Isoquinoline Derivatives Isolated from the Fruit of Annona muricata as 5-HTergic 5-HT1A Receptor Agonists in Rats: Unexploited Antidepressive (Lead) Products

The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [³H]rauwolscine to 5-HTergic 5-HT_1A receptors in calf hippocampus, and three alkaloids, annonaine ( 1 ), nornuciferine ( 2 ) and asimilobine ( 3 ), isolated from the fruit have been shown to have IC50 values of 3 μm , 9 μm and 5 μm , respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids. The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT_1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT_1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (K_i) for 1, 2 and 3 were < 10 μm . Inhibition of the binding of the radioligand to the 5-HT_1A receptor was observed in every ligand-binding assay performed with the alkaloids; the K_i values for 1, 2 and 3 were in the μm range. These results imply that the fruit of Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3 , and that in the past potent leads for the development of anti-depressive therapeutics have not been used.     

Granular cell tumours of the lower respiratory tract

Granular cell tumours rarely involve the lower respiratory tract. We report eight cases surgically resected at our institution. There were four females and four males, aged between 18 to 56 years (mean 40). One tumour associated with a peripheral lung adenocarcinoma was asymptomatic. The other lesions presented with obstructive pneumonitis (3 cases), haemoptysis (2), dyspnea (1) or cough (1). These tumours were tracheal (1) or bronchial (6) and one case was located in the lung parenchyma. Four cases were multicentric with associated lesions located in a bronchus (2), the oesophagus (1) or a mediastinal lymph node (1). All tumours, with the largest diameter ranging from 0.5–4.5 cm, were histologically invasive. The tumours were positive for S-100 protein, neuron specific enolase, KP1 (CD68) and vimentin. No tumour expressed desmin, keratin or p53 oncoprotein. Our study demonstrates that, in spite of marked anatomical and clinical polymorphism, the rare granular cell tumours of the lower respiratory tract have a constant histological appearance. Our observations confirm that large tumours (> 8–10 mm) usually extend beyond the tracheo-bronchial cartilages and, therefore, only surgical treatment may avoid recurrence.     

Effect of exercise on plasma atrial natriuretic factor and cardiac function in men and women

In order to provide an integrated view of the physiology of atrial natriuretic factor (ANF) during exercise, we studied changes of its plasma concentrations in 13 normal subjects (seven males, six females) during three graded exercise levels and two periods of recovery (5 and 30 min), concomitantly with an assessment of cardiac function and ventricular volumes by multigated radionuclide angiography. Mean ANF levels (+/- SEM) increased in all patients at the second (P less than 0.002) and third (P less than 0.002) exercise levels, and after 5-min recovery (P less than 0.01): in males from 16 +/- 7 to 30 +/- 11 pg ml-1 at the third level, in females from 27 +/- 12 to 61 +/- 33 pg ml-1. Normal values were observed after 30-min recovery. Even if mean ANF levels were all higher in females, this difference did not reach statistical significance (P = 0.06). Significant decreases of ventricular volumes, as well as increases of ejection fraction and rate pressure product, were noted during exercise and were similar in both sexes. The kinetics of plasma ANF concentrations, compared with the increase of rate pressure product, was characterized by a latency and a remanence in recovery. This remanence, also present in the changes of ventricular volumes, supports the hypothesis that other factor(s) like catecholamines might still exert their influence after the exercise stops.     

Universities as resources to state health agencies.

In a survey of the 50 State health agencies in the spring of 1992, officials were asked about their manpower and research needs in the specific areas of administration, behavioral and social science, education and information, environmental health, environmental protection, epidemiology, laboratory, law, occupational health, policy and planning, and statistics. In all, 40 agencies (80 percent) responded. Indepth telephone interviews to determine whether universities and schools and graduate programs in public health filled these needs completed the data collection process. Agency officials indicated that their resources were least adequate in environmental protection, behavioral and social science, and occupational health. They did not feel their research needs were being met. There was a general feeling that universities and schools and programs in public health have different agendas than State agencies and that practical solutions to the shortage of research resources are not forthcoming from these sources. Suggestions are made as to what can be done to improve relationships between those who train public health personnel and those who employ them.     

Interactions between peripheral blood CD8 T lymphocytes and intestinal epithelial cells (iEC)

Intestinal intraepithelial lymphocytes (iIEL) are primarily CD8 cells and most of them have a CD28^? phenotype, the phenotype of effector cytotoxic T cells. We asked whether the predominance of CD8⁺ CD28^? T cells in the gut may result from peripheral blood T cells preferentially migrating to the iIEL compartment and adhering to iEC. Compared with CD4 cells, adhesion of resting CD8⁺ T cells to iEC cell lines was significantly higher. Adhesion could be blocked with a MoAb to gp180, a molecule expressed on iEC which is known to interact with CD8/lck. No significant difference in the level of adhesion was observed between CD8⁺ CD28⁺ and CD8⁺ CD28^? T cells. Thus CD8 cells may preferentially migrate to the iIEL compartment, but loss of CD28 expression could occur in situ after migration. Consistent with this hypothesis, the CD8⁺ CD28^? cells became enriched after co-culturing T cells with iEC cell lines and primary iEC. Induction of the CD8⁺ CD28^? phenotype in cord blood and adult T cells was observed in co-cultures with iEC and also with mitogens and superantigens. In the latter case, CD28 down-modulation was seen specifically in the Vβ subset targeted by the superantigen, indicating that loss of CD28 expression is a direct result of T cell receptor (TCR)-mediated stimulation. The combined results suggest that CD8⁺ CD28^? T cells are antigen experienced T cells, and that they may have a survival advantage in the presence of gut epithelial cells in vitro. This may contribute to the predominance of CD8⁺ CD28^? T cells in the iIEL compartment.     

Immunomodulation by hydatid cyst fluid toxin (Echinococcus granulosus)

Since the experimental infection by hydatid cysts ( Echinococcus granulosus ) in mice causes immunomodulation of the host, the effects of hydatid fluid (HF) and fractions of HF were compared in vitro and in vivo . Fractions of HF were obtained using ammonium sulphate precipitation, chloroform/methanol extraction and thin-layer chromatography (TLC). HF proved to be toxic to murine peritoneal macrophages in vitro , and when macrophages were incubated with the different fractions of HF, most toxicity was found in a single TLC-purified fraction with an adjuvant-like effect on the production of specific antibodies against bovine albumin and human red blood cells in mice. Treatment of mice with the toxin caused a drop in the percentage of peripheral blood lymphocytes. Flow-cytometric analysis showed that T-cells from toxin-treated mice had lower membrane-CD3, CD4 and CD8 density, and had higher percentages of CD8⁺ splenocytes and CD4⁺ thymocytes expressing CD25. The toxin caused a down-regulation of CD4 and CD8 expression on thymocytes in vitro , that was dependent on the presence of macrophages. The results may attribute to these toxins a role in the host-parasite relationship of hydatidosis.     

The potency of D-1 and D-2 receptor antagonists is inversely related to the reward value of sham-fed corn oil and sucrose in rats

Intraperitoneal injection of 50 micrograms.kg-1 of the selective dopamine D-1 receptor antagonist, SCH 23390, significantly decreased sham feeding of 6% and 10% sucrose solutions, but not sham feeding of 100% corn oil. Intraperitoneal injection of raclopride, a D-2 antagonist, elicited a significant dose-dependent (200-400 micrograms.kg-1) decrease in sham intake of both sucrose concentrations and corn oil at doses that did not increase the latency to sham feed or produce overt motor impairment. The rank order of inhibitory potency for both SCH 23390 and raclopride was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a second experiment, we found that in 2-bottle preference tests, the rank order of preference for these three liquids was 100% corn oil greater than 10% sucrose greater than 6% sucrose. Assuming that preference measured the relative reward value of the liquids, the potencies of the two antagonists were inversely related to the reward value of the liquid that was sham fed. This result supports but does not prove the dopamine hypothesis of the positive reinforcing effect of orosensory stimulation by nutrients. In addition, the differential selectivity of the two antagonists for different classes of nutrients suggests that normal sensory and/or hedonic processing of sham-fed sucrose depends on stimulation of both D-1 and D-2 receptors, but the normal sensory and/or hedonic processing of sham-fed corn oil depends primarily, perhaps exclusively, on stimulation of D-2 receptors.     

The decay of house dust mite allergens, Der p I and Der p II, under natural conditions

Background: Fluctuations in the level of mite allergens in domestic house dust are the result of changes in the balance between synthesis, removal and decay. Purely physical forces as well as enzymatic degradation, mediated by house dust inhabiting microbes, may contribute to the decay of allergens in domestic dust. Knowledge about the speed of decay is essential for an understanding of the dynamics of allergen levels. Objective: The present study is a quantitative assessment of the speed of decay at nine combinations of temperature (15°C, 20°C and 25°C) and relative humidity (33%, 55% and 75%). Methods: Samples of mite infested material of an old rug were stored at these temperature/relative humidity-combinations for 6, 12 or 18 months, after the mites were killed by cither a freezing treatment or an acaricide (lindane). The microbes living in the rug presumably survive these treatments. Concentrations of Der p I and Der p II + Der f II. in extracts of the rug material, were measured by a radio immunoassay. Results: No significant changes in the levels of Der p I and Der p II +Der f II, could be detected even after 1¹/₂ year at a high temperature and humidity. Conclusion: These findings incidate that mite allergens can be extremely stable under normal domestic circumstances.     

Assessing reflective writing on a pediatric clerkship by using a modified Bloom's Taxonomy.

OBJECTIVE: Reflection enables learners to analyze their experiences and capture the wisdom that lies within. Effective teaching requires reliable methods of assessment. Several methods of assessing reflective writing have been described; however, they often require significant training, and reliability has seldom been assessed. This study was designed to determine the interrater reliability of a method of assessing reflective writing by using a modified Bloom's Taxonomy. METHODS: Twenty-one third-year medical students maintained reflective journals throughout their pediatric clerkship. A coding schema based on Bloom's Taxonomy was developed to assess the level of cognitive processing evident in the journals. Journals were independently assessed by 3 raters. Percent agreement, kappa statistics, and intraclass correlation coefficients (ICC [2,1]) were used to assess interrater reliability. RESULTS: Three hundred eight entries from 21 journals were assessed. Percent agreement ranged from 78.2% to 100%. Kappa statistic for each level ranged from 0.57 +/- 0.04 to 0.73 +/- 0.04, and for the highest level of processing evident it ranged from 0.52 +/- .04 to 0.58 +/- 0.04. ICC (2,1) for each level of cognitive processing ranged from 0.62 (F = 6.20; P = .000) to 1.00, and for the highest level of cognitive processing evident, it was 0.79 (F = 12.42; P = .000). Substantial to almost perfect agreement was attained. CONCLUSIONS: Reflective journals allow learners to revisit their experiences for critical analysis and deeper learning. This study describes a reliable method, based on Bloom's Taxonomy, of determining whether learners have achieved higher order thinking through reflective journal writing. This method can provide a baseline for facilitating higher order processing, critical thinking, and reflective practice.