Personality disorders in bipolar and depressive disorders.

The association of mood disorders with personality disorders (PDs) is relevant from a clinical, therapeutic and prognostic point of view. To examine this issue, we compared the prevalence of DSM-III-R personality disorders assessed with SCID-II in patients with depressive (n = 117) and bipolar (n = 71) disorders both recovered from a major depressive index episode that needed hospital admission. PDs prevalence and comorbidity with axis I were calculated. Avoidant PD (31.6%) (O.R. = 1.7, C.I. = 1.06-2.9. P < 0.01), borderline PD (30.8%) and obsessive-compulsive PD (30.8%) were the most prevalent axis II diagnoses among patients with depressive disorder. In bipolar disorder group, patients showed more frequently obsessive-compulsive PD (32.4%), followed by borderline PD (29.6%) and avoidant PD (19.7%). Avoidant PD showed a trend toward being significantly more prevalent among depressives (P < 0.07). A different pattern of PDs emerges between depressive and bipolar patients.

[Personality disorders prevalence study among inpatients with mood disorders, psychoactive use disorders and anxiety disorders]. / Valutazione della prevalenza di disturbi di personalità in una popolazione di pazienti psichiatrici ospedalizzati per disturbi dell'umore, disturbi da uso di sostanze psicoattive e disturbi d'ansia.

OBJECTIVE: The aim of this study was to asses type and prevalence of Personality Disorders (PDs) and their patterns of comorbidity with Axis I disorders in a sample of psychiatric inpatients. SETTING: The sample consisted of 300 subjects admitted to a psychiatric unit on a voluntary bases for an index episode. The study was conducted over a period of 12 months, from 1.11.1997 to 31.10.1998. MAIN OUTCOME MEASURES: The Italian version of SCID-II-PQ (Structured Clinical Interview for DSM-III-R personality disorders, with Personality Questionnaire--PQ--a self report questionnaire). RESULTS: More than half the patients had at least one personality disorder. The mean of disorders per patient was 2.83 +/- 1.93 (+/- SD). The most prevalent Axis II disorders were Borderline PD (30.7%), Obsessive-compulsive PD (30.7%) and Avoidant PD (25.3%). Women were significantly more likely than men to meet criteria for Dependent PD and Avoidant PD. Man showed significantly more frequently than women Antisocial PD. Significant associations (p < 0.05) were found for comorbidity of Mood Disorders and Avoidant PD, and for Psicoactive Use Disorders and Antisocial PD. CONCLUSIONS: Our study confirms the high prevalence of PDs in psychiatric inpatients and showe some interesting associations between Axis I and Axis II disorders. These results can't be generalized to outpatients because our clinical sample involved mainly severely ill inpatients, but they raise questions about the exact nature of PDs and of the relationship with Axis I disorders. Further research involving outpatients and general population is needed to examine factors that could affect development and course of Personality Disorders.

Patterns of comorbidity among DSM-III-R personality disorders.

The aim of this study was to examine patterns of comorbidity among personality disorders (PDs) in a sample of 156 psychiatric inpatients. PDs were assessed with Semistructured Clinical Interview for DSM-III-R Personality Disorders. To determine significant co-occurrence among axis II diagnoses, odds ratio and the percent of co-occurrence of pairs of disorders were calculated. Both statistical methods revealed high rates of comorbidity: significance association was found for 36 pairs of disorders using the percent of co-occurrence, and for 22 pairs of disorders using the odds ratio. These results support the concept of 'apparent comorbidity' for most PDs, deriving from conceptual and definitional artifacts or from a 'state-biasing effect'. In light of these observations, a categorical approach to PDs, resulting in a list of diagnoses, appears useless in psychiatric practice. A dimensional classification is probably better suited for PDs, improving the understanding of personality psychopathology and its clinical implications.

Role of brain biopsy in the management of focal brain lesions in HIV-infected patients. Gruppo Italiano Cooperativo AIDS & Tumori.

In this multicenter, retrospective study of 160 brain biopsies in the assessment of HIV-related focal brain lesions, diagnostic sensitivity was acceptable (87%), but the procedure carried considerable morbidity (7.5%) and mortality (3.1%). Moreover, it is not always possible to initiate the changes in therapy indicated by the results, and overall survival remains poor, with a median of 2 months. Criteria for brain biopsy for the diagnosis of focal brain lesions should be redefined to include selected patients for whom a less invasive approach does not yield a definitive diagnosis.

Pattern of comorbidity among anxious and odd personality disorders: the case of obsessive-compulsive personality disorder.

