[Prediction by means of endogenous and exogenous evoked potentials of the favorable evolution of a prolonged coma]. / Prédiction au moyen des potentiels évoqués endogènes et exogènes de l'évolution favorable d'un coma prolongé.

A neurophysiological follow-up (EEG, exogenous and endogenous evoked potentials--EP) was performed over a 4-month period in a patient who presented a long-lasting coma following a cardiac arrest and an amniotic embolism. A pure anoxic aetiology was ruled out starting from the second day on the basis of a dissociation between mildly altered flash visual EP and markedly altered somatosensory EP, indicating focal brain-stem pathology. Endogenous EP reappeared after 12 days. This patient recovered consciousness after 51 days. Despite the absence of MRI abnormalities, we put forward the hypothesis that a brain-stem embolism had, in fact, worsened the clinical picture of an actually moderate anoxia. This case exemplifies the interest of an integrated neurophysiological approach (EEG, exogenous three-modality EP and endogenous EP) in the early evaluation of coma. It also illustrates the complement between structural imaging and functional assessment of the nervous system.

Quality of parenting and vulnerability to depression: results from a family study.

BACKGROUND: We examined a group of subjects at familial risk of depression and explored the relationship between the perceptions of parents and a history of depression. We also investigated: (a) whether any difference in perceived parenting found between those with and without a past history of depression was an artefact of the depression; and (b) whether the relationship between parenting and depression was explained by neuroticism. METHOD: We took a sample of first-degree relatives selected from a family study in depression and subdivided them by their history of mental illness on the SADS-L, into those: (a) without a history of mental illness (N = 43); and (b) those who had fully recovered from an episode of RDC major depression (N = 34). We compared the perceptions of parenting, as measured by the Parental Bonding Instrument (PBI), in these two groups having adjusted for the effect of neuroticism and subsyndromal depressive symptoms. We also had informants report on parenting of their siblings, the latter being subdivided into those with and without a past history of depression. RESULTS: Relatives with a past history of depression showed lower care scores for both mother and father combined compared with the never ill relatives. The presence of a history of depression was associated with a non-significant reduction in the self-report care scores compared to the siblings report. Vulnerable personality (as measured by high neuroticism) and low perceived care were both found to exert independent effects in discriminating between the scores of relatives with and without a history of depression and there was no interaction between them. CONCLUSION: This study confirmed that low perceived parental care was associated with a past history of depression, that it was not entirely an artefact of having been depressed, and suggested that this association was partially independent of neuroticism.

Does the method of data collection affect the reporting of depression in the relatives of depressed probands?

BACKGROUND: Data is usually collected from different sources in family studies in depression. We sought to determine what effect different methods of data collection had on the reporting of the lifetime prevalence of depression in the relatives of depressed probands. METHOD: We examined the psychiatric histories of 519 first-degree relatives of a consecutive series of 89 hospitalised depressed probands to ascertain their lifetime prevalence of RDC Major Depression. These data on relatives were obtained either directly with the SADS-L (n = 116), indirectly with the Family History RDC (FH-RDC) (n = 283) or by examining the casenotes of the probands (n = 120). RESULTS: The method of data collection had a marked effect on the reported prevalence of depression, with direct interview being much more sensitive in detecting the less severe forms of the illness. The lifetime prevalence of hospitalised depression in relatives, however, was unaffected by the method of the data collection. Variation in lifetime prevalence of depression between the SADS-L and FH-RDC appeared to be due mainly to differences in the sensitivity of the instrumentation rather than to biases in sampling. CONCLUSION: We confirm that indirect sources of family information have reduced sensitivity for the detection of depression in relatives compared with direct interview. LIMITATIONS: The numbers of relatives directly interviewed were small and the probands represented a severely affected sample which limits the generalisability of the findings. CLINICAL RELEVANCE: Combining data from different methods of collection in family studies is therefore problematic unless a narrow definition of caseness is used (e.g. depression requiring hospitalisation).

Family history as a predictor of poor long-term outcome in depression.

BACKGROUND: We investigated whether family history had prognostic significance in depression in a study which addressed some of the methodological shortcomings of previous studies. METHOD: We collected family history data on a consecutive series of 89 patients admitted with RDC major depression, blind to the outcome of the proband. This comprised 116, 283 and 120 first-degree relatives examined with the SADS-L, FH-RDC and case note data, respectively. The outcome of 74 of these probands (83%), previously categorised into four operationally defined groups, was then examined. RESULTS: A positive family history of severe psychiatric illness (i.e. a relative with a history of either a psychosis, hospitalised depression or suicide) was associated with poor outcome in the proband. This association persisted after controlling for variable family size, age structure and gender. As family history was correlated with neither Kendell's neurotic/psychotic index nor the proband's neuroticism score, an individual with high scores an all three would have a greatly increased chance of having a poor outcome. CONCLUSIONS: A family history of severe psychiatric illness in a first-degree relative may be useful as one of the vulnerability factors for predicting poor long-term outcome in depression.

Transfection of IL-2 augments CTL response to human melanoma cells in vitro: immunological characterization of a melanoma vaccine.

We have transfected human melanoma cell line 518A2 with the cDNA encoding interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and compared cytokine-producing clones for their ability to induce melanoma-specific cytotoxic T lymphocytes (CTL) from autologous peripheral blood mononuclear cells (PBMC) in vitro. The parental cell line expressed HLA-A1, HLA-A2, ICAM-1, LFA-3, in addition to the common CTL antigens MAGE-1, MAGE-3, tyrosinase, gp100, and Melan-A/MART-1. Stimulation of autologous PBMC responders with the IL-2-transfected clone 518/IL2.14 specifically induced CTL lines reactive with all cell lines derived from the autologous patient. Strikingly, GM-CSF-transfected 518A2 cells did not induce anti-tumor CTL reactivity. CTL induction against 518/IL2.14 was independent of HLA class II expression or CD4 help. The parental cell line 518A2 gained immunogenic properties when high concentrations of IL-2 were supplied exogenously, indicating that IL-2 produced and present at high levels locally by itself enhanced immunogenicity. From the autologous CTL line reactive with 518/IL2.14, clones were generated against an as yet unknown antigen, which was present in all autologous melanoma cell lines as well as in 7 of 15 HLA-A2+ melanoma cell lines tested, but not in melanocytes. These results will be discussed with respect to the possibility of using IL-2-transfected melanoma cells as a vaccine for treatment of patients with melanoma.

UV-induced N-ras mutations are T-cell targets in human melanoma.

Human cutaneous melanoma is heterogeneous with respect to the genetic aberrations involved and the genes altered are potential targets for the immune system. The incidence of cutaneous melanoma is known to be linked to UV peak exposure, and the N-ras oncogene is clearly one of the genes involved in the UV carcinogenesis in melanoma. It is mutated in a significant proportion of melanomas and therefore may serve as a target for T cells. Here, we report that an human leukocyte antigen-A2 binding peptide CLLDILDTAGL, encompassing the frequently found 61-Leu mutation in N-ras, induces cytotoxic T lymphocytes from healthy donor blood that lyse 61-Leu N-ras transfected melanoma cells. Furthermore, we have found an association between the presence of N-ras mutations and clinical response to immunotherapy with interleukin-2 plus interferon in a group of stage IV melanoma patients. Although the overall survival of these patients was not affected by the N-ras status of their melanomas, these studies suggest that mutated N-ras may provide a target for cytotoxic T lymphocytes in melanoma patients.

Peptide-pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA-A*0201-binding peptides from the Melan-A/MART-1 self antigen.

The melanoma antigen Melan-A/MART-1 was screened for the presence of potential HLA-A*0201-binding cytotoxic T lymphocytes (CTL) epitopes. The immunodominant nonamer epitope AAGIGILTV demonstrated weak binding to T2 but a significant half-life of binding to HLA-A*0201 in contrast to the decamer EAAGIGILTV. In addition to the immunodominant CTL epitope, we describe two peptides, GILTVILGV and ALMDKSLHV, that display stable binding to HLA-A*0201. Using cultured autologous dendritic cells pulsed with these peptides, CTL lines were induced from peripheral blood lymphocytes that displayed reactivity with HLA-A2+, Melan-A/MART-1+ melanoma cells. CTL reactivity against the immunodominant epitope could be induced with the nonamer epitope alone, but not with the decamer variant. CTL clones generated from an (EAAGIGILTV + AAGIGILTV)-induced CTL line recognize the appropriate melanoma cells and normal melanocytes. Upon further characterization of one of these CTL clones, it was found to be of surprisingly high affinity considering that it is directed against a self antigen. This study demonstrates that immunogenic peptides can be selected based on stability (half-life) of peptide/HLA binding. In addition, cultured DC were found to efficiently induce CTL responses in vitro against such selected peptides, and some of these CTL were capable of recognizing endogenously processed antigen.

Neuroticism: a vulnerability marker for depression evidence from a family study.

