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A Rare Case of Paraumbilical Hernia Containing and Obstructing the Stomach
No full textBackground:
Abdominal hernias occur when peritoneal lined organs protrude through the abdominal wall. They are common with an estimated prevalence of 25% in adults. Patients may be asymptomatic but surgical intervention may be advised if patients are at risk for complications such as incarceration and strangulation. Initial diagnosis of abdominal hernias is made clinically but may be assisted with imaging. Computed tomography (CT) is the current modality of choice. In this case report, we specifically focus on midline abdominal hernias. These include epigastric, paraumbilical, umbilical, and hypogastric hernias. The most frequent abdominal hernia is the paraumbilical/umbilical hernia which account for 13.9% of all hernias. These occur due to weakness or defect in the linea alba and/or abdominal rectus muscles. Patient presentation varies but many have a visible bulge that may or may not be tender to palpation. Typical contents of paraumbilical/umbilical hernias include peritoneal fat, omentum, small bowel, and large bowel. We present a unique case of stomach herniation into a pre-existing ventral abdominal hernia that has been described only a few times in the last century. Identification with CT allowed for appropriate anatomical resolution to assess for bowel obstruction and strangulation of hernia contents.
Case Presentation:
A 72-year-old female presented to the emergency department with abdominal pain, nausea, and emesis. Prior computed tomography (CT) studies completed one month before presentation showed a large, ventral abdominal paraumbilical hernia without obstruction or strangulation. However, one month later she presented with worsening symptoms of abdominal pain, nausea, and emesis. Repeat abdominal and pelvis CT showed interval herniation of the distal stomach and proximal bowel into the patient’s known paraumbilical hernia. This resulted in gastric outlet obstruction. Immediate management included intravenous fluids, nasogastric tube placement and surgical correction. Operative report revealed a large ventral abdominal hernia with viable stomach, proximal duodenum (D1), cecum, ascending and transverse colon, and multiple loops of small bowel without evidence of strangulation. The patient successfully recovered after surgery.
Conclusion:
A rare complication in paraumbilical/umbilical hernias is gastric herniation into an existing hernia. Patients may present with red flag symptoms such as abdominal pain, nausea, and emesis. Quick identification of these symptoms and rapid visualization with CT will help identify the extent of herniation and other complications such as bowel obstruction, strangulation, and incarceration. A major risk factor for gastric herniation is weakened abdominal muscles and increased laxity of stomach ligaments found in populations such as multiparous women of middle to late ages. Healthcare professionals should be aware of patients who fit this demographic to educate them on the risk of herniation and recommend them for prophylactic surgical treatment
Barriers to Attendance of Pediatric Patients to the Nephrology Clinic: a Single Center Study
No full textPurpose: No-shows are defined as when a patient does not attend their scheduled clinic appointment without prior notification. Studies have been conducted in other specialties to show the effect of no-shows on patient and clinic outcomes, however there is limited research surrounding non-attendance in the pediatric nephrology population. Kidney conditions not diagnosed promptly can lead to serious complications including kidney failure and the need for dialysis. Therefore, it is imperative patients attend appointments so these conditions can be properly diagnosed and treated. Our study aimed to identify barriers to attendance of these appointments in the pediatric nephrology population at Cook Children’s Medical Center. This quality improvement project will promote future research into other barriers as well as interventions to improve attendance to nephrology clinics. Methods: A retrospective chart review of pediatric nephrology patients referred to Cook Children’s outpatient nephrology clinics from August 1, 2018 to June 30, 2023 was conducted. Data collection was limited to: patients between 0-21 years old at time of missed appointment, new or established patients with at least one documented no-show, and patients who canceled and did not reschedule. Demographic data was collected from each patient. Data analysis composed of descriptive statistics and frequencies of independent variables. Study data was managed using REDCap (Research Electronic Data Capture) tools hosted at Cook Children’s. Results: Our study found significant associations between no-show/cancellation rates and certain variables. Males were 1.1 times more likely to no-show and cancel. Black/African-American patients were more likely to no-show and cancel than expected. Patients on public insurance were 1.6 times more likely to no-show. Patients older than 12 were more likely to no-show. Patients whose primary language was English were less likely to cancel. Established patients were 1.1 times more likely to cancel. Telemedicine patients were 1.5 times more likely to no-show and 1.4 times more likely to cancel. Conclusion: Our results echo similar studies in other specialties. Socioeconomic disparities and specific diagnoses may be an explanation for increased no-show/cancellation rates in certain groups. Addressing these inequities with interventions designed to ease patient accessibility can improve rates of retention and follow-up. Further studies are necessary to qualify our data and evaluate the effects of implementation measures
Can Nicotinamide Treatment Overcome the Effect of Monocarboxylate Transporter 2 Loss on Retinal Ganglion Cell Survival and Function? dm
No full textPurpose: There is currently no cure for the vision loss in glaucoma that is characterized by retinal ganglion cell (RGC) loss and irreversible optic neuropathy. Monocarboxylate transporter 2 (MCT2), which transports pyruvate, lactate, and ketone bodies, is exclusively found in neurons such as the RGCs. We have previously shown that MCT2 is lost during glaucoma, in advance of RGC loss, and MCT2 overexpression protects RGC number and function. We sought to determine if MCT2 is necessary for RGC survival by knocking it out, and to establish whether providing oral nicotinamide (NAM) could compensate for the anticipated metabolic disruption to RGCs.
