Faculty Bibliography

OBJECTIVE:To evaluate cannabidiol (CBD) in pediatric patients with autism spectrum disorder (ASD), fluent verbal language and an estimated full-scale IQ of 80 or above. BACKGROUND:Preliminary evidence suggests CBD may ameliorate challenges associated with ASD. Whether CBD benefits pediatric ASD without accompanying intellectual or language impairment remains unknown. METHODS:, 100 mg/mL) at 3, 6, or 9 mg/kg/day using a Bayesian optimal interval dosing design. The primary endpoint was the CBD dose associated with the highest response rate (i.e., Clinical Global Impression Scale-Improvement [CGI-I] score = 1 or 2) on a target symptom domain designated individually based on informant report, standardized scales, and clinical observation. Secondary endpoints were effect sizes of changes from baseline in measures assessing ASD core and associated symptoms, and global functioning. Adverse events (AEs) were assessed weekly. Plasma CBD levels and clinical labs were obtained at the final visit. RESULTS:= 1.36, 95% CI [0.78-1.93]).Of 222 reported AEs, 27 unique AEs were considered treatment-related. Most AEs (93%) were mild and expected (82%); none was severe. The most frequent related AEs were increased salivation (30%), increased sleep duration (39%), sleepiness/sedation (26%), increased dream activity (35%), and polyuria (22%). Vital signs, physical exams, weight, liver function tests, and complete blood counts were unaffected. CBD plasma levels did not correlate with response. CONCLUSIONS:In this preliminary study, CBD was well tolerated; AEs were mild-moderate. Mean SRS2-T and subscores decreased significantly with large effect sizes, shifting from the severe to the moderate range. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier NCT03900923.

The role of genetic testing for kidney stone formers remains incompletely resolved. The purpose of this paper is to review the role of genetics in kidney stone disease and provide guidance on the utility of genetic testing to overall reduce the burden of the disease for our patients. Genetic testing is a send-out laboratory test for most medical centers in the United States. However, access to such testing has been easier with options for genetic kit delivery to health care offices and even conveniently to patients' homes. The rise of genetic testing in medicine has advanced the field of nephrology in general and kidney stones specifically. It is our aim to provide basic knowledge on the approach to kidney stone disease to physicians, especially nephrologists and nephrology fellows, while also considering the appropriateness of genetic testing.

Urolithiasis is increasingly common, with rising rates driven by obesity, diabetes and metabolic syndrome. Patients with cancer have additional, unique risks of stone formation owing to effects on fluid and electrolyte balance, systemic cancer therapies, tumour lysis syndrome and anatomical alterations after urinary diversion or nephrectomy. Moreover, urolithiasis itself has been linked to increased rates of renal cell carcinoma, urothelial carcinoma and bladder cancer, potentially mediated by chronic inflammation, recurrent infections and shared metabolic or environmental factors. Management in this setting is complex and must be individualized. Percutaneous nephrolithotomy achieves the highest stone-free rates in patients with altered urinary tract anatomy, whereas retrograde intrarenal surgery and shock wave lithotripsy have more selective roles. Preventive strategies focus on thorough metabolic evaluation, hydration optimization and addressing cancer-specific risk factors such as hypercalcaemia, acidosis and chronic urinary stasis. Despite these insights, data on the epidemiology, mechanistic underpinnings and optimal management of urolithiasis in patients with cancer remain limited. Prospective studies are needed to clarify causal relationships, refine preventive strategies and develop evidence-based treatment algorithms for this growing and complex population.

OBJECTIVES/UNASSIGNED:Although cardiac function is truly vital, and can be adversely affected by many diseases, conventional quantitative global function analysis from images is largely limited to assessing the cardiac volumes at end-diastole and end-systole, and the associated ejection fraction, due to the time-consuming associated image segmentation. Advances in AI-assisted cardiac image segmentation can potentially enable more detailed analysis of the dynamic changes in cardiac volumes over the cardiac cycle, in clinically practical times, but there are now no standardized ways to analyze such data. In this work, we propose a systematic approach to the analysis of dynamic global cardiac function from imaging data. DESIGN/UNASSIGNED:We use some cardiac magnetic resonance imaging (CMR) data here to illustrate this approach, but the methods are not limited to MRI. The focus here is on the technical approach, rather than on potential clinical applications. Representative short-axis cine CMRs from 19 normal subjects and 22 patients with clinical diagnosis of "heart failure with preserved ejection fraction" were analyzed for ventricular volumes over the cardiac cycle. The resulting data were used to calculate a set of dynamic global function variables. RESULTS/UNASSIGNED:A set of representative measures of the timing and rates of ventricular emptying and filling is promising as compact means to characterize dynamic global function. CONCLUSIONS/UNASSIGNED:More efficient cardiac segmentation offers the potential to characterize dynamic global cardiac function, through a set of representative measures of the timing and rates of ventricular emptying and filling.

Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.

