Lower expression of Th1-related cytokines and inducible nitric oxide synthase in mice with streptozotocin-induced diabetes mellitus infected with Mycobacterium tuberculosis

Diabetes mellitus is an important predisposing factor for tuberculosis. The aim of this study was to investigate the mechanism underlying this association using a murine model. Mice with streptozotocin-induced diabetes mellitus were prone to Mycobacterium tuberculosis infection, as indicated by increased numbers of live bacteria in lung, liver and spleen. In diabetic mice, the levels of IL-12 and IFN-gamma in the lung, liver and spleen were lower than those in control animals on day 14 postinfection, while the opposite was true for IL-4 levels in the lung and liver. The expression pattern of inducible nitric oxide synthase (iNOS), in the two mice types was as for IL-12 and IFN-gamma. In addition, peritoneal exudate cells obtained from diabetic mice produced lower amounts of IL-12 and NO than those from control mice, when stimulated in vitro with M. bovis BCG. Spleen cells from diabetic mice infected with M. tuberculosis produced a significantly lower amount of IFN-gamma upon restimulation with purified protein derivatives (PPD) than those from infected nondiabetic mice. Interestingly, addition of high glucose levels (33 mM) to the cultures of PPD-restimulated spleen cells reduced the synthesis of IFN-gamma only in diabetic mice, and not in nondiabetic mice. Finally, control of blood glucose levels by insulin therapy resulted in improvement of the impaired host protection and Th1-related cytokine synthesis. Our results suggest that the reduced production of Th1-related cytokines and NO account for the hampered host defense against M. tuberculosis infection under diabetic conditions.     

Application of personal computer to an analysis of small de novo chromosomal insertion: a case of de novo 3q2 trisomy with ins(8;3)

To identify the origin of a small inserted segment in a de novo 8p+ chromosome, an originally programmed computerized database for chromosomal aberration syndromes was utilized. The system selected 3q2 trisomy and 10q2 trisomy as candidates. As a result of a careful comparison of several high-resolution banding patterns among chromosomes 3, 10 and the inserted segment, her karyotype was disignated as: 46,XX,-8,+der(8), inv ins(8;3)(p21.1;q26.32q24) de novo. A small segment from 3q24 to 3q26.32 was trisomic, and invertedly inserted into the short arm of chromosome 8. This computerized database was considered to be useful for analyses of the small de novo inserted chromosomal segment.     

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.     

The National Health Plan 2030: Its Purpose and Directions of Development

The National Health Plan 2030 (HP2030) started to be prepared in 2017 and was completed and announced in December 2020. This study presents an overview of how it was established, the major changes in policies, its purpose, and future directions. This study analyzed the steps taken in the past 4 years to establish HP2030 and reviewed major issues at the international and governmental levels based on an evaluation of HP2020 and its content. HP2030 establishes 6 divisions and 28 topic areas, and it will continue to expand investments in health with a total budget of 2.5 trillion Korean won. It also established goals to enhance health equity for the first time, with the goal of calculating healthy life expectancy in a way that reflects the circumstances of Korea and reducing the gap in income and healthy life expectancy between regions. The establishment of HP2030 is significant in that it constitutes a sustainable long-term plan with sufficient preparation, contains policy measures that everyone participates in and makes together, and works towards improvements in universal health standards and health equity. With the announcement of HP2030, which includes goals and directions of the national health policy for the next 10 years, it will be necessary to further strengthen collaboration with relevant ministries, local governments, and agencies in various fields to concretize support for prevention-centered health management as a national task and to develop a health-friendly environment that considers health in all policy areas.