Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled,randomized multicenter study

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

     

Activity and concentration of lipoprotein lipase in post-heparin plasma and the extent of coronary artery disease

Numerous studies have found polymorphisms in the lipoprotein lipase (LPL) gene to be associated with the risk of coronary artery disease (CAD), implicating LPL in the development of atherothrombotic disease. It remains controversial, however, whether LPL acts in a pro- or anti-atherogenic fashion. We quantitated activity and concentration of LPL in post-heparin plasma from 194 male patients undergoing coronary angiography. HDL cholesterol was significantly associated with LPL activity quartiles (1.09+/-0.26 the highest vs. 0.96+/-0.25 mmol/l the lowest quartile, P<0.01). There was also a trend towards higher total (5.61+/-1.33 vs. 5.16+/-1.44 mmol/l, P=0.059) and LDL cholesterol (3.92+/-1.39 vs. 3.46+/-1.06 mmol/l, P=0.09) with higher LPL activity. In contrast, measures of CAD extent showed no differences between LPL quartiles (P>0.30 for prior myocardial infarction, number of diseased vessels, Gensini and extent scores). Additionally, there was no difference in LPL activity (CAD: n=158, 168+/-70 nmol/ml/min, no CAD: n=36, 180+/-89 nmol/ml/min, P=0.47) or concentration (280+/-121 ng/ml and 288+/-111 ng/ml, P=0.72) between patients with and without CAD. Our data show that, in spite of an association with lipoprotein parameters, LPL in post-heparin plasma is unrelated to the presence or the extent of CAD. Therefore, lipoprotein lipase determination in plasma does not appear to be a useful marker in the assessment of CAD risk.     

Characterization and longitudinal monitoring of melanoma growth in ret‐transgenic mice using a single‐sequence MRI protocol

Spontaneous melanoma models in transgenic mice are increasingly used in preclinical research as they most closely match the progression of melanoma in humans. While optical inspection only allows analysis of tumors located on the skin, the accurate measurement and growth of subcutaneous tumors have not been adequately assessed. To improve the measurement accuracy of melanoma tumors, we used a fast single‐sequence MRI protocol at 9.4 Tesla for longitudinal characterization of a ret‐transgenic mouse model. Repeated MRI (average acquisition time 30 min per animal) of the trunk (excluding head and distal limbs) in six siblings revealed an increase in the mean total tumor volume (TTV) from 102.0 ± 80.5 mm³ at 35 days of age to 434.8 ± 154.9 mm³ by 77 days. The main tumor load was located within the pelvis (>40%), followed by the proximal hind limbs and groins (>30%). The smallest detectable tumor measured 0.07 mm³. Inter‐rater reliability between a radiologist and a veterinarian analysing MRI data was 0.993 for TTV and 0.840 for number of tumors (both p < 0.001). We thus conclude that because of the high variance of TTV of same‐aged mice, MRI should be used (i) to establish treatment groups matched for TTV and (ii) for longitudinal examination of the TTV in mice over the course of treatments.     

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.