Oral cancer is one of the most painful malignancies, with pain driven primarily by algogenic mediators in the tumor microenvironment, including nerve growth factor (NGF). Although NGF monoclonal antibodies alleviate cancer pain in patients, clinical development was halted because of adverse effects, highlighting the need for safer alternatives. Neuropilin-1 (NRP1), a nonenzymatic NGF coreceptor, mediates NGF and tropomyosin receptor kinase A (TrkA) signaling, yet its role in cancer pain is unknown. We found that NRP1 is robustly coexpressed with TrkA in peptidergic nociceptors of mouse trigeminal ganglia. NRP1 antagonists inhibited NGF-induced sensitization of transient receptor potential vanilloid 1 in isolated trigeminal nociceptors and reduced NGF-induced periorbital mechanical allodynia in mice. Conditioned medium from human tongue squamous carcinoma HSC-3 cells contained NGF and sensitized transient receptor potential vanilloid 1 in trigeminal nociceptors and induced periorbital mechanical allodynia. Immunoneutralization of NGF and NRP1 blockade inhibited these effects. Our results show that NRP1 is a necessary coreceptor for the pronociceptive effects of NGF/TrkA signaling in the trigeminal system and implicate NGF and NRP1 in oral cancer pain. Current oral cancer pain management strategies, including opioids, are inadequate and are burdened by unacceptable side effects. By abrogating the actions of growth factors, including NGF, NRP1-targeted therapies represent an alternative approach to mitigate cancer pain and possibly slow tumor growth.

RATIONALE/BACKGROUND:Aggression is an innate social behavior prevalent across animal species. However, in modern human society, inter-personal aggression is considered disruptive and detrimental to both families and communities. Clinically, antipsychotics, which primarily target dopamine (DA) receptors, have been widely used to suppress hyper-aggression. However, the mechanisms underlying the effect of the antipsychotics remain incompletely understood. OBJECTIVES/OBJECTIVE:We reviewed key steps in brain DA synthesis and summarized genetic and pharmacological evidence supporting the role of the mesolimbic DA system in aggression. Next, we discussed recent circuit studies that elucidate the DA action in modulating aggression-related brain regions. These lines of evidence collectively suggest that DA acts on different brain regions to facilitate aggression and self-learning, and signals the valence of the fighting experience.

Toxicity of prenatal ethanol leading to fetal alcohol spectrum disorders (FASDs) has been linked to disturbances in retinoic acid (RA) signaling necessary for embryonic development. While ethanol exposure in the postnatal day 7 (P7) mice, which induces immediate neurodegeneration and long-lasting GABAergic cell loss and behavioral deficits, has been used for the third trimester FASD model, involvement of RA signaling in the process has not been well explored. Using RARE-LacZ reporter mice that express β-galactosidase (β-Gal) under the control of retinoic acid response element (RARE), we examined RA signaling activity of the forebrains of P8 and P30 mice with or without P7 ethanol treatment. In all experimental groups, β-Gal was expressed mainly in the hippocampus with the strongest expression in the granule cell layer of dentate gyrus. In addition, β-Gal was expressed in pyramidal neurons and parvalbumin (PV) neurons in CA1-3 pyramidal layer and in astrocytes scattered around the CA1-3 region although PV neurons were only examined at P30 because of the low PV expression at P8. β-Gal was also expressed in the anteroventral/anteromedial (AV/AM) thalamus and the retrosplenial (Rs) and Tbr1-positive (+) layer 6 cortices. β-Gal-expressing PV neurons were also found in the cortex such as Rs, while β-Gal was barely detected in somatostatin neurons in any brain regions examined. Such region and cell specific β-Gal expression was significantly higher in P8 brains than P30 brains in various brain regions. P7 ethanol reduced β-Gal expression in the CA1-3 pyramidal layer, Tbr1 + cortical layer 6, and the AV/AM thalamus at P8 or P30 or both. Although P7 ethanol decreased PV cells in CA2-3 pyramidal layers as reported, it decreased β-Gal+ PV cells more drastically. The active RA signaling found in PV neurons and the effects of P7 ethanol on the signaling suggest that reduced RA signaling by P7 ethanol may disturb PV cell maturation and enhance long-lasting brain abnormalities.

BACKGROUND: ("Dutch") transgenic mice develop aging-related learning deficits and accumulate endogenously generated non-fibrillar aggregates (NFAs) of amyloid beta (Aβ) and amyloid precursor protein α-carboxy terminal fragments. NFA-Aβ correlates with synaptic loss and memory deficits more closely than does fibrillar Aβ. METHODS: mice. RESULTS: mice developed physiological abnormalities in post-tetanic potentiation, synaptic fatigue, synaptic vesicle replenishment, and an aging-related reduction in mitochondrial complex I activity. Single-cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving "protein translation" and "oxidative phosphorylation." DISCUSSION/CONCLUSIONS:Accumulation of NFA-Aβ alters neuronal metabolism but does not activate inflammation. Depletion of all forms of Aβ may be required to eliminate Aβ toxicity with anti-amyloid antibodies.