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A Novel Scanning and Staining Methodology for Visualizing Skeletal and Soft Tissue Using Micro-CT
No full textWhile there are many forms of radiological imaging that can be used to gather anatomical data from biological specimens, micro-computed tomography (micro-CT) imaging has been the standard for visualizing dense tissue, such as bone, with detailed resolution. However, this imaging modality is not well suited for soft tissues due to their decreased tissue density. This inability to distinguish between soft tissues in CT scans limits our ability to investigate bone-muscle interactions that are thought to stimulate and direct bone modeling during early postnatal development. The goal of this project was to develop a novel CT protocol that incorporates at least two new methods for visualizing soft tissue in CT imaging: iodine staining intended to capture muscle, and ruthenium red staining intended to capture cartilage. The ultimate goal is to enable the creation of an anatomical model that shows the development of both skeletal and soft tissue structures in the crania of neonatal mice from birth to weaning
The process and outcomes of chronic low back pain treatment provided by osteopathic and allopathic physicians: a retrospective cohort study
No full textCONTEXT: Osteopathic physicians are trained to treat patients with musculoskeletal symptoms, to treat somatic dysfunction with osteopathic manipulative treatment (OMT), and to avoid unnecessarily prescribing drugs such as opioids. It is also generally believed that osteopathic physicians provide a unique patient-centered approach to medical care that involves effective communication and empathy. Such training and characteristics of osteopathic medical care (OMC) may enhance clinical outcomes among patients with chronic pain. OBJECTIVES: The objectives of this study were to measure and compare the process and longitudinal outcomes of chronic low back pain (CLBP) treatment provided by osteopathic and allopathic physicians and to identify mediators of the treatment effects of OMC. METHODS: This retrospective cohort study was conducted utilizing adult participants with CLBP within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) from April 2016 through December 2022. Participants having an osteopathic or allopathic physician for at least 1 month prior to registry enrollment were included and followed at quarterly intervals for up to 12 months. Physician communication and physician empathy were measured at registry enrollment. Opioid prescribing and effectiveness and safety outcomes were measured at registry enrollment and for up to 12 months and were analyzed with generalized estimating equations to compare participants treated by osteopathic vs. allopathic physicians. Multiple mediator models, including physician communication, physician empathy, opioid prescribing, and OMT, with covariate adjustments, were utilized to identify mediators of OMC treatment effects. RESULTS: A total of 1,079 participants and 4,779 registry encounters were studied. The mean (SD) age of participants at enrollment was 52.9 (13.2) years, 796 (73.8%) were female, and 167 (15.5%) reported having an osteopathic physician. The mean physician communication score for osteopathic physicians was 71.2 (95% CI, 67.6-74.7) vs. 66.2 (95% CI, 64.8-67.7) for allopathic physicians (p=0.01). The respective mean scores for physician empathy were 41.6 (95% CI, 39.9-43.2) vs. 38.3 (95% CI, 37.6-39.1) (p<0.001). There was no significant difference in opioid prescribing for low back pain between osteopathic and allopathic physicians. Although participants treated by osteopathic physicians reported less severe nausea and vomiting as adverse events potentially attributable to opioids in a multivariable model, neither result was clinically relevant. OMC was associated with statistically significant and clinically relevant outcomes pertaining to low back pain intensity, physical function, and health-related quality of life (HRQOL) over 12 months. Physician empathy was a significant mediator of OMC treatment effects in each of the three outcome domains; however, physician communication, opioid prescribing, and OMT were not mediators. CONCLUSIONS: The study findings indicate that osteopathic physicians provide a patient-centered approach to CLBP treatment, particularly involving empathy, that yields significant and clinically relevant outcomes pertaining to low back pain intensity, physical function, and HRQOL over 12 months of follow-up.This work was supported by the American Osteopathic Association (grant number 21011842)
Effect of Sigma-1 Receptor Activation on Renal Injury and Hypertension in Female Mice with Lupus
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Department of Physiology & Anatomy-Integrative Physiology Program - 2nd PlaceSystemic lupus erythematosus (SLE) is a female-dominant autoimmune disease with prominent renal injury and hypertension, contributing to its morbidity and mortality. Novel therapies to reduce these detrimental outcomes could be beneficial to SLE patients. The sigma-1 receptor (S1R) is a cytoprotective ligand-regulated chaperone protein that decreases protein aggregation, cellular stress, and cell death, thus preventing tissue injury. S1R activation with pharmacological ligands enhances cytoprotection in autoimmune diseases like multiple sclerosis and Huntington’s disease; however, the efficacy of S1R agonists in SLE is unknown. We hypothesize that S1R activation via the agonist LS-1-127 will reduce renal injury and halt the progression of hypertension in SLE mice.