The aim of this study was to examine the pattern of comorbidity among obsessive-compulsive personality disorder (OCPD) and other personality disorders (PDs) in a sample of 400 psychiatric inpatients. PDs were assessed using the Semistructured Clinical Interview for DSM-III-R Personality Disorders (SCID-II). Odds ratios (ORs) were calculated to determine significant comorbidity among OCPD and other axis II disorders. The most elevated odds ratios were found for the cooccurrence of OCPD with cluster A PDs (the "odd" PDs, or paranoid and schizoid PDs). These results are consistent with those of previous studies showing a higher cooccurrence of OCPD with cluster A than with cluster C ("anxious") PDs. In light of these observations, issues associated with the nosologic status of OCPD within the Diagnostic and Statistical Manual of Mental Disorders clustering system remain unsettled.

Expression of the JAK and STAT superfamilies in human meningiomas.

OBJECT: The goal of this study was to investigate whether the janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is present and active in meningiomas. The results of these investigations are important for all meningioma therapies that, similar to interferon-alpha-2B (IFNalpha-2B), depend on activation of this pathway for their effect. The authors were interested in evaluating the importance, if any, of the JAK/STAT pathway in the biology and therapy for these tumors. METHODS: Total proteins were extracted from 17 meningioma samples and the levels of JAKs and STATs were determined by using Western blot analysis. Levels of these proteins in meningiomas were compared with those found in normal dura. The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied. In tumors JAK and STAT levels were always significantly higher than those found in normal dura. Differences in relative levels were found when meningiomas were subdivided according to the current neuropathological criteria and the highest levels were found in transitional meningiomas. The authors also investigated, using tyrosine-phosphorylated Statl and Stat3 antibodies, whether STATs were activated in meningiomas and normal dura in vivo. Their results indicate that both Statl and Stat3 are phosphorylated in vivo in meningiomas and in the dura. Furthermore, in vitro experiments in which two independent short-term cultures obtained from freshly dissected meningioma samples were used indicated that Statl and Stat3 are phosphorylated in response to treatment with IFNalpha-2B. Exposure of meningioma cells to IFNalpha-2B leads to nuclear translocation of tyrosine-phosphorylated Statl and Stat3, as demonstrated by immunocytochemical analysis. CONCLUSIONS: The results of this study indicate that the JAK and STAT families of proteins are important effectors in brain tumors and support the idea that the effects of IFNalpha in vivo are direct and not mediated by the immune system. This suggests a role for modulation of STAT transcription factors in inhibiting meningioma cell proliferation.

Vitamin D metabolites activate the sphingomyelin pathway and induce death of glioblastoma cells.

1 alpha, 25-dihydroxyvitamin D3 was previously shown to induce cell death in brain tumour cell lines when added to the medium at micromolar concentration. In this paper we show that Cholecalciferol, a poor ligand of the vitamin D receptor, also induces cell death of HU197 human glioblastoma cell line and early passages cultures derived from a recurrent human glioblastoma. This finding suggests that the effects of vitamin D metabolites on brain tumour cells are at least partially independent from the activation of the classic nuclear receptor pathway. Vitamin D metabolites have been shown to activate the sphingomyelin pathway inducing an increase in cellular ceramide concentration. We determined the levels of sphingomyelin ceramide and ganglioside GD3 in Hu197 cells after treatment with cholecalciferol. A significant increase in ceramide concentration and a proportional decrease in sphingomyelin was already present after 6 hours of cholecalciferol treatment when no morphological changes were visible in the cultures. Treatment with ceramides (N-acetylsphingosine or natural ceramide from bovine brain) of the same cells also induces cell death. Similarly, treatment of the same cells with bacterial Sphingomyelinase also results in cell death. The demonstration of an increase in intracellular ceramide after cholecalciferol treatment and the ability of ceramide to induce cell death suggest that the sphingomyelin pathway may be implicated in the effect of vitamin D metabolites on human glioblastoma cells. Inhibition of ceramide biosynthesis by fumonisin B1 treatment did not alter the dose response curve of HU197 cells to cholecalciferol. Insensitivity to fumonisin B1 together with a decrease in sphingomyelin content after cholecalciferol treatment indicate that activation of sphingomyelinase should be responsible for the increase in intracellular ceramide concentration.

Variations in the levels of the JAK/STAT and ShcA proteins in human brain tumors.

