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1.
Proc Natl Acad Sci U S A ; 121(24): e2320517121, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38848301

ABSTRACT

Self-propelling organisms locomote via generation of patterns of self-deformation. Despite the diversity of body plans, internal actuation schemes and environments in limbless vertebrates and invertebrates, such organisms often use similar traveling waves of axial body bending for movement. Delineating how self-deformation parameters lead to locomotor performance (e.g. speed, energy, turning capabilities) remains challenging. We show that a geometric framework, replacing laborious calculation with a diagrammatic scheme, is well-suited to discovery and comparison of effective patterns of wave dynamics in diverse living systems. We focus on a regime of undulatory locomotion, that of highly damped environments, which is applicable not only to small organisms in viscous fluids, but also larger animals in frictional fluids (sand) and on frictional ground. We find that the traveling wave dynamics used by mm-scale nematode worms and cm-scale desert dwelling snakes and lizards can be described by time series of weights associated with two principal modes. The approximately circular closed path trajectories of mode weights in a self-deformation space enclose near-maximal surface integral (geometric phase) for organisms spanning two decades in body length. We hypothesize that such trajectories are targets of control (which we refer to as "serpenoid templates"). Further, the geometric approach reveals how seemingly complex behaviors such as turning in worms and sidewinding snakes can be described as modulations of templates. Thus, the use of differential geometry in the locomotion of living systems generates a common description of locomotion across taxa and provides hypotheses for neuromechanical control schemes at lower levels of organization.


Subject(s)
Lizards , Locomotion , Animals , Locomotion/physiology , Lizards/physiology , Snakes/physiology , Biomechanical Phenomena , Models, Biological
2.
Clin Neuropsychol ; : 1-17, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38378478

ABSTRACT

Objective: We report a neuropsychological evaluation for a 39-year-old, right-handed, white female who 8 years ago developed delayed post-hypoxic leukoencephalopathy (DPHL), a rare demyelinating syndrome, two-weeks following an anoxic brain injury due to an overdose from benzodiazepines. Methods: An extensive record review documenting her medical timeline and treatment over the last 8 years was conducted using the available EMR system, which also included both EEG and neuroimaging data. Eight years post injury, a comprehensive neuropsychological battery was administered with corrected normative data for age, race, education, and other demographic factors when available. Collected data was compared with other case reports of DPHL. Results: The neuropsychological profile indicated difficulties across multiple cognitive domains that appeared driven by executive dysfunction, likely related to fronto-subcorto-striatal dysfunction. Conclusion: As a rare disease, the process by which DPHL occurs is not fully understood. Our results revealed similar findings in the literature for learning and memory, attention, processing speed, and executive functions. This is discussed in the context of available neuroimaging while highlighting the value of comprehensive neuropsychological assessment in DPHL even years post-injury.

3.
PLoS One ; 18(12): e0295823, 2023.
Article in English | MEDLINE | ID: mdl-38128010

ABSTRACT

The study of plant root growth in real time has been difficult to achieve in an automated, high-throughput, and systematic fashion. Dynamic imaging of plant roots is important in order to discover novel root growth behaviors and to deepen our understanding of how roots interact with their environments. We designed and implemented the Generating Rhizodynamic Observations Over Time (GROOT) robot, an automated, high-throughput imaging system that enables time-lapse imaging of 90 containers of plants and their roots growing in a clear gel medium over the duration of weeks to months. The system uses low-cost, widely available materials. As a proof of concept, we employed GROOT to collect images of root growth of Oryza sativa, Hudsonia montana, and multiple species of orchids including Platanthera integrilabia over six months. Beyond imaging plant roots, our system is highly customizable and can be used to collect time- lapse image data of different container sizes and configurations regardless of what is being imaged, making it applicable to many fields that require longitudinal time-lapse recording.


Subject(s)
Oryza , Robotics , Plant Roots , Montana
4.
Sci Robot ; 8(85): eadi2243, 2023 12 20.
Article in English | MEDLINE | ID: mdl-38117866

ABSTRACT

Limbless locomotors, from microscopic worms to macroscopic snakes, traverse complex, heterogeneous natural environments typically using undulatory body wave propagation. Theoretical and robophysical models typically emphasize body kinematics and active neural/electronic control. However, we contend that because such approaches often neglect the role of passive, mechanically controlled processes (those involving "mechanical intelligence"), they fail to reproduce the performance of even the simplest organisms. To uncover principles of how mechanical intelligence aids limbless locomotion in heterogeneous terradynamic regimes, here we conduct a comparative study of locomotion in a model of heterogeneous terrain (lattices of rigid posts). We used a model biological system, the highly studied nematode worm Caenorhabditis elegans, and a robophysical device whose bilateral actuator morphology models that of limbless organisms across scales. The robot's kinematics quantitatively reproduced the performance of the nematodes with purely open-loop control; mechanical intelligence simplified control of obstacle navigation and exploitation by reducing the need for active sensing and feedback. An active behavior observed in C. elegans, undulatory wave reversal upon head collisions, robustified locomotion via exploitation of the systems' mechanical intelligence. Our study provides insights into how neurally simple limbless organisms like nematodes can leverage mechanical intelligence via appropriately tuned bilateral actuation to locomote in complex environments. These principles likely apply to neurally more sophisticated organisms and also provide a design and control paradigm for limbless robots for applications like search and rescue and planetary exploration.


Subject(s)
Caenorhabditis elegans , Robotics , Animals , Locomotion , Snakes , Biomechanical Phenomena
6.
Semin Nephrol ; 41(5): 405-415, 2021 09.
Article in English | MEDLINE | ID: mdl-34916001

ABSTRACT

Chronic kidney disease (CKD) progression is typically characterized as either time to a clinically meaningful event (such as dialysis or transplant), or longitudinal changes in kidney function. This review describes pediatric kidney disease progression using these two distinct frameworks by reviewing and discussing data from the Chronic Kidney Disease in Children study. We first describe new equations to estimate glomerular filtration rate (GFR) for patients younger than age 25 years, and how the average of serum creatinine-based and cystatin C-based GFR equations yield valid estimates than either alone. Next, we present a life course description of CKD onset to kidney replacement therapy, prediction models based on clinical measurements, and show the importance of diagnosis (broadly classified as nonglomerular and glomerular in origin), GFR level, and proteinuria on progression. Literature on longitudinal GFR in children and young adults are reviewed and new data are presented to characterize nonlinear changes in estimated GFR in patients younger than age 25 years. These models showed accelerated progression associated with glomerular diagnosis, lower GFR level, and higher proteinuria, which was congruent with time-to-event analyses. Descriptions of online tools for GFR estimation and risk stratification for clinical applications are presented and we offer key epidemiologic considerations for the analysis of longitudinal pediatric CKD studies.


Subject(s)
Renal Insufficiency, Chronic , Adult , Child , Disease Progression , Female , Glomerular Filtration Rate , Humans , Kidney , Male , Proteinuria/epidemiology , Young Adult
7.
J Vis Exp ; (170)2021 04 21.
Article in English | MEDLINE | ID: mdl-33970145

ABSTRACT

Polymersomes are membrane-bound, bilayer vesicles created from amphiphilic block copolymers that can encapsulate both hydrophobic and hydrophilic payloads for drug delivery applications. Despite their promise, polymersomes are limited in application due to their spherical shape, which is not readily taken up by cells, as demonstrated by solid nanoparticle scientists. This article describes a salt-based method for increasing the aspect ratios of spherical poly(ethylene glycol) (PEG)- based polymersomes. This method can elongate polymersomes and ultimately control their final shape by adding sodium chloride in post-formation dialysis. Salt concentration can be varied, as described in this method, based on the hydrophobicity of the block copolymer being used as the base for the polymersome and the target shape. Elongated nanoparticles have the potential to better target the endothelium in larger diameter blood vessels, like veins, where margination is observed. This protocol can expand therapeutic nanoparticle applications by utilizing elongation techniques in tandem with the dual-loading, long-circulating benefits of polymersomes.


Subject(s)
Osmotic Pressure/physiology , Polyesters/chemistry , Polymers/chemistry
8.
ACS Appl Bio Mater ; 4(4): 2853-2862, 2021 04 19.
Article in English | MEDLINE | ID: mdl-35014381

ABSTRACT

This paper highlights the potential benefits of using self-assembled polymeric nanoparticles of various shapes to enhance drug uptake. First, we highlight the growth and development of the polymersome, using a liposome as a blueprint for amphiphilic codelivery. Then, we focus on the advantages of nanoparticle elongation, drawing from the field of solid nanoparticles, as opposed to self-assembled vesicles which have not yet been extensively explored in shape-modulated drug delivery applications. Notably, regardless of the material used in the solid nanoparticle systems, more elongated shapes lead to greater cellular uptake, decreased interaction with the reticuloendothelial system macrophages, and increased circulation times. Finally, we highlight the methods currently being developed to modulate polymersome shape, thus providing a drug delivery system with the benefits derived from amphiphilicity and elongated structures. Current methods employed to modulate polymersome shape involve osmotic pressure gradients, solvent switching, and the use of cross-linking agents. Although these methods are successful in modulating polymersome shapes and the benefits of elongated nanoparticles in therapeutic targeting are clear, these methods have not yet been explored for applications in drug delivery.


Subject(s)
Biocompatible Materials/chemistry , Drug Delivery Systems , Nanoparticles/chemistry , Pharmaceutical Preparations/chemistry , Polymers/chemistry , Materials Testing , Particle Size
9.
Kidney Int ; 99(4): 948-956, 2021 04.
Article in English | MEDLINE | ID: mdl-33301749

ABSTRACT

Using data (2655 observations from 928 participants) from the Chronic Kidney Disease in Children Study, we developed and internally validated new glomerular filtration rate estimating equations for clinical use in children and young adults: two forms of K × [heigh(ht) / serum creatinine(sCr)] and two forms of K × [1 / cystatin C(cysC)]. For each marker, one equation used a sex-dependent K; in the other, K is sex-and age-dependent. Glomerular filtration rate (GFR) was measured directly by plasma iohexol disappearance. The equations using ht/sCr had sex-specific constants of 41.8 for males and 37.6 for females. In the age- dependent models, K increased monotonically for children 1-18 years old and was constant for young adults 18-25 years. For males, K ranged from 35.7 for one-year-olds to 50.8 for those 18 and older. For females, the values of K ranged from 33.1 to 41.4. Constant K values for cystatin-C equations were 81.9 for males and 74.9 for females. With age-dependency, K varied non-monotonically with the highest values at age 15 for males (K of 87.2) and 12 years for females (K of 79.9). Use of an age-dependent K with ht/sCr models reduced average bias, notably in young children and young adults; age-dependent cystatin-C models produced similar agreement to using a constant K in children under 18 years, but reduced bias in young adults. These age-dependent proposed equations were evaluated alongside estimated GFRs from 11 other published equations for pediatrics and young adults. Only our proposed equations yielded non- significant bias and within 30% accuracy values greater than 85% in both the pediatric and young adult subpopulations.


Subject(s)
Renal Insufficiency, Chronic , Adolescent , Biomarkers , Child , Child, Preschool , Creatinine , Female , Glomerular Filtration Rate , Humans , Infant , Iohexol , Male , Renal Insufficiency, Chronic/diagnosis , Young Adult
10.
J Eat Disord ; 8: 35, 2020.
Article in English | MEDLINE | ID: mdl-32760588

ABSTRACT

BACKGROUND: The purpose of this study was to quantify cognitive deficits in severe anorexia nervosa (AN) before and after medical stabilization. METHODS: This was a prospective study of 40 females between the ages of 18 and 50 admitted to a medical stabilization unit with severe AN (%IBW < 70). The primary outcome of the study was change in test scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at baseline and after medical stabilization. RESULTS: There were no statistically significant differences in baseline RBANS scores between AN patients overall and controls (p = 0.0940). There was a statistically significant change in RBANS from baseline 94.1 + 12.7 to medical stabilization 97.1 + 10.6 (p = 0.0173), although notably both mean values fell within the average range. There were no significant differences in baseline RBANS scores between controls and AN-BP patients (p = 0.3320) but significant differences were found between controls and AN-R patients (p = 0.0434). CONCLUSIONS: No baseline deficits in cognition were found in this sample of women with severe AN.

