had one or more non-severe illnesses. Most GPs refused the request; half of them proposed an alternative treatment, which the patient often refused. Nineteen people who did not receive any treatment persisted in their wish to die; the request for EAS from 5 out of 10 patients who received one or more types of treatment was withdrawn or became less explicit. CONCLUSIONS: Most physicians in The Netherlands refuse requests for EAS in the absence of severe disease. Most patients persist in their request. In an ageing population more research is needed to provide physicians with practical interventions to prevent suicide and to make life bearable and satisfactory for elderly people who wish to die.     

Low elementary movement speed is associated with poor motor skill in Turner's syndrome

The article aims to discriminate between 2 features that in principle both may be characteristic of the frequently observed poor motor performance in girls with Turner's syndrome (TS). On the one hand, a reduced movement speed that is independent of variations in spatial accuracy demands and therefore suggests a problem in motor execution. On the other hand, a disproportional slowing down of movement speed under spatial-accuracy demands, indicating a more central problem in motor programming. To assess their motor performance problems, 15 girls with TS (age 9.6-13.0 years) and 14 female controls (age 9.1-13.0 years) were tested using the Movement Assessment Battery for Children (MABC). In additionally, an experimental procedure using a variant of Fitts' graphic aiming task was used to try and disentangle the role of spatial-accuracy demands in different motor task conditions. The results of the MABC reestablish that overall motor performance in girls with TS is poor. The data from the Fitts' task reveal that TS girls move with the same accuracy as their normal peers but show a significantly lower speed independent of task difficulty. We conclude that a problem in motor execution is the main factor determining performance differences between girls with TS and controls.     

A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth

Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). We show here, using both Xenopus laevis embryonic neuronal culture and intact X. laevis embryos, that the nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue. Expression of a mutated form of synapsin that prevents phosphorylation at this site, or introduction of phospho-specific antibodies directed against this site, decreased basal and dibutyryl cAMP-stimulated neurite outgrowth. Expression of a mutation mimicking constitutive phosphorylation at this site increased neurite outgrowth, both under basal conditions and in the presence of a PKA inhibitor. These results provide a potential molecular approach for stimulating neuron regeneration, after injury and in neurodegenerative diseases.     

Nest building in nulligravid,primigravid and primiparous C57BL/6J and DBA/2J mice (Mus musculus)

C57BL/6J (B6) and DBA/2J (D2) mice differ in maternal behavior and nest building, but previous observations on nest building appear to be contradictory. Lactating B6 females spent more time nest building than lactating D2 females [Physiol. Behav. 67 (1999) 599.]; however, pregnant D2 females have been reported to build better nests than pregnant B6 females [Physiol. Behav. 29 (1982) 153.]. To resolve this apparent discrepancy, virgin B6 and D2 females were mated, and the nest quality of nulligravid, primigravid and lactating primiparous females was compared between groups and with that of virgin females. There were no strain differences in the nest ratings of virgin or mated nulligravid females, nor did these groups differ within strains. Pregnant and lactating females of both strains built better nests than nonpregnant females. There was an increase in nest ratings in both strains on the day of parturition. The nest ratings of pregnant and lactating females were higher in B6 than D2 females. The largest strain differences were observed between pregnant B6 and D2 females. One hypothesis to account for these results is that females of these two strains differ in their levels of or sensitivity to hormones during pregnancy and parturition.     

Chromosome 13q neocentromeres: molecular cytogenetic characterization of three additional cases and clinical spectrum

We report three new cases of chromosome 13 derived marker chromosomes, found in unrelated patients with dysmorphisms and/or developmental delay. Molecular cytogenetic analysis was performed using fluorescence in situ hybridization (FISH) with chromosome-specific painting probes, alpha satellite probes, and physically mapped probes from chromosome 13q, as well as comparative genomic hybridization (CGH). This analysis demonstrated that these markers consisted of inversion duplications of distal portions of chromosome 13q that have separated from the endogenous chromosome 13 centromere and contain no detectable alpha satellite DNA. The presence of a functional neocentromere on these marker chromosomes was confirmed by immunofluorescence with antibodies to centromere protein-C (CENP-C). The cytogenetic location of a neocentromere in band 13q32 was confirmed by simultaneous FISH with physically mapped YACs from 13q32 and immunofluorescence with anti-CENP-C. The addition of these three new cases brings the total number of described inv dup 13q neocentic chromosomes to 11, representing 21% (11/52) of the current overall total of 52 described cases of human neocentric chromosomes. This higher than expected frequency suggests that chromosome 13q may have an increased propensity for neocentromere formation. The clinical spectrum of all 11 cases is presented, representing a unique collection of polysomy for different portions of chromosome 13q without aneuploidies for additional chromosomal regions. The complexity and variability of the phenotypes seen in these patients does not support a simple reductionist view of phenotype/genotype correlation with polysomy for certain chromosomal regions.     

Computational fluid dynamics modeling of impeller designs for the HeartQuest left ventricular assist device

To finalize the design of the next generation of the HeartQuest left ventricular assist device, a suitable impeller had to be designed and tested. The new prototype was based on calculations and test results of previous designs, but required several changes to decrease the size. For most pump designs, this is a simple matter of altering impeller geometry and rotational speed to achieve the desired pressure rise and flow rate. However, this particular pump was limited by housing geometry and the magnetic bearings that support the impeller. Without much freedom in the overall impeller size, the only parameters open to the designers were the blade profiles and the rotating speed. Rather than build several candidates and test them in a rig at enormous cost, computational models of several designs were tested and analyzed. This not only saved money, but also sped up the development time for the project. The computer models were developed in TASCflow, a computational fluid dynamics software package from AEA Technologies. This paper analyzes the data from several of the selected models, paying close attention to pumping performance and general trends from specific design changes.     

Viral hemagglutinin augments peptide-specific cytotoxic T cell responses

In attempt to increase the induction of peptide-specific cytolytic T cells (CTL) we investigated the effect of the Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) gene product on the activation of peptide-specific CTL. Spleen cells of CH3 mice immunized against the influenza nucleoprotein peptide 50–63 (NP 50–63) were restimulated in vitro (i) with peptide-pulsed syngeneic fibroblast cells (Ltk^?) as antigen-presenting cells, which were in addition (ii) infected with NDV or (iii) stably transfected with the HN cDN A of NDV. A greater than sixfold increase in peptide-specific CTL responses was observed in cultures restimulated with peptide-pulsed Ltk^? cells which co-expressed viral hemagglutinin due to either infection or transfection. A similar augmentation was seen in CTL responses against other types of antigen (major histocompatibility complex alloantigens, minor histocompatibility antigens or tumor antigens) when suboptimal cultures were stimulated with the respective antigen-presenting cells modified by NDV infection. These findings suggest that NDV or viral HN expressed on antigen-presenting cells or tumor cells can exert a T cell co-stimulatory function.     

Reduced primary antibody responses in a genetic animal model of depression

OBJECTIVE: Clinical depression is associated with multiple abnormalities of immune function, including reduced virus-specific responses. This study tested the hypothesis that the Flinders Sensitive Line (FSL) rat, a promising genetic animal model of depression, would exhibit reductions in antigen-specific primary antibody responses to immunization. METHODS: FSL (N = 13) and control Flinders Resistant Line (FRL; N = 14) rats were immunized with the protein antigen keyhole limpet hemocyanin (KLH; 300 microg/kg), and KLH-specific immunoglobulin (Ig)M, IgG, IgG1, and IgG2a responses were measured before and 3, 5, 7, 11, and 14 days after immunization. In separate experiments, production of interferon-gamma (IFN-gamma) by cells from naive and KLH-immunized animals was measured in vitro to determine whether strain differences in antibody production might be associated with differential production of this regulatory cytokine. RESULTS: KLH-specific production of IgM (p <.01) and IgG2a (p <.05) was significantly reduced in the FSL rats compared with the FRL controls. There were no strain differences in IgG or IgG1 production. Although IFN-gamma production between the two strains was similar in naive animals, cells from KLH-immunized FSL rats produced significantly less IFN-gamma when stimulated with KLH in vitro than cells from KLH-immunized FRL controls (p =.01). CONCLUSIONS: This study extends previous reports of altered immune function in the FSL rats to include reduced in vivo antigen-specific antibody responses. Moreover, diminished production of IFN-gamma by KLH-primed lymphocytes may contribute to lower antibody production in these animals. Collectively, these data suggest deficiencies in type 1 T-helper cell-mediated immunity in the FSL rats.     

Dose-intensive therapy for extensive-stage small cell lung cancer and extrapulmonary small cell carcinoma: long-term outcome.

Treatment for extensive-stage small cell lung cancer (ES SCLC) or extrapulmonary small cell carcinoma (EPSC) is typically palliative. We set out to determine progression-free survival (PFS) and overall long-term survival of ES SCLC and EPSC patients, physiologically aged < or = 60 years, responding to first-line chemotherapy followed by high-dose combination alkylating agents with hematologic stem cell support. Patients in first-line chemotherapy response underwent stem cell collection (marrow, peripheral blood progenitor cells, or both) followed by high-dose therapy with 1 of 2 regimens: CBP (cyclophosphamide, cisplatin, and carmustine) or ICE (ifosfamide, carboplatin, and etoposide) with or without etanidazole. Involved-field radiotherapy was given to selected patients with oligometastatic disease distributed in sites allowing for reasonable radiation ports, and prophylactic cranial radiotherapy was given upon recovery to patients in complete response (CR) or near-CR. A total of 36 patients were treated. Of 29 patients with ES SCLC, 6 (21%) had achieved CR, 18 near-CR, and 5 partial response prior to high-dose therapy. Of 7 patients with EPSC, 3 (43%) had achieved CR, 3 had achieved near-CR, and 1 had progression of disease prior to high-dose therapy. Thirteen ES SCLC patients received high-dose CBP. Of the remaining 23 patients with SCLC or EPSC, 17 were treated with ICE and 6 with ICE plus etanidazole, a hypoxic cell sensitizer. Treatment-related mortality was 11% (4 of 36 patients). For all patients, the median event-free survival (EFS) was 5 months. The 2- and 5-year survivals after intensification were 12% (95% confidence interval [CI], 5%-31%) and 9% (95% CI, 3%-27%), respectively. Of the 30 patients in or near CR prior to high-dose therapy, 5 remain continuously progression-free (2 ES SCLC, 3 EPSC) for a median of 55 months (range, 1-96 months) after high-dose therapy. By multivariate analysis, factors associated with more favorable EFS were the use of a more aggressive induction regimen (ICE), and the EPSC histology. These factors were also associated with more favorable overall survival. Other factors associated with more favorable overall survival were the use of short induction therapy (< or = 4 cycles) and younger age (<50 years). Except for high-dose ICE with etanidazole, the use of high-dose systemic therapy in ES SCLC and EPSC was associated with low treatment-related morbidity and mortality over the past 5 years. Late complications were infrequent, and most patients returned to full-time work and activity, barring disease recurrence. Nonetheless, few patients with ES SCLC have progression-free long-term survival. We conclude that high-dose therapy is not indicated as an approach for ES SCLC, except as part of an investigative trial. Conversely, 3 of the 7 patients with EPSC remain relapse-free (range, 1-96 months), warranting further phase II evaluation of this approach in this population.