Paul Seed

Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial

BACKGROUND Oxidative stress could play a part in pre-eclampsia, and there is some evidence to suggest that vitamin C and vitamin E supplements could reduce the risk of the disorder. Our aim was to investigate the potential benefit of these antioxidants in a cohort of women with a range of clinical risk factors. METHODS We did a randomised, placebo-controlled trial to which we enrolled 2410 women identified as at increased risk of pre-eclampsia from 25 hospitals. We assigned the women 1000 mg vitamin C and 400 IU vitamin E (RRR alpha tocopherol; n=1199) or matched placebo (n=1205) daily from the second trimester of pregnancy until delivery. Our primary endpoint was pre-eclampsia, and our main secondary endpoints were low birthweight (<2.5 kg) and small size for gestational age (<5th customised birthweight centile). Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 62368611 . FINDINGS Of 2404 patients treated, we analysed 2395 (99.6%). The incidence of pre-eclampsia was similar in treatment placebo groups (15% [n=181] vs 16% [n=187], RR 0.97 [95% CI 0.80-1.17]). More low birthweight babies were born to women who took antioxidants than to controls (28% [n=387] vs 24% [n=335], 1.15 [1.02-1.30]), but small size for gestational age did not differ between groups (21% [n=294] vs 19% [n=259], 1.12 [0.96-1.31]). INTERPRETATION Concomitant supplementation with vitamin C and vitamin E does not prevent pre-eclampsia in women at risk, but does increase the rate of babies born with a low birthweight. As such, use of these high-dose antioxidants is not justified in pregnancy.

Gender-Linked Hypertension in Offspring of Lard-Fed Pregnant Rats

Abstract—Epidemiological studies suggest an association between maternal nutrition and offspring cardiovascular disease. We previously demonstrated endothelial dysfunction and abnormal aortic fatty acid composition in adult female offspring of rats fed animal lard during pregnancy. We have now further investigated this model. Female Sprague-Dawley rats were fed a control breeding diet (5.3% fat) or a diet rich in lard (25.7% fat) 10 days before and throughout pregnancy and lactation. Male and female offspring were implanted with radiotelemeters for recording of blood pressure, heart rate, and activity at 80, 180, and 360 days of age. Reactivity to acetylcholine and to nitric oxide were assessed in isolated small mesenteric arteries from 80- and 180-day-old littermates. Systolic blood pressure (awake phase) was raised in female offspring (180 days: offspring of control, 130.7±1.6 mm Hg, n=5, versus offspring of lard-fed, 138.1±2.9, n=5, P =0.029; 360 days: offspring of control, 129.7±3.7 mm Hg, n=6, versus offspring of lard-fed, 142.1±3.2, n=6, P =0.005). Diastolic blood pressure was also raised at 180 days (offspring of control, 87.6±1.0 mm Hg, n=5, versus offspring of lard-fed, 94.7±2.6, n=5, P =0.011). Blood pressure was not raised in male offspring. Endothelium-dependent relaxation to acetylcholine was blunted in male and female offspring of lard-fed dams (80 and 180 days). Feeding a diet rich in lard to pregnant rats leads to gender-related cardiovascular dysfunction in normally fed offspring.

Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria

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 < 25% of baseline weekly UAS and relapse as a return 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.

Quality of Life, Employment Status, and Anginal Symptoms After Coronary Angioplasty or Bypass Surgery 3-Year Follow-up in the Randomized Intervention Treatment of Angina (RITA) Trial