Methods: To test these hypotheses, we injected tamoxifen into Thy1-ERT2-cre: MCT2fl/fl mice to conditionally knock out MCT2 from Thy1-positive RGCs. Control mice carried the MCT2 flox’d allele but were Thy1-ERT2-cre-negative. Control and experimental mice were subjected to ocular hypertension using the magnetic microbead model; separate naïve controls from each genotype were also evaluated. To test the effect of nicotinamide intervention, we repeated the same groups but added the administration of oral nicotinamide to each before inducing ocular hypertension. Intraocular pressure (IOP) was measured using the TonoLab rebound tonometer. Pattern electroretinogram (PERG) and Visual Evoked Potential (VEP) were used to analyze the RGC function. We used unbiased stereology (Stereo Investigator, Micro Brightfield) to count the number of retinal ganglion cells in the wholemount retina, and ATP levels in the retina were also measured. Axon counts were done from plastic-embedded optic nerves.
Results: IOP was higher in the ocular hypertension (OHT) groups. MCT2 knockout alone did not impact IOP, nor did it exacerbate RGC function loss post-OHT. After OHT, PERG amplitude was significantly lower in the OHT and KO + OHT treatment groups (p<0.005). RGC function was preserved in the KO + NAM and OHT+NAM groups but was significantly decreased in the KO+OHT group. After OHT, MCT2 KO alone did not alter RGC density but OHT and KO + OHT groups had significantly decreased RGC density (p<0.005). There was no significant decline in RGC density in any of the nicotinamide groups. ATP production in the KO + OHT group was significantly higher (1.81 +/- 0.89 µg/µl) than in the naïve control group (0.68 +/- 0.42 µg/µl).
Conclusions: MCT2 knockout alone from RGCs did not change IOP, RGC density, or PERG, suggesting that MCT2 is not necessary for RGC function and survival. Ocular hypertension decreased PERG amplitude and RGC density, and the magnitude of the decrease was not significantly worsened by MCT2 knockout. The nicotinamide groups had no significant loss in RGC density, supporting the proposed neuroprotective effect of NAM administration. These data suggest that RGCs can meet their immediate metabolic needs through means beyond MCT2, and nicotinamide can rescue RGCs in the context of glaucoma.NIH EY026662 (DMI)
Structure-Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels
No full textGain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC(50) values between 0.59 and 0.71 microM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels.This research was funded by the National Institute of Neurological Disorders and Stroke, grant number R33NS109521 (C.D.W. and K.A.E.). Portions of this work has been supported by certain funds managed by Deerfield Management Company, L.P. Funding for the WaveFront Biosciences Panoptic and the Syncropatch 768 PE platform was provided by the Office of The Director (OD) of the National Institutes of Health under the award numbers 1S10OD021734 and 1S10OD021734, respectively. These instruments are housed and maintained in the Vanderbilt Institute of Chemical Biology's High-throughput Screening Cente
Resources and Opportunities Available for Allopathic and Osteopathic Medical Students Pursuing Otolaryngology: A Comprehensive Analysis
No full textIntroduction: Otolaryngology, commonly known as Ear, Nose, and Throat (ENT), is a surgical subspecialty dedicated to addressing conditions of the head and neck. It is no surprise that matching into surgical subspecialties such as otolaryngology - head and neck surgery becomes more and more competitive each year. Data indicates that each year on average, students are performing at higher levels than years previous. This increase in competitiveness prompts the development of resources including specialty-specific information to be made more readily available to students. This review aims to identify key ENT organizations in the United States that may provide pivotal tools for medical students. Through an analysis of these organizations, this study reveals opportunities available to medical students through organizations such as research opportunities, conference scholarships, mentorship programs, and avenues for leadership roles. Furthermore, emphasizes the significance of research experience, leadership roles, academic performance, and compelling letters of recommendation, which are crucial in the application process. By focusing on these critical aspects, the primary aim is to highlight resources that can equip medical students with the necessary skills and experiences to apply for an ENT residency successfully.Methods:147 organizations were identified by the University of North Texas Health Science Center (UNTHSC) Gibson Library. A search conducted then by three independent researchers via Google Search contributed an additional 30 organizations. The combination of these sources resulted in a preliminary list of 177 organizations. Three duplicates were eliminated, thus decreasing the list to 174 unique organizations. The next stage of screening was predicated on the relevance of these organizations to the field of Otolaryngology. Three independent researchers excluded 129 entities sourced from the UNTHSC Gibson Library. Further reviews were conducted and a finalized