BST-1, a surface molecule of bone marrow stromal cell lines that facilitates pre-B-cell growth.

Bone marrow stromal cells are essential for B-lymphocyte development. However, how stromal cells regulate B lymphopoiesis is not clear. In this paper, we report the molecular cloning of a stromal cell line-derived glycosyl-phosphatidylinositol-anchored molecule, BST-1, that facilitates pre-B-cell growth. The deduced amino acid sequence of BST-1 exhibited 33% identity with CD38. BST-1 was expressed in a wide range of tissues and in umbilical vein endothelial cells, whereas it was scarcely expressed in a variety of hematopoietic cell lines. The gene for BST-1 was assigned to chromosome 14q32.3, where immunoglobulin heavy-chain genes are clustered. BST-1 expression was enhanced in rheumatoid arthritis patient-derived bone marrow stromal cell lines that were previously shown to have an enhanced ability to support the growth of a pre-B-cell line as compared with stromal cell lines derived from healthy donors.     

Multidetector row computed tomography for identification of left atrial appendage filling defects in patients undergoing pulmonary vein isolation for treatment of atrial fibrillation: Comparison with transesophageal echocardiography

BACKGROUND: Advances in multidetector computed tomography (MDCT) technology now permit three-dimensional cardiac imaging with high spatial and temporal resolution. Historically, transesophageal echocardiography (TEE) has been the gold standard for assessment of the left atrial appendage (LAA) in patients with atrial fibrillation and other atrial arrhythmias. Findings on TEE, including demonstration of LAA thrombus and dense nonclearing spontaneous echocardiographic contrast (SEC), predict future fatal and nonfatal thromboembolic events. OBJECTIVE: The purpose of this study was to compare the diagnostic performance of 64-detector row MDCT in detecting LAA thrombus and dense nonclearing SEC as identified by TEE in patients undergoing pulmonary vein isolation for treatment of atrial fibrillation. METHODS: A total of 72 consecutive patients (69.4% male; mean age 56.1 +/- 10.3 years) underwent both MDCT and TEE for evaluation of the LAA (median intertest interval 0 days, interquartile range 0-5 days). MDCT assessment of the LAA was performed by two methods: (1) comparison of Hounsfield unit (HU) densities in the LAA apex to the ascending aorta (AscAo) in the same axial plane and (2) nonquantitative visual identification of a filling defect in the LAA. TEE evaluation of the LAA included identification of echodense intracavitary masses in the LAA as well as pulsed-wave Doppler interrogation of the LAA ostium. RESULTS: Patients with LAA thrombus or dense nonclearing SEC by TEE exhibited significantly lower LAA/AscAo HU ratios than patients who did not (0.82 +/- 0.22 vs 0.39 +/- 0.19, P <.001). LAA/AscAo HU cutoff ratios < or = 0.75 correlated to LAA thrombus or dense nonclearing SEC by TEE, with 100% sensitivity, 72.2% specificity, 28.6% positive predictive value, and 100% negative predictive value. HU ratios < or = 0.75 were associated with pulsed-wave Doppler velocities <50 cm/s of the LAA ostium (P <.001). In multivariable analysis, LAA/AscAo HU ratio < or = 0.75 remained a robust predictor of LAA thrombus or dense nonclearing SEC by TEE (P <.001). In contrast, MDCT identification of TEE-identified LAA thrombus or dense nonclearing SEC by visual detection of LAA filling defects resulted in lower sensitivity (50%) and negative predictive value (95.1%). CONCLUSION: Current-generation MDCT successfully identifies LAA thrombus and dense nonclearing SEC with high sensitivity and moderate specificity. Importantly, LAA/AscAo HU ratios >0.75 demonstrate 100% negative predictive value for exclusion of LAA thrombus or dense nonclearing SEC. These results suggest that in patients undergoing pulmonary vein isolation procedures, MDCT examinations that demonstrate LAA/AscAo HU ratios >0.75 may preclude the need for preprocedural TEE.     

Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters

Upon activation by with-no-lysine kinases, STE20/SPS1-related proline–alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na⁺-Cl⁻ cotransporter (NCC) and Na⁺-K⁺-2Cl⁻ cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.     

