The effect of sustained-release theophylline granules in the inhibition of exercise-induced asthma]

We studied the protective effect of sustained-release theophylline granules on early or late response in exercise-induced asthma (EIA) in 16 patients ranging in age from 7 to 18 years. A standardized exercise test was examined 2 hours after administration of theophylline granules on one day and after no medication on another day. On both days, the lung functions and the serum theophylline and cortisol concentrations of the patients were examined before exercise and over a period of 8 hours after exercise. On days without medication, early response was seen in 16 patients and late response in 6. On days with medication, the theophylline granules inhibited early response in 13 of the 16 patients and late response in 5 of the 6 patients. This suggests that theophylline preparation is a useful drug for inhibiting the dual responses of EIA.     

Effects of high and low dietary fat and indomethacin on tumour growth, hormone receptor status and growth factor expression in DMBA-induced rat breast cancer.

The effects of high and low dietary fat (20% vs. 0.5% corn oil), and of the prostaglandin synthetase inhibitor indomethacin (0.005% w/w), on tumour incidence, tumour growth, hormone-receptor status and growth-factor expression were examined in dimethylbenzanthracene (DMBA)-induced rat breast cancer. The high dietary-fat group showed a significantly higher tumour incidence, larger tumour size and larger number of bromodeoxyuridine(BrdU)-positive cells of tumours as compared with those in the low dietary-fat group. Indomethacin reduced tumour incidence significantly, but conversely increased the tumour size and the number of BrdU-positive cells in both the high and the low dietary-fat groups. No significant difference was noted in the hormone-receptor status of the tumours. Growth factors (TGF-alpha and IGF-II) were somewhat highly expressed in the high dietary-fat group as compared with the low dietary-fat group, but indomethacin rather reduced the growth-factor expression. It is concluded that high dietary fat stimulates tumour incidence and tumour proliferation, while indomethacin has dual effects: a stimulating effect on tumour proliferation, but an inhibiting effect on tumour incidence. It is also suggested that hormone-receptor status and growth-factor expression do not play an important role in their stimulating effects on tumour proliferation.     

Thyroid dysfunction and histologic correlation using thyroid needle biopsy specimens

In this article, we describe the usefulness of thyroid needle biopsy in the differential diagnosis of thyroid disorders revealing unusual thyroid function. Firstly, we describe the relationship between thyroid function and its histology in 601 cases of chronic thyroiditis. In the histologic group A, the majority of the cases showed a latent or overt hypothyroidism and in histologic group B, hyperthyroid, euthyroid and latent hypothyroid cases were found in nearly equal frequency, respectively. In histologic group C, most cases were in euthyroid and in histologic group D, most cases showed a hyperthyroidism. In the silent thyroiditis and postpartum thyroiditis, known to show a characteristic clinical and laboratory finding, the histologic features of thyroid gland were as follows: the observed characteristic histologic changes in both diseases were an extensive follicular destruction associated with chronic diffuse thyroiditis. These destructive changes disappeared in association with the clinical and laboratory recovery. In the patients with iodine-excess hypothyroidism, the thyroid glands also revealed characteristic histologic changes. A marked hyperplastic change of follicular cells and a lack of colloid material in the follicular lumen was the predominant histologic feature. Based on our personal experiences, thyroid needle biopsy should be recommended as a useful tool for differentiation of causes of hyper- or hypothyroidism.     

Hindquarters vasoconstriction through central GABA(B) receptors in conscious rats

The exogenous application of GABA into the cisterna magna of the freely moving rat decreases hindquarters vascular tone as well as arterial pressure. GABA could influence GABA receptor subtypes A, B or C. However, the hindquarters vascular response to the stimulation of each receptor subtype has not yet been investigated. The present study therefore characterized the response to the GABA(B) receptor agonist baclofen injected into the cisterna magna of the conscious rat. Intracisternally injected baclofen induced long-lasting increases in hindquarters vascular resistance and arterial pressure in a dose-dependent manner. Both actions induced by baclofen were completely blocked by a prior intracisternal injection with the GABA(B) receptor antagonist CGP 35348 (p-[3-aminopropyl]-p-diethoxymethylphosphinic acid), and systemically by ganglionic blockade. These actions of baclofen were also abolished centrally by sodium pentobarbital anaesthesia. The results suggest that GABA(B) receptor stimulation via the cisterna magna induced hindquarters vasoconstriction, probably due to central disinhibition of sympathetic activity.     

Lysosome is a primary organelle in B cell receptor-mediated apoptosis: an indispensable role of Syk in lysosomal function

To investigate the mechanism of B cell receptor (BCR)-mediated apoptosis, we utilized immature B cell lines, DT40 and WEHI-231. In both cell lines, BCR-crosslinking caused the increase in lysosomal pH with early apoptotic changes characterized by chromatin condensation and phosphatidylserine exposure. This increase was detected in c-Abl-deficient DT40 cells but not in Syk-deficient cells, which corresponded to the fact that the former cells but not the latter revealed BCR-induced apoptosis. In contrast, BCR-crosslinking caused no apparent change in mitochondrial transmembrane potential. Therefore, the lysosomal change might be a primary event in BCR-induced apoptosis in DT40 cells. The increased activity of cathepsin B and apoptosis-preventing effect of a cathepsin inhibitor suggested a significant role of lysosomal enzymes in this apoptosis. By microscopic studies, lysosomes of wild-type DT40 cells fused to BCR-carrying endosomes became enlarged and accumulated one another. In contrast, these changes of lysosomal dynamics did not occur in Syk-deficient cells but transfer of wild-type Syk restored the lysosomal changes and apoptosis. These results demonstrated that the lysosomal change accompanied with the activation of lysosomal enzymes is a primary step in BCR-crosslinking-mediated apoptosis and Syk is responsible for this step through the fusion of BCR-carrying endosomes to lysosomes.     

Appearance of the LAT protein at an early stage of B-cell development and its possible role

The linker protein LAT is expressed mainly in T and natural killer (NK) cells. LAT-deficient mice have an arrest of intrathymic T-cell development at the CD4+ CD8+ stage and lack mature T cells in the periphery. However, no gross abnormality in development and function of the B and NK cells has been described. Here we report that LAT is expressed in mouse progenitor B (pro-B) and precursor B (pre-B) cells, but not in immature or mature B cells. LAT in pre-B cells becomes tyrosine phosphorylated upon cross-linking of the pre-B-cell receptor (pre-BCR) by anti- micro antibody. Incubation of 1xN/2b (mouse pre-B-cell line) cells or bone marrow cells from microMT/ microMT mice, which lack B cells after the small pre-B-cell stage, with anti-Ig beta antibody resulted in the downregulation of LAT expression. Transgenic mice which expressed LAT protein in B-lineage cells showed an increased proportion of pro- and large pre-B cells in the bone marrow and a remarkable reduction in the numbers of mature B cells in peripheral lymphoid tissues. Collectively, the present results indicate that LAT is expressed in the cells at the early stages of B-lineage development, but is absent in immature and mature B cells. LAT may play a crucial role in the negative regulation of B-cell development at the transition from pre-B to mature B-cell stages, and signal(s) via the pre-BCR may extinguish LAT expression, thus allowing pre-B-cell differentiation towards the mature B-cell stage.     

A neuroactive steroid, allotetrahydrocorticosterone inhibits sensory nerves activation in guinea-pig airways

We examined the effects of a neuroactive steroid, allotetrahydrocorticosterone on the activation of capsaicin-sensitive afferent sensory nerves (C-fibers). Allotetrahydrocorticosterone (0.0001-1.0 microg/ml) dose-dependently inhibited electrical field stimulation-induced guinea-pig bronchial smooth muscle contraction, but not the substance P-induced contraction at 1.0 microg/ml. Allotetrahydrocorticosterone (0.01-1.0 microg/ml) also reduced the capsaicin-induced release of substance P-like immunoreactivity from guinea-pig airway tissues in a dose-dependent manner. The inhibitory effect of allotetrahydrocorticosterone on electrical field stimulation-induced bronchial contraction were reduced by the pretreatment of voltage-dependent K+ channel blockers, tetraethylammonium (1 mM). This evidence suggests that allotetrahydrocorticosterone negatively modulate the activation of C-fibers and substance P release from their endings in airway tissues via the opening of voltage-dependent K+ channels.     

Mediolateral intercalation in planarians revealed by grafting experiments.

We investigated how planarians organize their left-right axis by using ectopic grafting. Planarians have three body axes: anteroposterior (A-P), dorsoventral (D-V), and left-right (L-R). When a small piece is implanted into an ectopic region along the A-P and D-V axes, intercalary structures are always formed to compensate for positional gaps. There are two hypotheses regarding L-R axis formation in this organism: first, that the left and right sides of the animal may be recognized as different parts, and L-R intercalation can induce midline structures (asymmetry hypothesis); second, that both sides may have symmetrical positional values, and mediolateral (M-L) intercalation creates positional values along the L-R axis (symmetry hypothesis). We performed ectopic grafting experiments in the head region of the planarian, Dugesia japonica, to examine these hypotheses. A left lateral fragment containing a left auricle was implanted into the medial region of the host. Ectopic structures were always formed only on the left side of the graft, where lateral tissues abutted onto the medial tissues. However, no morphologic change was induced on the right side of the graft, where left-sided tissues faced onto right-sided tissues. Molecular marker analyses indicated that ectopic structures formed on the left side of the graft were induced by M-L intercalation, supporting the "symmetry hypothesis." When the midline tissues were implanted into a lateral region, they induced a complete ectopic head, demonstrating that M-L intercalation may be sufficient to establish the L-R axis in planarians.     

Comparison of various bone marrow fractions in the ability to participate in vascular remodeling after mechanical injury

In contrast to conventional assumption, recent reports propose the possibility that hematopoietic stem cells (HSCs) may have broader potential to differentiate into various cell types. Here, we tested the pluripotency of HSCs by comparing vascular lesions induced by mechanical injury after bone marrow reconstitution with total bone marrow (TBM) cells, c-Kit+ Sca-1+ Lin- (KSL) cells, or a single HSC cell (Tip-SP CD34-KSL cell, CD34- c-Kit+ Sca-1+ Lin- cell with the strongest dye-efflux activity) harboring green fluorescent protein (GFP). The lesions contained a significant number of GFP-positive cells in the TBM and KSL groups, whereas GFP-positive cells were rarely detected in the HSC group. These results suggest that transdifferentiation of a highly purified HSC seems to be a rare event, if it occurs at all, whereas bone marrow cells including the KSL fraction can give rise to vascular cells that substantially contribute to repair or lesion formation after mechanical injury.