11.
J Extra Corpor Technol ; 52(2): 96-102, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32669735

ABSTRACT

The American Society of Extracorporeal Technology Board of Directors, consistent with the American Society of Extracorporeal Technology's safe patient care improvement mission, charged the International Board of Blood Management to write a knowledge and skill certification examination for healthcare personnel employed as adult extracorporeal membrane oxygenation (ECMO) specialists. Nineteen nationally recognized ECMO subject-matter experts were selected to complete the examination development. A job analysis was performed, yielding a job description and examination plan focused on 16 job categories. Multiple-choice test items were created and validated. Qualified ECMO specialists were identified to complete a pilot examination and both pre- and post-examination surveys. The examination item difficulty and candidate performance were ranked and matched using Rasch methodology. Candidates' examination scores were compared with their profession, training, and experience as ECMO specialists. The 120-item pilot examination form ranked 76 ECMO specialist candidates consistent with their licensure, ECMO training, and clinical experience. Forty-three registered nurses, 28 registered respiratory therapists, four certified clinical perfusionists, and one physician assistant completed the pilot examination process. Rasch statistics revealed examination reliability coefficients of .83 for candidates and .88 for test items. Candidates ranked the appropriateness for examination items consistent with the item content, difficulty, and their personal examination score. The pilot examination pass rate was 80%. The completed examination product scheduled for enrollment in March 2020 includes 100 verified test items with an expected pass rate of 84% at a cut score of 67%. The online certification examination based on a verified job analysis provides an extramural assessment that ranks minimally prepared ECMO specialists' knowledge, skills, and abilities (KSA) consistent with safe ECMO patient care and circuit management. It is anticipated that ECMO facilities and ECMO service providers will incorporate the certification examination as part of their process improvement, safety, and quality assurance plans.


Subject(s)
Extracorporeal Membrane Oxygenation , Adult , Certification , Humans , Reproducibility of Results , Surveys and Questionnaires
12.
Heart Fail Clin ; 16(3): 295-303, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32503753

ABSTRACT

Continuous-flow left ventricular assist devices are frequently used for management of patients with advanced heart failure with reduced ejection fraction. Although technologic advancements have contributed to improved outcomes, several complications arise over time. These complications result from several factors, including medication effects, physiologic responses to chronic exposure to circulatory support that is minimally/entirely nonpulsatile, and dysfunction of the device itself. Clinical presentation can range from chronic and indolent to acute, life-threatening emergencies. Several areas of uncertainty exist regarding best practices for managing complications; however, growing awareness has led to development of new guidelines to reduce risk and improve outcomes.


Subject(s)
Emergency Treatment/methods , Heart Failure , Heart-Assist Devices , Shock, Cardiogenic , Heart Failure/etiology , Heart Failure/physiopathology , Heart Failure/therapy , Humans , Shock, Cardiogenic/etiology , Shock, Cardiogenic/therapy , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/therapy
13.
J Cardiovasc Electrophysiol ; 31(7): 1784-1792, 2020 07.
Article in English | MEDLINE | ID: mdl-32412126

ABSTRACT

INTRODUCTION: The novel two-lead cardiac resynchronization therapy (CRT)-DX system utilizes a floating atrial dipole on the implantable cardioverter-defibrillator lead, and when implanted with a left ventricular (LV) lead, offers a two-lead CRT system with AV synchrony. This study compared complication rates and CRT response among subjects implanted with a two-lead CRT-DX system to those subjects implanted with a standard three-lead CRT-D system. METHODS AND RESULTS: A total of 240 subjects from the Sentus QP-Extended CRT Evaluation with Quadripolar Left Ventricular Leads postapproval study were selected to identify 120 matched pairs based on similar demographic characteristics using a Greedy algorithm. The complication-free rate was evaluated as the primary endpoint. All-cause mortality, heart failure hospitalizations, device diagnostic data, New York Heart Association (NYHA) class improvement, and defibrillator therapy were evaluated from clinical data, in-office interrogations, and remote monitoring throughout the follow-up period. Complication-free survival favored the CRT-DX group with 92.5% without a major complication compared to 85.0% in the CRT-D cohort (P = .0495; 95% confidence interval: 0.1%-14.9%) over a mean follow-up of 1.3 and 1.4 years, respectively. Incidence of all-cause mortality, heart failure hospitalizations, NYHA changes at 6 months postimplant, and percent of LV pacing during CRT therapy were similar in both device cohorts. Inappropriate shocks were more frequent in the CRT-D cohort with 5.8% of subjects receiving an inappropriate shock vs 0.8% in the CRT-DX cohort. CONCLUSION: The results of this subanalysis demonstrate that the CRT-DX system can provide similar CRT responses and significantly fewer complications when compared to a similar cohort with a conventional three-lead CRT-D system.


Subject(s)
Cardiac Resynchronization Therapy , Defibrillators, Implantable , Heart Failure , Cardiac Resynchronization Therapy Devices , Defibrillators, Implantable/adverse effects , Heart Failure/diagnosis , Heart Failure/therapy , Humans , New York , Registries , Treatment Outcome
14.
Clin J Am Soc Nephrol ; 14(12): 1711-1718, 2019 12 06.
Article in English | MEDLINE | ID: mdl-31712386

ABSTRACT

BACKGROUND AND OBJECTIVES: Dyslipidemia, a risk factor for cardiovascular disease, is common in CKD but its change over time and how that change is influenced by concurrent progression of CKD have not been previously described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the CKD in Children study we prospectively followed children with progressive CKD and utilized multivariable, linear mixed-effects models to quantify the longitudinal relationship between within-subject changes in lipid measures (HDL cholesterol, non-HDL cholesterol, triglycerides) and within-subject changes in GFR, proteinuria, and body mass index (BMI). RESULTS: A total of 508 children (76% nonglomerular CKD, 24% glomerular CKD) had 2-6 lipid measurements each, with a median follow-up time of 4 (interquartile range [IQR], 2.1-6.0) years. Among children with nonglomerular CKD, dyslipidemia was common at baseline (35%) and increased significantly as children aged; 43% of children with glomerular CKD had dyslipidemia at baseline and demonstrated persistent levels as they aged. Longitudinal increases in proteinuria were independently associated with significant concomitant increases in non-HDL cholesterol (nonglomerular: 4.9 [IQR, 3.4-6.4] mg/dl; glomerular: 8.5 [IQR, 6.0-11.1] mg/dl) and triglycerides (nonglomerular: 3% [IQR, 0.8%-6%]; glomerular: 5% [IQR, 0.6%-9%]). Decreases in GFR over follow-up were significantly associated with concomitant decreases of HDL cholesterol in children with nonglomerular CKD (-1.2 mg/dl; IQR, -2.1 to -0.4 mg/dl) and increases of non-HDL cholesterol in children with glomerular CKD (3.9 mg/dl; IQR, 1.4-6.5 mg/dl). The effects of increased BMI also affected multiple lipid changes over time. Collectively, glomerular CKD displayed stronger, deleterious associations between within-subject change in non-HDL cholesterol (9 mg/dl versus 1.2 mg/dl; P<0.001) and triglycerides (14% versus 3%; P=0.004), and within-subject change in BMI; similar but quantitatively smaller differences between the two types of CKD were noted for associations of within-subject change in lipids to within-subject change in GFR and proteinuria. CONCLUSIONS: Dyslipidemia is a common and persistent complication in children with CKD and it worsens in proportion to declining GFR, worsening proteinuria, and increasing BMI.


Subject(s)
Dyslipidemias/etiology , Glomerular Filtration Rate , Proteinuria/etiology , Renal Insufficiency, Chronic/complications , Adolescent , Body Mass Index , Child , Cholesterol/blood , Dyslipidemias/physiopathology , Female , Humans , Male , Prospective Studies , Proteinuria/blood
15.
Biophys J ; 117(7): 1250-1257, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31540710

ABSTRACT

One of the most common swimming strategies employed by microorganisms is based on the use of rotating helical filaments, called flagella, that are powered by molecular motors. Determining the physical properties of this propulsive system is crucial to understanding the behavior of these organisms. Furthermore, the ability to dynamically monitor the activity of the flagellar motor is a valuable indicator of the overall energetics of the cell. In this work, inherently magnetic bacteria confined in micromagnetic CoFe traps are used to directly and noninvasively determine the flagellar thrust force and swimming speed of motile cells. The technique permits determination of the ratio of propulsive force/swimming speed (the hydrodynamic resistance) and the power output of the flagellar motor for individual cells over extended time periods. Cells subjected to ultraviolet radiation are observed to experience exponential decays in power output as a function of exposure time. By noninvasively measuring thrust, velocity, and power output over time at a single-cell level, this technique can serve as the foundation for fundamental studies of bacterial hydrodynamics and also provides a novel, to our knowledge, tether-free probe of single-cell energetics over time.


