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Changes in cerebral inflammation and blood pressure in postpartum preeclamptic rats
No full textIntroduction: Postpartum (PP) preeclamptic (PE) women have an increased risk of developing hypertension (HTN) and cerebrovascular diseases later in life. Studies show that women who experience preeclampsia go on to develop HTN 7-8 years earlier than women with normal pregnancies, increasing their risk for developing cerebrovascular diseases such as stroke. While the timing and mechanisms contributing to a rise in blood pressure (BP) and cerebrovascular dysfunction in postpartum preeclamptic women are unknown, they are hypothesized to be influenced by inflammation. Previous studies in our lab indicate postpartum PE rats at 10 weeks have HTN and increased inflammation (PMID: 34727994). Our current study will examine BP and inflammation in postpartum PE rats at an earlier time point, 6 weeks (PP6), to determine the relationship between cerebral inflammation and the pathophysiology of HTN. We hypothesize that postpartum PE rats will have an increase in BP and cerebral inflammation 6 weeks after delivery.
Methods: Pregnant Sprague Dawley rats were divided into 2 groups: normal pregnant (NP) rats, and preeclamptic (RUPP) rats. Placental ischemia was surgically induced in the preeclamptic group via the reduced uterine perfusion pressure (RUPP) model. All rats gave birth naturally and were weaned for 3 weeks. At PP6, BP was measured via carotid catheterization, and brain tissue was collected to measure pro-inflammatory (TNF-α and IL-17) and anti-inflammatory (IL-4 and IL-10) factors via colorimetric assays and ELISAs.
Results: Blood pressure was elevated in RUPP PP vs NP PP (128±6 vs 106±4mmHg, p<0.05). Cerebral TNF-α drastically increased by ~2.4 fold in RUPP PP vs NP PP (2576±445.6 vs 1058±212.5pg/mL, ns). Cerebral IL-17(331.2±41.1 vs 297.6±48.6pg/mL, ns) and IL-4 (178.4±23.4 vs 154.8±14pg/mL, ns) also increased in RUPP PP vs NP PP. Cerebral IL-10 (103.9±21.4 vs 147.6±11.3pg/mL, ns) was decreased in RUPP PP vs NP PP rats.
Conclusion: PP6 preeclamptic rats have HTN and increased cerebral inflammation. It is yet to be determined whether cerebral inflammatory markers are the cause or consequence of HTN in PP6 PE rats. Future studies will explore the sequence of HTN and cerebral inflammation in postpartum PE rats and determine how brain inflammation contributes to HTN and cerebral damage. We will also target specific areas of the brain that modulate autonomic function and BP. This study is clinically relevant because it will inform providers on the pathophysiology of HTN and/or cerebral damage in women after a PE pregnancy. Our findings suggest that the use of inflammatory therapeutic targets improves HTN and cerebrovascular dysfunction in postpartum PE women.This research was supported by start-up funds and the American Heart Association Early Career Development Award [AHA 18CDA34110264 (Cunningham)]. Also the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health Award [5R25HL007786-29(Jones)
MIEN1 promoter ablation provides novel evidence for colorectal cancer genome editing-based therapeutics.
No full textPurpose: Colorectal cancer (CRC) is one of the leading causes of cancer associated mortalities worldwide. It starts with hyperproliferation of epithelial cells forming a polyp & leads to stages 3 & 4 which are associated with acquisition of metastasis. Chemotherapy majorly focuses on attenuating symptoms with no promising cure. Hence, studying the underlying mechanism of CRC progression & identifying novel therapeutic targets is critical for early diagnosis & treatment.
The process of metastasis involves a complex interplay of signaling pathways, where various proteins play crucial roles. One such important protein that aids the process of migration is Migration & Invasion ENhancer 1 (MIEN1). In CRC, MIEN1 expression is predominantly upregulated in cancerous tissue in comparison to normal colorectal tissue, which is closely associated with invasive behavior. But the exact mechanism involved in the process of metastasis is yet unexplored.
Methods: It is established that MIEN1 overexpression is a result of 17q12 chromosomal amplification, & such dysregulated expression is linked to the trans-regulation of its minimal promoter region. Therefore, we aim to investigate the effect of MIEN1 promoter ablation on CRC migration properties. CRISPR-Cas9 gene editing technology was used for deleting MIEN1 promoter region in the CRC cell line HT29. RNA seq & bioinformatics tools were employed to assess the transcriptomic consequences of genome-editing. Several DEGs discerned by RNA seq analysis were involved in different biological processes & molecular pathways such as cell adhesion, migration, invasion, & angiogenesis. Out of these the genes vital to CRC biogenesis were evaluated at both RNA & protein levels.
Results: We analyzed the effect of MIEN1 knock-out on CRC metastatic potential using functional assays such as wound healing, Matrigel invasion, hanging drop cell – cell adhesion, & found that migration potential of HT29 cells was significantly reduced in absence of MIEN1 protein. We also successfully demonstrated that MIEN1 deletion disrupts the cytoskeletal rearrangement by affecting F-actin reorganization using phalloidin staining. Confocal staining of different proteins participating in actin cytoskeleton rearrangement such as paxillin, FAK, MIEN1 gave us an insight about the role of MIEN1 in mediating phosphorylation of FAK at different phosphorylation sites such as Tyr 397 & 925. Immunoblotting analysis of an array of proteins further confirmed the role of MIEN1 in actin cytoskeleton dynamics.
Conclusion: MIEN1 is an important metastatic protein that is specifically overexpressed in cancerous cells. Taken together, our results prove that MIEN1 is involved in different signaling pathways responsible for CRC migration & its deletion leads to perturbation of several biological processes especially the actin cytoskeleton rearrangement, involved in metastasis. Hence, targeting MIEN1 would be a potentially effective therapeutic strategy for CRC patients
Structural Determinants of Health Among Transgender Populations: Policing, Sex Work, and HIV
Get PDFTransgender (trans) populations experience disproportionately high rates of HIV infection compared to cisgender populations. Additionally, due to overlapping layers of discrimination in education, housing, healthcare, and employment, trans populations are more likely to engage in a criminalized form of work, such as sex work. Policing has been identified as a potential structural determinant of HIV infection among individuals engaging in sex work. Trans populations, including those engaging in sex work, are more likely to interact with police and experience some form of police violence. This dissertation investigated policing as a potential structural determinant of HIV status and HIV testing among trans individuals who engage in sex work. Unadjusted and adjusted logistic regression analyses were utilized to identify associations between HIV status/HIV testing and police interactions. Mediation analyses were utilized to investigate police interactions as a potential mediating variable between HIV status/HIV testing and trans individuals who have engaged in street-based sex work. Statistically significant associations were identified between police interactions and HIV status in unadjusted (OR: 2.564, 95% CI: 1.166, 5.641, p-value = 0.019) and adjusted (aOR: 12.055, 95% CI: 3.076, 47.232, p-value <0.001) logistic regression models. Additionally, police interactions were not identified as a statistically significant mediating variable between HIV status/HIV testing and trans individuals engaging in street-based sex work. These findings suggest policing may act as a contributing factor towards HIV infection among trans individuals engaged in sex work, but further research is needed to elucidate this interaction. HIV infection prevention interventions need to include an intersectional lens that incorporates trans identities and address the structural issues that trans populations experience including discrimination in housing, employment, and healthcare
Touchscreen-Based Cognitive Training Alters Functional Connectivity Patterns in Aged But Not Young Male Rats
