RNA Pol IV induces antagonistic parent-of-origin effects on Arabidopsis endosperm.

Gene expression in endosperm-a seed tissue that mediates transfer of maternal resources to offspring-is under complex epigenetic control. We show here that plant-specific RNA polymerase IV (Pol IV) mediates parental control of endosperm gene expression. Pol IV is required for the production of small interfering RNAs that typically direct DNA methylation. We compared small RNAs (sRNAs), DNA methylation, and mRNAs in Arabidopsis thaliana endosperm from heterozygotes produced by reciprocally crossing wild-type (WT) plants to Pol IV mutants. We find that maternally and paternally acting Pol IV induce distinct effects on endosperm. Loss of maternal or paternal Pol IV impacts sRNAs and DNA methylation at different genomic sites. Strikingly, maternally and paternally acting Pol IV have antagonistic impacts on gene expression at some loci, divergently promoting or repressing endosperm gene expression. Antagonistic parent-of-origin effects have only rarely been described and are consistent with a gene regulatory system evolving under parental conflict.

Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Regioselective synthesis of 4-arylamino-1,2-naphthoquinones in eutectogel as a confined reaction medium using LED light.

Predicting selectivity and conversion in a confined reaction medium under photochemical conditions is highly challenging as compared to the corresponding conventional synthesis. Herein, we report the use of a simple carbohydrate-derived eutectogel to facilitate LED-light-induced regioselective synthesis of 4-arylamino-1,2-naphthoquinones in good yield. This methodology, by including a reusable reaction medium, proved to have the potential of affording the regioselective formation of various desired products in good yields.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. METHODS: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. RESULTS: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). DISCUSSION: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Water lily (Nymphaea thermarum) genome reveals variable genomic signatures of ancient vascular cambium losses.

For more than 225 million y, all seed plants were woody trees, shrubs, or vines. Shortly after the origin of angiosperms ∼140 million y ago (MYA), the Nymphaeales (water lilies) became one of the first lineages to deviate from their ancestral, woody habit by losing the vascular cambium, the meristematic population of cells that produces secondary xylem (wood) and phloem. Many of the genes and gene families that regulate differentiation of secondary tissues also regulate the differentiation of primary xylem and phloem, which are produced by apical meristems and retained in nearly all seed plants. Here, we sequenced and assembled a draft genome of the water lily Nymphaea thermarum, an emerging system for the study of early flowering plant evolution, and compared it to genomes from other cambium-bearing and cambium-less lineages (e.g., monocots and Nelumbo). This revealed lineage-specific patterns of gene loss and divergence. Nymphaea is characterized by a significant contraction of the HD-ZIP III transcription factors, specifically loss of REVOLUTA, which influences cambial activity in other angiosperms. We also found the Nymphaea and monocot copies of cambium-associated CLE signaling peptides display unique substitutions at otherwise highly conserved amino acids. Nelumbo displays no obvious divergence in cambium-associated genes. The divergent genomic signatures of convergent loss of vascular cambium reveals that even pleiotropic genes can exhibit unique divergence patterns in association with independent events of trait loss. Our results shed light on the evolution of herbaceousness-one of the key biological innovations associated with the earliest phases of angiosperm evolution.

The Zinc-BED Transcription Factor Bedwarfed Promotes Proportional Dendritic Growth and Branching through Transcriptional and Translational Regulation in Drosophila.

Dendrites are the primary points of sensory or synaptic input to a neuron and play an essential role in synaptic integration and neural function. Despite the functional importance of dendrites, relatively less is known about the underlying mechanisms regulating cell type-specific dendritic patterning. Herein, we have dissected the functional roles of a previously uncharacterized gene, CG3995, in cell type-specific dendritic development in Drosophila melanogaster. CG3995, which we have named bedwarfed (bdwf), encodes a zinc-finger BED-type protein that is required for proportional growth and branching of dendritic arbors. It also exhibits nucleocytoplasmic expression and functions in both transcriptional and translational cellular pathways. At the transcriptional level, we demonstrate a reciprocal regulatory relationship between Bdwf and the homeodomain transcription factor (TF) Cut. We show that Cut positively regulates Bdwf expression and that Bdwf acts as a downstream effector of Cut-mediated dendritic development, whereas overexpression of Bdwf negatively regulates Cut expression in multidendritic sensory neurons. Proteomic analyses revealed that Bdwf interacts with ribosomal proteins and disruption of these proteins resulted in phenotypically similar dendritic hypotrophy defects as observed in bdwf mutant neurons. We further demonstrate that Bdwf and its ribosomal protein interactors are required for normal microtubule and F-actin cytoskeletal architecture. Finally, our findings reveal that Bdwf is required to promote protein translation and ribosome trafficking along the dendritic arbor. These findings shed light on the complex, combinatorial, and multi-functional roles of transcription factors (TFs) in directing the diversification of cell type-specific dendritic development.

