A feasibility trial of Acetic acid-targeted Biopsies versus nontargeted quadrantic biopsies during BArrett's surveillance: the ABBA trial.

BACKGROUND: The aims of this study were to compare neoplasia detection rates for nontargeted biopsies (Seattle protocol) versus acetic acid-targeted biopsies (Portsmouth protocol) during Barrett's surveillance and to explore feasibility, patient/clinician experience, acceptance, and barriers/enablers to study participation and implementation of the acetic acid technique. METHODS: This was a mixed-methods feasibility study including a pilot multicenter, randomized, crossover trial with qualitative interviews. Patients under Barrett's surveillance with no history of neoplasia were included. Patients underwent two endoscopies, one with each protocol, 8 weeks apart. Outcomes included recruitment and retention rates, neoplasia yield, and number of biopsies. RESULTS: 200 patients were recruited from 6 centers, and 174 (87.0 %) underwent both procedures. Neoplasia prevalence was 4.7 % (9/192). High grade dysplasia and cancer were detected with both protocols. Five low grade dysplasias were detected (two with acetic acid, four with nontargeted biopsies; one lesion was detected with both techniques). A total of 2139 biopsies were taken in the nontargeted arm and 226 in the acetic acid arm. Both patients and clinicians found the acetic acid technique acceptable. Based on these data, a noninferiority, tandem, crossover trial would require an estimated 2828 patients. CONCLUSIONS: We demonstrated the feasibility of performing a crossover endoscopy trial in Barrett's surveillance. Low neoplasia yield makes this design necessary and qualitative results demonstrated patient and clinician acceptance. The reduced numbers of biopsies suggest that the acetic acid technique could result in cost savings, providing the lack of missed pathology can be proven in a fully powered definitive trial.

High-definition endoscopy with i-Scan for evaluation of small colon polyps: the HiSCOPE study.

BACKGROUND: Traditional white-light endoscopy cannot reliably distinguish between small (<10 mm) adenomatous and hyperplastic colon polyps. High-definition white-light (HDWL) endoscopy and i-Scan may improve in vivo characterization of small colon polyps. OBJECTIVE: To compare HDWL endoscopy and HDWL plus i-Scan for the assessment of small colon polyps and to measure performance against the American Society for Gastrointestinal Endoscopy (ASGE) thresholds for assessment of diminutive colon polyps. DESIGN: Prospective cohort study. SETTING: Single academic hospital. PATIENTS: Patients undergoing bowel cancer screening colonoscopy. INTERVENTION: In vivo assessment of all polyps <10 mm by using HDWL and i-Scan image enhancement. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was overall diagnostic accuracy of in vivo assessment of colon polyps <10 mm. Secondary outcome measures were sensitivity and specificity for adenomatous histology, negative predictive value for adenomatous histology of diminutive rectosigmoid polyps, and accuracy of prediction of polyp surveillance intervals. RESULTS: A total of 209 polyps in 84 patients were included. There were no significant differences between HDWL endoscopy and i-Scan in characterization of polyps <10 mm (accuracy 93.3% vs 94.7%; P = 1.00; sensitivity 95.5% vs 97.0%; P = .50; specificity 89.3% vs 90.7%; P = 1.00). The negative predictive value for adenomatous histology of diminutive rectosigmoid polyps was 100% with both HDWL endoscopy and i-Scan. U.K. and U.S. polyp surveillance intervals were predicted with 95.2% accuracy with HDWL endoscopy and 97.2% accuracy with i-Scan. LIMITATIONS: Single-center study. CONCLUSION: HDWL endoscopy may be as accurate as HDWL with i-Scan image enhancement for the in vivo characterization of small colon polyps. Both modalities fulfil the ASGE performance thresholds for the assessment of diminutive colon polyps. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01761279.).

S(p)O(2) values in acute medical admissions breathing air--implications for the British Thoracic Society guideline for emergency oxygen use in adult patients?

