Search

Bipolar disorder (BD) largely begins in adolescence, but diagnosis lags for years, causing significant morbidity and mortality, and demonstrating the need for better diagnostic tools. Suggesting an association between BD and immune activity, elevated levels of peripheral inflammatory markers, including C-reactive protein (CRP), have been found in adults with BD. As similar data are extremely limited in adolescents, this study examined CRP levels in adolescents with BD (n = 37) compared to those with anxiety disorders (ADs, n = 157) and healthy controls with no psychiatric diagnoses (HCs, n = 2760). CRP blood levels for patients aged 12-17 years were retrieved from a nationwide repository of deidentified clinical data. After excluding patients with inflammatory conditions, differences in CRP were examined using multivariate and weighted regressions (covariates: demographics and BMI). Mean CRP levels were significantly elevated in adolescents with BD relative to those with ADs and HCs. Mean CRP levels were lower in the ADs cohort versus HCs. Although CRP levels were significantly higher in males and younger patients, the significant between-cohort differences in CRP remained after controlling for multiple confounders. To our knowledge, our study is the first to compare CRP levels between adolescent BD, ADs, and HCs, comprising a novel and essential contribution. Our results suggest the presence of a unique immune process in adolescents with BD and indicate that CRP may represent a biomarker with a crucial role in the diagnostic assessment of adolescent BD., Competing Interests: Declaration of competing interest MSW, SLS, JAP, and SB declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MKM receives Research Support from Allergan, Inc., Neurological & Behavioral Outcomes Center at CWRU. MKM also receives royalties from American Psychiatric Publishing, Inc., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Bipolar and depressive disorders (bipolar disorder [BD], major depressive disorder [MDD]), as well as menopause affect millions of women. Although there are three known cognitive behavioral group treatment (CBGT) protocols to help women with problematic menopause symptoms, they do not target women on the BD or MDD spectrum. The purpose of this qualitative study was to learn more about the treatment needs and group experiences of women with problematic menopause symptoms and diagnosed on the BD and MDD spectrum, who participated in a CBGT intervention for menopausal symptoms. Methods: Narrative data recorded by clinicians (Interventionists' notes) and participants (Evaluation of Groups Survey) were analyzed using content analyses. Results: Several themes emerged from ( n  = 11 BD; n  = 48 MDD) what women wanted help with (specific symptoms and general aspects of menopause), what women liked about CBGT (specific and general aspects of the program), and changes needed in the CBGT intervention (things wished for and barriers that interfered with the program). The two diagnostic groups differed in their responses, although both groups identified content and delivery gaps they wished would be addressed. Specifically related to their diagnosis, women most commonly talked about problems with worsening mood and mood instability and multiple stressors interfering with their ability to follow through with the intervention. Conclusions: These findings can help refine existing CBGT protocols for women diagnosed on the BD and MDD spectrum seeking help for menopause symptoms. Trial Registry: Parent study ClinicalTrials.gov [identifier: NCT02860910]., Competing Interests: Dr. D.Y.C., Ms. D.O., Dr. S.D., Dr. C.B. and Dr. M.S.W. report no disclosures and no competing financial interests exist. Dr. J.S.C. reports personal fees from RoundGlass Inc., personal fees from Astellas Pharma Inc., personal fees from Kappa Sante, personal fees from Sojournix, personal fees from Mapi/ICON, and other from QUE oncology. Dr. M.M., reports royalties from American Psychiatric Publishing and grant funding from The Hartwell Foundation. Dr. M.S., in the last 3 years, has received research grants from Nuromate, Otsuka, Alkermes, International Society for Bipolar Disorders (ISBD), National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and Patient-Centered Outcomes Research Institute (PCORI). She has been a consultant to Alkermes, Otsuka, Janssen, Myriad, Health Analytics, and Frontline Medical Communications. She has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, and UpToDate. She has received compensation for the preparation of continuing medical education (CME) Activities form Physician's Institute, MCM Education, CMEology, Potomac Center for Medical Education, Global Medical Education, and Creative Educational Concepts., (© Danette Conklin et al., 2021; Published by Mary Ann Liebert, Inc.)

