Search PubMed⌕ Search

Biomedical subjects

James A Koziol

Publications and source records attributed to James A Koziol.

At least 19 recordsLinked to original sources
PubMed2006

On the analysis and interpretation of outcome measures in stroke clinical trials: lessons from the SAINT I study of NXY-059 for acute ischemic stroke.

BACKGROUND AND PURPOSE: A variety of primary end points have been used in acute stroke trials. We focus on the modified Rankin Scale, a reliable and valid ordinal outcome measure that assesses disability on a 7-point scale. METHODS: We provide an abbreviated discussion of analytical methods for ordinal scales, and related effect size measures; we illustrate these methods and their interpretation with outcome data from the SAINT I study of NXY-059 in acute ischemic stroke. RESULTS: The nonparametric Mann-Whitney statistic provides a straightforward method for analysis of the modified Rankin Scale, and incorporates associated measures of effect size. These measures are directly related to the concepts of Number Needed to Treat and Number Needed to Harm. CONCLUSIONS: Our re-examination of the outcome data from the SAINT I study provides little evidence for the purported efficacy of NXY-059. More broadly, analysis and interpretation of ordinal outcome scales based on ascribed numerical values to the steps of the scale should be done cautiously. Statistical treatment of multiple primary outcome measures in acute stroke clinical trials should be established before analysis. Lastly, conflating statistical and clinical significance should be avoided.

Acute Disease↗
PubMed2006

Application of capture-recapture models to estimation of protein count in MudPIT experiments.

MudPIT is an automated shotgun proteomics approach that enhances the separation of peptides for sequencing by mass spectrometry analysis.We here adapt a mathematical model from ecology, namely, the capture-recapture model with a closed population and time-varying and heterogeneous individual probabilities of capture, to model the number of peptide identifications across the various cycles of a typical MudPIT experiment. In the absence of any prior information on abundance levels, the model can be used to estimate the total number of proteins in the experimental sample. We apply the model to a recent MudPIT-based experiment to estimate the total number of rat lung endothelial cell surface proteins. The model provides some practical guidelines for planning MudPIT experiments.

Animals↗
PubMed2005

Asymmetries in the spatial distributions of enhancing lesions and black holes in relapsing-remitting MS.

Magnetic resonance imaging (MRI) is the most important paraclinical test in the diagnosis of multiple sclerosis (MS) and for delineating its natural history. We investigate MRIs from a longitudinal study of 24 relapsing-remitting MS patients who had monthly MRI examinations for one year, and were not receiving active MS therapy during this period. We hypothesized that lesions occur randomly throughout the brain, and that patients are homogeneous with regard to spatial patterns of lesion presentation. We recorded the numbers and locations of enhancing lesions and hypointense lesions (black holes) in all scans, and found asymmetrical patterns of lesions about the mid-transaxial, mid-coronal, and mid-sagittal planes. Furthermore, in distinct subsets of patients, enhancing lesions and black holes tend to occur in the same locations. Clustering in lesion locations may be of functional significance, with consequent therapeutic implications.

Adult↗
PubMed2005

A note on generalized Genome Scan Meta-Analysis statistics.

BACKGROUND: Wise et al. introduced a rank-based statistical technique for meta-analysis of genome scans, the Genome Scan Meta-Analysis (GSMA) method. Levinson et al. recently described two generalizations of the GSMA statistic: (i) a weighted version of the GSMA statistic, so that different studies could be ascribed different weights for analysis; and (ii) an order statistic approach, reflecting the fact that a GSMA statistic can be computed for each chromosomal region or bin width across the various genome scan studies. RESULTS: We provide an Edgeworth approximation to the null distribution of the weighted GSMA statistic, and, we examine the limiting distribution of the GSMA statistics under the order statistic formulation, and quantify the relevance of the pairwise correlations of the GSMA statistics across different bins on this limiting distribution. We also remark on aggregate criteria and multiple testing for determining significance of GSMA results. CONCLUSION: Theoretical considerations detailed herein can lead to clarification and simplification of testing criteria for generalizations of the GSMA statistic.

Chromosome Mapping↗
PubMed2005

CT-ultrasound fusion prostate brachytherapy: a dynamic dosimetry feedback and improvement method. A report of 54 consecutive cases.

PURPOSE: The authors describe a prostate brachytherapy technique with dynamic dosimetry feedback, using coregistered CT and ultrasound (US) images, to map initial dosimetry deficiencies and guide remedial source placement. METHODS AND MATERIALS: Fifty-four consecutive patients treated with this method were analyzed for coregistration accuracy and dosimetry outcomes by evaluating the prostate V100, V150, D90, and urethral D50 and D10. Dosimetric improvements created by remedial source placement and preplan/postplan prostate D90 agreement were evaluated. RESULTS: Median CT-US coregistration discrepancy with this technique ranged from 0 to 4mm, with the posterior midline prostate and base prostate providing the least consistent and the urethra providing the most consistent coregistration agreement. Final prostate V100 values ranged from 96.1% to 99.8% for all patients. The addition of remedial sources directed by CT-US fusion produced V100 and D90 improvements whose magnitude inversely correlated with the initial result and exceeded the effect of adding quantitatively identical randomly distributed increased millicuries. The final prostate D90 result agreed within (-) 5% to (+) 10% of the preplan result in 98% of all patients. CONCLUSIONS: CT-US fusion prostate brachytherapy represents a dynamic dosimetry feedback and remediation method that consistently produced high prostate V100 and D90 values with acceptably low urethra D50 and D10 values in our study. The degree of prostate V100 and D90 dosimetry improvement created by remedial source placement effectively matched the degree of initial dosimetry deficiency. This method produced a high level of correlation between the preplan and final prostate D90 values.

Adult↗
PubMed2005

Genetic dissection of innate immunity to infection: the mouse cytomegalovirus model.

Resistance to infection is largely inherited rather than acquired, and is encoded by a definable set of host genes designated the 'resistome'. Logically speaking, piecemeal disruption of the resistome gives us the best chance to define it, and the most spectacular advances in understanding innate immunity have grown from spontaneous or induced germline mutations of the resistome. Mutations induced by random germline mutagenesis have now become so numerous that we are nearly in a position to define the size of the resistome, and both random and targeted mutations give us a fairly nice sketch of its components and how they interact. Our own N-ethyl-N-nitrosourea mutagenesis effort, which recently showed that components of Toll-like receptor signaling are essential constituents of the arsenal against MCMV infections, validated the forward genetic approach as a powerful tool to define the resistome.

Animals↗
PubMed2005

Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels.

Developing cerebral infarction obscures the relationship of neurons to their local supply microvessels. We tested the notion that in the basal ganglia (i) an ordered relationship between neurons and their nearest neighboring microvessel exists, and (ii) focal ischemia predictably affects neuron integrity based on microvessel-neuron proximity. Distances between individual microvessels and their nearest neurons ([m-n distance]s) were measured in normal primates and ischemic subjects undergoing middle cerebral artery occlusion for 2 hours. An ordered microvessel-neuron relationship exists in the normal nonischemic basal ganglia within the early hours of focal ischemia. During ischemia normal (n) and sensitive (n*) neurons are interspersed. On average, neurons more distant from their nearest microvessel are most sensitive ([m-n distance]=16.2+/-11.2 microm versus [m-n* distance]=22.2+/-13.0 microm, 2P<0.00000001). Neurons not expressing glutamic acid decarboxylase were more likely to be sensitive than those with a normal microvessel-neuron relationship. In contrast, the [m-n distance] distribution of injured tyrosine hydroxylase-containing neurons was similar to those without tyrosine hydroxylase. Hence, the [m-n distance] relationship in the normal and ischemic basal ganglia is highly ordered, and distant neurons are consistently perturbed by ischemia, although this is not uniformly dependent on neurotransmitter type.

Animals↗
PubMed2005

Utility and efficacy of fluticasone propionate and salmeterol inhaled from a single inhaler for persistent asthma.

The utility of a new therapy, in this instance fluticasone and salmeterol combination (FSC), is determined by multiple uncontrollable factors in individual patients and can be measured by continued use and efficacy over time. Over one year from April 2001, 186 patients with persistent asthma were switched from controller pharmacotherapy to FSC at equidose to prior inhaled corticosteroid. Follow-up data on 171 (92%) indicated 129 (75%) had continued FSC for one year. Compared to the 42 who discontinued FSC, those who continued had significant reduction of asthmatic exacerbations, improved spirometry, and reduced usage of inhaled reliever and systemic corticosteroid.

Adolescent↗
PubMed2005

Quantifying symptoms in men with interstitial cystitis/prostatitis, and its correlation with potassium-sensitivity testing.

OBJECTIVE: To determine whether men previously diagnosed with prostatitis also have pathology originating in the bladder. PATIENTS, SUBJECTS AND METHODS: We administered the pelvic pain and urgency/frequency (PUF) questionnaire and the potassium-sensitivity test (PST) to 50 patients with prostatitis presenting in urological and primary care, and to 14 controls. In a separate control group of 22 men, the urethra was irrigated with KCl or NaCl (11 each) before and after experimental injury of the urethral mucosa. RESULTS: All 50 patients with prostatitis had PUF scores of > or = 7; 77% were positive for the PST. All 14 controls had PUF scores of 1 or 0 and a negative PST. In the urethral irrigation study in controls, KCl but not NaCl provoked urethral pain after mucosal injury. Before injury, neither KCl nor NaCl caused symptoms. CONCLUSION: The high rate of positive PST in patients with "classic" prostatitis indicates that pathology originating in the bladder may be an important source of symptoms in most. In patients with prostatitis and female patients with interstitial cystitis, symptoms may arise not from separate disease entities but from a continuum of epithelial dysfunction and potassium cycling that may be present throughout the lower urinary tract.

Chronic Disease↗
PubMed2004

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees.

von Willebrand disease (VWD) type 1 is difficult to diagnose because of bleeding variability and low heritability of von Willebrand factor (VWF) levels. We compared a bleeding severity score and bleeding times to candidate gene haplotypes within pedigrees of 14 index cases, using a covariance components model for multivariate traits (Mendel: QTL Association). These pedigrees included 13 affected and 40 unaffected relatives, as defined by plasma ristocetin cofactor (VWF:RCo) levels. The bleeding severity score was derived from a detailed history. Donors were genotyped using a primer extension method, and 9 candidate genes were selected for analysis. VWF:RCo levels had the strongest influence on bleeding severity score and bleeding time. ITGA2 haplotype 2 (807C) and ITGA2B haplotype 1 (Ile(843)) were each associated with increased bleeding severity scores (P < .01 and P < .01, respectively). GP6 haplotype b (Pro(219)) was also associated with increased scores (P = .03) after adjustment for donor age. No association was observed with 6 other candidate genes, GP1BA, ITGB3, VWF, FGB, IL6, or TXA2R. Increased plasma VWF:Ag levels were associated with VWF haplotype 1 (-1793G; P = .02). These results establish that genetic differences in the adhesion receptor subunits alpha(2), alpha(IIb,) and GPVI can influence the phenotype of VWD type 1.

Bleeding Time↗
PubMed2004

Focal cerebral ischemia induces active proteases that degrade microvascular matrix.

BACKGROUND AND PURPOSE: Focal cerebral ischemia causes microvessel matrix degradation and generates proteases known to degrade this matrix. However, proof that the proteases generated do indeed degrade vascular matrix is lacking. Here we demonstrate that active proteases derived from ischemic tissue after middle cerebral artery occlusion (MCAO) and transferred to normal tissue can degrade vascular matrix. METHODS: In an ex vivo bioassay, the effects of supernatants from ischemic and normal basal ganglia of nonhuman primates, proteases, and control buffer on the immunoreactivity of vascular matrix constituents in normal brain tissue sections were quantified. Protease families were identified with specific inhibitors. RESULTS: Plasmin, active matrix metalloproteinase (MMP)-2, and active MMP-9 significantly reduced microvessel-associated collagen, laminin, and heparan sulfate proteoglycans (HSPG). The vascular HSPG perlecan was more sensitive than collagen or laminin in the bioassay and in the ischemic core 2 hours after MCAO. Two-hour and 7-day ischemic tissue samples significantly degraded matrix perlecan and collagen. Inhibitor studies confirmed that while active MMPs were generated, active cysteine proteases significantly degraded microvessel perlecan. The cysteine proteases cathepsins B and L were generated in the microvasculature and adjacent neurons or glial cells 2 hours after MCAO and decreased perlecan in the bioassay. CONCLUSIONS: This is the first direct evidence that active proteases are generated in ischemic cerebral tissues that are acutely responsible for vascular matrix degradation. Degradation of vascular perlecan, the most sensitive matrix component thus far identified, may be due to cathepsins B and L, generated very rapidly after MCAO.

Animals↗
PubMed2004

MMP-9 polymorphisms are not associated with spontaneous cervical artery dissection.

BACKGROUND AND PURPOSE: Cervical artery dissection (CAD) is a common cause of ischemic stroke in young adults. Alteration in the structure of the vascular extracellular matrix has been described in CAD. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and can lead to vascular damage. METHODS: We tested 2 different MMP-9 DNA polymorphisms, a CA repeat and a cytosine to thymidine transition in the promotor sequence, for frequency in 52 patients with CAD. We compared the results with those of 52 healthy controls. RESULTS: No differences were found in the allelic distribution of either polymorphism. CONCLUSIONS: Alleles of these well-characterized functional polymorphisms of MMP-9 gene are not associated with structural alterations in the matrix of vessels of patients with CAD.

Adult↗
PubMed2004

Prostate brachytherapy seed migration and dosimetry: analysis of stranded sources and other potential predictive factors.

PURPOSE: The purpose of this study was to evaluate the influence of potential contributing factors to the incidence of seed migration and quality of prostate brachytherapy dosimetry. METHODS AND MATERIALS: Sixty patients were evaluated with day one and 3-12 month plain films of the pelvis and chest, and day 1 CT-based dosimetry analysis. The incidence and types of seed migration were quantified. The seed migration outcome was evaluated with respect to source type (free vs. stranded), prostate volume, number of seeds, and needles. The day one prostate V100, V150, D90, and urethra D10 outcomes were evaluated with respect to source type, radiation type ((125)I vs. (103)Pd), prostate volume, prostate swelling, and quantity of migrating seeds. RESULTS: An increased incidence of day one and cumulative seed migration was predicted by free vs. stranded source type, with a relative risk of 6.97 and 3.08, respectively. Pulmonary and distal (toward the perineum) migration patterns were significantly reduced in the stranded group. An increased day one prostate V100, V150, D90, and urethra D10 outcome was predicted by stranded source type. CONCLUSION: Stranded source type was associated with decreased seed migration as well as higher prostate and urethra dosimetry values, resulting in an implant in which more radiation resided within the target volume, and less radiation metastasized to undesirable locations.

Brachytherapy↗
PubMed2004

Plasma adrenomedullin and carotid atherosclerosis in atherothrombotic ischemic stroke.

OBJECTIVE: Adrenomedullin is known to exert anti-atherosclerotic actions by inhibiting proliferation and migration of smooth muscle cells in vitro. Here we examine the relationship between the plasma concentration of adrenomedullin and ultrasonographic characteristics of carotid arteries both in ischemic stroke and in the absence of cerebrovascular disease. METHODS: We studied 61 patients with atherothrombotic ischemic stroke in the chronic phase and 50 patients without any cerebrovascular disease. Intima-media thickness and vascular lumen diameters were evaluated by carotid ultrasonography. Plasma mature-adrenomedullin was determined by radioimmunoassay. RESULTS: Plasma mature-adrenomedullin in the patients with atherothrombotic ischemic stroke in the chronic phase (2.01 +/- 0.58 fmol/ml) was significantly higher than that in the patients without any cerebrovascular disease (1.24 +/- 0.18 fmol/ml, P < 0.001). With multiple regression analysis, plasma mature-adrenomedullin was found to be predicted by: stroke status (atherothrombotic ischemic stroke versus no cerebrovascular disease), diabetes status (yes/no), left ventricular ejection fraction, internal carotid artery intima-media thickness, and common carotid artery pressure strain elastic modulus (R = 0.79; F5,105 = 85.39, P < 0.0001). CONCLUSION: Plasma mature-adrenomedullin showed significantly positive associations with carotid atherosclerosis and atherothrombotic ischemic stroke, independent of systolic blood pressure.

