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Background: Application of the Stewart-Hamilton equation in the thermodilution technique requires flow to be constant. In patients in whom ventilation of the lungs is controlled, flow modulations may occur leading to large errors in the estimation of mean cardiac output., Methods: To eliminate these errors, a modified equation was developed. The resulting flow-corrected equation needs an additional measure of the relative changes of blood flow during the period of the dilution curve. Relative flow was computed from the pulmonary artery pressure with use of the pulse contour method. Measurements were obtained in 16 patients undergoing elective coronary artery bypass surgery. In 11 patients (group A), pulmonary artery pressure was measured with a catheter tip transducer, in a partially overlapping group of 11 patients (group B), it was measured with a fluid-filled system. For reference cardiac output we used the proven method of four uncorrected thermodilution estimates equally spread over the ventilatory cycle., Results: A total of 208 cardiac output estimates was obtained in group A, and 228 in group B. In group B, 48 estimates could not be corrected because of insufficient pulmonary artery pressure waveform quality from the fluid-filled system. Individual uncorrected Stewart-Hamilton estimates showed a large variability with respect to their mean. In group A, mean cardiac output was 5.01 l/min with a standard deviation of 0.53 l/min, or 10.6%. After flow correction, this scatter decreased to 5.0% (P < 0.0001). With no bias, the corresponding limits of agreement decreased from +/- 1.06 to +/- 0.5 l/min after flow correction. In group B, the scatter decreased similarly and the limits of agreement also became +/- 0.5 l/min after flow correction., Conclusion: It was concluded that a single thermodilution cardiac output estimate using the flow-corrected equation is clinically feasible. This is obtained at the cost of a more complex computation and an extra pressure measurement, which often is already available. With this technique it is possible to reduce the fluid load to the patient considerably.

We compared intraindividual and interindividual variability in the plasma levels of fibrinogen, tissue-type plasminogen activator (TPA) antigen, plasminogen activator inhibitor (PAI) activity, and C-reactive protein (CRP) in 20 healthy, young individuals and 26 patients with stable angina pectoris (AP) who were at higher risk for cardiovascular disease. For each of the four parameters, the contribution of the intraindividual variation to the total variance (13% and 9% for fibrinogen, 3% and 5% for TPA antigen, 4% and 20% for In[PAI activity], and 14% and 9% for In[CRP] for the healthy volunteers and AP patients, respectively) was smaller than the contribution from the interindividual variation. These results indicate that single sampling is sufficient to assess an individual level for TPA antigen and PAI activity, whereas duplicate sampling for fibrinogen and triplicate sampling for CRP are recommended. In an epidemiological study the sample sizes, based on the variances found in the transverse part of the study, needed to detect a 15% difference between the two groups (with alpha = 0.01 and a statistical power = .90) are 31 and 40 for fibrinogen, 568 and 146 for TPA antigen, 603 and 119 for PAI activity, and 1490 and 2263 for CRP in healthy volunteers and patients with AP, respectively. Additionally, we studied the contribution of genetic polymorphisms of the B beta-fibrinogen (Bcl I and G-->A-455) and PAI activity (HindIII and CA-repeat) genes to intraindividual and interindividual variation. Fibrinogen genotypes were associated with plasma fibrinogen levels in the volunteers but not in the AP patients. No effects of fibrinogen or PAI polymorphisms on intraindividual variation were observed in either healthy individuals or AP patients. In this study intraindividual variation in plasma levels of the cardiovascular risk indicators fibrinogen, TPA antigen, PAI activity, and CRP was small when compared with the interindividual variation in healthy, young volunteers and patients with stable AP.

Background: The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. PHASE 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid (BA + CS) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) than treatment with a beta 2-agonist plus anticholinergic (BA + AC) or placebo (BA + PL). PHASE 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 micrograms beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA +/- AC) could also improve FEV1 and PC20 to the same degree. A distinction was made between patients with predominantly asthma (high baseline reversibility, delta FEV1 > or = 9% of predicted), and predominantly COPD (low baseline reversibility, delta FEV1 < 9% of predicted)., Results: Improvement of FEV1 percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p = 0.31) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively). PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p = 0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p = 0.19)., Conclusions: Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1, improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility.

At the present time, there is still controversy concerning the presence of a late asthmatic response (LAR) to exercise challenge in asthma. We have, therefore, investigated the occurrence of a LAR after exercise in asthmatic children visiting an out-patient clinic, using time-matched baseline and histamine control days, and a statistical analysis according to recently published recommendations. After a screening exercise day, 17 children (aged 7-14 yrs) randomly performed, on three subsequent study days, either: a second standardized exercise challenge; or a histamine challenge whilst matching the bronchoconstriction after exercise; or measurement of baseline lung function without any challenge. Measurements of forced expiratory volume in one second (FEV1) were made repeatedly during 8 h. Analysis was performed using multiple regression analysis for each patient, with FEV1 as the dependent, and test day (exercise or control) and clock time as independent variables during the period 2-8 h after exercise. A significant interaction (p < 0.05) between test day and clock time was considered to be indicative of a LAR. Fifteen children completed the study. All children showed an early asthmatic reaction to exercise (range 14-62% fall in FEV1). In two children, a significant interaction (p < 0.05) was found between test day and clock time. However, the difference in FEV1 between exercise and control days for each clock time did not exceed the 99.6% confidence limits of normal diurnal variation in any of the children. We conclude that, in children with mild-to-moderate asthma, a LAR to exercise does not occur. This suggests that exercise is only a symptomatic trigger of asthma. Whether exercise is capable of inducing inflammation needs to be further investigated.

Background: The role of antigen presenting cells (APC) in allergic rhinitis is underexposed. Allergen presentation to T lymphocytes is probably an important aspect of the pathophysiological mechanism of allergic rhinitis., Objectives: The aim of the study was to investigate the presence and dynamics of APC with special emphasis on Langerhans cells (LC) in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season., Methods: Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with allergen during a 2-week period in the winter. Biopsy specimens were obtained once before, six times during and once after the provocation period. Biopsy sections were stained with monoclonal antibodies: OKT6 (CD1a-Langerhans cells), Ki-M6 (CD68-macrophages), L25 (dendritic cells), anti-IgE, HLA-DR and HLA-DQ (Major Histocompatibility Complex Class II-antigen presenting cells), as well as staining with acid phosphatase., Results: APC with different characteristics are present in the epithelium and lamina propria of the nasal mucosa. The number of LC increased significantly in epithelium and lamina propria. IgE(+)-LC were present in the nasal mucosa and increase during provocation. HLA-DR+ cells with dendritic and lymphocytic morphology and HLA-DQ+ cells were found. The number of these cells increased during provocation in epithelium and lamina propria. The number of HLA-DR+ epithelial cells did not change. A significant increase in the number of Ki-M6+ cells (macrophages) was found in the lamina propria. However, Ki-M6+ cells increased to the same extent in the lamina propria in the control group., Conclusion: APC are influenced by allergen provocation. This study supports the hypothesis that (IgE+) LC are involved in allergic rhinitis. The role macrophages play remains doubtful.

