Early onset of treatment effects with oral risperidone

BACKGROUND: The dogma of a delayed onset of antipsychotic treatment effects has been maintained over the past decades. However, recent studies have challenged this concept. We therefore performed an analysis of the onset of antipsychotic treatment effects in a sample of acutely decompensated patients with schizophrenia. METHODS: In this observational study, 48 inpatients with acutely decompensated schizophrenia were offered antipsychotic treatment with oral risperidone. PANSS-ratings were obtained on day 0, day 1, day 3, day 7 and day 14. RESULTS: Significant effects of treatment were already present on day 1 and continued throughout the study. The PANSS positive subscore and the PANSS total score improved significantly more than the PANSS negative subscore. CONCLUSION: Our results are consistent with the growing number of studies suggesting an early onset of antipsychotic treatment effects. However, non-pharmacological effects of treatment also need to be taken into consideration

Inducible microRNA-200c decreases motility of breast cancer cells and reduces filamin A

Cancer progression and metastases are frequently related to changes of cell motility. Amongst others, the microRNA-200c (miR-200c) was shown to maintain the epithelial state of cells and to hamper migration. Here, we describe two miR-200c inducible breast cancer cell lines, derived from miR-200c knock-out MCF7 cells as well as from the miR-200c-negative MDA-MB-231 cells and report on the emerging phenotypic effects after miR-200s induction. The induction of miR-200c expression seems to effect a rapid reduction of cell motility, as determined by 1D microlane migration assays. Sustained expression of miR200c leads to a changed morphology and reveals a novel mechanism by which miR- 200c interferes with cytoskeletal components. We find that filamin A expression is attenuated by miRNA-200c induced downregulation of the transcription factors c-Jun and MRTF/SRF. This potentially novel pathway that is independent of the prominent ZEB axis could lead to a broader understanding of the role that miR200c plays in cancer metastasis

Whole genome and exome sequencing of monozygotic twins discordant for Crohn's disease

Background Crohn's disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. Results We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. Conclusion Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses

Whole genome and exome sequencing of monozygotic twins discordant for Crohn's disease

Background Crohn's disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. Results We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. Conclusion Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses

Identification of novel immune phenotypes for allergic and nonallergic childhood asthma

BACKGROUND Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success. OBJECTIVE We sought to identify novel immune phenotypes for childhood AA and NA. METHODS The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4- to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and TH17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes. RESULTS The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL-5, IL-13, and IFN-γ secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1β levels, neutrophil counts, and IL-17-shifted immunity. In parallel, expressions of anti-inflammatory IL37, proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and the neutrophil-associated genes CD93, triggering receptor expressed on myeloid cells 1 (TREM1), and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared TH2 immunity was present in both asthma phenotypes. CONCLUSION Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17-shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention