Bright Light Therapy as Add-On to Inpatient Treatment in Youth With Moderate to Severe Depression: A Randomized Clinical Trial.

Importance: Major depressive disorder is one of the most common mental disorders among adolescents, entailing severe, long-term psychosocial impairment and a high risk of chronicity. In view of the large number of patients requiring treatment, along with insufficient treatment responses with small effect sizes, innovative adjunctive treatment strategies are urgently needed. Objective: To investigate whether the effect of adolescent psychiatric inpatient treatment as usual for major depressive disorder can be enhanced by simultaneous use of morning bright light therapy. Design, Setting, and Participants: This was a double-blind, placebo-controlled randomized parallel-group trial with enrollment between March 2018 and November 2020 and follow-up completed in May 2021. The study took place among inpatients at 4 university hospitals for child and adolescent psychiatry across Germany. Of 248 eligible youth aged 12 to 18 years fulfilling ICD-10 criteria for major depressive disorder, 227 were randomized to bright light therapy (n = 116) or placebo red light (n = 111); 151 participants completed the study. Interventions: Up to 20 sessions of either morning bright light therapy with an intensity of 10 000 lux or placebo red light (100 lux) in addition to multimodal inpatient treatment as usual over 4 weeks. Main Outcomes and Measures: The primary outcome was the change in Beck Depression Inventory-II (BDI-II) score from baseline to posttreatment in the intention-to-treat sample. Results: Among the 224 patients included in the intention-to-treat analyses (192 girls and 32 boys; mean [SD] age, 15.5 [1.4] years), the mean (SD) BDI-II score at baseline was 37.3 (8.7). BDI-II scores were significantly reduced after 4 weeks (postassessment) by a mean of -7.5 (95% CI, -9.0 to -6.0; Hedges g = 0.71). Bright light therapy had no impact on this change (no significant group × time effect). Loss to follow-up was 31% (n = 69) at 16 weeks and 49% (n = 110) at 28 weeks. There were 10 serious adverse events throughout the whole trial, which were not considered related to study treatment. Conclusions and Relevance: The findings in this study did not indicate superiority of bright light therapy over placebo red light therapy in a large sample of adolescent inpatients with moderate or severe major depressive disorder. Both groups benefited equally from treatment as usual, showing relevant symptom reduction. Trial Registration: German Clinical Trials Register: DRKS00013188.

Multimodal home-based rehabilitation intervention after discharge from inpatient geriatric rehabilitation (GeRas): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Geriatric rehabilitation aims to maintain the functional reserves of older adults in order to optimize social participation and prevent disability. After discharge from inpatient geriatric rehabilitation, patients are at high risk for decreased physical capacity, increased vulnerability, and limitations in mobility. As a result, ageing in place becomes uncertain for a plethora of patients after discharge from geriatric rehabilitation and effective strategies to prevent physical decline are required. Collaboration between different health-care providers is essential to improve continuity of care after discharge from inpatient geriatric rehabilitation. The aim of this study is to evaluate the effectiveness of a multi-professional home-based intervention program (GeRas) to improve functional capacity and social participation in older persons after discharge from inpatient geriatric rehabilitation. METHODS: The study is a multicenter, three-arm, randomized controlled trial with a three-month intervention period. Two hundred and seventy community-dwelling older people receiving inpatient geriatric rehabilitation will be randomized with a 1:1:1 ratio to one of the parallel intervention groups (conventional IG or tablet IG) or the control group (CG). The participants of both IGs will receive a home-based physical exercise program supervised by physical therapists, a nutritional recommendation by a physician, and social counseling by social workers of the health insurance company. The collaboration between the health-care providers and management of participants will be realized within a cloud environment based on a telemedicine platform and supported by multi-professional case conferences. The CG will receive usual care, two short handouts on general health-related topics, and facultative lifestyle counseling with general recommendations for a healthy diet and active ageing. The primary outcomes will be the physical capacity measured by the Short Physical Performance Battery and social participation assessed by the modified Reintegration to Normal Living Index, three months after discharge. DISCUSSION: The GeRas program is designed to improve the collaboration between health-care providers in the transition from inpatient geriatric rehabilitation to outpatient settings. Compared to usual care, it is expected to improve physical capacity and participation in geriatric patients after discharge from inpatient geriatric rehabilitation. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00029559). Registered on October 05, 2022.

A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial.

The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point. Sixty-eight patients were evaluated, median age was 75 years, median number of prior lines was three (range 1-10), 52 patients (76.5%) were diagnosed with DLBCL and 16 (23.5%) patients had transformed indolent lymphoma or follicular lymphoma (FL) IIIB. ORR was 35.3% for all and 40% for evaluable patients (16.6% complete response), median progression-free survival (PFS) and overall survival (OS) were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal centre B-cell-like) phenotype [median OS not reached (n.r.) vs 5.2 months]. Patients with one prior line had an improved outcome over patients treated in later lines (PFS n.r. vs 2.5 months). Disease progression was the main reason for premature termination. Adverse events were mainly haematologic. The combination treatment revealed no unexpected adverse events. Most relevant non-haematologic toxicity was infection in 28% of patients. In summary, pixantrone-obinutuzumab showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary end-point.