BACKGROUND: Recent demonstrations that the JAK/STAT and ShcA signalling proteins are abundant in the developing CNS at the stage of maximal cell proliferation prompted us to determine whether these proteins were expressed in various human brain tumors. MATERIALS AND METHODS: Using Western blot assay, we analyzed specimens from control peritumoral brain tissue, medulloblastomas, ependimomas, astrocytomas, anaplastic astrocytomas and glioblastomas. RESULTS: Our analyses revealed that Jak1 and Stat3 were consistently more elevated in low grade gliomas (LG) (tumors characterized by a more pronounced glial phenotype) as compared to high grade gliomas (HG) (less differentiated glial tumors). The other STAT proteins were equally expressed, while Stat1 was slightly higher in LG gliomas. Among the other tumors analyzed, medulloblastoma contained the highest level of Jak1 and Stat3, while ependymoma showed elevated levels of ShcA proteins. CONCLUSIONS: These differences may reflect differences in the biological characteristics of the various tumors and may provide insight for further mechanistic studies to investigate the importance of particular signal transduction pathways in CNS tumors.

Basal ganglia precursors found in aggregates following embryonic transplantation adopt a striatal phenotype in heterotopic locations.

Transplantation of immature CNS-derived cells into the developing brain is a powerful approach to investigate the factors that regulate neuronal position and phenotype. CNS progenitor cells dissociated from the embryonic striatum and implanted into the brain of embryos of the same species generate cells that reaggregate to form easily recognizable structures that we previously called clusters and cells that disperse and integrate as single cells into the host brain. We sought to determine if the neurons in the clusters differentiate according to their final location or acquire a striatal phenotype in heterotopic positions. We transplanted dissociated cells from the E14 rat medial and lateral ganglionic eminences, either combined or in isolation, into the E16 embryonic rat brain. At all time points, we found clusters of BrdU- and DiI-labelled donor cells located in the forebrain and hindbrain, without any apparent preference for striatum. Immunocytochemical analyses revealed that cells in the clusters expressed DARPP-32 and ARPP-21, two antigens typically co-expressed in striatal medium-sized spiny neurons. In agreement with observations previously noted by several groups, isolated cells integrated into heterologous host areas do not express basal ganglia phenotypes. These data imply that immature striatal neuronal progenitors exert a community effect on each other that is permissive and/or instructive for development of a striatal phenotype in heterotopic locations.

Disseminated encephalitis following streptococcal infection.

Various neurological disorders have been related to Streptococcus pyogenes infection. Only recently, and for the first time, it has been suggested that acute disseminated encephalitis may also complicate a streptococcal infection. The case reported in this paper seems to confirm this hypothesis.

Hyperthermia in the treatment of brain metastases from lung cancer. Experience on 17 cases.

Medium or long-term survival in metastatic "non oat cell" lung tumors is seldom possible only if surgery can eradicate the lesion. Out of 17 patients treated with hyperthermia plus nitrosoureas 16 (94%) responded, with clinical improvement, radiological regression or disease stabilization. The survival time of the improved patients was 12.7 months. Hyperthermia in combination with nitrosoureas seems to allow clinically and radiologically satisfactory responses in lung tumors metastatic to the brain.

In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N-nitrosourea] by simvastatin.

The effects of a combination of simvastatin, a cholesterol-lowering agent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on experimental C6 glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 microM) markedly and synergistically increased the BCNU toxicity to C6 glioma cells. The cytofluorimetric analysis of DNA from simvastatin-treated C6 glioma cells showed, besides the already described arrest in G1, an arrest/retardation in G2-M. Mitotic index from C6 cells incubated with simvastatin (10 microM) decreased by about 90%, indicating a specific C6 arrest/retardation in G2. The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultured cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G2-M compartment of the cell cycle. In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of the lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) resulted in a significant growth delay (compared to either drug alone) in C6 glioma (P < 0.05). There was no significant increase in toxicity as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in vivo support for the combined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment.

Effects of vitamin D and retinoic acid on human glioblastoma cell lines.

The biological significance of vitamin D receptors expressed by glioblastoma and other glial tumours is still unclear. In an effort to clarify this issue we studied the effects of increasing concentrations of 25-dihydroxyvitamin D3 and its metabolite 1 alpha,25-dihydroxyvitamin D3 on two human glioblastoma cell lines. Both substances were capable of inducing a significant (> 50%) reduction in growth of the two glioblastoma cell lines at dosages over 5 microM. When the HU 70 cell line was treated by increasing dilutions of 25-dihydroxyvitamin D3 combined with 1 microM all trans-retinoic acid, significant inhibition was apparent even after addition of 25-dihydroxyvitamin D3 in the nanomolar range. Reduction of growth index was mainly due to induced cell death. Our results provide in vitro evidence that vitamin D metabolites alone or in combination with retinoids may be potentially useful agents in the differentiation therapy of human malignant gliomas.

