Modulation of Valpha19 NKT cell immune responses by alpha-mannosyl ceramide derivatives consisting of a series of modified sphingosines

We have demonstrated that analogues of alpha-mannosyl ceramide (alpha-ManCer) consisting of a series of immunosuppressive 2-aminoalcohol derivatives in place of sphingosine promote a greater immune response from mouse invariant Valpha19-Jalpha26 (AV19-AJ33) TCR-bearing NKT (Valpha19 NKT) cells than alpha-ManCer itself. To further characterize the immune responses of Valpha19 NKT cells to the alpha-ManCer analogues, cytokine production by the cells was examined in detail. We found that certain alpha-ManCer derivatives individually induced either Th1- or Th2-dominant cytokine production in culture. The Th1- or Th2-biased immune responses of Valpha19 NKT cells were dependent on MHC class I-like MR1, since they were induced by coculture with the MR1 transfectants previously loaded with the glycolipids and were inhibited in the presence of anti-MR1 antiserum. Presumably, the recognition of the alpha-mannosyl residue of the alpha-ManCer analogues by the invariant TCR is individually modulated, depending on the altered interaction with the groove of the antigen-presenting MR1. Priming of the Valpha19 invariant TCR-transgenic mice in vivo with these glycolipid derivatives resulted in the induction of the Th1- or Th2-biased immune responses. Thus, these alpha-ManCer derivatives are likely to be useful in immunotherapy for either Th1 or Th2 excess autoimmune diseases, modulating the function of Valpha19 NKT cells.     

Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation

CONTEXT: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth. OBJECTIVE: We hypothesized that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR). PATIENTS: Twenty-four children with unexplained IUGR (birth weight < -1.5 SD) and short stature (<-2.0 SD) were screened for abnormalities of the IGF-IR gene. METHODS: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and beta-subunit autophosphorylation. RESULTS: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 +/- 26% of normal) and less mature beta-subunit protein (63 +/- 12%); 3) [125I]IGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 +/- 0.16 x 10(6) vs. 1.14 +/- 0.12 x 10(6) sites per cell; P < 0.05); and 4) both IGF-I-stimulated [3H]thymidine incorporation and IGF-IR beta-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05). CONCLUSIONS: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.     

Co-existence of Mycobacterium tuberculosis and Mycobacterium intracellulare in one sputum sample

An 81-year-old man was admitted to the hospital with a severe sore throat and a low grade fever. A chest radiograph showed bilateral diffuse reticulonodular shadows. By fluorescent stain for mycobacteria, his sputum smear showed acid-fast bacteria. The initial polymerase chain reaction (PCR) of his sputum revealed Mycobacterium intracellulare (M. intracellulare), but not Mycobacterium tuberculosis (M. tuberculosis). However, a repeat PCR was performed because M. tuberculosis could not be ruled out due to his clinical symptoms and chest imaging. The second PCR detected both M. intracellulare and M. tuberculosis. From the standpoint of infection control, this case illustrates the possibility that M. tuberculosis could be a threat if a second PCR is not done. While PCR is a useful exam for diagnosing M. tuberculosis, it can produce false negative results. Therefore, for diagnosing tuberculosis, particularly in a case such as the present case, a second PCR, which is not normally necessary, should be done.     

Structures of triterpenoids from the leaves of Lansium domesticum

Journal of Natural Medicines - From the methanolic extract of the leaves of Lansium domesticum, three new onoceranoid-type triterpenoids, lansium acids X–XII and a new cycloartane-type...     

Alpha1-adrenoceptor-mediated breakdown of phosphatidylinositol 4,5-bisphosphate inhibits pinacidil-activated ATP-sensitive K+ currents in rat ventricular myocytes

Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates ATP-sensitive K+ (K(ATP)) channel activity. Because phospholipase C (PLC) hydrolyzes membrane-bound PIP2, which in turn may potentially decrease K(ATP) channel activity, we investigated the effects of the alpha1-adrenoceptor-G(q)-PLC signal transduction axis on pinacidil-activated K(ATP) channel activity in adult rat and neonatal mouse ventricular myocytes. The alpha1-adrenoceptor agonist methoxamine (MTX) reversibly inhibited the pinacidil-activated K(ATP) current in a concentration-dependent manner (IC50 20.9+/-6.6 micromol/L). This inhibition did not occur when the specific alpha1-adrenoceptor antagonist, prazosin, was present. An involvement of G proteins is suggested by the ability of GDPbetaS to prevent this response. Blockade of PLC by U-73122 (2 micromol/L) or neomycin (2 mmol/L) attenuated the MTX-induced inhibition of K(ATP) channel activity. In contrast, the MTX response was unaffected by protein kinase C inhibition or stimulation by H-7 (100 micro mol/L) or phorbol 12,13-didecanoate. The MTX-induced inhibition became irreversible in the presence of wortmannin (20 micro mol/L), an inhibitor of phosphatidylinositol-4 kinase, which is expected to prevent membrane PIP2 replenishment. In excised inside-out patch membranes, pinacidil induced a significantly rightward shift of ATP sensitivity of the channel. This phenomenon was reversed by pretreatment of myocytes with MTX. Direct visualization of PIP2 subcellular distribution using a PLCdelta pleckstrin homology domain-green fluorescent protein fusion constructs revealed reversible translocation of green fluorescent protein fluorescence from the membrane to the cytosol after alpha1-adrenoceptor stimulation. Our data demonstrate that alpha1-adrenoceptor stimulation reduces the membrane PIP2 level, which in turn inhibits pinacidil-activated K(ATP) channels.     

Hodgkin's disease preceded by unique neurological symptoms

This is the first case report of Hodgkin's disease (HD) which showed both remission and exacerbation of neurological signs before a confirmed diagnosis of HD. The episodes occurred three times and multiple lesions were involved. Immunoabsorption plasmapheresis and double filtration plasmapheresis were effective for the first episode, whereas, corticosteroids partly improved the second and third episodes. Fever and lymph node swelling were apparent afterward and she was diagnosed as having HD from a supraclavicular lymph node biopsy. The remaining neurologic deficits responded to chemotherapy and radiotherapy. The neurological symptoms were considered as a paraneoplastic syndrome of HD.     

Influence of Strain Gradient on Fatigue Life of Carbon Steel for Pressure Vessels in Low-Cycle and High-Cycle Fatigue Regimes

This paper discusses how the strain gradient influences the fatigue life of carbon steel in the low-cycle and high-cycle fatigue regimes. To obtain fatigue data under different strain distributions, cyclic alternating bending tests using specimens with different thicknesses and cyclic tension–compression tests were conducted on carbon steel for pressure vessels (SPV235). The crack initiation life and total failure life were evaluated via the strain-based approach. The experimental results showed that the crack initiation life became short with decreasing strain gradient from 10² to 10⁶ cycles in fatigue life. On the other hand, the influence of the strain gradient on the total failure life was different from that on the crack initiation life: although the total failure life of the specimen subjected to cyclic tension–compression was also the shortest, the strain gradient did not affect the total failure life of the specimen subjected to cyclic bending from 10² to 10⁶ cycles in fatigue life. This was because the crack propagation life became longer in a thicker specimen. Hence, these experimental results implied that the fatigue crack initiation life could be characterized by not only strain but also the strain gradient in the low-cycle and high-cycle fatigue regimes.