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Biomedical subjects

B J Williams

Publications and source records attributed to B J Williams.

At least 19 recordsLinked to original sources
PubMed2003

The prevalence of men with National Institutes of Health category IV prostatitis and association with serum prostate specific antigen.

PURPOSE: We evaluated the prevalence and relationship of serum prostate specific antigen (PSA) levels in a screening population of men diagnosed with National Institutes of Health (NIH) category IV prostatitis. MATERIALS AND METHODS: In September of 2001, 300 men were randomly selected from our prostate cancer awareness screening program to be evaluated for NIH category IV prostatitis. After informed consent was obtained all patients completed the NIH prostate cancer awareness survey and had a serum sample obtained for PSA before examination. Expressed prostatic secretions were obtained from 227 of the 300 participants. Patients were classified according to findings on examination of the expressed prostatic secretions. The records were entered into our data base and subsequently reviewed. RESULTS: The prevalence of NIH category IV prostatitis was 32.2% in our population of men. Patient age, American Urological Association symptom scores and clinical prostate gland size did not differ between men with or without evidence of prostatitis on expressed prostatic secretion examination. Men with NIH category IV prostatitis had a mean serum PSA level of 2.3 which was significantly higher (p <0.0004) than those without prostatitis (mean PSA 1.4). CONCLUSIONS: These data suggest that NIH category IV prostatitis is fairly prevalent (32.2%) among men in the general population who present for prostate cancer screening and appears to contribute to increased serum PSA levels in some men.

Humans↗
PubMed2001

An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration.

1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

Administration, Oral↗
PubMed2001

CaT1 expression correlates with tumor grade in prostate cancer.

Ca(2+) signaling is important for growth and survival of prostatic carcinoma (PCa) cells. Here we report that the gene for CaT1, a channel protein highly selective for Ca(2+), is expressed at high levels in human PCa and in the LNCaP PCa cell line. CaT1 mRNA levels were elevated in PCa specimens in comparison to benign prostatic hyperplasia (BPH) specimens and positively correlated with Gleason grade in a PCa series. CaT1 mRNA was suppressed by androgen and was induced by a specific androgen receptor antagonist in LNCaP cells, suggesting that the gene is negatively regulated by androgen. These findings are the first to implicate a Ca(2+) channel in PCa progression and suggest that CaT1 may be a novel target for therapy.

Androgen Antagonists↗
PubMed2001

Stereocontrolled syntheses of epimeric 3-aryl-6-phenyl-1-oxa-7-azaspiro(4.5)decane NK-1 receptor antagonist precursors.

[structure: see text]. Complementary stereoselective syntheses of individual C3 epimers of the NK-1 receptor antagonist precursor 1 have been developed. Both diastereomers were derived from the common intermediate 3; introduction of the 3S stereocenter in 1a was achieved through hydrogenation of an arylated dihydrofuran, whereas the corresponding stereogenic center in 1b was installed using a stereo- and regioselective alkene hydroarylation.

Aza Compounds↗
PubMed2001

Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients.

BACKGROUND: Hyperlipidemia is common after cardiac transplantation and it is a risk factor for post-transplantation coronary artery disease. Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia. Pravastatin, a HMG-CoA reductase inhibitor, has been shown to be effective and safe for cholesterol reduction in adult heart transplant recipients. To our knowledge the safety and efficacy of pravastatin therapy in pediatric and adolescent heart transplant populations have not been previously analyzed. Therefore, we evaluated lipid profiles, liver transaminases, rejection data, and possible side effects in pediatric and adolescent cardiac transplant recipients treated with pravastatin. METHODS: The study group consisted of 40 cardiac transplant recipients 10 to 21 years old (mean age 16.9 years). Twenty-two patients received pravastatin in addition to an immunosuppressive regimen of either cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Serial determinations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides were available for all pravastatin-treated patients. Pre-treatment lipid values and hepatic transaminases were compared with those measured after therapy with pravastatin. Comparison of pravastatin-induced lipid reduction between groups treated with cyclosporine vs tacrolimus was also made. RESULTS: Patients receiving pravastatin experienced a mean 32 mg/dl decrease in TC (p < 0.005) and a mean 31 mg/dl decrease in LDL (p < 0.005), regardless of their immunosuppressive regimen. No statistical differences occurred in the magnitude of mean lipid reduction induced by pravastatin between the groups treated with cyclosporine vs tacrolimus. No significant changes in hepatic transaminase levels were noted, and no clinical evidence of pravastatin-induced myositis occurred in any subjects. CONCLUSION: Pravastatin therapy is effective and safe when used in pediatric and adolescent cardiac transplant recipients. Although the pravastatin-induced reduction in TC and LDL was more pronounced in patients receiving cyclosporine, the reduction was not statistically different from that in the tacrolimus group. No evidence of hepatic dysfunction or rhabdomyolysis in patients treated with pravastatin was noted. Long-term studies are required to evaluate the effect of pravastatin therapy on the incidence of accelerated coronary atherosclerosis in this population.

Adolescent↗
PubMed2001

Tensile strength of cadaveric fascia lata compared to small intestinal submucosa using suture pull through analysis.

PURPOSE: The modified pubovaginal sling has become popular as first line treatment for stress urinary incontinence. With the increasing use of cadaveric fascia as a sling material, widespread shortages are prevalent, hence limiting its availability. The increased morbidity with the use of synthetic sling materials and autologous fascia has stimulated investigation of other sling materials. We evaluated the tensile strength of 4 suture types, and compared tensile strength of cadaveric fascia lata to porcine small intestinal submucosa using suture pull through analysis to assess their efficacy and durability for use in anti-incontinence procedures. MATERIALS AND METHODS: Suture breaking load was determined using 2 and 1-zero polypropylene suture, and 2 and 1-zero polyglactin suture. Freeze dried gamma irradiated human fascia lata and freeze-dried small intestinal submucosa were evaluated. Suture was fixed to sling material using the cross fold technique. Mean suture breakage and suture pull through were determined using a tensionometer by measuring the load applied to the sling/suture system. Statistical analysis was performed. RESULTS: Mean suture breakage load was greatest with 1-zero polyglactin (8.10 pounds) and least with 2-zero polypropylene (3.68 pounds). Mean suture breakage strength was similar for 1-zero polypropylene and 2-zero polyglactin at 5.26 and 5.40 pounds, respectively. Mean suture pull through load using 1-zero polypropylene suture and the cross fold technique was 5.64 pounds for cadaveric fascia and 2.74 pounds for small intestinal submucosa (p <0.0001). Maximum load was limited by the suture strength when using cadaveric fascia, whereas, maximum load was limited in small intestinal submucosa by its inherent tensile strength. However, using a new technique for suture fixation to the small intestinal submucosa, we were able to increase significantly mean suture pull through load to 3.36 pounds (p = 0.008). Additionally, with this new technique small intestinal submucosa allowed gross stretching before suture pull through that was not seen with cadaveric fascia. CONCLUSIONS: Despite the current standard use of 1-zero polypropylene suture for pubovaginal sling fixation, our data suggest that 1-zero polyglactin suture is the strongest, and its use with pubovaginal sling fixation warrants further investigation. Using the cross fold technique and 1-zero polypropylene suture, tensile strength was greatest with cadaveric fascia compared to small intestinal submucosa. Although small intestinal submucosa was not as strong as cadaveric fascia, our persuasive preliminary data suggest that further investigation is warranted in the use of small intestinal submucosa and other suture fixation techniques, and its observed stretch capacity. Hence, with further studies small intestinal submucosa may remain a viable option for pubovaginal sling material.

Cadaver↗
PubMed2001

Design and analysis of robust total joint replacements: finite element model experiments with environmental variables.

Computer simulation of orthopaedic devices can be prohibitively time consuming, particularly when assessing multiple design and environmental factors. Chang et al. (1999) address these computational challenges using an efficient statistical predictor to optimize a flexible hip implant, defined by a midstem reduction, subjected to multiple environmental conditions. Here, we extend this methodology by: (1) explicitly considering constraint equations in the optimization formulation, (2) showing that the optimal design for one environmental distribution is robust to alternate distributions, and (3) illustrating a sensitivity analysis technique to determine influential design and environmental factors. A thin midstem diameter with a short stabilizing distal tip minimized the bone remodeling signal while maintaining satisfactory stability. Hip joint force orientation was more influential than the effect of the controllable design variables on bone remodeling and the cancellous bone elastic modulus had the most influence on relative motion, both results indicating the importance of including uncontrollable environmental factors. The optimal search indicated that only 16 to 22 computer simulations were necessary to predict the optimal design, a significant savings over traditional search techniques.

Arthroplasty, Replacement, Hip↗
PubMed2001

Serum resistance in an invasive, nontypeable Haemophilus influenzae strain.

A common feature of many different organisms causing bacteremia is the ability to avoid the bactericidal effects of normal human serum. In Haemophilus influenzae encapsulated strains are particularly serum resistant; however, we found that a nonencapsulated strain (R2866) isolated from the blood of an immunocompetent child with meningitis who had been successfully immunized with H. influenzae type b conjugate vaccine was serum resistant. Since serum resistance usually involves circumventing the action of the complement system, we defined the deposition of various complement components on the surfaces of this H. influenzae strain (R2866), a nonencapsulated avirulent laboratory strain (Rd), and a virulent type b encapsulated strain (Eagan). Membrane attack complex (MAC) accumulation correlated with the loss of bacterial viability; correspondingly, the rates of MAC deposition on the serum-sensitive strain Rd and the serum-resistant strains differed. Analysis of cell-associated immunoglobulin G (IgG), C1q, C3b, and C5b indicated that serum-resistant H. influenzae prevents MAC accumulation by delaying the synthesis of C3b through the classical pathway. Among the initiators of the classical pathway, IgG deposition contributes most of the C3 convertase activity necessary to start the cascade ending with MAC deposition. Despite similar IgG binding, strain R2866 delays C3 convertase activity compared to strain Rd. We conclude that strain R2866 can persist in the bloodstream, in part by inhibiting or delaying C3 deposition on the cell surface, escaping complement mediated killing.

Bacterial Capsules↗
PubMed2000

Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys.

In this study we examined several behavioral, personality, and cognitive characteristics of boys with FG syndrome. We confirmed high rates of attention and activity level problems, which were described previously. Nine of the 11 patients met criteria for attention deficit/hyperactivity disorder. The boys did not manifest autistic behavior, and none met criteria for an autism spectrum disorder, though their parents reported substantial repetitive behavior. The personalities of the participants often were described as friendly, good-natured, and cheerful, but they did not differ empirically on a standardized measure of personality structure from typically developing comparison children, even after controlling for the effects of IQ. Specifically, higher rates of agreeableness and extraversion were not confirmed, though these constructs do not correspond perfectly with the traits of affability and gregariousness described in earlier published case studies of FG syndrome. In terms of neuropsychological assessment, the boys had relatively less developed language, fine motor, and executive function skills, and visual-spatial abilities were a relative strength. Limitations and suggestions for future research are discussed.

Adolescent↗
PubMed2000

Suppression of primary tumor growth and the progression to metastasis with p53 adenovirus in human prostate cancer.

PURPOSE: Numerous advances have been made in gene therapy approaches for the treatment of solid tumors, including prostate cancer. While treatment of the primary tumor has been well investigated, little information is available regarding gene therapy techniques which might impact on the progression to metastatic disease. We investigate the ability of p53 adenovirus to suppress not only primary tumor growth, but also the progression to metastatic disease. Mutation of the p53 tumor suppressor gene has been associated with the progression of prostate cancer. In this study, we utilized a metastatic model for human prostate cancer to determine if introduction of the wild-type p53 gene using an adenoviral vector (rAd-p53) impacted on primary tumor growth as well as the progression to metastatic disease. MATERIALS AND METHODS: For our studies, we used the human prostate cancer cell line PC-3, which has a homozygous loss of p53 expression. Expression of exogenous p53 as well as p21 induction at various time points after infection with rAd-p53 was determined in vitro. In vivo studies were performed in nude mice following orthotopic (intraprostatic) injection of PC-3 cells. Primary tumor growth as well as the progression to metastatic disease was assessed following rAd-p53 treatment. RESULTS: In vitro studies demonstrated high levels of p53 gene expression as well as the induction of p21 gene expression. Infection of PC-3 cells with rAd-p53 resulted in marked growth inhibition, as well as wide-spread fragmentation of nuclei and secretion of nuclear matrix proteins into the culture medium consistent with the process of apoptosis. In vivo studies demonstrated that a single injection of rAd-p53 into an established orthotopic prostate tumor resulted not only in primary tumor growth suppression (treated = 97.5 +/- 25.3 mm.3 versus control = 393.4 +/- 67.2 mm.3; p = 0.0002) but also reduced the frequency of progression to metastatic disease (treated = 8 of 19 versus control = 18 of 19; p = 0.001). CONCLUSION: These experiments demonstrate that a single injection of rAd-p53 into an established orthotopic prostate tumor results not only in suppression of primary tumor growth, but also in a reduction of the frequency of progression to metastatic disease. These results suggest that a rAd-p53 gene therapy strategy may be useful in the treatment of human prostate cancer.

Adenoviridae↗
PubMed2000

Clinical and biopsy specimen features in black and white men with clinically localized prostate cancer.

BACKGROUND: The incidence of prostate cancer in black men is estimated to be 30% to 50% higher than among age-matched white men, and black men have a twofold higher mortality rate. To determine whether racial differences exist in men with similarly staged disease, we compared clinical and pathologic features in black and white men with clinical stage T1-T2 prostate cancer. METHODS: We retrospectively reviewed the records of all men who had prostate biopsy at our facilities. Men were included in this study if they were of black or white race, if the clinical stage of their prostate cancer was T1-T2, and if detailed information regarding their prostate biopsy was available. RESULTS: Black men were found to have significantly higher serum prostate-specific antigen (PSA) levels, but no other differences were noted in the other clinical or pathologic features studied. CONCLUSION: While racial differences in the incidence and mortality of prostate cancer are well known, differences in the clinical and pathologic features between black and white men with similarly staged disease have been poorly studied. Our results suggest that serum PSA levels are higher in black men, but no other differences were noted. This suggests that early detection programs for prostate cancer in black men can potentially decrease prostate cancer mortality.

Black People↗
PubMed1999

ETO-2, a new member of the ETO-family of nuclear proteins.

The t(8;21) is associated with 12-15% of acute myelogenous leukemias of the M2 subtype. The translocation results in the fusion of two genes, AML1 (CBFA2) on chromosome 21 and ETO (MTG8) on chromosome 8. AML1 encodes a DNA binding factor; the ETO protein product is less well characterized, but is thought to be a transcription factor. Here we describe the isolation and characterization of ETO-2, a murine cDNA that encodes a new member of the ETO family of proteins. ETO-2 is 75% identical to murine ETO and shares very high sequence identities over four regions of the protein with ETO (domain I-III and zinc-finger). Northern analysis identifies ETO-2 transcripts in many of the murine tissues analysed and in the developing mouse embryo. ETO-2 is also expressed in myeloid and erythroid cell lines. We confirmed the nuclear localization of ETO-2 and demonstrated that domain III and the zinc-finger region are not required for nuclear localization. We further showed that a region within ETO, containing domain II, mediates dimerization among family members. This region is conserved in the oncoprotein AML-1/ETO. The recent identification of another ETO-like protein, myeloid translocation gene-related protein 1, together with the data presented here, demonstrates that at least three ETO proteins exist with the potential to form dimers in the cell nucleus.

Amino Acid Sequence↗
PubMed1999

Serum testosterone levels in African-American and white men undergoing prostate biopsy.

OBJECTIVES: Because androgen levels are known to influence prostate growth, we performed a prospective analysis of serum testosterone levels in all African-American and white men who underwent transrectal ultrasound-guided prostate biopsies to evaluate an abnormal digital rectal examination (DRE) and/or serum prostate-specific antigen (PSA) level greater than 4 ng/mL. METHODS: From June 1996 through July 1998, we evaluated 453 men (189 African-American and 264 white men) who underwent prostate needle biopsy because of an abnormal DRE or serum PSA greater than 4 ng/mL, or both. All men had morning serum testosterone levels determined just before undergoing prostate needle biopsy. Serum testosterone levels were compared on the basis of the prostate biopsy result (positive or negative for prostate cancer) and by race. RESULTS: A total of 453 men underwent prostate biopsy and had morning serum testosterone levels available for comparison. Of the 264 white men who underwent biopsy, 88 (33%) were found to have prostate cancer compared with 67 (35%) of 189 African-American men who underwent biopsy. In the white men without cancer, the mean serum testosterone level was 380. 19 ng/dL; those with prostate cancer had a mean serum testosterone level of 419.52 ng/dL. The mean serum testosterone level in African-American men without cancer was 424.30 ng/dL; it was 386.55 ng/dL in those with prostate cancer. There was no statistical difference in serum testosterone levels based on biopsy result or race. CONCLUSIONS: Although several studies have suggested that African-American men have higher serum testosterone levels than white men, these differences were noted only in men 40 years of age or younger. As was noted in our study, after age 40, African-American and white men have comparable serum testosterone levels. In addition, although prostate growth is androgen dependent, we found no difference in serum testosterone levels in men with and without prostate cancer.

Adult↗
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↗