[The Role of Bronchoalveolar Lavage in the Diagnosis of Idiopathic Pulmonary Fibrosis: An Investigation of the Relevance of the Protein Content]. / Der Stellenwert der bronchoalveolären Lavage bei der Diagnostik der idiopathischen Lungenfibrose - eine Analyse unter Berücksichtigung des Proteingehaltes.

Although bronchoalveolar lavage (BAL) is often used in the diagnosis of interstitial lung diseases (ILDs), its importance in investigating, in particular, idiopathic pulmonary fibrosis (IPF) is controversial. The cell distributions in the BAL are taken into account in the clinical routine, non-cellular characteristics of the BAL play no role.Using mathematical modeling of data, the present work investigated the extent to which BAL features enable drawing conclusions about the underlying ILK or help exclude IPF. Included in the calculation are cellular findings of the BAL, in addition the protein and albumin content of the BAL, the nicotine history (pack years), and spirometry (FEV1, IVC).Using linear discriminant analysis and creating classification trees, the relevance of the characteristics of 806 patients with ILK was examined (183 IPF, 191 cryptogenic organizing pneumonia, 147 lung involvement in autoimmune disease, 97 respiratory bronchiolitis interstitial lung disease, 118 extrinsic allergic alveolitis, 41 lymphocytic interstitial pneumonia (LIP), 23 non-specific interstitial pneumonia (NSIP), 88 controls).There was a close positive relationship between protein levels and lymphocytes in the group as a whole. No such correlations were seen in IPF and NSIP. Albumin was closely correlated with the protein content in all groups.The lymphocytes are best suited to distinguish between different ILDs. Yet, a reliable calculation of the ILD is not possible on the basis of the investigated factors, the classification error ranged from 23.5 % (IPF) to 100 % (LIP, NSIP).Constellations that likely (> 99 %) speak against an IPF are lymphocytosis > 34 % or protein content > 347 mg/l. The same applies to the constellation: lymphocytes > 25 % together with protein > 250 mg/l.In ILD, BAL findings can narrow the diagnosis, but they are seldom diagnostic. BAL can make an important contribution to excluding of IPF.

Occurrence of Anguillicola crassus (Nematoda: Dracunculoidea) in Japanese eels Anguilla japonica from a river and an aquaculture unit in SW Taiwan.

The infection by swimbladder nematodes of the genus Anguillicola (Dracunculoidea: Anguillicolidae) was examined in 2 populations of the Japanese eel Anguilla japonica in SW Taiwan. Wild eels from the Kao-Ping river were compared with cultured eels from an adjacent aquaculture unit. Only the cosmopolitan species Anguillicola crassus was present. Among wild eels, prevalence of infection varied between 21 and 62%, and mean intensity between 1.7 and 2.7 for adult worms. Similar intensity values (1.3 to 2.8) were recorded for the larvae. In cultured eels, prevalence as well as mean intensities were higher. In the cultured hosts, mean larval intensities exceeded those of adult worms 2-fold, and maximum larval intensities were 4- to 5-fold higher than in eels from the river. In cultured eels, dead larvae were also more abundant than in wild eels. We conclude that infrapopulations of A. crassus in Japanese eels are regulated by the defense system of this host, intraspecific density-dependent regulation being less likely as the major regulatory mechanism. No influence of the parasite on eel condition was found in either wild or cultured eels, indicating a low or moderate pathogenic effect of A. crassus on this host. This study shows that A. crassus is moderately common in cultured and wild Japanese eels in Taiwan, where the parasite is endemic.

[Pulmonary sarcoidosis -- clinical and bronchoscopic findings in relation to the radiographic stage]. / Sarkoidose der Lunge -- klinische und bronchoskopische Befunde in Abhängigkeit vom radiologischen Stadium.

UNLABELLED: The classification of pulmonary involvement in sarcoidosis is based upon the radiographic stage of disease. We investigated 170 patients with new detected sarcoidosis (stage I / II / III: 79 / 39 / 52) for differences between the stages in demographic data, lung function values and results of BAL. With a multinomial logistic regression model to estimate probabilities, we found an increased probability for stage I with lower age (p < 0.001), higher IVC and FEV1 (p < 0.001), a less intensive smoking history (p<0.035), in BAL with a lower count of eosinophils (p < 0.014), mast cells (p < 0.004), CD8 lymphocytes (p < 0.015) and a less content of alkaline phosphatase (p < 0.004). For stage III the opposite results apply. With higher cell counts in BAL the probability of stage II increased, of stage III decreased (p < 0.013). The most relevant diagnostic BAL parameter in sarcoidosis, i.e. the count of lymphocytes and CD4 cells, was not different between the radiographic stages. CONCLUSION: Between patients with different radiographic stages of sarcoidosis there are differences in demographic data, lung function values and the pattern of alveolitis.

