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This work contributes to the understanding of damage of adhesive layers generated during the manufacturing process and its effect on the subsequent load carrying capacity of the joint. A temperature dependent cohesive zone model is used to predict damage during the manufacturing process. Therefore, parameters for a temperature-dependent as well as a strain rate-dependent model were determined on various specimens. It is shown, that it is possible to predict the manufacturing induced damage within the adhesive layer with sufficient accuracy using a cohesive zone model. Furthermore, a continuous process chain for numerical simulations is developed, which allows to determine the adhesive layer damage by means of a process simulation and to consider the changed mechanical properties in a subsequent crash simulation. To simplify the procedure, a software tool is presented that automatically performs the described steps. The developed method is applied to a car body simulation to investigate the effects caused by the manufacturing process.

Byline: M. Griese, C. Wilnhammer, S. Jansen *, C. Rinker Abstract: Objective: Infants younger than 1 year of age undergoing cardiopulmonary bypass surgery often have severe lung injury necessitating increased postoperative respiratory mechanical support. Inasmuch as the mechanisms may involve an impairment of the pulmonary surfactant system, our aim was to determine whether changes of surfactant occur in such infants. Methods: From the day of the operation to day 7 after the operation, serial tracheobronchial small-volume lavages of 19 infants (aged 166 [+ or -] 29 days) were fractionated into a small and a large surfactant aggregate fraction and compared with those of 13 infants without lung disease (aged 203 [+ or -] 33 days). Results: After cardiac operations with cardiopulmonary bypass surgery, total protein in lavages was increased 3-fold to 4-fold and decreased linearly with time. Surfactant protein A was increased on day 1 and day 2 and then decreased, whereas surfactant protein B and total phospholipids were increased on day 1. The ratio of phospholipids in small and large surfactant fractions was unchanged, but the surface activity of the large-aggregate surfactant was impaired on days 1 to 3. Conclusions: Lung injury in infants after cardiopulmonary bypass surgery involves significant biochemical and functional disturbances of the pulmonary surfactant system. Inasmuch as substitution with natural surfactant might correct these deficiencies, the potential of this approach to reduce postoperative morbidity needs to be investigated. (J Thorac Cardiovasc Surg 1999;118:237-44) Article History: Received 22 September 1998; Revised 4 March 1999; Revised 1 April 1999; Accepted 2 April 1999 Article Note: (footnote) [star] From Kinderklinik and Kinderpoliklinik im Dr von Haunerschen Kinderspital, Ludwig-Maximilians-University, Munich, Germany., [star][star] Address for reprints: Matthias Griese, MD, The Lung Research Group, Kinderklinik and Kinderpoliklinik im Dr von Haunerschen Kinderspital, Ludwig-Maximilians-University, Pettenkoferstr 8a, D-80336 Munich, Germany., a *This article contains parts of the medical thesis of S. Jansen., aa 0022-5223/99 $8.00 + 0 12/1/99098

The number of electric and hybrid vehicles on the roads has increased significantly in recent years. The high weight of these vehicles requires the use of lightweight construction technologies and materials. In this context, adhesively bonded multi-material structures are increasingly being used. However, the combination of different materials with the production processes established in the automotive industry is a challenge to the manufacturers. Especially the drying process after cataphoretic dip coating can lead to adhesive failure. In order to detect and solve these problems as early as possible, a forecast using the finite element simulation is necessary in the early stage of the project. The objective is to show that a temperature-dependent cohesive zone model can be used to predict damage during the drying process. Therefore, the parameters for such a model were identified on different temperature levels using tubular butt joints, tapered double cantilever beams, and tapered end notched flexure specimens. Finally, the material model was validated on heated lap shear specimens. It could be shown that it is generally possible to predict damage within the adhesive layer using a cohesive zone model. Furthermore, it was shown that the way the stiffnesses are determined has a decisive influence on the calculation accuracy under temperature influence.

Adhesive bonding is a commonly used technology for joining dissimilar materials. However, production-related effects on the performance of the bondline have to be considered for an accurate joint design. In case of an adhesive joint in an automotive multi-material body in white, these effects arise from the so-called mismatch in thermal expansion coefficients, which leads to distortions of the adhesive in an uncured state or even damage in the cured one. The distortion of the uncured adhesive in the normal direction is called the ‘viscous fingering effect’, which reduces the adhesively bonded cross section by changing the adhesive bondline's shape to thin ‘fingers’ and therefore influences the materials properties. To investigate the effect of viscous fingering on the modulus, strength and energy release rate, linear butt bonded specimens and Tapered Double Cantilever Beams (TDCB) with different elongations of the adhesive bondline in the viscous state are investigated. The results are used to parameterize a cohesive zone model (CZM) and perform numerical analysis of the TDCB specimen for validation and to build up a model of a dissimilar joint consisting of a steel hatprofile and an adhesively bonded aluminum panel subjected to thermal distortions.

Lightweight body-in-white is often based on a mix of materials that causes problems in the production process. More specifically, the paint oven process after cathodic dip-coating can lead to damaged adhesive layers due to mismatches in thermal expansion of the materials. The understanding of the curing behavior of the structural adhesive cured in this oven process is of crucial interest to determine the damaging in numerical analyses. Therefore, the curing behavior of a one-component toughened hot curing structural adhesive is modeled using three model-based and a model-free approach as well as experimental data from differential scanning calorimetry. After the parameter identification of the models, the parameters are validated using an oven-process-like temperature profile to compare experimental and numerical data.

Surfactant associated protein-A (SP-A) is the most abundant pulmonary surfactant protein and belongs to the family of innate host defense proteins termed collectins. Besides pulmonary host defense, SP-A is also involved in the formation of pulmonary surfactant, as it is essential for the structure of tubular myelin. The human SP-A gene locus includes two functional genes, SFTPA1 and SFTPA2 which are expressed independently, and a pseudo gene. The largest amount of SP-A1 proteins assemble to larger molecular complexes, whereas SP-A2 forms mainly dimers and trimers. SPA polymorphisms play a role in respiratory distress syndrome, allergic bronchopulmonary aspergillosis and idiopathic pulmonary fibrosis. The levels of SP-A are decreased in the lungs of patients with cystic fibrosis, respiratory distress syndrome and further chronic lung diseases. Future areas for clinical research include disease specific SP-A expression pattern and their functional consequences, the differential roles of SP-A1 and SP-A2 in human lung diseases, and therapeutical approaches to correct altered SP-A levels.

In order to identify the optimum particle size and breathing pattern for high peripheral deposition of inhaled drugs in patients with cystic fibrosis, regional deposition in these patients was studied systematically as a function of particle size, inhalation volume and flow rate. Regional deposition was assessed using the single-breath regional deposition technique in which the concentration profile of inhaled and exhaled non-radioactive, monodisperse test particles is analyzed. Using this technique particle deposition within the functional dead space volume and peripherally can be assessed. Regional deposition was measured in 12 patients with cystic fibrosis using 2, 3, 4, and 5.5 µm particles, inhalation volumes of 500, 1000, 1500, and 2000 cm3, and inhalation flow rates of 100, 250, 500, and 750 cm3/sec. Peripheral deposition was highest when 2–3-µm particles were inhaled with air-flow rates of 250–500 cm3/sec. With these parameters peripheral deposition increased with increasing inhalation volume and reached values of about 60% of the total drug inhaled. It has been shown that high peripheral drug deposition can be achieved in patients with CF when inhalations are performed using an optimized combination of particle size and breathing pattern.

The inhalation of α1-protease inhibitor (α1-PI) was assessed in a pilot study to restore the protease-antiprotease balance in the lungs of cystic fibrosis (CF) patients. In addition, the effect of this treatment on the surface active properties of lung surfactant and the metabolic conversion of aggregate forms was studied. Eight young adults with CF inhaled 100 mg of α1-PI twice daily over 8 weeks and bronchoalveolar lavages (BAL) were obtained before and 12 h after the last inhalation. Large aggregate (LA) forms of surfactant were isolated from the in vivo material by ultracentrifugation and their conversion into small aggregates (SA) was assessed by an in vitro surface area cycling assay. Although α1-PI partially restored the protease–anti-protease imbalance and reduced BAL protein content, no effects were noted on the impaired minimal surface tension and on the in vivo and in vitro conversion of LA to SA. Antiserum against the specific carboxyl esterase ES-2, previously identified in mice and rats as the putative surfactant convertase, did not detect a protein of the appropriate size in CF BAL. Whereas short-term inhalation of α1-PI was beneficial for the proteolytic aspects of CF lung injury, this appeared not to be the case for surfactant conversion and surface activity.

ß-adrenoceptor binding in lymphocytes of asthmatic and non-asthmatic children and healthy adult volunteers was investigated with the radioligand 125-iodocyanopindolol (ICYP). Binding studies were performed with 4 to 5 different concentrations of ICYP. Receptor density and affinity were calculated by Scatchard plots. Resolution of ß-adrenoceptors into those of high and low affinity state was obtained from inhibition curves with salbutamol using Hofstee plots. Receptor density in B-cell enriched fractions was two to three-fold higher than in T-cells for all patients and volunteers studied (P less than 0.025). No difference in ß-adrenoceptor density on B and T-cells occurred neither in age-matched asthmatic and non-asthmatic children nor in adult volunteers. The affinity of ß-adrenoceptors did not differ for B and T-cells nor for the patients or volunteers studied. However, when two distinct binding states for ß-adrenoceptor agonists were obtained using salbutamol displacement curves it appeared that ß-adrenoceptors on T-cells were at a higher affinity state compared to those on B-cells in asthmatic and non-asthmatic children, as well as in adults. Since the ability of an agonist to activate adenylate cyclase correlates closely with the amount of high affinity receptor state formed in the presence of the agonist, increased intrinsic activity of the ß-adrenoceptor agonist on T-cells may be postulated. In conclusion, age-related control groups and determination of the B/T ratio are neccessary for interpretation of ß-adrenoceptor changes in bronchial asthma.

The number and affinity of glucocorticoid binding sites in peripheral mononuclear cells (MNC) of asthmatic and healthy children were determined by a whole cell (3H)dexamethasone binding assay at 37°C. Using HPLC determination, corresponding serum levels of non-protein-bound (free) cortisol, whole cortisol and cortisone as well as urine excretion of free cortisone and cortisol were assessed. The average number of binding sites (BS) per cell and the dissociation constant (KD) respectively, in atopic asthmatics (7768±666 BS/MNC resp. KD=17.2±2 nM) did not differ from the values measured in our control group (8333±691 BS/MNC resp. 25.4±4.8 nM). Within the age range 1 month-15.8 years neither age-dependent changes nor sex-related differences in the number of binding sites or the KD values could be detected. Active or currently inactive asthmatics, and patients under different antiasthmatic drug regimes, had similar binding sites on MNC. No differences in serum levels of cortisol, cortisone and free cortisol or in free cortisol and free cortisone of 24-h urine samples were found between healthy children and asthmatics. After a short course of prednisolone therapy for an acute severe asthmatic attack the number of glucocorticoid binding sites in peripheral MNC decreased to an average of 4632±421 BS/MNC, whereas the dissociation constant did not change significantly (14.5±3.6 nM). The corticod-hormone pattern in the serum, 24-h urine excretion, and the normal number and affinity of glucocorticoid receptors on peripheral MNC suggest that there is no primary, general impairment of glucocorticoid metabolism in asthmatic children. Short-term glucocorticoid administration resulted in suppression of endogenous corticoids to undetectable levels accompanied by down-regulation of glucocorticoid-receptor BS to about 55% of control levels.

The influence of childhood pertussis infection and of purified pertussis toxin on histamine relase from human basophil leucocytes was investigated. Three different stimuli, the peptide N-formyl-Met-Phe (NFMP), anti-IgE, and the calciuminnophore A23187 were used to challenge the cells. When NFMP was the stimulus, histamine release in the control group (age 0.5–17 years) increased in an age-dependent fashion, whereas anti-IgE and A23187 stimulated release did not vary with age. During the convulsive state of pertussis infection there was a significant reduction of histamine release in response to 10 μM NFMP (from 9.5±1.4 [n=21] to 6.7±1.5 [n=19],P<0.05) and in response to 800 and 80 U/ml anti-IgE (from 28.5±5 [n=19] to 16.3±5 [n=13],P<0.05, and from 6.9±1.7 [n=16] to 2±0.8 [n=13],P<0.01), whereas histamine release stimulated by A23187 was unchanged compared to release in control children. In vitro pretreatment of basophils from healthy children and adults with pertussis toxin also inhibited histamine release. When NFMP was the stimulus, release was completely blocked by pertussis toxin with an IC50 of about 11 ng/ml whereas anti-IgE stimulated release was only inhibited by 20%–30% and release induced by A23187 was reduced to 40%–50% by toxin treatment. In conclusion we have demonstrated a functional impairment of histamine release during the convulsive state of pertussis and that this inhibition is likely to be mediated by pertussis toxin.

