Biomedical subjects

Alan D Hutson

Publications and source records attributed to Alan D Hutson.

At least 19 recordsLinked to original sources

PubMed2006

Acid aspiration-induced lung inflammation and injury are exacerbated in NADPH oxidase-deficient mice.

Increased reactive oxidant intermediates (ROIs) from primed leukocytes have been implicated in the pathogenesis of acid aspiration lung injury. To evaluate the specific role of the phagocyte NADPH oxidase-derived ROIs in acid lung injury, the p47phox-/- knockout mouse model of chronic granulomatous disease was used. p47phox-/- mice developed a significantly greater alveolar neutrophilic leukocytosis compared with wild-type mice at all time points after acid injury, with the difference between genotypes being most marked at 48 h. In contrast, the p47phox-/- mice had a decreased number of macrophages in bronchoalveolar lavage (BAL) compared with wild-type at 48 h after acid or saline aspiration. Albumin concentration in BAL reflecting capillary leak was also greater in p47phox-/- compared with wild-type mice. BAL concentrations of proinflammatory cytokines and chemokines were greater in p47phox-/- compared with wild-type mice. These findings suggest that NADPH oxidase, directly or indirectly, plays a role in attenuating the acute neutrophilic response after acid lung injury. We speculate that this downmodulating effect may be mediated by promoting the transition from production of cytokines and chemokines involved in neutrophilic infiltration to a less injurious, chronic inflammatory response.

Acids↗

PubMed2006

Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methods.

BACKGROUND: In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD. OBJECTIVES: PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality. METHODS: Patients with documented ischemic cardiomyopathy, an ejection fraction of <or=35%, and with no plans for coronary revascularization will be recruited. Major exclusion criteria include: history of resuscitated SCD, sustained VT, ICD discharge, or unexplained syncope; recent myocardial infarction (30 days), percutaneous coronary intervention (3 months), coronary bypass surgery (1 year); or comorbidities that would be expected to reduce life expectancy to <2 years. All patients will undergo transthoracic echocardiography, and dynamic cardiac positron emission tomography to quantify resting perfusion (13N-ammonia), norepinephrine uptake as an index of sympathetic innervation (11C-meta-hydroxyephedrine), and metabolic viability (18F-2-deoxyglucose during glucose-insulin clamp). The development of SCD or cardiovascular mortality will be determined by telephone follow-up every three months. In patients with an implantable cardiac defibrillator, appropriate device discharge will be considered a surrogate for SCD. CONCLUSION: The PAREPET study will prospectively determine whether the amount of viable dysfunction myocardium and/or cardiac sympathetic dysinnervation is associated with the risk of SCD. It is anticipated that the results of this trial will more specifically identify myocardial substrates of SCD. This will help target therapies intended to reduce arrhythmic death to those patients with the greatest likelihood of benefit.

Arrhythmias, Cardiac↗

PubMed2006

Statistical prediction of the type of gastric aspiration lung injury based on early cytokine/chemokine profiles.

BACKGROUND: Unwitnessed gastric aspiration can be a diagnostic dilemma, and early discrimination of different forms may help to identify individuals with increased risk of development of severe clinical acute lung injury or acute respiratory distress syndrome. The authors hypothesized that inflammatory mediator profiles could be used to help diagnose different types of gastric aspiration. METHODS: Diagnostic modeling using a newly modified receiver operator characteristic approach was applied to recently published data from our laboratory on lavaged inflammatory mediators from rodents given intratracheal normal saline, hydrochloric acid, small nonacidified gastric particles, or a combination of acid and small gastric particles. Multiple animal groups and postaspiration times of injury were analyzed to gauge the applicability of the predictive approach: rats (6 and 24 h), C57/BL6 wild-type mice (5 and 24 h), and transgenic mice on the same background deficient in the gene for monocyte chemoattractant protein 1 (MCP-1 [-/-] mice; 5 and 24 h). RESULTS: Overall, the four types of aspiration were correctly discriminated in 85 of 96 rats (89%), 72 of 78 wild-type mice (92%), and 59 of 73 MCP-1 (-/-) mice (81%) by models that used a maximum of only two mediators. The severe "two-hit" aspirate of the combination of acid and small gastric particles was correctly predicted in 21 of 24 rats, 23 of 23 wild-type mice, and 21 of 21 MCP-1 (-/-) mice. Specific best-fit mediators or mediator pairs varied with aspirate type, animal type, and time of injury. Cytokines and chemokines that best predicted the combination of acid and small gastric particles were cytokine-induced neutrophil chemoattractant 1 (6 h) and MCP-1 (24 h) in rats, tumor necrosis factor alpha/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor alpha/MCP-1 (24 h) in wild-type mice, and tumor necrosis factor alpha/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor alpha/keratinocyte-derived cytokine (24 h) in MCP-1 (-/-) mice. CONCLUSIONS: These results support the potential feasibility of developing predictive models that use focused measurements of inflammatory mediators to help diagnose severe clinical forms of unwitnessed gastric aspiration, such as the combination of acid and small gastric particles, that may have a high risk of progression to acute lung injury/acute respiratory distress syndrome.

Animals↗

PubMed2006

Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.

OBJECTIVE: Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS: Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME: There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor delta-aminolevulinate. CONCLUSIONS: In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.

Acidosis, Lactic↗

PubMed2005

Medical diagnostic testing models for multifactorial disease classifications.

In this note we extend the logistic regression receiver operating characteristic (ROC) analysis framework to diagnosing disease that can be classified in a 2 x 2 factorial setting. Similar to the standard ROC curve analysis these new models accommodate prediction of cross-classifications for treatment success and diagnosis of disease. A didactic example is given for jointly diagnosing malaria positive and respiratory distress in children in Ghana.

Biomarkers↗

PubMed2005

Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1.

A model of aspiration lung injury was developed in WT C57BL/6 mice to exploit genetically modified animals on this background, i.e., MCP-1(-/-) mice. Mice were given intratracheal hydrochloric acid (ACID, pH 1.25), small nonacidified gastric particles (SNAP), or combined acid plus small gastric particles (CASP). As reported previously in rats, lung injury in WT mice was most severe for "two-hit" aspiration from CASP (40 mg/ml particulates) based on the levels of albumin, leukocytes, TNF-alpha, IL-1beta, IL-6, MCP-1, KC, and MIP-2 in bronchoalveolar lavage (BAL) at 5, 24, and 48 h. MCP-1(-/-) mice given 40 mg/ml CASP had significantly decreased survival compared with WT mice (32% vs. 80% survival at 24 h and 0% vs. 72% survival at 48 h). MCP-1(-/-) mice also had decreased survival compared with WT mice for CASP aspirates containing reduced particulate doses of 10-20 mg/ml. MCP-1(-/-) mice given 5 mg/ml CASP had survival similar to WT mice given 40 mg/ml CASP. MCP-1(-/-) mice also had differing responses from WT mice for several inflammatory mediators in BAL (KC or IL-6 depending on the particle dose of CASP and time of injury). Histopathology of WT mice with CASP (40 mg particles/ml) showed microscopic areas of compartmentalization with prominent granuloma formation by 24 h, whereas lung tissue from MCP-1(-/-) mice had severe diffuse pneumonia without granulomas. These results indicate that MCP-1 is important for survival in murine aspiration pneumonitis and appears to act partly to protect uninjured lung regions by promoting isolation and compartmentalization of tissue with active inflammation.

Animals↗

PubMed2004

The utility of partial cross-over designs in early phase randomized prevention trials.

In this note, we outline the benefits of a partial cross-over design for a class of experiments where the interest is the cumulative effect of dose versus placebo. The goal of our design strategy is to answer several complex question efficiently in a phase II setting with a minimal number of assumptions with an eye towards planning a phase III study.

Clinical Trials, Phase II as Topic↗

PubMed2004

The concentration of circulating megakaryocyte progenitors in preterm neonates is a function of post-conceptional age.

Circulating megakaryocyte (Mk) progenitors have been used as a measure of megakaryocytopoiesis in neonates. Prior studies have shown a gestational age-dependent decrease in their concentration, but it is unclear how this process continues after birth in preterm neonates. To answer this question, we quantified the Mk progenitors in the blood of 42 neonates of varying post-conceptional ages (gestational age+days of life). We found an inverse relationship between concentration of circulating Mk progenitors and post-conceptional age (r=-0.54, p=0.0002).

Blood Cell Count↗

PubMed2004

A semiparametric bootstrap approach to correlated data analysis problems.

In this note, we outline a simple to use yet powerful bootstrap algorithm for handling correlated outcome variables in terms of either hypothesis testing or confidence intervals using only the marginal models. This new method can handle combinations of continuous and discrete data and can be used in conjunction with other covariates in a model. The procedure is based upon estimating the family-wise error (FWE) rate and then making a Bonferroni-type correction. A simulation study illustrates the accuracy of the algorithm over a variety of correlation structures.

Algorithms↗

PubMed2004

Methods and design considerations for randomized clinical trials evaluating surgical or endovascular treatments for cerebrovascular diseases.

OBJECTIVE: The results of clinical trials affect the practice of surgery and endovascular therapy for cerebrovascular diseases. The purpose of this report is to review the basic components of the designs and methods for randomized clinical trials and to describe the influence of those components on the interpretation of trial results. METHODS: The goal of an optimal clinical trial of a new procedure is to provide the most objective and rigorous evaluation of the safety and effectiveness of that procedure. Anything in the design, performance, or analysis that impairs such an assessment decreases the ability of the trial to achieve its goal and answer the research question. To highlight the components of a clinical trial, this report uses examples of Phase III clinical trials that have influenced the practice of cerebrovascular surgery and endovascular therapy in the past three decades, including the International Cooperative Study of Extracranial/Intracranial Arterial Anastomosis, the North American Symptomatic Carotid Endarterectomy Trial, the Asymptomatic Carotid Atherosclerosis Study, the Prolyse in Acute Cerebral Thromboembolism II study, and the International Subarachnoid Aneurysm Trial. RESULTS: The research question (objective) of the trial must be clearly defined, with an objective measure of efficacy and a specified quantitative difference to define the superiority of one intervention over another, in a relatively homogeneous patient population. Allocation concealment, randomization with or without stratification, and blinding (or masking) are important strategies to prevent differences in the study populations that could adversely affect the conclusions of the study. The primary end point must correspond to the specific aims of the trial. It should be objectively defined, quantifiable, reliable, and reproducible. Commonly defined end points in surgical trials include changes from baseline illness or disease severity scores, morbidity and mortality rates, and relative risks of reaching an end point with time. The statistical methods used for interim and final analyses are important. The effects of dropouts, crossovers, and missing data should be understood in the context of the final analysis. Additional concepts, such as intention-to-treat analysis and use of actual versus predicted outcomes, are important with respect to interpretation of the final results of the study. CONCLUSION: The neurosurgical and neuroendovascular communities are currently planning or conducting several clinical trials to evaluate new procedures for the treatment of cerebrovascular diseases. It is hoped that a better understanding of the components of clinical trials will facilitate the design and implementation of effective studies.

Angioplasty↗

PubMed2004

Reticulated platelet percentages in term and preterm neonates.

OBJECTIVES: The authors aimed to determine whether their reticulated platelet percentage (RP%) analysis technique was suitable for use in term and preterm neonates and to characterize RP% values among nonthrombocytopenic neonates. METHODS: The authors modified a whole blood method that uses dual-color CD41 staining for platelet gating and thiazole orange for RNA content, combined with RNase treatment of half the sample to subtract non-RNA fluorescence. The RP% was measured in samples from 10 healthy adults and then a longitudinal study was performed in 15 nonthrombocytopenic preterm neonates on days of life 0 to 1, 2 to 5, 6 to 10, and then weekly until day 28. The authors also performed a cross-sectional study of RP% in 22 nonthrombocytopenic neonates of different gestational age (GA) and postconceptional age (PCA). RESULTS: Overall, neonates had a higher RP% (2.7 +/- 1.6%) than adults (1.1 +/- 0.5%; P < 0.01). In preterm neonates, an increase in the RP% occurred between days 0 and 1 (3.3 +/- 1.3%) and days 2 and 5 (5.1 +/- 1.8%; P = 0.003). By days 6 to 10, the RP% decreased to 3.2 +/- 1.1% and remained unchanged throughout the rest of the study period. In neonates less than 7 days old, an inverse relationship was observed between RP% and GA (n = 20, r = -0.70; P = 0.0005). A correlation between RP% and PCA was not seen in neonates 7 days of age or older. CONCLUSIONS: This method for determining RP% is suitable for use in term and preterm neonates. In preterm infants, the RP% significantly increases over the first 2 to 5 days of life and then decreases to a stable level over the first 28 days. RP% is generally higher in neonates than in adults. Among preterm infants in the first week of life, the RP% is inversely related to GA.