Female SLE (NZBWF1) and control (NZW) mice were weighed and urine collected via metabolic cages weekly starting at 30 weeks of age. Albuminuria was measured via dipsticks. At 33 weeks of age, SLE and control mice were treated with LS-1-127 (10 mg/kg IP) or equal volume of vehicle (10% DMSO; IP) three times a week for two weeks. At 35 weeks, mean arterial pressure (MAP) was measured in conscious mice using indwelling carotid catheters for two consecutive days and then mice were euthanized. Wire myography was used to assess potassium chloride (KCl)-induced contraction and acetylcholine (ACh)-induced relaxation in excised aorta. Markers of renal injury – urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine – as well as plasma double-stranded (ds)DNA autoantibodies were measured by ELISA.
Albuminuria was present in 44.4% (4 of 9) of SLE mice and no controls. LS-1-127 did not improve albuminuria in SLE mice (50%; 3 of 6). NGAL:creatinine ratio (ng/mg) was higher in SLE mice compared to controls (327.3 ± 119.8 vs 63.2 ± 4.3 ng/mg; n=9–12; P=0.0007). LS-1-127 did not significantly alter NGAL:creatinine ratio in SLE mice (484.3 ± 209.0; n=6) or controls (71.7 ± 5.2; n=10). KIM1:creatinine ratio (ng/mg) did not differ between groups. dsDNA autoantibodies were higher in SLE mice compared to controls (6.9e5 ± 1.1e5 vs. 1.4e5 ± 3.1e4 U/mL; n=9–10; P<0.0001). LS-1-127 did not significantly alter dsDNA autoantibodies in SLE mice (7.1e5 ± 1.2e5; n=6) or controls (1.5e5 ± 4.0e4; n=10). MAP was higher in SLE mice compared to controls (146 ± 4 vs. 123 ± 3 mmHg; n=9–10; P <0.0001). LS-1-127 did not significantly alter MAP in SLE mice (150 ± 8; n=6) or controls (124 ± 2; n=10). KCl-induced aortic contraction was similar in SLE and controls (21 ± 7 vs. 25 ± 4 mM, n=3–4). Sensitivity to KCl after LS-1-127 treatment was 11 ± 3 and 21 ± 2 mM in SLE and controls (n=2–4). ACh-induced aortic relaxation did not differ between groups.
In conclusion, two weeks of S1R activation with LS-1-127 did not significantly alter markers of renal injury, autoimmunity, blood pressure, or vascular reactivity in female SLE mice with advanced disease. Further inquiry into the effect of LS-1-127 on the expression of renal proinflammatory cytokines will be conducted. S1R activation at different stages of SLE disease progression also warrants future investigation.NIH (K01HL139859
Intravitreal Endothelin-1 (ET-1) Injection Reduces Mitophagy in Retinal Ganglion Cells in MitoQC Mice
No full textPurpose: The peptide endothelin-1 (ET-1), and its receptors are upregulated in the aqueous humor and retina in animal models of experimentally induced ocular hypertension, and have been shown to have a causative role in retinal ganglion cell (RGC) neurodegeneration. The purpose of this experiment was to assess the role of mitophagy in RGC neurodegeneration following intravitreal ET-1 administration in MitoQC mice.
