Unexplained heterogeneity in response to ventricular assist device (VAD) implantation for the management of advanced heart failure impedes our ability to predict favorable outcomes, provide adequate patient and family education, and personalize monitoring and symptom management strategies. The purpose of this paper is to describe the background and design of a study entitled Profiling Biobehavioral Responses to Mechanical Support in Advanced Heart Failure (PREMISE).
Study Design and Methods
PREMISE is a prospective cohort study designed to a) identify common and distinct trajectories of change in physical and psychological symptom burden, b) characterize common trajectories of change in serum biomarkers of myocardial stress, systemic inflammation, and endothelial dysfunction, and c) quantify associations between symptoms and biomarkers of pathogenesis in adults undergoing VAD implantation. Latent growth mixture modeling, including parallel process and cross-classification modeling, will be used to address the study aims and will entail identifying trajectories, quantifying associations between trajectories and both clinical and quality-of-life outcomes, and identifying predictors of favorable symptom and biomarker responses to VAD implantation.
Research findings from PREMISE will be used to enhance shared patient and provider decision-making, and shape a much-needed new breed of interventions and clinical management strategies that are tailored to differential symptom and pathogenic responses to VAD implantation.
This retrospective cohort study compared clinical and radiographic outcomes of endodontic treatment performed in immature non-vital permanent teeth, by apexification (calcium hydroxide or apical barrier with Mineral Trioxide Aggregate (MTA)), versus revascularization.
A comprehensive chart review was performed to obtain a cohort of sequential previously completed cases with recalls. Clinical and radiographic data were collected for 31 treated teeth (19 revascularization and 12 apexification) with an average follow up time of 17 months and a recall rate of 63%. Tooth survival, success rate, and adverse events were analyzed. Changes in radiographic root length, width and area were quantified.
The majority of treated teeth survived throughout the study period with 30/31 (97%) teeth surviving (18/19 (95%) revascularization, 12/12 apexification). Most cases were also clinically successful with 27/31 (87%) meeting criteria for success, (15/19 (78%) revascularization and 12/12 apexification; non-significant difference). A greater incidence of adverse events was observed in the revascularization group (8/19 (42%) versus 1/12 (11%) in apexification (Risk Ratio= 5.1, p=0.04, 95%CI (0.719, 35.48)). Although more revascularization cases than apexification cases demonstrated an increase in radiographic root area and width, the effect was not statistically significant.
In this study, revascularization was not superior to other apexification techniques in either clinical or radiographic outcomes. Studies with large subject cohorts, and long follow up periods are needed to evaluate outcomes of revascularization and apexification, while accounting for important co-variants relevant to clinical success.
Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance.
Staphylococcus aureus; MRSA; virulence; antibiotic resistance
Background: People with multiple sclerosis (MS) fall frequently, and there are few clinically valid tools to measure the risk factors for falls. We assessed the unidimensionality of the 7-item Falls Efficacy Scale–International (FES-I), a measure of fear of falling, and determined whether the 7-item FES-I is associated with recurrent falls in people with MS.
Methods: Falls were counted prospectively for 6 months using fall calendars in 58 people with MS (age, 18–50 years; Expanded Disability Status Scale score, 0–6). The FES-I was administered at baseline, and its unidimensionality was assessed by confirmatory factor analysis. The relationship between FES-I score and future falls, after adjusting for recurrent falls in the past year, was assessed by logistic regression.
Results: Fifty-four participants who completed all assessments were included in the analysis. Goodness-of-fit indices confirmed a single-factor solution for the 7-item FES-I (discrepancy χ2, P = .101; Tucker-Lewis index, 0.953; comparative fit index, 0.969; root mean square error of approximation, 0.098). There was a significant association between fear of falling and falls in the following 3 months, independent of recurrent falls in the past year (odds ratio = 1.22, 95% confidence interval, 1.04–1.43, P = .016).
Conclusions: The 7-item FES-I demonstrates good construct validity, allowing the total score to be used as a measure of fear of falling in people with MS. Fear of falling, as measured by the 7-item FES-I, is associated with future recurrent falls independent of past recurrent falls in people with MS.
Although the intracellular Cl−/H+ exchanger Clc-5 is expressed in apical intestinal endocytic compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the hypothesis that loss of CLC-5 modulates the immune response, thereby inducing susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5 knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index, histological activity index, and myeloperoxidase activity were significantly elevated in DSS-induced Clcn5 KO mice compared with those in WT mice. Comprehensive serum multiplex cytokine profiling demonstrated a heightened Th1–Th17 profile (increased TNF-α, IL-6, and IL-17) in DSS-induced Clcn5 KO mice compared with that in WT DSS colitis mice. Interestingly, Clcn5 KO mice maintained on a high vitamin D diet attenuated DSS-induced colitis. Immunofluorescence and Western blot analyses of colonic mucosa validated the systemic cytokine patterns and further revealed enhanced activation of the NF-κB pathway in DSS-induced Clcn5 KO mice compared with those in WT mice. Intriguingly, high baseline levels of IL-6 and phospho-IκB were observed in Clcn5 KO mice, suggesting a novel immunopathogenic role for the functional defects that result from the loss of Clc-5. Our studies demonstrate that the loss of Clc-5 1) exhibits IL-6–mediated immunopathogenesis, 2) significantly exacerbated DSS-induced colitis, which is influenced by dietary factors, including vitamin D, and 3) portrays distinct NF-κB–modulated Th1–Th17 immune dysregulation, implying a role for CLC-5 in the immunopathogenesis of UC.
Model search strategies play an important role in finding simultaneous susceptibility genes that are associated with a trait. More particularly, model selection via the information criteria, such as the BIC with modifications, have received considerable attention in quantitative trait loci (QTL) mapping. However, such modifications often depend upon several factors, such as sample size, prior distribution, and the type of experiment, e.g., backcross, intercross. These changes make it difficult to generalize the methods to all cases. The fence method avoids such limitations with a unified approach, and hence can be used more broadly. In this paper, this method is studied in the case of backcross experiments throughout a series of simulation studies. The results are compared with those of the modified BIC method as well as some of the most popular shrinkage methods for model selection.
high-dimensional variable seleciton; restricted fence (RF); model selection
Heart failure (HF) self-care is an important component of disease management and the focus of many interventions.
The aim of this study was to evaluate the validity and reliability of the 9-item European HF Self-Care Behavior Scale (EHFScB-9) in a sample of 200 adults from the United States with symptomatic HF.
Psychometric tests included item and confirmatory factor analyses, convergent and discriminant validity, and internal consistency.
Item-total correlations ranged from 0.25–0.65. Many fit indices for the EHFScB-9 and the 4-item consulting behaviors reached thresholds of acceptability. As expected, the EHFScB-9 was associated with other measures of HF self-care but not with quality-of-life. Coefficient α was 0.80 for the EHFScB-9 and and 0.85 for the consulting behaviors subscale.
The EHFScB-9 was a valid and reliable measure of HF self-care among English-speaking U.S. adults with symptomatic HF.
To compare pulmonary function testing including respiratory compliance (Crs) and time to peak tidal expiratory flow: expiratory time (Tptef:Te) at term corrected age in healthy infants born at 33-36 weeks of gestation versus healthy infants delivered at term.
We performed a prospective cohort study of late preterm infants born at 33-36 weeks without clinical respiratory disease (<12 hours of >0.21 FiO2) and studied at term corrected age. The comparison group was term infants matched for race and sex to the preterm infants and studied within 72 hours of delivery. Crs was measured with the single breath occlusion technique. A minimum of 50 flow-volume loops were collected to estimate Tptef:Te.
Late preterm infants (n=31; mean gestational age 34.1 weeks, birth weight 2150 g) and 31 term infants were studied at term corrected age. The late preterm infants had decreased Crs (1.14 vs 1.32 mL/cm H2O/kg; p<0.02) and decreased Tptef:Te (0.308 vs 0.423; p<0.01) when compared with the term infants. Late preterm infants also had an increased respiratory resistance (0.064 vs 0.043 cm H2O/mL/sec; p<0.01).
Healthy late preterm infants (33-36 weeks of gestation) studied at term corrected age have altered pulmonary function when compared with healthy term infants.
Expiratory flow ratio; late preterm infants; pulmonary function; respiratory compliance
Cystic Fibrosis pulmonary disease is characterized by intermittent episodes of acute lung symptoms known as “pulmonary exacerbations”. While exacerbations are classically treated with parenteral antimicrobials, oral antibiotics are often used in “mild” cases.
We determined how often management progressed to IV therapy. We also examined multiple courses of oral antimicrobials within one exacerbation and identified patient factors associated with unsuccessful treatment.
We performed a retrospective chart audit of oral antibiotic use in CF patients from March 2009 through March 2010, for “mild” CF exacerbations.
Administration of a single versus multiple courses of oral antibiotics for treatment of “mild” CF exacerbation avoided progression to IV therapy 79.8% and 50.0% of the time, respectively. Overall, oral antibiotics circumvented the need for IV therapy 73.8% of the time. Using multi-variant analysis, we found multiple patient characteristics to be independent risk factors for oral antibiotic failure including a history of Pseudomonas infection (OR 2.13, CI 1.29 – 3.54), Cystic Fibrosis Related Diabetes (OR 1.85, CI 1.00 – 3.41), Allergic Bronchopulmonary Aspergillosis (OR 3.81, CI 1.38 – 10.56), low socioeconomic status (OR 1.67, CI 1.04 – 2.67), and calculated Baseline FEV1 < 75% of predicted prior to an acute exacerbation (OR 1.93, CI 1.20 – 3.08). Decline in FEV1 > 10%, weight for age, body mass index, distance from the CF center, and gender were not significant.
Our observations suggest that one course of oral antimicrobials is frequently effective in outpatient CF pulmonary exacerbations but exacerbations requiring more than one course of oral antibiotics are likely to require IV therapy.
Cystic Fibrosis; exacerbation; antibiotics; pneumonia
In medical and social studies, it is often desirable to assess the correlation between characteristics of interest that are not directly observable. In such cases, repeated measures are often available, but the correlation between the repeated measures is not the same as that between the true characteristics that are confounded with the measurement errors. The latter is called the hidden correlation. Previously, the problem has been treated by assuming prior knowledge about the measurement errors, or by using relatively complex statistical models, such as the mixed effects models, with no closed-form expression for the estimated hidden correlation. We propose a simple estimator of the hidden correlation that is very much like the Pearson correlation coefficient, with a closed-form expression, under assumptions much weaker than the mixed effects model. Simulation results show that the proposed simple estimator performs similarly as the restricted maximum likelihood (REML) estimator in mixed models, but is computationally much more efficient than REML. Simulation comparison with the Pearson correlation is also made. A real data example is considered.
Correlation Coefficient; Hypothesis Testing; Repeated Measures
Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.
Background and Purpose
Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.
We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI.
Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter.
A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.
Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.
The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT.
One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization).
Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=−4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories.
For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging.
Prostate cancer; Real-time motion tracking; Intrafraction variation; Treatment margin; Treatment time
Objective. The objective of this study was to test the efficacy of the Healing Pathways (HP) program in reducing clinically significantly depressive symptoms in women with physical disabilities (WPD). Healing Pathways is a peer-implemented group mental health treatment program targeting WPD who have clinically significant cooccurring depressive symptoms. Participants. Eighty women were randomized in this trial. Design. This study used a community-based participatory intervention research design. Using community-based recruiting methods, participants were recruited from Centers for Independent Living, local disability service organizations, via Craig's list as well as other community locations such as grocery stores and bus stops. Women participated in the HP program for 14 weeks. Results. The primary outcome variable for this study was reduction in depressive symptoms as measured by the Center for Epidemiologic Depression Scale (CES-D). We found that there was a significant interaction effect of treatment by time on depression scores, F(3,210) = 9.51, P < 0.0001, partial η2 = 0.101. Investigation of the predicted mean profile over time in the intervention group demonstrated that depression scores decreased greatly from baseline to the first posttest and remained stable in the two followups, whereas there was a little change in the mean profile over time in the control group. Conclusion. The HP program has demonstrated initial efficacy in reducing depressive symptoms in women with physical disabilities.
The major form of MRI-defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested pre-oligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions.
A retrospective autopsy series (1983–2000) was selected for cases with diffuse WMI and analyzed relative to prospectively-collected contemporary cases (2003–2010). Controls were age and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodelling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44.
In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool.
Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. Pre-oligodendrocyte maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis.
The aim of this study was to compare two-dimensional (2D) and three-dimensional (3D) methods for computing left ventricular (LV) rotation.
A two-axis linear/rotary system was designed using rotary motors controlled through a digital interface, and 10 freshly harvested pig hearts were studied. Each heart was mounted on the rotary actuator with the base being rotated at different known degrees of rotation (10°, 15°, 20°, and 25°) and was passively driven by a pump with calibrated stoke volume (50 mL) at a constant rate (60 beats/min) simultaneously. Cardiac motion was scanned to acquire 2D short-axis views using a GE Vivid 7 system for assessing rotation, and 3D apical full-volume loops were acquired using a Toshiba Applio Artida ultrasound system. Full-volume 3D image loops were analyzed online with Toshiba Wall Motion Tracking software, and short-axis 2D images were analyzed offline for LV rotation in GE EchoPAC PC at corresponding LV levels.
At each state, both 2D and 3D echocardiography detected the changes in LV rotation but overestimated the rotation degrees. The biases for overestimation from 3D imaging were smaller compared with 2D imaging at each LV level. Both methods, when compared with each other, showed a linear correlation (r = 0.84, P < .0001). Bland-Altman comparison showed 99% of data points within range, with a constant bias between both methods (adjusted values of 3D = 1.892 + 0.964 × 3D).
Although 3D echocardiography showed smaller bias, the results between 2D and 3D echocardiography were comparable.
LV twist; Validation study; 3D echocardiography
Although MRI is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of pre-oligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.
We employed a preterm fetal sheep model of global cerebral ischemia where acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically defined lesions with contrast- and diffusion-weighted high-field ex vivo MRI data.
Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, pre-myelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined two novel hypo-intense signal abnormalities on T2-weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity.
These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.
The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. Herein we demonstrate a novel approach of comprehensive serum multiplex cytokine profiling to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNFα, IL6, IL-17 and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNFα, IL6, IL-17 and KC) in the chronic state. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa. Moreover, advanced multivariate analyses identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD.
Cytokines; Multiplex ELISA; DSS Colitis; TNBS Colitis; Inflammatory Bowel Disease
TNFAIP3 encodes the ubiquitin modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). In order to further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case/control datasets (1453 total cases, 3381 total controls) and 713 SLE trio families. The best result was found at rs5029939 (P = 1.67 × 10−14, OR = 2.09, 95% CI 1.68–2.60). We then imputed SNPs from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 controls. Imputation identified eleven SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a two-fold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.
systemic lupus erythematosus; TNFAIP3; imputation; meta-analysis
Lipopolysaccharides (LPS), play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. The only therapeutic option aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide is Toraymyxin™, an extracorporeal hemoperfusion device using solid phase-immobilized polymyxin B (PMB). While PMB is known to effectively sequester LPS, its severe systemic toxicity proscribes its parenteral use, and hemoperfusion may not be feasible in patients in shock. In our continuing efforts to develop small-molecule mimics which display the LPS-sequestering properties, but not the toxicity of PMB, a series of mono- and bis-substituted dialkylpolyamines were synthesized and evaluated. We show that EVK-203, analkylpolyamine compound specifically binds to, and neutralizes, the activity of LPS, and affords complete protection in a murine model of endotoxic shock. EVK-203 is without any apparent toxicity when administered to mice at multiples of therapeutic doses for several days. The specific endotoxinsequestering property along with a very favorable therapeutic index renders this compound an ideal candidate for preclinical development.
Endotoxin; Lipopolysaccharide; Sepsis; Septic Shock; Alkylpolyamine; Lipopolyamine
Because hydronephrosis and reflux are reversible, we believe cortical loss represents true renal deterioration in children with spinal dysraphism. Our goal was to better define risk factors for cortical loss.
After institutional review board approval, we reviewed the medical records of 272 children with spinal dysraphism. The following factors were evaluated: age, sex, renal and bladder imaging, urodynamic parameters, medications, catheterization program, continence, infections, and surgical history. Renal cortical loss was defined by scarring or a differential function greater than 15% using a nuclear scan. Univariate and multivariate logistic regression models were fitted to test the associations of specific variables with cortical loss.
Renal cortical loss was found in 41% of children with high-grade reflux vs 2% of children without reflux. Univariate analysis showed only high-grade reflux and female sex to be independent risk factors. Controlling for age and sex, reflux and initiation of catheterization after 1 year of age are significant risk factors. High bladder pressure and hydronephrosis in the absence of reflux were not associated with cortical loss. Multivariate analysis showed that girls with reflux have a 55-fold increased risk of cortical loss.
By limiting the definition of renal deterioration to cortical loss, we identified relevant risk factors: reflux, female sex, and delayed initiation of clean intermittent catheterization. We have also discounted other suspected risk factors: hydronephrosis and elevated bladder pressure. Rather than continuing our focus on hydronephrosis and urodynamics, we believe more research and management debate should be afforded to females with reflux.
Spinal dysraphism; Kidney; Vesicoureteral reflux; Bladder; Urodynamics; Hydronephrosis; Spina bifida; Catheterization; Outcomes research; Myelodysplasia
Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N1,mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.