Background/aim: CA19-9 is a tumor marker present in the serum of 70-90% of patients with pancreatic carcinoma. In order to investigate the value of CA19-9 determination in the clinical management of patients with pancreatic cancer, we performed a retrospective study., Material and Methods: We reviewed the records of 122 patients who were admitted to the Surgical Department of the Dijkzigt University Hospital in Rotterdam, the Netherlands, with a diagnosis of pancreatic cancer., Results: Patients with distant metastases at the time of diagnosis show a significantly higher serum CA19-9 level than patients without distant metastases. Unfortunately there is much overlap between the levels in both groups. There was no statistically significant difference in CA19-9 level between patients with a resectable tumor and a tumor that was unresectable due to local conditions. In the postoperative follow-up, there was a statistical relationship between the postoperative CA19-9 level and the development of distant metastases. However, since there is no known therapy for metastases of pancreatic carcinoma, it is not useful to detect these in an early stage., Conclusions: No useful information can be obtained from postoperative CA19-9 determinations. In the preoperative workup of a patient with a pancreatic tumor CA19-9 determination is at least helpful in estimating the probability of metastatic disease.

Background: Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and stimulators of T cells. Dendritic cells are also likely to be essential for the initiation of allergic immune responses in the lung. However, there are not many data on the presence of dendritic cells in the airways of patients with atopic asthma and on the effects of corticosteroid-treatment on such dendritic cells., Objective: We investigated the distribution of dendritic cells in the bronchial epithelium and mucosa of 16 non-smoking atopic asthmatic patients and eight healthy control subjects using detailed immunohistochemistry (CD1a, HLA-DR, L25 as markers for dendritic cells)., Methods: Eleven asthmatics were treated for 2.5 years with bronchodilators only and five with bronchodilators and inhaled beclomethasone dipropionate (BDP), 800 micrograms daily. The patients were randomly sampled from a double-blind multicentre study., Results: There were higher numbers of CD1a+ DC (P = 0.003), L25+ DC (P = 0.002) and HLA-DR expression (P = 0.042) in the bronchial mucosa of asthmatic patients compared with healthy controls. After 2.5 years of treatment, we found a significant increase in flow expiratory volume in 1 second (FEV1) (P = 0.009) and a significant decrease in hyperresponsiveness (PC20 histamine) (P = 0.013) in the corticosteroid group (n = 5) compared with the bronchodilator group (n = 11). This clinical improvement in the corticosteroid-treated group was accompanied by significantly lower numbers of CD1a+ DC (P = 0.008), and HLA-DR expression (P = 0.028) in the bronchial mucosa than in the bronchodilator-treated group., Conclusion: Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulate the number of dendritic.

Inhaled corticosteroids (ICS) in dosages above 1,000 micrograms/d may influence parameters of bone metabolism. Fluticasone propionate (FP) is a new ICS with a higher clinical potency than beclomethasone dipropionate (BDP) combined with negligible oral bioavailability. The aim of this study was to evaluate the effects of FP and BDP in clinically equipotent dosages on indices of bone metabolism and morning cortisol. FP 750 micrograms/d and BDP 1,500 micrograms/d were compared in a randomized, double-blind, crossover study consisting of two 6-wk treatment periods, each preceded by a 3-wk single-blind placebo period. Twenty-one nonsmoking asthmatic completed the study. FP had the same effect on FEV1 and peak expiratory flow as the double dose of BDP. Both treatments did not change morning cortisol. BDP decreased both osteocalcin and procollagen type 1 carboxyterminal propeptide, indices of bone formation, significantly by 18.5 and 21.9%, respectively. In contrast, FP did not change any variable of bone formation. FP and BDP did not increase type 1 collagen carboxyterminal telopeptide and deoxypyridinoline crosslinks, both markers of bone resorption. In changes in parameters of bone metabolism indicate adverse effects on bone quality in the long term, FP may offer an advantage over BDP.

Background: Eosinophils are thought to play an important role in the symptomatology and pathophysiology of allergic rhinitis. Most quantitative studies on eosinophils in nasal mucosa have focused on the dynamics of eosinophils in the acute and late phases of the allergic reaction by using different cell sampling techniques. Little is known about the dynamics of eosinophils during a more prolonged period of allergen exposure and the activation of eosinophils induced by allergen challenge., Objective: The aim of this study was to investigate the dynamics and activation of the eosinophils in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season., Methods: Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with the allergen during a 2-week period in the winter. Nasal brush specimens were obtained before provocation and each day during the provocation period. Biopsy specimens were obtained once before, six times during, and once after the provocation period. Preparations made of nasal brush and nasal biopsy specimens were stained with the monoclonal antibody BMK 13 and Giemsa stain as paneosinophil markers and with the monoclonal antibody EG2 to identify activated eosinophils., Results: We found significant increases in the total number of eosinophils and the number of activated eosinophils in the epithelium and lamina propria. These increases were most explicit in the second week. BMK 13 was found to be a paneosinophil marker superior to Giemsa staining., Conclusion: Eosinophils are not only involved in the acute and late phases of the allergic reaction but are probably even more involved in the chronic phase.

Recently, we showed that it is possible to distinguish between three common interstitial lung diseases (ILD) with similarities in clinical presentation by using a number of selected variables derived from bronchoalveolar lavage fluid (BALF) analysis. The aim of this study was to develop a more general discriminant model, based on polychotomous logistic regression analysis. The 277 patients involved in the study belonged to diagnostic groups with sarcoidosis (n = 193), extrinsic allergic alveolitis (EAA; n = 39), and idiopathic pulmonary fibrosis (IPF; n = 45). The diagnosis had been established independently of the BALF-analysis results. The variables used to discriminate among these patient groups were the yield of recovered BALF, total cell count, and percentages of alveolar macrophages, lymphocytes, neutrophils, and eosinophils. In order to test the predictive power of the logistic model, we used 128 patients having sarcoidosis (n = 91), EAA (n = 5), or IPF (n = 32) from another hospital. In this test set the agreement of predicted with actual diagnostic-group membership was the same as in the learning set in which the logistic model was fitted: 94.5% of the cases were correctly classified. A validated computer program based on the polychotomous logistic regression model can be used to predict the diagnosis for an arbitrary patient with information provided by BALF analysis, and is thought to be of diagnostic value in patients suspected of having ILD.

Absenteeism among 161 Dutch forestry workers was investigated in a cohort study. The rate of taking sick leave was related to the concentrations of sulfate and ozone in ambient air, the air temperature, and the relative humidity. The incidence of absenteeism was treated as a Poisson process, with the size of population at risk as the offset factor and with the environmental monitoring data as hazard factors. There appeared to be some overdispersion; therefore, in a second analysis the incidence of absenteeism was also treated as a negative binomial outcome. With the exception of a separate overdispersion parameter in the negative binomial approach, both methods yielded approximately the same results. Although no significant association was found between absence rate and the measured ambient-air-quality data, there appeared to be a time lag of 3 d between a peak in temperature and 1 d in absenteeism.

Hyperresponsiveness of the airways to nonspecific stimuli is a characteristic feature of asthma. Airway responsiveness is usually characterized in terms of the position and shape of the dose-response curve to methacholine (MDR). In the study we have investigated the influence of fluticasone propionate (FP), a topically active glucocorticoid, on arachidonic acid (AA) metabolites in broncho-alveolar lavage (BAL) fluid (i.e. TxB(2), PGE(2), PGD(2), 6kPGF(1alpha) and LTC(4)) on the one hand and MDR curves on the other hand. The effect of FP was studied in a randomized, double-blind, placebo-controlled design in 33 stable nonsmoking asthmatics; 16 patients received FP (500 mug b.i.d.) whereas 17 patients were treated with placebo. We found that the forced expiratory volume in 1s (FEV(1) % predicted) increased, the log(2)PC(20) methacholine increased and the plateau value (% fall in FEV(1)) decreased after a 12 week treatment period. No changes in AA-metabolites could be determined after treatment except for PGD(2) which decreased nearly significantly (p = 0.058) within the FP treated group, whereas the change of PGD(2) differed significantly (p = 0.05) in the FP treated group from placebo. The levels of the other AA metabolites (i.e. TxB(2), PGE(2), 6kPGF(1alpha) and LTC(4)) remained unchanged after treatment and were not significantly different from the placebo group. Our results support the hypothesis that although FP strongly influences the position, the shape and also the maximum response plateau of the MDR curve, this effect is not mainly achieved by influence on the level of AA metabolites. Other pro-inflammatory factors may be of more importance for the shape of the MDR curve. It is suggested that these pro-inflammatory factors are downregulated by FP.

Information on the relationships between gastro-oesophageal reflux (GOR), reflux symptoms, hiatal hernia (HH) and oesophagitis, and the response to antisecretory treatment is lacking. In a multicentre study endoscopy, ambulatory 24-h pH monitoring and symptom assessment were carried out in 142 patients with symptomatic reflux disease before and during treatment with ranitidine. Using a randomized, double-blind design, patients took ranitidine 150 mg bid or 300 mg bid. Macroscopic oesophagitis (grade I or II) was found in 85 patients; the remaining 57 patients had normal oesophageal mucosa. A significant correlation was found between the presence of an HH and the presence of oesophagitis. Symptom scores were similar in patients with and without oesophagitis, and in patients with and without HH. Patients with oesophagitis had significantly greater oesophageal acid exposure during the night, and in the total 24-h period, but not during the day. Likewise, patients with HH had greater acid exposure during the night (p < 0.008). Both doses of ranitidine significantly decreased oesophageal acid exposure and the effect was independent of baseline acid exposure. Reflux symptoms cannot be used to differentiate between presence or absence of oesophagitis and/or HH. Reflux patients without oesophagitis have less night-time reflux. Ranitidine dose-dependently decreases oesophageal acid exposure, and the effect is independent of baseline reflux.

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a beta(2)-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.

The present study was set up to investigate whether salmeterol in children with asthma already treated with inhaled corticosteroids (ICS) leads to a sustained bronchodilator effect and decreased bronchial responsiveness, both during the day and night. Furthermore, we investigated whether cessation of salmeterol leads to a rebound increase in bronchial responsiveness. Forty children with asthma (aged 7-15 yrs) using ICS participated in a randomized, double-blind, parallel study. They received either twice daily 50 micrograms salmeterol or placebo. FEV1 and provocative concentration of methacholine that caused a 20% fall in FEV1 (PC20) were measured at 4:00 P.M. and 4:00 A.M. at baseline and after 16 wk. The same measurements were performed at 4:00 P.M. at 8 h after the first dose, and after 1 and 8 wk. After cessation of the study drug, FEV1 and PC20 were measured at 12 and 20 h and after 1 wk. Overall mean FEV1 from 1 to 16 wk of treatment was significantly higher in the salmeterol group than in the placebo group (difference, 4.9 +/- 2.0%, p = 0.01). Evolution in time of FEV1 did not differ significantly between the two groups (p = 0.09). Overall mean PC20 from 1 to 16 wk of treatment was not significantly higher with salmeterol than with placebo (difference, 0.7 +/- 0.4 doubling dose [DD] p = 0.07); evolution in time of PC20 did not differ significantly between the two groups (p = 0.58).(ABSTRACT TRUNCATED AT 250 WORDS)

The electromyographic activity of the peroneus longus and anterior tibial muscles of 25 patients with chronic ankle instability (18 patients with bilateral symptoms and 7 patients with unilateral complaints) and 10 controls was registered during the stance phase under different walking conditions. With balance secured by external support, there was a variable amount of peroneal activity, most of which was found in the third quarter of stance. A high increase in peroneus longus activity starting after foot-flat was found when subjects had to maintain balance in a natural way. No difference in peroneal activity was found in relation to instability complaints. It is thought that the peroneus longus serves to maintain balance, that this function decreases with increase of speed and that one cannot rely on this muscle to prevent an inversion injury during normal walking. The anterior tibial muscle was predominantly active in the first quarter after heel contact. An increase in activity in the second quarter as an effect of loss of secured balance suggests that this muscle plays some part in balance control, but this is not its main function. A significant increase in tibialis anterior activity was found in patients with bilateral instability. No significant difference was found between the symptomatic and asymptomatic leg of patients with unilateral instability under the same walking conditions. These findings suggest changes in central control.

Background: Patients with perennial allergic rhinitis develop nasal symptoms not only after allergen exposure, but generally also after non-specific stimuli., Objective: To evaluate the effect of 2 week's treatment with fluticasone propionate aqueous nasal spray (FPANS) on the nasal clinical response, inflammatory mediators and nasal hyperreactivity., Methods: Twenty-four rhinitis patients allergic to house dust mite (HDM), participated in a double-blind, placebo-controlled crossover study. After 2 week's treatment with placebo or 200 micrograms FPANS twice daily, patients were challenged with HDM extract. Symptoms were recorded and nasal lavages were collected for up to 9.5 h after challenge. Nasal hyperreactivity was determined by histamine challenge 24 h later., Results: Because of a carry-over effect for the immediate symptom score, for this variable only the data from the first treatment period were used. FPANS treatment resulted in a significant decrease of nasal symptoms with 70%, 69% and 63% after 100, 1000 and 10,000 Biological Units (BU)/mL of HDM extract respectively. Active treatment resulted in a 76% decrease of the late-phase symptoms. FPANS treatment significantly reduced albumin influx after HDM 1000 BU/mL with 62% and tended to reduce tryptase release after HDM 1000 BU/mL (P = 0.0629). During the late phase FPANS treatment reduced albumin influx with 67% and eosinophil cationic protein (ECP) release with 83%. No effect of FPANS was seen on histamine levels. FPANS significantly decreased histamine-induced symptom score with 34%, secretion with 32% and sneezes with 41%., Conclusion: FPANS significantly inhibits the immediate and late allergic response, and nasal hyperreactivity, probably by suppressing mast cells and eosinophils in the nasal mucosa.

Background: Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test., Methods: Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study., Results: Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate., Conclusions: These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.

Background: The relationship between cell types in bronchoalveolar lavage (BAL) fluid and the clinical course of patients with idiopathic pulmonary fibrosis (IPF) has been the subject of several studies. However, the results of these studies are not conclusive. The aim of this study was to investigate the relationship between the absolute and relative cell numbers in BAL fluid from patients with IPF and their survival., Methods: Results obtained from the initial BAL fluid analyses of all histologically proven cases of IPF (n = 49) were selected retrospectively. Cox's proportional hazards survival analysis was used for estimating the relationship between absolute and relative cell numbers and survival., Results: A negative relationship was found between both the absolute numbers and percentages of eosinophils in BAL fluid samples and survival. No such relationship was demonstrated for the absolute numbers or the percentages of any other cell type., Conclusions: Although this study has restrictions, these findings suggest a negative relationship between the absolute numbers and percentages of eosinophils in BAL fluid samples and survival in patients with IPF.

To assess the diagnostic and prognostic value of interleukin-6, interleukin 1 beta, and tumor necrosis factor-alpha assays in plasma and ascites, we measured these cytokines in eight patients with malignancy-related ascites and 32 patients with decompensated cirrhosis. Five patients had an episode of bacterial peritonitis, during which one or more ascitic fluid samples were analyzed. Interleukin-6 and tumor necrosis factor-alpha were not significantly different between the cirrhotic and the malignant groups: ascitic interleukin-6 13,816 +/- 15,314 vs 28,138 +/- 23,403 pg/ml, plasma interleukin-6 542 +/- 719 vs 559 +/- 604 pg/ml; ascitic tumor necrosis factor-alpha 19 +/- 50 vs 12 +/- 31 pg/ml, plasma tumor necrosis factor-alpha 3.4 +/- 8.2 vs 6.1 +/- 13.8 pg/ml. During an episode of bacterial peritonitis there was a significant increase only in ascitic interleukin-6 (133,268 +/- 99,743 pg/ml), which declined after antibiotic treatment. None of the parameters was associated with 6-month survival (11 of the 40 patients died within 6 months). There was a correlation (r = 0.675; p = 0.002) between plasma interleukin-6 levels and the Child-Pugh score in patients with cirrhosis, but not with the etiology of the liver disorder. Plasma interleukin-6 levels correlated with IgA levels (r = 0.649; p = 0.004) but not with C reactive protein, sedimentation rate, fibrinogen, IgM or IgG. These results do suggest that interleukin-6 is produced within the peritoneal cavity in hepatic and malignant ascites. There is a sharp increase in the local production of interleukin-6 during an episode of bacterial peritonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

A continuous influx of peripheral blood monocytes (PBM) to the lung is thought to maintain the local population of alveolar macrophages (AM). However, local proliferation of a small subpopulation of AM has been demonstrated in animal studies and in humans. AM exhibit a great heterogeneity with regard to their morphology (cell size, shape of nucleus), immunophenotype (expression of CD14 and RFD9 antigen), and function. Part of this heterogeneity may be explained by the presence of different maturation stages of AM, ranging from small immature, CD14+ RFD9- PBM-like cells to large, CD14- RFD9+ mature AM. These findings prompted us to study whether proliferation of PBM and AM is related to their stage of maturation. The expression of the proliferation marker Ki-67 was studied in AM from both healthy volunteers and patients suffering from sarcoidosis. Using double immunofluorescence staining, we studied proliferation of immature, CD14+ AM, and mature, RFD9+ AM in sarcoidosis, and we compared this with PBM. A significantly larger percentage of AM in general expressed Ki-67 antigen in sarcoidosis (3.0 (median); range 1.1-5.5) as compared with healthy volunteers (0.8; 0.2-1.3). In sarcoidosis, proliferation was observed in both the immature and the mature subpopulation of AM. Proliferating PBM were rarely observed [less than 0.2% of the CD14+ mononuclear cells (MNC)] both in healthy volunteers and sarcoidosis patients. A small subpopulation of PBM showed a weak expression of RFD9 antigen (less than 1% of MNC). Interestingly, proliferation of PBM was concentrated in this subpopulation (15% of the RFD9+ MNC). These data show that even mature AM, which are generally thought to be terminally differentiated cells with little capacity to replicate, are able to proliferate, whereas a relatively very low percentage of their precursors in the blood circulation proliferates. Furthermore, the findings suggest that lung tissue in sarcoidosis creates an environment which promotes proliferation of monocytic cells. Pulmonary alveolar macrophages (AM) were originally recognized as phagocytosing scavenger cells (Ham & Cormack 1979), but presently they are also known to initiate and regulate inflammatory and immunological processes in several lung diseases (Herscowitz 1985, Unanue & Allen 1987, Sibille & Reynolds 1990). AM are thought to represent more mature cells of the mononuclear phagocyte system, and to be derived from peripheral blood monocytes (PBM) (Van Furth 1982, Ginsel 1993). As AM are continuously lost (mainly through a transport from the peripheral airways, via the trachea to the pharynx), the local AM population must be constantly replenished.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: It has been demonstrated that some oral antihistamines reduce nasal nonspecific reactivity and that topical levocabastine reduces cellular influx after nasal allergen challenge. This suggests that antihistamines possess other properties besides classical H1-receptor antagonism., Objective: To evaluate the effect of 1 week's treatment with topical levocabastine on the nasal clinical response, inflammatory mediators, and nasal hyperreactivity., Methods: In a double-blind, placebo-controlled, 2-period, 2-treatment, crossover study, 21 rhinitic patients allergic to house dust mite participated. After each treatment period patients were challenged with house dust mite extract. Symptom scores and nasal lavages were collected for nine and one-half hours after challenge. Allergen-induced nasal hyperreactivity was determined by nasal methacholine challenge 24 hours after allergen challenge. A nasal histamine challenge was performed as well., Results: Patients showed only an immediate nasal response. Levocabastine significantly reduced the symptom score after 100 (P = .0063), 1000 (P = .0035), and 10,000 biological units (BU)/mL (P = .0013) of house dust mite extract. Albumin influx and tryptase release were not significantly reduced by levocabastine. No release of histamine and eosinophil cationic protein was seen. Levocabastine did not reduce nasal response to methacholine. Active treatment significantly reduced histamine-induced nasal secretion (P = .0009) and the number of sneezes (P = .0001)., Conclusion: A significant effect of levocabastine was shown on the immediate clinical response to house dust mite and to histamine challenge only. Our findings suggest that levocabastine is an effective H1-receptor antagonist without anti-inflammatory properties.

To obtain insight into the hemodynamics of abnormal cardiac development, a chick embryo model was recently developed in which a spectrum of double outlet right ventricle was induced with all-trans-retinoic acid. In Hamburger and Hamilton (HH) stage 34 white Leghorn chick embryos, we simultaneously measured dorsal aortic flow velocities with a 20 MHz pulsed Doppler velocity meter and vitelline artery blood pressures with a servonull system. These measurements were performed in embryos treated at HH stage 15 with 1 microgram of all-trans-retinoic acid (n = 47), or with the solvent DMSO (n = 15), and in control embryos (n = 21). After the wave form recordings were collected, all embryos were examined histologically. Embryos treated with all-trans-retinoic acid showed in 15 cases hearts with a rightward positioned aorta with an additional subaortic ventricular septal defect and 32 cases without septation abnormalities of the heart. The hemodynamic data were correlated with the morphology. Statistical comparison was performed between control and experimental values. There was no significant discrepancy in hemodynamics of sham-operated and control embryos. Heart rate, peak systolic and mean velocities, peak systolic and mean blood flows, and peak acceleration and stroke volume were reduced in embryos treated with all-trans-retinoic acid (p < 0.01). Furthermore, in the presence of a subaortic ventricular septal defect the diameter of the dorsal aorta was reduced. Pressure readings were not statistically significant. Our findings suggest that the hemodynamic changes are the result of a decrease in cardiac contraction force.

Stretch tests are attractive in the diagnosis of nerve root or peripheral nerve lesion. Interpretation of the test results is often difficult since the distribution of tensile forces along the nerve caused by the test manoeuvre is not known. In this study the effect on median nerve tension of 22 positions of the arm was measured with 'buckle' force transducers. With the elbow in full extension and the hand in neutral position, altering the position of the shoulder significantly influenced tension in the proximal part of the median nerve; tension in the distal part was not influenced. With the shoulder in 90 degrees abduction, dorsiflexion of the hand combined with an extended elbow resulted in an increased tension in both distal and proximal parts of the median nerve. Dorsiflexion of the hand combined with flexion of the elbow caused an increase in tension only in the distal part. At all sites of the median nerve the median nerve upper limb tension test caused a significantly higher tension than the radial and ulnar nerve upper limb tension tests. This study provides insight in the normal distribution of tensile forces along the median nerve and can have clinical consequences. For differentiating nerve root from peripheral nerve lesions a specific provocative tension test for the median nerve is advocated. The results of this study provide a theoretical basis for differentiating between lesions in the proximal and distal parts of the median nerve. RELEVANCE: In the diagnosis of nerve(root) lesions, tests in which stretching the nerve provokes the symptoms are widely used, but no data are available on the distribution of tensile forces along nerves and nerve roots during such tests. In this study a human cadaver model is presented to analyse tensile force distribution on the median nerve; it can be an aid to evaluate the specificity of a clinical provocation test for the median nerve.

Various joint positions of the upper extremity were used to study the tensile forces on the median nerve. To analyse the effect of embalmment, tensile forces were measured in situ in unembalmed and embalmed human bodies. A positive correlation was found between tensile force data from unembalmed and embalmed nerves. This finding justifies, for comparative studies, the use of embalmed human bodies, although the absolute tensile forces are higher. RELEVANCE: In daily activities or during certain operations positions of the upper extremity vary, hence creating tensile forces of different magnitude on peripheral nerves. Tensile forces are also applied in the diagnosis of nerve (root) lesions of the upper extremity. To analyse these tensile forces, in-situ experiments on unembalmed human bodies, though problematic, are supposed to be the most realistic approach. In this study it has been shown that in comparative studies on peripheral nerve tension, data obtained from embalmed human bodies can be used.

Background: In allergic contact dermatitis (ACD) previously sensitized T cells cause skin damage. If an ubiquitous allergen such as nickel is involved, no effective treatment is available. Down-regulation of this allergic response has been described after antigen presentation in the absence of adequate costimulatory signals. UV exposure can enhance such hyposensitization., Objective: The aim of this study was to establish the capability of a hyposensitization procedure to induce antigen-specific tolerance., Methods: Twenty-one patients with nickel ACD were randomly assigned to either a hyposensitized or control group. A schedule consisting of UVB treatment and subcutaneous nickel sulfate administration (hyposensitization) or UVB only (control) was applied. During the ensuing 2 years, several clinical and immunologic features were monitored., Results: During UVB treatment we observed a significant clinical improvement in both groups that persisted in the hyposensitized group. Except for increased slope variances of specific lymphocyte proliferation in time, no clear changes were seen in the immunologic findings., Conclusion: Despite significant clinical improvement induced by UVB, hyposensitization did not induce significant changes in the immunologic findings in patients with nickel ACD.

In a series of 126 meningiomas, tumor and patient characteristics were investigated and statistically analyzed. A combined cytogenetic and molecular genetic approach was used to study chromosomal abnormalities and loss of markers on chromosome 22q. This approach was successfully applied to 93 meningiomas. In 66 cases, complete or partial loss of chromosome 22 was observed and in at least 12 of them this chromosome was involved in structural aberrations. In addition to chromosome 22 changes, chromosomes 1, 6, 11, 13, 14, 18, 19, X, and Y were also frequently involved in structural and numerical aberrations. Statistical analysis revealed a significant association between the number of chromosomal abnormalities and tumor grade. Complex karyotypes predominated in the group of grade II/III meningiomas. Furthermore, other variables showed statistically (or marginally statistically) significant differences. Meningiomas from the convexity were more often grade II/III, displayed predominantly (partial) loss of chromosome 22 and had complex karyotypes more often. These features were frequently found in meningiomas from males. Base meningiomas, on the other hand, occurred more often in females; they were usually grade I, showed loss of (parts of) chromosome 22 less often and displayed fewer additional chromosomal abnormalities.

The effect of nasal corticosteroid therapy on allergic rhinitis is uncertain. In a double-blind, placebo-controlled study over 3 months, we investigated the influence of a new corticosteroid spray, fluticasone propionate aqueous nasal spray (FPANS), on Langerhans cells (CD1a+ cells), HLA-DR+ cells, and T cells in nasal mucosa. Efficacy was evaluated by nasal symptom score. This treatment significantly decreased the number of CD1a+ cells and HLA-DR+ cells in the nasal mucosa. Furthermore, a clear trend of decreasing numbers of T cells in nasal epithelium was found. No change in nasal symptom score was found after the treatment period. These findings suggest that fluticasone propionate aqueous nasal spray decreases the antigen presentation in nasal allergy.

The effect of combined administration of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) was studied in 24 non-dialyzed patients with chronic renal insufficiency (CRI), matched pairwise as to age, sex, and creatinine clearance (Cr.cl). Low Ca intake had been supplemented beforehand. Then, 1 alpha-(OH)D3 (mean dose 0.55 micrograms daily) was given orally to all patients for 3 months (T0 to T3). Subsequently, patients were assigned randomly to 6 months further treatment either with 1 alpha-(OH)D3 alone (Group A) or with 1 alpha-(OH)D3 plus a high dosage of 24,25-(OH)2D3 (50 micrograms orally, twice weekly) (Group B). Histomorphometry was performed at T0, T3, and T9. In both groups iPTH was equally suppressed, into the lower normal range. Whereas in Group A, serum Ca rose steadily and Cr.cl declined, in Group B both parameters levelled off between T6 and T9. At T9, in Group A the elevated resorption and osteoid indices had normalized markedly, but osteoblasts (Ob.Pm) and mineralizing boundaries (M.Bd) were depressed considerably between T3 and T9. In contrast, in Group B, preservation of Ob.Pm and improved mineralizing activity were observed (M.Bd at T9 > T3 > T0). Resorption indices hardly changed. In the patients with high Ob.Pm at T0, cancellous bone area increased significantly. This was not observed in Group A. Thus, in Group B, osteoblast recruitment appeared maintained and M.Bd appeared normalized. Decline of remodeling toward an adynamic state with an increased risk of hypercalcemia appeared prevented.

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS)

To gain insight in the effects of shockwaves on human cells the relationship between the energy density and the number of shockwaves as well as their effect on suspensions of normal cells was studied. At energy densities of 0.37, 0.6, 0.78, and 1.20 mJ/mm2 fibroblasts were subjected to 50, 100, 250, 500, and 1,000 shockwaves. Each test was performed three times and one sample was used as control. A decrease in viability related to the logarithm of both the number (P = 0.0000) and the energy density (P = 0.001) of the shockwaves was statistically demonstrable 1 hr after the shockwave application. The energy density of the shockwaves has less influence on the viability than the number of applied shockwaves. Seeding of viable cells 1 hr after the shockwave application showed that the decrease in the 48-hr growth potential was statistically dependent of the number of applied shockwaves only (P = 0.0007). After 24 hr no difference in the 48-hr growth potential could be demonstrated between viable shockwave-treated cells and control cells. The literature as well as our own investigations in vitro and in vivo indicate that shockwaves have a logarithmic dose-dependent destructive effect on cells in suspension, but they also seem to have a dose-dependent stimulating influence on the healing process in damaged tissues. Due to the logarithmic relationship between the viability and both the number and energy density of the applied shockwaves it might be expected that even excessive numbers of high-energy-density shockwaves don't soon lead to total destruction of all cells in the suspension.(ABSTRACT TRUNCATED AT 250 WORDS)

IgE-mediated contact urticaria syndrome (CUS) is one of the manifestations of allergy in childhood atopic dermatitis (AD). Allergens such as foods and animal products penetrate the skin easily. They can then cause urticarial reactions in sensitized individuals. A provocation test system for foods, called the skin application food test (SAFT), has been developed. Over more than 5 years, a group of 175 patients with AD was built-up and investigated in a prospective follow-up study with SAFT. SAFT was more frequently positive in AD children aged 0-2 years than in older children. In several children of this population (Group 1), we repeated SAFT within a period of 1 year. In another unrelated group of children (Group 2-1), we compared the results of 'original' SAFT and SAFT using square chambers (Van der Bend) or Silver patches. In the 3rd group (Group 2-2) we compared 'original' SAFT with SAFT using big Finn Chambers. The agreement between the tests was high: in Group 1, we observed 88 to 93% concordant scores, and in Group 2, the scores were 96% to 100%. Statistically, the kappa coefficient ranged from 0.71-0.87 in Group 1, and from 0.83-1.00 in Group 2. SAFT is therefore highly reproducible. Agreement was at least > or = 88% between the scores (the lowest kappa value observed was at least 0.71).

Minor neurological dysfunction (MND) and quality of movement were studied in relation to neonatal cerebral damage and developmental assessments at 3 1/2 years of age in 66 very low-birthweight children without obvious disability. MND was found in 19 children and was significantly related to the quality of movement. The results demonstrate that MND is associated with neonatal cerebral damage at preschool-age, but that the assessment of quality of movement is associated with more complex sensory motor tasks and simultaneous processing. At preschool-age, quality of movement might therefore be a better marker of later learning problems than traditional signs of minor neurological dysfunction.

We studied the reproducibility of measurement of ultrasonographically assessed common carotid intima-media thickness and assessed whether measurement error of intima-media thickness occurred randomly or was associated with potential determinants of atherosclerosis. Eighty participants of the Rotterdam Study underwent a second ultrasound scan of both carotid arteries within 3 months of the first scan. The replicate measurements involved the posterior intima-media thickness of the distal common carotid artery. Mean differences (SD) in intima-media thickness of the right common carotid artery between paired measurements of sonographers, readers and visits were -0.004 mm (0.10), 0.066 mm (0.07), and -0.013 mm (0.13), respectively. Similar results were obtained for the left common carotid artery. Measurement error of intima-media thickness, i.e. the absolute difference in measurements between two subsequent visits, increased significantly with increasing common carotid intima-media thickness. This association disappeared after logarithmical transformation of the intima-media thickness data. Age, sex, smoking, body mass index, serum lipids, fibrinogen, and systolic and diastolic blood pressure were not significantly associated with the measurement error of intima-media thickness. Our findings indicate that measurements of common carotid intima-media thickness are highly reproducible. Measurement error of intima-media thickness is small and appears to be proportional with the level of intima-media thickness and is not significantly associated with most risk factors for atherosclerotic vessel wall disease.

After cataract extraction with implantation of an intraocular lens the increased transmission of ultraviolet and blue light may accelerate the development of age-related macular degeneration by producing free radicals in the retina. The maculae of 82 randomly selected postmortem human pseudophakic eyes and 16 fellow phakic eyes were examined by light microscopy. The presence of a basal laminar deposit, hard and soft drusen, thickening and calcification of Bruch's membrane, geographic atrophy, subretinal neovascularisation, and disciform scars was assessed in a standardised way. An age-matched series of 126 postmortem phakic eyes was used as control group. There was no difference between the two groups, except for a higher prevalence of hard drusen (exact trend test, p = 0.038) and disciform scars for the pseudophakic eyes (Fisher's exact test, p = 0.007). There was no significant correlation between either age-related changes in the macula or disciform degeneration and the length of time between cataract surgery and death. No significant difference was found between pseudophakic eyes with or without ultraviolet filter. These findings do not confirm that disciform scar formation is caused by an increase in ultraviolet or blue light.

Purpose: To quantify changes in choriocapillary density and in thickness of Bruch's membrane, the choriocapillaris, and the choroid in 95 unpaired, histologically normal human maculae aged 6 to 100 years and in 25 maculae with advanced age-related macular degeneration., Methods: Light microscopic, computer-aided, morphometric quantitative analysis., Results: In ten decades, Bruch's membrane thickness increased by 135%, from 2.0 to 4.7 microns; the choriocapillary density decreased by 45%; the diameter of the choriocapillaris decreased by 34%, from 9.8 to 6.5 microns; and the choroidal thickness decreased by 57%, from 193.5 to 84 microns in normal maculae. In maculae with basal laminar deposit, geographic atrophy, or disciform scarring, the density of the choriocapillaris was 63%, 54%, and 43% of normal and the choriocapillary diameter was 81%, 73%, and 75% of normal, respectively. Choroidal thickness remained unchanged., Conclusions: Thickness of Bruch's membrane was only related to age (rs = 0.63) and not to age-related atrophy of the choriocapillaris. Age was also the strongest factor related to choriocapillary density (rs = -0.58). In advanced stages of age-related macular degeneration, the decrease in choriocapillary density and diameter was significantly larger than in normal maculae, but the thickness of the choroid and Bruch's membrane was the same. The latter was significantly thinner (81% of normal) in disciform scarring.

Objective: To assess mortality and functional results of Thompson's hemiarthroplasty for fractured neck of femur in patients with and without senile dementia., Design: Retrospective study., Setting: District hospital., Subject: 543 Unselected patients who had intracapsular fractures of the femoral neck treated by hemiarthroplasty between 1979 and 1988., Main Outcome Measures: Mortality and functional results during a median follow up period of 14.9 months (range 0.0-111) for patients with senile dementia and 27.4 months (range 0.1-131) for patients who were not demented., Results: 156 of 215 demented patients (73%) died during the follow up period compared with 169 of 328 of those who were not demented (52%). Of the 109 patients with dementia who were mobile before operation only 59 were mobile after operation (54%), compared with 199 of the 215 patients (93%) who were not demented (p < 0.001). Senile dementia seemed to be the only coexisting condition that had a significant effect on mortality., Conclusion: Hemiarthroplasty is probably too major an operation with which to treat fractures of the femoral neck in demented patients.

Breast cancer is the most frequent malignancy in the western world, and increases in the incidence have been observed worldwide. We investigated temporal trends in breast cancer incidence in the southeastern Netherlands between 1960 and 1989 by birth cohort analysis, using data of the Eindhoven Cancer Registry. An overall time-trend in incidence rate was estimated, based on age and year of diagnosis. Rate ratios were calculated, as the ratio of the observed versus the expected incidence rates, which was based on the estimated time-trend. In this unscreened population the age-specific incidence increased for every successive birth cohort in the period 1880-1949. Women born between 1940 and 1949 had the highest age-specific incidence rates with an excess of 10% (relative risk 1.10, 95% confidence interval 1.01-1.22). The incidence rates in women born after 1949 declined and were 21% lower than expected by the estimated secular trend (relative risk 0.79, 95% confidence interval 0.64-0.96). This decrease in incidence for women aged under 40 suggests that the peak in incidence of female breast cancer may be in sight. It remains unclear which risk factors are responsible for this changing trend.

Objective: This study was set up to identify patient-related factors favoring the application of either surgery or endoprostheses in the palliation of obstructive jaundice in subsets of patients with cancer of the head of the pancreas or periampullary region., Summary Background Data: In the palliation of obstructive jaundice, surgical biliodigestive anastomosis has traditionally been performed. Surgical biliary bypass is associated with high mortality (15% to 30%) and morbidity rates (20% to 60%) but little recurrent obstructive jaundice (0% to 15%). Biliary drainage with endoscopically placed endoprostheses has a lower complication rate, but recurrent obstructive jaundice is seen in up to 20% to 50% of patients., Methods: Patients with advanced cancer of the head of the pancreas or periampullary region treated at the University Hospital Dijkzigt, Rotterdam, The Netherlands, between 1980 and 1990 were reviewed. In 148 patients, data were compared concerning the morbidity and hospital stay after the palliation of obstructive jaundice with endoscopic endoprostheses or surgical biliary bypasses. These patients were stratified for long (> 6 months) and short (< 6 months) survival times., Results: In short-term survivors, the higher late morbidity rates after endoprostheses were offset by higher early morbidity rates and longer hospital stays after the surgical bypass. In long-term survivors, there was no difference in the hospital stay between the two groups, but the late morbidity rate was significantly higher in the endoprosthesis group., Conclusions: These data suggest that endoscopic endoprosthesis is the optimal palliation for patients surviving less than 6 months and surgical biliary bypass for those surviving more than 6 months. This policy necessitates the development of prognostic criteria, which were obtained by Cox proportional-hazards survival analysis. Advanced age, male sex, liver metastases, and large diameters of tumors were unfavorable prognostic factors. With these factors, the risk of short- or long-term survival can be predicted. It is hoped that the application of these data may allow a rational approach toward optimal palliative treatment of this form of malignant obstructive jaundice.

Objective: Current studies concerning selective decontamination of the digestive tract have failed to demonstrate a decrease in the length of hospital stay and mortality rate, despite the finding of a significantly lower number of infections. To evaluate this issue in more detail, the relationship between the mortality rate and length of stay with respect to colonization and infections was studied within a group of patients receiving selective decontamination. Special attention was given to the efficacy of decontamination within each patient. The main question addressed was whether an effect on mortality rate was present, and if so, why this effect was not apparent until now., Design: Prospective observational cohort study., Setting: Surgical intensive care unit (ICU) in a university hospital., Patients: Ninety-seven patients primarily admitted into the surgical ICU who received selective decontamination. Transferred patients were excluded. The majority of the surgeries were elective, and all patients completed the follow-up., Interventions: All patients received polymyxin E, amphotericin B, and norfloxacin four times a day in a 2% solution of Orabase orally and enterally as suspensions of 200, 500, and 50 mg, respectively. Assessment of the efficacy of selective decontamination was done by identification of Gram-negative microorganisms in surveillance cultures from the oropharynx and rectum. Predicted mortality rates for each patient were calculated with a logistic regression formula., Measurements and Main Results: A possible benefit of selective decontamination of the digestive tract would be expressed by lower actual mortality rates compared to predicted mortality rates. Since we expected the efficacy of decontamination to have an influence on infection and mortality rates, we evaluated these rates in terms of successful or unsuccessful decontamination. Most patients (n = 72) were successfully decontaminated. Actual death rates in these patients were significantly lower than the expected rates (as calculated by the Acute Physiology and Chronic Health Evaluation [APACHE] II scoring system) (18% vs. 40%, p = .006), whereas no difference was found in those patients with failed decontamination (n = 25, death rate 44%). The patients with unsuccessful selective decontamination had significantly longer hospital (52 vs. 34 days) and ICU lengths of stays (23 vs. 9 days; p = .002) and higher mortality rates (44% vs. 18%, p = .020) when compared with those patients who were successfully decontaminated., Conclusions: These results indicate that selective decontamination is beneficial in terms of mortality rate and length of stay in surgical patients only when successful decontamination has been achieved. The subgroup of patients for whom decontamination is not successful might be responsible for the obscurity in mortality effects of selective decontamination in studies until now. It is expected that identification and subsequent elimination of possible risk factors that cause a failure of selective decontamination can result in lower morbidity and mortality rates in critically ill, surgical patients admitted to the ICU.

Interventive action aimed at reducing the incidence of an irreversible chronic noncommunicable disease in a population has various effects. Hopefully, it increases total longevity in the population and it causes the disease to develop later in time in a smaller portion of the population. In this paper a statistical model is built by which these effects can be estimated. A three dimensional probability density function that underlies this model is changed by the interventive action. It is shown how a three dimensional utility function can be defined to appropriately judge this change.

The value of the trichogram as a prognostic tool in alopecia areata was investigated in 93 patients with not more than three lesions on the scalp. Evaluation of the clinical features was one year later. In each patient, two regions were investigated: the margin of one of the lesions and the control region. In 80% of the patients with a normal trichogram at the margin of the lesional hair at the first visit, hair growth was restored one year later, whereas in those with an abnormal trichogram, hair growth was restored in 62.5%. In 11.5% of the patients an alopecia totalis or universalis developed. At the margin of the lesion, no significant association was observed between the trichogram and the clinical features. In the control region, however, the prognosis was much better (p < 0.001) in patients with a normal trichogram than in those with an abnormal trichogram. Out of the 62 patients with a normal trichogram, hair growth was restored in 53 (85%), whereas out of the 31 patients with an abnormal trichogram hair growth was restored in only 6 (19%). These findings indicate that a normal trichogram in the control region is a valuable prognostic tool in alopecia areata.

Background: Plasma cells are usually absent in bronchoalveolar lavage (BAL) fluid. Extrinsic allergic alveolitis is associated with increased numbers of T and B lymphocytes in BAL fluid, as well as the presence of a few plasma cells. The aim of this study was to investigate whether there is a relationship between the presence of plasma cells and other cells, and immunoglobulin levels in BAL fluid of patients with extrinsic allergic alveolitis., Methods: Thirty non-smoking patients with extrinsic allergic alveolitis who had a bronchoalveolar lavage 2-7 days after their last exposure to the causative antigen were selected, retrospectively., Results: Patients suffering from extrinsic allergic alveolitis with plasma cells in the BAL fluid (n = 18) had increased absolute numbers of lymphocytes, eosinophils and mast cells, a decreased percentage of alveolar macrophages and lower CD4/CD8 ratio, as well as higher immunoglobulin levels, when compared with patients with extrinsic allergic alveolitis having no plasma cells in the BAL fluid (n = 12)., Conclusions: The results suggest a relationship between the presence of plasma cells and the other constituents in BAL fluid and a more intense alveolitis. In addition there was a positive relationship between the number of plasma cells in BAL fluid and immunoglobulin levels. These data support the concept of local production of immunoglobulins by plasma cells in the lung following antigen exposure in susceptible individuals.