Methods: MitoQC mice (Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl on a C57BL/6 background) at the age of 3 months were used for the study. The mitochondria in these mice display both red and green fluorescence due to expression of a mCherry-GFP tag fused to the mitochondrial targeting sequence of an outer mitochondrial membrane protein, FIS1. When these mitochondria are trafficked to the lysosome for degradation, the green fluorescence is quenched, leaving only the red fluorescence. The MitoQC mice were intravitreally injected in both eyes with either ET-1 (1 nmole) or vehicle (water), and 72 hours following the injections the mice eyes were enucleated and retinal flat mounts were live-imaged using a Zeiss LSM 880 super resolution confocal microscope. Z-stack imaging was used to image the ganglion cell layer. For each Z layer, a threshold algorithm was used to define a region of interest (ROI) that included only areas with red fluorescence, after which red and green fluorescence were quantified for that ROI. Red/green fluorescence intensity was calculated and averaged per image. A red/green ratio larger than 1 is indicative of active mitophagy. This ratio was compared between ET-1 and vehicle-injected mice using a Mann-Whitney test (n=4 eyes per group).
Results: At 72 hours after injection with ET-1, the average red/green fluorescence ratio in the RGCs was 0.86, while the vehicle-injected mice had an average red/green ratio of 1.29. These ratios were significantly different (P=0.0003), and the smaller red/green ratio in the ET-1 group indicates lesser mitophagy than the vehicle group.
Conclusion: Mitophagy is known to be an important quality control mechanism for neuronal cell survival, and this study provides evidence that mitophagy is impaired by ET-1. The finding indicates that a decline in mitophagy may be associated with endothelin-mediated neurodegeneration in RGCs.This study is funded by the National Institutes of Health R01 EY028179 and T32 AG02049
Peripheral Vascular Function is Not Correlated to Subjective Sleep Quality in Young Healthy Humans
No full textBackground: Peripheral vascular dysfunction (including endothelial dysfunction) may be an early biomarker of cardiovascular disease. Prior studies have shown a relationship between poor sleep quality and impaired vascular function, indexed by flow-mediated dilation (FMD) of the brachial artery. However, these investigations did not allometrically scale for baseline artery diameter, nor control for shear stress, which both affect the magnitude of flow-mediated vasodilation. Without scaling for baseline artery diameter, FMD may overestimate the magnitude of dilation in individuals with small baseline diameters. Additionally, greater shear stress will elicit a greater magnitude of vasodilation via release of vasoactive mediators from the endothelium, such as nitric oxide. With the quality of sleep declining in the United States, and cardiovascular disease remaining a leading cause of mortality, we sought to further explore the relationship between sleep quality and peripheral vascular function corrected for both baseline artery diameter and the magnitude of shear stress. Hypothesis: Poor sleep quality is associated with impaired peripheral vascular function indexed by "corrected” brachial artery FMD. Methods: Thirteen young and healthy human participants (7M, 6F) completed the Pittsburgh Sleep Quality Index (PSQI) survey prior to assessment of brachial artery FMD. PSQI scores range from 0-21, with higher scores indicating worse sleep quality. Brachial artery diameter and blood velocity were then obtained via duplex Doppler ultrasound during a 2-min baseline, a 5-min occlusion of the brachial artery, and a 3-min reactive hyperemia period. FMD of the brachial artery was calculated as the percent change from baseline diameter to the maximum diameter induced by reactive hyperemia. Shear stress was estimated as shear rate, calculated as eight times the ratio of brachial artery blood velocity to diameter. FMD was corrected for baseline diameter, and the shear stress area under the curve up to maximum diameter via ANCOVA (i.e., "corrected FMD”). Pearson correlations were calculated between PSQI score and uncorrected FMD, and between PSQI score and ANCOVA corrected FMD. Results: The mean PSQI score was 5.3 ± 4.5 (range, 0-17), and mean FMD was 5.0 ± 2.2 % (range, 2.7-9.4 %). While an unexpected modest positive correlation was observed between uncorrected FMD and PSQI score (r=0.51, p=0.08), corrected FMD and PSQI score were not correlated (r=0.38, p=0.25). Conclusion: There was no relationship between subjective sleep quality and peripheral vascular function as measured by corrected FMD in this cohort of young and healthy participants. These findings likely reflect the multivariate nature of vascular function in young healthy adults with lower cardiovascular risk, and the subsequent narrow range of both flow-mediated dilation and subjective sleep quality.American Heart Association Transformational Project Award (19TPA34910743
Novel use of Light Adjustable Lenses to improve visual acuity in patients with corneal abnormalities: a case report.
