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Biomedical subjects

W Brown

Publications and source records attributed to W Brown.

At least 19 recordsLinked to original sources
PubMed2001

Tinidazole therapy for metronidazole-resistant vaginal trichomoniasis.

Treatment of patients with metronidazole-refractory vaginal trichomoniasis constitutes a major therapeutic challenge, and treatment options are extremely limited. Although the majority of patients infected with trichomonads, who demonstrate reduced in vitro susceptibility to metronidazole, respond to high-dose but poorly tolerated regimens of metronidazole, clinical failure is by no means uncommon. We report a cure rate of 22 (92%) of 24 patients with refractory trichomoniasis treated with high doses of oral and vaginal tinidazole. This series included 15 cases with increased in vitro minimal lethal concentration values of metronidazole. Tinidazole, despite the high doses used, was extremely well tolerated, with few side effects. Topical paromomycin was effective in 7 (58%) of 12 patients treated, but frequent local vulvovaginal adverse reactions precluded extensive use. Widespread reports of metronidazole resistance and limited treatment options emphasize the need for additional trichomonacidal agents.

Adult↗
PubMed2001

CENP-H, a constitutive centromere component, is required for centromere targeting of CENP-C in vertebrate cells.

CENP-H has recently been discovered as a constitutive component of the centromere that co-localizes with CENP-A and CENP-C throughout the cell cycle. The precise function, however, remains poorly understood. We examined the role of CENP-H in centromere function and assembly by generating a conditional loss-of-function mutant in the chicken DT40 cell line. In the absence of CENP-H, cell cycle arrest at metaphase, consistent with loss of centromere function, was observed. Immunocytochemical analysis of the CENP-H-deficient cells demonstrated that CENP-H is necessary for CENP-C, but not CENP-A, localization to the centromere. These findings indicate that centromere assembly in vertebrate cells proceeds in a hierarchical manner in which localization of the centromere-specific histone CENP-A is an early event that occurs independently of CENP-C and CENP-H.

Amino Acid Sequence↗
PubMed2001

Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors.

Galanin is a 29-aa neuropeptide with a complex role in pain processing. Several galanin receptor subtypes are present in dorsal root ganglia and spinal cord with a differential distribution. Here, we describe a generation of a specific galanin R2 (GalR2) agonist, AR-M1896, and its application in studies of a rat neuropathic pain model (Bennett). The results show that in normal rats mechanical and cold allodynia of the hindpaw are induced after intrathecal infusion of low-dose galanin (25 ng per 0.5 microl/h). The same effect is seen with equimolar doses of AR-M1896 or AR-M961, an agonist both at GalR1 and GalR2 receptors. In allodynic Bennett model rats, the mechanical threshold increased dose-dependently after intrathecal injection of a high dose of AR-M961, whereas no effect was observed in the control or AR-M1896 group. No effect of either of the two compounds was observed in nonallodynic Bennett model rats. These data indicate that a low dose of galanin has a nociceptive role at the spinal cord level mediated by GalR2 receptors, whereas the antiallodynic effect of high-dose galanin on neuropathic pain is mediated by the GalR1 receptors. Thus, a selective GalR1 agonist may be used to treat neuropathic pain.

Analgesics, Non-Narcotic↗
PubMed2001

Novel C-terminus modifications of the Dmt-Tic motif: a new class of dipeptide analogues showing altered pharmacological profiles toward the opioid receptors.

The design, synthesis and pharmacological evaluation of a novel class of Dmt-Tic dipeptide analogues are described. These resulting analogues bearing different C-terminal functionalities were found to bind to the human delta receptor with high affinity. One specific class of dipeptides bearing urea/thiourea functionalities showed partial to full activation of the delta receptor. Several dipeptides also showed good binding affinities with full activation of the human kappa receptor, a novel property for those ligands.

Dipeptides↗
PubMed2001

Longitudinal analysis of bacterial vaginosis: findings from the HIV epidemiology research study.