Comparison of the effects of caffeine, aminophylline, and saline on the recovery from total intravenous anesthesia in laparoscopic surgeries: A randomized controlled trial.

Background and Aims: The return of consciousness (ROC) after general anesthesia (GA) is by stopping the administration of anesthetic agents. At present, no drug is given to reverse the loss of consciousness produced by general anesthetic agents. This study is conducted to find whether caffeine and aminophylline hasten the ROC. Material and Methods: This study was conducted on 75 American Society of Anesthesiologists (ASA) I and II female patients undergoing laparoscopic hysterectomy, aged between 18 and 60 years. The patients were divided into three equal groups (Group C: caffeine citrate, Group A: aminophylline, and Group S: saline) of 25 each by a computer-generated random number table. GA was induced with propofol, fentanyl, and maintained with propofol infusion. On completion of the surgery, the neuromuscular blocking agent was reversed and then the infusion of propofol was stopped. The study drug was administered intravenously when the BIS 60 was achieved. Time to achieve BIS 90, return of first gag reflex, eye-opening on verbal command, and extubation after study drug administration were noted. Hemodynamic parameters and SpO2 were also monitored. Results: The time for BIS 60 to 90 was 10 (4.25) min in the caffeine group, 13 (4.25) min in the aminophylline group, and 26 (9.0) min in the saline group. The time to return of gag reflex and time to extubation were shorter in the caffeine and aminophylline group compared to the saline group. The time to eye-opening on verbal command was shorter in the aminophylline group compared to the saline group. Hemodynamic parameters after infusion of the study drug were comparable in all three groups. Conclusion: Caffeine hastens the recovery from total intravenous anesthesia with propofol and fentanyl in laparoscopic hysterectomy as effectively as aminophylline.

Preoperative Prostate MRI Predictors of Urinary Continence Following Radical Prostatectomy.

Background Urinary continence after radical prostatectomy (RP) is an important determinant of patient quality of life. Anatomic measures at prostate MRI have been previously associated with continence outcomes, but their predictive ability and interrater agreement are unclear in comprehensive clinical models. Purpose To evaluate the predictive ability and interrater agreement of MRI-based anatomic measurements of post-RP continence when combined with clinical multivariable models. Materials and Methods In this retrospective cohort study, continence outcomes were evaluated in men who underwent RP from August 2015 to October 2019. Preoperative MRI-based anatomic measures were obtained retrospectively by four abdominal radiologists. Before participation, these radiologists completed measure-specific training. Logistic regression models were developed with clinical variables alone, MRI variables alone, and combined variables for predicting continence at 3, 6, and 12 months after RP; some patient data were missing at each time point. Interrater agreement of MRI variables was assessed by using intraclass correlation coefficients (ICCs). Results A total of 586 men were included (mean age ± standard deviation: 63 years ± 7). The proportion of patients with incontinence was 0.2% (one of 589) at baseline, 27% (145 of 529) at 3 months, 14% (63 of 465) at 6 months, and 9% (37 of 425) at 12 months. Longer coronal membranous urethra length (MUL) improved the odds of post-RP continence at all time points (odds ratio per 1 mm: 0.86 [95% CI: 0.80, 0.93], P < .001; 0.86 [95% CI: 0.78, 0.95], P = .003; and 0.79 [95% CI: 0.67, 0.91], P = .002, respectively) in models that incorporated both clinical and MRI predictors. No other MRI variables were predictive. Age and baseline urinary function score were the only other predictive clinical variables at every time point. Interrater agreement was moderate (ICC, 0.62) for MUL among readers with measure-specific prostate MRI training and poor among those without the training (ICC, 0.38). Conclusion Preoperative MRI-measured coronal membranous urethra length was an independent predictor of urinary continence after prostatectomy. © RSNA, 2022 Online supplemental material is available for this article.