Posttranscriptional gene regulation by RNA-binding proteins, such as HuR ( elavl1 ), fine-tune gene expression in T cells, leading to powerful effects on immune responses. HuR can stabilize target mRNAs and/or promote translation by interacting with their 3' untranslated region adenylate and uridylate-rich elements. It was previously demonstrated that HuR facilitates Th2 cytokine expression by mRNA stabilization. However, its effects upon IL-2 homeostasis and CD4 + Th2 differentiation are not as well understood. We found that optimal translation of Il2ra (CD25) required interaction of its mRNA with HuR. Conditional HuR knockout in CD4 + T cells resulted in loss of IL-2 homeostasis and defects in JAK-STAT signaling, Th2 differentiation, and cytokine production. HuR-knockout CD4 + T cells from OVA-immunized mice also failed to proliferate in response to Ag. These results demonstrate that HuR plays a pivotal role in maintaining normal IL-2 homeostasis and initiating CD4 + Th2 differentiation., Competing Interests: DISCLOSURES The authors have no financial conflicts of interest.

CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult brain tryptophan hydroxylase 2 ( Tph2 ), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT-depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task. Tph2 -targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT-depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.

Unlabelled: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior., Significance Statement: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder., (Copyright © 2016 the authors 0270-6474/16/369828-15$15.00/0.)

The posttranscriptional mechanisms by which RNA binding proteins (RBPs) regulate T-cell differentiation and cytokine production in vivo remain unclear. The RBP HuR binds to labile mRNAs, usually leading to increases in mRNA stability and/or translation. Previous work demonstrated that HuR binds to the mRNAs encoding the Th2 transcription factor trans-acting T-cell-specific transcription factor (GATA-3) and Th2 cytokines interleukin (IL)-4 and IL-13, thereby regulating their expression. By using a novel conditional HuR knockout (KO) mouse in which HuR is deleted in activated T cells, we show that Th2-polarized cells from heterozygous HuR conditional (OX40-Cre HuR(fl/+)) KO mice had decreased steady-state levels of Gata3, Il4 and Il13 mRNAs with little changes at the protein level. Surprisingly, Th2-polarized cells from homozygous HuR conditional (OX40-Cre HuR(fl/fl)) KO mice showed increased Il2, Il4 and Il13 mRNA and protein via different mechanisms. Specifically, Il4 was transcriptionally upregulated in HuR KO T cells, whereas Il2 and Il13 mRNA stabilities increased. Additionally, when using the standard ovalbumin model of allergic airway inflammation, HuR conditional KO mice mounted a robust inflammatory response similar to mice with wild-type HuR levels. These results reveal a complex differential posttranscriptional regulation of cytokines by HuR in which gene dosage plays an important role. These findings may have significant implications in allergies and asthma, as well as autoimmune diseases and infection.

Objective: To determine whether apparently healthy captive-born wild felids that were not native to North America and were housed in an area endemic for Cytauxzoon felis harbored the pathogen., Design: Prospective observational case series., Animals: 11 captive-born wild felids that were (1 bobcat [Lynx rufus] and 1 cougar [Puma concolor]) or were not (1 lion [Panthera leo] and 8 tigers [Panthera tigris]) native to North America and 6 domestic cats (5 pets and 1 feral)., Procedures: Blood was collected, and a PCR assay for C felis was performed. The C felis 18S rRNA gene sequence was characterized in samples that tested positive. Blood smears were evaluated microscopically for intraerythrocytic organisms consistent with C felis. Blood smears from an additional 6 feral domestic cats found dead on the study premises were also evaluated., Results: 4 tigers and 6 domestic cats without clinical signs of disease tested positive for C felis infection via PCR assay; intraerythrocytic organisms consistent with C felis were identified in smears from 1 C felis-infected tiger (which also had azotemia) and in smears from 11 of 12 domestic cats. Possible erythrocytic inclusions were identified in 1 tiger that tested negative for C felis. Sequences of C felis 18S rRNA amplicons from all infected tigers shared > 99.8% identity with reported C felis sequences from North American domestic cats and were identical to amplicons from domestic cats on the premises., Conclusions and Clinical Relevance: Captive tigers without clinical signs of disease tested positive for C felis. The PCR assay for C felis appeared to be more reliable than cytologic detection of piroplasms in tigers.

Spirochetemia was diagnosed in 2 Siberian Huskies and a Rottweiler from the northwestern region of Texas between June 1999 and October 2001. Clinical findings were nonspecific; tick exposure was documented in 2 of the dogs. Hematologic abnormalities included anemia (n=2), neutrophilia (n=2, including 1 with a left shift), lymphopenia (n=3), eosinopenia (n=3), and thrombocytopenia (n=2). One anemic dog had a positive Coombs' test. In 1 dog, Western blot analysis of serum yielded multiple positive bands with B turicatae lysate, indicating the spirochetemia most likely was due to B turicatae infection. In 2 dogs, spirochetes were cultured from the blood and identified using DNA analysis as Borrelia turicatae; 1 of these dogs also was seropositive for Ehrlichia canis and B burgdorferi. In 2 cases, spirochetemia was more prominent in blood smears prepared immediately after sample collection than in smears prepared from EDTA blood. Two dogs recovered with doxycycline treatment; 1 dog declined clinically despite treatment and was euthanized. B turicatae is the agent of tick-borne (endemic) relapsing fever in humans and is distinct from B burgdorferi, the agent of Lyme disease; however, serologic cross-reactivity may occur. B turicatae is transmitted by the soft tick, Ornithodoros turicata, and infection should be considered in dogs with spirochetemia and possible exposure to the tick vector.