Subject(s)
Bacterial Physiological Phenomena , Flagella/metabolism , Magnetic Fields , Mechanical Phenomena , Single-Cell Analysis/methods , Biomechanical Phenomena , Hydrodynamics , Rotation
17.
Article in English | MEDLINE | ID: mdl-30042929

ABSTRACT

We have previously identified a small molecule compound, N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (9029936), that exerts potent inhibitory activity against filamentation and biofilm formation by the Candida albicans SC5314 strain and represents a lead candidate for the development of anti-virulence approaches against C. albicans infections. Here we present data from a series of experiments to further characterize its in vitro activity and drug-like characteristics. We demonstrate the activity of this compound against a panel of C. albicans clinical isolates, including several displaying resistance to current antifungals; as well as against a set of C. albicans gain of function strains in key transcriptional regulators of antifungal drug resistance. The compound also inhibits filamentation and biofilm formation in the closely related species C. dubliniensis, but not C. glabrata or C. tropicalis. Combinatorial studies reveal the potential of compound 9029936 to be used together with currently available conventional antifungals. Results of serial passage experiments indicate that repeated exposure to this compound does not elicit resistance. Viability staining of C. albicans in the presence of high concentrations of compound 9029936 confirms that the compound is not toxic to fungal cells, and cytological staining using image flow cytometry analysis reveals that treatment with the lead compound affects hyphal length, with additional effects on cell wall and integrity of the membrane system. In vitro pharmacological profiling provides further evidence that the lead compound displays a safe profile, underscoring its excellent "drug-like" characteristics. Altogether these results confirm the potential of this compound to be further developed as a true anti-virulence agent for the treatment of C. albicans infections, including those refractory to treatment with conventional antifungal agents.


Subject(s)
Amides/pharmacology , Antifungal Agents/pharmacology , Biofilms/drug effects , Candida albicans/drug effects , Candida albicans/pathogenicity , Candida albicans/growth & development , Candida albicans/isolation & purification , Candidiasis/microbiology , Drug Synergism , Flow Cytometry , Humans , Hyphae/drug effects , Hyphae/growth & development , Microbial Viability/drug effects , Virulence/drug effects
18.
Hypertension ; 71(3): 444-450, 2018 03.
Article in English | MEDLINE | ID: mdl-29295853

ABSTRACT

Uncontrolled hypertension in children with chronic kidney disease (CKD) has been identified as one of the main factors contributing to progression of CKD and increased risk for cardiovascular disease. Recent efforts to achieve better blood pressure (BP) control have been recommended. The primary objective of this analysis was to compare BP control over 2 time periods among participants enrolled in the CKiD study (Chronic Kidney Disease in Children). Casual BP and 24-hour ambulatory BP monitor data were compared among 851 participants during 2 time periods: January 1, 2005, through July 1, 2008 (period 1, n=345), and July 1, 2010, through December 31, 2013 (period 2, n=506). Multivariable logistic regression to model the propensity of a visit record being in period 2 as a function of specific predictors was performed. After controlling for confounding variables (age, sex, race, socioeconomics, CKD duration, glomerular filtration rate, proteinuria, body mass index, growth failure, and antihypertensives), no significant differences were detected between time periods with respect to casual BP status (prehypertension: 15% versus 15%; uncontrolled hypertension: 18% versus 17%; P=0.87). Analysis of ambulatory BP monitor data demonstrated higher ambulatory BP indices, most notably masked hypertension in period 2 (36% versus 49%; P<0.001). Average sleep BP index (P<0.05) and sleep BP loads (P<0.05) were higher in period 2. Despite publication of hypertension recommendations and guidelines for BP control in patients with CKD, this study suggests that hypertension remains undertreated and under-recognized in children with CKD. This analysis also underscores the importance of routine ambulatory BP monitor assessment in children with CKD.


