Phencyclidine-Like Abuse Liability and Psychosis-Like Neurocognitive Effects of Novel Arylcyclohexylamine Drugs of Abuse in Rodents.

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

Approaches to the identification and management of depression in people living with chronic kidney disease: A scoping review of 860 papers.

BACKGROUND: Depression is prevalent across the spectrum of Chronic Kidney Disease and associated with poorer outcomes. There is limited evidence regarding the most effective interventions and care pathways for depression in Chronic Kidney Disease. OBJECTIVES: To investigate how depression is identified and managed in adults with Chronic Kidney Disease. DESIGN: Scoping review. METHODS: Systematic search of eight databases with pre-defined inclusion criteria. Data relevant to the identification and/or management of depression in adults with Chronic Kidney Disease were extracted. RESULTS: Of 2147 articles identified, 860 were included. Depression was most identified using self-report screening tools (n = 716 studies, 85.3%), with versions of the Beck Depression Inventory (n = 283, 33.7%) being the most common. A total of 123 studies included data on the management of depression, with nonpharmacological interventions being more frequently studied (n = 55, 45%). Cognitive Behavioural Therapy (n = 15) was the most common nonpharmacological intervention, which was found to have a significant effect on depressive symptoms compared to controls (n = 10). However, how such approaches could be implemented as part of routine care was not clear. There was limited evidence for antidepressants use in people with Chronic Kidney Disease albeit in a limited number of studies. CONCLUSIONS: Depression is commonly identified using validated screening tools albeit differences exist in reporting practices. Evidence regarding the management of depression is mixed and requires better-quality trials of both pharmacological and nonpharmacological approaches. Understanding which clinical care pathways are used and their evidence, may help facilitate the development of kidney care specific guidelines for the identification and management of depression.

Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones.

Substitutions to the phenethylamine structure give rise to numerous amphetamines and cathinones, contributing to an ever-growing number of abused novel psychoactive substances. Understanding how various substitutions affect the pharmacology of phenethylamines may help lawmakers and scientists predict the effects of newly emerging drugs. Here, we established structure-activity relationships for locomotor stimulant and monoamine transporter effects of 12 phenethylamines with combinations of para-chloro, ß-keto, N-methyl, or N-ethyl additions. Automated photobeam analysis was used to evaluate effects of drugs on ambulatory activity in mice, whereas in vitro assays were used to determine activities at transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT) in rat brain synaptosomes. In mouse studies, all compounds stimulated locomotion, except for 4-chloro-N-ethylcathinone. Amphetamines were more potent stimulants than their ß-keto counterparts, while para-chloro amphetamines tended to be more efficacious than unsubstituted amphetamines. Para-chloro compounds also produced lethality at doses on the ascending limbs of their locomotor dose-effect functions. The in vitro assays showed that all compounds inhibited uptake at DAT, NET, and SERT, with most compounds also acting as substrates (i.e., releasers) at these sites. Unsubstituted compounds displayed better potency at DAT and NET relative to SERT. Para-chloro substitution or increased N-alkyl chain length augmented relative potency at SERT, while combined para-chloro and N-ethyl substitutions reduced releasing effects at NET and DAT. These results demonstrate orderly SAR for locomotor stimulant effects, monoamine transporter activities, and lethality induced by phenethylamines. Importantly, 4-chloro compounds produce toxicity in mice that suggests serious risk to humans using these drugs in recreational contexts.

MEN1 in a Patient With Nonsyndromic Familial Nonmedullary Thyroid Carcinoma.

Clinical syndromes involving multiple endocrine glands have been well recognized for over a century. Multiple reports describing hereditary multiple endocrine neoplasia (MEN) syndromes involving pituitary, parathyroid, and pancreatic neuroendocrine tumors have been published. Differentiated (nonmedullary) thyroid cancer can also present as a hereditary syndrome with or without a specific genetic predisposition. We report the case of a man with nonsyndromic familial nonmedullary thyroid carcinoma, a pituitary adenoma, hyperparathyroidism, an adrenal adenoma, and pancreatic adenocarcinoma. Genetic testing did not reveal mutations in the commonly reported genes associated with MEN syndromes. MEN1 is characterized by endocrine neoplasia in at least 2 of the following glands: pituitary, parathyroid, and the gastro-entero-pancreatic (GEP) tract. Co-occurrence of MEN1 with familial nonmedullary thyroid carcinoma, however, has not been reported in the medical literature. This unique case of MEN1 co-existing in a patient with nonsyndromic familial thyroid carcinoma was not associated with any common MEN syndrome germline mutations.

Effects of ambient temperature on locomotor activity and place conditioning elicited by abused psychostimulants in mice: Role of 3,4-methylenedioxy moiety.

