Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: A positron emission tomography study in healthy subjects

The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D(2/3)-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[(18)F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [(18)F]fluorodopamine formed in brain (k(loss)) and the storage for FDOPA and its brain metabolites (V(d)). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [(18)F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [(18)F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in individuals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D(1)-receptor mediated transmission during D(2) blockade.     

Hemodynamic effects of thoracic epidural analgesia in ovine hyperdynamic endotoxemia

BACKGROUND AND OBJECTIVES: Thoracic epidural analgesia (TEA) is increasingly used for perioperative analgesia. If patients with TEA develop sepsis or systemic inflammatory response subsequent to extended surgery the question arises if it would be safe to continue TEA with its beneficial effects of improving gastrointestinal perfusion and augmenting tissue oxygenation. A major concern in this regard is hemodynamic instability that might ensue from TEA-induced vasodilation. The objective of the present study was to assess the effects of TEA on systemic and pulmonary hemodynamics in a sepsis model of hyperdynamic endotoxemia. METHODS: After a baseline measurement in healthy sheep (n = 14), Salmonella thyphosa endotoxin was continuously infused at a rate of 10 ngxkg(-1)xmin(-1) over 16 hours. The surviving animals (n = 12) were then randomly assigned to 1 of 2 study groups. In the treatment group (n = 6), continuous TEA was initiated with 0.1 mLxkg(-1) bupivacaine 0.125% and maintained with 0.1 mLxkg(-1)xh(-1). In the control group (n = 6) the same amount of isotonic sodium saline solution was injected at the same rate through the epidural catheter. RESULTS: In both experimental groups cardiac index increased and systemic vascular resistance decreased concurrently (each P < .05). Functional epidural blockade in the TEA group was confirmed by sustained suppression of the cutaneous (or panniculus) reflex. During the observational period of 6 hours neither systemic nor pulmonary circulatory variables were impaired by TEA. CONCLUSIONS: From a hemodynamic point of view, TEA presents as a safe treatment option in sepsis or systemic inflammatory response syndrome.     

Targeting cytotoxic T cells to antigen-specific B lymphocytes

A recent development in immunomanipulation involves the targeting of cytotoxic T lymphocytes (CTL) to cell-bound antigens using bispecific antibodies. These antibodies have been engineered such that specificity is directed against the T cell receptor (TCR) or TCR-associated T3 molecules, as well as against the chosen antigen. The present study was aimed to force interactions between T and B cells by bridging their receptors. F23.1 antibodies, which are specific for gene products of the TCR V beta 8 gene family, were conjugated with TNP (2,4,6-trinitrophenyl) and this construct was used to bridge the receptors of V beta 8+ T cells with the receptors of TNP-specific B cells. The bridging was demonstrated by direct killing of both a TNP-specific B hybridoma and of blast cells from mice transgenic for mu, kappa of the TNP-specific antibody Sp6. Further, F23.1-TNP constructs in conjunction with V beta 8+ CTL were shown to specifically deplete Ig-secreting B cells from Sp6 transgenic mice. Conjugates of TCR-specific antibodies and antigen are theoretically useful in vivo to either deplete or expand B cells of a given specificity by coupling their receptors to the TCR of CTL or T helper cells, respectively.     

Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0–3, 7–10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4⁺ and CD8⁺ T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.     

Intraindividueller Vergleich von α- und β-TCP-Keramik im Tierexperiment

In the quest for bioinert adaptable alloplastic materials, TCP ceramics have gained a new application in craniofacial bone substitutes. Therefore, a histomorphological, intraindividual, comparative study was conducted on seven adult Goettingen miniature pigs (GMP) to analyze the difference of the degradation and remodelling processes of α-TCP and β-TCP in critical size defects of the proximal tibiae. In addition, primary insertion of dental implants followed to study osseous integration. The critical size defects, which were created in the proximal tibiae in GMPs, were filled on the left side with β-TCP and on the right side with α-TCP. Two GMPs were used as control group. After 4–68 weeks of investigation, the GMPs were sacrificed by narcosis. The histological investigation showed that these ceramics have an osteoconductive effect. It was noted that ossification proceeds centripetally. It could be demonstrated that the degradation of the materials follows a hydrolytical process and that the intratrabecular integrated ceramic remnants follow a dynamic remodelling process. Within 68 weeks after implantation, 90% of the TCP granulae were degraded. Macrophages were found in the marrow space, containing microparticles of TCP, especially after α-TCP implantation. In conclusion, defined degradation of these ceramics allows early functional bone regeneration with an additional undisturbed biofunctional unisotrop orientation of new trabeculae. Furthermore, dental implants should be inserted 5–6 months after TCP implantation.     