The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL - Results From the Phase-II STORM Trial.

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m2 (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m2 day 3, cytarabine 2 × 2 g/m2 day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg for temsirolimus were predefined. Based on the observed toxicity profile, a temsirolimus dose of 25 mg was defined as recommended dose for the part II extension cohort of the trial. The intention-to-treat cohort comprised 53 patients. Median age was 63 years and median number of prior regimen was 1. All but 1 patient had prior rituximab exposure. Temsirolimus dose was 50 mg on day 1 and 8 in 6 patients from the part I of the trial and 25 mg in the remaining 47 patients. In general, treatment was well tolerated with leucopenia and thrombocytopenia as most frequent severe adverse events. The overall response rate after the last cycle of temsirolimus R-DHAP was 66% with 24% complete responses. The ability to mobilize stem cells was not impaired by the treatment regimen. Twenty-eight patients received consolidation treatment with high-dose therapy (HDT) and stem cell transplantation. Median duration of response was not reached. The total 2-year progression-free survival (PFS) and overall survival (OS) were 53% and 59%. Patients who were consolidated with HDT achieved a 2-year PFS and a 2-year OS of 77.8% and 82.1%, respectively. We conclude that temsirolimus can be safely added to rituximab and DHAP with promising activity.

Efficacy of Short-term Treatment of Internet and Computer Game Addiction: A Randomized Clinical Trial.

Importance: Internet and computer game addiction represent a growing mental health concern, acknowledged by the World Health Organization. Objective: To determine whether manualized cognitive behavioral therapy (CBT), using short-term treatment for internet and computer game addiction (STICA), is efficient in individuals experiencing internet and computer game addiction. Design, Setting, and Participants: A multicenter randomized clinical trial was conducted in 4 outpatient clinics in Germany and Austria from January 24, 2012, to June 14, 2017, including follow-ups. Blinded measurements were conducted. A consecutive sample of 143 men was randomized to the treatment group (STICA; n = 72) or wait-list control (WLC) group (n = 71). Main inclusion criteria were male sex and internet addiction as the primary diagnosis. The STICA group had an additional 6-month follow-up (n = 36). Data were analyzed from November 2018 to March 2019. Interventions: The manualized CBT program aimed to recover functional internet use. The program consisted of 15 weekly group and up to 8 two-week individual sessions. Main Outcomes and Measures: The predefined primary outcome was the Assessment of Internet and Computer Game Addiction Self-report (AICA-S). Secondary outcomes were self-reported internet addiction symptoms, time spent online on weekdays, psychosocial functioning, and depression. Results: A total of 143 men (mean [SD] age, 26.2 [7.8] years) were analyzed based on intent-to-treat analyses. Of these participants, 50 of 72 men (69.4%) in the STICA group showed remission vs 17 of 71 men (23.9%) in the WLC group. In logistic regression analysis, remission in the STICA vs WLC group was higher (odds ratio, 10.10; 95% CI, 3.69-27.65), taking into account internet addiction baseline severity, comorbidity, treatment center, and age. Compared with the WLC groups, effect sizes at treatment termination of STICA were d = 1.19 for AICA-S, d = 0.88 for time spent online on weekdays, d = 0.64 for psychosocial functioning, and d = 0.67 for depression. Fourteen adverse events and 8 serious adverse events occurred. A causal relationship with treatment was considered likely in 2 AEs, one in each group. Conclusions and Relevance: Short-term treatment for internet and computer game addiction is a promising, manualized, short-term CBT for a broad range of internet addictions in multiple treatment centers. Further trials investigating the long-term efficacy of STICA and addressing specific groups and subgroups compared with active control conditions are required. Trial Registration: ClinicalTrials.gov identifier: NCT01434589.

Rationale and design of the RE-LATED AF--AFNET 7 trial: REsolution of Left atrial-Appendage Thrombus--Effects of Dabigatran in patients with Atrial Fibrillation.

BACKGROUND: Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients. OBJECTIVE: The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon. METHODS: The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2-3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. CONCLUSION: This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF.

Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against ß-amyloid (Aß) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against Aß (NAbs-Aß) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs-Aß recognized the mid-/C-terminal end of Aß and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs-Aß were able to interfere with Aß peptide toxicity, but NAbs-Aß did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs-Aß in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs-Aß to dispose of proteins or peptides that are prone to forming toxic aggregates.

Role of macrophage migration inhibitory factor in primary glioblastoma multiforme cells.