S(p)O(2) is routinely used to assess the well-being of patients, but it is difficult to find an evidence-based description of its normal range. The British Thoracic Society (BTS) has published guidance for oxygen administration and recommends a target S(p)O(2) of 94-98% for most adult patients. These recommendations rely on consensus opinion and small studies using arterial blood gas measurements of saturation (S(a)O(2)). Using large datasets of routinely collected vital signs from four hospitals, we analysed the S(p)O(2) range of 37,593 acute general medical inpatients (males: 47%) observed to be breathing room air. Age at admission ranged from 16 to 105 years with a mean (SD) of 64 (21) years. 19,642 admissions (52%) were aged <70 years. S(p)O(2) ranged from 70% to 100% with a median (IQR) of 97% (95-98%). S(p)O(2) values for males and females were similar. In-hospital mortality for the study patients was 5.27% (range 4.80-6.27%). Mortality (95% CI) for patients with initial S(p)O(2) values of 97%, 96% and 95% was 3.65% (3.22-4.13); 4.47% (3.99-5.00); and 5.67% (5.03-6.38), respectively. Additional analyses of S(p)O(2) values for 37,299 medical admissions aged ≥18 years provided results that were distinctly different to those upon which the current BTS guidelines based their definition of normality. Our findings suggest that the BTS should consider changing its target saturation for actively treated patients not at risk of hypercapnic respiratory failure to 96-98%.

Sensory environment on health-related outcomes of hospital patients.

BACKGROUND: Hospital environments have recently received renewed interest, with considerable investments into building and renovating healthcare estates. Understanding the effectiveness of environmental interventions is important for resource utilisation and providing quality care. OBJECTIVES: To assess the effect of hospital environments on adult patient health-related outcomes. SEARCH METHODS: We searched: the Cochrane Central Register of Controlled Trials (last searched January 2006); MEDLINE (1902 to December 2006); EMBASE (January 1980 to February 2006); 14 other databases covering health, psychology, and the built environment; reference lists; and organisation websites. This review is currently being updated (MEDLINE last search October 2010), see Studies awaiting classification. SELECTION CRITERIA: Randomised and non-randomised controlled trials, controlled before-and-after studies, and interrupted times series of environmental interventions in adult hospital patients reporting health-related outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and 'Risk of bias' assessment. We contacted authors to obtain missing information. For continuous variables, we calculated a mean difference (MD) or standardized mean difference (SMD), and 95% confidence intervals (CI) for each study. For dichotomous variables, we calculated a risk ratio (RR) with 95% confidence intervals (95% CI). When appropriate, we used a random-effects model of meta-analysis. Heterogeneity was explored qualitatively and quantitatively based on risk of bias, case mix, hospital visit characteristics, and country of study. MAIN RESULTS: Overall, 102 studies have been included in this review. Interventions explored were: 'positive distracters', to include aromas (two studies), audiovisual distractions (five studies), decoration (one study), and music (85 studies); interventions to reduce environmental stressors through physical changes, to include air quality (three studies), bedroom type (one study), flooring (two studies), furniture and furnishings (one study), lighting (one study), and temperature (one study); and multifaceted interventions (two studies). We did not find any studies meeting the inclusion criteria to evaluate: art, access to nature for example, through hospital gardens, atriums, flowers, and plants, ceilings, interventions to reduce hospital noise, patient controls, technologies, way-finding aids, or the provision of windows. Overall, it appears that music may improve patient-reported outcomes such as anxiety; however, the benefit for physiological outcomes, and medication consumption has less support. There are few studies to support or refute the implementation of physical changes, and except for air quality, the included studies demonstrated that physical changes to the hospital environment at least did no harm. AUTHORS' CONCLUSIONS: Music may improve patient-reported outcomes in certain circumstances, so support for this relatively inexpensive intervention may be justified. For some environmental interventions, well designed research studies have yet to take place.

Routine laboratory tests can predict in-hospital mortality in acute exacerbations of COPD.

