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A Multi-Disciplinary Approach To Chronic Cough In Children, Shraddha S Mukerji, Naga Jaya Smitha Yenduri, Eric Chiou, Siby P Moonnumakal, Joshua R Bedwell

Faculty, Staff and Students Publications

OBJECTIVES: (1) To highlight the important causes of chronic and recurrent cough in children. (2) To discuss multidisciplinary approach to management of chronic/recurrent pediatric cough.

METHODS: Review of scholarly articles, guidelines, expert panels via PubMed and Google Scholar.

CONCLUSION: Chronic cough (CC) in children is mainly attributed to persistent bacterial bronchitis, asthma, nonspecific cough, and gastroesophageal reflux disease (GERD) symptoms. A multi-disciplinary approach is cost-effective and aids with earlier diagnosis and appropriate treatment. Congenital or acquired narrowing of the subglottis is the leading ENT cause for recurrent croup (RC) in children. Laryngeal cleft-type 1 is commonly seen in children with …

Exposure To Per- And Polyfluoroalkyl Substances And Markers Of Liver Injury: A Systematic Review And Meta-Analysis, Elizabeth Costello, Sarah Rock, Nikos Stratakis, Sandrah P Eckel, Douglas I Walker, Damaskini Valvi, Dora Cserbik, Todd Jenkins, Stavra A Xanthakos, Rohit Kohli, Stephanie Sisley, Vasilis Vasiliou, Michele A La Merrill, Hugo Rosen, David V Conti, Rob Mcconnell, Leda Chatzi

Faculty, Staff and Students Publications

BACKGROUND: Experimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver.

OBJECTIVE: The objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies.

METHODS: PubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For …

Vestibular Rehabilitation For Peripheral Vestibular Hypofunction: An Updated Clinical Practice Guideline From The Academy Of Neurologic Physical Therapy Of The American Physical Therapy Association, Courtney D Hall, Susan J Herdman, Susan L Whitney, Eric R Anson, Wendy J Carender, Carrie W Hoppes, Stephen P Cass, Jennifer B Christy, Helen S Cohen, Terry D Fife, Joseph M Furman, Neil T Shepard, Richard A Clendaniel, J Donald Dishman, Joel A Goebel, Dara Meldrum, Cynthia Ryan, Richard L Wallace, Nakia J Woodward

Faculty, Staff and Students Publications

BACKGROUND: Uncompensated vestibular hypofunction can result in symptoms of dizziness, imbalance, and/or oscillopsia, gaze and gait instability, and impaired navigation and spatial orientation; thus, may negatively impact an individual's quality of life, ability to perform activities of daily living, drive, and work. It is estimated that one-third of adults in the United States have vestibular dysfunction and the incidence increases with age. There is strong evidence supporting vestibular physical therapy for reducing symptoms, improving gaze and postural stability, and improving function in individuals with vestibular hypofunction. The purpose of this revised clinical practice guideline is to improve quality of care …

Maternal Low Protein Diet And Fetal Programming Of Lean Type 2 Diabetes, Vidyadharan Alukkal Vipin, Chellakkan Selvanesan Blesson, Chandra Yallampalli

Faculty, Staff and Students Publications

Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood. Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy, and impaired nutrition has been an immense issue across the globe. In recent years, type 2 diabetes (T2D) has reached epidemic proportion and is a severe public health problem in many countries. Although plenty of research has already been conducted to tackle T2D which is associated with obesity, little is known regarding the etiology and pathophysiology of lean T2D, a variant of T2D. Recent studies have focused on …

Prenatal Low-Protein Diet Affects Mitochondrial Structure And Function In The Skeletal Muscle Of Adult Female Offspring, Vipin A Vidyadharan, Ancizar Betancourt, Craig Smith, Chandrasekhar Yallampalli, Chellakkan S Blesson

Faculty, Staff and Students Publications

Gestational low-protein (LP) diet leads to glucose intolerance and insulin resistance in adult offspring. We had earlier demonstrated that LP programming affects glucose disposal in females. Mitochondrial health is crucial for normal glucose metabolism in skeletal muscle. In this study, we sought to analyze mitochondrial structure, function, and associated genes in skeletal muscles to explore the molecular mechanism of insulin resistance LP-programmed female offspring. On day four of pregnancy, rats were assigned to a control diet containing 20% protein or an isocaloric 6% protein-containing diet. Standard laboratory diet was given to the dams after delivery until the end of weaning …

Defining The Mammalian Coactivation Of Hepatic 12-H Clock And Lipid Metabolism, Huan Meng, Naomi M Gonzales, Sung Yun Jung, Yue Lu, Nagireddy Putluri, Bokai Zhu, Clifford C Dacso, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

The 12-h clock coordinates lipid homeostasis, energy metabolism, and stress rhythms via the transcriptional regulator XBP1. However, the biochemical and physiological bases for integrated control of the 12-h clock and diverse metabolic pathways remain unclear. Here, we show that steroid receptor coactivator SRC-3 coactivates XBP1 transcription and regulates hepatic 12-h cistrome and gene rhythmicity. Mice lacking SRC-3 show abnormal 12-h rhythms in hepatic transcription, metabolic functions, systemic energetics, and rate-limiting lipid metabolic processes, including triglyceride, phospholipid, and cardiolipin pathways. Notably, 12-h clock coactivation is not only preserved, with its cistromic activation priming ahead of the zeitgeber cue of light, but …

Identification Of The Global Mir-130a Targetome Reveals A Role For Tbl1xr1 In Hematopoietic Stem Cell Self-Renewal And T(8; 21) Aml, Gabriela Krivdova, Veronique Voisin, Erwin M Schoof, Sajid A Marhon, Alex Murison, Jessica L Mcleod, Martino M Gabra, Andy G X Zeng, Stefan Aigner, Brian A Yee, Alexander A Shishkin, Eric L Van Nostrand, Karin G Hermans, Aaron C Trotman-Grant, Nathan Mbong, James A Kennedy, Olga I Gan, Elvin Wagenblast, Daniel D De Carvalho, Leonardo Salmena, Mark D Minden, Gary D Bader, Gene W Yeo, John E Dick, Eric R Lechman

Faculty, Staff and Students Publications

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed …

Glynac (Glycine And N-Acetylcysteine) Supplementation In Mice Increases Length Of Life By Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities In Mitophagy And Nutrient Sensing, And Genomic Damage, Premranjan Kumar, Ob W Osahon, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis …

Prognostic And Predictive Biomarkers In Patients With Coronavirus Disease 2019 Treated With Tocilizumab In A Randomized Controlled Trial, Jennifer Tom, Min Bao, Larry Tsai, Aditi Qamra, David Summers, Montserrat Carrasco-Triguero, Jacqueline Mcbride, Carrie M Rosenberger, Celia J F Lin, William Stubbings, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H Van Der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Farrah Kheradmand, Ivan O Rosas, Fang Cai

Faculty, Staff and Students Publications

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.

DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

SETTING: Hospitals in North America and Europe.

PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.

INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.

MEASUREMENTS AND MAIN …

Isoform-Specific Functions Of Pparγ In Gene Regulation And Metabolism, Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar

Faculty, Staff and Students Publications

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, …

Symptom Clusters, Physical Activity, And Quality Of Life: A Latent Class Analysis Of Children During Maintenance Therapy For Leukemia, Mary C Hooke, Michelle A Mathiason, Audrey Blommer, Jessica Hutter, Pauline Mitby, Olga Taylor, Michael E Scheurer, Alicia S Kunin-Batson, Wei Pan, Marilyn J Hockenberry

Faculty, Staff and Students Publications

BACKGROUND: Children undergoing treatment for acute lymphocytic leukemia (ALL) report co-occurring symptoms of fatigue, sleep disturbances, and depression as a symptom cluster. Physical activity (PA) may influence symptom severity and quality of life (QOL).

OBJECTIVES: This study examined changes in symptoms and QOL during ALL maintenance in children categorized by symptom cluster and explored the influence of PA and symptoms on QOL.

METHODS: Self-report of fatigue, sleep disturbance, and depression; QOL; and PA were measured at the beginning and end of maintenance in 42 children aged 3 to 18 years with ALL. Children were categorized into symptom cluster groups based …

Randomised Trial: Peppermint Oil (Menthol) Pharmacokinetics In Children And Effects On Gut Motility In Children With Functional Abdominal Pain, Robert J Shulman, Bruno P Chumpitazi, Susan M Abdel-Rahman, Uttam Garg, Salma Musaad, Gregory L Kearns

Faculty, Staff and Students Publications

AIMS: Little is known regarding the pharmacokinetics and pharmacodynamics of menthol, the active ingredient in peppermint oil (PMO). Our aim was to investigate the pharmacokinetics of menthol at 3 dose levels in children and determine their effects on gut motility and transit.

METHODS: Thirty children ages 7-12 years with functional abdominal pain underwent wireless motility capsule (WMC) testing. Approximately 1 week later they were randomized to 180, 360 or 540 mg of enteric coated PMO (10 participants per dose). Menthol pharmacokinetics were determined via blood sampling over 24 hours. They then took their respective dose of PMO (180 mg once, …

Effect Of Domperidone Therapy On Gastroparesis Symptoms: Results Of A Dynamic Cohort Study By Niddk Gastroparesis Consortium, Irene Sarosiek, Mark Van Natta, Henry P Parkman, Thomas Abell, Kenneth L Koch, Braden Kuo, Robert J Shulman, Gianrico Farrugia, Madhusudan Grover, Frank A Hamilton, Pankaj J Pasricha, Katherine P Yates, Laura Miriel, Laura Wilson, Goro Yamada, James Tonascia, Richard W Mccallum

Faculty, Staff and Students Publications

BACKGROUND & AIMS: The use of domperidone (DOM) for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) Registries (GpR).

METHODS: The GpCRC cohort consisted of patients with GP (75%) and with GP-like symptoms but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and GpR2. Patients who had previously taken or who were on DOM therapy at enrollment were excluded from this analysis. …

Constipation In Patients With Symptoms Of Gastroparesis: Analysis Of Symptoms And Gastrointestinal Transit, Henry P Parkman, Emily Sharkey, Richard W Mccallum, William L Hasler, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Braden Kuo, Robert J Shulman, Madhusudan Grover, Gianrico Farrugia, Ron Schey, James Tonascia, Frank Hamilton, Pankaj J Pasricha, Nih/Niddk Gastroparesis Consortium

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Constipation can be an important symptom in some patients with gastroparesis. The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; and 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and wireless motility capsule (WMC).

METHODS: Patients with symptoms of gastroparesis underwent gastric emptying scintigraphy (GES), wireless motility capsule (WMC) assessing gastric emptying, small bowel transit, and colonic transit, and questionnaires assessing symptoms using a modified Patient Assessment of Upper …

The Impact Of Response To Iron Therapy On Maternal And Neonatal Outcomes Among Pregnant Women With Anemia, Sarah E Detlefs, Michael D Jochum, Bahram Salmanian, Jennifer R Mckinney, Kjersti M Aagaard

Faculty, Staff and Students Publications

BACKGROUND: Anemia during pregnancy is associated with increased risks of preterm birth, preeclampsia, cesarean delivery, and maternal morbidity. The most prevalent modifiable cause of pregnancy-associated anemia is iron deficiency. However, it is still unclear whether iron therapy can reduce the risks of adverse outcomes in women with anemia.

OBJECTIVE: This study aimed to determine whether response to iron therapy among women with anemia is associated with a change in odds of adverse maternal and neonatal outcomes.

STUDY DESIGN: This was a population-based cohort study (2011-2019) using an institutional database composed of obstetrical patients from 2 delivery hospitals. Patients with adequate …

'Analogy-Based Comprehensive Diabetes Education' (Abcde) Improves Glycemic Control Of Diabetic Patients In An Underserved Population: Results Of A Retrospective Chart Analysis, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Diabetes is the leading global cause for blindness, kidney failure and amputations. Preventing these complications requires optimal glycemic control, and it is imperative that diabetic patients understand the fundamental concepts of diabetes care. Although patients attend formal diabetes education classes, many do not comprehend basic concepts of diabetes, and are often noncompliant with diet, exercise and medications. A novel approach termed 'analogy-based comprehensive diabetes education' (ABCDE) was developed to educate HIV-patients with diabetes about basic concepts of diabetes care. The object of this manuscript is to report the results of a retrospective chart review on the impact of ABCDE on …

The Influence Of Preoperative Dialysis On Survival After Continuous-Flow Left Ventricular Assist Device Implantation, Harveen K Lamba, Fadi I Musfee, Subhasis Chatterjee, Ajith P Nair, Andrew B Civitello, Leo Simpson, O H Frazier, George V Letsou

Faculty, Staff and Students Publications

OBJECTIVES: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation.

METHODS: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed.

