Immunomodulatory effects of mesenchymal stem cells on leukocytes with emphasis on neutrophils

Mesenchymal stem cells (MSCs) are a population of multipotent cells with the ability of expansion and plastic-adherence in vitro. MSCs can differentiate into chondrocytes, osteocytes and adipocytes; they lack co-stimulatory molecules and have small amount of MHC-I that makes no immunogenicity. These characteristics are empowering MSCs’ huge in vivo applications. In addition, MSCs possess the ability of regulating the immune responses in many diseases. Many studies have shown that MSCs have immunosuppressive as well as immunoenhancing properties such as inhibition of T-lymphocytes proliferation and cytokines production which lead to the balance of Th1 and Th2. Some other immunomodulatory features of MSCs are increasing suppressive capacity of T_reg, reducing activity of B-lymphocytes and immunoglobulins secretion, inhibition of dendritic cells maturation and antigen presenting capacity, and inhibition of NK-cells activity. MSCs also exert inhibitory effects on neutrophil apoptosis and reduce reactive oxygen species production. The purpose of this paper is to focus on the MSCs? effects on immune cells, especially neutrophils.     

NK cell-mediated lysis of autologous HCMV-infected skin fibroblasts is highly variable among NK cell clones and polyclonal NK cell lines

Lysis of human cytomegalovirus (HCMV)-infected fibroblasts by autologous natural killer (NK) cells was examined in vitro. For NK cell clones, receptor expression was determined at the level of mRNA and cell-surface protein and compared to the lysis of HCMV AD169 strain-infected fibroblasts in which HLA class I was >70% downregulated. The clones ranged broadly in their ability to lyse AD169-infected fibroblasts, correlating neither with the expression of inhibitory KIR, leukocyte inhibitory receptor-1, or CD94:NKG2A receptors nor with the number of different inhibitory KIR expressed per clone. Some lines of polyclonal NK cells preferentially lysed AD169-infected cells and similarly lysed fibroblasts infected with mutant virus RV798, which lacks the genes for downregulating HLA class I. These results demonstrate that NK cell lysis of HCMV-infected autologous fibroblasts is more complex than a simple missing-self mechanism involving downregulation of HLA class I and failure to engage inhibitory self-specific KIR.     

Mortality among recent purchasers of handguns

BACKGROUND: There continues to be considerable controversy over whether ownership of a handgun increases or decreases the risk of violent death. METHODS: We conducted a population-based cohort study to compare mortality among 238,292 persons who purchased a handgun in California in 1991 with that in the general adult population of the state. The observation period began with the date of handgun purchase (15 days after the purchase application) and ended on December 31, 1996. The standardized mortality ratio (the ratio of the number of deaths among handgun purchasers to the number expected on the basis of age- and sex-specific rates among adults in California) was the principal outcome measure. RESULTS: In the first year after the purchase of a handgun, suicide was the leading cause of death among handgun purchasers, accounting for 24.5 percent of all deaths and 51.9 percent of deaths among women 21 to 44 years old. The increased risk of suicide by any method among handgun purchasers (standardized mortality ratio, 4.31) was attributable entirely to an excess risk of suicide with a firearm (standardized mortality ratio, 7.12). In the first week after the purchase of a handgun, the rate of suicide by means of firearms among purchasers (644 per 100,000 person-years) was 57 times as high as the adjusted rate in the general population. Mortality from all causes during the first year after the purchase of a handgun was greater than expected for women (standardized mortality ratio, 1.09), and the entire increase was attributable to the excess number of suicides by means of a firearm. As compared with the general population, handgun purchasers remained at increased risk for suicide by firearm over the study period of up to six years, and the excess risk among women in this cohort (standardized mortality ratio, 15.50) remained greater than that among men (standardized mortality ratio, 3.23). The risk of death by homicide with a firearm was elevated among women (standardized mortality ratio at one year, 2.20; at six years, 2.01) but low among men (standardized mortality ratio at one year, 0.84; at six years, 0.79). CONCLUSIONS: The purchase of a handgun is associated with a substantial increase in the risk of suicide by firearm and by any method; the increase in the risk of suicide by firearm is apparent within a week after the purchase of a handgun. The magnitude of the increase and the relation between handgun purchase and the risk of death by homicide differ between men and women.     

