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Biomedical subjects

B J Williams

Publications and source records attributed to B J Williams.

At least 37 records · Page 2Linked to original sources
PubMed1999

Bootstrap prediction and confidence bands: a superior statistical method for analysis of gait data.

Gait analysis studies typically utilize continuous curves of data measured over the gait cycle, or a portion of the gait cycle. Statistical methods which are appropriate for use in studies involving a single point of data are not adequate for analysis of continuous curves of data. This paper determines the operating characteristics for two methods of constructing statistical prediction and confidence bands. The methods are compared, and their performance is evaluated using cross-validation methodology with a data set of the sort commonly evaluated in gait analysis. The methods evaluated are the often-used point-by-point Gaussian theory intervals, and the simultaneous bootstrap intervals of Sutherland et al. The Development of Mature Walking, MacKeith Press, London, 1988 and Olshen et al. Ann. Statist. 17 (1989) 1419-40. The bootstrap bands are shown to provide appropriate coverage for continuous curve gait data (86% coverage for a targeted coverage of 90%). The Gaussian bands are shown to provide inadequate coverage (54% for a targeted coverage of 90%). The deficiency in the Gaussian method can lead to inaccurate conclusions in gait studies. Bootstrap prediction and confidence bands are advocated for use as a standard method for evaluating gait data curves because the method is non-parametric and maintains nominal coverage levels for entire curves of gait data.

Gait↗
PubMed1999

Robust optimization of total joint replacements incorporating environmental variables.

Direct search techniques for the optimal design of biomechanical devices are computationally intensive requiring many iterations before converging to a global solution. This, along with the incorporation of environmental variables such as multiple loading conditions and bone properties, makes direct search techniques infeasible. In this study, we introduced new methods that are based on the statistical design and analysis of computer experiments to account efficiently for environmental variables. Using data collected at a relatively small set of training sites, the method employs a computationally inexpensive predictor of the structural response that is statistically motivated. By using this predictor in place of the simulator (e.g., finite element model), a sufficient number of iterations can be performed to facilitate the optimization of the complex system. The applicability of these methods was demonstrated through the design of a femoral component for total hip arthroplasty incorporating variations in joint force orientation and cancellous bone properties. Beams on elastic foundation (BOEF) finite element models were developed to simulate the structural response. These simple models were chosen for their short computation time. This allowed us to represent the actual structural response surface by an exhaustive enumeration of the design and environmental variable space, and provided a means by which to validate the statistical predictor. We were able to predict the structural response and the optimal design accurately using only 16 runs of the computer code. The general trends predicted by the BOEF models were in agreement with previous three-dimensional finite element computer simulations, and experimental and clinical results, which demonstrated that the important features of intramedullary fixation systems were captured. These results indicate that the statistically based optimization methods are appropriate for optimization studies using computationally demanding models.

Algorithms↗
PubMed1999

A randomized efficacy trial of citicoline in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Citicoline (cytidine-5'-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects. METHODS: The current trial was a 33-center, randomized, double-blind, efficacy trial in 394 patients comparing placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week posttreatment follow-up period. Patients with acute (24 hours) ischemic strokes clinically assessed to be in the middle cerebral artery territory with National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled. RESULTS: Mean time to treatment was 12 hours, and mean age was 71 for placebo and 70 for citicoline. Although mean baseline NIHSS were similar for both groups, there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%; P<0.01). The incidence and type of side effects were similar between the groups. The planned primary analysis (logistic regression: 5 categories Barthel) failed the proportional odds assumption and was rendered unreliable. There were no between-group differences seen on the planned secondary assessment analyses at 90 days, including the Barthel Index > or = 95 at 12 weeks (last observation carried forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline 17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS > or = 8 found that citicoline-treated patients were more likely to have a full recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no difference was seen in patients with baseline NIHSS<8 (placebo 77%; citicoline 69%; P>0.1. CONCLUSIONS: The results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit.

Aged↗
PubMed1999

Autism and autistic behavior in Joubert syndrome.