Chronic obstructive pulmonary disease (COPD) has a rising global incidence and acute exacerbation of COPD (AECOPD) carries a high health-care economic burden. Classification and regression tree (CART) analysis is able to create decision trees to classify risk groups. We analysed routinely collected laboratory data to identify prognostic factors for inpatient mortality with AECOPD from our large district hospital. Data from 5,985 patients with 9,915 admissions for AECOPD over a 7-year period were examined. Randomly allocated training (n = 4,986) or validation (n = 4,929) data sets were developed and CART analysis was used to model the risk of all-cause death during admission. Inpatient mortality was 15.5%, mean age was 71.5 (±11.5) years, 56.2% were male, and mean length of stay was 9.2 (±12.2) days. Of 29 variables used, CART analysis identified three (serum albumin, urea, and arterial pCO(2)) to predict in-hospital mortality in five risk groups, with mortality ranging from 3.0 to 23.4%. C statistic indices were 0.734 and 0.701 on the training and validation sets, respectively, indicating good model performance. The highest-risk group (23.4% mortality) had serum urea >7.35 mmol/l, arterial pCO(2) >6.45 kPa, and normal serum albumin (>36.5 g/l). It is possible to develop clinically useful risk prediction models for mortality using laboratory data from the first 24 h of admission in AECOPD.

Up-regulation of the extrinsic coagulation pathway in acute asthma--a case study.

INTRODUCTION: In the normal airway, the hemostatic balance is antithrombotic and favors fibrinolysis. Acute asthma is associated with inflammatory cell infiltrate and plasma exudation in the airways. Postmortem specimens following status asthmaticus suggest a role for the activation of the extrinsic coagulation cascade and intraluminal fibrin formation. The authors report a chance observation of fibrin formation in the airways of a patient with moderate asthma 5 days before a severe exacerbation requiring hospital admission. METHODS: Alpha-2 macroglobulin, an index of plasma leakage, coagulation factors, and D-dimers were measured by enzyme-linked immunosorbent assay (ELISA) in hypertonic saline-induced sputum, as part of a study into airway repair in stable asthma. All subjects were required to have stable symptoms and measures of asthma prior to sampling. RESULTS: The subject's baseline forced expiratory volume in one second (FEV(1)) was 94% predicted and fraction of exhaled nitric oxide (FeNO) level was 30 ppb prior to sputum induction. Differential sputum cell count revealed an airways neutrophilia (neutrophils 81.1%, eosinophils 0.19%). D-dimers were 70-fold and 22-fold higher than the median value for patients with stable moderate and severe asthma, respectively. Plasma exudation was 42-fold higher than in stable moderate asthma, but on a par with levels found in severe stable asthma, and locally produced coagulation factors may therefore be involved. Levels of fibrinogen, plasminogen, plasminogen activator inhibitor (PAI)-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) were all at least an order of magnitude higher than those seen in stable moderate or severe asthma. CONCLUSIONS: Acute exacerbation of moderate asthma appears to be associated with a shift to a profibrinogenic, possibly antifibrinolytic, environment in the airways.

Interventions for cellulitis and erysipelas.

BACKGROUND: Cellulitis and erysipelas are now usually considered manifestations of the same condition, a skin infection associated with severe pain and systemic symptoms. A range of antibiotic treatments are suggested in guidelines. OBJECTIVES: To assess the efficacy and safety of interventions for non-surgically-acquired cellulitis. SEARCH STRATEGY: In May 2010 we searched for randomised controlled trials in the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and the ongoing trials databases. SELECTION CRITERIA: We selected randomised controlled trials comparing two or more different interventions for cellulitis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: We included 25 studies with a total of 2488 participants. Our primary outcome 'symptoms rated by participant or medical practitioner or proportion symptom-free' was commonly reported. No two trials examined the same drugs, therefore we grouped similar types of drugs together.Macrolides/streptogramins were found to be more effective than penicillin antibiotics (Risk ratio (RR) 0.84, 95% CI 0.73 to 0.97). In 3 trials involving 419 people, 2 of these studies used oral macrolide against intravenous (iv) penicillin demonstrating that oral therapies can be more effective than iv therapies (RR 0.85, 95% CI 0.73 to 0.98).Three studies with a total of 88 people comparing a penicillin with a cephalosporin showed no difference in treatment effect (RR 0.99, 95% CI 0.68 to 1.43).Six trials which included 538 people that compared different generations of cephalosporin, showed no difference in treatment effect (RR 1.00, 95% CI 0.94 to1.06).We found only small single studies for duration of antibiotic treatment, intramuscular versus intravenous route, the addition of corticosteroid to antibiotic treatment compared with antibiotic alone, and vibration therapy, so there was insufficient evidence to form conclusions. Only two studies investigated treatments for severe cellulitis and these selected different antibiotics for their comparisons, so we cannot make firm conclusions. AUTHORS' CONCLUSIONS: We cannot define the best treatment for cellulitis and most recommendations are made on single trials. There is a need for trials to evaluate the efficacy of oral antibiotics against intravenous antibiotics in the community setting as there are service implications for cost and comfort.