A nonlinear model of stress hormone levels in rats-the interaction between pollution and parasites.

The impact of an infection with a parasite and a simultaneous cadmium exposure on the stress hormone levels of rats was studied. To this end, we introduce a nonlinear heteroscedastic model, which is able to describe the temporal evolution of cortisol concentrations in groups of rats treated by cadmium or parasite infection. A thorough analysis gives strong evidence that parasitic infection and cadmium exposure affect the stress hormone level of rats in an additive manner. Therefore, the host's response to environmental pollution should be studied in relation to parasite infections.

[Mast cells in bronchoalveolar lavage fluid of patients with interstitial lung diseases]. / Die Mastzelle in der bronchoalveolären Lavage bei interstitiellen Lungenerkrankungen.

Mast cells play an important role in tissue inflammation, fibrosis and remodelling. They are found in bronchoalveolar lavage fluid (BAL) of healthy persons only in small numbers. We investigated the number of mast cells in interstitial lung diseases and analysed our data for correlations with clinical parameters, cellular and non-cellular parameters of BAL. We found following counts of mast cells in % of total BAL cells: Sarcoidosis (n = 123); 0.22 +/- 0,04 %, idiopathic pulmonary fibrosis (IPF) (n = 35); 0.39 +/- 0.47 %, cryptogenic organising pneumonia (COP) (n = 27); 2.05 +/- 2.19 %, hypersensitivity pneumonitis (HP) (n = 24); 1.02 +/- 1.05 %, rheumatoid lung (n = 20); 0.21 +/- 0.21 %, respiratory bronchiolitis-associated interstitial lung disease (RBILD) (n = 11); 0.16 +/- 0.29 %) and control group (n = 16); 0.06 +/- 0.16 %. Compared to controls mast cells were increased in COP (p < 0.001) and HP (p < 0,01). Correlation analysis showed that an increased mast cell count correlated with: Higher age (sarcoidosis (p = 0.03); smaller vital capacity (sarcoidosis (p = 0.01)), smaller FEV 1 (sarcoidosis (p = 0.04), RBILD (p = 0.04)); higher alkaline phosphatase in BAL (sarcoidosis (p = 0.004), HP (p = 0.02), COP (p = 0.04); higher albumin level in BAL (sarcoidosis (p = 0.000), IPF (p = 0.003); higher cell counts in BAL (sarcoidosis (p = 0.013), COP (p = 0.04)); lower portion of macrophages in BAL cells (sarcoidosis (p = 0.001), HP (p = 0.02), COP (p = 0.02)); higher portion of lymphocytes in BAL cells (sarcoidosis (p = 0.03)); higher portion of neutrophils in BAL cells (sarcoidosis (p = 0.007)); higher portion of eosinophils in BAL cells (sarcoidosis (p = 0.001), HP (p = 0.006)). Correlations to smoking history in pack years and to lymphocyte surface markers CD3, CD4, CD8 were not found. In conclusion comparing different interstitial lung diseases we found significantly increased mast cell counts in COP and HP. Moreover there were correlations of increased mast cell counts with more intensive alveolitis and exudation.

Interaction between cadmium exposure and infection with the intestinal parasite Moniliformis moniliformis (Acanthocephala) on the stress hormone levels in rats.

The impact of an infection with the acanthocephalan Moniliformis moniliformis and a simultaneous Cd-exposure on the stress hormone levels of rats was studied. Immediately after the application of cadmium to some rats, cortisol levels in all groups of rats, as quantified by radioimmunoassay (RIA), significantly increased. However, infections with M. moniliformis as well as the uptake of Cd reduced significantly the cortisol release compared to untreated controls. While catecholamine concentrations, as determined by high-performance liquid chromatography (HPLC), showed no clear tendency during the experimental period, the ratio of C(adrenaline)/C(noradrenaline) in the controls showed the significantly lowest value of all four groups after killing the animals. Thus, the acanthocephalan infection as well as the Cd-exposure and the combination of both treatments affect hormone homeostasis in the rats which probably lead to negative effects on the health of the rat. Therefore parasite infections must be carefully considered in environmental impact studies, as an important factor affecting the host's health.

[Airway challenge testing - accuracy of the interrupter technique]. / Die Bestimmung der bronchialen Sensitivität - ist die Widerstandsmessung mittels Unterbrechermethode ein zuverlässiges Verfahren?

According to national and international recommendations the bronchial sensitivity should be determined based on the decrease of the FEV1 by 20 % (FEV1 - 20) or the increase of the airway resistance by means of body plethysmography by 100 % (Raw + 100). Measurement of airway resistance by interrupter technique (Rint) is a simple method and needs no active cooperation of the patient, but is not recommended in airway challenge testing. We investigated the role of the increase of Rint by 100 % (Rint + 100) compared to Raw + 100 and FEV1 - 20 during carbachol airway challenge testing by means of dosimetry. We examined 123 patients with following symptoms: 85 x coughing, 31 x coughing and dyspnea, 7 x medical opinion. Significant correlations between Rint and Raw were found before and after the challenge tests (Rint before/after 0,3 +/- 0,13/0,36 +/- 0,25 kPa*s/l; Raw before/after 0,24 +/- 0,09/0,50 +/- 0,41 kPa*s/l; r = 0,504/0,672; p < 0,001 [Pearson]). The median values of Rint and Raw were significantly different (p < 0,001 [Wilcoxon]). Moreover Rint systematically overestimated airway resistance in the normal range and underestimated the increase of airway resistance during challenge testing (r = 0,783; p < 0,001 [Pearson]). In 58 patients an increased airway responsiveness was found. In 21 oft these patients there was no increase of Rint above the initial value. Sensitivity/specificity/positive predictive value/negative predictive value in % to the detection of airway hyperresponsiveness were in Rint + 100 9/95/63/54, in FEV1 - 20 61/100/100/66 and in Raw + 100 98/100/100/98. In conclusion we found significant correlations between Rint and Raw, but the median values were systematically and significantly different. Rint + 100 had a low sensitivity to detect airway hyperresponsiveness and is not comparable with FEV1 - 20 or Raw + 100.

[Concentration of alkaline phosphatase (AP) and AP/albumin ratio in bronchoalveolar lavage (BAL) for the diagnosis of interstitial lung diseases]. / Wert der Bestimmung der alkalischen Phosphatase (AP) und des AP/Albumin-Quotienten in der bronchoalveolären Lavage (BAL) für die Diagnostik interstitieller Lungenkrankheiten.

As a result of several studies with different animal models there is evidence that the concentration of AP in BAL is produced in the pneumocyte II and that an increase of AP in the BAL is a marker of tissue damage. By measuring AP in the BAL of patients with interstitial lung diseases we investigated its potential role as a diagnostic tool. To detect plasma leakage we also measured the concentration of albumin in the BAL. We studied 85 patients with following diagnoses: Sarcoidosis in 34 patients (Stage 1/2/3 14/7/13), idiopathic pulmonary fibrosis (IPF) in 14, bronchiolitis obliterans with organizing pneumonia (BOOP) in 7, hypersensitivity pneumonitis (HP) in 6. The control group consisted in 24 patients (13 nonsmokers, 11 smokers). In IPF and BOOP we observed significantly higher concentrations of AP than in controls and sarcoidosis (42.4 +/- 36.6 and 35.6 +/- 16 vs. 15.8 +/- 12.7 and 15.0 +/- 9.8 U/l, p < 0.05, ANOVA). Compared with controls in sarcoidosis higher concentrations of albumin (5.7 +/- 4 vs. 13.2 +/- 10 mg/dl, p < 0.05, ANOVA) and a lower AP/albumin-ratio (3.6 +/- 3.0 vs. 1.3 +/- 0.9 U/10 mg, p < 0.05, ANOVA) were seen. This result is an argument against plasma leakage as the source of AP in BAL. There were no differences in AP and albumin between the different stages of sarcoidosis and between smokers and nonsmokers in the control group. We conclude, that there are different concentrations of AP and albumin in BAL in different interstitial lung diseases. Compared with controls we observed higher concentrations of AP and an AP/albumin-ratio in the normal range in IPF, a normal concentration of AP and a lowered AP/albumin-ratio in sarcoidosis.

Hydrolytic stability versus ring size in lactams: implications for the development of lactam antibiotics and other serine protease inhibitors.

beta-Lactam antibiotics act by acylating a serine hydroxyl group in the catalytic center of bacterial proteases. This requires, among other things, suitable reactivity of the lactam moiety. To evaluate the possible suitability of other lactam systems, kinetic studies were performed using the model reaction of lactams with hydroxide. Following the pace of the reaction by NMR, we found gamma-butyrolactam to be hydrolyzed considerably slower than beta-propiolactam. Surprisingly, delta-valerolactam and beta-propiolactam had the same reactivity. beta-Lactam antibiotics were more reactive than both by approximately a factor of 10(3). Medium-sized lactams were least susceptible to hydrolysis. The study highlights the as yet overlooked six-membered lactam ring as a promising vantage point for the development of new classes of antiinfectives and other serine protease inhibitors.

CME and the role of the Journal of the Royal College of Physicians of London. Results of a survey of consultant and trainee physicians.

AIM: To assess (a) the views of Members and Fellows of the College on the role of reading general medical journals in continuing medical education (CME); (b) the place of the Journal of the Royal College of Physicians of London (JRCPL) in relation to seven other general medical journals; (c) the possible need for change in the content of the JRCPL and the demand for a systematic series of articles designed specifically for CME; (d) the extent of home ownership and use of computers and of readers' readiness for interactive teaching and electronic books and journals. METHOD: Distribution of a questionnaire to all Fellows and Collegiate members of the College, mailed with the JRCPL in May 1995. RESULT: Responses were received from 2,600 (26.4% home recipients and 8.4% overseas recipients). Journal reading was rated the most important form of CME. All eight journals listed play a part in CME, the three weekly journals playing the most prominent role. There was strong support for the introduction of a series of articles covering topics systematically as part of CME. Seventy-six per cent of respondents own a home computer and 40% of these have either a CD-ROM drive or full multimedia facilities. Most use their computers mainly as word-processors and few have access to the Internet or E-mail.

[Bisphosphonate therapy of Paget's disease of bone with pamidronate]. / Bisphosphonattherapie des Morbus Paget des Knochens mit Pamidronat.

BACKGROUND: Paget's disease of bone is a disease with massive focal increase of bone turnover. Bisphosphonates like etidronate inhibit of osteoclastic bone resorption and are therefore established in the treatment of Paget's disease. The aminobisphosphonate pamidronate is 100 times more potent than etidronate. To assess the therapeutic potential for Paget's disease, we have investigated the long-term efficacy of two different dosages of pamidronate. PATIENTS AND METHODS: 40 consecutive patients with Paget's disease received a total dose of either 180 mg (n = 21) or 100 mg (n = 19) of pamidronate i.v. over 9 or 5 days respectively in two independent phases of a prospective trial. Efficacy and side effects were monitored for a follow up period of up to two years. RESULTS: For both dosages a significant reduction of urinary 24-h-hydroxyprolin excretion and serum alkaline phosphatase (AP) levels as parameters of disease activity was recorded. AP levels fell to a minimum of 31 +/- 3% (180 mg) and 41 +/- 5% (100 mg) of pretreatment values, respectively. Two years after treatment, a significant reduction of disease activity could still be detected. Side effects, including transient fever, head ache or bone pain occurred in one third of the patients. CONCLUSION: Pamidronate treatment for Paget's disease of bone leads to a sustained inhibition of elevated bone turnover.

Evidence for agonist-induced export of intracellular Ca2+ in epithelial cells.

There is increasing evidence that some agonists not only induce intracellular Ca2+ increases, due to store release and transmembranous influx, but also that they stimulate Ca2+ efflux. We have investigated the agonist-stimulated response on the intracellular Ca2+ activity ([Ca2+]i) in the presence of thapsigargin (10(-8) mol/l, TG) in HT29 and CFPAC-1 cells. For CFPAC-1 the agonists ATP (10(-7)-10(-3) mol/l, n = 9), carbachol (10(-6)-10(-3) mol/l, n = 5) and neurotensin (10(-10)-10(-7) mol/l, n = 6) all induced a concentration-dependent decrease in [Ca2+]i in the presence of TG. Similar results were obtained with HT29 cells. This decrease of [Ca2+]i could be caused by a reduced Ca2+ influx, either due to a reduced driving force for Ca2+ in the presence of depolarizing agonists or due to agonist-regulated decrease in Ca2+ permeability. Using the fura-2 Mn2+ quenching technique we demonstrated that ATP did not slow the TG-induced Mn2+ quench. This indicates that the agonist-induced [Ca2+]i decrease in the presence of TG was not due to a reduced influx of Ca2+ into the cell, but rather due to stimulation of Ca2+ export. We used the cell attached nystatin patch clamp technique in CFPAC-1 cells to examine whether, in the presence of TG, the above agonists still led to the previously described electrical changes. The cells had a mean membrane voltage of -49 +/- 3.6 mV (n = 9). Within the first 3 min ATP was still able to induce a depolarization which could be attributed to an increase in Cl- conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of extracellular ATP on contraction, cytosolic calcium activity, membrane voltage and ion currents of rat mesangial cells in primary culture.

1. The effects of extracellular ATP on contraction, membrane voltage (Vm), ion currents and intracellular calcium activity [Ca2+]i were studied in rat mesangial cells (MC) in primary culture. 2. Addition of extracellular ATP (10(-5) and 10(-4) M) to MC led to a cell contraction which was independent of extracellular calcium. 3. Membrane voltage (Vm) and ion currents were measured with the nystatin patch clamp technique. ATP induced a concentration-dependent transient depolarization of Vm (ED50: 2 x 10(-6) M). During the transient depolarization ion currents were monitored simultaneously and showed an increase of the inward- and outward current. 4. In a buffer with a reduced extracellular chloride concentration (from 145 to 30 mM) ATP induced a depolarization augmented to -4 +/- 4 mV. 5. ATP-gamma-S and 2-methylthio-ATP depolarized Vm to the same extent as ATP, whereas alpha,beta-methylene-ATP (all 10(-5) M) had no effect on Vm. 6. The Ca2+ ionophore, A23187, depolarized Vm transiently from -51 +/- 2 to -28 +/- 4 mV and caused an increase of the inward current. 7. The intracellular calcium activity [Ca2+]i was measured with the fura-2 technique. ATP stimulated a concentration-dependent increase of [Ca2+]i (ED50: 5 x 10(-6) M). The increase of [Ca2+]i was biphasic with an initial peak followed by a sustained plateau. 8. The [Ca2+]i peak was still present in an extracellular Ca(2+)-free buffer, whereas the plateau was abolished. Verapamil (10(-4) M) did not inhibit the [Ca2+]i increase induced by ATP. 9. The data indicate that extracellular ATP contracts MC and is able to increase [Ca2+]i by the release of Ca2+ from intracellular stores and recruitment from the extracellular space. In addition ATP depolarizes Vm of MC by activating a Cl- conductance. The ATP-induced depolarization is mediated by a P2y receptor.

Neutron diffraction of alpha, beta and gamma cyclodextrins: hydrogen bonding patterns.

Cyclodextrins (CD's) have proved useful as model systems for the study of hydrogen bonding. They are torus-shaped molecules composed of six(alpha), seven(beta) or eight(gamma) (1----4) linked glucoses. Because of their particular geometry, they are able to act as a "host" to form inclusion complexes with "guest" molecules very much like enzymes. Cyclodextrins have been shown to exert catalytic activity on suitable included-substrate molecules; they catalyze the hydrolysis of phenylacetates, of organic pyrophosphates and of penicillin derivatives. They also accelerate aromatic chlorinations and diazo coupling by means of their primary and/or secondary hydroxyl groups, so that the rates of hydrolysis are enhanced by up to a factor of 400. In order to understand the hydrogen bonding in these enzyme models, neutron diffraction data were collected to unambiguously determine the hydrogen atom positions, which could not be done from the x-ray diffraction data. alpha-CD has been shown to have two different structures with well-defined hydrogen bonds, one "tense" and the other "relaxed". An "induced-fit"-like mechanism for alpha-CD complex formation has been proposed. Circular hydrogen bond networks have also been found for alpha-CD due to the energetically favored cooperative effect. beta-CD with a disordered water structure possesses an unusual flip-flop hydrogen bonding system of the type O-H...H-O representing an equilibrium between two states: O-H...O in equilibrium O...H-O. gamma-CD with a disordered water structure similar to beta-CD also possesses the flip-flop hydrogen bond. This study demonstrates that hydrogen bonds are operative in disordered systems and display dynamics even in the solid state.