To determine whether individuals with Joubert syndrome exhibit features of autism as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), we examined 11 children with Joubert syndrome using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. Three children met DSM-IV criteria for autistic disorder and one for pervasive developmental disorder not otherwise specified. The other seven all demonstrated at least one DSM-IV symptom of autism, but did not meet criteria for a pervasive developmental disorder. Both total number of DSM-IV symptoms and number of social symptoms distinguished the autism and nonautism subgroups. In contrast, the two subgroups displayed similar levels of communication impairments and repetitive or stereotyped behavior. The key to diagnosing autism in Joubert syndrome is to focus on social behaviors, particularly milestones typically achieved very early in life (eg, attending to human voices, showing objects of interest, enjoyment of social interactions). Implications for the role of the cerebellum in nonmotor behavior and for clinical management of Joubert syndrome also are discussed.

Adolescent↗
PubMed1999

Effect of sodium cloprostenol and flunixin meglumine on luteolysis and the timing of birth in bitches.

At birth, the physiological role of prostaglandins in bitches is unclear. Bitches were treated before parturition with either saline, the prostaglandin analogue, sodium cloprostenol, or the prostaglandin synthetase inhibitor, flunixin meglumine. The animals were examined regularly to determine the onset of parturition and a series of blood samples were taken to define the hormonal profiles before, during and after birth. Animals treated with cloprostenol whelped earlier than did controls. In addition, the prostaglandin F2 alpha metabolite surge and decrease in plasma progesterone concentration and rectal temperature were earlier than in controls. Flunixin meglumine disrupted the normal 13,14-dihydro-15-keto prostaglandin F2 alpha profile but did not abolish prostaglandin synthesis completely or delay the onset of labour in treated animals. This study confirms that prostaglandins induce luteolysis and the onset of labour in the bitch. However, the partial inhibition of prostaglandin synthesis does not prevent parturition.

Analysis of Variance↗
PubMed1998

Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2.

Chromosomal abnormalities in acute leukemia have led to the discovery of many genes involved in normal hematopoiesis and in malignant transformation. We have identified the fusion partners in an inv(8)(p11q13) from a patient with acute mixed lineage leukemia. We show by fluorescence in situ hybridization (FISH) analysis, Southern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) that the genes for MOZ, monocytic leukemia zinc finger protein, and TIF2, transcriptional intermediary factor 2, are involved in the inv(8)(p11q13). We demonstrate that the inversion creates a fusion between the 5' end of MOZ mRNA and the 3' end of TIF2 mRNA maintaining the translational frame of the protein. The predicted fusion protein contains the zinc finger domains, the nuclear localization domains, the histone acetyltransferase (HAT) domain, and a portion of the acidic domain of MOZ, coupled to the CREB-binding protein (CBP) interaction domain and the activation domains of TIF2. The breakpoint is distinct from the breakpoint in the t(8;16)(p11;p13) translocation in acute monocytic leukemia with erythrophagocytosis that fuses MOZ with CBP. The reciprocal TIF2-MOZ fusion gene is not expressed, perhaps as a result of a deletion near the chromosome 8 centromere. The MOZ-TIF2 fusion is one of a new family of chromosomal rearrangements that associate HAT activity, transcriptional coactivation, and acute leukemia.

Acetyltransferases↗
PubMed1997

Spontaneous exfoliation of teeth following severe elemental mercury poisoning: case report and histological investigation for mechanism.

BACKGROUND: Although the spontaneous exfoliation of teeth and breakdown of oral tissues from severe mercury intoxication have been noted for over a century, there are no published reports investigating the mechanisms of these phenomena. Severe mercury poisoning is rare in modern times, but it does occur. We present a case report and a histopathologic investigation into the mechanism of the associated tooth loss. METHODS: An exfoliated tooth and periodontal and gingival tissues were obtained from a 15-month-old patient who had been severely intoxicated with elemental mercury over a period of months and hospitalized for severe neurologic and renal effects. The tissues were examined both by routine hematoxylin and eosin stain and by autometallography specific for mercury. For comparison, control tissue from an age-matched subject was examined with the autometallography technique. RESULTS: Under light microscopy, the gingival tissue showed evidence of moderate to severe acute and chronic inflammation. The tooth pulp tissue showed evidence of moderate vascular dilatation and congestion, and it was infiltrated by many neutrophils. The autometallographic sections showed intense accumulations of mercury in the soft tissues of the mercury-exposed subject, but not in the tissues of the control subject. The deposits were primarily found in fibroblasts, which are essential to maintaining the integrity of the oral tissues. CONCLUSIONS: Histopathologic and autometallographic examination of the affected tissue indicates that the primary mechanism of the spontaneous sloughing of tissue and loss of teeth may be the cytotoxic effects of the accumulation of mercury in fibroblasts. Studies of additional cases would be valuable to confirm this hypothesis.