Interrater Agreement of Bosniak Classification Version 2019 and Version 2005 for Cystic Renal Masses at CT and MRI.

Background The Bosniak classification system for cystic renal masses was updated in 2019 in part to improve agreement compared with the 2005 version. Purpose To compare and investigate interrater agreement of Bosniak version 2019 and Bosniak version 2005 at CT and MRI. Materials and Methods In this retrospective single-center study, a blinded eight-reader assessment was performed in which 195 renal masses prospectively considered Bosniak IIF-IV (95 at CT, 100 at MRI, from 2006 to 2019 with version 2005) were re-evaluated with Bosniak versions 2019 and 2005. Radiologists (four faculty members, four residents) who were blinded to the initial clinical reading and histopathologic findings assessed all feature components and reported the overall Bosniak class for each system independently. Agreement was assessed with Gwet agreement coefficients. Uni- and multivariable linear regression models were developed to identify predictors of dispersion in the final Bosniak class assignment that could inform system refinement. Results A total of 185 patients were included (mean age, 63 years ± 13 [standard deviation]; 118 men). Overall interrater agreement was similar between Bosniak version 2019 and version 2005 (Gwet agreement coefficient: 0.51 [95% CI: 0.45, 0.57] vs 0.46 [95% CI: 0.42, 0.51]). This was true for experts (0.54 vs 0.49) and novices (0.50 vs 0.47) and at CT (0.56 vs 0.51) and MRI (0.52 vs 0.43). Nine percent of masses prospectively considered cystic using Bosniak version 2005 criteria were considered solid using version 2019 criteria. In general, masses were more commonly classified in lower categories when radiologists used Bosniak version 2019 criteria compared with version 2005 criteria. The sole predictor of dispersion in Bosniak version 2019 class assignment was dispersion in septa or wall quality (ie, smooth vs irregular thickening vs nodule; 72% [MRI] and 60% [CT] overall model variance explained; multivariable P < .001). Conclusion Overall interrater agreement was similar between Bosniak version 2019 and version 2005; disagreements in septa or wall quality were common and strongly predictive of variation in Bosniak class assignment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Eberhardt in this issue.

Paternally Acting Canonical RNA-Directed DNA Methylation Pathway Genes Sensitize Arabidopsis Endosperm to Paternal Genome Dosage.

Seed development is sensitive to parental dosage, with excess maternal or paternal genomes creating reciprocal phenotypes. Paternal genomic excess frequently results in extensive endosperm proliferation without cellularization and seed abortion. We previously showed that loss of the RNA polymerase IV gene NUCLEAR RNA POLYMERASE D1 (NRPD1) in tetraploid fathers represses seed abortion in paternal excess crosses. Here, we show genetically that RNA-directed DNA methylation (RdDM) pathway activity in the paternal parent is sufficient to determine the viability of paternal excess Arabidopsis (Arabidopsis thaliana) seeds. We compared transcriptomes, DNA methylation, and small RNAs from the endosperm of seeds from balanced crosses (diploid × diploid) and lethal (diploid × tetraploid) and viable paternal excess crosses (diploid × tetraploid nrpd1). Endosperms from both lethal and viable paternal excess seeds share widespread transcriptional and DNA methylation changes at genes and transposable elements. Interploidy seed abortion is thus unlikely to be caused by transposable elements or imprinted gene misregulation, and its repression by the loss of paternal RdDM is associated with only modest gene expression changes. Finally, using allele-specific transcription data, we present evidence for a transcriptional buffering system that increases the expression of maternal alleles and represses paternal alleles in response to excess paternal genomic dosage. These findings prompt reconsideration of models for dosage sensitivity in endosperm.

Genomic regions associated with resistance to Fusarium wilt in castor identified through linkage and association mapping approaches.

Fusarium wilt, caused by Fusarium oxysporum f. sp. ricini, is the most destructive disease in castor. Host plant resistance is the best strategy for the management of wilt. Identification of molecular markers linked to wilt resistance will enhance the efficiency and effectiveness of breeding for wilt resistance. In the present study, genomic regions linked to wilt resistance were mapped using a bi-parental population of 185 F6-RILs and a genetically diverse panel of 300 germplasm accessions. Quantitative trait loci (QTL) analysis performed using a linkage map consisting of 1090 SNP markers identified a major QTL on chromosome 7 with an LOD score of 18.7, which explained 44% of the phenotypic variance. The association mapping performed using genotypic data from 3465 SNP loci revealed 69 significant associations (p < 1 × 10-4) for wilt resistance. The phenotypic variance explained by the individual SNPs ranged from 0.063 to 0.210. The QTL detected in the bi-parental mapping population was not identified in the association analysis. Thus, the results of this study indicate the possibility of vast gene diversity for Fusarium wilt resistance in castor.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

Effect of Prostate MRI Interpretation Experience on PPV Using PI-RADS Version 2: A 6-Year Assessment Among Eight Fellowship-Trained Radiologists.

BACKGROUND. Understanding the effect of specific experience in prostate MRI interpretation on diagnostic performance would help inform the minimum interpretation volume to establish proficiency. OBJECTIVE. The purpose of this article is to assess for an association between increasing experience in prostate MRI interpretation and change in radiologist-level PPVs for PI-RADS version 2 (v2) categories 3, 4, and 5. METHODS. This retrospective study included prostate MRI examinations performed between July 1, 2015, and August 13, 2021, that were assigned a PI-RADS v2 category of 3, 4, or 5 and with an MRI-ultrasound fusion biopsy available as the reference standard. All examinations were among the first 100-200 prostate MRI examinations interpreted using PI-RADS v2 by fellowship-trained abdominal radiologists. Radiologists received feedback through a quality assurance program. Radiologists' experience levels were classified using progressive subsets of 50 interpreted examinations. Change with increasing experience in distribution of individual radiologists' whole-gland PPVs for Gleason sum score 7 or greater prostate cancer, stratified by PI-RADS category, was assessed by hierarchic linear mixed models. RESULTS. The study included 1300 prostate MRI examinations in 1037 patients (mean age, 66 ± 7 [SD] years), interpreted by eight radiologists (median, 13 years of postfellow-ship experience; range, 5-22 years). Aggregate PPVs were 20% (68/340) for PI-RADS category 3, 49% (318/652) for category 4, and 71% (220/308) for category 5. Interquartile ranges (IQRs) of PPVs overlapped for category 4 (51%; IQR, 42-60%) and category 5 (70%; IQR, 54-75%) for radiologists' first 50 examinations. IQRs of PPVs did not overlap between categories of greater experience; for example, at the 101-150 examination level, PPV for category 3 was 24% (IQR, 20-29%), category 4 was 55% (IQR, 54-63%), and category 5 was 81% (IQR, 77-82%). Hierarchic modeling showed no change in radiologists' absolute PPV with increasing experience (category 3, p = .27; category 4, p = .71; category 5, p = .38). CONCLUSION. Absolute PPVs at specific PI-RADS categories did not change during radiologists' first 200 included examinations. However, resolution of initial overlap in IQRs indicates improved precision of PPVs after the first 50 examinations. CLINICAL IMPACT. If implementing a minimum training threshold for fellowship-trained abdominal radiologists, 50 prostate MRI examinations may be sufficient in the context of a quality assurance program with feedback.

Lessons Learned from Peer Learning Conference in Cardiothoracic Radiology.

Medical errors may lead to patient harm and may also have a devastating effect on medical providers, who may suffer from guilt and the personal impact of a given error (second victim experience). While it is important to recognize and remedy errors, it should be done in a way that leads to long-standing practice improvement and focuses on systems-level opportunities rather than in a punitive fashion. Traditional peer review systems are score based and have some undesirable attributes. The authors discuss the differences between traditional peer review systems and peer learning approaches and offer practical suggestions for transitioning to peer learning conferences. Peer learning conferences focus on learning opportunities and embrace errors as an opportunity to learn. The authors also discuss various types and sources of errors relevant to the practice of radiology and how discussions in peer learning conferences can lead to widespread system improvement. In the authors' experience, these strategies have resulted in practice improvement not only at a division level in radiology but in a broader multidisciplinary setting as well. The online slide presentation from the RSNA Annual Meeting is available for this article. ©RSNA, 2022.

G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells.

Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear membrane GPCR in the regulation of renal sodium through epigenetic gene regulation.

Analytical Method Validation for Estimation of Neurotransmitters (Biogenic Monoamines) from Cerebrospinal Fluid Using High Performance Liquid Chromatography.

Biogenic amine neurotransmitters such as serotonin and dopamine are essential for signaling in both central and peripheral nervous system. Their metabolism is a multistep pathway and any defect in this results in alteration in metabolites of serotonin 5-Hydroxyindole acetic acid (5HIAA) and dopamine homovanillic acid (HVA) and 3-O-Methyl Dopa (3-OMD). Estimation of these metabolites in cerebrospinal fluid (CSF) assists in diagnosis of neurotransmitter defects. Their estimation is technically demanding and is currently available only in referral centers. We aimed to optimize a method for analysis of 5HIAA, HVA and 3-OMD. A high performance liquid chromatography (HPLC) method with electro chemical detector (ECD) was standardized for estimation. Analysis for method validation, reference range verification and clinical correlation was performed. Linearity obtained for 5-HIAA, HVA and 3-OMD was 65.35-2615.0 nmoles/l, 68.62-2745.0 nmoles/l and 236.5-4730.0 nmoles/l respectively. The coefficient of variation for internal quality controls ranged from 5 to 14% and the external proficiency testing samples (n = 16) were within peer group range. CSF metabolite levels of samples for reference range analysis overlapped with age matched ranges reported in literature. Among the 40 suspected patients analyzed for clinical testing four were found to have a neurotransmitter defect. These patients were then confirmed with molecular testing and clinical correlation. The method is validated and can be adapted in a clinical laboratory with analytical competence in HPLC.

Testing-Related Health Impact of Transrectal and Transperineal Prostate Biopsy as Assessed by Health Utilities.

PURPOSE: We sought to assess the temporary health-related quality of life (health utility) of nonmagnetic resonance imaging-guided transrectal and transperineal prostate biopsy. MATERIALS AND METHODS: This is a 2-arm, prospectively enrolled, observational, patient-reported outcomes study, performed between June 2019 and November 2020 at a single academic medical center. Inclusion criteria were men undergoing an outpatient ultrasound-guided prostate biopsy (transrectal or transperineal approach, without magnetic resonance imaging guidance). Patients with a history of Gleason 7+ prostate cancer were excluded. Validated survey instruments were utilized to assess baseline (Short Form 12) and testing-related (Testing Morbidities Index [TMI]) health utility states. The primary outcome was the TMI summary testing-related quality-of-life score (summary utility score; scale: 0=death and 1=perfect health). The TMI is comprised of 7 domains, spanning before, during and after testing experiences. Each domain is scored from 1 (no health impact) to 5 (extreme health impact). Testing-related quality-of-life measures were compared with Mann-Whitney U test. RESULTS: Enrollment rates were 80% (60/75; transrectal) and 86% (60/70; transperineal). All patients (120/120) completed the questionnaire. The TMI summary score for transrectal biopsy was not significantly different from transperineal biopsy (0.86, 95% CI 0.84-0.88 vs 0.83, 95% CI 0.81-0.85; p=0.0774). The largest difference in the testing experiences was related to intraprocedural pain (transrectal biopsy: 2.3, 95% CI 2.1-2.4; transperineal biopsy: 2.9, 95% CI 2.6-3.1; p <0.001). CONCLUSIONS: Transperineal and transrectal prostate biopsies have similar effect on temporary health-related quality-of-life. Transient differences relate to intraprocedural pain. These data can inform clinical decision making and future cost-utility models.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.