Macrophage migration inhibitory factor (MIF) is a protein that is overexpressed in many tumors, such as colon and prostate cancer, melanoma, and glioblastoma multiforme (GBM). In its function as a cytokine, MIF induces angiogenesis, promotes cell cycle progression, and inhibits apoptosis. Recently, the molecular signal transduction has been specified: MIF has been found to be a ligand to the CD74/CD44-receptor complex and to activate the ERK1/2 MAPK cascade. In addition MIF binds to the chemokine receptors CXCR2 and CXCR4. This effects an integrin-dependent leukocyte arrest and mediates leukocyte chemotaxis. Recent work has described a clearer role of MIF in GBM tumor cell lines. The current study used human primary GBM cells. We show that inhibition of MIF with ISO-1, an inhibitor of the D-dopachrome tautomerase site of MIF, reduced the growth rate of primary GBM cells in a dose-dependent manner, and in addition ISO-1 increased protein expression of MIF and its receptors CD74, CXCR2, and CXCR4 in vitro but decreased expression of CD44. Furthermore, hypoxia as cell stressor increases the protein expression of MIF in primary GBM cells. These results underscore the importance of MIF in GBM and show that MIF and its receptors may be a promising target for the treatment of malignant gliomas.

The role of macrophage migration inhibitory factor in Alzheimer's disease.

Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.

Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown.

BACKGROUND: Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. RESULTS: Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. CONCLUSION: Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.

The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors.

Macrophage migration inhibitory factor (MIF) has been described as a protein that plays an important role in both innate and acquired immunity. Further research has shown that MIF plays a particularly critical part in cell cycle regulation and therefore in tumorigenesis as well. Over the past few years, the significance of the role of MIF in a variety of both solid and hematologic tumors has been established. More recently, interest has increased in the role of MIF in the development of central nervous system (CNS) tumors, in which it appears to influence cell cycle control. In addition, MIF has been identified as an essential actor in metastasis and angiogenesis. Vascular growth factor concentration raises because of increased levels of MIF in brain tumors. Recently, the MIF receptor complex has been described, and it appears that this may be a suitable drug target for treatment of brain tumors. In light of these findings, the authors chose to conduct a systematic search for information regarding MIF that has been published within the past 15 years using the terms "inflammation," "glioblastoma," "brain tumor," "astrocytoma," "microglia," "glioblastoma," "immune system and brain tumors," "glioblastoma and MIF," and "brain tumor and MIF." The aim of this article was thus to present a detailed review of current knowledge regarding the role of MIF in CNS tumor pathophysiology.

Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer's disease.

Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer's disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-alpha, IL-6 and IFN-gamma, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-alpha, IL-6 and IFN-gamma, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p=0.003) and MCI patients (p<0.001) compared to controls. The levels of TNF-alpha, IL-6 and IFN-gamma did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-alpha in the AD group (r=0.407; p=0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage.

Novel genes of the dsr gene cluster and evidence for close interaction of Dsr proteins during sulfur oxidation in the phototrophic sulfur bacterium Allochromatium vinosum.

Seven new genes designated dsrLJOPNSR were identified immediately downstream of dsrABEFHCMK, completing the dsr gene cluster of the phototrophic sulfur bacterium Allochromatium vinosum D (DSM 180(T)). Interposon mutagenesis proved an essential role of the encoded proteins for the oxidation of intracellular sulfur, an obligate intermediate during the oxidation of sulfide and thiosulfate. While dsrR and dsrS encode cytoplasmic proteins of unknown function, the other genes encode a predicted NADPH:acceptor oxidoreductase (DsrL), a triheme c-type cytochrome (DsrJ), a periplasmic iron-sulfur protein (DsrO), and an integral membrane protein (DsrP). DsrN resembles cobyrinic acid a,c-diamide synthases and is probably involved in the biosynthesis of siro(heme)amide, the prosthetic group of the dsrAB-encoded sulfite reductase. The presence of most predicted Dsr proteins in A. vinosum was verified by Western blot analysis. With the exception of the constitutively present DsrC, the formation of Dsr gene products was greatly enhanced by sulfide. DsrEFH were purified from the soluble fraction and constitute a soluble alpha(2)beta(2)gamma(2)-structured 75-kDa holoprotein. DsrKJO were purified from membranes pointing at the presence of a transmembrane electron-transporting complex consisting of DsrKMJOP. In accordance with the suggestion that related complexes from dissimilatory sulfate reducers transfer electrons to sulfite reductase, the A. vinosum Dsr complex is copurified with sulfite reductase, DsrEFH, and DsrC. We therefore now have an ideal and unique possibility to study the interaction of sulfite reductase with other proteins and to clarify the long-standing problem of electron transport from and to sulfite reductase, not only in phototrophic bacteria but also in sulfate-reducing prokaryotes.