Importance of trial design in studies using high-dose intravenous immunoglobulin.
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Dermatitis, Atopic↗
Biomedical subjects
J Hughes
Publications and source records attributed to J Hughes.
Lymph node metastases in the lower neck.
Current knowledge suggests that lymph node metastases in the lower neck (supraclavicular fossa and posterior triangle) are associated with a poor survival. Very little systematic work has been published on this subject. This was a retrospective study carried out on a database where all patients were entered in a prospective manner over a 35-year period using a standard pro-forma. Data on 168 patients presenting with a lower neck node metastasis were retrieved. The main outcome measures were: association between variables and tumour-specific survival. Data were displayed in contingency tables and analysed by chi-square and categorical modelling. Recurrence and survival were plotted in a cause-specific manner using the Kaplan Meir method. Differences in curves were analysed using the log rank test. Multivariate analysis was carried out using Cox's proportional hazard model. The only association was between site and node level and histology. Head and neck tumours were associated with squamous histology (P = 0.0004) and supraclavicular nodes (P = 0.0047). Survival time was not significantly different when lower-neck lymph node metastasis from the head and neck was compared to non-head and neck metastasis: 5-year survival 30% and 10% respectively (P = 0.1363). Survival with posterior triangle metastases was significantly better than supraclavicular metastases (P = 0. 0059), confirmed on multivariate analysis. Laterality of metastasis had no effect on survival (P < 0.0001). There was no significant difference in survival between squamous and non-squamous metastases on Cox regression (P = not significant). There were 85 head and neck primaries including lymphomas, 53 infraclavicular primaries and 30 unknown primaries. There were 73 squamous cell carcinomas, 27 adenocarcinomas, 34 lymphomas, 28 undifferentiated tumours and six other tumours. Nearly half the primary tumours were below the clavicle. Survival was unaffected by laterality, primary site or histology, but was better for posterior triangle nodes.
Adenocarcinoma↗
Nutritional management of rheumatoid arthritis: a review of the evidence.
Rheumatoid arthritis (RA) is a debilitating disease and is associated with increased risk of cardiovascular disease and osteoporosis. Poor nutrient status in RA patients has been reported and some drug therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), prescribed to alleviate RA symptoms, may increase the requirement for some nutrients and reduce their absorption. This paper reviews the scientific evidence for the role of diet and nutrient supplementation in the management of RA, by alleviating symptoms, decreasing progression of the disease or by reducing the reliance on, or combating the side-effects of, NSAIDs. Supplementation with long-chain n-3 polyunsaturated fatty acids (PUFA) consistently demonstrates an improvement in symptoms and a reduction in NSAID usage. Evidence relating to other fatty acids, antioxidants, zinc, iron, folate, other B vitamins, calcium, vitamin D and fluoride are also considered. The present evidence suggests that RA patients should consume a balanced diet rich in long-chain n-3 PUFA and antioxidants. More randomized long-term studies are needed to provide evidence for the benefits of specific nutritional supplementation and to determine optimum intake, particularly for n-3 PUFA and antioxidants.
Anti-Inflammatory Agents, Non-Steroidal↗
The Food Standards Agency's antioxidants in food programme--a summary.
BACKGROUND: In 2001, the British Nutrition Foundation (BNF) was contracted to evaluate projects from the Antioxidants in Food research programme, now funded by the Food Standards Agency and previously the Ministry of Agriculture, Fisheries and Food. The programme aimed at testing the 'antioxidant hypothesis'. METHODS: The evaluation was conducted with support and guidance from a Steering Group of experts. The final report sets out BNF's recommendations for the future of the Antioxidants in Food research programme. RESULTS: It was recommended that future research should consider a wider scope of potential mechanisms of action of substances within foods; more emphasis should be placed on studying bioavailability of a range of plant derived substances, and the impact of genotype, age and disease should be investigated. CONCLUSIONS: The research programme has been important as it has focused attention on disease prevention rather than on treatment, and has helped progress identification of biomarkers. From human observational and intervention studies there is evidence of an association between a diet rich in plant foods (particularly fruit and vegetables) and health benefits. However, as there is no evidence that any particular nutrient or class of bioactive substances makes a special contribution, currently the most prudent public health advice is to increase vegetable and fruit consumption.
Antioxidants↗
The use of the Box-Behnken experimental design in the optimisation and robustness testing of a capillary electrophoresis method for the analysis of ethambutol hydrochloride in a pharmaceutical formulation.
