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The impact of tyrosine hydroxylase loss on dopamine signaling during nigrostriatal neuron loss in a rat Parkinson’s disease model
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Center for Healthy Aging - 1st PlacePurpose: Parkinson’s disease (PD) is a neurological disorder resulting from the degeneration of nigrostriatal dopamine (DA) neurons. DA plays a major role in the control of movement initiation via the nigrostriatal pathway. The relationship between DA tissue levels and synaptic levels is poorly understood, and the impact of tyrosine hydroxylase (TH) loss upon synaptic DA levels is not well defined either. As the rate limiting enzyme of DA synthesis, tyrosine hydroxylase (TH) protein was evaluated against these indices of DA function. Since PD involves progressive loss of the nigrostriatal neurons and TH protein, understanding how synaptic DA levels may change against this decrease will shed light on whether compensatory processes are engaged to maintain synaptic DA levels, and can outline possible limits of such processes and their influence upon the timing of onset of hypokinesia, a major PD symptom.
Methods: We used the established rat neurotoxin model 6-hydroxydopamine (6-OHDA) utilizing stereotactic surgery to lesion the nigrostriatal pathway and emulate the pathological course of human PD, which features DA and TH loss in the Str proceeding at a faster rate than in the SN. Following microdialysis, brain tissue punches from the SN and Str regions of both lesioned and control rats were harvested at 7 and 28 days, and then analyzed by high-performance liquid chromatography to quantify both synaptic and tissue DA. We followed with TH protein analyses to statistically quantify the relationships between TH protein, DA tissue, and synaptic DA.
Results: Our results show that TH protein levels had a highly significant correlation against DA tissue levels in the lesioned Str and SN; however, only synaptic DA release levels in the Str following depolarizing stimulation had a significant correlation with TH protein. Additionally, only 15% of the variance in lesioned Str synaptic DA levels can be explained by tissue DA and TH concentrations when using a multivariate linear regression model. These results show that compensatory processes are engaged during nigrostriatal lesion to maintain synaptic levels, but these mechanisms are inadequate to offset major TH protein loss in the Str.
Conclusions: The particular significance of this study lies in its focus on extracellular neurotransmitter analysis – something that has not been extensively explored. Our findings will provide novel insight into how synaptic DA levels are affected by expected decreases in tissue content, thus deepening the current understanding on transmission within the basal ganglia and generating areas for further research
Sprouting Change: You, Food, and the Environment
Get PDFThis book was created by the Gibson D. Lewis Library in partnership with the Office of Sustainability at the UNT Health Science Center at Fort Worth. This book contains a variety of information including nutritional literacy, environmental sustainability, how to grow your own food, and ways for cutting back on food waste. Besides this educational material, there are instructions on how to grow your own sprouts and recipes intended to be created with the sprouts that you grow.This project was supported by the National Library Of Medicine of the National Institutes of Health under Award Number UG4LM012345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health
Past-Year Blunt Smoking among Youth: Differences by LGBT and Non-LGBT Identity
Get PDFBlunt use (co-use of tobacco and marijuana) is a growing phenomenon among youth and disproportionately affects minority populations. LGBT+ populations are significantly more likely to use marijuana and tobacco, but this relationship has yet to be examined among LGBT+ adolescents. This analysis aimed to investigate past-year blunt use among a national sample of youth and delineate the differences between non-LGBT and LGBT+ youth. We used Wave 2 of the Population and Tobacco Health (PATH) study. We analyzed data from 7518 youth, comparing past-year blunt use between LGBT+ and non-LGBT youth, controlling for biological sex, race, and age using weighted logistic regression models. Greater than 1 in 10 youth (10.6%) reported using blunts in the past year. More than one in five (21.6%) LGBT+ youth reported using blunts in the past year. There were no significant differences between boys and girls. Older youth (17 years old) were more likely to use blunts in the past year (aPR: 3.04, 95% CI 2.48, 3.79) than younger youth. Compared with non-LGBT youth, LGBT+ youth were 2.17 times (95% CI 1.86, 2.54) more likely to report using blunts in the past year. Blunt use and its respective impact on health outcomes among developing youth are of concern to public health. These findings demonstrate that certain subgroups of youth are more at risk for use and emphasize the need for tailored interventions to mitigate initiation and current use, given that one of the goals of the Healthy People 2030 initiative is to "Improve the health, safety, and well-being of lesbian, gay, bisexual, and transgender (LGBT) individuals."No funding was used for this project
P1-CPP promotes Foxo1 and Creb signaling and reduces apoptosis in Neurotrophic Factor-Deprived Primary Retinal Ganglion Cells
No full textPurpose: To elucidate the intracellular mechanisms underlying neuroprotective effects of the core peptide of a-B crystallin, peptain-1 (P1) conjugated to a cell-permeable peptide CPP (P1-CPP) in primary retinal ganglion cells (RGCs). Targets of the investigation were limited to Creb1, Bak1/Bad, and Foxo1, based upon RNA sequencing data obtained from RGCs of IOP-elevated rats treated with P1-CPP in comparison with the vehicle.
