Showing papers by "Paul T. Seed published in 2000"

Randomized double‐blind study of cyclosporin in chronic ‘idiopathic’ urticaria

Abstract: Background Histamine-releasing activity (HRA) is detectable in up to 50% of patients with chronic ordinary urticaria. Objectives To determine the effect of cyclosporin on clinical features and HRA in patients with chronic urticaria. Methods Thirty patients with severe unremitting disease, responding poorly to antihistamines and showing a positive autologous serum skin test (ASST) as a marker of HRA, were randomized to 4 mg kg−1 daily of cyclosporin (Sandimmun®, n = 20) or placebo (n = 10) for 4 weeks. Non-responders were offered open-label cyclosporin for 4 weeks. All were followed for up to 20 weeks or until clinical relapse; all took cetirizine 20 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score 42 per week). A positive response was defined as a reduction to 75%. The effect of cyclosporin on serum HRA was assessed by in vitro basophil histamine release assays and ASSTs before and after treatment. Results Twenty-nine patients (19 active, 10 controls) completed the randomized trial medication. Eight of 19 on active treatment but none on placebo had responded at 4 weeks (P < 0·05). Three others on active drug met the criterion for response at 2 weeks but not at 4 weeks. Mean reduction in UAS between weeks 0 and 4 was 12·7 (95% confidence interval, CI 6·6–18·8) for active and 2·3 (95% CI − 3·3–7·9) for placebo (P = 0·005). Seventeen non-responders (seven randomized to active and 10 to placebo) chose open-label cyclosporin and 11 responded after 4 weeks. Six of the eight randomized active drug responders relapsed within 6 weeks. Of the 19 responders to randomized and open-label cyclosporin, five (26%) had not relapsed by the study end-point. Mean in vitro serum HRA fell from 36% (95% CI 22–49%) to 5% (95% CI 1–8%) after cyclosporin treatment (n = 11, P < 0·0001). The ASST response to post-treatment serum was also reduced (P < 0·05). Conclusions This study shows that cyclosporin is effective for chronic urticaria and provides further evidence for a role of histamine-releasing autoantibodies in the pathogenesis of this chronic ‘idiopathic’ disease.

Monitoring blood glucose control in diabetes mellitus: a systematic review.

Abstract: Searching The authors searched MEDLINE from 1976 to 1999, EMBASE from 1980 to 1998, IBSS from 1975 to 1998, and the database of the Diabetes Health Economic Study Group (search dates unclear). The MEDLINE search strategy was provided in full in the report, as were the keywords used to search EMBASE and IBSS. The authors also listed the Science Citation Index and the Social Sciences Citation Index as sources but gave no further details. Additional studies were identified by searching the authors' personal collections of articles, by handsearching Diabetic Medicine and Diabetes Care journals from 1990 to 1999, and by contacting the British Diabetic Association, and Bayer and Roche Diagnostics. The citations in retrieved papers were also examined. Non-English language papers were included as too few articles were retrieved by searches restricted to English language publications only.

Do Hospital Fall Prevention Programs Work? A Systematic Review

Abstract: OBJECTIVES: To analyze published hospital fall prevention programs to determine whether there is any effect on fall rates. To review the methodological quality of those programs and the range of interventions used. To provide directions for further research. DESIGN: Systematic review of published hospital fall prevention programs. Meta-analysis. METHODS: Keyword searches of Medline, CINAHL, monographs, and secondary references. All papers were included that described fall rates before and during intervention. Risk ratios and 95% Confidence Intervals (95% CI) were estimated and random effects meta-analysis employed. Begg's test was applied to detect possible publication bias. Separate meta-analysis regressions were performed to determine whether individual components of multifaceted interventions were effective. RESULTS: A total of 21 papers met the criteria (18 from North America), although only 10 contained sufficient data to allow calculation of confidence intervals. A rate ratio of <1 indicates a reduction in the fall rate, resulting from an intervention. Three were randomized controlled trials (pooled rate ratio 1.0 (CI 0.60, 1.68)), seven prospective studies with historical control (0.76 (CI 0.65, 0.88)). Pooled effect rate ratio from these 10 studies was 0.79 (CI 0.69, 0.89). The remaining 11 studies were prospective studies with historical control describing fall rates only. Individual components of interventions showed no significant benefit. DISCUSSION: The pooled effect of about 25% reduction in the fall rate may be a result of intervention but may also be biased by studies that used historical controls not allowing for historical trends in the fall rate before and during the intervention. The randomized controlled trials apparent lack of effect might be due to a change in practice when patients and controls were in the same unit at the same time during a study. Studies did not analyze compliance with the intervention or opportunity costs resulting from the intervention. Research and clinical programs in hospital fall prevention should pay more attention to study design and the nature of interventions.

