Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia

Background: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. Methods: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. Results: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. Conclusions: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia D. Osmanova(1), A.S. Boiko(1), O.Y. Fedorenko(1), I.V. Pozhidaev(1), M.B. Freidin(2), E.G. Kornetova(3), S.A. Ivanova(1), B. Wilffert(4), A.J.M. Loonen(5) (1)Mental Health Research Institute- Tomsk NRMC, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Research Institute of Medical Genetics, Tomsk NRMC, Laboratory of Population Genetics, Tomsk, Russia (3)Mental Health Research Institute- Tomsk NRMC, Department of Clinical and Social Psychiatry and Addiction, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1,2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorphisms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36–0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accordingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed. References [1] Ivanova, S.A., Osmanova, D.Z., Boiko, A.S., Pozhidaev, I.V., Freidin, M.B., Fedorenko, O.Y., Semke, A.V., Bokhan, N.A., Kornetova, E.G., Rakhmazova, L.D., Wilffert, B., Loonen, A.J., 2016. Prolactin gene polymorphism (-1149G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics. Schizophrenia Research Oct 21, pii: S0920-9964 (16)30473-X. doi: 10.1016/j.schres.2016.10.029. [2] Ivanova, S.A., Osmanova, D.Z., Freidin, M.B., Fedorenko, O.Y., Boiko, A.S., Pozhidaev, I.V., Semke, A.V., Bokhan, N.A., Agarkov, A.A., Wilffert, B., Loonen, A.J., 2017. Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia. World J Biol Psychiatry 18 (3), 239–246. [3] Miura, I., Zhang, J.P., Hagi, K., Lencz, T., Kane, J.M., Yabe, H., Malhotra, A.K., Correll, C.U., 2016. Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology 72, 1–10. [4] Al Hadithy, A.F.Y., Ivanova, S.A., Pechlivanoglou, P., Semke, A., Fedorenko, O., Kornetova, E., Ryadovaya, L., Brouwers, J.R.B.J., Wilffert, B., Bruggeman, R., Loonen, A.J.M., 2009. Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia. Progress in NeuroPsychopharmacology and Biological Psychiatry 33, 475–481. Keywords: Dopamine Genetics / Molecular genetics Schizophrenia: basi

Index estimates for free boundary minimal hypersurfaces

We show that the Morse index of a properly embedded free boundary minimal hypersurface in a strictly mean convex domain of the Euclidean space grows linearly with the dimension of its first relative homology group (which is at least as big as the number of its boundary components, minus one). In ambient dimension three, this implies a lower bound for the index of a free boundary minimal surface which is linear both with respect to the genus and the number of boundary components. Thereby, the compactness theorem by Fraser and Li implies a strong compactness theorem for the space of free boundary minimal surfaces with uniformly bounded Morse index inside a convex domain. Our estimates also imply that the examples constructed, in the unit ball, by Fraser–Schoen and Folha–Pacard–Zolotareva have arbitrarily large index. Extensions of our results to more general settings (including various classes of positively curved Riemannian manifolds and other convexity assumptions) are discussed

MAPPIN'SDM – The Multifocal Approach to Sharing in Shared Decision Making

BACKGROUND: The wide scale permeation of health care by the shared decision making concept (SDM) reflects its relevance and advanced stage of development. An increasing number of studies evaluating the efficacy of SDM use instruments based on various sub-constructs administered from different viewpoints. However, as the concept has never been captured in operable core definition it is quite difficult to link these parts of evidence. This study aims at investigating interrelations of SDM indicators administered from different perspectives. METHOD: A comprehensive inventory was developed mapping judgements from different perspectives (observer, doctor, patient) and constructs (behavior, perception) referring to three units (doctor, patient, doctor-patient-dyad) and an identical set of SDM-indicators. The inventory adopted the existing approaches, but added additional observer foci (patient and doctor-patient-dyad) and relevant indicators hitherto neglected by existing instruments. The complete inventory comprising a doctor-patient-questionnaire and an observer-instrument was applied to 40 decision consultations from 10 physicians from different medical fields. Convergent validities were calculated on the basis of Pearson correlation coefficients. RESULTS: Reliabilities for all scales were high to excellent. No correlations were found between observer and patients or physicians neither for means nor for single items. Judgements of doctors and patients were moderately related. Correlations between the observer scales and within the subjective perspectives were high. Inter-perspective agreement was not related to SDM performance or patient activity. CONCLUSION: The study demonstrates the contribution to involvement made by each of the relevant perspectives and emphasizes the need for an inter-subjective approach regarding SDM measurement

Symptom clusters in COVID-19: A potential clinical prediction tool from the COVID Symptom Study app

As no one symptom can predict disease severity or the need for dedicated medical support in coronavirus disease 2019 (COVID-19), we asked whether documenting symptom time series over the first few days informs outcome. Unsupervised time series clustering over symptom presentation was performed on data collected from a training dataset of completed cases enlisted early from the COVID Symptom Study Smartphone application, yielding six distinct symptom presentations. Clustering was validated on an independent replication dataset between 1 and 28 May 2020. Using the first 5 days of symptom logging, the ROC-AUC (receiver operating characteristic - area under the curve) of need for respiratory support was 78.8%, substantially outperforming personal characteristics alone (ROC-AUC 69.5%). Such an approach could be used to monitor at-risk patients and predict medical resource requirements days before they are required

Insights into corn genes derived from large-scale cDNA sequencing

We present a large portion of the transcriptome of Zea mays, including ESTs representing 484,032 cDNA clones from 53 libraries and 36,565 fully sequenced cDNA clones, out of which 31,552 clones are non-redundant. These and other previously sequenced transcripts have been aligned with available genome sequences and have provided new insights into the characteristics of gene structures and promoters within this major crop species. We found that although the average number of introns per gene is about the same in corn and Arabidopsis, corn genes have more alternatively spliced isoforms. Examination of the nucleotide composition of coding regions reveals that corn genes, as well as genes of other Poaceae (Grass family), can be divided into two classes according to the GC content at the third position in the amino acid encoding codons. Many of the transcripts that have lower GC content at the third position have dicot homologs but the high GC content transcripts tend to be more specific to the grasses. The high GC content class is also enriched with intronless genes. Together this suggests that an identifiable class of genes in plants is associated with the Poaceae divergence. Furthermore, because many of these genes appear to be derived from ancestral genes that do not contain introns, this evolutionary divergence may be the result of horizontal gene transfer from species not only with different codon usage but possibly that did not have introns, perhaps outside of the plant kingdom. By comparing the cDNAs described herein with the non-redundant set of corn mRNAs in GenBank, we estimate that there are about 50,000 different protein coding genes in Zea. All of the sequence data from this study have been submitted to DDBJ/GenBank/EMBL under accession numbers EU940701–EU977132 (FLI cDNA) and FK944382-FL482108 (EST)

Patients' and Observers' Perceptions of Involvement Differ. Validation Study on Inter-Relating Measures for Shared Decision Making

OBJECTIVE: Patient involvement into medical decisions as conceived in the shared decision making method (SDM) is essential in evidence based medicine. However, it is not conclusively evident how best to define, realize and evaluate involvement to enable patients making informed choices. We aimed at investigating the ability of four measures to indicate patient involvement. While use and reporting of these instruments might imply wide overlap regarding the addressed constructs this assumption seems questionable with respect to the diversity of the perspectives from which the assessments are administered. METHODS: The study investigated a nested cohort (N = 79) of a randomized trial evaluating a patient decision aid on immunotherapy for multiple sclerosis. Convergent validities were calculated between observer ratings of videotaped physician-patient consultations (OPTION) and patients' perceptions of the communication (Shared Decision Making Questionnaire, Control Preference Scale & Decisional Conflict Scale). RESULTS: OPTION reliability was high to excellent. Communication performance was low according to OPTION and high according to the three patient administered measures. No correlations were found between observer and patient judges, neither for means nor for single items. Patient report measures showed some moderate correlations. CONCLUSION: Existing SDM measures do not refer to a single construct. A gold standard is missing to decide whether any of these measures has the potential to indicate patient involvement. PRACTICE IMPLICATIONS: Pronounced heterogeneity of the underpinning constructs implies difficulties regarding the interpretation of existing evidence on the efficacy of SDM. Consideration of communication theory and basic definitions of SDM would recommend an inter-subjective focus of measurement. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN25267500

CUT-PCR: CRISPR-mediated, ultrasensitive detection of target DNA using PCR

Circulating tumor DNA (ctDNA) has emerged as a tumor-specific biomarker for the early detection of various cancers. To date, several techniques have been devised to enrich the extremely small amounts of ctDNA present in plasma, but they are still insufficient for cancer diagnosis, especially at the early stage. Here, we developed a novel method, CUT (CRISPR-mediated, Ultrasensitive detection of Target DNA)-PCR, which uses CRISPR endonucleases to enrich and detect the extremely small amounts of tumor DNA fragments among the much more abundant wild-type DNA fragments by specifically eliminating the wild-type sequences. We computed that by using various orthologonal CRISPR endonucleases such as SpCas9 and FnCpf1, the CUT-PCR method would be applicable to 80% of known cancer-linked substitution mutations registered in the COSMIC database. We further verified that CUT-PCR together with targeted deep sequencing enables detection of a broad range of oncogenes with high sensitivity (<0.01%) and accuracy, which is superior to conventional targeted deep sequencing. In the end, we successfully applied CUT-PCR to detect sequences with oncogenic mutations in the ctDNA of colorectal cancer patients' blood, suggesting that our technique could be adopted for diagnosing various types of cancer at early stages