Identification of Resting and Active State EEG Features of Alzheimer’s Disease using Discrete Wavelet Transform

Alzheimer’s disease (AD) is associated with deficits in a number of cognitive processes and executive functions. Moreover, abnormalities in the electroencephalogram (EEG) power spectrum develop with the progression of AD. These features have been traditionally characterized with montage recordings and conventional spectral analysis during resting eyes-closed and resting eyes-open (EO) conditions. In this study, we introduce a single lead dry electrode EEG device which was employed on AD and control subjects during resting and activated battery of cognitive and sensory tasks such as Paced Auditory Serial Addition Test (PASAT) and auditory stimulations. EEG signals were recorded over the left prefrontal cortex (Fp1) from each subject. EEG signals were decomposed into sub-bands approximately corresponding to the major brain frequency bands using several different discrete wavelet transforms and developed statistical features for each band. Decision tree algorithms along with univariate and multivariate statistical analysis were used to identify the most predictive features across resting and active states, separately and collectively. During resting state recordings, we found that the AD patients exhibited elevated D₄ (~4–8 Hz) mean power in EO state as their most distinctive feature. During the active states, however, the majority of AD patients exhibited larger minimum D₃ (~8–12 Hz) values during auditory stimulation (18 Hz) combined with increased kurtosis of D₅ (~2–4 Hz) during PASAT with 2 s interval. When analyzed using EEG recording data across all tasks, the most predictive AD patient features were a combination of the first two feature sets. However, the dominant discriminating feature for the majority of AD patients were still the same features as the active state analysis. The results from this small sample size pilot study indicate that although EEG recordings during resting conditions are able to differentiate AD from control subjects, EEG activity recorded during active engagement in cognitive and auditory tasks provide important distinct features, some of which may be among the most predictive discriminating features.     

Cyclin D1 overexpression and p53 mutation status in epithelial ovarian cancer

OBJECTIVE: To examine the cyclin D1 mRNA expression level in ovarian tumor samples as compared with normal ovaries and to determine the relationship between cyclin D1 overexpression and p53 mutation status in ovarian tumors. METHODS: mRNA was isolated and cDNA was prepared from 27 epithelial ovarian tumors (3 tumors of low malignant potential (LMP) and 24 cancers) and 6 normal ovaries. The cyclin D1 sequences were amplified by using a thermal cycler in parallel with the beta-tubulin gene as an internal control. The cyclin D1 mRNA expression level relative to beta-tubulin was determined by 32P phosphoimager analysis. To confirm the overexpression of the cyclin D1 protein in ovarian tumor cells, immunostaining was performed. The p53 gene mutation status was examined by direct cDNA sequencing. RESULTS: mRNA levels of cyclin D1 were significantly higher in 21 (78%) of the 27 ovarian tumors than in normal ovaries. Cyclin D1 overexpression was detected in ovarian LMP tumors as well as in ovarian cancer cases. Positive immunostaining of cyclin D1 protein was observed in 10 of 18 (56%) ovarian tumors examined. p53 mutations were found in 11 (61%) of 18 ovarian tumors. Of 11 ovarian tumor cases with p53 mutations, 5 showed overexpression of cyclin D1. All 7 ovarian tumor cases without p53 mutations showed significant cyclin D1 mRNA overexpression. CONCLUSION: Cyclin D1 overexpression seems to be an early genetic event in ovarian tumor development. Although p53 may be one of the proteins whose function regulates the expression of G1 cyclins, ovarian tumors with no p53 mutation consistently showed cyclin D1 overexpression. Cyclin D1 overexpression may play an important role in the tumorigenesis of epithelial ovarian tumors.     

Heavy chain of HLA-A and HLA-B antigens is conformationally labile: a possible role for beta 2-microglobulin.

The three-dimensional organization of HLA antigens has been investigated by spectroscopic and immunochemical techniques. Measurement of the circular dichroism shows that in papain-solubilized HLA the heavy chain as well as the previously studied light chain (beta 2-microglobulin) consists predominantly of beta-pleated sheet structures. When heavy chain is separated from the light chain under denaturing conditions and is allowed to renature, about 50% of the beta structure is lost, concomitantly with most of the alloantigenic activity. Analysis of the two acid-cleaved fragments of HLA-B7 heavy chain shows that beta structure is preferentially lost from the COOH-terminal region of the heavy chain. Exposure to denaturants per se does not inevitably result in irreversible loss of antigenic activity. However, recovery of antigenic properties does seem to depend on reassociation of the two chains. The results reported here provide further evidence for (i) the similarity of HLA antigens and immunoglobulins at the three-dimensional level and (ii) two distinct and physiologically important conformations of the HLA heavy chain, depending upon whether it is associated with the light chain.