Is elevated neutrophil count and neutrophil-to-lymphocyte ratio a cause or consequence of schizophrenia?—a scoping review

Background: Several studies have found an association between elevated neutrophil count or neutrophil-to-lymphocyte ratio (NLR) in peripheral blood from patients with schizophrenia. The etiology behind this effect is unknown, and it is unclear if changes in neutrophil count and NLR may be induced by antipsychotics or if these parameters relate to the diagnosis and symptoms of schizophrenia. The purpose of this scoping review was to map research that explores this association, and to identify gaps in the current knowledge base. Method: The work was conducted in accordance with established methodological standards for scoping reviews. Studies on neutrophil count and NLR in schizophrenia were identified through search in relevant databases, and a parallel screening procedure was performed to ensure validity and reproducibility of the search. Articles that included different comparison groups, with differences in medication status (drug-naïve or drug-free vs. medicated), current disease state (relapse vs. remission), or treatment response, were included, as well as studies evaluating the association between symptomatology and neutrophil count or NLR. Results: The available literature was limited with substantial differences in aims, methods, and outcomes. In total, 13 articles were included for the synthesis of this review. Some interesting trends were identified: Neutrophil count and NLR seem to be elevated in schizophrenia patients regardless of current or past use of antipsychotic therapy. Neutrophil count and NLR correlated significantly with positive symptoms of schizophrenia. Still, these findings should be interpreted with caution due to considerable methodological differences and weaknesses in the literature, particularly concerning the blood sampling procedure. Conclusion: By including longitudinal studies and by comparing patient groups based on medication status, disease state and response, our study provides a basis for dissecting the associations between increased neutrophil count or NLR and a diagnosis of schizophrenia. Further research should investigate and quantify the apparent strong correlation between neutrophil count or NLR and positive symptoms in schizophrenia, to evaluate its clinical potential to guide diagnostics, treatment, or as a predictor of outcome. This review also exposes important methodological weaknesses in the literature on neutrophil count and NLR measurements. Standardization of blood sampling and processing is crucial to reduce bias, and factors that are known to influence leukocyte levels need to be accounted for.publishedVersio

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.publishedVersio

Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day

Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00–19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00–19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00–14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.publishedVersio

Full production cycle performance of gene-edited, sterile Atlantic salmon - growth, smoltification, welfare indicators and fillet composition

Using germ cell-free (GCF), sterile, dnd-knockout salmon for farming could solve the problems associated with precocious maturation and genetic introgression of farmed breeds into wild populations. However, prior to using GCF fish in the salmon farming industry, it is crucial to understand if, or how, the GCF phenotype differs from wild type (WT) counterparts in terms of growth and welfare. To characterize the GCF phenotype throughout a production cycle, we reared GCF and WT salmon in indoor common garden tanks for 3 years, until harvest size. Regarding body size, smoltification markers (mRNA levels of gill Na+/K+-ATPase [NKA] subunits), plasma stress indicators (pH, glucose, sodium, chloride, calcium), relative heart size, prevalence of vertebra deformities and fillet proximate composition, GCF fish could not be distinguished from WTs. Transient differences were detected in plasma concentrations of lactate and osmolality, and only a few genes were differentially expressed in WT and GCF transcriptomes of muscle and pituitary. At harvest, fillets from GCF and WT salmon contained the same amount of omega-3 fatty acids, however the relative content of omega-3 fatty acids was higher in GCF compared to WT males. Towards harvest size, body growth rate, condition factor and relative liver size were significantly higher in WT than in GCF fish, probably relating to initiation of puberty in WTs. Since GCF salmon never become sexually mature, it is possible to postpone the time of harvest to exploit the growth potential uninhibited by sexual maturation. In conclusion, GCF salmon performed to a large extent similarly to their WT counterparts but had the clear advantage of never maturing.publishedVersio

Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling

Is elevated neutrophil count and neutrophil-to-lymphocyte ratio a cause or consequence of schizophrenia?—a scoping review

Background: Several studies have found an association between elevated neutrophil count or neutrophil-to-lymphocyte ratio (NLR) in peripheral blood from patients with schizophrenia. The etiology behind this effect is unknown, and it is unclear if changes in neutrophil count and NLR may be induced by antipsychotics or if these parameters relate to the diagnosis and symptoms of schizophrenia. The purpose of this scoping review was to map research that explores this association, and to identify gaps in the current knowledge base. Method: The work was conducted in accordance with established methodological standards for scoping reviews. Studies on neutrophil count and NLR in schizophrenia were identified through search in relevant databases, and a parallel screening procedure was performed to ensure validity and reproducibility of the search. Articles that included different comparison groups, with differences in medication status (drug-naïve or drug-free vs. medicated), current disease state (relapse vs. remission), or treatment response, were included, as well as studies evaluating the association between symptomatology and neutrophil count or NLR. Results: The available literature was limited with substantial differences in aims, methods, and outcomes. In total, 13 articles were included for the synthesis of this review. Some interesting trends were identified: Neutrophil count and NLR seem to be elevated in schizophrenia patients regardless of current or past use of antipsychotic therapy. Neutrophil count and NLR correlated significantly with positive symptoms of schizophrenia. Still, these findings should be interpreted with caution due to considerable methodological differences and weaknesses in the literature, particularly concerning the blood sampling procedure. Conclusion: By including longitudinal studies and by comparing patient groups based on medication status, disease state and response, our study provides a basis for dissecting the associations between increased neutrophil count or NLR and a diagnosis of schizophrenia. Further research should investigate and quantify the apparent strong correlation between neutrophil count or NLR and positive symptoms in schizophrenia, to evaluate its clinical potential to guide diagnostics, treatment, or as a predictor of outcome. This review also exposes important methodological weaknesses in the literature on neutrophil count and NLR measurements. Standardization of blood sampling and processing is crucial to reduce bias, and factors that are known to influence leukocyte levels need to be accounted for

U-251 revisited: genetic drift and phenotypic consequences of long-term cultures of glioblastoma cells

It is well known that in vitro subculture represents a selection pressure on cell lines, and over time this may result in a genetic drift in the cancer cells. In addition, long-term cultures harbor the risk of cross-contamination with other cell lines. The consequences may have major impact on experimental results obtained in various laboratories, where the cell lines no longer reflect the original tumors that they are supposed to represent. Much neglected in the scientific community is a close monitoring of cell cultures by regular phenotypic and genetic characterization. In this report, we present a thorough characterization of the commonly used glioblastoma (GBM) model U-251, which in numerous publications has been wrongly identified as U-373, due to an earlier cross-contamination. In this work, the original U-251 and three subclones of U-251, commonly referred to as U-251 or U-373, were analyzed with regard to their DNA profile, morphology, phenotypic expression, and growth pattern. By array comparative genomic hybridization (aCGH), we show that only the original low-passaged U-251 cells, established in the 1960s, maintain a DNA copy number resembling a typical GBM profile, whereas all long-term subclones lost the typical GBM profile. Also the long-term passaged subclones displayed variations in phenotypic marker expression and showed an increased growth rate in vitro and a more aggressive growth in vivo. Taken together, the variations in genotype and phenotype as well as differences in growth characteristics may explain different results reported in various laboratories related to the U-251 cell line