No full textBackground: Keratoconus is characterized by thinning and protrusion of the cornea that produces an irregular astigmatism and decreased visual acuity. Individuals with these corneal abnormalities commonly experience undesirable visual acuity outcomes due to lack of effective traditional treatment options. We postulate Light Adjustable Lens (LAL) may be a safe and effective treatment where neither multifocality nor Laser-Assisted In Situ Keratomileusis (LASIK) are a viable method to achieve decreased spectacle dependence following surgery. This report presents a single patient diagnosed with forme fruste keratoconus undergoing LAL intraocular lens (IOL) replacement surgery. The patient was selected based on their history of corneal abnormalities and ability to benefit from IOL replacement. Potential benefit from IOL replacement was determined based on the patient’s ocular complaints and visual test results in clinic. Lens selection parameters were made based on keratotomy and biometry data obtain from the Lenstar LS900. Visual acuities after LAL implantation and postoperative light treatments were recorded and compared with preoperative visual acuities. The patient received LAL, made of foldable silicone, implanted through phacoemulsification and standard IOL implantation techniques in both eyes (OU), and after completion of 1-month postsurgical healing received postoperative light treatments for lens adjustment.
Case Presentation: A 69-year-old man presented in clinic with complaints of decreased central vision. His brightness acuity test (BAT) was 20/40 OU and slit lamp examination (SLE) and oxidative stability index (OSI) revealed nuclear sclerotic (NS) cataracts of 2+ grade OU. Scheimpflug imaging (Figure 1.1) showed corneal abnormalities consistent with FFK OU. Imaging measured a topographic irregularly irregular astigmatism of 0.50 D at 115 degrees with a total corneal power (TCP) of 0.44 D at 127 degrees in the right eye (OD) and 0.33 D at 80 degrees with a TCP of 0.32 D at 88 degrees in the left eye (OS). Keratotomy measurements can be found in Table 1. The patient’s primary goal was to achieve reduced spectacle dependency. Preoperative serial refraction established refractive stability OU. RxSight LAL of +20.5 D and +20.0 D were selected for the OD and OS respectively. 1-month UDVA was 20/20 in the OS and UNVA was Jager 5 (20/50) OD. Following 2 postoperative UV light treatments spaced 4 days apart and 1 lock-in UV light treatment after 3 days, the patient maintained UDVA of 20/20 in the OS and achieved UNVA of Jager 1 (20/25) OD.
Conclusions: This case shows the potential of LAL to be a reliable and reproducible treatment method that can result in positive visual acuity outcomes in patients with corneal abnormalities. It also demonstrates that in patients with FFK and mild keratoconus, LAL has potential to utilize spherical aberration to successfully achieve extend depth of the focus (EDOF) vision
It’s not a GIST: A Histopathological Investigation of a Rare Gastric Schwannoma
No full textBackground: Gastric schwannomas are rare gastrointestinal mesenchymal tumors, accounting for <0.2% of all gastric neoplasms. Gastric schwannomas are benign, arise from the gastrointestinal nerve plexus, and are often misdiagnosed as gastrointestinal stromal tumors (GISTs). Gastric schwannomas are typically incidental findings on conventional imaging studies, surgery, or autopsy. Reported patients are usually asymptomatic. Gastric schwannomas can be differentiated from GIST and other mesenchymal gastrointestinal tumors through the use of immuno-histochemical markers such as S100, Vimentin, and glial fibrillary acidic protein (GFAP).
