Integrated Treatment at the First Stage: Increasing Motivation for Alcohol Patients with Comorbid Disorders during Inpatient Detoxification.

AIMS: Co-occurring mental disorders can complicate the detoxification treatment process and outcome. The aim of this study is to examine whether a brief psychoeducational group counseling session during detoxification treatment can increase the motivation for and utilization of subsequent treatments. SHORT SUMMARY: Interventions increased utilization of post-detoxification treatment and reduced alcohol-related readmissions. Higher depression or trauma scores were associated with higher rates of utilization of treatment. METHODS: Patients received either a brief manualised group intervention on the interrelation of alcohol use disorder (AUD) and major depression (MD) or AUD and post-traumatic stress disorder (PTSD) or a cognitive training session (control group). Of the 784 patients treated in the study period, 171 participants were quasi-randomly allocated to groups. Self-reported motivation was measured before and after intervention, transition into AUD treatment and readmissions were collected after detoxification treatment. RESULTS: Participating in any of the intervention groups increased the utilization of AUD treatment after inpatient detoxification (χ2 = 6.15, P = 0.02) and decreased readmissions 6 months after discharge (χ2 = 7.46, P = 0.01). Depression and trauma scores moderated the effect: associations with the utilization of post-detoxification treatment were found in participants with higher depression (OR = 5.84, 95% CI = 1.17-29.04) or trauma scores (OR = 10.17, 95% CI = 1.54-67.1). CONCLUSIONS: An integrated intervention approach for dual diagnosis at the beginning of the treatment can increase motivation for continued AUD treatment. Especially affected dual diagnosis patients can benefit from this treatment.

A multimerized form of recombinant human CD40 ligand supports long-term activation and proliferation of B cells.

BACKGROUND AIMS: CD40-activated B cells have long been studied as potent antigen-presenting cells that can potentially be used for cancer immunotherapy. Nevertheless, their use in human clinical trials has been limited by the lack of a Good Manufacturing Practice-grade soluble human CD40 ligand that is able to induce activation and proliferation of primary B cells. We describe an in vitro method to effectively generate and expand B cells through the use of a multimerized form of human recombinant CD40 ligand (rCD40L). METHODS: Human B cells were isolated from healthy donors and cultivated with either rCD40L or on a monolayer of murine NIH3T3 cells stably expressing human CD40L (NIH3T3/tCD40L) as a widely used standard method. Morphology, expansion rate, immune phenotype and antigen presentation function were assessed. RESULTS: B cells efficiently proliferated in response to rCD40L over 14 days of culture in comparable amounts to NIH3T3/tCD40L. B-cell division in response to CD40L was also confirmed by carboxyfluorescein succinimidyl ester dilution. Moreover, rCD40L induced on B cells upregulation of co-stimulatory molecules essential for antigen presentation. Additionally, proliferation of T cells from allogeneic healthy volunteers confirmed the immunostimulatory capacities of CD40-activated B cells. CONCLUSIONS: We demonstrated that B cells with potent antigen presentation capacity can be generated and expanded by use of a non-xenogeneic form of CD40L that could be implemented in future human clinical settings.

CD40-activated B cells induce anti-tumor immunity in vivo.

The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naïve and memory CD4+ and CD8+ and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T-cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy.

In vitro and in vivo imaging of initial B-T-cell interactions in the setting of B-cell based cancer immunotherapy.

There has been a growing interest in the use of B cells for cancer vaccines, since they have yielded promising results in preclinical animal models. Contrary to dendritic cells (DCs), we know little about the migration behavior of B cells in vivo. Therefore, we investigated the interactions between CD40-activated B (CD40B) cells and cytotoxic T cells in vitro and the migration behavior of CD40B cells in vivo. Dynamic interactions of human antigen-presenting cells (APCs) and T cells were observed by time-lapse video microscopy. The migratory and chemoattractant potential of CD40B cells was analyzed in vitro and in vivo using flow cytometry, standard transwell migration assays, and imaging of fluorescently labeled murine CD40B cells. Murine CD40B cells show migratory features similar to human CD40B cells. They express important lymph node homing receptors which were functional and induced chemotaxis of T cells in vitro. Striking differences were observed with regard to interactions of human APCs with T cells. CD40B cells differ from DCs by displaying a rapid migratory pattern undergoing highly dynamic, short-lived and sequential interactions with T cells. In vivo, CD40B cells are home to the secondary lymphoid organs where they accumulate in the B cell zone before traveling to the B/T cell boundary. Moreover, intravenous (i.v.) administration of murine CD40B cells induced an antigen-specific cytotoxic T cell response. Taken together, this data show that CD40B cells home secondary lymphoid organs where they physically interact with T cells to induce antigen-specific T cell responses, thus underscoring their potential as cellular adjuvant for cancer immunotherapy.

Impaired word stress pattern discrimination in very-low-birthweight infants during the first 6 months of life.

Prosodic information, such as word stress and speech rhythm, is important in language acquisition, and sensitivity to stress patterns is present from birth onwards. Exposure to prosodic properties of the native language occurs prenatally. Preterm birth and an associated lack of exposure to prosodic information are suspected to affect language acquisition in preterm infants. Fifty healthy very low birthweight (<1500 g) preterm German infants (24 males, 26 females; mean gestational age [GA] 27.6 wks, range 26.4-29.9) and 103 comparison term infants (48 males, 55 females; mean GA 40 wks, range 39.4-40.8) were recruited. Prosodic discrimination performance was assessed using the head-turn preference paradigm, an objective behavioural psycholinguistic test for measuring orientation time (OT) to auditory stress patterns. Among matched preterm and term infants, preterm infants (n=30) did not differentiate stress patterns at the corrected age of 4 or 6 months. In term infants (n=30), the OT was longer towards the trochaic (stress on first syllable, characteristic for German) than the iambic (second syllable) stress patterns (11.64 vs 9.18s, p<0.001, and 11.02 vs 8.32s, p<0.001, at 4 and 6 mo respectively). Neurodevelopmental scores (Bayley Scales of Infant Development, 2nd edn) were not different from reference values in both groups of infants. Preterm birth and deficient early prosodic information affect prosodic processing during the first half year of life.