RESULTS: Of 621 patients who underwent CF-LVAD implantation during the …

Novel Role Of Ghrelin Receptor In Gut Dysbiosis And Experimental Colitis In Aging, Ji Yeon Noh, Chia-Shan Wu, Jennifer A A Deluca, Sridevi Devaraj, Arul Jayaraman, Robert C Alaniz, Xiao-Di Tan, Clinton D Allred, Yuxiang Sun

Faculty, Staff and Students Publications

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout …

Repair-Assisted Damage Detection Reveals Biological Disparities In Prostate Cancer Between African Americans And European Americans, Kimiko L Krieger, Jie H Gohlke, Kevin J Lee, Danthasinghe Waduge Badrajee Piyarathna, Patricia D Castro, Jeffrey A Jones, Michael M Ittmann, Natalie R Gassman, Arun Sreekumar

Faculty, Staff and Students Publications

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than …

Myocardial Rev-Erb-Mediated Diurnal Metabolic Rhythm And Obesity Paradox, Shiyang Song, Chih-Liang Tien, Hao Cui, Paul Basil, Ningxia Zhu, Yingyun Gong, Wenbo Li, Hui Li, Qiying Fan, Jong Min Choi, Weijia Luo, Yanfeng Xue, Rui Cao, Wenjun Zhou, Andrea R Ortiz, Brittany Stork, Vatsala Mundra, Nagireddy Putluri, Brian York, Maoping Chu, Jiang Chang, Sung Yun Jung, Liang Xie, Jiangping Song, Lilei Zhang, Zheng Sun

Faculty, Staff and Students Publications

BACKGROUND: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear.

METHODS: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) …

Head And Neck Cancer Survivorship Consensus Statement From The American Head And Neck Society, Neerav Goyal, Andrew Day, Joel Epstein, Joseph Goodman, Evan Graboyes, Scharukh Jalisi, Ana P Kiess, Jamie A Ku, Matthew C Miller, Aru Panwar, Vijay A Patel, Assuntina Sacco, Vlad Sandulache, Amy M Williams, Daniel Deschler, D Gregory Farwell, Cherie-Ann Nathan, Carole Fakhry, Nishant Agrawal

Faculty, Staff and Students Publications

OBJECTIVES: To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship.

METHODS: Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence.

RESULTS: Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho-oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and …

Extensive Identification Of Genes Involved In Congenital And Structural Heart Disorders And Cardiomyopathy, Nadine Spielmann, Gregor Miller, Tudor I Oprea, Chih-Wei Hsu, Gisela Fobo, Goar Frishman, Corinna Montrone, Hamed Haseli Mashhadi, Jeremy Mason, Violeta Munoz Fuentes, Stefanie Leuchtenberger, Andreas Ruepp, Matias Wagner, Dominik S Westphal, Cordula Wolf, Agnes Görlach, Adrián Sanz-Moreno, Yi-Li Cho, Raffaele Teperino, Stefan Brandmaier, Sapna Sharma, Isabella Rikarda Galter, Manuela A Östereicher, Lilly Zapf, Philipp Mayer-Kuckuk, Jan Rozman, Lydia Teboul, Rosie K A Bunton-Stasyshyn, Heather Cater, Michelle Stewart, Skevoulla Christou, Henrik Westerberg, Amelia M Willett, Janine M Wotton, Willson B Roper, Audrey E Christiansen, Christopher S Ward, Jason D Heaney, Corey L Reynolds, Jan Prochazka, Lynette Bower, David Clary, Mohammed Selloum, Ghina Bou About, Olivia Wendling, Hugues Jacobs, Sophie Leblanc, Hamid Meziane, Tania Sorg, Enrique Audain, Arthur Gilly, Nigel W Rayner, Impc Consortium, Genomics England Research Consortium;, Marc-Phillip Hitz, Eleftheria Zeggini, Eckhard Wolf, Radislav Sedlacek, Steven A Murray, Karen L Svenson, Robert E Braun, Jaqueline K White, Lois Kelsey, Xiang Gao, Toshihiko Shiroishi, Ying Xu, Je Kyung Seong, Fabio Mammano, Glauco P Tocchini-Valentini, Arthur L Beaudet, Terrence F Meehan, Helen Parkinson, Damian Smedley, Ann-Marie Mallon, Sara E Wells, Harald Grallert, Wolfgang Wurst, Susan Marschall, Helmut Fuchs, Steve D M Brown, Ann M Flenniken, Lauryl M J Nutter, Colin Mckerlie, Yann Herault, K C Kent Lloyd, Mary E Dickinson, Valerie Gailus-Durner, Martin Hrabe De Angelis