Case Information: During routine dissection of a 78-year-old female, a 1.5 x 1.2 x 1.0 cm tan, firm nodule protruding from the anterior stomach wall was identified. The nodule was located 11 cm from the gastroesophageal junction, 7 cm from the incisura angularis, and 6 cm from the pyloric sphincter. Sectioning revealed white, whorled, and rubbery cut surfaces. No hemorrhage, necrosis, or cystic spaces were grossly appreciated. Subsequently, the tissue underwent routine fixation, processing, paraffin embedding, sectioning, and hematoxylin and eosin (H&E) staining. Using light microscopy, histopathologic findings included a well-circumscribed area containing mostly eosinophilic spindle cells with nuclear palisading, foci of lymphoid infiltration,and a micro-trabecular pattern noted centrally. Additionally, a peripheral lymphoid cuff was present. No mitotic figures were identified. Based on our histopathology findings, we hypothesized the presented nodule to be a gastric schwannoma. This diagnosis was corroborated by immunohistochemistry to demonstrate positive S100b protein expression. Common differential diagnoses include gastrointestinal stromal tumors (GISTs), leiomyomas, and solitary fibrous tumors, all of which lack S100 protein reactivity.
Conclusion: This case aims to contribute an additional report about gastric schwannomas to better enhance our collective understanding of this rare lesion
Effects of Amyloid β on Recollective Memory: Sex and Hormone Differences
No full textPURPOSE:
Alzheimer’s disease (AD) is linked with increased memory loss and inability to learn new topics. One of the defining neuropathological features of AD is amyloid beta (Aβ) plaques in brain regions, such as the hippocampus. The hippocampus brain region is important for memory and learning. AD risk is elevated in individuals older than 65 years old, especially menopausal women. Menopause is an aging associated endocrine event in which the ovaries stop producing estradiol but continue producing testosterone. Testosterone can be aromatized to estradiol, but aromatase is not functional in women with AD. Therefore, post-menopausal women with AD have more androgens than estrogens than pre-menopausal women and aged men. Androgens can be neuroprotective or neurotoxic depending on the cellular environment. It is unknown what the impact of androgens and sex are on amyloid beta’s effects on the brain, (e.g., hippocampus) and behavior (e.g., memory). We hypothesize that females with the hormonal condition of androgens in the absence of estrogens will exhibit increased recollective memory in response to hippocampal injection of Aβ.
METHODS:
To investigate the role of androgens and sex on Aβ associated memory impairments, adult male and female Sprague-Dawley rats were gonadectomized to remove circulating sex hormones. A subset of these rats was given either cholesterol or dihydrotestosterone (DHT), which cannot be converted into estrogen. To model AD, rats were injected with 5ug/ul of Aβ oligomer fibrils 1-40 or vehicle shams in the CA1 region of the hippocampus. One week after Aβ hippocampal injections, the rats were assayed for short term and long-term recollective memory via a 1-hour and 24-hour Novel Object behavioral test. The Novel Objective behavioral tests examines recollective memory by quantifying the time spent with a novel object versus the time spent with a known object. Data was quantified with a three-way ANOVA with sex, hormone, and Aβ as independent variables. Tukey’s was used as a post-hoc test.
RESULTS:
Sex differences were observed between hormone-deficient rats exposed to Aβ. Specifically, males exhibited worse short term recollective memory (1 hour novel object) compared to females. DHT had no effect on recollective memory, regardless of Aβ exposure. No effects were observed in the long-term recollective memory (24-hour novelty test).
CONCLUSIONS:
Our results indicate that Aβ 's effects on short term recollective memory is influenced by sex chromosomes, as we observed sex differences in the hormone deficient (cholesterol) treated animals. However, DHT did not impact these recollective memory. These results indicate that recollective memory in AD is impacted by the sex chromosomes and not androgens.NIH; Promoting Diversity in Research Trainin
How did we get here? A historical look at the early clinical trial data investigating Covid-19 monoclonal antibody therapy and implications for the future
No full textBACKGROUND: The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic to mild, moderate, severe, and clinical illness. Current recommendations for the use of monoclonal antibody (mAb) therapy - including Ritonavir-boosted Nirmatrelvir, Remdesivir, and Molnupiravir - for the treatment of SARS-CoV-2 infection include use in patients who are at risk of progressing to severe COVID-19. Given the unprecedented process and speed of research conducted on the use of antibody therapies, beginning with polyclonal antibodies developed from patients recovered from COVID-19 to the development of monoclonal antibodies targeting the spike protein(s) of various COVID-19 variants, it is important to reflect on early data to better understand the early challenges pertaining to mAb and early COVID 19 research.