cohort of fourteen national otolaryngology - head and neck surgery organizations were selected for comprehensive evaluation. Information regarding the following information was gathered and compiled for review and comparison: Organization Focuses on a Subspecialty of Otolaryngology, Organization Allows Both MD and DO Student Membership, Medical Student Cost to Join Organization, Annual Meeting, Research Presented at Annual Meeting, Medical Students can Present at Annual Meeting, Medical Student Registration Fee for Annual Meeting, Annual Meeting Registration / Travel Scholarships Available for Medical Students, Mentorship Available Within the Organization for Medical Students, Leadership Opportunities Available for Medical Students, Scholarships/Grants Available for Medical Students, Educational Material Available to Medical Students. Results: The comprehensive analysis highlighted resources and opportunities available for allopathic and osteopathic medical students pursuing otolaryngology. These entities offer numerous benefits, including research opportunities, educational materials, annual meetings, and access to subspecialties. These organizations can provide a competitive edge to medical students who take advantage of these benefits. Conclusion: In conclusion, this analysis underscores the vital support that professional organizations offer to medical students pursuing otolaryngology, highlighting the significance of mentorship, research opportunities, and educational materials. It urges medical students to actively engage with these organizations to enhance their career prospects in this field. However, identified gaps in mentorship, travel financial aid, and leadership roles point towards areas needing enhancement
Hyperbaric Oxygen as Potential Treatment for Chemotherapy-Related Cognitive Impairments
No full textPurpose: “Chemobrain”, characterized by impaired attention, learning and memory retention, is a prevalent condition affecting approximately 75% of patients undergoing cancer treatments. Chemotherapy-related cognitive impairment (CRCI), a subtype of “chemobrain”, can persist for up to 20 years post-treatment, significantly diminishing the daily quality of life for survivors and caretakers. Very few interventions are available to alleviate the effects of chemotherapy on the brain. One potential treatment is hyperbaric oxygen therapy (HBOT), which has shown neuroprotective effects in conditions such as Alzheimer’s disease, traumatic brain injury, and stroke. The current study investigated the effects of HBOT on cognitive impairments induced by commonly used chemotherapeutic agents, and studied the underlying mechanisms with a focus on cellular senescence.
Methods: Four-month-old male and female C57BL/6 mice were injected (i.p.) with saline or chemotherapeutic cocktails (Methotrexate (37.5 mg/kg) + 5-Fluorouracil (50 mg/kg)) once a week for three weeks. Simultaneously, half of the mice underwent daily HBOT session (2.4 ATM for 90 min). Morris water maze was used to measure spatial learning and memory. Hippocampus was evaluated for markers of cellular senescence using western blot analyses.
Results: Chemotherapy exposure impaired spatial learning and memory, which was attenuated by HBOT in male mice only. The exposure was also associated with increased levels of p16INK4a, ɣH2AX, and b-galactosidase (cellular senescence markers), and increased levels of cleaved-Lamin B1 (a surrogate marker of caspase-6 activity relating to apoptosis) in male hippocampus. HBOT seemed to reduce the effects of chemotherapy on ɣH2AX, b-galactosidase, and cleaved-Lamin B1, but not on p16INK4a in males.
Conclusion: HBOT reduced cognitive impairments associated with chemotherapy exposure. Interestingly, females were not impaired by the chosen chemotherapeutic cocktail. Cellular senescence and apoptosis may play a role in the beneficial effects of HBOT.The Feddersen Foundation and the Cancer Prevention and Research Institute of Texas (RP210046)
Design and Synthesis of D(3)R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies
Get PDFA series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D(3)R-selective compound. The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP110(3.32) of the D(3)R, thereby reducing the D(3)R affinity to a suboptimal level.This work was supported by a grant from the National Institute on Drug Abuse, grant number DA029840
Prediction of Ligand Selectivity and Efficacy Using Artificial Intelligence Algorithms
No full textIntroduction:
Bringing new pharmaceuticals to market is a time-intensive and expensive process. The purpose of this project is to combine computational structure based approaches such as docking and machine learning methodologies to yield ideal pharmaceutical candidates for future exploration. The ligands of interest were those that bind to the Dopamine 4 (D4) and Sigma 1 (S1) receptors, serving as prime candidates for treatment of neurological ailments. Design of more efficacious and selective ligands could allow researchers and clinicians to improve treatment of patients with such conditions. The primary objective is to leverage advancements in computational chemistry to approach the problem of identifying ideal drug candidates using both ligand based and structure-based approaches.
