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Biomedical subjects

C T Brown

Publications and source records attributed to C T Brown.

At least 19 recordsLinked to original sources
PubMed2006

Self-management in lower urinary tract symptoms: the next major therapeutic revolution.

The standard treatments for men with lower urinary tract symptoms (LUTS) range from watchful waiting to medical and finally surgical intervention. However, the role of self-management interventions such as education and reassurance, lifestyle modification and behavioural changes has not been formally investigated, although they are widely advocated and utilised for LUTS. Self-management interventions are well established in other chronic diseases such as diabetes, arthritis and asthma. These interventions, if successfully organised within a structured program for LUTS, could improve patient outcomes as well as reduce the economic burden of LUTS treatment, by replacing or augmenting other treatments. Recent studies showing that long-term urodynamic and symptomatic deterioration of LUTS is minimal suggest that this is a safe and valid treatment option. This is supported by a recent pilot study of a LUTS self-management program which showed significant improvements in I-PSS and frequency-volume parameters. The results of a recently completed randomised controlled trial are awaited.

Humans↗
PubMed2004

Evolutionary comparisons suggest many novel cAMP response protein binding sites in Escherichia coli.

The cAMP response protein (CRP) is a transcription factor known to regulate many genes in Escherichia coli. Computational studies of transcription factor binding to DNA are usually based on a simple matrix model of sequence-dependent binding energy. For CRP, this model predicts many binding sites that are not known to be functional. If they are indeed spurious, the underlying binding model is called into question. We use a species comparison method to assess the functionality of a population of such predicted CRP sites in E. coli. We compare them with orthologous sites in Salmonella typhimurium identified independently by CLUSTALW alignment, and find a dependence of mutation probability on position in the site. This dependence increases with predicted site binding energy. The positions where mutation is most strongly suppressed are those where mutation would have the biggest effect on predicted binding energy. This finding suggests that many of the novel sites are functional, that the matrix model correctly estimates their binding strength, and that calculated CRP binding strength is the quantity that is conserved between species. The analysis also identifies many new E. coli binding sites and genes likely to be functional for CRP.

Binding Sites↗
PubMed2004

Antibiotics on urethral catheter withdrawal: a hit and miss affair.

Globally, millions of patients undergo urethral catheterization every year. Our objective was to study the current use of prophylactic antibiotics on urinary catheter withdrawal. A questionnaire (N = 300) was sent to healthcare professionals involved in the management of patients with urinary catheters (consultant microbiologists, infection control nurses, consultant urologists, specialist nurses in urology, continence advisers and consultants in the care of older people). The questionnaire asked about their use of prophylactic antibiotics on the withdrawal of a urethral catheter. Sixty percent of healthcare professionals advocated the use of antibiotics for either all or selected groups of patients. The remainder did not. The use of prophylactic antibiotics varied among different groups. Of the healthcare professionals who used antibiotics, the majority cited more than one reason for their use (prevent bacteraemia, avoid an infection in a prosthesis or urinary tract infection). The course and type of antibiotic used varied. Our study has shown diversity in practice that is of concern. At present, just over one-half of patients with urinary catheters are being given antibiotics, although there is no evidence to suggest that such an intervention confers any benefit. If benefits do not exist, these patients are being exposed to the harm of antibiotics and providers are incurring costs unnecessarily. A formal trial to address this issue is urgently needed.

Aged↗
PubMed2004

Eliciting preferences for drug treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