Adult↗

PubMed2003

Effects of anoxia on megakaryocyte progenitors derived from cord blood CD34pos cells.

BACKGROUND: Severe hypoxic insults to the fetus and neonate are associated with the development of thrombocytopenia. The thrombocytopenia in some cases is the result of disseminated intravascular coagulation, but that mechanism fails to account for all, perhaps the majority, of cases. OBJECTIVE: We hypothesized that human fetal megakaryocyte (Mk) progenitors are directly adversely affected by transient anoxia. DESIGN AND METHODS: To test this, we isolated CD34pos cells from the umbilical cord blood of 10 healthy term neonates, and exposed these to 0% or 20% O2 for 24 h, with or without recombinant thrombopoietin (rTpo, 50 ng/mL). After 24 h, a portion of the CD34pos cells were harvested for flow cytometric evaluation of apoptosis. The remaining cells were cultured for an additional 10-12 days, under normoxic conditions, in a collagen-based serum-free system containing rTpo, IL-3, and IL-6. In this way, we sought to determine the effect of transient anoxia on clonogenic capacity of Mk progenitors. RESULTS: Contrary to our hypothesis, anoxia did not increase either apoptosis or cell death of the CD34pos cells. The addition of rTpo was protective, with a significant decrease in apoptosis and cell death (P < 0.0001), and an increase in the number of Mk colonies cultured (P = 0.04). There was no difference between the normoxic and anoxic groups in proliferative potential of the Mk progenitor cells. CONCLUSIONS: The thrombocytopenia observed in neonates following an acute hypoxic event is not likely due to a direct deleterious effect of hypoxia on Mk progenitors.

Antigens, CD34↗

PubMed2003

Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children.

The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic-pharmacodynamic indirect-response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drug's lactate-lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.

Acidosis, Lactic↗

PubMed2003

Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults.

OBJECTIVE: To determine the effects of exercise, without weight loss, on insulin sensitivity (S(I)), postheparin plasma lipase activity (PHPL), intravenous fat clearance rate (K(2)), and fasting lipids in sedentary adults. RESEARCH DESIGN AND METHODS: At baseline and after 6 months of walk training (intensity 45-55 or 65-75% heart rate reserve, frequency 3-4 or 5-7 days/week, duration 30 min/session), anthropometric indexes, S(I), PHPL, K(2), and fasting lipids were measured in 18 sedentary adults (12 women, 6 men; 51.9 +/- 5.8 years of age, BMI 28.9 +/- 4.6 kg/m(2)). RESULTS: Exercise increased S(I) (2.54 +/- 2.74 vs. 4.41 +/- 3.30 microU ml(-1) x min(-1), P < 0.005) and both lipoprotein lipase (LPL) (1890 +/- 1380 vs. 4926 +/- 1858 nEq free fatty acid [FFA]. ml(-1). h(-1)) and hepatic lipase (HL) activities (3326 +/- 1605 vs. 4636 +/- 1636 nEq FFA. ml(-1) x h(-1)) (both P < 0.001), without altering BMI, waist circumference, K(2), or fasting lipids. Correlations between changes in LPL and the total:HDL cholesterol ratio (r = -0.54) and changes in the LPL:HL ratio and waist circumference (r = -0.50) were significant (P < 0.05). CONCLUSIONS: Exercise, without weight loss, increases S(I) and PHPL activity in previously sedentary adults, without changing K(2) or fasting lipid levels. Furthermore, increased LPL is associated with a decreased total:HDL ratio, and an increased LPL:HL ratio is associated with a decreased waist circumference. Therefore, even modest amounts of exercise in the absence of weight loss positively affect markers of glucose and fat metabolism in previously sedentary, middle-aged adults.

Biomarkers↗

PubMed2003

Efficacy of dichloroacetate as a lactate-lowering drug.

Dichloroacetate (DCA) decreases blood, cerebral spinal fluid, and intracellular lactate concentrations by activating the mitochondrial pyruvate dehydrogenase enzyme complex. The authors reviewed the efficacy of this investigational drug in the treatment of acquired or congenital forms of lactic acidosis from data in 40 English-language publications. The hypolactatemic effect of DCA occurs over a broad range of pretreatment lactate concentrations and is directly related to the baseline lactate level. The maximum lactate-lowering effect of the drug is dependent on its dose but independent of time following its administration. Recent clinical studies of acquired lactic acidosis suggest that DCA could be rapidly effective in reducing this risk factor of mortality in patients with mild hyperlactatemeia.

Acidosis, Lactic↗

PubMed2002

Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer.

CDC6 plays a critical role in regulation of the onset of DNA replication in eukaryotic cells. We have found that Cdc6 expression is down-regulated in prostate cancer as detected by semiquantitative reverse transcriptase-PCR of prostate cell lines and laser-captured microdissected prostate tissues. This result was substantiated by immunohistochemical analysis of paraffin-embedded tissue sections and immunoblot analysis of benign (BPH-1) and adenocarcinomatous prostatic cells. Furthermore, a 100-fold reduction in the transcription efficiency of the Cdc6 promoter-luciferase construct was noted in the metastatic PC3 cells compared with that in BPH-1 cells. Concentration of the E2F and Oct1 transcription factors that have putative binding sites in the Cdc6 promoter was substantially low in PC3 cells compared with BPH cells. Mutagenesis of the two E2F binding sites on the Cdc6 promoter resulted in increased promoter activity in PC3 cells owing to elimination of the negative regulation by pRb.E2F complex but not to the level of that obtained in BPH cells. We conclude that an altered interaction of transcription factors may be responsible for the down-regulation of Cdc6 transcription in PC3 cells. Our study suggests a potential use of the lack of CDC6 expression as an index of prostate cancer development.

Adenocarcinoma↗

PubMed2002

Effect of recombinant erythropoietin on "late" transfusions in the neonatal intensive care unit: a meta-analysis.

OBJECTIVES: Using the approach of a meta-analysis, we sought to determine whether the administration of recombinant erythropoietin (rEpo) to very low birth weight (VLBW) infants, after the first week of life, results in fewer "late" transfusions. STUDY DESIGN AND METHODS: The guidelines set forth by the Cochrane Neonatal Review Group were used to identify all relevant studies. Medline was searched from January 1990 to November of 2000. Studies that used a randomized, placebo-controlled, and double-masked design were deemed acceptable. RESULTS: Eight studies meet the inclusion criteria. These involved 357 VLBW neonates: 183 rEpo and 174 placebo recipients. The neonates in the rEpo group received fewer erythrocyte transfusions during the study period than did those in the placebo group; the common odds ratio (OR)=0.33; 95% confidence interval (CI) 0.21-0.51. Furthermore, the rEpo effect size was a function of the dose of rEpo administered (p=0.0001). CONCLUSION: A meta-analysis of the most scientifically rigorous studies on this topic indicates that administration of rEpo to VLBW infants reduces "late" erythrocyte transfusions in a dose-dependent manner.

Blood Transfusion↗

PubMed2002

Renal manifestations of congenital lactic acidosis.

Congenital lactic acidoses (CLAs) constitute a group of rare inborn errors of mitochondrial metabolism in which cellular energy failure is the defining biochemical abnormality. We report the principal manifestations of renal dysfunction in 35 children with CLA caused by defects in either the pyruvate dehydrogenase multienzyme complex or one or more components of the respiratory chain. The most prominent renal abnormalities included bicarbonaturia, phosphaturia, hypercalciuria, complete Fanconi's syndrome, proteinuria, and decreased glomerular filtration rate. These data were compared with those from 79 previously published cases. Clinical manifestations of renal dysfunction in CLA are common and may be the first presenting sign of the disease. The glomerulus and proximal renal tubule appear to be the anatomic sites most vulnerable to abnormal mitochondrial energy transduction. We propose that the primary defect in mitochondrial energy metabolism, together with the consequent intracellular accumulation of lactate and hydrogen ions, precipitates a state of tissue injury that, unless interrupted, becomes self-perpetuating and ultimately leads to renal cell death.

Acidosis, Lactic↗