Case-Control Studies↗
PubMed1997

Ability analysis of gender relevance and sex differences in cardiovascular response to behavioral challenge.

Cardiovascular effects of gender-specific ability perceptions (ability perceptions linked to one's identity as being female or male) were examined under different task conditions. In Study I, participants were led to believe that either men (masculine task) or women (feminine task) tend to do well on a memory task and then were provided the chance to avoid noise by attaining a low or high performance standard. As expected, sex differences in systolic blood pressure response during performance depended not only on task type but also on the degree of challenge. In Study 2, high standard effects were strengthened and extended through the use of an appetitive procedure and the inclusion of conditions in which the performance standard was extreme. Findings are discussed in terms of an interactional analysis of ability percepts, task demand, and cardiovascular responsivity.

Adolescent↗
PubMed1997

Variable memory profiles in Parkinson's disease.

Thirty-nine patients with Parkinson's disease (PD) were categorized into one of three subgroups using discriminant function analysis and three key indices from the California Verbal Learning Test (CVLT). Patients were classified as having one of three memory profiles: (a) a normal memory profile; (b) a memory profile often observed in patients with Huntington's disease (HD); or (c) a memory profile often observed in patients with Alzheimer's disease (AD). Twenty of the patients with PD were classified as having a normal profile, 10 as having an HD profile, and 9 as having an AD profile. The three subgroups did not differ on measures of global cognitive functioning, letter fluency, confrontation naming, or visuo-construction, suggesting that the patients with PD with an AD memory profile were not experiencing AD, per se. These results demonstrate that the memory deficits associated with PD can be similar to those found in patients with either HD or AD, and argues against the notion that the behavioral manifestations of PD are homogeneous.

Age Factors↗
PubMed1997

Performance of Parkinson's disease patients on the Visual Search and Attention Test: impairment in single-feature but not dual-feature visual search.

Nondemented patients with Parkinson's disease (PD) and a group of age and education matched controls were administered a modified version of the Visual Search and Attention Test (VSAT). This task measures subjects' speed at localizing letter or symbol targets based on either a single-feature or a dual-feature search. Three indices were derived from the VSAT: (a) the amount of time taken to complete each of the trials (completion time), (b) the number of target items not crossed out (omissions), and (c) the number of nontarget items crossed out (commissions). The results indicated that, in terms of completion time, the PD patients were impaired on the single-feature search conditions but not on the dual-feature search conditions, suggesting that PD patients are impaired in selective attention processes. It was also found that the number of target items omitted by the normal controls on the VSAT varied as a function of the nature of the target (letter or form) and the search requirements (single-feature or dual-feature search), whereas the number of targets omitted by the PD patients was not affected by these factors. Correlational analyses suggested that the three measures derived from the VSAT assessed different components of attentional performance in these patients. Overall, the results of this study suggest that the VSAT can be used to detect subtle attentional impairments in nondemented PD patients, and that the pattern of their impairment on this clinical test is similar to that found on experimental attentional measures.

Journal Article↗
PubMed1997

Allelic loss detected on chromosomes 8, 10, and 17 by fluorescence in situ hybridization using single-copy P1 probes on isolated nuclei from paraffin-embedded prostate tumors.

We have implemented a reliable new technique for preparing isolated prostate cancer nuclei from paraffin-embedded tissue sections followed by analysis with single-copy fluorescence in situ hybridization (FISH). Our initial validation is described by comparison of our data with fresh prostate tumor tissue and loss of heterozygosity (LOH) studies. We also describe evaluation of 36 previously unstudied prostate cancer patients. Fifteen archival samples were selected from patients who underwent radical prostatectomy in which direct FISH and LOH data were available. Isolated nuclei were prepared and allelic loss was detected on 17q using a single-copy DNA (P1 phage) probe by FISH. A high (80%) concordance was found when comparing isolated nuclei data with 17q results from fresh preparations and LOH studies. We also examined loss at sites on 8p, 10q, and 17q in samples from 36 patients for whom clinical information was available. Loss was found at any of the three loci in 32/36 (89%) of the specimens with specific loss in 53% of the cases at the 8p locus, 33% at the 10q locus, and 61% at the 17q locus. Studies indicate that, as well as providing potential clinical information, isolated nuclei preparations are as reliable as fresh tissue for single-copy FISH studies.

Aged↗
PubMed1997

Comparative genomic hybridization and molecular cytogenetic characterization of two prostate cancer xenografts.

Conventional cytogenetic analysis of two prostate tumor xenografts, LuCaP 23.1 and RP22090, was unsatisfactory for comprehensive genetic evaluation of the cell lines. Fluorescence in situ hybridization (FISH) for chromosome enumeration and comparative genomic hybridization (CGH) for numerical imbalance detection were performed and resulted in a more complete molecular cytogenetic characterization of these lines. Both xenografts were hypertriploid and had significant numerical imbalances. For example, LuCaP 23.1 had gain of all or part of chromosomes 3, 5, 6, 7, 8, 11, and 12 and the X chromosome and loss of all or part of chromosomes 2, 3 6, 8, 9, 10, 17, and 18. In RP22090, gain of all or part of chromosomes 5, 7, 8, 9, 10, 12, 14, and 15 was seen, whereas loss was seen for all or part of chromosomes 4, 6, 8, 15, 16, 17, 19, 20, and 22. Both xenografts reflect the high frequency of chromosomal changes seen in some late-stage prostate cancers, including many novel changes and some changes such as the loss of 8p and gain of 8q, which have been reported previously in primary and metastatic prostate cancers. Consistent changes in both lines, such as loss of chromosomes 6 and chromosome arm 8p and gain of chromosome 7 and chromosome arm 8q, may represent genetic events specific for prostate cancer development, but imbalances on other chromosomes such as 3, 9, 19, and 20, not frequently reported in prostate cancers, may reflect potentially important changes that should also be examined.

Adenocarcinoma↗
PubMed1996

Evidence for a tumor suppressor gene distal to BRCA1 in prostate cancer.

PURPOSE: The breast-ovarian cancer susceptibility gene, BRCA1, has been implicated by both epidemiologic and genetic studies to be involved in prostate cancer. We wished to test the frequency of BRCA1 deletion and that of other markers in the region of proximal 17q in prostate tumor cells. MATERIALS AND METHODS: We used a dual-color fluorescence in situ hybridization (FISH) assay using P1 phage probes for the BRCA1 gene and 3 flanking sites at 17q12-21, as well as a chromosome 17 centromere-specific alpha-satellite probe, to detect deletions in single-cell suspensions and touch preparations from 23 primary clinical stage B prostate tumors and adjacent nontumor prostate tissues. Lymphoblastoid cells and prostate cells from a normal donor were used to determine control loss values. RESULTS: Significant loss (p < 0.05) of at least 1 of the P1s was detected in 16 of 23 (70%) cases, and in 4 of those cases all markers were lost, consistent with whole chromosome loss. Of the 12 cases with subchromosomal loss, 8 had loss distal to BRCA1. Loss was detected in 5 cases previously reported by using allelic imbalance (AI) methodologies, and was detected in an additional 11 non-AI cases, suggesting that FISH is more sensitive than AI for deletion detection in prostate tumor cells. CONCLUSIONS: The data suggest that the region distal to BRCA1 may contain 1 or more prostate-specific tumor suppressor genes and that BRCA1 itself plays only a minor role in prostate cancer development.

BRCA1 Protein↗
PubMed1995

Loss of chromosome 17 loci in prostate cancer detected by polymerase chain reaction quantitation of allelic markers.

Using a polymerase chain reaction/microsatellite marker system, we demonstrated that 6 of 22 (27%) clinical stage B (early) primary prostate tumors showed loss of heterozygosity at one or more of five loci on chromosome 17. The sensitivity of this study was increased by use of a PhosphorImager and statistical analysis of replicate tumor-normal DNA pairs. Two patients showed tumor-specific interstitial loss at a locus in close proximity to the familial breast cancer gene BRCA1. These findings suggest that genes on the proximal long arm of chromosome 17 play a pivotal role in the early development of at least a subset of prostatic tumors.

Alleles↗