Box-Behnken experimental designs do not appear to be extensively used in optimisation of analytical methods using capillary electrophoresis (CE). This paper describes the use of the Box-Behnken experimental design to optimise the factors affecting the separation of ethambutol hydrochloride (EB), its impurity 2-amino-1-butanol and the internal standard (phenylephrine hydrochloride) in a CE method for a pharmaceutical tablet assay. The three factors studied simultaneously were: buffer pH, buffer concentration and applied electric field, each at three levels. The method was optimised with respect to three responses: resolution between peaks, theoretical plate count and the migration time of the EB peak. A statistical programme, which applies a multiple response optimisation algorithm, was used to calculate and optimise the three responses simultaneously. The optimum conditions were established to be 58.0 mM sodium borate buffer at pH 9.50 and an applied electric field of 412 V/cm. The robustness of the method was also determined and confirmed using a second Box-Behnken design, as part of the validation exercise. System suitability values for the method were derived from the regression surface analysis. The CE method for a pharmaceutical tablet formulation was further validated according to current regulatory requirements, with respect to linearity and range, precision, specificity, accuracy and limit of quantitation. The optimised method gives a fast and efficient separation under 4 min, with complete resolution between the three peaks, and represents an improvement over the existing USP method. It can be concluded that the Box-Behnken experimental design provides a suitable means of optimising and testing the robustness of a CE pharmaceutical method.
Amino Alcohols↗
Fluorescence investigation of the recombinant cyanobacterial phytochrome (Cph1) and its C-terminally truncated monomeric species (Cph1Delta2): implication for holoprotein assembly, chromophore-apoprotein interaction and photochemistry.
Recombinant dimeric full-length Cph1 holophytochrome and its C-terminally-truncated monomeric species [Cph1Delta2, comprising the chromophore-bearing N-terminal sensory module (residues 1 to 514)] from the cyanobacterium Synechocystis expressed in E. coli and reconstituted in vitro with phycocyanobilin (PCB) were investigated with the use of fluorescence spectroscopy and photochemistry in the temperature range from 85 to 293 K. Holoprotein assembly in Cph1 apparently proceeds via intermediate states with the emission maximum at 680-690 nm (I685) and 700 nm (I700) and a half-life time, at room temperature, of < or =5 s. Conversion of the putative I685 into mature Cph1 involves relaxation of the chromophore into a more flexible conformation. Cph1 and Cph1Delta2 were closely similar in their spectroscopic and photochemical characteristics (position of the emission band and its width, character of the temperature dependence of the fluorescence and activation energy of the fluorescence decay, kinetics and extent of the Pr conversion at low and ambient temperatures), suggesting that there is no immediate effect of the C-terminus on the photochemical properties of the chromophore in Cph1 and that chromophore-chromophore interactions in the dimer are not significant. The latter is also supported by the lack of energy transfer from the phycoerythrobilin (PEB) to PCB in the mixed PEB/PCB adduct of Cph1. At the same time, certain variations in the fluorescence and photochemical parameters of Cph1 with temperature of the sample and intensity of the excitation light and dependence of the emission spectra on excitation wavelength were observed. These variations are interpreted as a manifestation of the Cph1 heterogeneity which may be due to the existence of different conformers of the chromophore and photoproduct formation under excitation light.
Apoproteins↗
Development of a method in situ to study toothpaste abrasion of dentine. Comparison of 2 products.
BACKGROUND/AIMS: The abrasivity of toothpastes is usually determined using in vitro methods; as such, the clinical significance of the findings is uncertain. The aim of the present study was to develop and evaluate a method in situ to study abrasion of dentine by two toothpastes of different Relative Dentine Abrasivity (RDA). METHOD: The study was a single blind, randomised, 2 way cross over design involving 10 healthy dentate volunteers. Subjects wore an maxillary removable acrylic appliance containing two flat human dentine specimens, taped to expose a window of tissue, from 9 am to 4 pm during the two 10 working day study periods. No food or drink was consumed when the appliance was in place. On five occasions each day, the appliances were removed and the dentine windows brushed ex vivo with the allocated paste for 60 s each. Dentine abrasion at days 5 and 10 was measured using a profilometer. RESULTS: Both toothpastes produced measurable abrasion in all subjects and the depth increased in most subjects between 5 and 10 days. There was significant subject and specimen variation both within and between toothpastes. There was significantly increased abrasion by the toothpaste with the higher RDA value and in mean terms the ratio of abrasion between the two pastes was similar to the ratio of the RDA values. CONCLUSION: The method in situ, already used to study dental hard tissue erosion, appears ideally suitable to study dental abrasion alone and the interaction between aetiological factors involved in tooth wear.
Cross-Over Studies↗
The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).
OBJECTIVE: To assess the long-term effect of dietary advice on diet and mortality after a randomised trial of men with a recent history of myocardial infarction. DESIGN: Questionnaire survey and mortality follow-up after a trial of dietary advice. SETTING: Twenty-one hospitals in south Wales and south-west England. SUBJECTS: Former participants in the Diet and Reinfarction Trial. MAIN OUTCOME MEASURES: Current fish intake and cereal fibre intake. All-cause mortality, stroke mortality and coronary mortality. RESULTS: By February 2000, after 21147 person years of follow-up, 1083 (53%) of the men had died. Completed questionnaires were obtained from 879 (85%) of the 1030 men alive at the beginning of 1999. Relative increases in fish and fibre intake were still present at 10 y but were much smaller. The early reduction in all-cause mortality observed in those given fish advice (unadjusted hazard 0.70 (95% CI 0.54, 0.92)) was followed by an increased risk over the next 3 y (unadjusted hazard 1.31 (95% CI 1.01, 1.70). Fat and fibre advice had no clear effect on coronary or all-cause mortality. The risk of stroke death was increased in the fat advice group-the overall unadjusted hazard was 2.03 (95% CI 1.14, 3.63). CONCLUSIONS: In this follow-up of a trial of intensive dietary advice following myocardial infarction we did not observe any substantial long-term survival benefit. Further trials of fish and fibre advice are feasible and necessary to clarify the role of these foods in coronary disease.
Animals↗
Steroid responsive cutaneous Rosai-Dorfman disease associated with uveitis and hypothyroidism.
We report a patient with steroid responsive cutaneous Rosai-Dorfman disease (RDD) associated with bilateral anterior uveitis and hypothyroidism. RDD is a rare histiocytic disorder of unknown aetiology. There is characteristic histology in which large pale-staining histiocytes exhibit emperipolesis and stain positive for S-100 protein. This condition is thought to be a reactive process rather than a neoplastic one and viral and immune mediated causes have been postulated.
Aged↗
MR urography: evaluation of different techniques in non-dilated tracts.
OBJECTIVE: To assess the effectiveness of different MRI sequences for the visualisation of the different components of the non-dilated urinary tract. METHOD: 20 asymptomatic individuals were prospectively evaluated using 2 different heavily T2 weighted sequences, and after the injection of 2 different doses of gadolinium (Gd-DTPA). Images were independently scored. RESULTS: The low dose Gd-DTPA enhanced MR urography (MRU) sequence was the best overall sequence for the visualisation of both the pelvicalyceal systems and ureters. The combination of information from the other sequences was additive. CONCLUSIONS: Combined use of heavily T2 weighted and Gd-DTPA enhanced MRU produces diagnostic images and does not require pre-imaging preparation other than oral hydration.
Adult↗
A review of the MAFF Optimal Nutrition Status research programme: folate, iron and copper.
OBJECTIVE: The objective was to conduct a critical appraisal of research conducted within one of the UK government's research programmes, Optimal Nutrition Status, and to place the findings of this work in the context of the international research effort, to assist policy makers and advisers. Nine nutrients are addressed within the programme; the findings for three of these are reported here: folate/folic acid, iron and copper. DESIGN: To conduct the review, the researchers had access to all unpublished progress reports, submitted to officials, arising from the projects. The overall assessment criterion was whether the information generated by the research programme could be regarded as reliable experimental data of direct relevance to setting optimal dietary requirements for the particular micronutrients. However, findings were also assessed against specific scientific criteria concerning understanding of the bioavailability, interactions, development of functional markers and inter-individual variations in metabolism, for each of the nutrients scrutinised. RESULTS: The results of the review indicated that many important questions are indeed being addressed by the UK government's research programme, and that the work is contributing to the overall research effort being conducted world-wide on this important subject. CONCLUSIONS: Many major questions still need to be addressed before it will be possible to identify optimal intakes for various sub-populations. These priorities are summarised in the paper.
Copper↗
Osteopontin--a molecule for all seasons.
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Animals↗
Frequency of isolation of Staphylococcus lugdunensis in consecutive urine cultures and relationship to urinary tract infection.
Recent reports associate Staphylococcus lugdunensis with severe infection in humans. The frequency of this microorganism in urine cultures is unknown. Five hundred isolates of coagulase-negative staphylococci (CoNS) were recovered from 4,652 consecutive urine specimens submitted for culture to the Mayo Clinic Microbiology Laboratory. Thirty-one (6%) of 500 isolates of CoNS were identified as S. lugdunensis. In no case was S. lugdunensis isolated in pure culture; 29 (94%) of 31 S. lugdunensis isolates were part of mixed nonpathogenic flora. Medical records were reviewed for 30 of the 31 patients from whom these 31 isolates were isolated. Twenty-one (70%) of the 30 evaluable patients were not treated with antibiotics; the remaining 9 (30%) of 30 patients were treated with antibiotics that may be effective against S. lugdunensis. S. lugdunensis may be an unrecognized yet infrequent cause of urinary tract infection.
Aged↗
Height, body mass index, and survival in men with coronary disease: follow up of the diet and reinfarction trial (DART).
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Body Height↗
Oropharyngeal carriage and lower airway colonisation/infection in 45 tracheotomised children.
BACKGROUND: A study was undertaken to determine the oropharyngeal carrier state of potentially pathogenic microorganisms (PPM) and the magnitude of colonisation and infection rates of the lower airways with these PPM in children requiring long term ventilation first transtracheally and afterwards via a tracheotomy. METHODS: A 5 year, prospective, observational cohort study was undertaken in 45 children (33 boys) of median age 6.4 months (range 0-180) over a 5 year period at the Royal Liverpool Children's NHS Trust of Alder Hey, a university affiliated tertiary referral centre. The children were first admitted to the 20-bed paediatric intensive care unit (PICU) and, following placement of a tracheotomy, they were transferred to a four bedded respiratory ward. The two main indications were neurological disorders and airway obstruction. All children were ventilated transtracheally for a median period of 12 days (range 0-103) and, after placement of the tracheotomy, for a similar period of 12 days (range 1-281). Surveillance cultures of the oropharynx were taken on admission to the PICU and on the day of placement of the tracheotomy. Throat swabs were taken twice weekly during ventilation, both transtracheal and via the tracheotomy. Tracheal aspirates were taken once weekly and when clinically indicated (in cases where the lower airway secretions were turbid). RESULTS: Twenty five patients (55%) had abnormal flora, mainly aerobic Gram negative bacilli (AGNB), particularly Pseudomonas aeruginosa, while the community PPM Staphylococcus aureus was present in the oropharynx of 37% (17/45) of the study population. The lower airways were sterile in six children; the other 39 patients (87%) had a total of 82 episodes of colonisation. "Community" PPM significantly increased once the patients received a tracheotomy, independent of the number of patients enrolled, episodes of colonisation/infection, and the number of colonised/infected patients. "Hospital" PPM significantly decreased after tracheotomy only when episodes were compared. CONCLUSIONS: While P aeruginosa present in the admission flora caused primary endogenous colonisation/infection during mechanical ventilation on the PICU, S aureus not carried in the throat was responsible for the exogenous colonisation/infection once the patients had a tracheotomy. This is in sharp contrast to adult studies where exogenous infections are invariably caused by AGNB. This discrepancy may be explained by chronic underlying conditions such as diabetes, alcoholism, and chronic obstructive pulmonary disease which promote AGNB, whereas the children were recovering following tracheotomy.
Adolescent↗
Most nosocomial pneumonias are not due to nosocomial bacteria in ventilated patients. Evaluation of the accuracy of the 48 h time cut-off using carriage as the gold standard.
A prospective observational cohort study was undertaken with two endpoints: (1) to compare the time cut-off of 48h and the carrier state criterion for classifying lower airway infections in adult and paediatric long-term ventilated patients, and (2) to evaluate the potential of optimized time cut-offs for characterizing imported and ICU-acquired lower airway infections. All patients admitted to the general and paediatric intensive care units and expected to require mechanical ventilation for a period > or = 3 days were enrolled. Surveillance cultures of throat and rectum were obtained on admission and thereafter twice weekly to distinguish micro-organisms that were imported into the unit from those acquired during the stay on the unit. A total of 130 adults and 400 children were studied. In the adult population, 70% of lower airway infections were classified as ICU-acquired by the 48 h cut-off and 48% by the criterion of carriage; on the paediatric ICU the percentages were 65% and 20%, respectively. To separate imported from ICU-acquired infections, eight days was optimal in the adult population and 10 days in the paediatric population. Sensitivity, specificity, positive predictive value and negative predictive value for a time cut-off of eight days for adults were 86, 77, 80, 83%, respectively, and using 10 days for children were 87, 62, 90, 56%, respectively. The use of the 48 h cut-off rule classifies patients as having nosocomial pneumonia, when in fact the infections are commonly caused by microorganisms carried in by the patients. In contrast, using the carriage method, the proportion of lung infections due to nosocomial bacteria was relatively small and was a late phenomenon. Although in prolonging the time cut-off the difference between the two types of classification was shorter, time cut-offs were still found to be unreliable for distinguishing imported from unit-acquired lower airway infections.
Adult↗
Safety and immunogenicity of TETRActHIB (a vaccine combining DTP vaccine and Haemophilus influenzae type B conjugate vaccine) administered to infants at 6, 10 and 14 weeks of age.
The safety and immunogenicity of TETRActHIB (a vaccine combining diphtheria and tetanus toxoids-pertussis vaccine (DTP) with Haemophilus influenzae type b (Hib) conjugate vaccine (polyribosyl ribitol phosphate conjugated to tetanus protein) (PRP-T)) was assessed in 131 Cape Town infants immunized at 6, 10 and 14 weeks of age. Serological responses to all component antigens were measured before the first dose and at 18 weeks of age. In addition, anti-PRP antibodies were measured at 9 and 18 months of age to determine long-term immunogenicity. The vaccine was well tolerated by infants and no significant side-effects were reported. Responses to Hib at 18 weeks of age were good in that most infants achieved a level of anti-PRP antibodies > or = 0.15 microgram/ml, indicative of short-term protection, and 70% achieved a level > or = 1 microgram/ml, indicative of long-term protection. The proportions of children with protective levels > or = 0.15 microgram/ml and > or = 1 microgram/ml were similar at 9 and 18 months of age, i.e. approximately 75% and 45%, respectively. Responses to tetanus and diphtheria toxoids were excellent and all infants achieved protective serological levels. Responses to pertussis were moderate in that approximately 65% achieved 'protective' serum levels of pertussis agglutinins, i.e. titres > or = 320. In conclusion, this study has shown that the DTP/PRP-T vaccine is safe, immunogenic and well tolerated in infants immunised at 6, 10 and 14 weeks of age. TETRActHIB is therefore suitable for inclusion in the World Health Organisation Expanded Programme on Immunisation (WHO EPI) schedule.
Age Factors↗
Estimating the efficacy of interventions to prevent mother-to-child transmission of HIV in breast-feeding populations: development of a consensus methodology.
Postnatal transmission of HIV through breast milk complicates both the design of effective interventions to prevent mother-to-child transmission of HIV (PMTCT) and their evaluation. Estimated long-term efficacy in five African trials (four with peri-partum antiretrovirals and one with artificial feeding) varied from 25 to 50 per cent. This variation may be due, at least in part, to differences in analytical methodology. To facilitate direct comparison between trials, a methodological consensus approach to the analysis and presentation of the results of PMTCT trials was developed. The initial methodology used and results presented from African trials with available long-term efficacy data were reviewed during a workshop in Bordeaux, France, in September 2000. A consensus approach for evaluating efficacy applicable across PMTCT studies was developed. There are four typical situations defined by duration of follow-up (short versus long), and the available demographic (vital status) and biological data (single versus repeat HIV testing). Efficacy can be assessed from the risk of infection directly or from HIV-free survival by combining infection and death as a single endpoint. Studies should report results in a standardized format including infection, weaning, mortality and loss to follow-up. New statistical methods that account for the unknown date when a child would first test positive for HIV, for weaning as a competing risk for HIV infection, and for increased risk of death among HIV-infected children should be used in analysing data from PMTCT studies with repeat HIV testing. All estimates should be reported with confidence intervals. This standardized methodology that allows direct comparison between studies is now being applied to four randomized clinical trials.
Antiviral Agents↗