Blood pressure in 12-year-old children is associated with Fatty Acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort

Breastfed individuals have a lower blood pressure than formula-fed individuals. Supplementation with n-3 long-chain polyunsaturated fatty acids in adults is also associated with a lower blood pressure. We studied whether children receiving human milk with a relatively high content of n-3 long-chain polyunsaturated fatty acids have a lower blood pressure at age 12 years, and, if so, whether this association is explained by the n-3 long-chain polyunsaturated fatty acids content in erythrocyte membranes at age 12 years. Within a 12-year follow-up of a population-based birth cohort, we compared blood pressure of 205 never-breastfed children and 109 children who had fatty acid composition of their mothers' breast milk measured during lactation. In addition, 973 children had information on erythrocyte fatty acid composition and blood pressure at age 12 years. Children who received human milk with an n-3 long-chain polyunsaturated fatty acids content above the median (ie, 0.51 weight percentage) had a 4.79-mm Hg lower systolic (95% CI, -7.64 to -1.94) and a 2.47-mm Hg lower diastolic (95% CI, -4.45 to -0.49) blood pressure at age 12 years than never-breastfed children. N-3 long-chain polyunsaturated fatty acids levels in human milk below the median value and current n-3 long-chain polyunsaturated fatty acid status were not associated with blood pressure at age 12 years. Thus, a relatively high content of n-3 long-chain polyunsaturated fatty acids in human milk is associated with a lower blood pressure in children at age 12 years, a finding not explained by current n-3 long-chain polyunsaturated fatty acids status.     

TNF inhibitors to treat ulcerative colitis in a metastatic breast cancer patient:A case report and literature review

Adalimumab(ADA)is a tumor necrosis factor(TNF)inhibitor,used for the treatment of inflammatory bowel disease.Previous studies have reported an increased risk of cancer following exposure to TNF inhibitors,but little has been reported for patients with cancer receiving TNF-inhibitor treatment.We present a female patient with metastatic breast cancer and ulcerative colitis(UC)who was treated with ADA.A 54-year-old African American female with a past history of left-sided breast cancer(BC)diagnosed at age 30 was initially treated with left-breast lumpectomy,axillary dissection,followed by chemotherapy and radiation therapy.Years after initial diagnosis,she developed recurrent,bilateral BC and had bilateral mastectomy.Subsequent restaging computed tomography(CT)scan demonstrated distant metastases to the bone and lymph nodes.Three years into her treatment of metastatic breast cancer,she was diagnosed with UC by colonoscopy.Her UC was not controlled for 5 mo with 5-aminosalicylates.Subcutaneous ADA was started and resulted in dramatic improvement of UC.Four months after starting ADA,along with ongoing chemotherapy,restaging CT scan showed resolution of the previously seen metastatic lymph nodes.Bone scan and follow-up positron emission tomography/CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on ADA.While TNF-αinhibitors could theoretically promote further metastases in patients with prior cancer,this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after ADA initiation for UC.     

Corticosteroid-induced improvement in the PC20 of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC20 of methacholine.

It has been suggested in cross-sectional studies that provocation with adenosine 5'-monophosphate (AMP) more closely reflects the inflammatory process in asthma than does provocation with methacholine or histamine. We investigated whether the steroid-induced improvement in the provocative concentration of AMP producing a 20% decline in FEV1 (PC20 AMP) is more closely associated with the concomitant reduction in airway inflammation than is the improvement in PC20 methacholine. In 120 asthmatic patients, we measured PC20 methacholine and PC20 AMP as well as sputum induction and nitric oxide (NO) in exhaled air before and after 2 weeks of treatment with corticosteroids. Improvement in PC20 AMP was solely related to reduction in airway inflammation (i.e., change in the number of sputum eosinophils, lymphocytes, epithelial cells, and concentration of NO in exhaled air). In contrast, improvement in PC20 methacholine was related to both reduction in airway inflammation (i.e., change in the number of sputum eosinophils and lymphocytes) and increase in FEV1 %predicted. The total explained variance of the improvement in bronchial hyperresponsiveness was greater for AMP than for methacholine (36% versus 22%, respectively). We conclude that PC20 AMP is more sensitive to changes in acute airway inflammation than is PC20 methacholine, further reinforcing the notion that PC20 AMP can be a useful tool for monitoring the effects of antiinflammatory therapy.     