Faculty, Staff and Students Publications

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, …

Race/Ethnicity And Birthplace As Risk Factors For Gastric Intestinal Metaplasia In A Multiethnic United States Population, Mimi C Tan, Taher Jamali, Theresa H Nguyen, Amy Galvan, Robert J Sealock, Anam Khan, Neda Zarrin-Khameh, Ashley Holloman, Ourania Kampagianni, David Henriquez Ticas, Yan Liu, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

INTRODUCTION: Several US subgroups have increased risk of gastric cancer and gastric intestinal metaplasia (GIM) and may benefit from targeted screening. We evaluated demographic and clinical risk factors for GIM and examined the interaction between race/ethnicity and birthplace on GIM risk.

METHODS: We identified patients who had undergone esophagogastroduodenoscopy with gastric biopsy from 3/2006-11/2016 using the pathology database at a safety net hospital in Houston, Texas. Cases had GIM on ≥1 gastric biopsy histopathology, whereas controls lacked GIM on any biopsy. We estimated odds ratios and 95% confidence intervals (CI) for associations with GIM risk using logistic regression and developed …

Multidisciplinary Care For Refractory Pediatric Functional Abdominal Pain Decreases Emergency And Inpatient Utilization, Andrew S Chu, Laura Torres, Grace Kao, Caroyl Gilbert, Evelyn Caro Monico, Bruno P Chumpitazi

Faculty, Staff and Students Publications

Children with refractory functional abdominal pain (FAP) experience functional disability and may utilize emergency department (ED) and/or inpatient services. Whether multidisciplinary programs which help care for children with refractory FAP affect acute healthcare utilization is unknown. A retrospective chart review of children initially evaluated by the outpatient Multidisciplinary Abdominal Pain Program (MAPP) from October 2016 to May 2019 was completed. Patient characteristics and number of ED visits and hospitalizations for abdominal pain in the year prior to versus year after MAPP evaluation were captured. Thirty-eight children (ages 9-17 years [median 13 years]) were included. The median number of ED visits/patient/year …

Fecal Microbiota Transplantation Commonly Failed In Children With Co-Morbidities, Richard Kellermayer, Qinglong Wu, Dorottya Nagy-Szakal, Karen Queliza, Faith D Ihekweazu, Claire E Bocchini, Abria R Magee, Numan Oezguen, Jennifer K Spinler, Emily B Hollister, Robert J Shulman, James Versalovic, Ruth Ann Luna, Tor C Savidge

Faculty, Staff and Students Publications

OBJECTIVES: Fecal microbiota transplantation (FMT) is arguably the most effective treatment for recurrent Clostridioides difficile infection (rCDI). Clinical reports on pediatric FMT have not systematically evaluated microbiome restoration in patients with co-morbidities. Here, we determined whether FMT recipient age and underlying co-morbidity influenced clinical outcomes and microbiome restoration when treated from shared fecal donor sources.

METHODS: Eighteen rCDI patients participating in a single-center, open-label prospective cohort study received fecal preparation from a self-designated (single case) or two universal donors. Twelve age-matched healthy children and four pediatric ulcerative colitis (UC) cases from an independent serial FMT trial, but with a shared …

Maternal Lactobacillus Reuteri Supplementation Shifts The Intestinal Microbiome In Mice And Provides Protection From Experimental Colitis In Female Offspring, Mahesh Krishna, Melinda Engevik, Karen Queliza, Savini Britto, Rajesh Shah, Wenly Ruan, Hongtao Wang, James Versalovic, Richard Kellermayer

Faculty, Staff and Students Publications

The purpose of our experiment was to explore how stochastic (inter-individual variation) gut microbiome composition may link to inflammatory bowel disease (IBD) susceptibility and guide the development of a perinatal preventative probiotic. Dextran sodium sulfate (DSS) was introduced to C57BL/BJ mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach toward stochastic DSS susceptibility.

An Estrogen-Sensitive Hypothalamus-Midbrain Neural Circuit Controls Thermogenesis And Physical Activity, Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R Arenkiel, Yanlin He, Pingwen Xu, Yong Xu

Faculty, Staff and Students Publications

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed …

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

Glynac (Glycine And N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation And Lowers Insulin Resistance In Patients With Type 2 Diabetes: Results Of A Pilot Study, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA …

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …