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Item Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: Preliminary studies(Springer Nature, 2021) Mishra, Himanshu K.; Ying, Noelle M.; Luis, Angelica; Wei, Heather; Nguyen, Metta; Nakhla, Timothy; Vandenburgh, Sara; Alda, Martin; Berrettini, Wade H.; Brennand, Kristen J.; Calabrese, Joseph R.; Coryell, William H.; Frye, Mark A.; Gage, Fred H.; Gershon, Elliot S.; McInnis, Melvin G.; Nievergelt, Caroline M.; Nurnberger, John I.; Shilling, Paul D.; Oedegaard, Ketil J.; Zandi, Peter P.; The Pharmacogenomics of Bipolar Disorder Study; Kelsoe, John R.; Welsh, David K.; McCarthy, Michael J.; Psychiatry, School of MedicineBipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.Item A comparison of measurements of lithium concentrations using flame photometry and atomic absorption spectrophotometry(1984) Villescas, Patricia L.Item Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes(Karger Publishers, 2016-10) Anand, Amit; McClintick, Jeanette N.; Murrell, Jill; Karne, Harish; Nurnberger, John I.; Edenberg, Howard J.; Psychiatry, School of MedicineBackground This study investigated the effect of lithium monotherapy on peripheral lymphocyte gene expression in bipolar disorder (BD). Method Twenty-two medication-free bipolar subjects (11 hypomanic, 11 depressed) were started on lithium monotherapy. Closely matched healthy subjects (n = 15) were included as controls but did not receive treatment. Blood RNA samples were collected at baseline and after 2 and 8 weeks of treatment. RNA expression was measured using the Affymetrix GeneChip® Human Gene 1.0 ST Array followed by Ingenuity pathways analysis. The results for the contrast of weeks 2 and 8 were not significantly different and were combined. Results In BD subjects, 56 genes showed significant (false discovery rate <0.1) expression changes from baseline; the effect sizes and directions for all of these were similar at weeks 2 and 8. Among these were immune-related genes (IL5RA, MOK, IFI6, and RFX2), purinergic receptors (P2RY14, P2RY2, and ADORA3) and signal transduction-related genes (CAMK1 and PIK3R6). Pathway and upstream regulator analysis also revealed that lithium altered several immune- and signal transduction-related functions. Differentially expressed genes did not correlate with week 8 clinical response, but other genes involved in protein synthesis and degradation did. Conclusion Peripheral gene expression may serve as a biomarker of lithium effect.Item Effects of somatic treatments on suicidal ideation and completed suicides(Wiley, 2021-11) Hawkins, Elise M.; Coryell, William; Leung, Stephen; Parikh, Sagar V.; Weston, Cody; Nestadt, Paul; Nurnberger, John I., Jr.; Kaplin, Adam; Kumar, Anupama; Farooqui, Ali A.; El-Mallakh, Rif S.; Psychiatry, School of MedicineObjective: This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. Methods: Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increase or reduce the risk for suicide. The reviews ventured to include all relevant information about the risk for both suicide ideation and completed suicides. Results: Lithium and clozapine are the only two somatic treatments that have high-quality data documenting their antisuicide effects in mood disorders and schizophrenia, respectively. Lithium discontinuation is also associated with increased suicide risk. Ketamine and esketamine may have a small, but immediate, antisuicide effect. Despite the recent Food and Drug Administration approval of esketamine use in depressed suicidal patients, the small disproportional overrepresentation of suicide in subjects who had received esketamine versus placebo (3 vs. 0 among > 3500 subjects) requires ongoing evaluation. The purported antisuicide effect of electroconvulsive therapy is based on low-quality data. The effect of antidepressants is not at all clear. There appears to be direct evidence for antidepressants increasing suicidal ideation and the risk for suicide over the short-term in young people, but indirect (low quality) evidence that antidepressants reduce suicide risk over the long term. Conclusions: Clinicians have an expanding pharmacopeia to address suicide potential in their patients. Some of the agents with documented antisuicide effects may also increase suicidality under specific