Get PDFAge-related cognitive decline is related to cellular and systems-level disruptions across multiple brain regions. Because age-related cellular changes within different structures do not show the same patterns of dysfunction, interventions aimed at optimizing function of large-scale brain networks may show greater efficacy at improving cognitive outcomes in older adults than traditional pharmacotherapies. The current study aimed to leverage a preclinical rat model of aging to determine whether cognitive training in young and aged male rats with a computerized paired-associates learning (PAL) task resulted in changes in global resting-state functional connectivity. Moreover, seed-based functional connectivity was used to examine resting state connectivity of cortical areas involved in object-location associative memory and vulnerable in old age, namely the medial temporal lobe (MTL; hippocampal cortex and perirhinal cortex), retrosplenial cortex (RSC), and frontal cortical areas (prelimbic and infralimbic cortices). There was an age-related increase in global functional connectivity between baseline and post-training resting state scans in aged, cognitively trained rats. This change in connectivity following cognitive training was not observed in young animals, or rats that traversed a track for a reward between scan sessions. Relatedly, an increase in connectivity between perirhinal and prelimbic cortices, as well as reduced reciprocal connectivity within the RSC, was found in aged rats that underwent cognitive training, but not the other groups. Subnetwork activation was associated with task performance across age groups. Greater global functional connectivity and connectivity between task-relevant brain regions may elucidate compensatory mechanisms that can be engaged by cognitive training.This work was supported by National Institutes of Health (NIH) National Institute on Aging Grants R01/RF1 AG049722, AG060977, and P50 AG047266 and the McKnight Brain Research Foundation. Research reported in this publication was also supported by the University of Florida Clinical and Translational Science Institute: the NIH Center Grant UL1TR001427. This work was also supported by the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility (National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida)
Use of the General Movement Assessment as an Early Marker of CP
No full textUse of the General Movement Assessment as an Early Marker of CP
Authors: Yvette R. Johnson, MD, MPH; Treka L. Rogers, CPNP-AC; Chelsea L. Sapit, CPNP-PC; Kimberly Barber, PT; Robin Grady, OT; Betsy O’Hara, OTR; Heather Hilliard, DPT; Grace Rustom; Nisha Mistry, MS; Michelle Lee, MS; Tyler Hamby, PhD
Purpose:
Cerebral palsy (CP) is the most common physical disability in children affecting 1 in 500 live births. The average national standard of detecting CP occurs after 2 years of age by analysis of neurological signs. Since December 2014, the NICU Early Support and care Transition (N.E.S.T.) Clinic at Cook Children’s Medical Center has provided multidisciplinary comprehensive follow-up to high-risk NICU survivors. Cook Children’s Medical Center implemented an Early CP detection program in 2019 using the General Movement Assessment (GMA) in the NICU and NEST Clinic. There has been emerging evidence that evaluation of general movements in early infancy (writhing and fidgety periods) is predictive of a future CP diagnosis in an infant. This early diagnosis is key for better neurodevelopmental outcomes.
Methods:
Infants who met inclusion criteria had GMA videos captured shortly after birth during the NICU stay. Infants with abnormal GMA videos had further evaluation at 3-4 months corrected gestational age, during their NEST clinic visit. The data from the NEST clinic were then compiled to include high-risk variables. Retrospective review and analysis of data previously collected for the Early CP detection program was performed under the direction of Dr. Yvette Johnson and her Early Detection Team. Univariate Cox regression analyses were performed to determine which variables were predictive of CP diagnosis.
Results:
There were 471 patients who met inclusion criteria, including 292 (62%) very low birth weight (VLBW), 131 (28%) hypoxic-ischemic encephalopathy (HIE), 15 (3%) congenital diaphragmatic hernia (CDH), 8 (2%) extracorporeal membrane oxygenation (ECMO), and 25 (5%) congenital heart disease (CHD) infants. Four hundred ten (87%) had GMA’s in the writhing phase and 205 (44%) had GMA’s in the fidgety phase. The median (range) age of CP diagnosis was 1.07 (0.34-1.93) years, and 91% had been diagnosed by 1.50 years. The infants with HIE had a statistically significant increased risk of CP diagnosis compared to those in the VLBW category (10% vs. 6%, HR=2.50, p=0.014). The infants with an absent or abnormal fidgety GMA interpretation during the fidgety period had a statistically significant increased risk of CP diagnosis compared to those with other interpretations (46% vs. 3%, HR=15.69, p<0.0001).