BACKGROUND: Humans often administer psychostimulants in party or music festival settings characterized by warm ambient temperatures, which may impact drug effects; however, preclinical studies rarely investigate drug effects at multiple ambient temperatures. Work with 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) suggests that the presence of a 3,4-methylenedioxy ring moiety may influence ambient temperature-dependent effects. METHODS: Locomotor activity and conditioned place preference dose-response curves were generated at 20±2°C for two amphetamine analogues (MDMA and methamphetamine [METH]) and two cathinone analogues (MDPV and α-pyrrolidinopentiophenone [αPVP]) in mice. Effects were then redetermined at 29±2°C for each drug and assay. RESULTS: All four drugs elicited dose-dependent locomotor stimulation at the cool ambient temperature. At the warm ambient temperature, MDMA and MDPV produced sensitization to stereotypy, whereas METH and αPVP produced sensitization to locomotor activity. Regarding place conditioning, the warm ambient environment potentiated place preference elicited by doses of METH and αPVP that were sub-threshold in the cool ambient environment, but attenuated the effects of analogous doses of MDMA and MDPV. CONCLUSIONS: These studies suggest that warmer ambient temperatures may potentiate typical stimulant effects for the drugs lacking the 3,4-methylenedioxy ring, but may potentiate the behaviorally toxic/adverse effects for the drugs containing a 3,4-methylenedioxy ring. Thus, preclinical abuse liability studies conducted at standard laboratory temperatures may not fully capture the effects of psychostimulants and highlight the need to model the environments in which drugs are typically used by humans.

Presentation of cryopyrin-associated periodic fever syndrome as chronic, afebrile urticaria in a 12-month-old female.

A healthy 12-month-old female presented with relapsing and remitting urticaria since birth that was resistant to treatment with antihistamines. A thorough history revealed extensive rheumatic disease on the father's side of the family, and subsequent genetic testing was positive for a missense variant of NLRP3, indicating cryopyrin-associated periodic fever syndrome (CAPS). CAPS encompasses a spectrum of diseases, all related to a defect in the same gene; manifestations vary in severity and presentation, but most are associated with recurrent rash and fever. Because the patient's only presenting symptom was rash, this case highlights the importance of having a high index of suspicion for cryopyrin-associated periodic fever syndrome in infants with persistent, early urticaria.

Urinary neopterin reflects immunological variation associated with age, helminth parasitism, and the microbiome in a wild primate.

Neopterin, a product of activated white blood cells, is a marker of nonspecific inflammation that can capture variation in immune investment or disease-related immune activity and can be collected noninvasively in urine. Mounting studies in wildlife point to lifetime patterns in neopterin related to immune development, aging, and certain diseases, but rarely are studies able to assess whether neopterin can capture multiple concurrent dimensions of health and disease in a single system. We assessed the relationship between urinary neopterin stored on filter paper and multiple metrics of health and disease in wild geladas (Theropithecus gelada), primates endemic to the Ethiopian highlands. We tested whether neopterin captures age-related variation in inflammation arising from developing immunity in infancy and chronic inflammation in old age, inflammation related to intramuscular tapeworm infection, helminth-induced anti-inflammatory immunomodulation, and perturbations in the gastrointestinal microbiome. We found that neopterin had a U-shaped relationship with age, no association with larval tapeworm infection, a negative relationship with metrics related to gastrointestinal helminth infection, and a negative relationship with microbial diversity. Together with growing research on neopterin and specific diseases, our results demonstrate that urinary neopterin can be a powerful tool for assessing multiple dimensions of health and disease in wildlife.

Endovascular ascending aortic pseudoaneurysm repair under image fusion guidance and transcranial Doppler monitoring.

We describe a 78-year-old woman with a large ascending aortic pseudoaneurysm who underwent thoracic endovascular aortic repair under intraoperative image fusion guidance and real-time transcranial Doppler (TCD) monitoring. TCD monitoring revealed a total of 419 microembolic signals throughout the procedure, with the majority occurring as the first stent graft crossed the ascending aorta. Two days later, she underwent endovascular repair of a graft type IA endoleak. We highlight the role of image fusion guidance and TCD monitoring in enabling successful thoracic endovascular aortic repair in an elderly woman and in identifying procedural areas of improvement to minimize stroke risk.

Pro-inflammatory self-reactive T cells are found within murine TCR-αß(+) CD4(-) CD8(-) PD-1(+) cells.

TCR-αß(+) double negative (DN) T cells (CD3(+) TCR-αß(+) CD4(-) CD8(-) NK1.1(-) CD49b(-) ) represent a minor heterogeneous population in healthy humans and mice. These cells have been ascribed pro-inflammatory and regulatory capacities and are known to expand during the course of several autoimmune diseases. Importantly, previous studies have shown that self-reactive CD8(+) T cells become DN after activation by self-antigens, suggesting that self-reactive T cells may exist within the DN T-cell population. Here, we demonstrate that programmed cell death 1 (PD-1) expression in unmanipulated mice identifies a subset of DN T cells with expression of activation-associated markers and a phenotype that strongly suggests they are derived from self-reactive CD8(+) cells. We also found that, within DN T cells, the PD-1(+) subset generates the majority of pro-inflammatory cytokines. Finally, using a TCR-activation reporter mouse (Nur77-GFP), we confirmed that in the steady-state PD-1(+) DN T cells engage endogenous antigens in healthy mice. In conclusion, we provide evidence that indicates that the PD-1(+) fraction of DN T cells represents self-reactive cells.

Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment.

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2-year bioassay for TBBPA. The objective of the present study was to develop a cancer-based and a non-cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2-year and 13-week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg(-1) day(-1) based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg(-1) day(-1) based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E(-7) to 3.9 E(-6) mg kg(-1) day(-1) based on age-adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E (-7) to 8.4 E(-5) mg kg(-1) day(-1). Resulting margin of exposure (MOE) values were > 800 000 for non-cancer endpoints and > 32,000,000 for cancer-based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA.