Faculty Bibliography

Alzheimer's disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on Aβ and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FA's role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in Aβ40, Aβ42, and phosphorylated tau levels. To further examine FA's role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated Aβ40, Aβ42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.

OBJECTIVE:To determine factors associated with care-seeking in males with urinary incontinence (UI). METHODS:A cross-sectional study was performed using the National Association for Continence (NAFC) sponsored adult patient-reported survey data from November 2018 to January 2019. Descriptive statistics, chi-squared test, and multivariate logistic regression were used to identify factors associated with care-seeking behavior. RESULTS:Four hundred and forty-six men completed the survey during the study period. 84% of care-seeking men had initiated the discussion with their doctor about their UI, with 57% initially seeing their primary care provider. Statistically significant predictors of care-seeking were greater UI frequency (OR 1.68, CI 1.22-2.33), UI duration (OR 2.91, CI 1.88-4.65), cost of UI management (OR 1.53, CI 1.12-2.10), and comfort discussing UI (OR 2.83, 1.41-5.87). The top reasons cited for not seeking care for UI were embarrassment (29%) and the sentiment that UI is just a normal part of aging (22%). Non-care-seeking men were more likely to have their UI associated with feelings of shame and isolation. CONCLUSIONS:The majority of men who sought care for UI initiated the conversation with their PCP. Men with longer UI duration, higher UI frequency, higher cost expenditure on UI management, and those who felt comfortable discussing their UI were more likely to seek care.

Adipose-derived leptin contributes to energy homeostasis by balancing food intake and motor output, but how leptin acts in brain motor centers remains poorly understood. We investigated the influence of leptin on neuronal activity in two basal ganglia nuclei involved in motor control: the substantia nigra pars compacta (SNc) and pars reticulata (SNr). Using a mouse reporter line to identify cells expressing leptin receptors (LepRs), we found that in both sexes, a majority of SNc dopamine neurons express a high level of LepR. Whole-cell recording in ex vivo midbrain slices from male wild-type mice showed that leptin activates SNc dopamine neurons directly and increases somatodendritic dopamine release. Although LepR expression in SNr GABA output neurons was low, leptin also activated these cells. Additional experiments showed that the influence of leptin on SNr neurons is indirect and involves D1 dopamine receptors and TRPC3 channels. Administration of leptin to male mice increased locomotor activity, consistent with activation of dopamine neurons in the SNc coupled to previously reported amplification of axonal dopamine release by leptin in striatal slices. These findings indicate that in addition to managing energy homeostasis through its actions as a satiety hormone, leptin also promotes axonal and somatodendritic dopamine release that can influence motor output.Significance statement Dopamine neurons regulate motivated behaviors, but how they are influenced by metabolic hormones, like leptin, is incompletely understood. We show here that leptin increases the activity of substantia nigra (SN) pars compacta dopamine neurons directly, and that this enhances somatodendritic dopamine release. Leptin also increases the activity of GABAergic neurons in the SN pars reticulata, but does so indirectly via D1 dopamine receptors activated by locally released dopamine. Consistent with increased nigral dopamine neuron activity and previous evidence showing that leptin amplifies striatal dopamine release, systemic leptin increases locomotor behavior. This increase in motor activity complements the well-established inhibitory effect of leptin on food intake and adds an additional dimension to the regulation of energy balance by this hormone.

Alzheimer's and Parkinson's disease are the most common neurodegenerative diseases, significantly affecting the elderly with no current cure available. With the rapidly aging global population, advancing research on these diseases becomes increasingly critical. Both disorders are often studied using model organisms, which enable researchers to investigate disease phenotypes and their underlying molecular mechanisms. In this review, we critically discuss the strengths and limitations of using Drosophila, zebrafish, and mice as models for Alzheimer's and Parkinson's research. A focus is the application of single-cell RNA sequencing, which has revolutionized the field by providing novel insights into the cellular and transcriptomic landscapes characterizing these diseases. We assess how combining animal disease modeling with high-throughput sequencing and computational approaches has advanced the field of Alzheimer's and Parkinson's disease research. Thereby, we highlight the importance of integrative multidisciplinary approaches to further our understanding of disease mechanisms and thus accelerating the development of successful therapeutic interventions.

PURPOSE/OBJECTIVE:To compare 0.55 T and 3 T MRI for imaging patients with titanium total hip arthroplasty (THA). Patients with orthopedic metallic implants often require diagnostic imaging to evaluate adjacent tissues. MRI performance measures, including artifact levels and SNR, vary with field strength. METHODS:Six patients with titanium THA were scanned with similar protocols at 0.55 T and 3 T, including proton density (PD) weighted turbo spin echo (TSE), PD TSE with view-angle tilting (TSE + VAT), PD slice encoding for metal artifact correction (SEMAC), and short tau inversion recovery with SEMAC (STIR-SEMAC). Images from both field strengths were scored by two readers and qualitatively and quantitatively compared. RESULTS:Diagnostic confidence was significantly higher at 0.55 T compared to 3 T. Perceived metal artifact was substantially reduced at 0.55 T compared to 3 T. At 0.55 T, diagnostic imaging was achieved both without and with multi spectral imaging (MSI) for PD weighted images. CONCLUSION/CONCLUSIONS:Compared to 3 T, 0.55 T MRI offers substantially reduced metal artifacts and higher diagnostic confidence when imaging titanium THA. Advanced multi-spectral techniques may not be required when the metallic components are entirely titanium.

Pregnancy of unknown location is a condition in which a pregnancy test is positive, but no intrauterine or extrauterine pregnancy is visualized using transvaginal ultrasonography. We recommend using standardized nomenclature and definitions to describe intrauterine pregnancy (IUP), probable IUP, pregnancy of unknown location (PUL), probable ectopic pregnancy (probable EP), and ectopic pregnancy (EP) (Best Practice). Among abortion-seeking patients found to have a PUL, the incidence of ectopic pregnancy (EP) is 4-8%. We recommend clinical judgment in assessing the risk for EP in the setting of PUL; the absence of an intrauterine gestational sac (GS) or yolk sac should not delay care (GRADE 1B). In asymptomatic individuals with an undesired PUL who prefer to proceed with immediate treatment (medication or procedural management without delay) and have a low risk of EP, as determined by the clinician based on history, symptoms, and all other available data, we recommend medication management with mifepristone and misoprostol or procedural management via uterine aspiration and clear plans for ensuring pregnancy resolution in a timely fashion (GRADE 1B). While both medication and procedural management of undesired PUL are associated with earlier pregnancy resolution and identification of EP, the two main risks of inadequate follow-up include ongoing pregnancy and missing or delaying a subsequent diagnosis of EP. For individuals with PUL choosing immediate treatment with medication management, we recommend clinicians obtain a baseline serum quantitative hCG at the time of medication provision to aid in diagnosis and follow-up (GRADE 1A). Following medication management of PUL with mifepristone and misoprostol, we suggest a repeat serum quantitative hCG level, with pregnancy resolution defined as either a 50% decline or greater at 48-72 hours after misoprostol or an 80% decline or greater at seven days after mifepristone or 5-10 days after misoprostol (GRADE 2B). We recommend against direct extrapolation of follow-up recommendations from no-test abortion clinical protocols to individuals with a documented PUL treated with mifepristone and misoprostol, given the higher risk of EP among individuals with a known PUL (GRADE 1C). When uterine aspiration is performed at less than 42 days of gestation, including for individuals with PUL or probable IUP, and both chorionic villi and GS are not visualized, we recommend repeat ultrasonography (if an IUP or probable IUP was seen initially), serum quantitative hCG follow-up, or both (GRADE 1B). When both chorionic villi and GS are not visualized after uterine aspiration and serial serum hCG follow-up is warranted, we recommend testing on the day of the procedure and 24-72 hours later, with pregnancy resolution defined as greater than 50% decline 24 hours after aspiration, greater than 70% by 48 hours, or greater than 80% by approximately 72 hours (GRADE 1B).

PURPOSE/OBJECTIVE:Limited research has characterized how mental health changes or persists during reentry, particularly among women, who are a minority in the criminal legal system. We aimed to describe the mental health symptoms trajectory groups, suicide attempts, substance use dependence, and mental healthcare utilization among formerly incarcerated women in Santiago, Chile, during 1-year after release. METHODS:We assessed 200 women in a five-wave prospective cohort study using three different mental health indicators: the Symptom Checklist 90-Revised (SCL-90-R) scale before release and at one week, two, six, and twelve months after release, self-reported suicide attempts, and substance use dependence using the Mini Neuropsychiatric Interview. We used latent class growth analysis to identify groups following similar symptom trajectories using the Global Severity Index of the SCL-90-R. We performed multinomial and logistic regressions to identify correlates of these outcomes. RESULTS:Three trajectory groups were identified: Low (85.8%), Increasing (6.8%), and High (7.4%) symptom severity. 19.3% attempted suicide during follow-up. 18.9% met the criteria for substance use dependence at both baseline and twelve months. In multivariate regression analysis, the previous number of convictions and victimization experiences were associated with all outcomes. 10% or less received mental health services at any measurement. CONCLUSION/CONCLUSIONS:Most women had stable severity of mental health symptoms during the first year after release. Pre-release cross-sectional screening misses a group with increasing symptom severity and substance use dependence during reentry. Routine mental health assessments would be useful during reentry and guidance to make better use of services during this critical period.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The vaping epidemic is a public health crisis worldwide. E-cigarette, or vaping product, use-associated lung injury (EVALI) was recognised in the summer of 2019 and resulted in more than 2800 hospitalizations and 60 deaths per the Centres for Disease Control and Prevention (CDC). Vaping refers to the use of E-cigarettes, which are electronic nicotine delivery systems (ENDS) and mimic smoking without combustion. Over 40 million people in the United States vape, of which youth and young adults represent over half. We describe the evaluation and pulmonary complications in a large cohort of adolescents and young adults referred to a Pulmonary Complications of Vaping Clinic. METHODS:Youth ages 10-35 with a vaping history and respiratory symptoms underwent a comprehensive diagnostic evaluation. All patients were counselled for vaping cessation. Patients who met criteria for EVALI or probable EVALI with concurrent infection were reported to the Department of Health. RESULTS:One hundred and thirty patients were referred, and 103 patients underwent comprehensive diagnostic evaluation. Eighty-four percent of patients reported vaping both marijuana and nicotine products. Forty-six percent of patients were diagnosed with EVALI or probable EVALI. CONCLUSIONS:The evolving vaping epidemic demonstrates a need for subject matter expertise in the evaluation and diagnosis of youth with vaping-related lung injury, including EVALI. We report a higher number of youth who met criteria for EVALI with the implementation of a standardised vaping questionnaire and evaluation inclusive of outpatients.

The oral mucosal calcified nodule (OMCN) is a rare soft tissue lesion with only 7 cases reported in the English literature. It typically presents in the pediatric population as an asymptomatic submucosal nodule of less than 2 cm size affecting the maxillary ridge or palate, though other sites are reported. The histopathology displays stratified squamous epithelium overlying fibrous connective tissue with embedded calcified aggregates bordered by variable numbers of multinucleated giant cells. Surgical excision is curative. In this report, we present a new case of OMCN, outline the characteristic histopathologic features and review the cases reported in the English literature.

BACKGROUND/UNASSIGNED:Blood transfusion may precipitate adverse outcomes, including heart failure (HF), among patients with acute myocardial infarction (MI). This study characterizes the effects of a restrictive or liberal transfusion strategy on outcomes in patients with MI and anemia with and without baseline HF. METHODS/UNASSIGNED:In the MINT trial (Myocardial Ischemia and Transfusion), 3504 patients with MI and anemia (hemoglobin <10 g/dL) were randomized to a restrictive (hemoglobin <8 g/dL) or liberal (hemoglobin <10 g/dL) transfusion strategy. We compared the effects of transfusion strategy on outcomes among patients with and without baseline HF. The primary outcome was death or HF at 30 days. RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:A liberal transfusion strategy is safe for patients with MI and anemia, including those with baseline HF. Restrictive transfusion tended to result in worse outcomes, particularly in patients with baseline HF. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407.