Biomedical subjects

R Hughes

Publications and source records attributed to R Hughes.

At least 37 records · Page 2Linked to original sources

PubMed2004

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

Adolescent↗

PubMed2003

eThrombosis: the 21st century variant of venous thromboembolism associated with immobility.

The association between immobility with prolonged sitting and venous thromboembolism has been recognised for > 60 yrs, most recently with long distance air travel. The case of a 32-yr-old male, in whom immobility associated with sitting for long periods at a computer represented the major provoking risk factor for his life-threatening venous thromboembolism, is presented. The authors propose the term "eThrombosis" to describe this 21st Century variant of venous thromboembolism associated with immobility from prolonged sitting. In view of the widespread use of computers in relation to work, recreation and personal communication, the potential burden of eThrombosis may be considerable.

Adult↗

PubMed2002

The epidemiology and treatment of Bell's palsy in the UK.

The study consisted of a survey of all new cases of Bell's palsy occurring between 1992 and 1996 in practices contributing data to the UK General Practice Research Database (GPRD). Data were extracted on age, sex, date of episode of Bell's palsy, household number, episodes of herpes simplex, treatment prescribed and referral to relevant hospital departments. A total of 2473 cases of Bell's palsy were identified. The overall incidence for the study period was 20.2 per 100 000 person years of follow-up (95% CI 19.4-21.0). Incidence increased with age. There was no difference in incidence according to sex or season but there were significant changes over time: incidence was higher in the first year of the study period than in subsequent years. There was no clustering of cases in households and no evidence of any tendency for herpes simplex infections to precede Bell's palsy. About 36% of cases were treated with oral steroids and 19% of episodes resulted in hospital referral. In conclusion, Bell's palsy is seen mainly in a primary care setting. The majority of cases are treated expectantly without drugs. Lack of household clustering and lack of a tendency of herpes simplex infections to precede Bell's palsy do not support a viral aetiology.

Adolescent↗

PubMed2002

Mycophenolate in treatment-resistant inflammatory neuropathies.

There has been an increasing interest in the use of mycophenolate as an immunomodulatory drug in neuromuscular diseases. We report five consecutive patients with treatment-resistant chronic inflammatory demyelinating polyradiculoneuropathy or multifocal motor neuropathy who were treated with mycophenolate. None showed clinically significant benefit. The use of mycophenolate did not result in the reduction in the dose of corticosteroid or other immunosuppressive agents in any patient. Side-effects, although not serious, were troubling enough for two patients to stop mycophenolate.

Adjuvants, Immunologic↗

PubMed2002

Evaluation of the effects of controlled autolysis on the immunodetection of PrP(Sc) by immunoblotting and immunohistochemistry from natural cases of scrapie and BSE.

Seventeen clinically suspect scrapie sheep, and twelve suspected BSE-affected cattle were confirmed using routine histopathological examination by the detection of characteristic spongiform change in the medulla brain region taken at the level of the obex. Three sheep and four cows acquired as controls showed no spongiform change. Five aliquots of brain tissue from each of four brain regions were taken (cerebellum, medulla, frontal cerebral cortex and occipital cerebral cortex) from each of the 36 animals. One aliquot was frozen at -70 degrees C, the others were subjected to one of four autolysis regimes at 3 or 7 days at 25 degrees C or 37 degrees C. All samples were tested by Western immunoblotting for detection of PrP(Sc) using the Prionics - Check test (Prionics AG, Zurich, Switzerland). Further samples of medulla from 15 suspect scrapie cases, 10 healthy sheep, 13 suspect BSE cows and 5 healthy cows, were taken adjacent to the obex, and subjected to autolysis at 37 degrees C for 6, 12, 24 and 48 hours before being fixed in 10 per cent formal saline and subsequently examined by a routine immunohistochemical technique for detection of PrP(Sc) protein. The abnormal protein could not be detected in any of the control animals by either technique. PrP(Sc) could be detected by Western immunoblotting in at least one brain area from all the positive animals after autolysis for 7 days at 37 degrees C. The protein could be detected by immunohistochemistry in all cases which were positive by histopathological examination using all autolysis conditions. From the results of this study it is concluded that autolysis does not significantly compromise the diagnosis of scrapie or BSE by either of these diagnostic methods.

Animals↗

PubMed2002

A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee.

OBJECTIVES: A randomized, placebo-controlled, double-blind trial of the relative effectiveness of glucosamine sulphate and placebo in managing pain in osteoarthritis (OA) of the knee. METHODS: Eighty patients with OA of the knee were recruited from a rheumatology out-patient clinic and received either glucosamine sulphate 1500 mg daily for 6 months or dummy placebo. The primary outcome measure was patients' global assessment of pain in the affected knee. RESULTS: Area under the curve analysis for the primary outcome measure showed no difference between placebo and glucosamine [mean difference 0.15 mm, 95% confidence interval (CI) -8.78 to 9.07]. The placebo response was 33%. There was a statistically significant difference between groups in knee flexion (mean difference 13 degrees, 95% CI -23.13 to -1.97), but this difference was small and could have been due to measurement error. CONCLUSIONS: As a symptom modifier in OA patients with a wide range of pain severities, glucosamine sulphate was no more effective than placebo.

