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A vulnerable elderly man with prednisone-induced delirium Background Delirium always has an underlying cause, for example, medication. This article describes the case of a man with severe delirium caused by prednisone. Case description A 91-year-old vulnerable man developed severe delirium with agitation, verbal and physical aggression and visual hallucinations 3 days after starting treatment with low-dose prednisone. The delirium disappeared completely after prednisone was stopped. The delirium led to a long hospital stay of 36 days, weight loss of 10 kg due to undernourishment and extension of home care on discharge. Conclusion This case illustrates that delirium is always lurking around the corner in patients with multiple vulnerabilities. The provoking factor can be slight, for example 15 or 5 mg of prednisone. So be careful when starting prednisone in vulnerable elderly patients.

Nonencapsulated Haemophilus influenzae often causes chronic infections of the lower respiratory tract in both nonobstructive and obstructive chronic bronchitis. We assessed airway inflammation in clinically stable, chronically H. influenzae-infected patients with nonobstructive (CB-HI, n = 10) and in patients with obstructive chronic bronchitis (COPD-HI, n = 10) by analyses of the sol phase of spontaneously expectorated sputum (SSP). As compared with the CB-HI group, the COPD-HI group had significantly higher (p < 0.05) levels of myeloperoxidase (MPO) and tumor necrosis factor (TNF)-alpha in their SSP, whereas the degree of plasma protein leakage (SSP-to-serum ratio of plasma proteins) and the levels of interleukin (IL)-8, secretory IgA, and lactoferrin were similar in the two groups. These findings point to differences in pathophysiology in CB-HI and COPD-HI. The high level of TNF-alpha in the SSP of COPD-HI patients is in accord with the proposed role of TNF-alpha in the development of airway obstruction in COPD patients. In apparent contradiction, low levels of TNF-alpha were found in the SSP of noninfected but otherwise similar COPD patients (n = 9). This finding, however, does not exclude an exaggerated TNF-alpha response to infection or another stimulus in the airways of COPD patients. The SSP levels of MPO and IL-8, and the degree of plasma protein leakage in the COPD-HI group, were retrospectively compared with and found significantly higher than those of noninfected COPD patients, suggesting a more marked inflammatory response in COPD-HI. Whether this reflects a direct cause-and-effect relationship should be addressed in a future long-term prospective study involving repeated measurements in the same patients

Background: Segmental allergen challenge is a powerful tool to study inflammatory reactions in asthmatic airways. There is little information on the early events at 5 min and 4 h after allergen challenge with respect to the cell influx and the chemokine interleukin–8 (IL–8). Methods: Seven mild to moderate allergic asthmatics (AA group), 5 allergic nonasthmatics (ANA group) and 5 nonallergic controls underwent segmental allergen challenge, with allergen doses based upon skin reactivity. Bronchoalveolar lavage (BAL) samples were obtained before, 5 min and 4 h postchallenge, and were analyzed for cell numbers and differential counts, eosinophil and neutrophil chemotactic activity, and levels of IL–8. Results: At 5 min postchallenge, no changes were observed compared to baseline. At 4 h postchallenge, an increase was found in the number of neutrophils and the levels of IL–8, which was dependent on the dose of allergen in the AA and ANA group. At the same allergen dose, the increases in neutrophils and levels of IL–8 were calculated to be 91 and 67 times higher, respectively, in AA than in ANA. Levels of IL–8 correlated with the number of neutrophils and with the in vitro neutrophil chemotactic activities in BAL fluid. Conclusions: Neutrophil chemotactic activity is increased in BAL fluid at 4 h after segmental allergen challenge. We suggest that apart from IgE–mediated mast cell degranulation, additional local factors in the airways determine the degree of IL–8 increase and neutrophil influx.

Patients with allergic asthma have higher levels of nonspecific bronchial responsiveness than patients with allergic rhinitis. The aim of the study was to investigate whether this is caused by differences in the degree of allergy to inhalant allergens between asthmatics and rhinitics. Therefore, bronchial responsiveness to histamine was measured in 25 allergic patients with isolated upper airways symptoms. Nonspecific bronchial responsiveness in this group was compared with nonspecific bronchial responsiveness in a group of 136 patients with allergic asthma, with allergy and % predicted FEV1 as confounding variables. In addition, a matched pair analysis was performed. Twenty-five patients with nonallergic rhinitis served as controls to evaluate the influence of an IgE-independent inflammatory reaction in the upper respiratory tract on the level of bronchial responsiveness. Furthermore, we investigated the level of nonspecific responsiveness in 18 healthy controls. In the patients with allergic asthma, a correlation was found between nonspecific bronchial responsiveness and IgE against indoor allergens (n = 136, r = 0.34, p < 0.001) and % predicted FEV1 (n = 136, r = 0.37), p < 0.001). Patients with allergic asthma and patients with allergic rhinitis differed with respect to the level of bronchial responsiveness (p < 0.001), and the amount of specific IgE antibodies against indoor allergens (p = 0.01). The difference in level of bronchial responsiveness remained (p < 0.001) after correction with % predicted FEV1 and specific IgE against indoor allergens as confounding variables. Similarly, after matching of patients with allergic rhinitis (n = 25) with patients with allergic asthma (n = 25) regarding the specific IgE, total IgE and age of the patients, the difference in level of bronchial responsiveness remained (p < 0.001). Patients with nonallergic rhinitis had higher levels of nonspecific bronchial responsiveness than healthy controls and did not differ from patients with allergic rhinitis. In conclusion, the results confirm that IgE against common indoor allergens plays an important role in the mechanism underlying nonspecific bronchial hyperresponsiveness. However, differences in bronchial responsiveness between patients with asthma and patients with rhinitis are not merely explained by differences in the IgE antibody concentrations

The effects of disrupting the muscarinic or nicotinic systems on short-term spatial memory were investigated using a delayed matching to position (DMTP) procedure. Rats were trained on the DMTP until stability and then divided into two groups: one group was implanted with an indwelling cannula aimed at the lateral ventricle. The cannulated group received injections of selective muscarinic antagonists (pirenzepine, M1; AFDX 116, M2; UH-AH 37, M1/M3) or hemicholinium-3 (a choline uptake inhibitor). The remaining animals were treated with conventional muscarinic antagonists (scopolamine, methyl scopolamine) or nicotinic channel blockers (mecamylamine, hexamethonium). Scopolamine, methyl scopolamine and UH-AH 37 disrupted all performance parameters in a non-specific but dose related manner. Pirenzepine disrupted accuracy in a delay, but not dose dependent manner, and exerted no other negative effects on performance. Hemicholinium-3-induced performance deficits showed some elements of effects seen following pirenzepine and scopolamine (delay dependent effects on accuracy, some negative effects on other motoric aspects of performance). AFDX 116 and hexamethonium had no significant effects on performance with respect to control. Mecamylamine reduced accuracy and increased response latencies at the highest dose tested. These data indicate that muscarinic antagonists are more effective at disrupting mnemonic performance than nicotinic blockers, and moreover, that distinct muscarinic receptors may have differential effects on cognitive performance.

We describe three patients with progressive fibrosing interstitial lung disease (ILD) as the first and only manifestation of systemic sclerosis. In one patient the presence of anti-Scl-70 autoantibodies suggested systemic sclerosis to be the underlying cause of the disease. In the two other subjects, however, anti-Scl-70 antibodies were negative. In these patients the lung disease preceded other manifestations of systemic sclerosis by several years. Diagnosis, prognosis and treatment of systemic sclerosisassociated ILD is discussed.

It is presently unknown which factors determine the occurrence and persistence of asthma in house dust mite-allergic individuals. The level of allergen-specific IgE antibodies does not seem to be decisive for asthmatic symptoms. Moreover, levels of exposure to mite allergens do not seem to differ significantly between asthmatic and non-asthmatics individuals.It was hypothesized that the presence or absence of asthmatic symptoms in house dust mite-allergic patients is associated with quantitative or qualitative differences in the cellular bronchial inflammatory response during the late phase of the allergic reaction. This hypothesis was tested in the bronchial allergen challenge model.Whole lung challenges with house dust mite extract were performed in 52 house dust mite-allergic subjects, of whom 26 had asthma and 26 had perennial rhinitis without asthmatic symptoms. Primary outcomes were parameters for bronchial inflammation in serial samples of induced sputum (cell differentials, eosinophil cationic protein (ECP), interleukin-8 (IL-8), myeloperoxydase (MPO)). In addition, lung function, non-specific bronchial hyper-responsiveness and serial blood samples (eosinophils and IL-5) were analysed.At baseline sputum eosinophils and ECP were similar in both groups but neutrophils and IL-8 were higher in asthmatics. The early bronchoconstriction after allergen challenge was similar in asthma and non-asthmatic rhinitis (median decrease in FEV1: asthma -31.7% vs. non-asthmatics -29.1%, P0.1). The late phase bronchoconstriction was significantly greater in asthma (median decrease in FEV1: asthma -27.6% vs. non-asthmatics -18.9%, P = 0.02). Induction of bronchial hyper-responsiveness was similar in both groups. Bronchial allergen challenge elicited significant increases in sputum eosinophils and ECP, which were indistinguishable for both groups (P0.1 and P = 0.07, respectively). In contrast, higher numbers of neutrophils persisted in asthma 24h after challenge and were accompanied by significant increases in IL-8 and MPO, which were absent in non-asthmatics (difference between groups P = 0.007 and P = 0.05, respectively).Allergen challenge inducedvery similar increases in eosinophils and ECP in induced sputum in allergic asthmatics and in allergic non-asthmatic patients. The difference in bronchial inflammation between asthma and non-asthmatic rhinitis appeared to be more closely related to indices for neutrophilic inflammation.

Changes in airway inflammation can be studied with bronchoalveolar lavage, but the widespread use of this procedure is limited by its invasiveness. The aim of this study was to evaluate the usefulness of induced sputum as a non-invasive alternative to bronchoalveolar lavage for studying changes in airway inflammation in patients with asthma. Thirty patients were treated for 12 weeks with an inhaled corticosteroid (fluticasone propionate (FP), 250 microg twice daily) or a short-acting beta-agonist (salbutamol (Sb), 400 microg twice daily) in a double-blind, double-dummy, randomized parallel group study. Sputum induction with hypertonic saline solution was performed twice before treatment and after 4, 8, 10, and 11 weeks of treatment. Bronchoalveolar lavage fluid divided into two pools (first 60 mL portion as bronchoalveolar lavage/bronchial wash (BAL/BW) and subsequent 80 mL as bronchoalveoalar lavage (BAL)) was obtained before and after 12 weeks of treatment. Changes in cell differentials and plasma-protein leakage (alpha2-macroglobulin, albumin, and their ratio (relative coefficient of excretion, RCE)) were analyzed in induced sputum and were compared with changes in BAL/BW and BAL. During treatment with FP, the PC20histamine (interpolated concentration of histamine that caused a fall in FEV1 of 20% of the baseline value) increased (P < .0001), and the percentage of eosinophils (P = .004), levels of (alpha2-macroglobulin (P = .09) and RCE (P = .007) decreased in sputum. These changes were different from those in the Sb group (PC20histamine P

An immunocytochemical staining method has been developed for simultaneous staining of both cell surface markers (CD4 and CD8) and intracellular cytokine proteins IFN-gamma, IL-4 and IL-5. Cell surface molecules were visualized with alkaline phosphatase, which was developed by Fast Blue BB. Intracellular cytokine proteins were detected by amino-ethyl carbazole. We applied this technique to T cells from T-cell lines and T-cell clones, peripheral blood mononuclear cells and broncho-alveolar lavage fluid cells. Cells were used either unstimulated or stimulated for 4 h with 1 ng/ml PMA and 1 microg/ml ionomycin, which proved to be an optimal stimulus taking cytokine staining, cell recovery and cell viability into account. We studied peripheral blood mononuclear cells from healthy subjects and found that without in vitro stimulation on average 0.4% of the cells were IFN-gamma positive cells. In unstimulated broncho-alveolar lavage fluid cells of the 2 allergic asthmatic subjects studied so far we found higher numbers of cytokine-positive cells (up to 22% of the lymphocytes being IL-4+ cells). By in vitro stimulation, the numbers of cytokine-positive peripheral blood mononuclear cells from the healthy subjects were increased to maximally 5% IFN-gamma+ cells. In stimulated lavage fluid cells from allergic asthmatic subjects maximally 34% of the lymphocytes became IFN-gamma+. We conclude that this method allows detection of intracellular cytokine proteins in both CD4+ and CD8+ T cells without the need for stimulating the cells in vitro. In vitro stimulation may change the cytokine profile detected.

Increasing insights into the mechanism underlying the allergen-induced late asthmatic response (LAR) have been gained with implication of activated eosinophils and CD4+ T lymphocytes. However, the patient characteristics that indicate the individual capacity to develop a LAR are not well-defined.In 22 subjects with mild to moderate house dust mite-allergic asthma, we investigated the relationship between the LAR and two other models of late-phase allergic inflammation, i.e. the allergen-specific proliferative response of peripheral blood T lymphocytes in vitro and the late cutaneous response. Non-specific bronchial responsiveness (PC20histamine), lung function (FEV1), peripheral blood eosinophil count, early phase allergic skin sensitivity, and levels of total and specific immunoglobulin E (IgE) were determined prior to bronchial allergen challenge. Serum levels of interleukin-5 (IL-5) were measured before and at several time points after allergen inhalation.A significant correlation was found between the magnitude of the LAR and the allergen-specific proliferative response of peripheral T lymphocytes (r = 0.44, P = 0.04) but not the late cutaneous response. Stepwise-multiple linear regression of the magnitude of the LAR on the parameters analysed at baseline, resulted in a model combining PC20 histamine, early phase allergic skin sensitivity, and the allergen-specific proliferative response of peripheral T lymphocytes (R2 = 0.84, P0.001). No contribution of the late cutaneous response to the prediction of the LAR was found. Serum levels of IL-5 increased significantly at 6 h (P = 0.01) and 24 h (P = 0.003) after bronchial allergen challenge and correlated with the allergen-specific proliferative response of peripheral T lymphocytes in vitro (rho = 0.48, P = 0.02).The findings in this study point to a role of TH2-lymphocyte responses in the development of the allergen-induced LAR. In allergic asthmatic patients, allergen-specific responsiveness of peripheral T-lymphocytes in vitro may serve as a model to determine the individual capacity to develop a LAR after allergen inhalation.

Previous studies have shown the usefulness of divalent cobalt isotopes to visualize cerebral damage after stroke. The site of accumulation of cobalt ion is unknown but may be explained by neuronal influx, analogous to that of calcium ion. Additionally, uptake may be due to infiltrating leukocytes or protein-bound cobalt. The aims of this study were to compare 57Co-SPECT with leukocyte SPECT and to compare the SPECT findings with clinical outcome as scored by the Orgogozo scale.Ten patients with a CT scan positive for middle cerebral artery infarcts were included in the study (7 men, 3 women; mean age 70 yr). Technetium-99m leukocyte and cobalt-SPECT (interval 2-4 days) were made with a double-headed gamma camera, after the injection of 10-15 mCi 99mTc-HMPAO-labeled leukocytes and 0.4 mCi 57Co, respectively. Scans were performed within 5-30 days after onset of the first symptoms. Regions of interest (ROI) containing the area of infarction in the slices displaying enhanced radioactivity or the middle cerebral artery (MCA) region in four successive slices were defined for calculating enhancement ratios. The 99mTc leukocyte enhancement ratio (LER) and cobalt enhancement ratio (CER) were defined as the quotient of radioactivity in the ROI and an identical contralateral ROI. The MCA stroke-scale according to Orgogozo was used to assess neurological deficits at the time of scanning and discharge.Cobalt-57 and 99mTc-HMPAO showed uptake in the infarcted brain area in five patients; the quantitative uptake in the infarcted brain area of the two tracers correlated significantly (p0.05). Both the LER and the CER correlated significantly (p0.05) with the Orgogozo score at the time of scanning. Only the LER correlated significantly (p0.05) with the Orgogozo score at discharge.Uptake of cobalt and leukocytes in the peri-infarct tissue suggests that 57Co may visualize a component of the inflammatory response. Divalent 57Co may be convenient to predict clinical prognosis after stroke.

Several studies have shown the feasibility of Co-isotopes (55Co and 57Co) in imaging of neuronal damage in stroke, multiple sclerosis, cerebral tumors and trauma. These studies indicate that Co-isotopes allow visualization of brain pathology related to inflammatory processes, reactive gliosis and cell death. Until now, it is not clear if 55Co accumulation occurs in the core of infarction or in the penumbra. Therefore, in the present study, we compared 55Co-PET with functional parameters such as cerebral bloodflow (rCBF) using C15O2, oxygen metabolism (rCMRO2) using 15O2 and cerebral bloodvolume (CBV) using C15O in PET and with the anatomical parameter Gd-MRI.Seventeen patients (11 male; 6 female) age 43 to 84 (mean 69) with middle cerebral artery (mca) stroke, as proven by CT or MRI, were examined with 55Co-PET (0.5-1.0 mCi 55CoCl2), C15O2-, 15O2- and C15O-PET in one session 0-30 days after stroke-onset. Regions of infarction were defined by rCMRO2 being smaller than 65% or rCBF below 45% of the contralateral value and were subsequently superimposed on the cobalt scan. To compare the Cobalt uptake with the Gd-MRI, a realignment program was used that matches the MRI with the bloodflow images. Clinical status was established using the Orgogozo stroke scale at admission and at discharge (at least 6 weeks after admission) and the Barthel index.Eight patients showed a positive Co-PET scan and were used for further analysis. It appeared that Co accumulates in areas with a diminished oxygen metabolism and with a preserved bloodflow. We found Co-uptake in only a part of the Gd enhanced brain tissue with a tendency to be located peripherally or outside the Gd demarcated brain tissue.The results of the present study suggest that Co accumulates into infarcted brain tissue with a rather preserved flow independently of blood-brain barrier breakdown.

The usefulness of prostate specific antigen (PSA) in screening for prostatic carcinoma was studied in 262 inpatients of the department of internal medicine. All patients underwent a rectal digital examination and determination of PSA by the Tandem-E method (Hybritech). The plan was to perform biopsies if there were suspicious findings on the rectal examination or if the PSA value was more than 10 ng/ml. The PSA values wereor = 4 ng/ml in 219 patients (83.6%),4 to 10 ng/ml in 27 patients (10.3%) and10 ng/ml in 16 men (6.1%). In consideration of the severity of disease which limited life expectancy we did not perform a biopsy on 37.5% of the patients with PSA10 ng/ml. 7 patients with prostatic carcinoma were found. Their PSA values varied between 11.2 and 875 ng/ml. The cancer detection rate was highest for the combination of a suspicious rectal examination and a PSA value10 ng/ml (70%).

This study examined the clinical relevance of the determination of free PSA (f-PSA) in addition to total PSA (t-PSA).Both total PSA- and free PSA-values of frozen sera obtained pretherapeutically from 80 patients with carcinoma (PC) and 171 patients with benign hyperplasia of the prostate (BPH) were analysed by means of PSA IRMA and FREE PSA IRMA (IMMUNOCORP/IBL).At 95% specificity (true negative test results), a cut-off value of 16.8 [micrograms/L] was obtained for total PSA (9 patients with BPH [5%] were above this value). For this cut-off value we calculated a sensitivity (true positive test results) of 41%. Using the same criteria for the ratio Q = f-PSA:t-PSA a cut-off of 0.083 was found again at a specificity of 95%. In a second step only patients with total PSA values below the cut-off level of 16.8 [micrograms/L]) were considered. Of these patients 11 of 160 with BPH (missing values = 1) and 13 of 33 with PC (missing values = 2) were below the above mentioned ratio (Q = 0.083). Considering both steps (total PSA and Q) 46 patients with PC were detected correctly and 20 patients with BPH would have been biopsied unnecessarily (positive biopsy rate: 70%).High total PSA levels are a very good indicator for the presence of prostate cancer. There is still concern to improve the differentiation between the diagnosis between BPH and PC, when an intermediate or low value (or = 95% specificity) is observed. The determination of Q is only useful in this range and might be helpful for the clinician's decision to apply or avoid biopsy.

The isotopes 55Co and 57Co have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of 55Co in both rat and humans after intravenous (bolus)-administration was studied. Based on pharmacokinetic data, radiation dose calculations according to the MIRD system are presented. By combining present measurements with literature data on 60CoCl2, the radiation dose delivered by 56CoCl2 (T1/2 78.8 days) and 57CoCl2 (T1/2 = 270 days) could be assessed.Whole-body Co-PET was performed in two healthy volunteers and one rat after intravenous injection of 37 and 3.7 MBq (1 resp. 0.1 mCi) 55Co, respectively. Blood samples were withdrawn during 300 min in humans. In seven rats the 55Co-biodistribution was determined by postmortem analysis. The residence time of the liver (critical organ) was determined in rats and humans. Blood partition-data of 55Co were assessed resulting in basic pharmacokinetic data in humans. Based on these kinetic data, radiation dose was calculated using the MIRD protocol.In both the humans and the rat, the liver and bladder retained the highest fractions of 55Co (about 50% resp. 40% of the administered dose). The liver residence time in humans was 8.6 hr. The free fraction 55Co in the human plasma was at maximum 12%. The total-body mean transit time was 152 min. The volume of the central compartment = 2.8 liter and the steady-state distribution volume = 48 liter.From these results, according to the WHO recommendations for class II studies, 22.2 MBq (0.6 mCi) 55Co and 14.8 MBq (0.4 mCi) 57Co (excluding any radionuclide contamination) can be used.

We investigated the relation between IgE reactive with histamine-releasing factor (HRF) and clinical status in patients with asthma or rhinitis. Sera were used to passively sensitize purified, lactic-acid treated basophils. IgE-independent HRF due to chemokines was removed from mononuclear cell supernatants with heparin-Sepharose. IgE-dependent HRF was determined by measuring the increase in histamine release between 1 min and 60 min, which was designated delta HRF. HRF-reactive IgE was demonstrable in nine of 18 patients with allergic asthma, three of 19 patients with nonallergic asthma, five of 17 patients with allergic rhinitis, and none of 19 control patients. The presence of HRF-reactive IgE was associated with: (1) IgE to inhalant allergens; 40% of radioallergosorbent test (RAST)-positive individuals versus 8% of RAST-negative individuals were positive (OR = 7.8, p < 0.005); (2) bronchial sensitivity to histamine in all asthmatic patients (geometric mean PC20: 1.50 versus 0.51 mg/ml; p < 0.005); and (3) bronchial sensitivity to histamine in allergic asthmatic patients (geometric mean PC20: 1.27 versus 0.37 mg/ml, p < 0.02). These findings support the hypothesis that IgE-dependent HRF might contribute to the chronic allergic reaction

Objectives The new ACS prostate-specific antigen (PSA) assay was methodologically and clinically compared with the established Tandem-E PSA assay. We intended to find a possible advantage in primary diagnosis and monitoring the recurrence of prostate cancer due to the additional better recognition of the free PSA form by the ACS PSA assay. Methods Sera of 51 healthy men, 127 patients with hyperplasia, and 82 untreated patients with prostate cancer were analyzed by means of the Tandem-E PSA assay (Hybritech) and the ACS PSA assay (Ciba Corning). Follow-up was done on 12 cancer patients with recurrences. Results Both assays correlated very well (r = .98 for all studied men or hyperplasia patients or cancer patients). However, both assays did not yield comparable values: The ACS assay was characterized by nearly doubled values compared with the Tandem-E assay. At 95% specificity versus patients with benign hyperplasia, cutoff values were obtained as follows: 28.8 ng/mL for the ACS PSA assay and 15.2 ng/mL for the Tandem-E PSA assay. At 95% specificity versus hyperplasia patients, we calculated sensitivities of 60% (ACS PSA) and 63% (Tandem-E PSA). Our longitudinal study revealed more prominent slopes for the ACS assay in patients with recurrent cancer disease. However, using either the ACS assay or the Tandem-E assay, the PSA increase started at the same time. In 1 patient, the increasing ACS PSA accelerated 3 months earlier than the increasing Tandem-E PSA did. Conclusions The ACS assay has obviously higher PSA levels. The clinician is not familiar with such high PSA levels. The specificity-sensitivity profile nonetheless remains unchanged. If the PSA concentration is measured by the ACS assay, patients who relapse will reveal a more rapid PSA increase. Then, recurrent cancer disease may be detected earlier in some cases.

In animal experiments, the radionuclide 55Co2+ has been shown to accumulate in degenerating cerebral tissue similar to Ca2+.The potential role of 55Co2+ for in vivo brain PET imaging was investigated in four patients after ischemic stroke.PET showed uptake of 55Co2+ in damaged brain tissue irrespective of blood-brain barrier integrity, as affirmed by CT and MRI.Our preliminary results indicate that 55CoCl2 may prove to be a useful and relatively inexpensive PET radiopharmaceutical for visualization of degenerative processes in brain tissue.

67Ga lung uptake, obtained by a standardized computer-assisted quantitative method of 67Ga scintigraphy, was compared to carbon monoxide diffusion capacity (DLCO) in 45 patients with biopsy proven pulmonary sarcoidosis. Increased 67Ga lung uptake was found in 24 (53%) patients and DLCO was decreased in only 16 (36%) patients. An inverse relationship (r = -0.53; p0.001) was demonstrated between 67Ga lung uptake and DLCO. Eleven patients had an increased 67Ga lung uptake whereas the DLCO values were normal. There was no correlation between 67Ga lung uptake or DLCO and either chest radiographic stage or mode of clinical presentation. On the basis of the normal limits for 67Ga lung uptake and DLCO, 4 subgroups of patients could be identified. The use of the combined investigations may open an opportunity for an early identification of those patients who require therapy. An increased 67Ga accumulation within the lung seems to be considered as a factor indicating risk for pulmonary disability, which is supported by the follow-up of the 4 subgroups of patients.

The relationships between allergic symptoms after exposure to house dust, allergy parameters (skin test to house dust mite [HDM], total IgE, HDM-specific IgE, and blood eosinophil counts), and several confounding variables (age, sex, smoking habits, and airway hyperresponsiveness) were evaluated in 235 patients with asthma and chronic obstructive pulmonary disease (COPD).Skin tests had higher diagnostic value (sensitivity plus specificity) for symptomatic allergy than specific IgE (1.45 versus 1.36) or total IgE (1.16). The other allergy parameters gave no additional information on symptoms once the skin test was known. Expressing the skin test relative to the histamine control proved slightly better than uncorrected wheal size, but this probably has limited clinical value. The best cutoff level for a positive skin test was 0.7 when the histamine wheal size was accounted for by division, -6 mm when subtraction was used, and 7 mm for absolute wheal size. These cutoff levels proved equally applicable in various subgroups of patients with asthma and COPD. Only the skin test and female sex were independent predictors of allergic symptoms.We conclude that skin tests to HDM are better predictors for clinical allergy than total or specific IgE levels and eosinophil count, and that they are applicable in most patients with asthma and with COPD.

Immunoglobulins in the epithelial lining fluid of the respiratory tract either originate from the systemic circulation or they are locally produced by plasma-cells in the mucosa. For polymeric immunoglobulins (dimer IgA and IgM) specific receptors on the surface of epithelial cells allow facilitated transport of these immunoglobulins into the lining fluid. Local inflammatory reactions in the lung will damage the respiratory membrane, which results in an increased leakage of proteins into the lining fluid. This increased leakage complicates the differentiation between local production of immunoglobulins and passive permeation. In asthma patients inflammation of the respiratory epithelium is found. This inflammation may be the result of non-immunologically triggered processes as well as of immunological reactions. In the experimental part of this paper we analyse possible local production of immunoglobulins and other proteins within the lungs of patients with asthma. This is performed with the use of steady-state protein concentrations in serum and bronchoalveolar lavage fluid. Information on the permeability of the respiratory membrane can be obtained by the measurement of proteins that are not produced within the lungs. Information on local production can be obtained by comparing the epithelial lining fluid to serum concentration ratios of proteins with identical molecular masses.

Tetrahydroaminoacridine (THA: Tacrine) has previously been shown to reverse deficits in spatial discrimination learning induced by hemicholinium-3 (HC-3). In the present experiments the effects of prior depletion of serotonin (5-HT) or noradrenaline (NA) on this reversal were examined. In the first experiment 5-HT lesions were made by injecting 5,7-DHT (2×50 µg/5 µl) into the lateral ventricles of rats pretreated with desmethylimipramine (DMI 25 mg/kg IP). A permanently indwelling guide tube was then implanted over the right lateral ventricle. Subsequent testing, under drug-free conditions, revealed no effect of the lesion on the number of trials needed to attain criterion (nine consecutive correct choices) in two-platform spatial discrimination learning in a watermaze. Using a latin square design rats were then tested for the effects of HC-3 and THA. HC-3 (5 µg/5 µl ICV) or placebo (CSF) were injected 60 min before the start of a 30-trial training session. THA (4.6, 10 mg/kg SC) or placebo were then injected 15 min before training. Choice accuracy but not choice latency was significantly impaired by HC-3 and the effect was reversed by THA in both sham operated and 5-HT lesioned rats. In the second experiment two injections of DSP-4 (50 mg/kg IP) were given, following cannulation, to deplete forebrain NA. The lesion had no effect on spatial learning under drug-free conditions and failed to block the THA-induced reversal of spatial discrimination learning deficits following HC-3. These results confirm that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and that the deficit is reversed by THA. However, concommitant depletion of forebrain 5-HT or NA does not block the ameliorative effect of THA.

Lung function and respiratory symptoms were studied in 40 children aged 8-18 years who had been ventilated for hyaline membrane disease after birth; 11 had had bronchopulmonary dysplasia. Also studied were 38 age matched children who had had hyaline membrane disease but had not required ventilation, 25 unmatched children who were born prematurely but did not develop hyaline membrane disease, and 39 randomly selected pupils of similar age. There was no difference in thoracic gas volume, total lung capacity, inspiratory vital capacity, residual volume, or transfer factor for carbon monoxide between the groups. Respiratory symptoms during the three years before the study and the frequency of clinically diagnosed asthma in patients and their family were similar in all the children with hyaline membrane disease irrespective of whether they had been ventilated or had had bronchopulmonary dysplasia. The children with bronchopulmonary dysplasia, however, had a lower forced expiratory volume in one second (FEV1) before bronchodilator (73% predicted) than the other groups (88-95% predicted). Children who had required ventilation had lower values for specific airways conductance (sGaw) and a greater increase in FEV1 (delta FEV1) after salbutamol (13%) than non-ventilated children (6%); delta FEV1 was associated with the peak pressure of intermittent positive pressure ventilation, a family history of asthma and a history of wheezing, recurrent respiratory illnesses, and a doctor's diagnosis of asthma during the three years before the study. These findings indicate that after eight years of age patients with bronchopulmonary dysplasia have more reversible airways obstruction, compatible with increased bronchial smooth muscle tone.

Evidence is accumulating that the lung injury in classic collagen vascular diseases (CVD) is triggered by immune complexes (IC). Qualitative information about the antigens and the antibodies involved is meagre. Using a previously described indirect immunofluorescence test we were able to demonstrate various immunoglobulin (Ig) classes and complement (C) factors in bronchoalveolar lavage (BAL) — derived immune complexes of 13 patients with serologically positive CVD. In all the patients the diffuse pulmonary involvement was histologically proven. A control group (NC) consisted of nine healthy, non-smoking volunteers. Overall concentrations of soluble IC, measured using a solid phase Clq-ELISA assay, were statistically significant increased compared with NC, and also in comparison with the serum of the same individuals (P

A 25-yr-old man suffered from severe nocturnal asthma, which was shown to be provoked by pathological gastro-oesophageal reflux. A dramatic, immediate improvement of his pulmonary condition was achieved by treatment with omeprazole after failure of other therapeutic measures, including high doses of ranitidine.

Using the indirect ELISA technique, the IgM, IgG, and IgA antibody response to the primary test immunogen Helix pomatia haemocyanin (HPH) was studied in 30 patients with various clinical stages of primary squamous-cell bronchial carcinoma and compared with values obtained in 15 controls matched for sex, age, smoking habit, and presence of chronic bronchitis. Patients with disseminated disease (stage III) showed a significant decrease in IgG and IgA antibody response (P less than 0.001), but IgM antibodies were relatively high and not different from the controls. Although normal IgG and IgA antibody titres were found at the peak response two weeks after immunisation in patients with localised disease (stage I), these antibody titres showed a significantly more rapid decline after serial investigations at eight and 14 weeks after immunisation compared with the controls (P less than 0.001) despite total removal of the tumour burden at c four weeks after immunisation. In-vitro HPH-induced lymphocyte transformation was considerably decreased in state I patients (P less than 0.01) as well as in stage III patients (P less than 0.001). The results suggest that patients with squamous-cell bronchial carcinoma develop impaired T-cell function, which gives rise to a defective antibody response and in-vitro lymphocyte reactivity to the T-cell dependent primary immunogen HPH.

Of 225 patients in whom AIDS was diagnosed in the period January 1982 to March 1988 at the Academic Medical Centre, Amsterdam, the tuberculosis incidence and the clinical and demographic characteristics were recorded retrospectively. Tuberculosis was diagnosed in 18 patients (8%). The most frequent risk factor of AIDS-tuberculosis patients was intravenous drug abuse. The chest X-ray was frequently atypical and there were more extrapulmonary locations in comparison to patients with tuberculosis without AIDS. On September 1, 1988, 13 of the 18 patients had died. The response to tuberculostatic therapy was good. Our results are in agreement with comparable studies elsewhere. The expectation is that the tuberculosis incidence among AIDS patients will increase as more intravenous drug users become part of the whole AIDS patient population.

The effects of hemicholinium-3 (HC-3) on spatial discrimination learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical "float" (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 micrograms/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 micrograms/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46-460 micrograms/kg/SC) and tetrahydroaminoacridine (THA) (2.2-10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046-1 mg/kg/SC), aceclidine (1-10 mg/kg/SC), oxotremorine (30-100 micrograms/kg/SC) and RS-86 (0.46, 1.0 microgram/kg/SC) were also effective. Pilocarpine (0.22-2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6-10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The alpha 2 agonist, clonidine (46, 100 micrograms/kg SC) and the antagonist idazoxan (32, 100 micrograms/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 micrograms/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 micrograms/kg) or by the benzodiazapine antagonist ZK-93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.

In 14 patients with advanced stage pulmonary sarcoidosis the distribution of regional ventilation-perfusion ratios (V/Q) was obtained by quantitative analysis of ventilation-perfusion single photon emission computed tomography (SPECT) of the lungs. In 6 patients normal V/Q distributions were found with a decreased DLCO in only one of them. In 8 patients abnormal distributions of V/Q ratios were found. Six of these patients also had a decrease in diffusing capacity for CO (DLCO). It is suggested that the decrease in DLCO in these patients is partly a result of uneven distribution of V/Q ratios.

Eleven asthmatic patients with allergy and 10 age- and sex-matched controls were immunized subcutaneously with 1 mg of the primary test immunogen Helix pomatia hemocyanin (HPH). The HPH-specific IgE, IgG, IgA, and IgM antibody response was measured by ELISA. After immunization, not only the IgE but also the IgG antibody response of the patients exceeded that of the controls (p less than 0.01). IgA antibody response also tended to be higher in the asthmatic group (NS). Except for an earlier rise after immunization in the asthmatic group (p less than 0.05), IgM peak responses did not differ significantly between the two groups. There was a high correlation (r = 0.9) between the magnitude of the IgE and the IgG antibody responses. IgM antibody response did not correlate with the response in any of the other antibody classes measured. The total serum immunoglobulin concentration was determined before immunization. Only the IgE level was significantly higher in the asthmatic group (p less than 0.01). No correlation was found between serum immunoglobulin concentrations and the magnitude of the HPH-specific antibody response in the same class. We conclude that the increased humoral responsiveness of asthmatic patients with allergy is not restricted to the IgE class nor to a limited number of commonly encountered antigens (allergens).

Jansen, H M, The, T H, de Gast, G C, Esselink, M T, van der Wal, A M, and Orie, N G M (1978).Thorax, 33, 429-438. Adjuvant immunotherapy with BCG in squamous-cell bronchial carcinoma. Immune-reactivity in relation to immunostimulation (preliminary results in a controlled trial). Twenty-nine patients with, at operation, evidence of locally advanced primary squamous-cell bronchial carcinoma (stage II, UICC, Geneva, 1974) had lung resection to remove all the visible tumour. Postoperatively a randomly chosen group of 16 patients received adjuvant BCG immunostimulation by scarifications, while the control group received no adjuvant treatment. Follow-up studies were done from three to 23 months. Immune-reactivity in vivo with PPD and DNCB skin tests, and in vitro with E-rosetting tests and lymphocyte transformation tests with PHA, Con A, diphtheria toxoid, and PPD was monitored in 10 treated and in seven untreated patients. Recurrence rates decreased appreciably in the BCG-stimulated group after a six to 23 months' follow-up (p

Two experiments were conducted to determine the effects of the M1 muscarinic receptor antagonist pirenzepine on place navigation in a water maze. In the first experiment rats were required to learn the location of a hidden platform following intracerebroventricular injections of equimolar doses of pirenzepine or scopolamine methylbromide. Both drugs dose-dependently impaired spatial learning according to both escape latency data and transfer test analysis. Pirenzepine was approximately 3 times less potent than scopolamine, a potency ratio which suggests M1 receptor mediation of the impairment. In the second experiment pirenzepine (1 approximately 92.3 micrograms/rat ICV) was injected prior to training on a simultaneous place discrimination task in the water maze. Impairments of choice accuracy were found with a dose of 20 micrograms/rat in the absence of any marked increases in either errors of omission or choice latency. These data suggest that M1 receptor blockade impairs processes which are involved in spatial learning.

Eleven patients with asthma and ten sex and age matched healthy controls were immunized with the primary immunogen Helix pomatia Haemocyanin (HPH). The amplitude and the kinetics of in vitro cell-mediated immune response were measured by HPH-induced lymphocyte proliferation. Lymphocytes were also challenged in vitro with mitogens and recall antigens. In vivo cell-mediated immunity was determined by inducing delayed type hypersensitivity reactions with HPH. Anti-HPH antibody responses in the IgE, IgG and IgM classes were measured to gain an insight into the relation between cell-mediated and humoral immune responses in patients with asthma and healthy controls. The in vitro and in vivo cell-mediated response and the IgM antibody response did not differ between patients with asthma and controls. The IgE and IgG antibody responses, however, were increased in the patients. IgM antibody response correlated with both the in vitro and in vivo cell-mediated response (R = 0.45, P less than 0.05). IgE and IgG antibody responses however were not correlated with cell-mediated responses. These data suggest that the primary abnormality in immune regulation in patients with asthma concerns the control of the IgE and IgG class antibody responses.

The coexistence of interstitial pulmonary fibrosis and alveolar cell carcinoma is well known. The familial occurrence of a combination of these two entities, however, is very rare. We present a family of which five members had diffuse interstitial pulmonary fibrosis. Three of them had in addition alveolar cell carcinoma. In a sixth family member, evidence of alveolar cell carcinoma was present without proven interstitial fibrosis. An autosomal dominant trait is suggested as the mode of inheritance of both interstitial fibrosis and alveolar cell carcinoma in this family.

In order to obtain information about the nature of the local inflammatory process during late asthmatic reactions after house dust mite inhalation, bronchoalveolar lavage (BAL) was performed in 19 asthmatic patients and in 5 control subjects. In 16 of the patients and in all of the control subjects, BAL was performed 6 to 7 h after allergen inhalation. Six of the patients showed early and late asthmatic reactions (LAR), 5 showed early reactions, and 5 showed no reactions. Bronchoalveolar lavage was also performed shortly after the early reaction in 5 patients with documented combined early and late reactions. In the BAL fluid of the patients with LAR, a significant eosinophilia (0.01 less than p less than 0.05) was found compared with that in all other patient groups and with that in the control subjects. This bronchoalveolar eosinophilia was accompanied by elevated eosinophil cationic protein/albumin ratio in the BAL fluid (0.01 less than p less than 0.05). These observations suggest that eosinophils and their mediators might be involved in the development of LAR after allergen inhalation.