Self-monitoring in Type 2 Diabetes Mellitus: A Meta-Analysis

Abstract: Aims Self-monitoring of blood or urine glucose is widely used by subjects with Type 2 diabetes mellitus. This study evaluated the effectiveness of the technique at improving blood glucose control through a systematic review and meta-analysis. Methods Randomized controlled trials were identified that compared the effects of blood or urine glucose monitoring with no self-monitoring, or blood glucose self-monitoring with urine glucose self-monitoring, on glycated haemoglobin as primary outcome in Type 2 diabetes. Results Eight reports were identified. These were rated for quality and data were abstracted. The mean (SD) quality score was 15.0 (1.69) on a scale ranging from 0 to 28. No study had sufficient power to detect differences in glycated haemoglobin (GHb) of less than 0.5%. One study was excluded because it was a cluster randomized trial of a complex intervention and one because fructosamine was used as the outcome measure. A meta-analysis was performed using data from four studies that compared blood or urine monitoring with no regular monitoring. The estimated reduction in GHb from monitoring was -0.25% (95% confidence interval -0.61 to 0.10%). Three studies that compared blood glucose monitoring with urine glucose monitoring were also combined. The estimated reduction in GHb from monitoring blood glucose rather than urine glucose was -0.03% (-0.52 to 0.47%). Conclusions The results do not provide evidence for clinical effectiveness of an item of care with appreciable costs. Further work is needed to evaluate self-monitoring so that resources for diabetes care can be used more efficiently.

Sensitivity to Sunburn Is Associated with Susceptibility to Ultraviolet Radiation–Induced Suppression of Cutaneous Cell–Mediated Immunity

Abstract: Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P < 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer.

[(18)F]Fluorodeoxyglucose positron emission tomography and its prognostic value in lung cancer.

Abstract: Objective: Positron emission tomography (PET) is being increasingly used as an accurate and non-invasive modality in diagnosis, staging and post-therapy assessment in patients with lung cancer. In this study, we examine whether the uptake of [ 18 F]fluorodeoxyglucose (FDG), a marker of increased glucose metabolism in neoplastic cells, is of prognostic value in patients with primary lung cancer. Methods: We have retrospectively analyzed 77 patients (mean age, 63.0 years; male/female ratio, 53:24) with primary lung cancers who underwent whole body and localized thoracic PET as part of their diagnostic and staging procedures prior to consideration of surgical resection. The standardized uptake value (SUV) of injected FDG for each primary lesion was correlated with tumour histology and the patient’s clinical outcome. Results: A SUV of 20 or greater was found to be of significant prognostic value. The chance of survival (with 95% confidence intervals (CI)) at 12 months post-surgery for the various SUV groups was as follows: 75.2% (59.6‐85.5) for SUV , 10; 67.5% (29.0‐88.2) for SUV 10‐ , 12; 63.6% (29.7‐84.5) for SUV 12‐ , 15; 66.7% (19.5‐90.4) for SUV 15‐ , 20; 16.7% (0.01‐0.52) for SUV . 20. A SUV of 20 or more is associated with a 4.66 times increase in hazard, compared with lower levels of SUV. We found no significant correlation between tumour histology and SUV. Conclusion: We have previously reported on the significant advantages of PET in the staging and surgical care of patients with lung cancer. The present study adds further support for an additional prognostic role for PET in the management of thoracic malignancy as determined by the amount of labelled-FDG taken up by the primary lesion. q 2000 Elsevier Science B.V. All rights reserved.

Diagnosis of pemphigus by ELISA: a critical evaluation of two ELISAs for the detection of antibodies to the major pemphigus antigens, desmoglein 1 and 3.

Abstract: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are characterized by autoantibodies to the desmosomal glycoproteins desmoglein 3 (Dsg 3) and Dsg 1 (Dsg 1), respectively. In this study, two enzyme-linked immunosorbent assays (ELISA) which detect IgG autoantibodies to Dsg 1 and Dsg 3 have been evaluated. A total of 317 normal and disease controls, 82 patients with PV and 25 with PF were studied. The Dsg 3 ELISA was positive in all 34 patients with untreated PV and the Dsg 1 ELISA was positive in all 10 with untreated PF. When patients undergoing treatment were included, the sensitivities fell to 95% and 92%, respectively, but still compared favourably to the sensitivity of indirect immunofluorescence which was 79% in PV and 84% in PF. All PF sera were negative in the Dsg 3 ELISA and the specificity of both assays was 98% or greater. Large numbers of samples could be analysed simultaneously over a relatively short time period. The Dsg 1 and Dsg 3 ELISAs also provided objective, quantitative, reproducible data which allowed differentiation of PV from PF and in view of these advantages, they are likely to become a routine technique in diagnostic laboratories.

The frequency of fragrance allergy in a patch-test population over a 17-year period.

Abstract: Fragrances are widely encountered in our daily environment and are known to be a common cause of allergic contact dermatitis. We have reviewed our patch test data from 1980 to 1996 to establish whether the pattern of fragrance allergy has changed with time. During this period, 25,545 patients (10,450 male, 15,005 female) were patch tested with the European standard series. The mean annual frequency of positive reactions to the fragrance mix was 8.5% in females (range 6.1-10.9) and 6.7% in males (range 5.1-12.9). Females were 1.3 times more likely to be allergic to fragrance (P < 0.001, 95% confidence interval, CI 1.17-1.41). Males with fragrance allergy were older than females by 5.6 years (mean age 48.2 vs. 42.6 years; P < 0.001, 95% CI 3.9-7.3). The incidence of a concomitant positive patch test to balsam of Peru in fragrance-sensitive patients showed wide variation, suggesting that it is not a reliable marker of fragrance allergy. There was a positive correlation between the isomers isoeugenol and eugenol. Oak moss remained the most common overall allergen throughout the study, positive in 38.3% of females and 35.6% of males who were tested to the constituents of the fragrance mix. During the period of the study the incidence of positive tests to oak moss increased by 5% yearly (P = 0.001, 95% CI 2.2-8.7). The frequency of allergic reactions to eugenol and geraniol remained relatively constant. Isoeugenol and alpha-amyl cinnamic aldehyde sensitivity increased and hydroxycitronellal showed a slow decline. There was a striking reduction in the frequency of sensitivity to cinnamic aldehyde (by 18% yearly; P < 0.001, 95% CI 14.3-21.0) and cinnamic alcohol (by 9% yearly; P < 0.001, 95% CI 5.2-12.9); these are now uncommon fragrance allergens. These data show temporal trends which may reflect the frequency of population exposure to individual fragrances.

Effect of Antioxidants on the Occurrence of Pre-Eclampsia in Women at Increased Risk: A Randomised Trial

Abstract: Summary Background Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia. Methods 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16–22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study. Findings Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4–35, p=0·015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0·39 [0·17–0·90], p=0·02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0·24 (0·08–0·70, p=0·002). Interpretation Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations.

Significance of interictal bilateral temporal hypometabolism in temporal lobe epilepsy

Abstract: Objective: To assess the clinical implications and the pathophysiologic determinants of interictal bitemporal hypometabolism (BTH) in temporal lobe epilepsy (TLE) not associated with bilateral MRI abnormalities or intracranial space-occupying lesions. Methods: The authors compared the clinical, interictal, and ictal EEG, Wada test, and neuropsychology data of 15 patients with intractable complex partial seizures of temporal lobe origin and BTH with those of 13 consecutive patients with unilateral TLE associated with unilateral temporal hypometabolism (UTH) who remained seizure free for more than 3 years after anterior temporal lobectomy. 18 F-fluorodeoxyglucose PET scans were analyzed visually and semiquantitatively, and ratios of counts in individual temporal areas to the rest of the cerebrum were compared with the corresponding values from 11 normal control subjects and with the nonepileptogenic hemisphere of the 13 patients with UTH. BTH was defined as more than 2.5 SDs below control values for two or more temporal areas on each side irrespective of any asymmetry. Results: BTH reflected bilateral independent seizure onset in eight patients (53%). The topography of the metabolic depression was not a reliable predictor of epileptogenicity, but involvement of the inferior temporal gyrus was related specifically to ipsilateral seizure onset (70% sensitivity, 100% specificity). In patients with unilateral TLE, contralateral hypometabolism was associated with longer disease duration and worst memory performance during the Wada test, which amounted to global amnesia after ipsilateral injection in three patients, precluding surgical treatment. Contralateral seizure spread in the ictal EEG was significantly faster in patients with BTH. Conclusions: In TLE, symmetric or asymmetric BTH may signal bilateral independent seizure onset in approximately half the patients, especially when involving the inferior temporal gyrus. Alternatively, it may reflect an advanced stage of the disease process, characterized by a breakdown of the inhibitory mechanisms in the contralateral hemisphere, and secondary memory deficit associated with higher risk of postoperative memory decline. Patients with TLE and BTH but without bilateral MRI changes may still be operated on successfully, but surgical suitability should be proved by comprehensive intracranial EEG studies and Wada test.

Cervical lesions are associated with human papillomavirus type 16 intratypic variants that have high transcriptional activity and increased usage of common mammalian codons.

Abstract: Human papillomavirus type 16 (HPV-16) is a major cause of cervical neoplasia, but only a minority of HPV-16 infections result in cancer. Whether particular HPV-16 variants are associated with cervical disease has not yet been clearly established. An investigation of whether cervical neoplasia is associated with infection with HPV-16 intratypic variants was undertaken by using RFLP analyses in a study of 100 HPV-16 DNA-positive women with or without neoplasia. RFLP variant 2 was positively associated [odds ratio (OR)=2·57] and variant 5 was negatively associated with disease (OR=0·2). Variant 1, which resembles the reference isolate of HPV-16, was found at a similar prevalence among those with and without neoplasia. Variants 1 and 2 were also more likely to be associated with detectable viral mRNA than variant 5 (respectively P=0·03 and P=0·00). When HPV-16 E5 ORFs in 50 clones from 36 clinical samples were sequenced, 19 variant HPV-16 E5 DNA sequences were identified. Twelve of these DNA sequences encoded variant E5 amino acid sequences, 10 of which were novel. Whilst the associations between HPV-16 E5 RFLP variants and neoplasia could not be attributed to differences in amino acid sequences, correlation was observed in codon usage. DNA sequences of RFLP variant 2 (associated with greatest OR for neoplasia) had a significantly greater usage of common mammalian codons compared with RFLP pattern 1 variants.

Efficacy of short-course oral prednisolone in polymorphic light eruption: a randomized controlled trial

Abstract: Background Polymorphic light eruption (PLE) is the most common so-called idiopathic photosensitivity disorder and affects up to 15% of the population in the U.K.; brief courses of systemic steroids have been tried and anecdotally have apparently been dramatically effective in the treatment of acute attacks. Objectives To assess the efficacy and safety of a short course of moderate-dose oral prednisolone used from the earliest onset of the eruption in the treatment of PLE. Methods The study was double-blind placebo-controlled, all patients being given both prednisolone and placebo, but randomized to take either one or the other from the earliest sign of onset of rash; if within 48 h there was no improvement, they transferred to the other medication. Each participant also applied a broad-spectrum, highly protective sunscreen 2-hourly during sun exposure, continued his or her usual degree of exposure after any development of PLE, and kept a diary noting details of the eruption, amount of exposure, weather conditions and any adverse events. Statistical analysis was performed by means of the non-parametric log rank test based on Kaplan-Meier plots and bootstrapped confidence intervals (CIs) for the means, using the time in days for the itch and rash to clear as the end-points. Results Twenty-one patients entered the study but only 10 required medication. Eight who took prednisolone first and remained on it or transferred to it from placebo all improved, with the itch settling fully within a mean 2·8 days of starting the prednisolone and the rash clearing by 4·2. In the two who took placebo first and remained on it, the itch took a mean 5·4 days to settle and the rash a mean 7·8. No patient who started with prednisolone changed to placebo. Thus, the prednisolone as randomized was better than placebo at settling both the itch (mean 2·6 days less, CI 0·7–4·0, P = 0·015) and rash (mean 3·6 days less, CI 0·6–6·1, P = 0·036); only one patient experienced mild adverse effects of transient gastrointestinal upset and depressed mood. Conclusions The acute eruption of PLE is likely to respond rapidly to short courses of prednisolone therapy given from the earliest onset of the condition, and the treatment is safe.

Assessment of iron absorption from ferric trimaltol.

Abstract: Therapeutic iron compounds have limited absorption and often have side-effects, which limits patient compliance. Iron trimaltol is a novel, stable complex, formed between ferric iron (Fe3+) and maltol (3-hydroxy-2-methyl-4-pyrone), and is effective in the treatment of iron deficiency anaemia with few side-effects. However, the kinetics of iron absorption from ferric trimaltol and the reliability of normal colorimetric analysis in detecting iron absorbed from this complex have not been established. We measured increases in serum iron levels in 12 volunteers following oral challenge with four different pharmaceutical formulations of ferric trimaltol in a double-blind, cross-over, randomized study. The conventional colorimetric method for detecting serum iron was compared with thermal analyses after trichloroacetic acid (TCA) treatment of serum. Measurements of serum iron levels by TCA treatment and thermal analysis closely agreed with measurements by colorimetry. For all formulations, serum iron levels peaked at 90 min with a plateau of at least 5 h [mean (standard deviation) peak absorption 8.3% (6.3%) of ingested dose, n=48]. Absorption of iron, based on peak serum values or area under the serum curve, was not different for the four formulations (n=12 each) and correlated with the individual's iron status, as assessed by serum ferritin values (r = -0.6; P < 0.001). Normal colorimetry is suitable for analysis of serum iron levels following ingestion of ferric trimaltol. There is rapid and sustained absorption of iron from ferric trimaltol and, as with ferrous iron, uptake appears to be controlled through normal mechanisms of iron acquisition that depend upon body iron stores.

Does the antenatal detection of small-for-gestational-age babies influence their two-year outcomes?

Abstract: The aim of this paper is to determine whether antenatal detection of small-for-gestational-age (SGA) babies influences 2-year outcomes. All low-birth-weight (<2,500g) infants born in South-EastThames region, England from September 1, 1992 to August 31, 1993 were identified at birth. Antenatal "suspicion" and ultrasound assessment confirming growth restriction was categorized as "detection" of SGA. Postnatally, infants were classified as SGA if they had a birth weight for given gestation below the 10th centile. At 2 years, those below 32 weeks' gestation and a random 25% sample of infants of 32 weeks' gestation or more underwent pediatric assessments. Of 49,787 births, 3,456 (6.9%) were of low birth weight. One thousand four hundred and fifty one (42.5%) were SGA, of whom 611 (42%) were detected antenatally by ultrasound scan. At 2 years, 1,008 (75.8%) of 1,358 expected infants were assessed, 379 (37.6%) were SGA at birth, and 188 (49.6%) were confirmed antenatally. Although undetected infants had higher mean birth weights and gestational ages, they had a higher proportion of perinatal deaths (12.6 vs. 6.4%, RR 1.96: CI 1.32-2.86) than detected infants. At 2 years, detected SGA infants had smaller head circumferences (p = 0.026), a higher prevalence of febrile convulsions (8.0 vs. 3.1 %: p = 0.040) and lower scores on the locomotor (DQA) scale of Griffith's developmental test (p = 0.021) compared with undetected SGA infants. Despite detected SGA fetuses having lower weights and gestation at birth than undetected fetuses, they had significantly lower mortality without a parallel increase in severe 2-year neuro-developmental, clinical, or growth morbidity.

Current Literature: Effect of Antioxidants on the Occurrence of Pre-eclampsia in Women at Increased Risk: A Randomised Trial

Abstract: Background: Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia. Methods: 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study. Findings: Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p = 0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p = 0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p = 0.002). Interpretation: Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations. (Lancet 354:810-816, 1999)