Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.     

Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients

An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and alpha-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; chi2=6.062, P=0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P=0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P=0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.     

A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies

We describe a Japanese family with familial platelet disorder with propensity to develop myeloid malignancies (FPD/MM). Among the three affected individuals, two members developed myeloid malignancies. Sequence studies demonstrate that all affected individuals of the pedigree display a heterozygous single nucleotide deletion in exon 8 of the RUNX1 gene.     

Dosage of inactivated influenza vaccine for infants

BACKGROUND: In Japan, the inoculation dosage of inactivated influenza vaccine for children under 1 year old is 0.1 mL per dose. The dosage is not half as much as that in Europe and the U.S.A. We considered that low efficacy fate of influenza vaccine in children under 1 year old results from its less dosage. So we designed this study to verify this hypothesis. MATERIALS AND METHODS: This study was prospective in design. Subjects were divided into two groups by age: 8 to 11 months old (n = 26) and 12 to 16 months old (n = 22). Infants received 0.1 mL of inactivated influenza vaccine and over 1 year, 0.2 mL. Forty-eight children were inoculated twice at intervals of over 4 weeks. Serum samples were drawn before the first inoculation and 1 month after the second vaccination. Pre- and post-immunization antibody titers were measured. The titers of hemaglutinatinin inhibiting antibodies to the 3 viral strains were assayed. Antibody titers were determined using HAI. RESULTS: The post-vaccination proportions of children with protective HAI antibody titers were significantly smaller in infants than those in children over 1 year old (A/H1N1; 23% vs. 77%, A/H3N2; 39% vs. 73%, B; 0% vs. 32%). The number of children with >four-fold increased antibodies were significantly smaller in infants than that in 1 year old (A/H1N1; 74% vs. 91%, B; 0% vs. 39%). In the mean antibody titer, there were signficant differences between infants and children over 1 year old (A/H1N1; 19 times vs. 56 times, B; 8 times vs. 14 times). CONCLUSION: We consider that significant differences in antibody titers between infants and children over 1 year old were caused by the difference of dosage in influenza vaccines. To obtain protective levels of antibodies by influenza vaccines in infants, they must be inoculated with enough dosage.     

Association of human T-cell leukemia virus type 1 with prevalent rheumatoid arthritis among atomic bomb survivors: A cross-sectional study

Previous studies have suggested that human T-cell leukemia virus type 1 (HTLV-1) might act as a pathogen in rheumatoid arthritis (RA), but epidemiological evidence of an association is scarce. We measured anti-HTLV-1 antibodies among Nagasaki atomic bomb survivors to determine whether HTLV-1 is related to RA and whether radiation exposure is associated with HTLV-1 and RA prevalence.This is a cross-sectional study among atomic bomb survivors who participated in biennial health examinations from 2006 to 2010. Serum levels of anti-HTLV-1 antibodies were measured using a chemiluminescent enzyme immunoassay and confirmed by Western blotting. Association between HTLV-1 and RA was analyzed by a logistic regression model.Of 2091 participants (women 61.5%; median age, 73 years), 215 (10.3%) had anti-HTLV-1 antibodies. HTLV-1 prevalence was higher among women (13.1% vs 5.8%; P < .001). Twenty-two participants (1.1%) were diagnosed with RA. HTLV-1 prevalence among RA participants was significantly higher than that among non-RA participants (27.3% vs 10.1%; P = .020). After adjustment for age, sex, and hepatitis C virus infection, HTLV-1 was significantly associated with prevalent RA (odds ratio, 2.89; 95% confidence interval, 1.06, 7.03). There was no association between radiation dose and either the prevalence of HTLV-1 or RA.This study, among a well-defined group of atomic bomb survivors, suggests that HTLV-1 is associated with RA.     

Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels

The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.     

Sites of origin of ventricular premature beats in patients with and without cardiovascular disease evaluated by body surface mapping

The site of origin of ventricular premature beats (VPBs) was estimated by QRS maps and its distribution in two patient groups was studied. VPB origin was determined by comparing the body surface map of VPBs with that during electrical stimuli applied at various sites of the ventricle. Subjects were 100 patients without obvious underlying cardiovascular disease (Group N) and 289 patients with various heart diseases (Group D). Nine sites of origin of VPB were identified. In group N, VPBs of right ventricular origin were noted in 69%, those of left ventricular origin in 6%. There was a relatively high incidence of VPBs with foci estimated to be the divisions of the left bundle branch, and the age of patients with these VPBs was young. In Group D, VPBs of left ventricular origin showed a higher incidence (34.6%) and those of right ventricular origin a lower incidence (41.2%) than those in group N. The data suggest that VPBs originating from the apex and base of the ventricle strongly indicate the presence of basic heart disease and that VPBs originating in or near the divisions of the left bundle branch in younger subjects do not necessarily indicate cardiac disease.     

Knockdown of macrophage migration inhibitory factor disrupts adipogenesis in 3T3-L1 cells

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP)alpha, and C/EBPdelta decreased with MIF siRNA transfection, but C/EBPbeta expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1-3 d and from 14-20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPdelta expression.