OBJECTIVE: To determine the natural history of bacterial vaginosis in women with or at risk for human immunodeficiency virus (HIV). METHODS: A cohort of 854 HIV-infected women and 434 HIV-uninfected women from four US sites was followed prospectively with gynecologic exams every 6 months over a 5-year period. The prevalence, incidence, persistence, and severity of bacterial vaginosis, which was defined using a Gram-staining scoring system, were calculated using generalized estimating equation methods. RESULTS: In adjusted analyses, HIV-infected women had a higher prevalence of bacterial vaginosis than HIV-uninfected women (adjusted odds ratio [OR] 1.29; 95% confidence interval [CI] 1.08, 1.55). Although HIV-infected women were not more likely to have incident infections, they were more likely to have persistence of their infections (adjusted OR 1.49; 95% CI 1.18, 1.89). Similarly, immunocompromised women (CD4+ cell count less than 200 cells/microL) were more likely than HIV-infected women with higher CD4+ cell counts (more than 500 cells/microL) to have prevalent (adjusted OR 1.29; 95% CI 1.03, 1.60) and persistent (adjusted OR 1.38; 95% CI 1.01, 1.91) bacterial vaginosis infections, but not more likely to have incident infections. Immunocompromised women had more severe bacterial vaginosis by both clinical criteria (adjusted OR 1.40; 95% CI 1.08, 1.82) and by Gram-staining criteria (adjusted OR 1.50; 95% CI 1.12, 2.00). CONCLUSIONS: Bacterial vaginosis is more prevalent and persistent among HIV-infected women, particularly among those who are immunocompromised. Immunocompromised women are more likely than HIV-infected women with higher CD4+ cell counts to have severe bacterial vaginosis.

AIDS-Related Opportunistic Infections↗
PubMed2001

Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels.

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce tumour mass by increasing the rate of tumour cell apoptosis and decreasing cell proliferation. The classically recognized target for NSAID action are the two isoforms of the cyclooxygenase (COX) gene, which is responsible for prostaglandin production. In the rat, the COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) which may, at best, code for a truncated COX-1 protein. Previously, we reported that COX-1SV mRNA is differentially expressed in the ageing stomach. In this study, carcinogen treated rats were treated for 23 weeks with celecoxib, sulindac or sulindac sulfone, while untreated rats received vehicle alone. For each animal, the number and volume of tumour per animal was recorded and histology was performed. Using competitive polymerase chain reaction, we determined whether COX gene expression was altered in colorectal tumours and in regions of adjacent and distant macroscopically normal intestine, from vehicle or NSAID treated rats. In addition, we immunolocalized COX-1 and COX-2 in the same tumour and normal colonic tissue. Tumours from animals treated with vehicle or celecoxib expressed significantly elevated levels of COX-2 mRNA in comparison with the adjacent normal mucosa. In contrast, tumours from sulindac and sulindac sulfone treated rats expressed significantly less COX-2 mRNA than tumours from vehicle treated rats. The expression of COX-1 mRNA remained unchanged in all tissues examined. However, COX-1SV mRNA levels were elevated in colorectal tumours and reduced after NSAID treatment to the levels observed in normal colonic mucosa. Our results indicate that the anti-neoplastic actions of NSAIDs may be attributed to COX dependent and/or COX independent mechanisms of action. We also demonstrate the presence and differential expression of COX-1SV mRNA in colon tumours. COX-1SV mRNA represents 2% of the total COX-1 mRNA expressed and its role in colon cancer remains to be established.

Adenocarcinoma↗
PubMed2001

Heteroresistance to vancomycin in Enterococcus faecium.

This study presents the first report of vancomycin heteroresistance in an Enterococcus faecium isolate from a patient. The original isolate was susceptible in vitro to vancomycin. E-tests showed growth of subcolonies in a zone of inhibition with a vancomycin MIC of >256 microg/ml. Both the susceptible and resistant colonies were from the same strain as determined by PFGE, and both contained the vanA gene as determined by PCR.

Anti-Bacterial Agents↗
PubMed2001

A multicenter study of bacterial vaginosis in women with or at risk for human immunodeficiency virus infection.

BACKGROUND: Bacterial vaginosis is a common gynecologic infection that has been associated with a variety of gynecologic and obstetric complications, including pelvic inflammatory disease, postabortal infection and premature delivery. Recent studies suggest that bacterial vaginosis may increase a woman's risk for human immunodeficiency virus (HIV). We undertook this study to assess whether the prevalence and characteristics of bacterial vaginosis differed according to HIV status in high-risk US women. METHODS: Prevalence of bacterial vaginosis was assessed by Gram's stain and clinical criteria for 854 HIV-infected and 434 HIV-uninfected women enrolled in the HIV Epidemiology Research (HER) Study. Multiple logistic regression techniques were used to determine whether HIV infection independently predicted bacterial vaginosis. RESULTS: Almost half (46%) the women had bacterial vaginosis by Gram's stain. The prevalence of bacterial vaginosis was 47% in the HIV-positive women compared with 44% in the HIV-negative women; this difference was not statistically significant (p = 0.36). After adjustment for other covariates, HIV-positive women were more likely than HIV-negative women to have bacterial vaginosis (odds ratio (OR) 1.31; 95% confidence interval (CI) 1.01-1.70) by Gram's stain but not by clinical criteria (OR 1.16; CI 0.87-1.55). Among HIV-positive women, use of antiretroviral drugs was associated with a lower prevalence of bacterial vaginosis (adjusted OR 0.54; Cl 0.38-0.77). CONCLUSIONS: In this cross-sectional analysis of high-risk US women, HIV infection was positively correlated with bacterial vaginosis diagnosed by Gram's stain.

AIDS-Related Opportunistic Infections↗
PubMed2000

Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein.

Hedgehog (Hh) signalling plays a central role in many developmental processes in both vertebrates and invertebrates [1]. The multipass membrane-spanning proteins Patched (Ptc) [2-4] and Smoothened (Smo) [5-7] have been proposed to act as subunits of a putative Hh receptor complex. According to this view, Smo functions as the transducing subunit, the activity of which is blocked by a direct interaction with the ligand-binding subunit, Ptc [8]. Activation of the intracellular signalling pathway occurs when Hh binds to Ptc [8-11], an event assumed to release Smo from Ptc-mediated inhibition. Evidence for a physical interaction between Smo and Ptc is so far limited to studies of the vertebrate versions of these proteins when overexpressed in tissue culture systems [8,12]. To test this model, we have overexpressed the Drosophila Smo protein in vivo and found that increasing the levels of Smo protein per se was not sufficient for activation of the pathway. Immunohistochemical staining of wild-type and transgenic embryos revealed distinct patterns of Smo distribution, depending on which region of the protein was detected by the antibody. Our findings suggest that Smo is modified to yield a non-functional form and this modification is promoted by Ptc in a non-stoichiometric manner.

Animals↗
PubMed2000

New diarylmethylpiperazines as potent and selective nonpeptidic delta opioid receptor agonists with increased In vitro metabolic stability.

Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N, N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC(50) = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC(50) = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N, N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N, N-diethyl-4-[1-piperazinyl(8-quinolinyl)methyl]benzamide (56) which had an improved in vitro binding profile (IC(50) = 0.5 nM, mu/delta = 1239, EC(50) = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

Animals↗
PubMed2000

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues.

The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.

Administration, Oral↗
PubMed2000

Asymmetric wolff rearrangement reactions with alpha-alkylated-alpha-diazoketones: stereoselective synthesis of alpha-substituted-beta-amino acid derivatives

Photoinduced asymmetric Wolff rearrangement reactions were performed with alpha-amino-alpha'-methyl-alpha'-diazoketones to afford alpha-methyl-beta-amino acid esters with good stereoselectivity. Factors that may influence the stereochemistry were examined, including steric effects and temperature dependence, which had a great impact on the stereochemistry.

Journal Article↗
PubMed2000

Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists.

A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the delta opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the delta versus mu opioid receptor and proved to be delta receptor antagonists.

Benzamides↗
PubMed2000

The development and evaluation of an incontinence screening questionnaire for female primary care.

Although there is a high prevalence of leaking urine among Australian women, there are currently no standardized procedures for screening patients for incontinence in the primary care setting (known in Australia as general practice). In response to this, an incontinence screening questionnaire (ISQ) was developed and evaluated for use in general practice. Eighty-nine women completed an original compilation of 33 items that asked about situations associated with leaking urine, avoidance of leakage, and concern about leakage. Each item was assessed according to its acceptability for the population of female general practice patients, discriminative value, and test-retest reliability. These patients also underwent an objective test of incontinence, the 48-hour pad test, so that the screening items could be validated against an objective classification of incontinence. The study included women who had bladder control problems and those who did not. Eight items on the ISQ were shown to be acceptable to patients, discriminative, reliable, and valid indicators of objective incontinence. Five items were capable of predicting almost 70% of patients who showed objective leakage of urine and misclassified fewer than 15% of these patients. Those five items were selected for inclusion in the (refined) ISQ.

Adaptation, Psychological↗
PubMed2000

Constipation in Australian women: prevalence and associated factors.

A postal health survey was completed by 14761 young women (aged 18-23 years), 14070 middle-aged women (45-50 years) and 12893 older women (70-75 years). The prevalence of constipation was 14.1% (CI 13.5-14.7) in young women, 26.6% (CI 25.9-27.4) in middle-aged women, and 27% (CI 26.9-28.5) in the older women. The prevalence of hemorrhoids was 3.2% (CI 2.9-3.4 young), 17.7% (CI 17.1-18.4 middle-aged) and 18.3% (CI 17.6-19.0 older). In the middle-aged and older women, those who reported previous gynecologic surgery were between 18% and 63% more likely to report constipation; in the younger cohort, women with one or two children were also more likely to report constipation (adjusted OR 1.43-1.46). One-third of the young women and half the middle-aged and older women had sought help for constipation; the majority indicated that they were satisfied with the help available to them.

Adolescent↗
PubMed2000

Biotransformation of linoleic acid by Clavibacter sp. ALA2: heterocyclic and heterobicyclic fatty acids.

Clavibacter sp. ALA2 transformed linoleic acid into a variety of oxylipins. In previous work, three novel fatty acids were identified, (9Z)-12, 13, 17-trihydroxy-9-octadecenoic acid and two tetrahydrofuran-(di)hydroxy fatty acids. In this report, we confirm the structures of the tetrahydrofuran-(di)hydroxy fatty acids by nuclear magnetic resonance as (9Z)-12-hydroxy-13,16-epoxy-9-octadecenoic acid and (9Z)-7,12-dihydroxy-13,16-epoxy-9-octadecenoic acid. Three other products of the biotransformation were identified as novel heterobicyclic fatty acids, (9Z)-12,17;13, 17-diepoxy-9-octadecenoic acid, (9Z)-7-hydroxy-12,17;13,17-diepoxy-9-octadecenoic acid, and (9Z)-12,17;13,17-diepoxy-16-hydroxy-9-octadecenoic acid. Thus, Clavibacter ALA2 effectively oxidized linoleic acid at C-7, -12, -13, -16, and/or -17.

Biotransformation↗
PubMed2000

Helicobacter pylori culture and antimicrobial susceptibility from pediatric patients in Michigan.

BACKGROUND: We recently observed a high failure rate in the eradication of Helicobacter pylori infection in children with 2-week triple therapy using lansoprazole, amoxicillin and clarithromycin. We performed a prospective evaluation of antral biopsies of all children subsequently diagnosed with H. pylori gastritis for culture and antimicrobial susceptibility assessment. METHODS: All children with antral nodularity and/or an elevated anti-H. pylori IgG titer underwent antral biopsies for histology, urease test and culture while undergoing an upper endoscopy for routine indications. All positive cultures were tested for antimicrobial susceptibility by E-test for clarithromycin, amoxicillin, tetracycline and metronidazole. RESULTS: Thirty-one children (16 male, 15 female) between 2 and 19 years of age were diagnosed with H. pylori gastritis by histology. However, culture was positive in only 22 of 31 (71%) patients. The E-test in vitro antimicrobial susceptibility testing revealed that 95.6% of the isolates were susceptible to amoxicillin, 59% to clarithromycin and 54.6% to metronidazole. There was no resistance to tetracycline. CONCLUSION: Evaluation of antibiotic resistance profiles from pediatric patients from different geographic areas can help in optimizing therapeutic regimen to prevent treatment failures. Metronidazole and clarithromycin resistance is much higher in our pediatric population than reported in adults and could be a major contributor to failure of H. pylori eradication.

Adolescent↗