AbstractThe uptake of both lung surfactant and other particles from the alveolar space plays an essential role in surfactant metabolism, host defense and may be of relevance for targeting drugs into alveolar cells. To better understand the effect of particle size on the uptake by type II pneumocytes, rat type II cells in primary culture were investigated. We observed that inert latex particles of 15 nm were taken up to a much greater extent than bigger particles. No strong size dependency was observed in the range from about 200 to 1000 nm. A similar observation was made with a natural lipid extracted lung surfactant which was taken up to a greater extent when prepared at particles of about 100 nm than a preparation with a particle size range from about 200-2000 nm. Alveolar type II cells take up smaller particles better than larger ones, but the size selectivity is rather limited. These type II cell properties may contribute to a preferential elimination of the smaller particle fractions from the alveolar space.

Fatty acid (FA) composition of plasma phospholipids and phospholipids extracted from peripheral mononuclear white blood cells (MNC) was investigated in 11 allergic asthmatic children (age 8.9±4.6 years), in 10 age-matched non-allergic healthy controls and in 14 allergic and non-allergic children with an acute attack of asthma, who had received prednisolone medication for 2–4 days. In allergic asthmatics eicosapentaenoic acid (20∶5n−3) was significantly elevated in both plasma and MNC. The relative amount of 20∶5n−3 in MNC as well as in plasma correlated positively with increasing levels of total serum IgE (P<0.02). The pattern of the other FAs in plasma and of MNC phospholipids did not differ between allergic asthmatic and non-allergic control children. In children with an acute attack of asthma, who had been treated with glucocorticoids (2 mg prednisolone/kg body weight for 2–4 days), distinct changes of relative FA composition of phospholipids were restricted to plasma, where some very long chain FA (22∶4n−6, 22∶5n−6) were elevated. No significant changes in FA from MNC phospholipids could be observed after glucocorticoid treatment. These findings may indicate a possible role of 20∶5n−3, the precursor of “group 3” eicosanoids, in allergic asthmatic children.

The fatty acid (FA) status in young children with cystic fibrosis (CF) was investigated. The FA composition of the plasma cholesterol esters (CE) and phospholipids (PL) and of the erythrocyte phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was estimated in 11 patients with CF and pancreatic insufficiency (median age, 3.0 years; range, 3 months to 7 years) and in 10 age-matched controls. Linoleic acid values ranged widely but were not significantly reduced in the patients. However, arachidonic acid (20:4w6) and docosahexaenoic acid were decreased in all lipid classes. The ratio of dihomo-γ-linoleic acid to arachidonic acid (20: 3w6/20: 4w6) was significantly increased in the patients, indicating an impairment of FA metabolism (A5-desaturation). Plasma retinol concentrations were normal and did not differ between the supplemented patients and controls. Plasma total tocopherols and α-tocopherol and their ratios to total lipids were significantly reduced in the CF patients, but all values were within the normal ranges for the pediatric age group, and no child met the criterion for vitamin E deficiency.

Cystic fibrosis (CF) is caused by mutation in the gene for the CF transmembrane conductance regulator which leads to massive, abnormally viscous, purulent sputum, chronic destructive endobronchitis and early death. Purified recombinant human (rh) DNase can digest extracellular DNA and its inhalation in these patients significantly improves lung function. To evaluate the poorly understood mechanisms, saliva protected sputum from patients treated with and without rhDNase were evaluated. Therapy with rhDNase resulted in a soluble sputum fraction that had a higher percentage of phosphatidylethanolamine, a phospholipid present mainly in cellular membranes, a much lower percentage of phosphatidylcholine, but a higher surface activity. The rigidity was significantly lower and the ratio of viscosity in proportion to elasticity increased. All these data are consistent with an increased clearability of the sputum by coughing, but not by mucociliary activity. Thus the interaction of inhaled rhDNase with the purulent mucus and the endobronchial inflammatory processes may induce changes that result in rheological properties favoring clearance of sputum by cough.