Factors associated with maternal dietary intake, feeding and weaning practices, and the development of food hypersensitivity in the infant.

Maternal diet during pregnancy and breastfeeding, as well as infant feeding and weaning practices, may play a role in the development of sensitization to food and food hypersensitivity (FHS) and need further investigation. Pregnant women were recruited at 12 wk pregnancy. Information regarding family history of allergy was obtained by means of a questionnaire. A food frequency questionnaire was completed at 36 wk gestation. Information regarding feeding practices and reported symptoms of atopy was obtained during the infants' first 3 yr of life. Children were also skin-prick tested at 1, 2 and 3 yr to a pre-defined panel of food allergens. Food challenges were conducted where possible. Maternal dietary intake during pregnancy, and breast-feeding duration did not influence the development of sensitization to food allergens or FHS, but weaning age (>or=16 wk) did for sensitization at 1 yr (p = 0.03), FHS by 1 yr (p = 0.02), sensitization at 3 yr (p = 0.01) and FHS by 3 yr (p = 0.02). In contrast, children who were not exposed to a certain food allergen before the age of 3-6 months were less likely to become sensitized or develop FHS. Women with a family history of allergic disease were more likely to breastfeed exclusively at 3 months (p = 0.008) and avoid peanuts from the infant's diet at 6 months (p = 0.03). Maternal dietary intake during pregnancy, and breast-feeding duration did not appear to influence the development of sensitization to food allergens or FHS. Weaning age may affect sensitization to foods and development of FHS. A history of allergic disease has very little impact on maternal dietary, feeding, and weaning practices.

Role of chest CT in staging of oropharyngeal cancer: a systematic review.

BACKGROUND: The prevalence of synchronous or metastatic tumors in patients with head and neck squamous cell carcinoma (HNSCC) ranges from 6% to 20% and has implications for prognosis and management of the primary disease. There is no consensus about the role of chest CT prior to definitive treatment patients with HNSCC. METHODS: A systematic review of all chest CT studies in relation to HNSCC was performed, together with a review of our local database. RESULTS: Twenty-four studies were identified in addition to our local data. Prevalence of positive chest CT was 7.93%. Patients were significantly more likely to have a positive chest CT with N2 or N3 neck disease (p = .0062) and stage III or IV disease (p = .0001), and significantly less likely with tumors of the oral cavity (p = .0007). CONCLUSION: We advocate chest CT as part of the initial investigations for patients with HNSCC.

A review, and performance evaluation, of single-parameter "track and trigger" systems.

OBJECTIVES: There is no up-to-date literature review of physiologically-based, single-parameter weighted "track and trigger" systems (SPTTS) and little data on their sensitivity and specificity to predict adverse outcomes. The aim of this study was to describe the SPTTS in clinical use and measure their sensitivity and specificity when using admission vital signs data for predicting in-hospital mortality. MATERIALS AND METHODS: We performed a systematic review of the literature to describe the SPTTS, their components and their differences. We measured their sensitivity and specificity for predicting in-hospital mortality when using a database of 9987 admission vital signs datasets. RESULTS: We identified 39 unique classes of SPTTS, of which 30 were evaluated. There was considerable variation in the physiological variables used, together with significant variation in the physiological values used to trigger a medical emergency or critical care outreach team. There was marked variation in sensitivity (7.3-52.8%), specificity (69.1-98.1%), positive predictive values (13.5-26.1%), negative predictive values (92.1-94.2%) and the potential number of calls triggered (234-3271). CONCLUSIONS: There is a wide range of unique, but very similar, SPTTS in clinical use. Although specificities were high, sensitivities were too low to provide institutions with confidence that these SPTTS could identify patients at risk of in-hospital death using admission vital signs. Institutions may wish to consider these data when selecting which, if any, single-parameter track and trigger systems to introduce.