Conclusion:
The results showed that having an abnormal or absent fidgety general movements during the fidgety phase was a significantly strong predictor of CP outcomes. These data can be extrapolated in clinical settings to provide early and evidence-based interventions that can improve long-term functional motor outcomes
Acute sex difference in response to repeated mild traumatic brain injury in mice
No full textAcute sex difference in response to repeated mild traumatic brain injury in mice
Aaron Kuo, Philip Vann, Nathalie Sumien, Ahmed Affan, Derek Schreihofer
Background: Repetitive mild traumatic brain injury (rmTBI), such as that occurring in contact sports, is associated with the development of neurodegenerative diseases of aging. Severe TBI and repetitive concussions are associated with chronic traumatic encephalopathy (CTE), Alzheimer’s disease (AD), and Parkinson’s disease (PD), among others. However, less severe injuries may also lead to delayed neurological disfunction if repeated often and without sufficient rest time between injuries. Previously, we found that the progression of behavioral deficits in males and female mice differed from 5 to 15 weeks after 25 rmTBI. Both sexes showed motor deficits at 5 weeks, but only males showed affective and cognitive deficits at 15 weeks.
Purpose: This study tested the hypothesis that rmTBI neurological deficits in male mice will appear earlier after rmTBI than in female mice.
Methods: C57BL/6 male and female mice (8 wk old) were assigned to sham and rmTBI groups (n=20/group). Lightly anesthetized mice received 7 mild head injuries, once a day (M-F) using a weight drop model (75 g from 1 meter) that included a free fall with rotational injury. Five minutes after the final injury, mice were tested on a balance beam. Additional behavioral assessments began the following day.
Results: No sex differences in balance beam performance were observed 5 minutes after the final injury. There were no significant effects of rmTBI on vestibular motor function assessed with a rotarod; cognition assessed with the Morris water maze; or affective behavior assessed with the elevated plus maze. However, in the open field test there was a significant increase in total distance traveled in rmTBI mice (F1,35 = 6.47, P=0.016). Post-hoc analysis revealed that this effect was only significant in male mice (Fisher LSD, P<0.05), supporting the hypothesis that males exhibit earlier deficits than females.
Conclusion: At extended time points following rmTBI, both male and female mice develop motor deficits. However, up to 15 weeks after injury, only male mice experience cognitive and affective deficits. The current study reveals that male mice also display hyperactivity in the week after rmTBI that is not observed in female mice. Thus, sex differences in response to rmTBI are apparent both in the acute and chronic phase of injury and suggest that interventions to reduce brain injury may require different timing for males and females. Ongoing studies are examining potential differences in biochemical and histological responses in the brains of male and female mice.
AUP: 2021-0035JES Edwards Foundatio
OMT Efficacy for Chronic Pelvic Pain Secondary to a Delayed Diagnosis of Endometriosis
No full textBackground: Endometriosis is a gynecological disease characterized by ectopic growth of endometrial tissue. Common symptoms include dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Additionally, current research is showing an increased incidence of systemic inflammatory illnesses in those with endometriosis. Due the variability in the presentation of symptoms and location of endometrial lesions, patients are often told their symptoms are consistent with normal menstruation and their true diagnosis is significantly delayed. Recent research suggests most patient experience a 7–9-year delay in diagnosis. Furthermore, after years of these troubling symptoms, treatment is not always effective at achieving pain relief. It has been found that up to 59% of patients continue to have pain after treatment. OMT has been poorly researched in this area, but currently available research has shown success in achieving pain relief for these patients. Case Presentation: A 39-year-old female presented to the UNTHSC OMM clinic for evaluation of pelvic pain secondary to endometriosis. Though she experienced symptoms of severe dysmenorrhea and pelvic pain since menarche and dyspareunia, infertility, and other systemic inflammatory illnesses since early in her reproductive years, she was not given the diagnosis of endometriosis until she was 27, after a disproportionately painful pelvic exam prompted an ultrasound. This ultrasound revealed two endometriomas, measuring 5.7x3.6cm and 4.5x3.4cm. Six months later, after a failed trial of progesterone and continued growth of the lesions, she underwent