A short term analysis of the behaviour of conditionally immortalized neuronal progenitors and primary neuroepithelial cells implanted into the fetal rat brain.

Conditionally immortalized (temperature-sensitive) striatal-derived neuronal progenitor cell lines and primary neuroepithelial cells were transplanted into the CNS of gestational day 15-16 rat fetuses using an 'in utero' surgical procedure. Each fetus received 2.5-3 x 10(4) donor cells previously labelled in vitro by incubation with 5-bromo-2'-deoxyuridine (BrdU). At 5 days following transplantation, 69% of the fetuses were still alive. Engrafted cells were detected by BrdU immunohistochemistry, and the appearance of the engrafted cells and the time course of Nestin and PCNA expression were measured at 6, 24, 64 h and 5 days after transplantation. The evolution of Large T-Antigen immunoreactivity in engrafted temperature-sensitive (ts) cells was also evaluated at the above time intervals. The results indicate that the majority of the implanted cells were aggregated into clusters 24 h after transplantation. These clusters were not visible at 6 h, when most of the cells were isolated. The clusters were located in both the ventricles and parenchyma. These findings were common to both ts cells and striatal primary neuroepithelial cells. At 64 h and 5 days, isolated cells associated with the germinal layer and scattered throughout the parenchyma were also found. In the clusters, Nestin expression decreased proportionally with time following transplantation. Furthermore, Large T-Antigen immunoreactivity disappeared from ts cells between 6 and 24 h after transplantation. Finally, measurements of the temporal evolution of PCNA expression within the clusters indicate a progressive reduction in the mitotic activity of the transplanted cells. The results demonstrate that striatal primary neuroepithelial cells and conditionally immortalized neuronal progenitors can survive, migrate and/or compartimentalize into clusters whilst changing their antigenic properties and ability to proliferate.

The expression of genes of the steroid-thyroid hormone receptor superfamily in central nervous system tumors.

We studied the expression of ten genes (encoding the receptors for glucocorticoid, mineralocorticoid, progesterone, androgen, estrogen, thyroid, retinoid acid, vitamin D) belonging to the steroid-thyroid hormone receptor superfamily (STRS) in 12 neuroepithelial tumors, 12 meningiomas and 2 human glioblastoma cell lines. Our method, based on the polymerase chain reaction, allowed the simultaneous amplification of cDNAs of the STRS genes. On average, 7 STRS genes were simultaneously expressed in each sample. Our study indicates that many STRS gene are commonly co-expressed in human CNS tumors. The importance of our results for the ongoing and proposed hormonal treatment trials is discussed.

Proliferative effect of dexamethasone on a human glioblastoma cell line (HU 197) is mediated by glucocorticoid receptors.

The relationship between Dexamethasone proliferative activity and the presence of glucocorticoid receptors was studied on a human glioblastoma cell line (HU 197). For this purpose, the 17 beta-Carboxamide steroid DXB, a glucocorticoid antagonist that competes with Dexamethasone for binding to the intracellular glucocorticoid receptor but does not trigger the glucocorticoid effect, was used. Concurrent treatments with Dexamethasone and DXB caused an inhibition of the proliferative effect obtained by Dexamethasone. The results obtained demonstrated that the Dexamethasone activity on cell proliferation is a specific receptor-mediated effect.

Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells.

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.

Vitamin D receptor expression in human brain tumors.

Vitamin D receptor (VDR) has important effects not only on physiological processes related to Ca2+ metabolism but also on cell growth and differentiation. VDR is a member of the Steroid-Thyroid Receptors Superfamily (STRS). Work in our and other laboratories has shown that several other members of the STRS (androgen, estrogen, glucocorticoid, and progesterone receptors) are present in astrocytomas and glioblastomas. We now report the finding of VDR-like mRNA in human anaplastic astrocytomas and glioblastomas. VDR mRNA levels, as determined by a method, developed in our laboratory, based on the polymerase chain reaction, are significantly higher in glioblastomas compared to both low and high grade astrocytomas. We discuss the biological and clinical implications of our results.

[State of the art in the treatment of cerebral gliomas]. / Stato dell'arte sul trattamento dei gliomi cerebrali.

Current knowledge on the multiple aspects of intracranial glioma is presented. In particular, after illustrating the most recent epidemiological data and the latest acquisitions in the biological and biochemical fields, the present status of multidisciplinary treatment (surgery, radiotherapy, and chemo-immunotherapy) of these neoplasia is described.