Healthy HTLV-I carriers in Japan: the haematological and immunological characteristics

The haematological and immunological characteristics of 34 healthy anti-HTLV-I antibody-positive individuals (HTLV-I carriers) in southwestern Japan were examined. No significant difference was noted between carriers and the controls in counts of RBC, WBC and the absolute number of lymphocytes. The serum IgG in the carriers was higher than that of the controls. The percentages of OKT4, OKT8, OKIa1 and B1-positive cells were found to be normal in the peripheral blood of the carriers, whereas the percentages of OKT11 and anti-Tac-positive cells were significantly higher in the carriers than in the controls. A correlation was observed between the percentages of anti-Tac-positive cells and the titres of anti-HTLV-I antibody in the carriers. After a 72 h incubation of peripheral blood lymphocytes with medium alone, the percentage of anti-Tac-positive cells tended to decrease in the controls, but to increase in carriers, with the appearance of large blastoid cells resembling blastic transformed lymphocytes cultured with mitogen. Tac and Ia antigens were markedly expressed on these large blastoid cells.     

Identification of simultaneous mutation of fibrinogen alpha chain and protein C genes in a Japanese kindred

Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas protein C deficiency increases susceptibility to thrombosis in children or adolescence. Mutations of these genes have been, therefore, established as independent risk factors for coagulation disorders. We describe the homozygous mutation of the fibrinogen alpha chain gene and additional heterozygous mutation of the protein C gene in a male infant who showed prolonged umbilical bleeding after birth. On examination, the plasma fibrinogen was undetectable, and the activity and antigen level of protein C were reduced. The patient showed no fibrinogen Aalpha chain as well as Bbeta and gamma chains by Western blotting. The sequencing analysis showed the homozygous deletion of 1238 bases from intron 3 at position 2008 to intron 4 at position 3245 in the fibrinogen alpha chain gene. Both parents were heterozygous carriers of this mutation. In this patient, an additional mutation was also detected in the protein C gene: the heterozygous deletion of exon 7 at position 6161-6163 or 6164-6166, resulting the deletion of one amino acid (Lys150 or 151). His mother was also a carrier of this mutation. As the simultaneous mutation of the fibrinogen alpha chain and protein C genes has not been previously reported, the influence of the interaction between these two mutations on the clinical manifestations of this patient should be carefully monitored for a long period.     

Alu‐mediated large deletion of the CDSN gene as a cause of peeling skin disease

Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both telomeric and centromeric breakpoints existed within Alu‐S sequences that were oriented in opposite directions. These results suggest an Alu‐mediated recombination event as the mechanism underlying the deletion in our patient.     

Serum Magnesium Level Is Associated with Type 2 Diabetes in Women with a History of Gestational Diabetes Mellitus: The Korea National Diabetes Program Study

Gestational diabetes mellitus (GDM) is a strong predictor of postpartum prediabetes and transition to overt type 2 diabetes (T2DM). Although many reports indicate that low magnesium is correlated with deteriorated glucose tolerance, the association between postpartum serum magnesium level and the risk for T2DM in women with a history of GDM has not been evaluated. We analyzed postpartum serum magnesium levels and development of prediabetes and T2DM in women with prior GDM according to American Diabetes Association (ADA) criteria using the Korean National Diabetes Program (KNDP) GDM cohort. During a mean follow-up of 15.6±2.0 months after screening, 116 women were divided into three groups according to glucose tolerance status. Ultimately, eight patients (6.9%) were diagnosed with T2DM, 59 patients (50.9%) with prediabetes, and 49 patients (42.2%) with normal glucose tolerance (NGT) after follow-up. The T2DM group had the lowest serum magnesium level (0.65 [0.63-0.68] mM/L) in the postpartum period, but there was no significant difference between the prediabetes group (0.70 [0.65-0.70] mM/L) and the NGT group (0.70 [0.65-0.70] mM/L) (P=0.073) Multiple logistic regression analysis showed that postpartum HOMA-IR was a significant predictor of both prediabetes and T2DM. Moreover, we found that postpartum serum magnesium level was also a possible predictor for T2DM development. Serum magnesium level in the postpartum period may be a possible predictor for T2DM development in women with a history of GDM.