Adrenomedullin↗
PubMed2003

Recursive partitioning as an approach to selection of immune markers for tumor diagnosis.

PURPOSE AND EXPERIMENTAL DESIGN: Cancer sera contain antibodies which react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs), but the low frequency of positive reactions against any individual antigen has precluded use of autoantibodies as useful diagnostic markers. With enzyme immunoassay, we examined antibody frequencies to a panel of seven TAAs, c-myc, cyclin B1, IMP1, Koc, p53, p62, and survivin, in 527 cancer patients (64 breast cancer patients, 45 colorectal cancers, 91 gastric cancers, 65 hepatocellular carcinomas, 56 lung cancers, and 206 prostate cancers), and 346 normals. We used recursive partitioning to assess whether we could accurately classify individuals as either cancer patients or normals on the basis of the profile of antibody reactivity to the seven TAAs for each individual. RESULTS: Recursive partitioning resulted in the selection of subsets of the seven-panel TAA, which differentiated between tumors and controls, and these subsets were unique to each cancer cohort. The classification trees had sensitivities ranging from 0.77 to 0.92 and specificities ranging from 0.85 to 0.91 in the cancer cohorts when normal means +2 SDs were used as standard cutoffs for immunoassay positivity. Antibody to cyclin B1 was the initial discriminating node for gastric and lung cancers, and for hepatocellular carcinoma, and was a subsequent discriminating node in all of the other cancer cohorts. c-myc was the initial discriminating node in breast cancer, p62 in prostate cancer, and IMP1 in colon cancer. Recursive partitioning demonstrated that no more than three of the seven TAAs were needed for any cancer cohort to arrive at these levels of sensitivity and specificity. CONCLUSIONS: This initial study shows that multiple antigen miniarrays can provide accurate and valuable tools for cancer detection and diagnosis. Performance of the miniarrays might be enhanced by other combinations of TAAs appropriately selected for different cancer cohorts.

Antibodies, Neoplasm↗
PubMed2003

Comparison of magnetic resonance imaging and transesophageal echocardiography in detection of thrombus in the left atrial appendage.

BACKGROUND AND PURPOSE: A noninvasive technique of visualizing the left atrial appendage (LAA) and its thrombus in patients with atrial fibrillation would be of great interest. This study examined the utility of MRI for the assessment of thrombus in the LAA. METHODS: We evaluated 50 subjects with nonrheumatic continuous atrial fibrillation and a history of cardioembolic stroke. Each patient received an MRI and a transesophageal echocardiography (TEE) on the same day for thrombus detection in the LAA. Both double- and triple-inversion recovery sequences were used for the MRI evaluations. RESULTS: In all subjects, the LAA was readily visualized with MRI. High-intensity masses in the LAA were clearly distinguishable from the LAA wall in the triple-inversion recovery sequences. Concordance between detection of high-intensity mass with MRI and thrombus with TEE was high: no mass (MRI), no thrombus (TEE), 31 patients; mass (MRI), thrombus (TEE), 16 patients; and mass (MRI), no thrombus (TEE), 3 patients (overall kappa=0.876, SE=0.068). CONCLUSIONS: MRI is a noninvasive and reproducible modality for thrombus detection in the LAA of patients with nonrheumatic continuous atrial fibrillation and previous cardioembolic stroke.

Aged↗