Bradley Yoder - Academia.edu (original) (raw)

Papers by Bradley Yoder

Journal of Clinical Investigation, 2002

Polycystic kidney disease (PKD) represents a set of hereditary nephropathies characterized by pro... more Polycystic kidney disease (PKD) represents a set of hereditary nephropathies characterized by progressive cyst formation, massive renal enlargement, and often, progression to end-stage renal disease. Autosomal dominant PKD (ADPKD) occurs in 1 in 1,000 individuals and, in addition to renal cystic disease, is associated with cyst formation in other epithelial organs, most notably the liver, as well as connective tissue defects, such as intracranial aneurysms, aortic dissection, and cardiac valve defects (1). Mutations in either of two genes, PKD1 and PKD2, cause ADPKD phenotypes that are virtually indistinguishable (2). In comparison, autosomal recessive PKD (ARPKD) is much less frequent (1 in 20,000 live births). The clinical phenotype is dominated by renal collecting duct ectasia, biliary dysgenesis, and portal tract fibrosis (3). The principal disease locus, PKHD1, has been mapped to chromosome 6p21.1-p12 (4, 5), but the gene has yet to be identified. In the mouse, several distinct, recessively acting mutations cause PKD phenotypes that mimic human disease (6). Among these models, the congenital polycystic kidney (cpk) mutation is the most extensively characterized. The cpk locus on chromosome 12 is defined by a single recessive mutation that arose spontaneously in the C57BL/6J strain (7). The renal phenotype is fully expressed in homozygotes and is strikingly similar to human ARPKD (8, 9), whereas genetic background modulates the penetrance of the corresponding defect in the developing biliary tree (10, 11). Multiple cellular and extracellular matrix abnormalities have been described in cpk/cpk kidneys. These changes include: (a) enhanced expression of the protooncogenes, c-myc, c-fos, c-Ki-ras (12-14); (b) increased expression of the transcriptional repressor, Cux-1, a putative inhibitor of terminal differentiation (15); (c) enhanced growth factor expression (16); (d) apical mislocation of a functional EGF receptor (17); (e) increased expression of basement membrane constituents, laminin β1, and γ1, α1/α2 chains of collagen IV, collagen I, and fibronectin (18, 19); (f) overexpression of the basement membrane remodeling enzymes, matrix metalloproteinases (MMPs), and their specific tissue inhibitors, TIMPs (20); (g) abnormal expression of epithelial cell adhesion molecules (21, 22); and (h) alterations in steroid metabolism and lipid composition (23-25). These numerous abnormalities involving a wide range of developmentally regulated cellular processes suggest that cpk/cpk mutant kidneys are unable to complete the terminal phases of tubuloepithelial differentiation (26).

American Journal of …, 2002

Cilia are organelles that play diverse roles, from fluid movement to sensory reception. Polaris, ... more Cilia are organelles that play diverse roles, from fluid movement to sensory reception. Polaris, a protein associated with cystic kidney disease inTg737 rpk mice, functions in a ciliogenic pathway. Here, we explore the role of polaris in primary cilia on ...

Background: Cilia are found on nearly every cell type in the mammalian body, and have been histor... more Background: Cilia are found on nearly every cell type in the mammalian body, and have been historically classified as either motile or immotile. Motile cilia are important for fluid and cellular movement; however, the roles of non-motile or primary cilia in most tissues remain unknown. Several genetic syndromes, called the ciliopathies, are associated with defects in cilia structure or function and have a wide range of clinical presentations. Much of what we know about the formation and maintenance of cilia comes from model systems like C. elegans and Chalmydomonas. Studies of mammalian cilia in live tissues have been hampered by difficulty visualizing them. Results: To facilitate analyses of mammalian cilia function we generated an inducible Cilia GFP mouse by targeting mouse cDNA encoding a cilia-localized protein somatostatin receptor 3 fused to GFP (Sstr3::GFP) into the ROSA26 locus. In this system, Sstr3::GFP is expressed from the ubiquitous ROSA26 promoter after Cre mediated deletion of an upstream Neo cassette flanked by lox P sites. Fluorescent cilia labeling was observed in a variety of live tissues and after fixation. Both cell-type specific and temporally regulated cilia labeling were obtained using multiple Cre lines. The analysis of renal cilia in anesthetized live mice demonstrates that cilia commonly lay nearly parallel to the apical surface of the tubule. In contrast, in more deeply anesthetized mice the cilia display a synchronized, repetitive oscillation that ceases upon death, suggesting a relationship to heart beat, blood pressure or glomerular filtration. Conclusions: The ability to visualize cilia in live samples within the Cilia GFP mouse will greatly aid studies of ciliary function. This mouse will be useful for in vivo genetic and pharmacological screens to assess pathways regulating cilia motility, signaling, assembly, trafficking, resorption and length control and to study cilia regulated physiology in relation to ciliopathy phenotypes.

Archives of disease in childhood. Fetal and neonatal edition, Jan 10, 2015

To compare the rates of death or bronchopulmonary dysplasia (BPD) in infants who received nasal i... more To compare the rates of death or bronchopulmonary dysplasia (BPD) in infants who received nasal intermittent positive pressure ventilation (NIPPV) delivered by a conventional mechanical ventilator (CMV) or a bilevel device. A preplanned non-randomised comparison of infants randomised to the NIPPV arm of the NIPPV trial. Thirty-six tertiary neonatal units in three continents. Infants <1000 g and <30 weeks gestational age at birth. Infants received treatment with CMV NIPPV or bilevel NIPPV, as a primary mode of respiratory support or following first extubation. 241 received mainly bilevel NIPPV and 215 mainly CMV NIPPV. No difference was found in death or BPD at 36 weeks corrected age (adjusted OR 0.88 (95% CI 0.57 to 1.35)). More deaths occurred in infants receiving bilevel NIPPV (9.4%) than in CMV NIPPV (2.3%) (adjusted OR 5.01: 95% CI 1.74 to 14.4). There was a corresponding but not statistically significant decrease in BPD in the bilevel NIPPV group (30% vs 37%) (adjusted OR...

Pediatric research, Jan 21, 2015

Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or di... more Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t1/2). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. Thirty infants (n=10/arm) ≥36 weeks gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 hours of birth (1(st) dose/hypothermia condition) and at 7 days (2(nd) dose/normothermia condition). Adverse events were documented for 1 month. Serum samples were obtained to characterize Darbe pharmacokinetics. Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t1/2 was 24 and 32 hours, and the area under the curve (AUCinf) was...

Journal of pediatric surgery, 2015

Mortality rates with congenital diaphragmatic hernia (CDH) have remained at approximately 30% for... more Mortality rates with congenital diaphragmatic hernia (CDH) have remained at approximately 30% for the last 2 decades. Therapies targeting pulmonary hypertension (PHTN) have not been systematically studied in this population, but are increasingly used. We hypothesized that incremental changes in treatments for PHTN have improved mortality for CDH infants. Prospective data from 1998 to 2013 on all liveborn CDH patients treated at our institution were retrospectively analyzed. Based on management of PHTN, 4 eras were identified for comparison. Logistic and linear regression were used to compare characteristics. The primary outcome of death prior to discharge was analyzed by multivariable Cox regression modeling. The study included 192 infants who met inclusion criteria. Length of stay increased, whereas rates of primary repair decreased, suggesting a sicker cohort in the most recent eras. Analysis of mortality across 4 eras showed no difference. By post-hoc analysis, ECMO availability ...

American journal of perinatology, Jan 31, 2015

Background We previously reported on the overall incidence, management, and outcomes in infants w... more Background We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. Objective This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. Study Design The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. Results All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full...

American journal of obstetrics and gynecology, 2014

Neonatal diagnoses are often used as surrogate endpoints for longer-term outcomes. We sought to c... more Neonatal diagnoses are often used as surrogate endpoints for longer-term outcomes. We sought to characterize the correlation between neonatal diagnoses and early childhood neurodevelopment. We conducted secondary analysis of a multicenter randomized controlled trial of antenatal magnesium sulfate vs placebo administered to women at imminent risk for delivery <32.0 weeks to prevent death and cerebral palsy in their offspring. Singletons and twins delivering 23.0-33.9 weeks who survived to hospital discharge and had 2-year-old outcome data were included. Those surviving to age 2 years were assessed by trained physicians and the Bayley II Scales of Infant Development Mental Development and Psychomotor Development Indices. Neonatal diagnoses at the time of each baby's initial hospital discharge were examined singly and in combination to determine those most predictive of childhood neurodevelopmental impairment, defined as a childhood diagnosis of moderate/severe cerebral palsy an...

The Pediatric infectious disease journal, 2004

We report an increased occurrence of fluconazole-resistant Candida parapsilosis after a 4-year pe... more We report an increased occurrence of fluconazole-resistant Candida parapsilosis after a 4-year period of antifungal prophylaxis in a premature animal neonatal intensive care unit. Although prevention of nosocomial fungal infections in premature infants is desirable, implementation of fluconazole prophylaxis should be undertaken with caution. Where such programs are in place, evaluation of fungal isolates for drug resistance should be considered.

Journal of clinical microbiology, 1995

Latex particle agglutination (LPA) testing for antigen to group B streptococcus (GBS) has been us... more Latex particle agglutination (LPA) testing for antigen to group B streptococcus (GBS) has been useful in the diagnosis of GBS sepsis in newborns. However, recent reports have demonstrated that the sensitivity of LPA assays may be as low as 27 to 54%. The purposes of the present study were to directly compare the abilities of four urine antigen assays to detect GBS antigen with clinical urine samples from neonates with GBS bacteremia and to evaluate the effect of the urine concentration on the sensitivities and specificities of these assays. Urine samples were collected serially from neonates with blood cultures positive for GBS or on admission from healthy full-term infants. One milliliter of urine was removed, and the remainder was concentrated to a volume of 1 ml. Unconcentrated samples were serially diluted with normal saline and were assayed to determine the highest dilution which would produce a positive test result. The Wellcogen, Bactigen, and Directigen LPA tests and ICON im...

Pediatric Critical Care Medicine, 2005

To report two cases of severe early-onset neonatal sepsis due to Streptococcus pneumoniae, includ... more To report two cases of severe early-onset neonatal sepsis due to Streptococcus pneumoniae, including, to our knowledge, the first reported case of sepsis due to penicillin-resistant S. pneumoniae presenting as early-onset neonatal sepsis. Case reports. A level III military and civilian neonatal intensive care unit. Two infants (gestational ages of 38 and 35 wks), both of whom presented shortly after birth with severe septic shock presumed to be due to group B streptococcus. Both infants were treated with high-frequency oscillatory ventilation and inhaled nitric oxide, with one infant requiring venoarterial extracorporeal membrane oxygenation. Cultures of blood specimens from both infants yielded S. pneumoniae. For one infant, antibiotic sensitivity testing demonstrated resistance to penicillin, erythromycin, and trimethoprim/sulfamethoxazole. After treatment, both infants recovered well with normal results of examinations and neural imaging studies at the time of hospital discharge. Clinicians should consider S. pneumoniae as a possible cause of fulminant nonresponsive sepsis in neonates. In areas where antimicrobial-resistant S. pneumoniae is prevalent, when culture results are known, or with a clinical course unresponsive to ampicillin, septic infants may require the addition of a penicillinase-resistant antibiotic to their therapeutic regimen until results of antibiotic sensitivity testing are known. Early transfer to a center with extracorporeal membrane oxygenation should be considered for symptomatic neonates.

Critical Care Medicine, 1984

High-frequency ventilation (HFV) has been suggested as an alternative to conventional positive-pr... more High-frequency ventilation (HFV) has been suggested as an alternative to conventional positive-pressure ventilation (PPV) in the treatment of infants with hyaline membrane disease (HMD). Using a previously validated primate model of HMD, 15 baboon fetuses were delivered at 75% of gestation and randomly assigned to 1 of 3 ventilator treatment groups: PPV, HFV delivered by an oscillator (HFO), or HFV delivered by a flow interrupter (HFFI). All animals had clinical and radiographic evidence of HMD. At 96 h of life, all animals were sacrificed and clinical and pathologic findings were analyzed. During the first 10 h of the experiment, the HFO animals required higher mean proximal airway pressures than either the HFFI or PPV groups. However, both the HFFI and HFO animals had higher PaO2/PAO2 ratios than the PPV controls, suggesting earlier saccular recruitment. Thus, HFV is as effective as PPV in the treatment of HMD in baboons. Whether it will decrease the risk of bronchopulmonary dysplasia is not known.

American Journal of Obstetrics and Gynecology, 2014

Delayed umbilical cord clamping benefits extremely low gestational age neonates (ELGANs) but has ... more Delayed umbilical cord clamping benefits extremely low gestational age neonates (ELGANs) but has not gained wide acceptance. We hypothesized that milking the umbilical cord (MUC) would avoid resuscitation delay but improve hemodynamic stability and reduce rates for composite outcome of severe intraventricular hemorrhage, necrotizing enterocolitis, and/or death before discharge. We implemented a joint neonatal/maternal-fetal quality improvement process for MUC starting September 2011. The MUC protocol specified that infants who were born at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;30 weeks of gestation undergo MUC 3 times over a duration of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;30 seconds at delivery. Obstetric and neonatal data were collected until discharge. We compared the MUC group to retrospective ELGAN cohort delivered at our center between January 2010 and August 2011. Analysis was intention-to-treat. We identified 318 ELGANs: 158 eligible for MUC and 160 retrospective control neonates. No adverse events were reported with cord milking. There was no difference in neonatal resuscitation, Apgar scores, or admission temperature. Hemodynamic stability was improved in the MUC group with higher mean blood pressures through 24 hours of age, despite less vasopressor use (18% vs 32%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01). The initial hematocrit value was higher (50% vs 45%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01), and red cell transfusions were fewer (57% vs 79%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) in MUC vs control infants. Presence of the composite outcome was significantly less in MUC vs the historic control infants (22% v 39%; odds ratio, 1.81; 95% confidence interval, 1.06-3.10). There were also reductions in intraventricular hemorrhage, necrotizing enterocolitis, and death before hospital discharge. MUC improves early hemodynamic stability and is associated with lower rates of serious morbidity and death among ELGANs.

Critical Care Medicine, 1986

Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and re... more Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and respiratory failure while on conventional ventilation were treated with high-frequency oscillatory ventilation (HFOV). The mean birth weight was 1.2 kg (range 0.55 to 2) with gestational age of 28 wk (range 25 to 34). Ten patients died, six of whom had documented sepsis with shock and were therefore excluded from analysis. All patients showed initial improvement on HFOV. Surviving patients showed continued improvement in oxygenation and ventilation at increasingly lower fraction of inspired oxygen and proximal airway pressure with resolution of PIE, while nonsurvivors progressively developed chronic respiratory insufficiency with continued PIE from which recovery was not possible. Overall survival in nonseptic patients was 80% (16 of 20). We found HFOV to be effective in the treatment of PIE and hypothesize that interstitial airleak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures.

Most central neurons in the mammalian brain possess an appendage called a primary cilium that pro... more Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling. GPR54 | neuronal primary cilia | electrophysiology

Developmental Genetics, 1991

Micrococcal nuclease digestion of chromatin from growing cells reveals a structural organization ... more Micrococcal nuclease digestion of chromatin from growing cells reveals a structural organization which differs for genes transcribed at diverse rates. The late cAMP dependent prespore genes which are not transcribed in growing cells are found in growing cells in a regular nucleosomal repeat with an average spacing of 168 nucleotides. By contrast genes expressed at a low level in growing cells show an irregular pattern of bands with an average distance between bands of 80 nucleotides. The sizes of the bands generated from the transcribed genes are consistent with the concept that transcription results in the loss of the linker region histone H1 with concomitant sliding of nucleosomes to generate close packed ("slipped") di, tri, and tetra nucleosomes lacking the linker region. Further analysis of dinucleosomes released by micrococcal nuclease digestion reveals that transcriptionally active genes are found associated with dinucleosomes species which may be lacking histone H1. The length of DNA protected by these dinucleosomes is heterogeneous, ranging from 250 to 300 nucleotides. Methodology is described which has been adapted to allow two dimensional hybridization mapping of nucleoprotein complexes on single copy Dictyostelium genes.

Frontiers in pediatrics, 2014

Chronic neurological deficits are a significant complication of preterm birth. Magnesium suppleme... more Chronic neurological deficits are a significant complication of preterm birth. Magnesium supplementation has been suggested to have neuroprotective function in the developing brain. Our objective was to determine whether higher neonatal serum magnesium levels were associated with better long-term neurodevelopmental outcomes in very-low birth weight infants. A retrospective cohort of 75 preterm infants (<1500 g, gestational age <27 weeks) had follow-up for the outcomes of abnormal motor exam and for epilepsy. Average total serum magnesium level in the neonate during the period of prematurity was the main independent variable assessed, tested using a Wilcoxon rank-sum test. Higher average serum magnesium level was associated with a statistically significant decreased risk for abnormal motor exam (p = 0.037). A lower risk for epilepsy in the group with higher magnesium level did not reach statistical significance (p = 0.06). This study demonstrates a correlation between higher ne...

Cell, Jan 23, 2015

Primary cilia are cellular appendages that coordinate diverse sensory and signaling activities. T... more Primary cilia are cellular appendages that coordinate diverse sensory and signaling activities. They are important for proper mammalian development, adult tissue homeostasis, and vision and odorant detection, and their dysfunction contributes to disease pathology and developmental defects.