Gene transfer experiments imply instructive role of major histocompatibility complex class I molecules in cellular peptide processing.

DBA/2-derived mouse tumor cells were transfected with the H-2 Kb gene. Naturally processed minor histocompatibility (H) peptides were extracted from both transfected and non-transfected cells by acid elution, and were separated by high-performance liquid chromatography. Kb-restricted minor H epitopes corresponding to H-4b and mapki, both encoded by non-major histocompatibility complex genes of DBA/2, were readily detected by the respective cytotoxic T lymphocyte in peptides extracted from Kb-transfected, but not from non-transfected or Db-transfected cells. Titration experiments indicated at least 3000-fold less copies of correctly processed Kb-restricted epitopes in cells without Kb as compared to cells with Kb. Since we estimate the copy number of Kb-restricted H-4b epitopes in Kb-expressing transfectants to be less than 1000 per cell, the pool size of H-4b epitopes correctly processed in the absence of Kb should be less than 1/3 copy per cell.     

Copenhagen Community Psychiatric Project (CCPP): characteristics and treatment of homeless patients in the psychiatric services after introduction of community mental health centres

The main purpose of the study was to describe the characteristics of homeless psychiatric patients, and to compare the treatment they are offered to that offered to domiciled patients by the psychiatric services. Another purpose was to analyse the prevalence of homelessness among psychiatric patients before and after the introduction of community mental health centres in Copenhagen. Cross-sectional studies were conducted in two intervention and two control districts before and after introduction of the new treatment modalities. In 1991, 80 of 1008 patients (8%) were homeless. Male sex, young age, living on general welfare, schizophrenia and alcohol or substance abuse were the factors that most markedly differentiated homeless from domiciled patients. Compared with the treatment of domiciled patients, the homeless were more likely to be offered no further treatment after consultation in a psychiatric emergency and, if admitted, they were more likely to be placed in locked wards, given compulsory medication, and medicated with depot neuroleptics. The homeless were also less likely to be offered psychotherapy and consultation with a social worker. Schizophrenia and alcohol or substance abuse characterised the majority of the patients discharged homeless. In the intervention districts, the number of homeless patients in contact with the psychiatric services was found to increase at the same rate as the number of all patients in contact with the psychiatric services. In the control districts, no changes in prevalence of homeless patients or other patients in contact with the psychiatric services occurred. It is concluded that homeless psychiatric patients comprise a difficult patient group, with problems of schizophrenia, substance abuse and lack of motivation for treatment. It is recommended that special efforts be made to create housing facilities that fit the needs of different types of homeless patients, and that the homeless mentally ill are assisted in obtaining and maintaining an acceptable housing situation.     

Attachment, personality, and psychopathology among adult inpatients: self-reported romantic attachment style versus Adult Attachment Interview states of mind

The present study examined self-reported romantic attachment style and Adult Attachment Interview (AAI) states of mind regarding early attachment relationships, personality dimensions, and psychopathology in a psychiatric sample of trauma survivors. Inpatients (N = 80) admitted to a hospital trauma treatment program were administered the Experiences in Close Relationships Scale, AAI, Millon Clinical Multiaxial Inventory-III, Dissociative Experiences Scale, and Dissociative Disorder Interview Schedule. Self-report and AAI attachment classifications were not related, and different results emerged for the two measures. Self-reported romantic attachment style was significantly associated with personality dimensions, with fearful adults showing the most maladaptive personality profiles. Findings suggested that self-report dimensions of self and other independently contribute to different forms of psychological dysfunction. AAI unresolved trauma was uniquely associated with dissociation and posttraumatic stress disorder, whereas unresolved trauma and unresolved loss jointly contributed to schizotypal and borderline personality disorder scores. The differences in findings between the two measures are discussed with a view toward the developmental and clinical implications.