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

Several studies have demonstrated the presence of B-cell follicles and autoantibodies in chronic obstructive pulmonary disease (COPD). It is unclear against which antigens this B-cell response is directed and whether it contributes to development or worsening of disease. We assessed different B-cell subsets in blood and lung tissue from COPD patients and controls, and compared differences in B-cell responsiveness to stimulation with lung-specific antigens. Active smoking induced an adaptive immune response with relatively high levels of (class-switched) memory B-cells in blood and immunoglobulin (Ig)G memory B-cells in the lung. COPD smokers showed more switching to IgG, whereas healthy smokers switched more to IgA. COPD patients had higher levels of memory B-cells in the lung and stimulation with lung-specific antigens induced higher numbers of anti-decorin antibody-producing cells in COPD patients compared with healthy controls. Differential switching to IgG and IgA indicates that the adaptive immune response to smoke differs between COPD patients and healthy controls. A higher level of memory B-cells in the lungs of COPD patients may reflect an antigen-specific immune response, which could be directed against decorin, as suggested by the induction of anti-decorin antibody-producing cells in response to antigen-specific stimulation in COPD patients.     

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

BACKGROUND: The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD. METHODS: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV(1), 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [DeltaN(2)], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid. RESULTS: DeltaN(2) increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between DeltaN(2) and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV(1) percentage of predicted. CONCLUSIONS: The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.     

Prognosis of asthma from childhood to adulthood

The outcome of childhood asthma was studied in 101 adults who came from a group of 119 asthmatic children (85%) 6 to 14 yr of age who had originally been investigated between 1966 and 1969. Changes in respiratory symptoms, spirometry, and airway responsiveness to histamine in childhood and adult life were analyzed. It was found that 43 of the 101 adults (43%) had current symptoms; 29 of the 43 (67%) were receiving maintenance therapy. In the first study, 83 of the 101 children (82%) showed a response on inhalation of histamine (PC10-histamine less than or equal to 16 mg/ml). The number of subjects in the second study who still had a PC10-histamine less than or equal to 16 mg/ml fell to 29, suggesting that airway responsiveness decreases from childhood to adulthood. During the second survey (in adults), 25 of the 43 (59%) subjects with current symptoms and four of the 58 (7%) without respiratory symptoms responded to histamine. Adults with current symptoms had a significantly lower %FEV1 in both childhood and adulthood than did adults without current symptoms; %FEV1 was not different in females and males or in smokers and nonsmokers in either the first or the second survey. The outcome of childhood asthma is primarily predicted by the initial degree of bronchial obstruction (p = 0.041) and airway responsiveness to histamine (p = 0.050), and does not appear to be related to sex, smoking habits, or age of onset of respiratory symptoms.     

The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation.

Smoking is the main risk factor in the development of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only effective treatment for avoiding or reducing the progression of this disease. Despite the fact that smoking cessation is a very important health issue, information about the underlying mechanisms of the effects of smoking cessation on the lungs is surprisingly scarce. It is likely that the reversibility of smoke-induced changes differs between smokers without chronic symptoms, smokers with nonobstructive chronic bronchitis and smokers with COPD. This review describes how these three groups differ regarding the effects of smoking cessation on respiratory symptoms, lung function (forced expiratory volume in one second), airway hyperresponsiveness, and pathological and inflammatory changes in the lung. Smoking cessation clearly improves respiratory symptoms and bronchial hyperresponsiveness, and prevents excessive decline in lung function in all three groups. Data from well-designed studies are lacking regarding the effects on inflammation and remodelling, and the few available studies show contradictory results. In chronic obstructive pulmonary disease, a few histopathological studies suggest that airway inflammation persists in exsmokers. Nevertheless, many studies have shown that smoking cessation improves the accelerated decline in forced expiratory volume in one second, which strongly indicates that important inflammatory and/or remodelling processes are positively affected.     

Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability

BACKGROUND & AIMS: Current models of colorectal adenoma to carcinoma progression do not fully reflect the genetic heterogeneity and complexity of the disease. The aim of the present study was to identify genetic changes discriminating adenomas that have progressed to carcinoma from adenomas that have not progressed, and to refine the current genetic models of colorectal adenoma to carcinoma progression, based on a genome-wide analysis of chromosomal aberrations. METHODS: Sixty-six nonprogressed colorectal adenomas, 46 progressed adenomas (malignant polyps), and 36 colorectal carcinomas were screened for chromosomal aberrations by comparative genomic hybridization, and for mutations in the adenomatous polyposis coli (APC) and K-ras gene. Data analysis focused on cancer-associated genetic changes in adenomas. RESULTS: Accumulation of losses in 8p21-pter, 15q11-q21, 17p12-13, and 18q12-21, and gains in 8q23-qter, 13q14-31, and 20q13 were strongly associated with adenoma-to-carcinoma progression, independent of the degree of dysplasia. Hierarchic cluster analysis demonstrated the presence of 3 distinct subgroups of adenomas, characterized by unique combinations of genetic aberrations in the adenomas (17p loss and K-ras mutation, 8q and 13q gain, and 18q loss and 20q gain, respectively). CONCLUSIONS: The presence of 2 or more of the aforementioned 7 chromosomal changes was associated with progressed colorectal adenomas and colorectal cancer. In addition, evidence was found that these chromosomal abnormalities occurred in specific combinations of a few abnormalities rather than as a mere accumulation of events, indicating the existence of multiple independent chromosomal instability pathways of colorectal cancer progression.     

First study of infliximab treatment in patients with chronic obstructive pulmonary disease

RATIONALE: Tumor necrosis factor-alpha is believed to be important in the induction and maintenance of airway inflammation in chronic obstructive pulmonary disease. OBJECTIVES: We aimed to evaluate the effect of the anti-tumor necrosis factor-alpha drug infliximab in patients with chronic obstructive pulmonary disease, with percentage of sputum neutrophils as the primary endpoint. METHODS: We performed an exploratory single-center, double-blind, placebo-controlled, randomized, phase 2 trial in which 22 current smokers with mild-to-moderate chronic obstructive pulmonary disease participated. Fourteen patients received three infusions of infliximab (5 mg/kg) at Weeks 0, 2, and 6, and eight patients received placebo infusions. Sputum samples, respiratory symptoms, quality of life, exhaled nitric oxide, lung function parameters, bronchial hyperresponsiveness, resting energy expenditure, and side effects were evaluated. MEASUREMENTS AND MAIN RESULTS: This study did not show a positive short-term effect of infliximab on airway inflammation, lung function, resting energy expenditure, or quality of life. Exhaled nitric oxide increased significantly at Day 2, Week 6, and Week 8 in patients receiving infliximab compared with those receiving placebo. Eight patients in the infliximab group (vs. none in the placebo group) reported increased coughing, but no serious adverse events or increase in respiratory infections were reported during 9 weeks of follow-up. CONCLUSIONS: In this short-term study, no clinically beneficial effects of infliximab were observed, and there were no significant safety issues. Definite conclusions concerning the effectiveness of infliximab treatment in chronic obstructive pulmonary disease await additional studies, including those with a larger number of patients with more advanced disease.     

Recovery from cytomegalovirus infection is associated with activation of peripheral blood lymphocytes.

The number of CD8bright and CD56+ lymphocytes in the peripheral blood and their activation status were monitored by flow cytometry in 23 renal transplant recipients with cytomegalovirus (CMV) infection and were correlated with the virus load (as determined by CMV antigenemia) and clinical symptoms. Recovery from CMV infection coincided with expansion of the CD8bright and CD56+ subsets and with increased expression of the activation marker HLA-DR. Primary infection was associated with activation of both subsets, whereas during secondary infection, mainly CD8bright cells responded. Progressive CMV disease (requiring antiviral treatment) and relapse occurred in association with low numbers of activated CD8bright and CD56+ cells. Lymphocyte activation and antibody responses against CMV often occurred simultaneously, but different kinetics of these responses in some patients indicated that cellular responses are necessary to control viral replication, whereas humoral responses alone may be insufficient. Monitoring of lymphocyte activation may provide clinically useful information during CMV infection.