laparoscopic removal of the cysts which confirmed the composition of these endometriomas. She was then placed on oral contraceptive pills for management of her disease. Initially these were taken to allow for monthly menstruation, and she found enough relief to make her symptoms bearable for the next six years. However, at age 34, she was advanced to continuous use due to catamenial migraines. This regimen allowed her to return to roughly 50% of her normal daily activities, though she was still limited due to chronic pelvic pain and stress-induced flare-ups. Finally in 2020, at age 39, she found the UNTHSC OMM clinic and began bi-monthly treatments for her pelvic pain. She reported that after being treated here she experienced immediate relief of her pain. This relief initially would last for roughly 1 week and then her pain would slowly return. After several months of regular visits, she was able to gradually space out her visits to as far as six months apart without breakthrough pain. Conclusion: Endometriosis is a complex disease that leads to significant pain and diminished quality of life. Not only do these patients struggle with various gynecologic symptoms and systemic inflammatory flares, but they are also left to suffer for years without a diagnosis due to their pain being attributed to normal menstruation. After finally getting their diagnosis, many patients still do not get pain relief due to the reliance on medicinal treatments. This case is a clear example of the need for more intensive education for medical professionals in both the diagnosis of endometriosis and the addition of OMT to the treatment regimen
Prescription Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Incidence of Depression Among Older Cancer Survivors With Osteoarthritis: A Machine Learning Analysis
Get PDFOBJECTIVES: This study examined prescription NSAIDs as one of the leading predictors of incident depression and assessed the direction of the association among older cancer survivors with osteoarthritis. METHODS: This study used a retrospective cohort (N = 14, 992) of older adults with incident cancer (breast, prostate, colorectal cancers, or non-Hodgkin's lymphoma) and osteoarthritis. We used the longitudinal data from the linked Surveillance, Epidemiology, and End Results -Medicare data for the study period from 2006 through 2016, with a 12-month baseline and 12-month follow-up period. Cumulative NSAIDs days was assessed during the baseline period and incident depression was assessed during the follow-up period. An eXtreme Gradient Boosting (XGBoost) model was built with 10-fold repeated stratified cross-validation and hyperparameter tuning using the training dataset. The final model selected from the training data demonstrated high performance (Accuracy: 0.82, Recall: 0.75, Precision: 0.75) when applied to the test data. SHapley Additive exPlanations (SHAP) was used to interpret the output from the XGBoost model. RESULTS: Over 50% of the study cohort had at least one prescption of NSAIDs. Nearly 13% of the cohort were diagnosed with incident depression, with the rates ranging between 7.4% for prostate cancer and 17.0% for colorectal cancer. The highest incident depression rate of 25% was observed at 90 and 120 cumulative NSAIDs days thresholds. Cumulative NSAIDs days was the sixth leading predictor of incident depression among older adults with OA and cancer. Age, education, care fragmentation, polypharmacy, and zip code level poverty were the top 5 predictors of incident depression. CONCLUSION: Overall, 1 in 8 older adults with cancer and OA were diagnosed with incident depression. Cumulative NSAIDs days was the sixth leading predictor with an overall positive association with incident depression. However, the association was complex and varied by the cumulative NSAIDs days.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was, in part, supported by the National Institutes of Health (NIH) Agreement No. 1OT2OD032581-01 (Usha Sambamoorthi) and the National Institute on Minority Health and Health Disparities through the Texas Center for Health Disparities (NIMHD), 5U54MD006882-10 (Usha Sambamoorthi). The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. We thank the IMS personnel for helping us with data acquisition
Adult-Onset Still’s Disease Masquerading as Candida Sepsis
No full textBackground: Adult Onset Still’s Disease (AOSD) is a rare systemic inflammatory disorder characterized by daily fever, polyarthritis, and transient salmon-pink rash typically at the peak of fever. It is hypothesized to be a reactive syndrome triggered by an infectious process. However, the etiology is still unknown. The Yamaguchi diagnostic criteria is commonly used to classify AOSD. Although there is not a specific laboratory or imaging study used to diagnose AOSD, a serum ferritin > 1000 ng/mL is typically seen.