This paper provides an overview of a data system upgrade to the Pratt and Whitney facility designed for making acoustic measurements on aircraft gas turbine engines. A data system upgrade was undertaken because the return-on-investment was determined to be extremely high. That is, the savings on the first test series recovered the cost of the hardware. The commercial system selected for this application utilizes 48 input channels, which allows either 1/3 octave and/or narrow-band analyses to be preformed real-time. A high-speed disk drive allows raw data from all 48 channels to be stored simultaneously while the analyses are being preformed. Results of tests to ensure compliance of the new system with regulations and with existing systems are presented. Test times were reduced from 5 h to 1 h of engine run time per engine configuration by the introduction of this new system. Conservative cost reduction estimates for future acoustic testing are 75% on items related to engine run time and 50% on items related to the overall length of the test.

To evaluate changes in complete blood cell (CBC) counts, haptoglobin and fibrinogen in ovine lentivirus (OvLV)-infected lambs treated with recombinant ovine interferon-tau (rOVIFN-tau), 24 lambs were allocated to one of four groups (n = 6 per group): (1) virus + rOvIFN-tau, VI, (2) virus + placebo, VP, (3) no virus + rOVIFN-tau, NVI, and (4) no virus + placebo, NVP. Three lambs in each group were treated once a day for 12 weeks, and the remaining 3 lambs were treated for 33 weeks. Blood was collected at days 0, 7, and 10 and at weeks 2-10, 12, 32, and 33 to determine CBC counts, as well as haptoglobin and fibrinogen levels. Hematologic values remained within normal limits in all groups. However, hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and packed cell volume (PCV) values decreased (p < 0.05) in the two rOvIFN-tau-treated groups (VI and NVI) compared with the placebo-treated (VP and NVP) groups. Both rOvIFN-upsilon and OvLV had a mild negative effect on neutrophil numbers. Although Hb, MCV, MCHC, PCV, and neutrophil values declined in the rOvIFN-tau-treated lambs compared with the placebo-treated lambs, these values remained within the reference range for sheep. Experimental lambs did not show adverse clinical signs associated with OvLV infection or as a result of rOvIFN-tau treatment. The lack of significant side effects of high-dose rOvIFN-tau in sheep and previous reports of broad-spectrum and cross-species antiviral activity suggest that rOvIFN-tau warrants further investigation as an antiviral therapeutic agent.

To better characterize the idiopathic hyperlipoproteinemia of Miniature Schnauzer dogs, the plasma lipoproteins of 20 Miniature Schnauzers (MS) and 11 dogs of other breeds (DOB) were evaluated by ultracentrifugation, electrophoresis, and biochemical tests. Seventeen MS were healthy; 3 had diabetes mellitus. Plasma from 6 of 17 healthy and all 3 diabetic MS was visibly lipemic. Lipemia was slight to marked in healthy lipemic MS, and marked in diabetic ones. All DOB had clear plasma; 8 were healthy and 3 had diabetes. All healthy lipemic MS and diabetic lipemic MS had hypertriglyceridemia associated with excess very low density lipoproteins. Chylomicronemia was present in 4 of 6 healthy lipemic MS and all 3 diabetic lipemic MS. Lipoproteins with ultracentrifugal and electrophoretic characteristics of normal low density lipoprotein were lacking in 4 of 6 healthy lipemic MS. The lipoprotein patterns of 4 of 11 healthy nonlipemic MS were characterized by mild hypertriglyceridemia associated with increased very low density lipoproteins and a lack of lipoproteins with characteristics of normal low density lipoproteins. Lipoprotein patterns of diabetic DOB closely resembled those of healthy DOB; those of diabetic lipemic MS resembled those of markedly lipemic healthy lipemic MS. In conclusion, the hyperlipoproteinemia of Miniature Schnauzers is characterized by increased very low density lipoproteins with or without accompanying chylomicronemia; some affected dogs may have decreased low density lipoproteins.

