Browsing by Author "Lal, Kevin"
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Item Biological Characteristics of Lens Epithelial Cells from Grx1 and Grx2 Double Knockout Mice(2022) Zhang, Jinmin; Yu, Yu; Lal, Kevin; Dang, Terry; Ezugwu, Chimdindu; Tran, Myhoa; Wu, HongliPurpose: Glutaredoxins are glutathione (GSH) dependent enzymes that play an important role in repairing oxidized proteins, preventing subsequent protein misfolding and disrupting protein aggregation. The Grx system has two major isozymes: glutaredoxin 1 (Grx1) and the recently discovered glutaredoxin 2 (Grx2). To achieve a comprehensive understanding of the Grx system in the lens, our lab recently created a Grx1 and Grx2 double knockout (DKO) mouse model to observe how the double deletion of the enzymes may affect the lens epithelial cell (LEC) survival and lens transparency. Methods: Primary LECs were cultured from wild-type (WT) and DKO mice. Cell proliferation was tested via various assay kits, and cell cycle distribution was evaluated using flow cytometry analysis. Cell apoptotic markers including Bcl-2, Bax, and caspase 3 were detected using Western Blot. The mitochondrial function was evaluated via ATP concentration. Cytoskeletal arrangement and its intercellular connection were also examined by using fluorescent microscopy. Results: Compared to WT cells, DKO cells displayed a much slower growth. The number of DKO cells arrested in the M phase was twofold higher than that of WT cells. The population of DKO cells arrested in the S phase was 50% less than that of WT cells. For the apoptotic pathway, we found DKO cells have higher levels of Bax and cytochrome c with lower ATP production. Furthermore, we also found that DKO cells had higher levels of vimentin expression, which may lead to cytoskeleton reorganization and polarity. Conclusions: In conclusion, our data suggest that Grx function loss may inhibit cell proliferation, disrupt the normal cell cycle, trigger apoptosis pathway, and damage mitochondrial functions.Item A Case of Pediatric Tracheal Stenosis Secondary to Chronic Retching in the Setting of Bulimia Nervosa(2024-03-21) Patel, Arpan; Joshi, Eeshan; Srikalyani, Sathvik; Lal, Kevin; Saadeh, CharlesBackground: Tracheal stenosis is an important life threatening pathology in the pediatric population. The prompt diagnosis and management of tracheal stenosis is crucial to prevent complications of airway obstruction. Common etiologies include congenital anomalies, traumatic injury, complications of infection, and autoimmune disorders. Diagnosis is made with a combination of cross sectional imaging and rigid bronchoscopy. Endoscopic assessment and intervention will generally relieve acquired tracheal stenosis, with more severe cases requiring open surgical approaches. Historically, pediatric tracheal stenosis has had a poor prognosis; however, notable advances in endoscopic and open surgical treatments have led to a decline in morbidity and mortality. Case Information: A 14 year old female presented to the Emergency Department at Cook Children’s Medical Center with biphasic stridor and evidence of airway obstruction. The patient had never been tracheally intubated, and had no other significant medical history except for one year of frequent retching in the setting of bulimia nervosa. Symptoms were gradual in onset over the course of several weeks, with an initial working diagnosis of asthma with no improvement with inhaled steroids. A CT scan was obtained that revealed severe tracheal stenosis involving the cervical trachea. Initial lab work revealed an elevated WBC of 16.7, Potassium of 2.8mmol/L, Normal c-reactive protein, erythrocyte sedimentation rate, and procalcitonin. Her initial assessment was concerning for impending airway obstruction and she was taken to the operating room for emergent rigid bronchoscopy. She was found to have an irregular circumferential scar extending for 1.5cm, starting 2cm distal to the glottis involving the second through fourth tracheal rings. The initial stenosis was grade three with pinpoint 2-3mm patency. The scar was biopsied, and the stenosis easily dilated to normal caliber. Circumferential submucosal Kenalog was applied and the patient ultimately did very well clinically and was discharged on postoperative day 1 in stable condition. Her workup included anti-neutrophil cytoplastic antibodies, myeloperoxidase antibodies, serine proteinase 3 antibodies which were all normal. Her pathology revealed chronic tracheitis without evidence of