Summary Several in vivo and in vitro studies have suggested that children suffering from cystic fibrosis (CF) might have a general defect of beta-adrenoceptors on the cell surface which might account for an unbalanced secretory process. In order to investigate if this view holds true, we determined the beta-adrenoceptor density and affinity on lymphocytes by means of radioligand studies using 125-iodo-cyano-pindolol (125-ICYP) in 20 children with CF. Cyclic AMP (cAMP) response was also investigated after specific beta-adrenoceptor stimulation with isoprenaline (IPN) and after direct stimulation of the adenylate cyclase with forskolin in lymphocytes. Children with CF and controls have identical numbers and affinities of beta-adrenoceptors on lymphocytes. The cyclic AMP response was identical in CF- and in age-matched control children regardless whether adenylate cyclase was stimulated directly or via beta-adrenoceptors. In conclusion, the data support the view that no general adrenoceptor or adenylate cyclase defect exists in CF. As several studies have found abnormal reactions to adrenergic stimuli in CF patients, we presume that there is a defect beyond the level of adrenergic receptors and cAMP which remains to be identified.

Adhesive bonding of materials with different thermal expansion coefficients is a major challenge for the manufacturers. Especially the drying process after cathodic dip coating can lead to damage, residual stresses or failure in the adhesive layer. Loads caused by the production process influence the loading capacity of bonded joints in later use and therefore must already be taken into account during the design process. This paper investigates the loading conditions induced by the manufacturing process. Furthermore, the capacity of adhesive joints loaded by such manufacturing loads will be examined on a new designed specimen type. Therefore, experiments and simulations on bimetallic hat profiles are carried out to determine if the loading conditions between simulations and experiments can be matched by using a temperature-dependent cohesive zone model.

There is indirect evidence from clinical studies in human as well as in animal studies that infection and vaccination with B. pertussis might affect the β-adrenoceptor/cyclic AMP system. In order to study whether this view warks, the adrenergic system was investigated on lymphocytes in children within the paroxysmal stage of P, in children after vaccination (V.) with P-mono-vaccine, and in an age-matched control group.Methods: β-adrenoceptor (β-R) density was estimated by means of binding studies using 125-J-cyanopindolol. In children with P β-E number of lymphocytes was 2-3 fold lower compared to controls and after V. High and low affinity states of the β-R, indicating the intrinsic activity, were obtained by Hofstee-plot-transformation of salbutanol displacement curves. Basal levels, as well as maximum cAMP accumulation after specific (isoprenaline = IPN) and unspecific (forskoline = FO) β-R stimulation, were determined using a protein binding assay.Results: In children with P β-R number of lymphocytes was 2 to 3fold lower compared to controls. In addition, an increased number of low affinity state β-R indicated impaired function. Decreased cAMP levels in both, the vaccination children and those suffering from P were observed. However, the latter showed distinct reduction of IPN induced maximal cAMP accumulation.It is concluded that P-infection, as well as V., strongly affects the adrenergic system.

Therapeutic use of β-adrenoceptor (β-AR) agonists in infants is often ineffective. Since β-AR on lymphocytes (Ly) are low in infants, it has been suggested that this might be due to a relative deficiency of β-AR. However, low numbers of β-AR on different Ly subpopulations might mimic a β-AR defect in infants. Therefore we studied β-AR binding on B- and T-Ly enriched fractions (separated by E-rossettuig, railed B- and T-Ly) in infants (aged 4 to 18 months) and children (aged 7 to 15 years) using 125 iodocyanopin-dolol (ICYP). Receptor (R) density and affinity were calculated by Scatchard plots. Resolution of β-AR into those with high and low affinity state was obtained from inhibition curves with salbutairol using the Hofstee plot. β-AR density on B-cells of infants was nearly the same as on T-cells, whereas in children it was 2 to 3 fold higher on B- than on T-cells. Affinity of the β-AR to the antagonist ICYP was much lower on T-cells than on B-cells of infants, whereas no difference was observed among the children. However, using salbutamol displacement curves it appeared that β-AR on T-cells were at a higher affinity state compared to those on B-cells. No differences were observed between infants and children.In conclusion, β-AR deficiency postulated in infants may be a result of low β-AR density on B-cells, indicating a maturation process on B-cells during the first year of life.