PURPOSE: There are 2 main medical preparations available for lower urinary tract symptoms resulting from benign prostatic hyperplasia (BPH). Choosing between an alpha-blocker and a 5alpha-reductase inhibitor requires trade-offs between their attributes or characteristics. We investigated the relative importance of and trade-offs between the attributes of the 5alpha-reductase inhibitor dutasteride and alpha-blockers in community dwelling men using a validated technique. MATERIALS AND METHODS: A discrete choice experiment was administered to 211 men older than 40 years who were randomly selected from the general United Kingdom population. Attributes investigated in the discrete choice experiment were time to symptom improvement, sexual and nonsexual side effects, the risks of acute urinary retention (AUR) and surgery, cost and prostate size decrease. Using regression analysis the relative importance of these attributes, the trade-offs that men are willing to make between these attributes and the willingness to pay for each attribute were estimated. RESULTS: All attributes were important to respondents. The most important attribute was side effects. The least preferred side effects was impotence, followed by decreased libido and dizziness. Respondents were willing to wait 13, 2 and 8 months longer for symptom improvement in exchange for decreased prostate size, and the risks of AUR and surgery, respectively. Men reporting moderate symptoms were less concerned about sexual side effects, time to symptom improvement and the risk of AUR compared with men reporting mild symptoms. CONCLUSIONS: Given the attribute levels of BPH medical treatment, overall community dwelling men preferred the 5alpha-reductase inhibitor over alpha-blockers. In the interests of shared decision making it is important to consider the importance of eliciting the preferences of patients with BPH.

Adrenergic alpha-Antagonists↗
PubMed2003

The fear of prostate cancer in men with lower urinary tract symptoms: should symptomatic men be screened?

OBJECTIVE: To explore the concerns and worries in men with uncomplicated lower urinary tract symptoms (LUTS, but no evidence of prostate cancer) relating to their symptoms. PATIENTS AND METHODS: There is no current prostate cancer screening programme in the UK. Evidence suggests that men with LUTS have the same risk of prostate cancer as aged-matched asymptomatic men. However, most men with LUTS are 'screened' with a digital rectal examination (DRE) and prostate specific antigen (PSA) testing as part of routine assessment. Whether this screening offers any benefit to patients and whether national screening for prostate cancer and subsequent early treatment offer any long-term survival or quality of life benefit is uncertain. Thus 30 men with uncomplicated LUTS were qualitatively interviewed to explore their concerns and worries about their symptoms. Interviews were transcribed verbatim and subjected to content analysis using validated techniques. RESULTS: Of the 30 men, 22 (73%) expressed a fear of prostate cancer at the time of their initial presentation. This fear was independent of race, social class and symptom severity; older men were less worried. Of the 22, 15 (68%) stated that after reassurance their symptoms were less bothersome and easier to cope with. CONCLUSIONS: These findings suggest there is a considerable gain in health by explicitly addressing the concerns of prostate cancer in men with uncomplicated LUTS. Informing these men of their true risk of prostate cancer (before or after a DRE and PSA estimate) may alleviate much of the bother associated with their symptoms. Despite no evidence of any greater risk of prostate cancer than in asymptomatic men, symptomatic men should continue to be screened after appropriate counselling.

Decision Making↗
PubMed2003

Lifestyle and behavioural interventions for men on watchful waiting with uncomplicated lower urinary tract symptoms: a national multidisciplinary survey.

OBJECTIVE: To determine the use of lifestyle and behavioural interventions in the UK for symptom control in men with uncomplicated lower urinary tract symptoms (LUTS) on watchful waiting (WW). METHOD: Semi-structured interviews with urologists, nurse practitioners and continence advisors were used to obtain a list of lifestyle and behavioural interventions used in men with LUTS. From the 18 interventions identified, a survey was constructed asking how often these interventions were used in routine practice. The survey was sent to 100 consultant urologists (British Association of Urological Surgeons), 100 nurse practitioners (British Association of Urological Nurses), and 100 continence advisors (International Continence Society) with an interest in male urology, all randomly selected. RESULTS: Of 248 (83%) responses, 236 were suitable for analysis; 193 (82%) of the respondents reported using lifestyle or behavioural interventions in men on WW with uncomplicated LUTS. The most frequently used interventions were education about the prostate and bladder, avoiding caffeine, urethral milking and reassuring men that they do not have prostate cancer. The use of lifestyle and behavioural interventions showed an 'all-or-none' pattern. Respondents used either few or many of the 18 interventions identified. There was considerable variation in the extent to which these interventions were used among the survey groups (P < 0.01); urologists used these interventions the least and continence advisors the most. CONCLUSIONS: Lifestyle and behavioural interventions are advised by many medical professionals to men on WW with uncomplicated LUTS. However, the use varies considerably, with some medical professionals advising many of these interventions and some a few or none at all. Further research is required to define and test the effectiveness of these interventions in reducing LUTS.

Aged↗
PubMed2003

A review of guidelines on benign prostatic hyperplasia and lower urinary tract symptoms: are all guidelines the same?

OBJECTIVE: To compare overall and methodological quality with content in national and supra-national Clinical Practice Guidelines (CPGs) on benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), as the purpose of CPGs is to reduce unwanted variation in practice and improve patient care by setting agreed standards based on the best available evidence. METHODS: An electronic search was used to identify Internet-based national and supra-national CPGs on BPH and LUTS available in 2001. Two independent assessors analysed the content and appraised the methodological quality of the CPGs using an existing and validated instrument (St. George's Hospital Medical School Health Care Evaluation Unit Appraisal Instrument) comprising 37 items grouped into three broad areas, i.e. rigour of development, context and content, and clinical application. RESULTS: Eight CPGs were suitable for appraisal; there was much variation in overall and methodological quality. There was agreement that a patient history and physical examination (including a digital rectal examination) should be used in all symptomatic men. In addition, patients' symptoms should be assessed using a validated symptom score, e.g. the International Prostate Symptom Score. There was considerable variation in the number and type of diagnostic tests recommended for routine assessment. CPGs scoring low on the appraisal instrument (indicating poor overall and methodological quality) were more likely to recommend more diagnostic tests than those scoring high. There was general agreement between the guidelines on the treatment of BPH/LUTS and the importance of the patient's involvement in making management decisions. Guideline quality was independent of local health resources and publication year. CONCLUSION: The overall and methodological quality of CPGs on BPH/LUTS varies considerably. There appears to be an inverse relationship between guideline quality and the number of diagnostic tests recommended for routine assessment. Using CPGs of high quality may prevent men with BPH/LUTS being exposed to tests of doubtful utility. Although this may reduce both resource use and exposure to potential harm, moving to a more minimalist approach to diagnosis may itself be potentially harmful to patients.

Decision Making↗
PubMed2003

Dutasteride: a new 5-alpha reductase inhibitor for men with lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Dutasteride is a new 5-alpha reductase inhibitor for the treatment of men with moderate to severe lower urinary tract symptoms secondary to benign prostatic hyperplasia. It has been available in the UK since March 2003. It is a competitive inhibitor of both type I and type II isoforms of the 5-alpha reductase enzyme that converts testosterone to the more potent androgen, dihydrotestosterone. Randomised controlled studies have shown dutasteride to be statistically more effective than placebo in reducing lower urinary tract symptoms and increasing maximum urinary flow rates. This is a consequence of a reduction in serum dihydrotestosterone and hormone dependent prostate volume. Dutasteride has also been shown to decrease the absolute risk of urinary retention and the need for prostate-related surgery when compared to placebo taken over a 24-month period. In this review article we discuss the pharmacology and clinical effects of dutasteride, a new dual-acting 5-alpha reductase inhibitor.

5-alpha Reductase Inhibitors↗
PubMed2002

Assessment, diagnosis and management of lower urinary tract symptoms in men.

Lower urinary tract symptoms are very common and the approach to assessment and management has changed dramatically over the past few years. Previously referred to as prostatism, benign prostatic hyperplasia and bladder outflow obstruction, it is now recognised that in most men symptoms are due to a combination of benign prostatic enlargement and age-related bladder dysfunction. Most men require only simple tests for a diagnosis, with the more complex investigations reserved for when the diagnosis is not clear. Symptom bothersomeness and effect on quality of life are the critical factors when deciding how to treat a man. A cascade of treatments exists, including conservative management, medical therapy and surgery. A man moves up the cascade when the present management strategy fails to control symptoms. Traditional surgical techniques such as transurethral resection of the prostate are still appropriate for some men, although with improved medical treatments available the number of men undergoing surgery is declining.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2001

Hydrogen-bond-mediated photoinduced electron-transfer: novel dimethylaniline-anthracene ensembles formed via Watson-Crick base-pairing.