Methods: Primary RGCs isolated from Sprague Dawley rat pups were deprived of neurotrophic factors (NT) namely, BDNF, CNTF, and Forskolin for 48 hours, either in the presence or absence of P1-CPP (4µM). After the treatments, RNA isolation was carried out using Trizol reagent. Subsequently, cDNA synthesis and qPCR analysis of the target genes expression, including Creb1 (n=2), Foxo1 (n=3), and Bak1 (n=3), was performed. Another set of RGCs subjected to the same treatments was fixed with 4% paraformaldehyde for 20 minutes and used for immunocytochemical analyses of p-CREB (n=3), FOXO1 (n=3), and BAD (n=3) protein expression. Immunostaining with an RBPMS antibody was used as an RGC marker. N indicates experimental repeats.
Results: Following NT deprivation, there was an increase in mRNA expression of Creb1 (2-fold) in RGCs treated with P1-CPP, compared to the vehicle-treated RGCs. Moreover, the phosphorylated (active) form, p-CREB, was increased (by 102%; p=0.04) in primary RGCs treated with P1-CPP, compared to the vehicle-treated group. Pro-apoptotic Bak1 mRNA expression was not changed in the P1-CPP-treated RGCs compared to the vehicle-treated group. Primary RGCs stained for BAD protein showed a decrease (by 62%; p=0.08) in the P1-CPP treated group compared to the vehicle-treated RGCs. Foxo1 mRNA levels were increased by more than 2-fold in the P1-CPP treated RGCs, compared to the vehicle-treated RGCs. FOXO1 protein was also elevated in primary RGCs treated with P1-CPP compared to the vehicle group (by 59%).
Conclusions: P1-CPP is neuroprotective against neurotrophic factor deprivation through multiple mechanisms, including early changes in the expression of mitochondrial homeostasis regulator Foxo1, activation of the pro-survival CREB pathway, and inhibition of pro-apoptotic members of the BCL-2 family of proteins.T32 AG020494; NEI R01 DL
Extending the Life of Food
No full textThe Extending the Life of Food material details how to store food properly to increase the life of produce to avoid food waste. Within this content are details on which produce can be stored on the counter, fridge, or pantry to keep food fresh longer. There is also information on how long you can store food in the freezer and what different expiration dates mean.This project was supported by the National Library Of Medicine of the National Institutes of Health under Award Number UG4LM012345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health
A pilot case series for concurrent validation of inertial measurement units to motion capture in individuals who use unilateral lower-limb prostheses
No full textINTRODUCTION: Inertial measurement units (IMUs) may be viable options to collect gait data in clinics. This study compared IMU to motion capture data in individuals who use unilateral lower-limb prostheses. METHODS: Participants walked with lower-body IMUs and reflective markers in a motion analysis space. Sagittal plane hip, knee, and ankle waveforms were extracted for the entire gait cycle. Discrete points of peak flexion, peak extension, and range of motion were extracted from the waveforms. Stance times were also extracted to assess the IMU software's accuracy at detecting gait events. IMU and motion capture-derived data were compared using absolute differences and root mean square error (RMSE). RESULTS: Five individuals (n = 3 transtibial; n = 2 transfemoral) participated. IMU prosthetic limb data was similar to motion capture (RMSE: waveform </=4.65 degrees ; discrete point </=9.04 degrees ; stance </=0.03s). However, one transfemoral participant had larger differences at the microprocessor knee joint (RMSE: waveform </=15.64 degrees ; discrete </=29.21 degrees ) from IMU magnetometer interference. Intact limbs tended to have minimal differences between IMU and motion capture data (RMSE: waveform </=6.33 degrees ; discrete </=9.87 degrees ; stance </=0.04s). CONCLUSION: Findings from this pilot study suggest IMUs have the potential to collect data similar to motion capture systems in sagittal plane kinematics and stance time.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by an American Orthotics and Prosthetics Association research award administered by the Center for Orthotic and Prosthetic Learning and Outcomes/Evidence-Based Practice. MGF was supported by the National Institutes of Health/National Institute on Aging (T32 AG020494) and the Institute for Healthy Aging
Long-term intermittent fasting improves neurological function by promoting angiogenesis after cerebral ischemia via growth differentiation factor 11 signaling activation
No full textIntermittent fasting (IF), an alternative to caloric restriction, is a form of time restricted eating. IF conditioning has been suggested to have neuroprotective effects and potential long-term brain health benefits. But the mechanism underlying remains unclear. The present study focused on the cerebral angiogenesis effect of IF on ischemic rats. Using a rat middle cerebral artery occlusion model, we assessed neurological outcomes and various vascular parameters such as microvessel density (MVD), regional cerebral blood flow (rCBF), proliferation of endothelial cells (ECs), and functional vessels in the peri-infarct area. IF conditioning ameliorated the modified neurological severity score and adhesive removal test, increased MVD, and activated growth differentiation factor 11 (GDF11)/activin-like kinase 5 (ALK5) pathways in a time-dependent manner. In addition, long-term IF conditioning stimulated proliferation of ECs, promoted rCBF, and upregulated the total vessel surface area as well as the number of microvessel branch points through GDF11/ALK5 pathways. These data suggest that long-term IF conditioning improves neurological outcomes after cerebral ischemia, and that this positive effect is mediated partly by angiogenesis in the peri-infarct area and improvement of functional perfusion microvessels in part by activating the GDF11/ALK5 signaling pathway.Science and Technology Planning Project of Yuzhong District of Chongqing (20210161), Chongqing Municipal Health Commission (2020MSXM106, 2021ZY023818, 2018ZDXM022), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0071, CSTB2022NSCQ-MSX1457)
Evaluation of Create-Your-Own-Adventure Activities on Student Knowledge and Critical Thinking Skills in Second-Year Student Pharmacists
No full textPurpose: Create-your-own-adventure (CYOA) activities are educational innovations where students choose the "best pathway” of treatment. Current literature suggests increased student perception of knowledge and critical thinking skills with use of CYOA activities; however, evidence that such skills ultimately improve is lacking. The primary objective of this study is to assess changes in knowledge and critical thinking after completing a CYOA activity. Methods: Seventy-five second-year pharmacy students completed a CYOA activity on venous thromboembolism, with a six-question quiz immediately before and after. Questions were mapped to pre-set learning objectives with slight alterations to questions on each assessment. Four questions were then mapped to the final exam which occurred approximately three weeks after the activity. Friedman’s two-way analysis and Cochran’s Q test were used to evaluate differences in scores. Descriptive statistics were used to describe student perceptions and scores on a modified Need for Cognition scale. Results: There was a significant decrease in mean scores for each assessment (68.1% vs. 64.9%, vs. 40.0%; p<0.001). Similar results were found when stratifying scores by question. Of the 48 survey responses, 94% preferred the CYOA activity and perceived increased critical thinking skills. All Need for Cognition items scored >3.5, indicating satisfaction in critical thinking. Conclusions: Although we hypothesized an increase in scores with use of CYOA activities, there was a negative association between the activity and scores. Possible limitations include mapped questions that were too dissimilar, VTE management being too multivariate, and lower student retention of cumulative material on finals. These limitations will be addressed in future CYOA activities
A mendelian randomization analysis of obesity on the development of Alzheimer’s disease
No full textPurpose: To assess the causal associations between obesity and Alzheimer’s disease (AD) using Mendelian randomization analysis based on summary statistics from genome-wide association studies (GWAS). The most recent GWAS as of November 2021 for AD and obesity were used, including newly identified risk single nucleotide polymorphisms (SNPs) that were associated with AD and obesity. Specifically, the AD GWAS identified 42 new risk loci, which have not been utilized in other studies. Thus, this study provides novel evidence for the causal associations of AD and obesity.