circumstances.Item Extrinsic Characterization Sustainability in Zirconia Reinforced Lithium Silicate Ceramics(2021-04-08) Gadah, Thrya; May, Jaren; Levon, John; Chu, Tien-Min G; Gregory, Richard; Wei Shao, Lin; Feitosa, SabrinaABSTRACT OBJECTIVE. To investigate the effect of aging on the surface roughness and the color sustainability of externally characterized zirconia reinforced lithium silicate glass-ceramics treated with different surface protocols. METHODS. Sixty blocks (12-mm X 14-mm; 1.5-mm) of pre-crystalized zirconia reinforced-lithium silicate glass-ceramic (Vita Suprinity, Vita Zahnfabrick, Germany) CAD/CAM were crystalized and treated with different surface protocols, as extrinsic characterization (EC), mechanical polishing (MP), glaze layer (GL), surface adjustment (SA) and no treatment – control group (CG). Experimental groups (n=10) were divided as follow: CG; EC-MP-GZ; EC-GZ; EC-MP; EC-GZ-SA-GZ; EC-GZ-SA-MP and submitted to thermocycling (5,000 cycles, 5-55C) and toothbrushing simulation (5,000 cycles). Surface roughness (Ra and Rq), color change (CIED2000) and biofilm growth were evaluated. Statistical analysis was performed with a two-sided 5% significance level for all tests. RESULTS. For the parameter RaX, the control differed from EC-GZ and EC-MP (p = 0.04). For the parameter RqX, EC-GZ presented higher surface roughness compared than EC-MP-GZ and the group EC-GZ-SA-MP (p=0.02). EC-MP (p<0.01) and the EC-GZ-SA-MP (p<0.01) showed higher color change E00 after aging, while CG and EC-MP-GZ the least. For the biofilm growth, no significant group effect on bacteria counts was found (p=0.089). CONCLUSION. The aging protocol affected the surface roughness, and color of externally characterized zirconia reinforced lithium silicate glass-ceramics submitted to different surface treatment protocols. In the present study, when the mechanical polishing was performed before glaze application, the slightest color change and surface roughness were observed compared to the other surface treatments. Bacteria were not able to grow in the material surface, under the conditions tested in the present study.Item Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer’s disease(Nature Research, 2019-12-04) Maloney, Bryan; Balaraman, Yokesh; Liu, Yunlong; Chopra, Nipun; Edenberg, Howard J.; Kelsoe, John; Nurnberger, John I.; Lahiri, Debomoy K.; Psychiatry, School of MedicineLithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer’s disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium’s modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD.Item Relation of hyperparathyroidism and hypercalcemia to bipolar and psychotic disorders(Taylor & Francis, 2022-04-08) Enyi, Chioma O.; D’Souza, Brendan; Barloon, Linda; Ilonze, Onyedika J.; Chacko, Ranjit; Medicine, School of MedicinePrimary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone. PHPT leads to hypercalcemia and presents with renal, skeletal, and neuropsychiatric symptoms. Neuropsychiatric manifestations of PHPT such as psychotic, depressive, and anxiety disorders are rare. Delirium may also be present in patients with PHPT. Parathyroidectomy is the treatment of choice for patients with physically symptomatic PHPT, but it remains unclear if parathyroidectomy is indicated for its psychiatric manifestations. It is unclear if parathyroidectomy should be performed as a treatment for medication-refractory psychiatric symptoms or deferred until psychiatric symptoms have been better controlled. We present two cases of hyperparathyroidism (HPT)-associated hypercalcemia-one with lithium-associated HPT-in which psychiatric manifestations resolved with parathyroidectomy.Item Synthesis of lithium manganese phosphate by controlled sol-gel method and design of all solid state lithium ion batteries(2015) Penumaka, Rani Vijaya; Zhu, LikunDue to the drastic increase in the cost of fossil fuels and other environmental issues, the demand for energy and its storage has risen globally. Rather than being dependent on intermittent energy sources like wind and solar energy, focus has been on alternative energy sources. To eliminate the need for fossil fuels, advances are being made to provide energy for hybrid electric vehicles (HEV), plug-in hybrid vehicles (PHEV) and pure electric vehicles (EV) thus