BACKGROUND The Randomized Intervention Treatment of Angina (RITA) trial compares initial policies of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG) in 1011 patients with angina. This report assesses the impact of these revascularization procedures on angina, quality of life (according to the Nottingham Health Profile), and employment over 3 years of follow-up. METHODS AND RESULTS Both interventions produced marked improvement in all quality-of-life dimensions (energy, pain, emotional reactions, sleep, social isolation, and mobility) and seven aspects of daily living. Patients with angina at 2 years had more quality-of-life impairment than angina-free patients, whose perceived health was similar to population norms. This reflects the close link at baseline between angina grade and quality of life. The slightly greater impairment of quality of life in PTCA compared with CABG patients is a result of their significantly higher chances of having angina, especially after 6 months. Employment status was investigated mainly for men < or = 60 years old. PTCA patients returned to work sooner (40% at 2 months compared with 10% of CABG patients), but the latter caught up by 5 months. After 2 years, 22% and 26% of CABG and PTCA patients, respectively, were not working for cardiac reasons. Patients with angina at 2 years were much more likely to be unemployed than those without. CONCLUSIONS The impact of angina on quality of life and unemployment is greatly alleviated by PTCA or CABG. Angina is avoided more successfully with CABG, but PTCA offers a speedier return to work. Both intervention strategies then produce similar benefits for quality of life and employment over several years.

Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases.

The clinicopathologic characteristics of 69 cases of eccrine porocarcinoma (EP) have been studied. Seven cases of purely in situ disease are included. Forty patients were female, 29 male with ages ranging from 29 to 91 years (mean 73 years). The lower extremity represented the single most common site (44%). Other common sites were the trunk (15 cases, 24%) and head (11 cases, 18%). The histologic diagnosis of EP was predicated on the basis of an irregular tumor at least partly formed of characteristic poromatous basaloid epithelial cells displaying ductal differentiation, and significant cytologic atypia. Forty-seven tumors (68%) contained mature well-formed eccrine ducts having an eosinophilic luminal cuticle, with the remaining tumors containing small ill-formed ducts and/or intracytoplasmic lumina. All ducts were discernible via light microscopy and in 49 cases were highlighted with DPAS stain and/or CEA/EMA immunocytochemistry. A variant with a broad pushing tumor margin and marked nuclear pleomorphism showed some resemblance to proliferative bowenoid dysplasia. In 11 cases (18%) the tumors appeared to arise in continuity with a benign preexistent poroma. A variety of histologic patterns were displayed including clear, squamous, and spindle cell differentiation, mucus cell metaplasia, and colonization by melanocytes. Lymphovascular invasion was present in 9 cases (15%). Three cases showed pagetoid extension of malignant cells (epidermotropism) and appeared to be multifocal. Follow-up was available in 54 patients (78%) with 9 (17%) experiencing local recurrence, 10 developing lymph node metastases (19%), and 6 (11%) experiencing distant metastases or death. Mitoses, the presence of lymphovascular invasion, and tumor depth >7 mm were associated with a poorer prognosis. Dividing tumors into those with a “pushing” or “infiltrating” advancing margin was also predictive of outcome with the latter having an increased risk of local recurrence. This report, the largest series of EP to date, suggests that the incidence of aggressive behavior is less than popularly believed. Furthermore, EP can display a wide variety of histologic patterns that may lead to diagnostic error in the unwary. The large number of cases in this series enables a reliable evaluation of prognostic parameters. A more aggressive clinical course may be indicated by more than 14 mitoses per high power field (hazard ratio [HR] for death 17.0, 95% confidence interval [CI] 2.71–107), lymphovascular invasion by tumor (HR 4.41, CI 1.13–17.2), and depth >7 mm (HR 5.49, CI 1.0–30.3). Thus, mitoses, lymphovascular invasion, and tumor depth should be evaluated in these tumors. We also suggest that tumors presenting an “infiltrative” advancing margin are particularly prone to local recurrence and require wide excision with close attention to the surgical margins by the reporting pathologist.

Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease

Background : Azathioprine therapy is discontinued in one‐third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side‐effects.