Should age be included as a component of track and trigger systems used to identify sick adult patients?

AIM OF STUDY: Few published "track and trigger systems" used to identify sick adult patients incorporate patient age as a variable. We investigated the relationship between vital signs, patient age and in-hospital mortality and investigated the impact of patient age on the function as predictors of in-hospital mortality of the two most commonly used track and trigger systems. MATERIALS AND METHODS: Using a database of 9987 vital signs datasets, we studied the relationship between admission vital signs and in-hospital mortality for a range of selected vital signs, grouped by patient age. We also used the vital signs data set to study the impact of patient age on the relationship between patient triggers using the "MET criteria" and "MEWS", and in-hospital mortality. RESULTS: At hospital discharge, there were 9152 (91.6%) survivors and 835 (8.4%) non-survivors. As admission vital signs worsened, mortality increased for each age range. Where groups of patients had triggered a certain MET criterion, mortality was higher as patient age increased. Mortality varied significantly with age (p<0.05; Fishers exact test) for breathing rate >36breathsmin(-1), systolic BP<90mmHg and decreased conscious level. For each age group, mortality also increased as total MEWS score increased. As the number of simultaneously occurring MEWS abnormalities, or simultaneously occurring MET criteria, increased, mortality increased for each age range. CONCLUSIONS: Age has a significant impact on in-hospital mortality. Our data suggest that the inclusion of age as a component of these systems could be advantageous in improving their function.

Patterns of sensitization to food and aeroallergens in the first 3 years of life.

BACKGROUND: There is a paucity of longitudinal studies of allergen sensitization in childhood. OBJECTIVE: To investigate the pattern of sensitization in early childhood. METHODS: A nested cohort of children (n = 543) were followed up from birth and given a skin prick test (SPT) at 1, 2, and 3 years of age. A detailed clinical history was obtained. RESULTS: The prevalences of sensitization to aeroallergens were 1.3%, 6.4%, and 10.7% at 1, 2, and 3 years of age. The figures for food allergens were 2.8%, 3.9%, and 3.7%. There was a statistically significant increase in the prevalence of sensitization to >or=1 allergen between years 1 and 2 (P < .001) and years 2 and 3 (P = .032). Among those with a positive SPT at 1 year, 29% tested positive to additional allergens at 2 years (P = .0054). Sensitization to milk or egg at 1 year was a predictor for increased sensitization to peanut at 3 years (odds ratio, 34.8; P < .0001). Sensitization to egg at 1 year was associated with increased sensitization to aeroallergens at 3 years (odds ratios, house dust mite, 27.1, P < .001; cat, 8.9, P < .01; grass, 11.8, P = .005). For peanut and cat allergens, wheal size increases with the age of the child (P = .009 and P = .017, respectively). CONCLUSION: Sensitization to allergens as demonstrated by positive SPT tends to increase with age, and this change can be detected in the first 3 years of life. CLINICAL IMPLICATIONS: The high predictive value for early sensitization and a linear increase in SPT reactivity provide an opportunity for early intervention.

Continuous ambulatory peritoneal dialysis patients are unable to increase dietary intake to recommended levels.