Lithium carbonate administration to healthy cats was evaluated in 2 controlled studies (a dose-response study and a bone marrow evaluation study) to determine the effectiveness of lithium as a bone marrow stimulant. Lithium carbonate was administrated at dosage ranging from 300 to 1,050 mg/m2 of body surface/d. Complete blood count, serum lithium concentration determination, serum biochemical analysis, urinalysis, and bone marrow aspiration and biopsy were periodically performed. Serum lithium concentration greater than 2 mEq/L was associated with significant decrease in numbers of circulating segmented neutrophils (less than 1,200 cells/microliter; P less than 0.01) and lymphocytes (less than 1,300 cells/microliter; P less than 0.0001), as well as significant (P less than 0.05) decrease in urine specific gravity. Bone marrow evaluation revealed apparent maturation arrest of the neutrophil cell line. Coincident with the changes in laboratory values, the lithium-treated cats became ill. Changes in behavior and vocalization were seen, followed by anorexia, vomiting, and diarrhea. In later stages of intoxication, cats became hyperexcitable and manifested coarse muscular tremors. It was concluded that lithium carbonate does not have potential value as a bone marrow stimulant and is toxic to cats at serum concentration greater than 2 mEq/L.

Acute zinc toxicosis from the ingestion of pennies was diagnosed in a dog with Heinz body hemolytic anemia (PCV = 14%), leukocytosis (51,000 cells/ml) with a left shift (3,060 band neutrophils; 37,740 segmented neutrophils) and monocytosis (4,080 cells/ml), azotemia (BUN = 60 mg/dl), bilirubinemia (total bilirubin = 5.3 mg/dl), hypokalemia (3.0 mEq/L), high serum alkaline phosphatase activity (691 U/L), high total plasma solids (8.1 g/dl), hemoglobinuria, and proteinuria. Despite aggressive medical treatment, renal failure ensued, and the dog died of cardiac arrest. The clinical signs, clinical course, and laboratory findings in this dog were similar to what has been reported in other cases of acute zinc toxicosis in dogs, with the exception of a history of generalized seizures and the findings of Heinz bodies. Although a causative relationship between plasma zinc values and Heinz body formation cannot be proven, their association suggests that oxidative damage to erythrocyte hemoglobin and cell membrane proteins may be involved in the pathogenesis of zinc-induced hemolysis.

The British antilewisite butyrate-dithionitrobenzoate (BALB-DTNB) spectrophotometric serum lipase assay was evaluated for precision, accuracy, and diagnostic usefulness in analyzing canine sera. Sera samples from clinically healthy dogs, dogs with experimentally induced pancreatitis, and dogs with spontaneous pancreatitis were analyzed. A titrimetric method of serum lipase determination was used for comparison. Although the BALB-DTNB method was not found to be precise or accurate for determining the lipase activity of canine serum samples, it seemed to be at least as diagnostically useful as the titrimetric procedure. The small sample size requirement and the speed of analysis of the BALB-DTNB procedure are advantages of this method over the titrimetric method, and thus, its use in place of the titrimetric method is justified. A laboratory reference range of 3 to 37 IU/L was determined for canine serum.

Effects of acute pancreatitis on circulating lipids in dogs were evaluated by comparing the serum cholesterol and triglyceride concentrations and plasma lipoprotein electrophoretic patterns of 4 dogs with experimentally induced pancreatitis (EIP), 2 (healthy) sham-operated control (SOC) dogs, and 4 dogs with naturally acquired pancreatitis (NAP) with the concentrations and patterns of 23 healthy, nonoperated control (HNC) dogs. Blood samples were collected once from HNC dogs, 1 to 3 times during the course of the disease in dogs with NAP, and prior to and at 6, 12, 24, 48, 72, and 96 hours after induction of pancreatitis in dogs with EIP or after the sham operation in the SOC dogs. The dogs with EIP did not have turbid serum and did not develop hypercholesterolemia or hypertriglyceridemia. Three of the dogs with NAP had turbid serum and hypertriglyceridemia, and 3 had hypercholesterolemia. The electrophoretic tracings of HNC dogs had predominant alpha-1 peaks and small beta peaks; 2 of the HNC dogs also had small alpha-2 peaks. The tracings of dogs with EIP were similar to those of HNC dogs until 48 to 72 hours after induction of pancreatitis, when dogs with EIP developed increased beta lipoproteins, decreased alpha-1 lipoproteins, and movement of lipoproteins into the alpha-2 zone. The tracings of SOC dogs were similar to those of HNC dogs at all times. Compared with HNC dogs, dogs with NAP all had increased beta lipoproteins, and 2 had decreased alpha-2 lipoproteins. Two dogs with NAP had additional lipoprotein alterations, unlike any seen in dogs with EIP.