Case presentation: Here we present a case about a 66 year old male with a past medical history of hypertension, hyperlipidemia, uncontrolled type II diabetes mellitus (DMT2), atrial fibrillation, hypothyroidism, chronic knee pain, and tobacco abuse who presented to the hospital with subjective fevers, myalgias, and generalized weakness for 2 weeks. The patient also had a pruritic, erythematous rash in the bilateral lower abdominal region which extended to the inguinal folds over the last 15 days. Physical exam revealed oral thrush covering his tongue. The patient also had chronic, bilateral knee swelling, erythema, and warmth without formal diagnosis of arthritis in the past. The patient was febrile, tachycardic, and hypotensive on admission. Complete blood count was remarkable for leukocytosis with a white blood cell count of 12.35 K/mm3. Based on his initial presentation, the patient was diagnosed with sepsis secondary to candida infection. The patient’s history of DMT2, Jardiance use, and tobacco abuse further elevated suspicion of candidiasis. However, his fever was non-responsive to antifungals, antibiotics, or antivirals. Given his bilateral knee, elbow, and wrist swelling, we investigated possible rheumatologic processes. Further workup revealed an elevated erythrocyte sedimentation rate (ESR) of 106 mm/Hr, elevated C-reactive protein (CRP) of 353 mg/L, and elevated ferritin of 29125 ng/mL suggestive of severe inflammation. The patient’s daughter later revealed he had an erythematous rash most notable at the height of his fever. The Yamaguchi criteria were used to diagnose AOSD. Patient presentation was positive for four major criteria and two minor criteria. His elevated ferritin > 1000 ng/mL solidified the diagnosis. His fever ultimately improved after corticosteroid treatment.
Discussion: Diagnosis of AOSD still remains a challenge because it is a diagnosis of exclusion. Although the Yamaguchi criteria are the most sensitive criteria for identifying AOSD, cases do not always present classically. Sepsis is an exclusion criteria for AOSD. The patient’s initial presentation was highly suggestive of sepsis, which initially delayed identification of AOSD. Also the salmon-pink rash that is classically presented with AOSD masqueraded as candida infection in addition to his oral thrush. This case illustrates the diagnostic challenges of AOSD. Delay in diagnosis remains a problem with AOSD, because delay can lead to increased risk of complications including disseminated intravascular coagulopathy (DIC), thrombotic thrombocytopenic purpura (TTP), macrophage activation syndrome, pulmonary hypertension, and diffuse alveolar hemorrhage. Further investigation is critical for understanding the etiology of AOSD as well as diagnostic protocols to expedite management and prevent life-threatening complications
Design of Man-made Miniature CRISPR-Cas Proteins Using Computational and Artificial Intelligence Technologies
No full textPurpose: The CRISPR/Cas system is a popular genome editing technique that uses a guide RNA and specific proteins known as Cas proteins for its function. A major challenge in harnessing CRISPR-Cas technology for applications in living organisms is the lack of an efficient delivery system. Due to the larger size of available Cas proteins used in this tool, it is challenging to encapsulate the CRISPR components into a single vehicle for delivery. To address this issue, we have used computational and Artificial Intelligence (AI) tools on designing compact-size Cas proteins that have a similar function and are more efficient than available Cas proteins.
Methods: The available crystal structures of the smallest CRISPR-Cas systems were utilized and further reduced. A novel method termed the "Blocks and Gaps approach” was employed to design new mini-Cas proteins with a size range of 450-500 amino acids in length. The generated protein sequences (1 million) were subsequently used in machine learning-based two classification models to filter out the non-Cas proteins from it. The resultant Cas protein sequences were used in homology-modeling-based (Swiss-Model) and AI-based (Alphafold2) protein structure prediction methods to obtain their 3D structures. Further, the global and local structural features as well as the solubility of these proteins were analyzed, and top candidates were subjected to molecular dynamics (MD) simulations including substrate DNA and gRNA.
Results/Conclusions: A library of man-made miniature Cas proteins was generated, and these proteins are less than half the size of the widely used CRISPR-Cas such as Cas9 or Cas12a. 50% of these were predicted as Cas proteins by both the machine learning-based classification models used. And 90% of them show similar 3D structures as their original counterparts. 10% of these passed through the final validations. Experimental testing of the activity of these designed proteins is to be investigated at this point of the study