To assess the influence of treatment on the development of the somesthetic pathway in infants with congenital hypothyroidism receiving early treatment, median nerve somatosensory evoked potentials were measured during the 1st y of life. Twenty-nine infants were studied with six to seven somatosensory evoked potential tests per infant. The cervical latency (N13) divided by arm length and the first (N19) and second (N32) cephalic latencies as well as N13-N32 latency were measured. At diagnosis, all components showed a small but significant delay, which was not related to thyroxine (T4) levels before treatment. During treatment, T4 ranged from 50 to 290 nmol/L. At 12 mo, the cervical latency divided by arm length had normalized, whereas N19 and N13-N32 were more abnormal than at diagnosis. For N19, these abnormalities were related to a slow initial rise of T4 (< or = 100 nmol/L after 1 wk of treatment) and the initial N19 values. Abnormal N13-N32 values were associated with high T4 values during treatment (> 200 nmol/L) and the type of congenital hypothyroidism (partial or total deficiency in T4 production). Induction of therapy with l-triiodothyronine rather than l-thyroxine and the occurrence of low T4 values (< 100 nmol/L) after the 4th wk of therapy had no such effect. Our data suggest that, for normal CNS development, euthyroidism should be reached as soon as possible by adequate induction therapy. Thereafter, T4 supplementation should be strictly dosed, keeping the serum T4 values within narrow limits around the mean normal for age, because overtreatment, like initial undertreatment, may lead to CNS abnormalities at the end of the first year.

Hemodynamic parameters of the chick embryo from stage 20 (3 d of a 21-d incubation) up to stage 35 (8 d) are described. Normal values of dorsal aortic flow velocity wave forms were measured with a 20-MHz directional-pulsed Doppler velocity meter that was validated to be accurate above 5 mm/s. An analysis of variance was carried out for each of the flow velocity parameters. The correlation coefficient that represents the reproducibility was satisfactory (r > 0.90). There was a 17-fold rise in mean dorsal aortic blood flow (mm3/s). Heart rate doubled from 123 +/- 12 to 239 +/- 8 bpm, and stroke volume increased from 0.14 +/- 0.08 to 1.28 +/- 0.55 mm3. A stage-related rise was seen in peak systolic and mean velocities and peak acceleration. These data may serve as a basis for flow velocity wave form investigation and interpretation in developmental stages of cardiac malformations.

The aim of this study was to investigate the possibility of distinguishing between patients with similarities in clinical presentation, suffering from three frequently occurring interstitial lung diseases, by means of discriminant analysis, using a number of selected variables derived from bronchoalveolar lavage fluid (BALF) analysis. The study involved all 277 patients, who had an initial bronchoalveolar lavage (BAL) in the period 1980-1990. These patients belonged to the following diagnostic groups: sarcoidosis (n = 193), subacute extrinsic allergic alveolitis (EAA) (n = 39) and idiopathic pulmonary fibrosis (IPF) (n = 45). Thirty healthy volunteers were used as controls. Cellular and non-cellular constituents of BALF were evaluated. Variables, which could be used to discriminate among the three diagnostic groups were: yield of recovered BALF, total cell count, and percentages of alveolar macrophages, lymphocytes, polymorphonuclear neutrophils, eosinophils and plasma cells in BALF. When the set of data used to predict the membership of patients to diagnostic groups (test set) was the same as that in which the discriminant analysis was performed (learning set), 93% of the cases were correctly classified. This percentage decreased to 90%, however, when the test set was different from the learning set. It is possible to discriminate among patients with sarcoidosis, EAA or IPF with these selected variables. It appears that bronchoalveolar lavage (BAL) is useful as an adjunct in concert with other diagnostic methods.

In a randomized, double-blind, cross-over, multicenter study with a placebo run-in phase, the efficacy and safety of two oral formulations of diltiazem, standard three or four times daily (t.i.d. or q.i.d.) and controlled release twice daily (b.i.d.), were compared in 49 patients with stable angina pectoris. ST-segment depression at maximum exercise 12 h after tablet intake was less frequently observed with diltiazem controlled release than with standard diltiazem (34 of 49, 69% vs. 43 of 49, 88%, p = 0.007). In patients with ST-segment depression after both treatments (n = 33), the average time to 1-mm ST-segment depression was 55.4 +/- 19.9 s longer with diltiazem controlled release than with standard diltiazem [476 +/- 195 vs. 422 +/- 163 s, p = 0.009; 95% confidence interval (CI) 14.8-96 s]. Reduction in mean number of anginal attacks and nitroglycerin (NTG) intake was not significantly different between treatment with standard diltiazem and diltiazem controlled release. The incidence of side effects was low and not different between the two treatments. Both formulations are equally effective in reducing the number of anginal attacks and are well tolerated. Diltiazem controlled release is more effective than standard diltiazem in preventing myocardial ischemia 12 h after tablet intake. Thus, diltiazem controlled release allows twice-daily intake frequency and may therefore be preferable to standard diltiazem in treatment of stable angina pectoris.

Based on data from the Dutch Central Bureau of Statistics, the impact of influenza on mortality in The Netherlands was estimated for a 22.5-year period (1967-1989) in four age groups and three entities of disease, using Poisson regression techniques. Our analysis suggests that, on average, more than 2000 people died from influenza in The Netherlands each year, but in only a fraction of these deaths was influenza recognized as the cause of death. For each case of death registered as caused by influenza (registered influenza mortality), 2.6 additional cases of death registered as due to causes other than influenza, nevertheless, were influenza-related (non-registered influenza mortality). Therefore, the overall impact of influenza on mortality is estimated to be greater than registered influenza mortality by a factor of 3.6. Those under 60 years of age accounted for 5% of all non-registered influenza deaths, whereas people aged 60-69, 70-79 years and > 80 years accounted for 12%, 29% and 54% of such deaths, respectively. When extrapolating the figures for the Dutch population of 1989, we could attribute, on average per season-year, 82 deaths per 100,000 people > 60 years, 143 in people > 70 years, and 280 in people > 80 years. Of all non-registered influenza cases of death, 47% were estimated to occur in people with heart disease as a primarily reported cause of death, 23% in those with lung disease, and 30% in those with other diseases. This study stresses the serious effects of influenza, mainly in the elderly (95% of non-registered influenza mortality).(ABSTRACT TRUNCATED AT 250 WORDS)

Data from 23 twin pregnancies with one structurally affected fetus were compared with data from 23 twin pregnancies with proven absence of structural fetal anomalies and matched for maternal age, parity, and year of delivery. The preterm delivery rate (< 37 weeks) was high in both groups but not significantly different (57 vs. 48 per cent). Perinatal mortality was significantly higher in the structurally affected twin pregnancies (65 vs. 9 per cent). In the affected twins, birth weight of the anomalous fetus was significantly lower than that of the normal co-twin. Since there was no difference in the incidence of maternal disease (hypertensive disorders, diabetes), it was concluded that the higher perinatal mortality was determined mainly by the nature of the anomaly and not by the preterm delivery rate.

In 78 patients with primary plexogenic arteriopathy (PPA), numbers of organized and recanalized thrombi were established in histologic slides of lung tissue and expressed per square centimeter of section. Three control groups of ten individuals each were used: normal, plexogenic arteriopathy secondary to ventricular septal defect, and hypoxic pulmonary hypertension. Thrombotic lesions were scarce in normal individuals but numerous in all three groups with pulmonary hypertension. There is also a positive correlation with age. Thrombotic lesions are absent or scarce in children but more common in adults, even in normal control subjects and particularly in pulmonary hypertension by whatever cause. In PPA there is likely to be a relation with the duration of illness but not with the stage of the disease. The complete pattern of plexogenic arteriopathy may develop in the absence of thrombotic lesions, which clearly are not essential for its pathogenesis. Rather than being part specifically of PPA, as sometimes suggested, thrombotic lesions complicate various types of hypertensive pulmonary vascular disease. Apparently the combination of sustained pulmonary hypertension and age, possibly through endothelial injury, may elicit thrombosis and its sequelae, which in turn may aggravate the pulmonary arterial pressure.