INTRODUCTION: We investigated the relationship between depressive illness and personality traits from the Eysenck Personality Inventory (EPI) using data from a family study. METHODS: The first-degree relatives of a series of 89 probands with RDC major depression (MD) were subdivided by their lifetime RDC diagnosis into: (1) relatives recovered from MD (n = 34); (2) never-ill relatives (n = 45). The neuroticism (N) and extraversion (E) scores of these two groups were compared using a multilevel linear model, allowing for potential confounders. The relationship between age of onset and recurrence of MD and N scores in group 1 was also examined. RESULTS: (1) Raised N scores were associated with a past history of major depression. (2) There was no such relationship for E scores. (3) Current depressive symptoms were also associated with an increased N score but this did not explain the relationship between previous major depression and N scores. (4) Recurrent episodes of major depression in the recovered MD relatives were significantly associated with increased N scores. CONCLUSION: These data suggest that raised N may be a vulnerability marker for major depression.

Induction and characterization of cytotoxic T-lymphocytes recognizing a mutated p21ras peptide presented by HLA-A*0201.

The ras oncogene is frequently found to be activated in human cancer through point mutations at codons 12, 13 or 61. We explored whether these altered p21ras protein sequences contain peptide sequences that can activate naive CD8+ cytotoxic T lymphocytes (CTL). Several wild-type and mutated p21ras peptides were identified that carry a binding motif for human leukocyte antigen (HLA)-A*0201. Two peptides were found to bind strongly to this allele. CD8+ CTL bulk cultures specifically reacting with one of these peptides could be induced, using processing-defective T2 cells loaded with peptide CLLDILDTAGL as stimulators. The peptide is derived from p21ras, position 51-61, and carries a 61 Gln-->Leu mutation. In contrast, a 9-mer peptide CLLDILDTA corresponding to amino acid sequence 51-59 of wild-type p21ras did not yield reactive CTL cultures. T-cell clones with low affinity for the 11-mer peptide were isolated from CLLDILDTAGL-reactive bulk cultures. These T cells did not lyse melanoma cells transfected with 61-Leu N-ras, although lysis was found when these transfectants were pulsed with the 11-mer peptide. Possibly, T cells of higher affinity may be required to demonstrate processed peptide on the cell surface. The combined experiments suggest that a peptide derived from mutated p21ras can be recognized by HLA class I-restricted CTL, whereas an analogous wild-type p21ras peptide may not be immunogenic.

Questionnaire screening for comorbid pervasive developmental disorders in congenitally blind children: a pilot study.

Teachers and parents completed the Autism Behavior Checklist (ABC) on a clinical sample of 17 congenitally blind children. Of the 17 children, 4 had a definite or likely pervasive developmental disorder (PDD) as judged by independent case note review. The ABC was administered both in its original format and in a slightly modified format. Only teacher-completed ABCs detected group differences and had satisfactory test-retest reliability. The modified-format ABC completed by teachers detected 3 of the 4 children with PDDs without any false positives. Screening questionnaires may have a limited but useful role in locating subjects with blindness plus putative PDDs for further study.

Structure and function of the corpus callosum in schizophrenia: What's the connection?

Tests of both structure and function of the corpus callosum have revealed abnormalities in schizophrenic patients. One such functional test employed lateralised Stroop stimuli presented tachistoscopically, to measure the transfer of interference and facilitation between the cerebral hemispheres. An attempt was made to relate indices of callosal transfer to clinical and demographic variables, including family history, as well as to indices of brain morphology. The latter included ventricle: brain ratio (VBR) measured by computed tomography (CT) scanning on 31 DSMIII schizophrenics, and the cross-sectional area of the corpus callosum from magnetic resonance imaging (MRI), obtained from 20 of these patients. VBR did not relate to functional measures; however, anterior callosal area correlated with indices of callosal connectivity. Patients with auditory hallucinations had smaller anterior callosal areas and tended to show less connectivity. The results show links between functional and structural measures of the corpus callosum, but their precise nature remains unclear.

N-myc expression switched off and class I human leukocyte antigen expression switched on after somatic cell fusion of neuroblastoma cells.

Neuroblastomas often show amplification and high expression of the N-myc oncogene. N-myc expression could be explained as a consequence of gene amplification, but an alternative possibility is that expression primarily results from the inactivation or loss of some factor that normally represses the N-myc gene. To test this idea, we fused N-myc-overexpressing neuroblastoma cell lines with lines that do not express N-myc. In the resulting hybrids, N-myc expression turned out to be switched off, although amplified N-myc copies were still present. This suggests that N-myc overexpression in neuroblastomas results, at least in part, from the inactivation of a suppressor gene that is present in normal cells. In rat neuroblastomas, it has been found that N-myc can switch off class I major histocompatibility complex (MHC) expression. Therefore, we analyzed in our hybrid cells whether suppression of N-myc results in reexpression of human class I MHC genes. Because this was found to be the case, the picture emerges of a hierarchic pathway that connects a putative tumor-suppressor gene with the expression of N-myc and consequently of class I MHC, thus affecting the potential immunogenic properties of neuroblastomas.