OBJECTIVE: This study's objective was to determine whether offering dietary advice was effective in supporting patients in adjusting energy intake. DESIGN: We performed a prospective, randomized, controlled trial of dietary intervention involving 59 patients on continuous ambulatory peritoneal dialysis over a 4-month follow-up period. SETTING: The study involved outpatients on home-based renal replacement therapy. PARTICIPANTS: All participants were adult patients on continuous ambulatory peritoneal dialysis. All eligible patients were invited to take part. Subjects were randomized into two groups: control and intervention. Those with diabetes mellitus, malabsorption, malignancy, or eating disorders were excluded. INTERVENTION: Baseline measurements to assess current dietary intake and nutritional status were performed in all subjects. Measurements included a 5-day food diary, subjective global assessment (SGA), anthropometry, and serum biochemistry. After analysis of the food diaries, the participants in the control group were given follow-up dietary advice that would enable them to match intake with current dietary recommendations for this group of 1.2 g of protein per kilogram of ideal body weight, 25 cal/kg ideal body weight. Participants in the intervention group were given follow-up dietary advice that would encourage them to match energy intake with an estimate of total energy expenditure based on their calculated basal metabolic rate and physical activity level as designated using information from SGA, with a significantly lower protein intake of 0.8 to 1.0 g/kg ideal body weight and an emphasis on calories from carbohydrate and fat. Both groups completed further 5-day food diaries at 2 and 4 months to assess their ability to make the recommended changes. SGA, anthropometry, and biochemistry were all remeasured at the end of the study period. MAIN OUTCOME MEASURE: Differences in energy and protein intakes between and within the two groups from baseline to 4 months were assessed. RESULTS: Protein and energy intakes did not change during 4 months in either group, and there was no significant difference in intake between the two groups. In the control group (n = 27), 18 subjects (69%) matched their reported dietary energy intake to the recommended intake. In the intervention group (n = 28), 17 subjects (63%) matched their reported dietary intake to their estimated total energy expenditure. In the control group (n = 27), 8 subjects (28%) achieved the protein intake recommended to them of 1.2 g/kg. In the intervention group (n = 28), 23 subjects (85%) achieved the protein intake recommended to them of greater than 0.8 g/kg. CONCLUSION: Patients not meeting their dietary prescription did not adjust their intake to match the recommended advice they had been given from a dietitian. Food diary analysis showed that subjects ate less than the recommended intakes for energy and protein. This inability to change suggests that subjects may be eating to the limit of their appetite. SGA sections concerning appetite, body weight, body mass index, and estimates of energy expenditure support the view that energy intake matches requirements.

Presence and phenotype of dendritic cells in uveal melanoma.

BACKGROUND: Uveal melanoma arises in an immune-privileged site and can itself add to the immunosuppressive environment. Previous studies on cutaneous melanoma have shown the presence of tolerogenic dendritic cells (DCs), which could play an important role in the progression of the tumour. AIM: To examine the presence and functional status of DCs in a small series of uveal melanomas. METHODS: 10 cases of uveal melanoma were examined for the expression of FXIIIa, CD68, human leucocyte antigen (HLA)-DR, CD40, CD83, transforming growth factor betaR1 and indolamine 2,3 dioxygenase by immunohistochemical analysis on sections embedded in paraffin wax. RESULTS: CD68-positive macrophages were present in all of the tumours and were evenly distributed throughout. DCs expressing FXIIIa-positive were seen in 7 cases, and were often found concentrated in foci within the tumour mass. These cells were dendritic and expressed high levels of HLA-DR. The DCs did not express the maturation markers CD83 or CD40. In one case, concentration of DCs around the area of tumour necrosis was observed, and some of these cells expressed CD83. CONCLUSION: Numerous tolerising antigen-presenting cells may play a role in melanoma-related immunosuppression in the eye, although activation of DCs may be associated with tumour necrosis.

Calculating early warning scores--a classroom comparison of pen and paper and hand-held computer methods.

To assist in the early detection of critical illness, many hospitals now use a "track and trigger" system that allocates points to routine vital signs measurements on the basis of their derangement from an arbitrarily agreed "normal" range. These points are summed to provide an early warning score (EWS). Little is known about the accuracy with which EWS are calculated and charted. We compared the speed and accuracy of charting the weighted value attributed to each vital sign, and of calculating the EWS, using the traditional pen and paper method with that using a specially programmed, personal digital assistant (VitalPAC). Incorrect entries or omissions occurred in 24 (29%) of 84 EWS computed using pen/paper compared to 8 (10%) computed using the VitalPAC method. Fewer incorrect clinical actions were indicated using EWS derived via the VitalPAC method (4/84, 5%) than from those calculated using pen/paper (12/84, 14%). The mean time (+/-S.D.) taken for participants to calculate and chart a set of weighted values and EWS using the pen/paper method was 67.6+/-35.3 s (n=84). The corresponding time taken to enter a set of physiological data using the VitalPAC was 43.0+/-23.5 s (n=84). By comparison with the conventional pen/paper method, the use of VitalPAC was on average 1.6-times faster. The use of a device such as VitalPAC offers significant advantages both in speed and accuracy of recording of EWS.

Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life.

BACKGROUND: There are very few population-based studies investigating the incidence of food hypersensitivity during the first year of life. OBJECTIVE: To determine the incidence of parentally reported food hypersensitivity and objectively diagnosed food hypersensitivity during the first year of life. METHODS: A birth cohort was recruited (n = 969). At 3, 6, 9, and 12 months, information regarding feeding practices and reported symptoms of atopy were obtained. At 1 year, infants underwent a medical examination and skin prick testing to a battery of allergens. Symptomatic infants underwent food challenges. RESULTS: Adverse reactions to foods were reported by 132 (14.2%) parents at 3, 83 (9.1%) at 6, 49 (5.5%) at 9, and 65 (7.2%) at 12 months. Of the subjects, 1.0% (8/763) were sensitized to aeroallergens and 2.2% (17/763) to food allergens. Between 6 and 9 months and 9 and 12 months, 1.4% (14/969) and 2.8% (27/969) infants were diagnosed with food hypersensitivity on the basis of open food challenges and 0.9% (9/969) and 2.5% (24/969) on the basis of double-blind, placebo-controlled food challenges. Cumulative incidence of food hypersensitivity by 12 months was 4% (39/969; 95% CI, 2.9% to 5.5%) on the basis of open food challenges and 3.2% (31/969; 95% CI, 2.2% to 4.5%) on the basis of double-blind, placebo-controlled food challenges. CONCLUSION: Between 2.2% and 5.5% of infants have food hypersensitivity in the first year of life. The rate of parental perception of food hypersensitivity is higher than the prevalence of atopic sensitization to main food allergens or objectively assessed food hypersensitivity. CLINICAL IMPLICATIONS: In the first year of life, the rate of parentally perceived food hypersensitivity is considerably higher than objectively assessed food hypersensitivity.

Cancer cell adaptation to chemotherapy.

BACKGROUND: Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. METHODS: Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. RESULTS: In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIalpha (TOPOIIalpha). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIalpha in 6/7 colorectal tumors and 8/10 ovarian tumors. CONCLUSION: This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy.

Presence and maturity of dendritic cells in melanoma lymph node metastases.

Immune avoidance mechanisms play a key role in the successful dissemination of melanoma. One mechanism whereby this could be achieved is by interfering with dendritic cell (DC) presentation of tumour-associated antigens to naïve T cells. In particular, immature DCs characterized by the absence of accessory molecules are known to be immunosuppressive and to be involved in the induction of tolerance. The present study has investigated the presence and activation status of DCs within melanoma metastases in the regional lymph nodes. Using image analysis techniques, the expression of Factor XIIIa (FXIIIa), CD40, CD83 and HLA-DR and the morphological features of DCs were examined in paraffin sections from 26 lymph nodes containing melanoma metastases. DCs expressing FXIIIa were found in 70% of the lymph nodes. The number of DCs identified was generally small but there were more concentrated areas of DCs designated as hotspots. In these areas of high FXIIIa staining, the percentage area occupied by DCs varied between 0.1% and 10%. The majority of FXIIIa-positive cells did not express the DC maturation markers CD83 or CD40 and morphologically were rounded with few dendrites, indicating that they were immature. The cells did, however, express high levels of HLA-DR, suggesting that they have the ability to present antigen but lack the accessory molecules required to initiate an immune response. Immature DCs, characterized by phenotypic and morphological features, are therefore present within the tumour deposits in lymph nodes infiltrated by melanoma and may specifically modulate the anti-melanoma immune response.