METHODS: Articles published between January 1, 2019 and October 1, 2021 were identified from keyword search of Medline (via PubMed). Clinical trials evaluating the outcomes of monoclonal antibody (MAB) therapy for the treatment of Covid-19 infection were included. This study was IRB-exempt.
RESULTS: Initial search results yielded 493 papers. After title and abstract screen, full articles were read in their entirety. A total of 21 articles were included in this analysis, representing 7833 patients. Eight studies found a statistically significant benefit to MAB use, 12 found no benefit, and one study did not perform formal statistical hypothesis testing. Primary outcomes varied between studies and included mortality rate, ICU admission, mechanical ventilation requirements, Covid-related hospitalization, supplementary oxygen use, clinical composite scores, and viral load.
DISCUSSION: Early clinical trial data was inconclusive but suggested that monoclonal antibody therapy may have reduced hospitalizations and provided a mortality benefit in some populations with COVID-19. However, several important factors may have influenced treatment response. These factors included antibody type, dose, route, therapy initiation relative to symptom onset, and disease severity, varying COVID-19 treatment protocols throughout the pandemic, possible interactions between early vaccinations and mAb, and disease severity-dependent treatment response .
It is important to look back at the early data to understand the progression to current management protocols. Previously, biologics were analyzed for approval independently of other drug applications, and could be given priority as an "orphan drug” with accelerated status for patients with rare diseases needing treatment now, allowing for rapid market mobilization.
The COVID-19 pandemic sped up the process even further. The FDA was able to issue Emergency Use Authorizations (EUA) to companies with promising pharmaceuticals and biologics for direct care of patients with COVID-19, without the confirmatory trials and tests previously required. Although the healthcare system benefited from greater access to approved biologic treatments for COVID-19, many of the biologics were revoked due to concerns about both efficacy and safety. In the end, it remains to be seen if the proper avenues for the ethical development of pharmaceuticals were neglected in favor of the streamlined approval process by the pharmaceutical companies, and thus should be considered in future international medical events
Screening for Methylenetetrahydrofolate Reductase (MTHFR) Mutation
No full textPurpose: The C677T and A1298C allele codes for methylenetetrahydrofolate reductase enzyme in the liver that coverts folate to L-methylfolate (LMF). L-methlyfolate is the version of folate the brain can absorb. Once in the brain L-methyl folate is thought to help stimulate production of essential neurotransmitters. Mutations in this enzyme are strongly linked to depression, however it could also lead to other psychiatric conditions.1 Studies show that when L-methylfolate supplementation was used alongside antidepressants in 502 participants with depression, they reported improvement in depressive symptoms.2 With more people tested for this mutation we can identify people that need on proper L-methylfolate supplement and get them on it. Thus, improving their overall health.
Methods: We implemented a screening tool that comprised of multiple questions including a PHQ-9 and GAD-7. We gave it to all adult patients at the Hendrik Family Medicine Clinic in Abaline, Texas between August 2022 and October 2022. Positive screening results were based on the criteria of history of depression or a five or greater on the screening.
Results: We screened a total of 188 patients with 106 qualifying for the test. Fifty-three patients preformed the test, and the other half did not due to cost, loss to follow up, or other reasons. Forty-one, or 77%, of the patients screened tested positive for a mutation in one or both alleles. On average PHQ-9 scores were higher in patient who had a mutation in both alleles. 14 of the 41 positive mutation patients were on additional pain medication (Tylenol-3, Tramadol, or Both).
Conclusion: This study suggests that MTHFR gene mutations is prevalent in people who met criteria through the screening. Even though it was prevalent more research need to be done to know the impact of obtaining screenings and outcomes once starting supplementation. A future goal is to follow up with patients who have the mutation and test if there is any improvement in their symptoms after supplementation.
1. Wan L, Li Y, Zhang Z, Sun Z, He Y, Li R. Methylenetetrahydrofolate reductase and psychiatric diseases. Translational psychiatry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218441/#CR67. Published November 5, 2018. Accessed October 5, 2022.
2. Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord. 2013;15(4):PCC.13m01520. doi:10.4088/PCC.13m0152