Restorative Proctocolectomy in Ulcerative Colitis: Effect of Preoperative Immunomodulatory Therapy on Postoperative Complications and Pouch Failure.

BACKGROUND AND AIMS: Patients with ulcerative colitis are often treated with multiple immunomodulative agents to achieve remission. In refractory disease, the next option is frequently proctocolectomy with ileal pouch-anal anastomosis. No consensus exists as to whether immunomodulatory therapy at the time of ileal pouch surgery leads to any increase in postoperative complications. Our aim was to assess, in ulcerative colitis patients with restorative proctocolectomy, the effect of preoperative anti-tumor necrosis factor therapy and corticosteroids on postoperative complications and pouch failure. MATERIALS AND METHODS: A retrospective medical record review of 445 patients with ulcerative colitis who underwent proctocolectomy with ileal pouch-anal anastomosis in Helsinki University Hospital between January 2005 and June 2016. RESULTS: Anti-tumor necrosis factor agents were not associated with postoperative complications. Only high-dose corticosteroids (prednisolone ⩾20 mg or equivalent) were associated with higher incidence of anastomotic leak (12.6% vs 2.5%, P = 0.002) and wound dehiscence (4.2% vs 0%, P = 0.019), but pouch failure rate was no higher (2.1% vs 0%, P = 0.141) than in patients without corticosteroid treatment. A lower dosage of corticosteroids had no effect on early postoperative complications, but pouch failure rate was increased (4.4% vs 0%, P = 0.015). CONCLUSION: Corticosteroids, but not anti-tumor necrosis factor therapy, were associated with postoperative complications. Preoperative use of corticosteroids may increase pouch failure rate, but the risk is still minor in high-volume centers performing ileal pouch surgery.

Morbidity related to diverting ileostomy after restorative proctocolectomy in patients with ulcerative colitis.

AIM: Restorative proctocolectomy with ileal pouch-anal anastomosis is considered by many surgeons to be the standard procedure for surgical management of ulcerative colitis. There is controversy about whether or not a covering ileostomy should be constructed. The aim of this study was to evaluate the outcomes and morbidity for patients with ulcerative colitis who underwent restorative proctocolectomy with or without a diverting ileostomy. METHOD: This is a retrospective study of a consecutive series of 510 patients with ulcerative colitis who were operated on in Helsinki University Hospital between January 2005 and June 2016. A diverting ileostomy was performed in 119 patients (the stoma group) compared with 391 patients with no stoma. RESULTS: Dehydration and intestinal obstruction occurred more often in the stoma group (P < 0.0001). Clinical anastomotic leakage was more common among patients without an ileostomy (6.6% vs 1.7%, P = 0.04). However, the need for re-laparotomy because of any early complication did not differ between the groups (P = 0.58). Within 3 months, 50 patients with ileostomy (42.0%) and 51 patients without (13.0%) were readmitted (P < 0.0001). In total, 35 patients (29.3%) had a complication relating to ileostomy closure and four of them required surgery. There was no difference in the rate of fistulas, pouchitis or pouch failure between the groups. CONCLUSION: Our study shows that a diverting ileostomy is associated with considerable morbidity but it does not seem to prevent later failure of the pouch. We suggest that a diverting ileostomy should only be constructed for high-risk patients.

Molecular Changes During Acute Myeloid Leukemia (AML) Evolution and Identification of Novel Treatment Strategies Through Molecular Stratification.

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by impaired differentiation and uncontrollable proliferation of myeloid progenitor cells. Due to high relapse rates, overall survival for this rapidly progressing disease is poor. The significant challenge in AML treatment is disease heterogeneity stemming from variability in maturation state of leukemic cells of origin, genetic aberrations among patients, and existence of multiple disease clones within a single patient. Disease heterogeneity and the lack of biomarkers for drug sensitivity lie at the root of treatment failure as well as selective efficacy of AML chemotherapies and the emergence of drug resistance. Furthermore, standard-of-care treatment is aggressive, presenting significant tolerability concerns to the commonly advanced-age AML patient. In this review, we examine the concept and potential of molecular stratification, particularly with biologically relevant drug responses, in identifying low-toxicity precision therapeutic combinations and clinically relevant biomarkers for AML patient care as a way to overcome these challenges in AML treatment.

Physiotherapy for female stress urinary incontinence: individual therapy at the outpatient clinic versus home-based pelvic floor training: a 5-year follow-up study.