providing scope for much greener environment. Hence, focus has been on development in lithium ion batteries to provide with materials that have high energy density and voltage. Ortho olivine lithium transitional metals are known to be abundant and inexpensive; these compounds are less noxious than other cathode materials. Advancement in research is being done in finding iron and manganese compounds as cathode materials for advanced technologies. However, Lithium manganese phosphates are known to suffer with poor electrochemical performances due the manganese dissolution in the organic liquid electrolyte due to Jahn-Teller Lattice distortion. This problem was tried to endorse in this thesis. In the second chapter by synthesizing nano sized cathode particles with good electronic conductivity, good performance was achieved. In the third chapter additive olivine cathode was synthesized my modified sol gel process. A wt. % of TMSP was added as an additive in the organic liquid electrolyte. By comparing the properties between the two kinds of electrolytes it was observed that by the addition of the additive in the organic electrolyte good electrochemical properties could be achieved hindering the Mn dissolution in the electrolyte. In the final chapter, a composite solid electrolyte was fabricated by using NASICON-type glass ceramic of Lithium aluminum titanium phosphate (LATP) with organic binder of Polyethylene oxide. The flexible solid electrolyte exhibited good ionic conductivity. An all solid state cell was fabricated using the composite solid electrolyte using LiMn2O4 as the symmetric electrodes. At different pressures, the performance of the solid state cell was studied.Item Too Much of a Good Thing? Detrimental Health Effects Linked to Environmental Lithium Exposure through Drinking Water(The American Psychiatric Association, 2024) Patterson, Andrea; Bartlett, Zane; Fisher, Sarah; Stumpff, Julia C.; Schwab, Rebecca; Unfried, GregoryFor centuries, people have made pilgrimages to lithium springs in search of better health. In modern times, relatively high levels of lithium in drinking water are linked to lower suicide and homicide rates as well as possible neuroprotective benefits. However, with increased mining of lithium, metallic contaminants in the environment are a growing concern. The goal of this systematic review is to determine whether there is a risk to humans from higher levels of environmental lithium in the water supply. Methods: Systematic Review. Between searches in October 2021 and May 2023, a total of 10,234 citations were retrieved from three databases, one citation index, and one clinical trial registry. 6106 duplicates were removed. 4127 records were screened. 3873 were excluded. 254 reports were retrieved and assessed for eligibility based on population, study design, and outcomes. 26 studies were included in the final review. Results: Of the 26 studies selected for extraction, 12 showed negative effects related to lithium exposure through drinking water. The studies reviewed included data from five continents. Study subjects ranged from newborn to adult, including pregnant women. The data reflected the possibility for detrimental effects to the nervous system, the cardiovascular system, the endocrine system, the lymphatic system, the urinary system, and the integumentary system. Of note, the suggested effects included increased risk of autism spectrum disorder and up to 1.88-fold increase in the risk of schizophrenia spectrum disorder. It also indicated possible teratogenicity. Conclusion: The findings of this review indicate that lithium, even at the non-therapeutic levels found in drinking water, is linked to negative impacts on human health. This suggests the need for further studies and the development of clear guidelines regarding monitoring and maximum permissible concentrations of lithium in municipal and bottled water supplies [Note: Due to APA’s conference restrictions on the number of authors, Schwab, R was left off as an author on the poster. However, she contributed to the study by doing initial work on parameters.]Item Understanding the periodic table through the lens of the volatile Group I metals(The Conversation US, Inc., 2019-04-23) Boschmann, Erwin; Chemistry and Chemical Biology, School of Science