Methods: Genetic associations for the exposure (i.e., obesity; BMI ≥ 30kg/m2) were evaluated from a GWAS conducted on European individuals over age 18 in the FinnGen project (n = 218,792). Genetic associations for AD were evaluated from the whole exome sequencing data among European individuals aged 37-73 years in the UK Biobank study (n = 111,326 AD cases and 677,633 controls). Based on the above summary statistics, a Two Sample Mendelian randomization (MR) analysis using the Inverse-Variance Weighted (IVW) method was conducted to evaluate the causal association between obesity and AD. Sensitivity analyses including median-based, mode-based, and MR-Egger MR methods were conducted to confirm findings from the main MR analysis.
Results: Obesity was found to be associated with a decreased odds in the development of AD (Odds ratio = 0.91, 95% CI = [0.86, 0.95], p = 0.0001) according to the IVW method, suggesting a protective effect of obesity. The results of all sensitivity analyses were consistent with the main findings and determined the absence of horizontal pleiotropy and heterogeneity. Specifically, significant causal relationship between AD and obesity was identified in the IVW method and Weighted Median MR methods.
Conclusion: The protective effect of obesity on the development of AD is supported by the MR analysis in this study. Further research should be conducted on the underlying pathological mechanism to inform potential health interventions such as weight modification in mid versus late life
The Impact of the Social Determinants of Health on a Patient with Renal Cell Cancer: A Case Report
No full textBackground
Renal cancer is the seventh most common cancer and 90% of cases are renal cell carcinoma (RCC). Symptoms of RCC may include hematuria, abdominal/flank pain, or fatigue, but over half of those with RCC are asymptomatic and diagnosed incidentally by an unrelated abdominal imaging study. Renal tumor size provides the greatest insight into a patient’s chance of survival. For every 1 cm increase in tumor size there is a 16% increase in malignant potential and masses greater than 7 cm have only a 7% chance of being benign. RCC has a 40% mortality rate that disproportionately affects those of low socioeconomic status (SES) who often present with larger and more advanced RCC. This correlation with low SES reflects decreased healthcare access and an increased prevalence of poor prognostic factors including obesity, hypertension, and hyperlipidemia. Additionally, patients without health insurance are 5.6% less likely to survive RCC.
Case Information
A 56-year-old Hispanic male first presented to a community clinic in Fort Worth, Texas in early 2017 for occasional fatigue and right flank pain that began in 2002. In addition to managing his hypertension, diabetes mellitus, and hyperlipidemia, the physician ordered an abdominal and pelvic CT that revealed a 5.4cm cystic and solid-enhancing right renal mass that was highly suspicious for RCC. Further disease progression was suggested with a 2019 ultrasound showing internal blood flow to the solid component of the mass and 2022 laboratory studies that revealed an elevated BUN (21 mg/dL), serum calcium (10.6 mg/dL), and ALT (56U/L). At the end of 2022, the patient brought in his latest CT report that he could not read because it was only provided in English. The CT revealed the 6.4cm x 4.1cm x 3.7cm mass and while medical translators communicated with the patient, differences in language may have impacted his understanding of his condition. For five years imaging and labs were performed repeatedly to monitor the large tumor, but treatment was never initiated because the patient believed he could not afford care without health insurance. The patient was referred to a local charity program for evaluation, but the program had a policy of not providing cancer treatment. The patient was encouraged to seek treatment in the local county health system, but he believed he could not afford treatment there or the expenses to relocate for treatment elsewhere. At this point, no further options exist for the patient.
Conclusions
Surgery would provide the greatest odds of survival for this patient, and ideally, it would have been performed before the mass reached such a concerning size. However, the patient believed he could not afford care without health coverage. With such a dismal prognosis, one can only speculate how the outcome would have changed if prompt medical care had been accessible to the patient. His financial resources, health coverage, language barrier, documentation status, and lifestyle all contributed to the unfavorable disease progression. This case serves as a single example of how social determinants of health continue to alter patient outcomes