The synthesis of a new, noncovalent anthracene-dimethylaniline dyad (ensemble I) held together via guanosine-cytidine Watson-Crick base-pairing interactions is reported. Upon excitation at 420 nm, photoinduced electron-transfer from the dimethylaniline donor to the singlet excited state of the anthracene acceptor occurs, as inferred from a combination of time-resolved fluorescence quenching and transient absorption measurements. In toluene at room temperature, the rate constants for photoinduced intraensemble electron-transfer and subsequent back-electron-transfer (charge recombination) are k(CS) = (3.5 +/- 0.03) x 10(10) s(-1) and k(CR) = (1.42 +/- 0.03) x 10(9) s(-1), respectively.

Aniline Compounds↗
PubMed1999

Characterization of proteoglycans synthesized by cultured corneal fibroblasts in response to transforming growth factor beta and fetal calf serum.

A culture system was developed to analyze the relationship between proteoglycans and growth factors during corneal injury. Specifically, the effects of transforming growth factor beta-1 (TGF-beta1) and fetal calf serum on proteoglycan synthesis in corneal fibroblasts were examined. Glycosaminoglycan synthesis and sulfation were determined using selective polysaccharidases. Proteoglycan core proteins were analyzed using gel electrophoresis and Western blotting. Cells cultured in 10% dialyzed fetal calf serum exhibited decreased synthesis of more highly sulfated chondroitin sulfate and heparan sulfate compared with cells cultured in 1% dialyzed fetal calf serum. The amount and sulfation of the glycosaminoglycans was not significantly influenced by TGF-beta1. The major proteoglycan species secreted into the media were decorin and perlecan. Decorin was glycanated with chondroitin sulfate. Perlecan was linked to either chondroitin sulfate, heparan sulfate, or both chondroitin sulfate and heparan sulfate. Decorin synthesis was reduced by either TGF-beta1 or serum. At early time points, both TGF-beta1 and serum induced substantial increases in perlecan bearing chondroitin sulfate and/or heparan sulfate chains. In contrast, after extended periods in culture, the amount of perlecan bearing heparan sulfate chains was unaffected by TGF-beta1 and decreased by serum. The levels of perlecan bearing chondroitin sulfate chains were elevated with TGF-beta1 treatment and were decreased with serum. Because both decorin and perlecan bind growth factors and are proposed to modulate their activity, changes in the expression of either of these proteoglycans could substantially affect the cellular response to injury.

Animals↗
PubMed1999

Visualizing evolutionary activity of genotypes.

We introduce a method for visualizing evolutionary activity of genotypes. Following a proposal of Bedau and Packard [11], we define a genotype's evolutionary activity in terms of the history of its concentration in the evolving population. To visualize this evolutionary activity we graph the distribution of evolutionary activity in the population of genotypes as a function of time. Adaptively significant genotypes trace a salient line or "wave" in these graphs. The quality of these waves indicates a variety of neutral variation, and random genetic drift. We apply this method in an evolutionary model of self-replicating assembly language programs competing for room in a two-dimensional space. Comparison with fitness graphs and with a nonadaptive analogue of this model shows how this method highlights adaptively significant events.

Biological Evolution↗
PubMed1995

Synthesis of stromal glycosaminoglycans in response to injury.

Our goal is to examine the synthesis and deposition of corneal glycosaminoglycans (GAGs) in response to a wound created by the insertion of porous discs into stromal interlamellar pockets. The disc and the surrounding stromal tissue were assayed and compared to contralateral control stroma and to sham operated corneas at 14, 42, and 84 days. The tissue and/or discs were removed and labeled with 35S-sulfate for 18 h; GAGs were extracted with 4 M guanidine-HCl. Extracts were chromatographed on Q-Sepharose columns, bound proteoglycans were eluted with a linear salt gradient, and radioactive fractions were analyzed. Total GAG content was determined colorimetrically, using dimethylmethylene blue. Specific GAGs were determined using enzymatic digestion with selective polysaccharide lyases and protein cores were examined using SDS-PAGE. The nonbound fractions from the chromatography were assayed for TGF-beta using Western blot analysis and for hyaluronic acid using an 125I-radiometric assay. Specific GAGs were localized 42 days after the disc had been implanted in the stroma. The placement of the discs into the stroma resulted in a decrease in the total amount of GAG. However, the ratio of dermatan-chondroitin sulfate and heparan sulfate to keratan sulfate increased in the surrounding tissue and disc. Hyaluronic acid was elevated at day 14 in the surrounding tissue, and not until day 84 in the disc. Western blot analysis of surrounding tissue extracts revealed forms of TGF-beta that migrated with an apparent molecular mass of 63 and 43 kDa. The results indicate that the insertion of discs into interlamellar pockets causes changes in the sulfation and proportion of the glycosaminoglycans in the surrounding tissue and the disc. These changes are coincident with the appearance of TGF-beta. After 84 days, the population of glycosaminoglycans in the disc begins to resemble the surrounding stroma. This model will allow us to examine further the synthesis and deposition of proteins following an extensive wound in which cells must migrate to the wound site and then undergo extensive remodeling.

Animals↗
PubMed1994

Age-related changes of scleral hydration and sulfated glycosaminoglycans.

Human scleras were analyzed to determine if tissue hydration changed in an age-related fashion, and whether this change could be related to decreased levels of glycosaminoglycans. The anterior half of normal human scleras were examined with donor ages ranging from newborn to 99 years (n = 40). Tissue hydration was found to decrease by 1.06% per decade (P = 0.0012). Glycosaminoglycans were extracted from scleras with guanidine hydrochloride, purified by anion exchange chromatography and quantitated using dimethylene blue and selective enzymatic digestion. The glycosaminoglycans of the sclera were primarily dermatan sulfate and chondroitin sulfate with small quantities of hyaluronic acid. While no loss of chondroitin sulfate with age was detected, a significant age-related loss of dermatan sulfate was found (P = 0.0006, n = 14). An examination of the relationship between glycosaminoglycan concentration and scleral hydration showed that increased levels of sulfated glycosaminoglycans were associated with increased levels of scleral hydration (P < 0.02, n = 14). No improvement in the correlation could be achieved by considering either dermatan sulfate or chondroitin sulfate individually. Our results suggest that, as in other connective tissues, aging is associated with a loss of glycosaminoglycans, and their loss is coincident with decreased tissue hydration.

Adolescent↗
PubMed1994

Evaluation of anti-CD5 ricin A chain immunoconjugate for prevention of acute graft-vs.-host disease after HLA-identical marrow transplantation.

Anti-CD5 ricin A chain immunoconjugate (XZ-CD5) is an immunotoxin that inhibits proliferative and cytotoxic responses to alloantigen in vitro and has activity in the treatment of acute graft-vs.-host disease (GVHD). To determine if XZ-CD5 could be used to prevent acute GVHD, 11 adult recipients of HLA-identical allogeneic marrow received XZ-CD5 0.1 mg kg-1 day-1 intravenously with high-dose methyl-prednisolone for 10, 14 or 17 doses early post-transplant. Six additional patients received 17 doses of XZ-CD5 and cyclosporine (CSA). All patients engrafted. Severe capillary leak syndrome was the most common serious toxicity and occurred more frequently in patients receiving CSA (5/5 vs. 3/11, P = 0.03). All evaluable patients developed acute GVHD; 88% had grade II-IV GVHD. Flow cytometric analysis demonstrated a substantial number of circulating CD5+ and CD3+ lymphocytes during and early after administration of XZ-CD5. These results suggest that the immunotoxin did not eliminate alloreactive T cells in this setting.

Acute Disease↗