Subject(s)
Hypertension/drug therapy , Hypertension/epidemiology , Masked Hypertension/diagnosis , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Adolescent , Age Factors , Antihypertensive Agents/therapeutic use , Blood Pressure Determination/methods , Blood Pressure Monitoring, Ambulatory/methods , Child , Child, Preschool , Comorbidity , Female , Follow-Up Studies , Glomerular Filtration Rate/physiology , Humans , Hypertension/diagnosis , Longitudinal Studies , Male , Masked Hypertension/epidemiology , Masked Hypertension/physiopathology , Needs Assessment , Renal Insufficiency, Chronic/physiopathology , Retrospective Studies , Risk Assessment , Severity of Illness Index , Sex Factors , Statistics, Nonparametric , Treatment Outcome
19.
Pediatr Nephrol ; 33(4): 697-704, 2018 04.
Article in English | MEDLINE | ID: mdl-29214443

ABSTRACT

BACKGROUND: In pediatric chronic kidney disease (pCKD), traditional factors (proteinuria, etiology, and race) do not fully explain disease progression. The levels of methylated arginine derivatives (MADs: asymmetric and symmetric dimethylarginine, respectively) rise in CKD and increase with CKD progression. The impact of MADs on glomerular filtration rate (GFR) decline has not been examined in pCKD. The aim of this study was to examine the additive impact of baseline (BL) levels of MADs on directly measured GFR (mGFR) decline per year (ml/min/1.73 m2/year) for a period of up to 4 years. METHODS: Plasma and data, including mGFR by plasma iohexol clearance, were provided by the prospective, observational Chronic Kidney Disease in Children study. BL MADs were analyzed by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: For 352 pCKD subjects, the median [interquartile range] BL mGFR was 45 [35, 57] ml/min/1.73 m2. The levels of BL MADs were inversely related to the initial mGFR and its decline over time (p < 0.0005) but not to the rate of decline. Covariates, non-glomerulopathy and Tanner stage of ≥ 3 demonstrated weaker relationships between BL levels and beginning mGFR (p = 0.004 and p = 0.002, respectively). CONCLUSIONS: In pCKD, higher concentrations of BL MADs were inversely related to BL mGFR. MADs did not affect the CKD progression rate. Quantification of this relationship is novel to the pCKD literature.


Subject(s)
Arginine/analogs & derivatives , Glomerular Filtration Rate/physiology , Renal Insufficiency, Chronic/physiopathology , Adolescent , Arginine/blood , Child , Child, Preschool , Chromatography, High Pressure Liquid/methods , Disease Progression , Female , Humans , Infant , Kidney/physiopathology , Male , Mass Spectrometry/methods , Prospective Studies
20.
mBio ; 8(6)2017 Dec 05.
Article in English | MEDLINE | ID: mdl-29208749

ABSTRACT

Candida albicans remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated with these infections. The yeast-to-hypha transition represents the main virulence factor associated with the pathogenesis of C. albicans infections. In addition, filamentation is pivotal for robust biofilm development, which represents another major virulence factor for candidiasis and further complicates treatment. Targeting pathogenic mechanisms rather than growth represents an attractive yet clinically unexploited approach in the development of novel antifungal agents. Here, we performed large-scale phenotypic screening assays with 30,000 drug-like small-molecule compounds within ChemBridge's DIVERSet chemical library in order to identify small-molecule inhibitors of C. albicans filamentation, and our efforts led to the identification of a novel series of bioactive compounds with a common biaryl amide core structure. The leading compound of this series, N-[3-(allyloxy)-phenyl]-4-methoxybenzamide, was able to prevent filamentation under all liquid and solid medium conditions tested, suggesting that it impacts a common core component of the cellular machinery that mediates hypha formation under different environmental conditions. In addition to filamentation, this compound also inhibited C. albicans biofilm formation. This leading compound also demonstrated in vivo activity in clinically relevant murine models of invasive and oral candidiasis. Overall, our results indicate that compounds within this series represent promising candidates for the development of novel anti-virulence approaches to combat C. albicans infections.IMPORTANCE Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In Candida albicans, one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting C. albicans filamentation both in vitro and in vivo; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis.


Subject(s)
Antifungal Agents/therapeutic use , Benzamides/therapeutic use , Biofilms/drug effects , Candida albicans/drug effects , Candida albicans/pathogenicity , Candidiasis/drug therapy , Hyphae/drug effects , Small Molecule Libraries/therapeutic use , Animals , Antifungal Agents/toxicity , Benzamides/toxicity , Biofilms/growth & development , Candida albicans/growth & development , Candidiasis/microbiology , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Hyphae/growth & development , Mice , Mice, Inbred BALB C , Small Molecule Libraries/toxicity , Virulence/drug effects , Virulence Factors
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