AIMS: To compare the long-term effects of individual physiotherapy at an outpatient clinic, including electrical stimulation (ES), active pelvic floor muscle exercises (PFMEs), and training with a vaginal ball (VB), with home-based active PFMEs and training with a VB, in cases of female stress urinary incontinence (SUI). MATERIALS AND METHOD: Thirty-three women with SUI (outpatient clinic group [Group I, n = 16] and home group [Group II, n = 17]) participated in the 5-year follow-up study. Both groups had an active PFME program and they used a VB during daily activities for intensive pelvic floor muscle (PFM) training. Group I was also treated at the outpatient clinic with maximal interferential ES, using frequencies varying from 10 to 50 Hz, and individually instructed exercises with biofeedback were carried out at the same time, once a week, an average of nine times in the first year. After baseline examinations, both groups visited the outpatient clinic at 4 months, 12 months, and at 5 years. RESULTS: At 12 months, there were no statistically significant differences between the study groups in any of the outcome variables, but within the groups both the subjective and objective results were significantly better in comparison with the initial values. After 12 months, two (3%) patients in Group I continued physiotherapy and seven (41%) patients in Group II needed physiotherapy because of an unsatisfactory outcome. At 5 years, according to the urinary incontinence severity score (UISS) questionnaire, subjective discomfort had decreased in both groups (P < 0.01) and 21 of the 33 women (64%) perceived a subjective cure or improvement in their condition. The mean objective urine leakage verified by the pad test decreased from 23.0 to 1.0 g in Group I and from 13.0 to 1.0 g in Group II (P < 0.001 for both groups). The strength of PFMs tested in a standing position increased by 26% in Group I and by 19% in Group II (P values 0.001 and 0.084, respectively), and in a lying position by 28% in Group I and by 32% in Group II (P values 0.001 and 0.008, respectively). CONCLUSIONS: Home-based PFMEs and training with a VB proved to be equally effective as once-a-week supervised therapy, and the 5-year follow-up results demonstrated a successful response in the treatment of female SUI.

Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18-60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3 microm, P = 0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

Placebo-controlled study of inhaled budesonide on indices of airway inflammation in bronchoalveolar lavage fluid and bronchial biopsies in cross-country skiers.

BACKGROUND: Asthma-like symptoms, methacholine hyperresponsiveness, use of inhaled steroids, airway inflammation, and increased tenascin expression in the reticular basement membrane have been reported in competitive cross-country skiers. OBJECTIVE: To investigate the effect of inhaled budesonide, 400 mug twice daily, on indices of airway inflammation in 'ski asthma', defined as asthma-like symptoms within the previous year and bronchial hyperresponsiveness to methacholine. METHODS: A randomised double-blind placebo-controlled parallel-group bronchial biopsy and bronchoalveolar lavage (BAL) study of 25 (19 male) competitive cross-country skiers (mean age 18 (16-20) years for a mean (range) treatment period of 22 (10-32) weeks over the competitive season. RESULTS: No changes were seen regarding cellular inflammation in the bronchial mucosa or tenascin expression. In the BAL fluid, both groups had a significant decrease in activated T-suppressor (CD8) lymphocytes and an increase in macrophages, with no differences across the groups. Within the budesonide group, there was a decrease in IL2 receptor-activated T-helper lymphocytes and an improvement in FEV(1). Asthma-like symptoms were unchanged in 17 (68%) skiers. Methacholine provocation test was negative in 15 subjects, and remained positive in 5 subjects in each group. The improvement in bronchial responsiveness occurred in both groups and was not accompanied by a decrease in cellular inflammation. CONCLUSIONS: We were unable to show any clear beneficial effect of budesonide in 'ski asthma'. As changes in training intensity probably accounted for the spontaneous improvement in bronchial responsiveness, more attention should be directed at reducing environmental stress to the airways than at attempting pharmacological modulation of induced inflammatory changes.

Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine.

Asthma-like symptoms, methacholine hyperresponsiveness, and use of asthma medication are prevalent in elite cross-country skiers. We quantitated mucosal inflammatory cell infiltration and tenascin expression in the subepithelial basement membrane in endobronchial biopsy specimens of the proximal airways from 40 elite, competitive skiers (mean: 17.5; range: 16 to 20 yr) without a diagnosis of asthma, in 12 subjects with mild asthma, and in 12 healthy controls, through immunohistochemistry and indirect immunofluorescence, respectively. All of the subjects were nonsmokers. T-lymphocyte, macrophage, and eosinophil counts were, respectively, greater by 43-fold (p < 0.001), 26-fold (p < 0.001), and twofold (p < 0.001) in skiers, and by 70-fold (p < 0.001), 63-fold (p < 0.001), and eightfold (p < 0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than twofold greater than in asthmatic subjects, and mast cell counts were not significantly different than in controls. Tenascin expression (as measured through the thickness of the tenascin-specific immunoreactivity band in the basement membrane) was increased in skiers (median: 6.7 microm; interquartile range [IQR]: 5.3 to 8.5 microm, p < 0.001) and asthmatic subjects (mean: 8.8 microm; IQR: 7.2 to 10.8 microm, p < 0. 001) compared with controls (mean: 0.8 microm; IQR: 0 to 3.1 microm) and did not correlate with inflammatory cell counts. Inflammatory changes were present irrespective of asthmalike symptoms, hyperresponsiveness, or atopy. Prolonged repeated exposure of the airways to inadequately conditioned air may induce inflammation and remodeling in competitive skiers.

Histopathologic features of early and progressive asthma.

During the last decade, morphologic studies on bronchial biopsy specimens have led to our present understanding of asthma as an inflammatory airways disease. However, little knowledge exists about the sequence of cellular events during the disease or of possible mucosal changes early in asthma. So far the primary cause, the site of damage, and the mechanisms inducing the inflammatory reaction remain to be elucidated. A multifactorial genetic susceptibility may be important for the development of asthma. Suggested factors that may trigger changes in the cells' morphologic and functional phenotype are viral infections, allergen exposure, maternal factors, diet, and smoking. Current evidence has implied that interactions between epithelial cells and the subepithelial connective tissue in the mucosa are important for normal homeostatic balance. Changes in airway epithelial phenotype possibly resulting from altered gene expression in its lining cells may be very important even as a first line change in asthma.

Early interventions in asthma with inhaled corticosteroids.

We have earlier shown epithelial damage in the airway mucosa in patients with asthma. Later other structural changes have been recognized in asthma, such as deposition of collagen and tenascin in the subepithelial basement membrane and changes in the laminin subchain composition. These processes are modified by an inflammatory process in the airways. Both the United States National Institutes of Health and the British Thoracic Society guidelines on the management of asthma emphasize the need for early use of anti-inflammatory drugs. Many clinical studies that used airway biopsy specimens have shown a decrease in airway inflammatory cell numbers after inhaled corticosteroid therapy. However, there is very little information on the effects of asthma medication on the structural components of the airways. Both the synthesis and degradation of many extracellular matrix components may be affected by the disease process and the drugs resulting in altered remodeling and gene expression in the airways. Because there are only a few studies that try to identify early changes in asthma, it is not known whether the anti-inflammatory treatment of asthma proposed by the guidelines is started early enough.

Lymphoid aggregates in endobronchial biopsies from young elite cross-country skiers.

Observation of bronchus-associated lymphoid tissue (BALT) in whole lung specimens from healthy nonsmoking adults has questioned the hypothesis that BALT is not constitutively present in healthy adult human lungs. In our study, we investigated endobronchial biopsies of the second- and third-generation carinae from 44 cross-country ski athletes and 12 healthy control subjects, all nonsmoking young adults. The skiers had a prevalence of respiratory allergy (18%), asthma-like symptoms (59%), beta2 agonist medication (25%), and methacholine bronchial hyperresponsiveness (79%). Biopsy sections were stained by immunohistochemical and hematoxylin-eosin-saffran methods. Lymphoid aggregates of more than 50 cells were identified in 28 (64%) skiers and three (25%) control subjects (p = 0.02). They were small in comparison to those found in rabbits and rats, contained T and B lymphocytes and macrophages, and were seen more frequently in skiers using beta2 agonists (p = 0.04) and with bronchial hyperresponsiveness to methacholine (p = 0.053). The frequency of these aggregates was not significantly different at the two carinal levels (p = 0.6). The aggregates were not associated with a history of respiratory allergy or asthma-like symptoms. These aggregates share some resemblance with what is usually defined as BALT. However, their exact nature and function await further clarification.

Bee and wasp sting reactions in current beekeepers.

BACKGROUND: A majority of subjects allergic to bee venom are beekeepers, their relatives, or neighbors. Predetermining systemic reactivity to honeybee stings and risk assessment through laboratory tests have been unsatisfactory. OBJECTIVE: To estimate the prevalence and type of sting reactions, and especially to evaluate potential risk factors of systemic reactions in beekeepers. METHODS: A questionnaire concerning sting reactions and potential risk factors was mailed to all members of the regional beekeepers' association; 191 beekeepers were included in the study. RESULTS: Systemic bee sting reactions were present in 50 (26%) and large local reactions in 73 (38%) of the beekeepers. Similar reactions following wasp stings were present in 2% and 13%, respectively. Twenty-four (48%) of the systemic reactors and 39 (28%) of the remaining subjects had a history of atopic symptoms (allergic rhinitis, allergic bronchial asthma, or atopic dermatitis). While working at hives, nasal and eye symptoms were present in 54% of the systemic reactors and in 23% of the remaining subjects. Systemic reactors were younger and had been beekeepers for a shorter period than nonreactive subjects. Multiple logistic regression analysis showed that the risk of systemic sting reaction increased fourfold when nasal or eye symptoms were present while working at hives and twofold when the years in beekeeping were less than 15. CONCLUSIONS: The occurrence of systemic and large local reactions after bee stings is high among beekeepers. A history of atopy is associated with systemic reactions. Both the presence of nasal or eye symptoms while working at hives and a history of beekeeping less than 15 years significantly increase the risk of systemic reactions.

Clinical symptoms and immunologic reactivity to bee and wasp stings in beekeepers.

We compared the history of sting reactions with venom skin prick test (SPT) and CAP RAST reactions in beekeepers in order to assess the value of structured questions and symptom backgrounds. The study population consisted of 102 beekeepers, who were 25-75 years of age. Bee and wasp venom SPT was performed with concentrations of 10, 100, and 300 micrograms/ml. The CAP Phadiatop test was used in the screening of IgE antibodies against common inhalant allergens. Forty-two beekeepers had never experienced large local or systemic reactions after a bee sting. Of the 31 subjects with a history of systemic reactions, 13 had experienced these during the previous year. A significant difference (P < 0.01) between systemic reactors and nonreactors was found in bee venom CAP and SPT (300 micrograms/ml). However, due to considerable overlap, these tests are unable to discriminate between allergic and nonallergic beekeepers. Both bee venom SPT (300 micrograms/ml) and CAP tests were positive in 65% of systemic reactors and in 34% of nonreactors (P = 0.008). Venom SPT (300 micrograms/ml) correlated significantly with CAP for both venoms. No correlation was observed between venom allergy and atopy. Clinically, the most practical concentration for evaluating bee and wasp venom sensitization by SPT proved to be 300 micrograms/ml.

Finding the "natural" vector bases for multidimensional reference values.

The concept of reference values can be extended to multidimensional results. A probability function describes the relative density of the observations in the multivariate space. When the density of a given point is measured relative to all other points, we get an estimate of the density rank of a given point. If the rank of a point is lower than 95 per cent of all points, the multidimensional result is outside the multidimensional reference range. The single-dimensional case is a special case of this general concept. Many observations are needed to define multidimensional distributions. However, less points are needed if the dimensionality of the data matrix is reduced by statistical methods such as principal component analysis (PCA). Also other vector bases than the orthogonal solution produced by PCA are possible, and all of them compress data equally well. So the choice must be based on other criteria than compression. We propose using a vector basis that consists of positive numbers. The positive vectors can be found by direct methods such as Alternating Regression (AR) or they can be modified from the results of the PCA. Positive vectors resemble the spectra that are familiar in chemistry and physics. They are a "natural" way to describe multidimensional results. It is easier to name the positive vectors than the purely statistical vectors of PCA. To obtain a unique positive solution, additional constraints besides positivity are needed.

Mathematical isolation of component spectra in HPLC/UV-vis and GC-MS. How unique are the resolved spectra?

The resolution of overlapping spectra in GC-MS and HPLC/UV-vis is fundamentally limited by the quality of the experimental data. The narrowness of the solution range depends on the degree of overlap between components. If the components are dissimilar, the solutions obtained by all mathematical methods are robust. Small perturbations in the observations do not change the calculated solution very much. Alternating regression (AR) is a useful tool in the analysis of overlapping spectra because AR can be calculated very rapidly. The robustness of the solution can be easily checked with AR. The mathematical analysis is repeated several times after adding different sets of noise. Each time different random spectra are used as a starting point. The range of solutions thus obtained reflects the quality of the data for resolution purposes.

Relationship between occupation and lung cancer as analyzed by age and histologic type.

The information on occupations obtained in Finland's 1970 census was linked with the files of the Finnish Cancer Registry from 1971 through 1980 in order to establish the occupational group-specific relative risks (RR) of lung cancer. The distribution of lung cancers into histologic types varied with the age of the patients at the time of diagnosis. When 38 high-risk occupational groups were combined, the age-specific distribution of lung cancer into histologic types did not differ significantly from the corresponding distribution for other economically active men. Of individual occupational groups, young farmers had a higher RR of small cell carcinoma than older farmers or other economically active young men. Besides their high overall lung cancer risk, miners and quarriers had a very high risk of small cell carcinoma as compared with other economically active men. Servicemen and repairmen in the metal industry had a high risk of epidermoid carcinoma. Welders had a high risk of epidermoid carcinoma, but their risk of small cell carcinoma was lower than expected. There were no other excess risks of any histologic type of lung cancer attributable to occupational factors.