Changes in dopamine D2 and GluR-1 glutamate receptor mRNAs in the rat brain after treatment with phencyclidine.

In situ hybridization of slide-mounted brain sections from rats subjected to acute and chronic phencyclidine treatment was carried out using synthetic oligonucleotides complementary to dopamine D2-receptor and non-N-methyl-D-aspartate (NMDA) glutamate-receptor-subunit (GluR-1) mRNAs. There was no significant difference in either the D2-receptor or the GluR-1 mRNA levels in any brain region of the acute phencyclidine (10 mg/kg)-treated and control groups. However, chronic administration of phencyclidine (10 mg/kg/day, 14 days) significantly decreased the dopamine D2-receptor mRNA level in the caudate-putamen (by 27%, P &#60; 0.01) and significantly increased the GluR-1 mRNA level in the prefrontal cortex (by 29%, P &#60; 0.001). These results suggest that the chronic pharmaco-behavioral effects of phencyclidine may involve expression of both dopamine- and non-NMDA glutamate-receptor mRNAs.</p

Production of Nitric Oxide Using a Pulsed Arc Discharge

Nitric monoxide (NO) is increasingly being used in medical applications. Currently, a gas cylinder of N/sub 2/ mixed with a high concentration of NO is used. This arrangement is potentially risky due to the possibility of accidental leak of NO from the cylinder. The presence of NO in air leads to the formation of nitric dioxide (NO/sub 2/), which is toxic to the lungs. Therefore, an on-site generation of NO would be very desirable for patients with acute respiratory distress syndrome and other related illnesses. We have recently reported on the production of NO using a pulsed arc discharge. In the present work, the discharge reactor was made simpler and smaller. NO was generated using a pulsed arc discharge in dry air and in mixtures of oxygen and nitrogen. The composition of the gas mixture after treatment with an arc discharge followed by exposure to heated molybdenum was 540 ppm of NO, 48 ppm of NO/sub 2/, and the balance dry air at 0.1 MPa and 300 /spl plusmn/ 3 K. No ozone was detected at the outlet of the system by UV absorption. The density of the brass particles emitted from the electrodes, which had diameters over 0.3 /spl mu/m, was less than 1.39 /spl mu/g/L. A filter could readily capture and thus remove the brass particles

Production of Nitric Monoxide Using Pulsed Discharges for a Medical Application

Nitric monoxide (NO) is widely used in medical treatment of acute respiratory distress syndrome (ARDS). The production of NO is of interest to the medical community. In the present work, NO is generated by pulsed discharges between two rod electrodes in a mixture of nitrogen and oxygen. An arc discharge having a temperature of about 10000K was produced, which was sufficient to generate NO. Some of the important parameters affecting the production of NO have been investigated. These include the percentage of O2 (6-94%) in the mixture of N2 and O2, the energy of the discharge (0.5-12 J/pulse), the pulse repetition rate (0.5-4.5 pps) and the flow rate (1.35-5.4 l/min) of the gas mixture. NO2 produced in the discharge was successfully changed to NO using a heated molybdenum tube. NO2 must be extracted from the gas before clinical inhalation. The concentration of ozone was completely eliminated by bubbling the gas mixture through water. A maximum of NO and a minimum of NO2 concentrations were generated when the proportion of O2 in the gas mixture was in the range of 20-27%. The concentrations of NO and NO2 increased with increasing pulse repetition rate and with decreasing flow rate of the mixture. In all cases, NO2 was effectively removed using a heated molybdenum tube

Longitudinal Changes in Quantitative EEG and Event- related Potentials in Healthy Elderly VolunTFFrs : A 4-year Follow-up Study

Age-related changes of cognitive brain function are reflected by neurophysiological measurements such as quantitative electroencephalograms (EEG) and event -related potentials (ERP). However, longitudinal changes in these neurophysiological parameters in healthy elderly individuals have remained largely unreported. In the present study, quantitative EEG and ERP were measured prospectively twice, at an interval of 4 years, in 21 physically and cognitively healthy geriatric volunteers (age at first session, 66.3 ± 2.6 years). EEG data collected from 18 electrode sites on the cranial surface according to the 10-20 International System were used for quantitative analysis of waveform recognition for 1 mm under resting, awake, eyes-closed conditions. ERPs were elicited using an auditory oddball paradigm. With each subject, we compared EEG and ERP data obtained at the 2 sessions. The 4-year follow-up of quantitative BEG revealed a significant increase in the incidence of Qθ1 band waves and a significant decrease in the incidence of α2 band waves at nearly all sites. Although no changes in P300 amplitudes were observed, P300 latencies were significantly increased at the 2^ session at all sites, with mean prolongation of 4.7 ± 0.7 ms/year. These results are consistent with those of previous cross-sectional studies, and provide the first prospective demonstration of subtle slowing of cognitive processes in normal elderly subjects

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Bipolar afective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratifcation are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identifed genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × ­10−3; FDR< 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common infammatory/autoimmune processes, our fndings strongly suggest that HLA-mediated low infammatory background may contribute to the efcient response to Li in BD patients, while an infammatory status overriding Li anti-infammatory properties would favor a weak response

Prediction of lithium response using genomic data

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [-&nbsp;0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD