Browsing by Author "Kua, Kok Lim"
Now showing 1 - 10 of 10
Results Per Page
Sort Options
Item Decreased vascular reactivity associated with increased IL-8 in 6-month-old infants of mothers with pre-eclampsia(Springer Nature, 2024) Kua, Kok Lim; Rhoads, Eli; Slaven, James E.; Edwards, Shanique; Haas, David M.; Ren, Clement L.; Tiller, Christina; Bjerregaard, Jeffrey; Haneline, Laura S.; Tepper, Robert S.; Pediatrics, School of MedicineBackground: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy. Methods: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed. Results: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001). Conclusion: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers. Impact statement: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia.Item Efficacy of supplemental oxygen in reducing the need for laser or intravitreal bevacizumab in preterm infants with stage 2 retinopathy of prematurity(Springer Nature, 2024-05-24) Minturn, Robert; Hartigan, Kelly; Vegunta, Sravanthi; Boente, Charline; Golzarri-Arroyo, Lilian; Hynes, Elizabeth; Laughlin, Elleen; Haider, Kathryn; Kua, Kok Lim; Ophthalmology, School of MedicineBackground: Retinopathy of prematurity (ROP) is a disease that affects preterm infants born younger than 30 weeks of gestation. The pathophysiology of ROP involves an initial vaso-obliterative phase followed by vaso-proliferative phase that leads to disease progression. The use of supplemental oxygen during the vaso-proliferative phase of ROP has been associated with reduced disease progression, but how this impacts the need for ROP treatment is unclear. The goal of this study was to compare the rate of laser or intravitreal bevacizumab after implementation of a new supplemental oxygen therapy protocol in preterm infants with stage 2 ROP. Methods: This is a retrospective chart review of preterm infants diagnosed with stage 2 ROP at Riley Hospital for Children between 1/2017 and 12/2022. Patients diagnosed between 1/2017 and 6/2020 were classified as Cohort A, preprotocol implementation. Patients diagnosed from 8/2020 to 12/2022 were classified as Cohort B, postprotocol implementation. In Cohort A, oxygen saturation was kept at 91-95% through the entire hospitalization. In Cohort B, oxygen saturation was increased to 97-99% as soon as Stage 2 ROP was diagnosed. Statistical analyses were performed using chi-square and Student's T test, followed by multivariate analyses to determine the impact of the oxygen protocol on the need for ROP treatment. Results: A total of 211 patients were diagnosed with stage 2 ROP between 1/2017 and 12/2022. Of those patients, 122 were before protocol implementation therapy (Cohort A), and 89 were after implementation of supplemental oxygen protocol (Cohort B). Gestational age was slightly higher in Cohort B (Cohort A 25.3 ± 1.9, Cohort B 25.8 ± 1.84, p = 0.04). There was no difference in birth weight, NEC, BPD, or survival. Cohort B had lesser need for invasive mechanical ventilation and higher days on CPAP during hospitalization. Notably, Cohort A had 67 (55%) patients treated with laser photocoagulation or intravitreal bevacizumab versus 20 (22%) patients in Cohort B (OR 0.19, 0.08-0.40). Conclusion: The need for laser photocoagulation or intravitreal bevacizumab was significantly decreased in high-risk patients treated with the supplemental oxygen protocol. This result supports the idea that targeted supplemental oxygen therapy to keep saturations between 97 and 99% can reduce disease progression in infants with stage 2 ROP and potentially decrease the burden of additional procedures.Item Enterocolitis with fulminate sepsis in a newborn with tricho-hepato-enteric syndrome: A case report(OA Text, 2021-03) Lorant, Diane E.; Kua, Kok Lim; Pediatrics, School of MedicineTricho-hepato-enteric syndrome is a rare autosomal recessive enteropathy that first presents as intractable diarrhea in neonates. Diarrhea persists throughout life and patients are dependent on parenteral nutrition for growth. Additional features include facial dysmorphism, trichorrhexis nodosa (woolly hair), intra-uterine growth restriction, hepatic disease, skin anomalies and a depressed immune system. Tricho-hepato-enteric syndrome is a life limiting disease with variability in its manifestations and severity. Mutations in two different genes, TTC37 or SKIV2L, cause the disorder. In this case report we present a neonate with a novel mutation in TTC37 that resulted in a severe phenotype associated with fulminate sepsis. The infant presented at one week of age with sudden onset of diarrhea and dehydration. Tricho-hepato-enteric syndrome was diagnosed by whole exome sequencing but was not initially considered because the infant lacked many of the diagnostic clinical features. Soon after presentation, the infant developed pneumoperitoneum and necrosis of entire bowel. The blood culture was positive for Clostridium perfringens. Autopsy showed bacteria in the parenchyma and vasculature of all major internal organs as well as within the bone marrow, connective tissue and skeletal muscle but there was minimal inflammatory response. The lack of migration of white blood cells to the sites of infection is likely due to the combined immunodeficiency reported in patients with tricho-hepato-enteric syndrome. This case expands our knowledge on the clinical features of tricho-hepato-enteric syndrome. Whole-exome sequencing was instrumental in making the diagnosis in an infant with an atypical presentation and should be considered early in neonates with congenital diarrhea.Item Glucose intolerance as a consequence of hematopoietic stem cell dysfunction in offspring of obese mice(Elsevier, 2024) Denizli, Merve; Ropa, James; Beasley, Lindsay; Ghosh, Joydeep; DeVanna, Kelli; Spice, Taylor; Haneline, Laura S.; Capitano, Maegan; Kua, Kok Lim; Pediatrics, School of MedicineObjective: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. Methods: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. Results: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. Conclusions: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.Item High Glucose Alters Fetal Rat Islet Transcriptome and Induces Progeny Islet Dysfunction(BioScientifica, 2019-02) Casasnovas, Jose; Jo, Yunhee; Rao, Xi; Xuei, Xiaoling; Brown, Mary E.; Kua, Kok Lim; Pediatrics, School of MedicineOffspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.Item Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring(Frontiers, 2022-09) Denizli, Merve; Capitano, Maegan L.; Kua, Kok Lim; Pediatrics, School of MedicineThe prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring’s health in numerous disease contexts, including offspring’s risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells.Item Neonatal Extremity Compartment Syndrome: A Rare Diagnosis Requiring Prompt Recognition(Thieme, 2020-10) Severyn, Nicholas T.; Kua, Kok Lim; Pediatrics, School of MedicineNeonatal extremity compartment syndrome is an extremely rare diagnosis. Risk factors that predispose infants to a hypercoagulable state or trauma have been implicated, but the exact mechanisms remain poorly understood. The hallmark of the condition is extremity swelling with sentinel skin changes. We report a case of upper extremity compartment syndrome from initial presentation until 3 months after discharge and discuss the importance of prompt diagnosis and timely surgical evaluation.Item Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion(Frontiers Media, 2021-05-24) Casasnovas, Jose; Damron, Christopher Luke; Jarrell, James; Orr, Kara S.; Bone, Robert N.; Archer-Hartmann, Stephanie; Azadi, Parastoo; Kua, Kok Lim; Pediatrics, School of MedicineOffspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.Item SAT-158 Offspring Exposed to Maternal High Fat Diet Exhibits Systemic Inflammation and Pancreatic Islet Dysfunction(Oxford University Press, 2019-04-15) Casasnovas, Jose; Pineros, Annie; Jarrell, James; Kua, Kok Lim; Pediatrics, School of MedicineOffspring born to overweight mothers are more likely to develop dysregulated immune response1, obesity1 and pancreatic islet dysfunction2. These offspring have increased inflammation at birth3 and at least until childhood4. We hypothesize that heightened inflammation in offspring of overweight mothers increases offspring risks of pancreatic islet dysfunction. We induced maternal overweight by providing 45% high fat diet (HFD) to female mice 2 - 4 weeks before pregnancy until weaning. When compared to controls, P21 weanlings of HFD mothers had impaired glucose tolerance in dose and gender dependent manner [GTT AUC: male 2-week HFD* 30 ± 6% higher; male 4-week HFD* 37± 3% higher: 9-11/group; female 2-week HFD 13 ± 5% higher; female 4-week HFD* 22 ± 3% higher: 3-9/group, *p<0.05 compared to controls]. Glucose intolerance persisted in 8-week-old male from 2-week HFD mothers (p<0.05, n=6-9/group), with decreased pancreatic islets glucose induced calcium response measured using Fura-2AM calcium imaging (F1/F0 Con:2.00 ± 0.06, HFD2W: 1.69±0.12*, HFD4w: 0.71±0.09*, n =3/group). Cytokines production in the serum, macrophage response and metabolic phenotypes of offspring were assessed on postnatal day 21 (P21) and at 8 weeks old. Compared to control pups, weanling of HFD mothers had elevated serum/plasma IL-1b level along with increased polarization of M1 macrophages and decreased M2 macrophages, as well as an increase of IL-1b secretion in LPS-stimulated macrophages. At 8 weeks of age, HFD male offspring had increased activation markers of splenic dendritic cells indicating a development of systemic inflammatory response early in life. Taken together, our findings suggest that mice offspring from HFD mothers have pancreatic dysfunction, and an inflammatory response. This work is funded by the Riley Children’s Foundation. 1. Kelishadi, R., Roufarshbaf, M., Soheili, S., Payghambarzadeh, F. & Masjedi, M. Association of Childhood Obesity and the Immune System: A Systematic Review of Reviews. Child. Obes. Print 13, 332-346 (2017). 2. Graus-Nunes, F. et al. Pregestational maternal obesity impairs endocrine pancreas in male F1 and F2 progeny. Nutrition 31, 380-387 (2015). 3. Dosch, N. C. et al. Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. J. Pediatr. 172, 20-28 (2016). 4. Leibowitz, K. L. et al. Maternal obesity associated with inflammation in their children. World J. Pediatr. WJP 8, 76-79 (2012).Item Sex discrepancy in the reduction of mucosal‐associated invariant T cells caused by obesity(Wiley, 2021-03-09) Liu, Jianyun; Nan, Hongmei; Brutkiewicz, Randy R.; Casasnovas, Jose; Kua, Kok Lim; Microbiology and Immunology, School of MedicineIntroduction: Gut microbiota has been reported to contribute to obesity and the pathology of obesity-related diseases but the underlying mechanisms are largely unknown. Mucosal-associated invariant T (MAIT) cells are a unique subpopulation of T cells characterized by the expression of a semi-invariant T cell receptor (TCR) α chain (Vα19 in mice; Vα7.2 in humans). The expansion and maturation of MAIT cells require the gut microbiota and antigen-presenting molecule MR1, suggesting that MAIT cells may play a unique role in bridging gut microbiota, obesity, and obesity-associated inflammation. Methods: The levels of human MAIT cells from obese patients, as well as mouse MAIT cells from obese mouse models, were determined by flow cytometry. By comparing to controls, we analyzed the change of MAIT cells in obese subjects. Results: We found obese patients had fewer circulating MAIT cells than healthy-weight donors and the difference was more distinct in male patients. Consistently, male mice (but not female mice) have shown reduced MAIT cells in the liver and adipose tissue after a 10-week Western diet compared to mice on a control diet. We also explored the possibility of utilizing high-throughput technology (i.e., quantitative polymerase chain reaction [qPCR]), other than flow cytometry, to determine the expression levels of the invariant TCR of human MAIT cells. But a minimal correlation (R2 = 0.23, p = .11) was observed between qPCR and flow cytometry data. Conclusion: Our study suggests that there is a sex discrepancy in the impact of obesity on MAIT cells: MAIT cells in male (but not female) humans and male mice are reduced by obesity.