Methods:
Receptor structures were identified for both the D4 receptor using the PDB 5WIU, and the S1 receptor using the PDB 5HK1. A list of possible ligands was obtained from a DrugBank database, collaborators at the University of Nebraska Medical Center, and a similarity search. The DrugBank database of FDA approved drugs was scanned for ligands to both the D4 and S1 receptors, and a list of 1415 drug ligands was compiled. Using Autodock software, we docked each ligand with 10 poses. After docking, the ligands were ranked by binding affinity. Using Autodock software, the 83 ligands we received from our collaborators were also docked and ranked by binding affinity to the D4 and S1 receptors. To further expand our pool of potential candidates for further study, a similarity search was conducted by screening through a drug database (ZINC) to identify the FDA approved drugs that were most structurally similar to the 83 ligands. Ligands from both the DrugBank and the similarity search were integrated into a machine learning pipeline using graph neural networks to predict the Ki values, thereby identifying compounds with high binding affinity. Once the ligands of highest affinity are identified by the machine learning model, they will be sent to our collaborators for in vitro testing.
Results:
Of the top 50/1450 FDA approved drugs with the lowest Ki values for both D4, 18 overlapped with the top 50/1450 lowest Ki values for S1. Docking the 83 ligands to the D4 and S1 receptors showed that the ligands were generally more strongly bonded to S1 than D4. We will deliver the top ligand candidates belonging to both D4 and S1 ligand classes as identified by the machine learning model to our collaborators so they can perform further in vitro testing. This will allow us to validate our computational efforts with real world testing.
Conclusion:
We will leverage the trained machine learning model to search through more databases and identify other prime candidates for future exploration
Elucidating the role of MIEN1 in colorectal cancer metastasis
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Oral Presentation Award - 2nd PlacePurpose: Colorectal cancer (CRC) ranks among the foremost contributors to global cancer-related fatalities, with its progression marked by hyperproliferation of epithelial cells culminating in polyp formation. Stages 3 and 4 of CRC are notably associated with metastasis. Despite existing chemotherapy focusing on symptom attenuation, a definitive cure remains elusive. This study addresses the imperative need to comprehend the underlying mechanisms of CRC progression for timely diagnosis and effective treatment. The process of metastasis involves a complex interplay of signaling pathways, where various proteins play crucial roles. Migration and Invasion ENhancer 1 (MIEN1) is a significant protein facilitating migration, and its expression is notably upregulated in CRC tissue compared to normal colorectal tissue, correlating with invasive behavior. The exact mechanism of MIEN1 involvement in metastasis remains unexplored. MIEN1 overexpression results from 17q12 chromosomal amplification, and dysregulated expression is associated with trans-regulation of its minimal promoter region. This study aims to investigate the impact of MIEN1 promoter ablation on CRC migration properties. Methods: Utilizing CRISPR-Cas9 gene editing, we deleted the MIEN1 promoter region in the CRC cell line HT29. RNA sequencing and bioinformatics tools revealed differentially expressed genes (DEGs) associated with essential biological processes and molecular pathways, including cell adhesion, migration, invasion, and angiogenesis. Evaluation of critical genes in CRC biogenesis at RNA and protein levels demonstrated that MIEN1 knock-out significantly reduced the migration potential of HT29 cells, as evidenced by functional assays such as wound healing and Matrigel invasion. Furthermore, MIEN1 deletion disrupted cytoskeletal rearrangement, affecting F-actin reorganization, confirmed through phalloidin staining. Confocal staining of proteins involved in actin cytoskeleton rearrangement provided insights into MIEN1's role in mediating phosphorylation of FAK at different sites. Immunoblotting analysis further substantiated MIEN1's involvement in actin cytoskeleton dynamics. Results: Our findings indicate a significant reduction in the migration potential of HT29 cells in the absence of MIEN1 protein. Additionally, we demonstrated the disruption of cytoskeletal rearrangement, specifically affecting F-actin reorganization, upon MIEN1 deletion using phalloidin staining. Confocal staining of various proteins involved in actin cytoskeleton rearrangement, such as FAK and cofilin, further strengthened the evidence of MIEN1 in actin reorganization. Immunoblotting analysis of a diverse set of proteins further confirmed the involvement of MIEN1 in the dynamics of actin cytoskeleton. Conclusion: MIEN1, an influential metastatic protein overexpressed in cancerous cells, plays a crucial role in various signaling pathways governing CRC migration. Deletion of MIEN1 perturbs biological processes, particularly actin cytoskeleton rearrangement crucial for metastasis. Thus, targeting MIEN1 emerges as a promising therapeutic strategy for CRC patients