bacterial tracheitis or vasculitis. Intraoperative cultures were unremarkable. She was taken back to the operating room six weeks later with findings of a normal lumen trachea with no evidence of restenosis or granulation. Of note, she had refrained from further retching since her initial presentation. At the time of this report, the patient was doing well with no concern for recurrent stenosis and compliant with avoidance of retching. Conclusions: This case emphasizes the diverse etiologies of tracheal stenosis and, specifically, the potential development of acquired tracheal stenosis related to self-induced retching in patients with eating disorders. Furthermore, this case underscores the need to consider the systemic effects of mental health disorders in pediatric patients, and helps add to our fund of knowledge regarding aerodigestive complications of bulimia nervosa.Item Evaluating the Role of Arterial Stiffness on Amplitude of Cerebral Blood Flow Oscillations(2024-03-21) Lal, Kevin; Davis, Austin; Anderson, Garen; Bhuiyan, Nasrul; Rickards, CarolineBackground: Changing the pattern of cerebral blood flow by forcing oscillations in arterial pressure and blood flow at 0.1 Hz (10-second cycle) can limit reductions in cerebral tissue oxygenation during a condition of reduced cerebral perfusion. This method of inducing 0.1 Hz hemodynamic oscillations is called Pulsatile Perfusion Therapy (PPT). Sympathetic activation can increase the amplitude of 0.1 Hz hemodynamic oscillations, and acutely increase arterial stiffness. The impact of increasing carotid arterial stiffness on the magnitude of 0.1 Hz cerebral blood flow oscillations has not been examined. We hypothesize that the with application of 0.1 Hz PPT during a condition of cerebral hypoperfusion, 1) the subsequent increase in sympathetic activity will acutely increase carotid arterial stiffness, and; 2) greater carotid artery stiffness will result in a higher amplitude of oscillations in cerebral blood flow. Methods: 10 healthy participants (8 males, 2 females) were exposed to 10-min of oscillatory lower body negative pressure (OLBNP) at 0.1 Hz, which induced both a state of cerebral hypoperfusion, and 0.1 Hz hemodynamic oscillations. Middle cerebral artery velocity (MCAv), internal carotid artery (ICA) diameter, and beat-to-beat arterial pressure were measured. ICA stiffness was determined using the beta-stiffness index, incorporating ICA diameter and arterial pressure measurements. The amplitude of 0.1 Hz MCAv oscillations was assessed via fast Fourier transformation. Results: While OLBNP increased MCAv 0.1 Hz oscillations (36.1 ± 24.2 cm/s2 vs. 812.4 ± 668.0 cm/s2; P=0.01), ICA beta stiffness was not different between the baseline and OLBNP conditions (12.3 ± 4.9 au vs. 13.2 ± 5.7 au; P=0.56). There was no relationship between ICA stiffness and the amplitude of MCAv oscillations during OLBNP (r=0.17, P=0.68). Conclusions: Contrary to our hypothesis, ICA stiffness did not increase during 0.1 Hz OLBNP, and there was no correlation between ICA stiffness and the magnitude of MCAv oscillations induced at 0.1 Hz. These data suggest that ICA stiffness may not determine the magnitude of induced oscillations in cerebral blood flow. Future studies will examine these effects in older adults to determine the potential beneficial application of PPT for the treatment of low cerebral perfusion conditions (e.g., Alzheimer’s disease, stroke).Item Patient Perspectives Unveiled: An Analysis of Common Questions and Concerns to Empower Informed Healthcare Dialogues with Elderly Patients Taking Multiple Medications(2024-03-21) Schneider, Clara; Lal, Kevin; Espinoza, Anna; Xiao, Yan; Hendrix, Noah; Young, Richard; Fulda, KimberlyPurpose: Health literacy is often a barrier to patient understanding and effective communication with healthcare providers. Patients are often unaware of what questions to ask during their visits and leave their provider offices without fully understanding their conditions or medication regimens. Past studies have shown that facilitating patient dialogue through structured questions during the encounter results in fewer patient callbacks and improved comprehension. The goal of this study was to identify the most common questions and concerns that patients 50 years and older who are on five or more medications would like to discuss with their physicians about their medications. Such data could help physicians anticipate and educate patients with information most valuable to them during office visits. Methods: We designed a 20-question survey to better understand what patients desired from their primary care visit including questions to ask, concerns to tell, and positive behaviors to report to their provider. We focused on the ask and tell sections which involved presenting questions or concerns that were pertinent to the patient's conditions or medications. Participants included patients at family medicine clinics from a county hospital system (240) and a private practice (211) in Fort Worth who were 50 years of age or older and taking five or more medications. Surveys were administered at a clinical visit by the medical assistant before the physician/patient encounter. Descriptive statistics are provided. Results: Out of 451 surveys completed, the questions that patients were most interested in talking with their physician included: 1) What should I eat, and what should I not eat for my condition? (20.4%) 2) Can I take fewer medicines than I am taking? (15.3%) 3)How do I learn more about my condition? (14.6%) The least common questions were 1) Why do I need several medications for my condition? (8.2%) 2) Other questions: (8.6%) 3) How can I stop my blood sugar, heart rate, or blood pressure from getting too low? (9.1%) The most common concerns about their medications were: 1) I stopped or skipped these medicines, due to: cost, side effects, or other reasons (11.1%) 2) I have new medicines from other doctors (offices, hospitals or emergency rooms) (8%) 3) I have concerns with my medicines (examples: cost, hard to read, not helping much) (5.7%) Conclusions: It is evident that patients are interested in learning about their conditions and making appropriate lifestyle changes. The most commonly raised concerns were related to medication access, polypharmacy, and efficacy. These data show some of the potential topics patients want to discuss with their providers. The most common topics from this study can be implemented into a question prompt lists (QPL [https://onlinelibrary.wiley.com/doi/abs/10.1111/ecc.12489?casa_token=kGVvFBSWANEAAAAA:NOhQ46f92KtdNp9XgslcAiwEoB6MI0N4K1vOA2P7FyFQ_BBgv0BycKPBy4sLKk_e9Cki971trjdfoL1k]) specific to medications and chronic disease management. Providers could give lists to patients to review while waiting for care. Having these topics beforehand would help the patients be prepared when presented with “what questions do you have?”; thus, revealing the patient's perspective and helping to increase their health literacy.Item Retina-Targeted Estrogen Prodrug: A New Concept for Retinal Protection(2022) Lal, Kevin; Yu, Yu; Zhang, Jinmin; Tran, Myhoa; Ezugwu, Chimdindu; Prokai-Tatrai, Katalin; Liu, Yang; Wu, HongliRetinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, we developed a bioprecursor prodrug, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor from light-induced damage, male C57BL/6J mice were injected with or without 200 µg/kg DHED (n=9) and 200 µg/kg E2 (n=9) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) and retinal detachment. Additionally, DHED significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. The photoreceptor protective effects upon DHED treatment are stronger than that of E2, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. Our liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based bioassay indicated that DHED delivers the biologically active estrogen to the neuronal cells including the retinal cells without affecting other tissues - unlike the systemic exposure that is seen with estrogen. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection.Item RETINA-TARGETED ESTROGEN PRODRUG: A NEW CONCEPT FOR RETINAL PROTECTION(2022-05) Lal, Kevin; Wu, Hongli; Prokai-Tatrai, Katalin; Liu, YangRetinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, a bioprecursor prodrug was developed, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor cells from light-induced damage, male C57BL/6J mice were injected with or without 100 μg/kg DHED (n=15), 200 μg/kg DHED (n=15), 400 μg/kg DHED (n=15) and 200 μg/kg E2 (n=15) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) in groups that received no treatment. However, DHED treatment significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. Additionally, photoreceptor loss was decreased as indicated by increased outer nucellar layer thickness and SD-OCT data. The photoreceptor protective effects upon DHED-derived E2 treatment are stronger than that of the direct E2 treatment, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection.