Role of tumour necrosis factor-alpha receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.     

Hepatobiliary scintigraphy in a patient with bilhemia

A 4-year-old child referred for acute jaundice following percutaneous needle biopsy of the liver underwent hepatobiliary scintigraphy. Although all conventional liver tests suggested preservation of hepatocyte function, the tracer uptake in the liver appeared dramatically reduced at scintigraphy and the blood pool activity did not decrease significantly until the end of the study. Visualization of the bile ducts indicated, however, that the tracer was taken up by the hepatocyte and further excreted into the biliary tree. There was no tracer pooling in the biliary tree although no bowel activity was observed, even on delayed images. The association of persistent blood pool activity, bile duct visualization without tracer pooling, and nonvisualization of the bowel was caused by a continuous recirculation of the tracer from the biliary tree into the bloodstream. The presence of a biliovenous fistula was further proven by percutaneous transhepatic cholangiography performed 24 h later. Since 1975, only 16 cases of bilhemia have been reported. To the best of our knowledge the scintigraphic pattern of this rare but lifethreatening complication has not previously been reported.     

The value of pretreatment clinical and biochemical parameters in patients with newly diagnosed untreated prostate carcinoma and no indications for bone metastases on the bone scintigram

Between 10% and 25% of patients with newly diagnosed prostate cancer without bone metastases at the time of diagnosis will develop metastases during follow-up. To determine the value of clinical and biochemical parameters for assessment of prognosis at the time of diagnosis, a retrospective study was performed in 124 consecutive patients with newly diagnosed prostate cancer without bone metastases. The mean follow-up was 41 months, during which time 36 patients died and 15 patients developed metastases. Bone scans were classified from 0 (=normal) through 2 (=abnormal, but not typical for metastases) and were correlated with age, alkaline phosphatase (AP), prostate-specific antigen (PSA), tumour grade, T-stage and N-stage. In patients with a class 2 scan, additional roentgenograms and follow-up were used to exclude metastases at initial stage. All parameters, including therapy, were finally correlated with the development of metastases and survival. For survival 38 patients with proven metastases were used as controls. For all parameters tested, no statistically significant differences were found between the three bone scan classifications. The interval between diagnosis and the development of metastases ranged from 12 to 72 months. For the risk of development of metastases only PSA was found to be a significant correlate (P=0.0075). However, when tumour stages were clustered in limited disease (T0–2) and extensive disease (T3–4), the incidence of metastases was significantly higher in patients with extensive disease than in those with limited disease (P=0.0021). Finally, age, PSA and Anderson classification were found to be significant correlates of survival, but in stepwise analysis PSA was selected as the most prognostic variable (P<0.0001). In contrast with a typical pattern of metastases on bone scintigraphy, an abnormal scan (class 1 and 2) at the time of diagnosis is not a poor prognostic parameter of the risk of death. In conclusion, in patients with prostate cancer without bone metastases at the time of diagnosis, pretreatment PSA and tumour stage can be used for the assessment of risk of development of metastases during follow-up and survival. For this purpose, tumour stage should be clustered in limited and extensive disease. Received 14 April and in revised form 9 June 1997     

In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone.

Risperidone and ocaperidone are new benzisoxazol antipsychotics with particularly beneficial effects in schizophrenia. We report a comprehensive study on the in vitro and in vivo receptor binding profile of the new compounds, compared with haloperidol, and on the drug effects on monoamine and metabolite levels in various brain areas. The in vitro receptor binding and monoamine uptake inhibition profiles, comprising 29 receptors and four monoamine uptake systems, revealed that ocaperidone and risperidone bound primarily, and with the highest affinity thus far reported, to serotonin 5HT2 receptors (Ki values of 0.14 and 0.12 nM, respectively). Further, the drugs bound at nanomolar concentrations to the following receptors (Ki values, in nM, for ocaperidone and risperidone, respectively): alpha 1-adrenergic (0.46 and 0.81), dopamine D2 (0.75 and 3.0), histamine H1 (1.6 and 2.1), and alpha 2-adrenergic (5.4 and 7.3). In contrast, haloperidol showed nanomolar affinity for D2 receptors (1.55) and haloperidol-sensitive sigma sites (0.84) only. The in vitro binding affinity of ocaperidone, risperidone, and haloperidol for D2 receptors was exactly the same when measured in membranes from rat striatum, nucleus accumbens, tuberculum olfactorium, and human kidney cells expressing the cloned human D2 receptor (long form). In vivo binding in rats, using intravenous administration of [3H]spiperone, revealed very potent occupation by ocaperidone and risperidone of 5HT2 receptors in the frontal cortex (ED50 of 0.04-0.03 mg/kg); in this respect, they were 6, 30, and 100 times more potent than ritanserin, haloperidol, and clozapine, respectively. Ocaperidone occupied D2 receptors in the striatum and the nucleus accumbens with similar potency as did haloperidol (ED50 of 0.14-0.16 mg/kg). Risperidone revealed biphasic inhibition curves in the latter brain areas, indicating that [3H] spiperone labeled both 5HT2 receptors (occupied by risperidone at less than 0.04 mg/kg) and D2 receptors (risperidone ED50 of approximately 1 mg/kg). In the tuberculum olfactorium, 5HT2 and D2 receptors were also distinguished with risperidone. The ED50 values for occupation of the latter were for ocaperidone and risperidone 2 times lower and for haloperidol 2 times higher than in the striatum. Ocaperidone, risperidone, and haloperidol readily increased the levels of the dopamine metabolites 3,4-dihydroxybenzene acetic acid and homovanillic acid in the striatum, the nucleus accumbens, the tuberculum olfactorium, and, to some extent, the frontal cortex. Dose-response curve shapes were markedly different; with ocaperidone maximal levels were reached at 0.16 mg/kg and maintained to 10 mg/kg; with risperidone the levels tended to increase continuously up to 10 mg/kg. Haloperidol produced dome-shaped curves (maximum at 0.16-0.63 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)     

Presence of class II histocompatibility DR proteins on the envelope of human immunodeficiency virus demonstrated by FACS analysis.

Depending on the cell line used for virus propagation, human immunodeficiency virus (HIV) particles may possess class II MHC proteins, as demonstrated by FACS analysis. HLA-DR appeared in high amounts at the HIV envelope, if the virus was grown in HLA-DR+ cells, but was absent if the virus had been grown in HLA-DR- cells. No other cellular constituents, including HLA-DQ and HLA-DP, were detected in these virions. The presence of HLA-DR in the virion envelope itself in preparations used for diagnostic purposes may explain some of the false-positive results obtained in earlier serological tests for HIV infection. Possible implications of these virus-associated cellular antigens in the immunopathogenesis of AIDS should be considered.     

The severity of airways obstruction as a determinant of treatment response in COPD

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV₁) to decide when to initiate combination treatment with a long-acting β₂-agonist and an inhaled corticosteroid. Assessment of baseline FEV₁ as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 μg salmeterol (Sal), 500 μg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV₁ <50% and FEV₁ ≥50% predicted subgroups (n=949/513 respectively). Treatment effects on clinical outcomes – lung function, exacerbations, health status, diary card symptoms, and adverse events – were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV₁; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV₁ <50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV₁; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV₁, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.     

Microsomal Function in Hepatitis B Surface Antigen Healthy Carriers: Assessment of Cytochrome P450 1A2 Activity by the 14C-Caffeine Breath Test

Abstract: The hepatitis B surface antigen (HBsAg) carrier state is associated with changes in hepatocellular function involving the cytochrome P450 (CYP) system. Among this system, CYP1A2 enzyme plays an important role in chemical carcinogenesis and in the metabolism of several drugs. We have thus investigated CYP1A2 function using two ¹⁴C-caffeine breath tests (3-methyl-¹⁴C; C3BT and 7-methyl-¹⁴C caffeine; C7BT) in 12 HBsAg healthy carriers and 8 healthy volunteers matched for ¹⁴C-aminopyrine breath test values. HBsAg carriers exhibited lower C3- and C7BT values than normal controls. This difference, however, did not reach statistical significance except for C7BT values normalised for aminopyrine breath test values. Our data thus do not support the association between viral presence and CYP1A2 dysfunction.