GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis

High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.     

Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation

Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau’s ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.     

Penumbra around chronic cerebral infarction?

In a series of 13 patients with cerebrovascular occlusive disease regional cerebral blood flow (rCBF) measurements (two-dimensional intravenous ¹³³Xe clearance method) and quantitative EEG analysis (sensorimotor rhythms) as well as electronic measurement of handforce were performed before and during intravenous infusion of 1 μg kg/min of one of the lipophilic dihydropyridine calcium channel blocker nimodipine (Nimotop®). The aim of the study was to test the hypothesis of the existence of hypoperfusion (ischaemic penumbra) in the surroundings of chronic cerebral infarcts. All 3 parameters improved in one patient. Sensorimotor rhythms increased in 5 patients, rCBF in 3. EEG and rCBF improved in 2 patients. In 3 instances, a redistribution of rCBF in favour of the peri-infarct zone was noted (significant increase of rCBF from 35 ± 2 sem to 53 ± 4 ml/100 g/min (p > 0.01), whereas rCBF fell from 61 ± 5 to 46 ±2 ml/100 g/min on a collimator remote from the infarct but in the infarcted hemisphere. The parallel improvement of rCBF and EEG in brain regions surrounding chronic infarcts in 3 patients was interpreted as functional improvement as a consequence of nimodipine-induced normalization of peri-infarct hypoperfusion, i.e. reversal of flow-dependent neuronal silence and/or dysfunction.     

Associations among attachment characteristics,patients’ assessment of therapeutic factors,and treatment outcome following inpatient psychodynamic group psychotherapy

Abstract

Within a multisite study, including 289 inpatients from six different hospitals who underwent interpersonal-psychodynamic group psychotherapy, associations among attachment characteristics, therapeutic factors, and treatment outcome were investigated. Attachment characteristics were assessed with an interview-based measure (Adult Attachment Prototype Rating [AAPR]) as well as an attachment self-report (Bielefeld Questionnaire of Client Expectations [BQCE]). Therapeutic factors were measured retrospectively with the Düsseldorf Therapeutic Factors Questionnaire and treated as an individual- as well as a hospital-specific characteristic. On an individual level, only the group climate factor independently predicted treatment outcome (i.e., Symptom Checklist-90-R Global Severity Index and Inventory of Interpersonal Problems mean). If simultaneously but separately included into a path model, analyses revealed independent significant effects of AAPR-Security and BQCE-Security on group climate. If modeled as a latent variable (common attachment security), a substantially higher proportion of group climate variance could be explained. Further analyses revealed interactions between particular therapeutic factors and attachment characteristics, indicating a particular importance of these therapeutic factors for different attachment categories.     

Changes in the mental representations of relational behavior in depressive patients

Abstract

In this study the mental representations of interpersonal relations in depressive patients were assessed using the axis relationships of the operationalized psychodynamic diagnostics (OPD) system. The data were obtained at the beginning and at the end of inpatient psychotherapy. Although a link was assumed to exist between the severity of the symptoms and the variability of the mental representation of relational behavior, this was not proven. Also, contrary to expectations, an increase in the variability of the mental representations of the patients’ own relational behavior was not observed on completion of therapy. However, patients’ mental representation of their social partners’ relational behavior tends to become more variable. A shift in the focus of relationships was also observed.     

Attachment characteristics and treatment outcome following inpatient psychotherapy: Results of a multisite study

Abstract

Existential suffering may contribute to treatment-resistant depression. The “VITA” treatment model was designed for such patients with long-standing depression accompanied by existential and/or religious concerns. This naturalistic effectiveness study compared the VITA model (n = 50) with a “treatment as usual” comparison group (TAU; n = 50) of patients with treatment-resistant depression and Cluster C comorbidity. The TAU patients were matched on several characteristics with the VITA patients. The VITA model included existential, dynamic, narrative and affect-focused components. The VITA group had significantly greater improvement on symptom distress and relational problems during treatment and from pre-treatment to 1-year follow-up. Patients in the VITA, at follow-up, were more likely to be employed and less likely be using psychotropic medications.     

Combination therapy vs. monotherapy for Gram-negative bloodstream infection: matching by predicted prognosis

The utility of empirical combination antimicrobial therapy for Gram-negative bloodstream infection (BSI) remains unclear. This retrospective, quasi-experimental matched cohort study examined the impact of empirical combination therapy on mortality in patients with Gram-negative BSI. Hospitalized adults with Gram-negative BSI from 1 January 2010 to 31 December 2013 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Patients receiving combination therapy or beta-lactam monotherapy were matched 1:1 based on age, sex and Bloodstream Infection Mortality Risk Score (BSIMRS). Multivariate Cox proportional hazards regression with propensity score adjustment was used to examine overall 28–day mortality and within predefined BSIMRS categories (<5 and ≥5). A total of 380 patients receiving combination therapy or monotherapy for Gram-negative BSI were included in the study. Median age was 66 years and 204 (54%) were female. Overall, 28-day mortality in patients who received combination therapy and monotherapy was 13% and 15%, respectively (P?=?0.51). After stratification by BSIMRS, mortality in both combination therapy and monotherapy groups was 1.1% in patients with BSIMRS <5 (P?=?0.98) and 27% and 32%, respectively, in patients with BSIMRS ≥5 (P?=?0.47). After adjusting for propensity to receive combination therapy, risk of mortality was not significantly different for combination therapy compared to monotherapy (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.51–1.60). This finding persisted for both subgroups of BSIMRS <5 (HR 0.96, 95% CI 0.04–24.28) and BSIMRS ≥5 (HR 0.83, 95% CI 0.46–1.48). There is no survival benefit from empirical combination therapy over monotherapy in patients with Gram-negative BSI, regardless of predicted prognosis at initial presentation.     

BURDEN 2020—Burden of disease in Germany at the national and regional level

Background

Evidence-based policy measures need non-interest-guided information about the health status of a population and the diseases that affect the population the most. In such cases, a national burden of disease study can provide reliable insights at the regional level.

Aim

This article presents the potential of the BURDEN 2020 project and its expected outcome for Germany at the national and regional level.

Methods

The BURDEN 2020 project uses several indicators including years of life lost (YLL) to cover the impact of mortality and years lived with disability (YLD) to cover morbidity. The sum of both is the measure of population health called disability adjusted life years (DALY).

Results

The study ranks individual diseases and risk factors based on their impact on population health. The burden of disease approach is assumed to be sensitive to subnational differences and may generate immediate benefits for regional planning. The BURDEN 2020 study will pilot a national burden of disease study for Germany that will later be transformed into a continuous data processing and visualization tool. This is done by using, modifying and supplementing the methodology employed by the Global Burden of Disease (GBD) study to better fit the needs of health policy in Germany. This study is aimed at calculating the disease burden for up to 17 preselected diseases. Furthermore, the estimates of burden of disease are attributed to a selected set of risk factors.

Conclusion

The Burden 2020 study will provide the results of a new, health-related data processing system to the public. This includes a noninterest-guided presentation of the burden of disease (DALY) in Germany at the national and regional level.