Adult↗

PubMed2001

Combinatorial synthesis through disulfide exchange: discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.

Anti-Bacterial Agents↗

PubMed2001

Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

As described in the preceding article, utilizing a novel combinatorial disulfide exchange strategy, a library of psammaplin A (1) analogues was constructed and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of highly potent antibacterial agents (e.g. 17, 57, 58, 69, and 70), some possessing greater than 50-fold higher activities than the natural product. Evaluation of the selectivity and serum binding properties of some of the most promising compounds and preliminary studies directed at deciphering the mechanism of action of this novel class of antibacterial agents are also included.

Anti-Bacterial Agents↗

PubMed2001

Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria.

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.

Anti-Bacterial Agents↗

PubMed2001

Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis.

Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria.

Anti-Bacterial Agents↗

PubMed2001

Identification of the isoflavonoid genistein in bleached kraft mill effluent.

Plants synthesize many phytochemicals, including flavonoids, which may be present in the heartwood of trees used in the pulp and paper industry. Extracts were prepared from wood pulp and mill effluent collected from a bleached kraft mill in Ontario, Canada, and these extracts were subfractionated by LH-20 gel filtration chromatography and analyzed by liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) and LC-ESI-tandem mass spectrometry (LC-ESI-MS-MS). Initial LC-MS analysis in negative ion mode was conducted by monitoring ions corresponding to the deprotonated molecular ions of a range of flavonoid compounds. The presence of chromatographic peaks generated by selected ion monitoring (SIM) in samples of both mill effluent and wood pulp encouraged further analysis. Of the compounds highlighted by LC-ESI-MS-SIM analysis, the isoflavonoid genistein was positively identified by LC-ESI-MS-MS. Genistein was quantified at a concentration of 30.0 microg/kg in air-dried wood pulp and concentrations of 13.1 microg/L and 10.5 microg/L in untreated and treated (final) effluent, respectively. Genistein is a known endocrine disruptorsubstance and,therefore, could contribute to the alterations in sex steroid levels and reduced reproductive capacity observed in fish captured near the discharges of pulp mills.

Animals↗

PubMed2001

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.

This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Administration, Oral↗

PubMed2001

Delayed diagnosis of disseminated strongyloidiasis.

We report the case of a 51-year-old woman who presented with a confusing spectrum of systemic symptoms after starting steroid therapy for a rheumatological disorder. The diagnosis of disseminated strongyloidiasis was made after a delay of 2 weeks. This paper outlines the symptom complex with which this critically ill woman presented, the course of her disease and the treatment of her disseminated strongyloidiasis.

Chronic Disease↗

PubMed2001

Heroin smoking by "chasing the dragon" in young opiate users in Ireland: stability and associations with use to "come down" off "Ecstasy".

We explored the frequency of commencing opiate use by "chasing the dragon" to "come down" off Ecstasy and the stability of heroin smoking in young opiate takers by assessing 102 subjects in Dublin using a semistructured interview. Ninety-two subjects had used Ecstasy. Of these, 68 reported "chasing" to "come down" off Ecstasy at some point in their history and were found to have used Ecstasy more frequently and in larger amounts. Thirty-six reported that their first experience of using opiates was to "come down" off Ecstasy, 28 citing this as their main reason for commencement.Eighty-six of the 102 commenced opiates by "chasing" heroin, 61 of whom progressed to injecting after a mean of 2.9 years. This was associated with starting illicit drug use earlier, starting heroin earlier, and a history of using Ecstasy. Implications for service planners in developing responses to illicit drug use among adolescents are discussed.

Administration, Inhalation↗

PubMed2001

Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B(0).

Addition of the amino acids threonine, serine, proline, and arginine to fermentations of the fungus Glarea lozoyensis influenced both the pneumocandin titer and the spectrum of analogues produced. Addition of threonine or serine altered the levels of the "serine analogues" of pneumocandins B(0) and B(5) and allowed for their isolation and identification. Proline supplementation resulted in a dose-dependent increase in the levels of pneumocandins B(0) and E(0), whereas pneumocandins C(0) and D(0) decreased as a function of proline level. Moreover, proline supplementation resulted in an overall increase in the synthesis of both trans-3- and trans-4-hydroxyproline while maintaining a low trans-4-hydroxyproline to trans-3-hydroxyproline ratio compared to the unsupplemented culture. Pneumocandin production and the synthesis of hydroxyprolines was also affected by addition of the proline-related amino acid arginine but not by the addition of glutamine or ornithine. Zinc, cobalt, copper, and nickel, trace elements that are known to inhibit alpha-ketoglutarate-dependent dioxygenases, affected the pneumocandin B(0) titer and altered the levels of pneumocandins B(1), B(2), B(5), B(6), and E(0), analogues that possess altered proline, ornithine, and tyrosine hydroxylation patterns.

Amino Acids↗

PubMed2001

Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation.

Human male volunteers were studied in a metabolic facility whilst they were fed randomized controlled diets. In eight volunteers there was a significant increase in faecal apparent total N:-nitroso compounds (ATNC) and nitrite excretion (P < 0.0001 and P = 0.046, respectively) when randomized doses of meat were increased from 0 to 60, 240 and 420 g/day over 10 day periods. Mean (+/- SE) faecal ATNC levels were 54 +/- 7 microg/day when the diets contained no meat, 52 +/- 11 microg/day when the diets contained 60 g meat/day, 159 +/- 33 microg/day with 240 g meat and 199 +/- 36 microg/day with 420 g meat. Higher concentrations of NOC were associated with longer times of transit in the gut (r = 0.55, P = 0.001) and low faecal weight (r = -0.51, P = 0.004). There was no significant decline in levels in individuals fed 420 g meat for 40 days. The exposures found on the higher meat diets were comparable with other sources of N:-nitroso compounds (NOC), such as tobacco smoke. Many NOC are known large bowel initiators and promotors in colon cancer, inducing G-->A transitions in codons 12 and 13 of K-ras. Endogenous NOC formation, combined with prolonged transit times in the gut, may explain the epidemiological associations between high meat/low fibre diets and colorectal cancer risk.

Adult↗

PubMed2001

Stimulation of apoptosis by two prebiotic chicory fructans in the rat colon.

Prebiotics, in particular the chicory derived beta(2-1) fructans, have been shown to exert cancer protective effects in animal models. The present study was carried out to determine the effects of two chicory fructans--oligofructose (RaftiloseP95; average degree of polymerization DP = 4) and long chain inulin (RaftilineHP; average DP = 25), on apoptosis and bacterial metabolism associated with carcinogenesis. Eighteen rats were fed a stock diet for one week. Three groups of six animals were then fed one of three diets: basal, basal with oligofructose (5%w/w) or basal with long chain inulin (5%w/w), for a three week period. All animals were then dosed with 1,2-dimethylhydrazine and killed 24 h later. The mean number of apoptotic cells per crypt was significantly higher in the colon of rats fed oligofructose (P = 0.049) and long chain inulin (P = 0.017) as compared to those fed the basal diet alone. This suggests that oligofructose as well as the long chain inulin exert protective effects at an early stage in the onset of cancer, as the supplements were effective soon after the carcinogen insult. Comparison of the apoptotic indices between the two oligosaccharide diets showed no significant difference even though the mean apoptotic index was higher in animals fed long chain inulin. For all animals, apoptosis was significantly higher in the distal colon as compared to the proximal colon (P = 0.0002) however no significant site specific effect of diet occurred. There were no significant dietary effects on bacterial enzyme activities or ammonia concentration despite a trend towards increased colonic beta-glucosidase and reduced ammonia concentration during the oligosaccharide diets. This is the first time that a significant effect of chicory fructans on apoptosis has been shown and the results contribute to the growing evidence that chicory fructans may have cancer preventing properties.

Ammonia↗

PubMed2001

Comparison of hydrogen peroxide contact lens disinfection systems and solutions against Acanthamoeba polyphaga.

Acanthamoeba is a free-living amoeba causing a potentially blinding infection of the cornea. Contact lens wearers are most at risk and account for some 95% of cases. Hydrogen peroxide is used for contact lens disinfection due to its broad antimicrobial activity. Lenses must be neutralized before use to avoid pronounced stinging and possible corneal damage. Neutralization is achieved by adding a catalyst during the disinfection process (one-step) or afterwards (two-step). Here, the activities of commercial peroxide systems and individual solutions against trophozoites and cysts of Acanthamoeba polyphaga were compared. All disinfection systems were active against trophozoites, giving a > or = 3-log (99.9%) kill within 1 h. Of the four one-step systems, only one showed some cysticidal activity, giving a 1.28 +/- 0.41-log reduction. Both two-step systems were cysticidal, giving a > or = 3-log kill at 4 h. All system peroxide solutions were cysticidal, giving a > or = 3-log kill by 4 to 6 h. Variation in the cysticidal rate was observed with two solutions that gave a 1.8- to 2.1-log kill at 4 h compared with 3.0 to 4.0 for the rest (P < 0.05). No cysticidal activity was found with the peroxigen sodium perborate or the contact lens protein remover subtilisin A. Two-step systems are cysticidal providing contact times of at least 4 h are employed. Variation in cyst killing occurs between peroxide solutions, possibly due to formulation differences. One-step systems are less effective against Acanthamoeba cysts due to rapid peroxide neutralization. The cysticidal activity of one-step systems could be improved if neutralization rates were retarded.

Acanthamoeba↗