Chronic idiopathic urticaria: Comparison of the clinical features of patients with and without anti-FcϵRI or anti-IgE autoantibodies

BACKGROUND Previous studies defining the clinical features of patients with chronic idiopathic urticaria (CIU) were performed before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE Our purpose was to determine whether there are differences between patients with and those without autoantibodies in the clinical features or severity of CIU. METHODS The clinical features of 107 patients with CIU were evaluated prospectively. Patients were identified as having functional autoantibodies on the basis of the serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS Patients with autoantibodies (31%) had more wheals (P = .005), a wider distribution of wheals (P = .009), higher itch scores for the most severe episodes of itching (P = .002), more systemic symptoms (P = .03), and lower serum IgE levels (P < .0005) than patients without autoantibodies. CONCLUSION The presence of autoantibodies indicates a subset of patients with more severe CIU.

Self-monitoring in Type 2 diabetes mellitus: a meta-analysis

SUMMARY

Adverse Perinatal Outcomes and Risk Factors for Preeclampsia in Women With Chronic Hypertension A Prospective Study

Prospective contemporaneous data on the outcome of pregnancies in women with chronic hypertension are sparse. Indices of maternal and perinatal morbidity and mortality were determined in 822 women with chronic hypertension with data prospectively collected and rigorously validated. The incidence of superimposed preeclampsia was 22% (n=180) with early-onset preeclampsia (≤34 weeks gestation) accounting for nearly half of these cases. Delivering an infant <10th customized birthweight centile complicated 48% (87/180) of those with superimposed preeclampsia and 21% (137/642) in those without (relative risk [RR] 2.30; 95% confidence intervals [CI] 1.85 to 2.84). Delivery at <37 weeks gestation occurred in 51% of those with superimposed preeclampsia (98% of these iatrogenic) and 15% without (66% iatrogenic) (RR 3.52; 95% CI 2.79 to 4.45). Using multiple logistic regression, black ethnic origin, raised body mass index, present smoking, booking systolic blood pressure of 130 to 139 mm Hg, and diastolic blood pressure of 80 to 89 mm Hg, a previous history of preeclampsia or eclampsia and chronic renal disease were identified as risk factors for superimposed preeclampsia. Adverse maternal and perinatal outcomes occur in women with chronic hypertension; the prevalence of infants born small for gestational age and preterm is considerably higher than background rates, and is increased further in women with superimposed preeclampsia. Use of customized birthweight centiles provides more accurate determination of fetal growth restriction and highlights the need for greater fetal surveillance in these women. Paradoxically, smoking is an independent risk factor for superimposed preeclampsia in chronic hypertension, in contrast to the protective effect in low-risk pregnant women.

A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses.

BACKGROUND Photodynamic therapy (PDT) has not been compared with topical 5-fluorouracil (5-FU) in the treatment of epidermal dysplasia. OBJECTIVE The purpose of this study was to assess the efficacy and tolerability of these two treatment modalities in 17 patients with actinic keratoses on the backs of the hands. METHODS Each patients right and left hands were randomized to receive either a 3-week course of topical 5-FU applied twice per day or PDT using topical 5-aminolevulinic acid (5-ALA) and then, after 4 hours, irradiation with an incoherent light source consisting of a 1200 W metal halogen lamp emitting red light (580 to 740 nm). Each hand randomized for PDT received 150 J/cm(2). The observed median fluence rate was 86 mW/cm(2) (interquartile range, 53 to 100 mW/cm(2)). All patients were reviewed at 1, 4, and 24 weeks after starting treatment. RESULTS Fourteen of 17 patients (82%) completed the study. The mean lesional area treated with topical 5-FU decreased from 1390 mm(2) (standard deviation [SD], 1130) to 297 mm(2) (SD, 209). This represents a mean reduction in lesional area of 70% (confidence interval [CI], 61%-80%). The mean lesional area treated with topical PDT decreased from 1322 mm(2) (SD, 1280) to 291 mm(2) (SD, 274), representing a mean reduction in lesional area of 73% (CI, 61%-84%). The reduction in lesional area elicited by the two treatment methods was similar (CI, -25% to 17%). There was no statistically significant difference between the treatment methods in overall symptom scores for pain and redness. CONCLUSION One treatment with PDT using topical 5-ALA appears to be as effective and well tolerated as 3 weeks of twice-daily topical 5-FU, a cheap and widely available alternative.