Inhibition of p38 mitogen-activated protein kinase protects human islets from cryoinjury and improves the yield, viability, and quality of frozen-thawed islets

The development of an optimal islet cryopreservation method will permit transplantation of islets from multiple donors in a single procedure and contribute to alleviation of the islet shortage. In this study, we have improved human islet cryopreservation methods under serum-free conditions using an intracellular-based islet cryopreservation solution (ICS), especially supplemented with a p38 pathway inhibitor (p38IH) to suppress p38 mitogen-activated protein kinase (MAPK) activation. Three different solutions were compared for freezing and thawing of human islets (1) conventional RPMI1640 medium, (2) ICS, and (3) ICS supplemented with a p38IH, SD-282 (ICS-p38IH). Islet cryopreservation with ICS-p38IH significantly improved islet recovery, viability, and quality after thawing of cryopreserved islets. This improvement may allow the use of cryopreserved islets in clinical islet transplantation.     

Facilitation of the purinergic contractile response of the guinea pig vas deferens by sodium orthovanadate

Experiments were carried out to examine the effects of protein tyrosine kinase (PTK) and protein tyrosine phosphatase inhibitors on the purinergic contraction of the guinea pig vas deferens. Sodium orthovanadate (SOV) produced a robust increase of the amplitude of contractions evoked by both neurogenic electrical field stimulation and exogenous ATP. This effect of SOV was concentration- and time-dependent, as well as, reversible and reproducible. Genistein, a PTK inhibitor, but not its inactive structural analog daidzein, inhibited the SOV-induced facilitation of the purinergic contraction. Another PTK inhibitor, 2,5-dihydroxycinnamic acid methyl ester, which is structurally unrelated to genistein, also inhibited the facilitation effects of SOV. Although an application of as low as 3 microM of these inhibitors significantly decreased the effect of SOV, other PTK inhibitors, namely, butein, levandustin C, and thyrphostin 23, were less effective even at concentrations of 100 microM. Western blot experiments showed that the facilitation of the purinergic contraction by SOV is associated with a prominent increase in the level of tyrosine phosphorylation of proteins with estimated molecular sizes of 180 and 123 kDa, which was reversed in the presence of genistein. Evidence is also presented that argue against the possibility that inhibition of the Na(+)/K(+)-ATPase or ATPases, responsible for the clearance of ATP is involved in the SOV-induced facilitation of the purinergic contraction. Together, these results suggest that the responsiveness of the smooth muscle of the vas deferens to the actions of ATP is modulated via a previously unidentified mechanism, which may involve protein tyrosine phosphorylation.     

The malignancy of dementias

Sruvival times were determined for 982 patients admitted over a ten-year period to the Geneva Psychiatric Clinic. Patients with dementia had one-third the life expectancy of controls. Among patients classed as having Alzheimer disease, the longest survival times were in those with neurofibrillary tangles involving the neocortex, while those lacking this anatomical abnormality had the shortest survival times. Except for women with Alzheimer disease, patients with dementia had less than 10% life expectancy from the time of their admission to the clinic compared to the life expectancy of Geneva's population.     

Optimality principles in sensorimotor control

The sensorimotor system is a product of evolution, development, learning and adaptation-which work on different time scales to improve behavioral performance. Consequently, many theories of motor function are based on 'optimal performance': they quantify task goals as cost functions, and apply the sophisticated tools of optimal control theory to obtain detailed behavioral predictions. The resulting models, although not without limitations, have explained more empirical phenomena than any other class. Traditional emphasis has been on optimizing desired movement trajectories while ignoring sensory feedback. Recent work has redefined optimality in terms of feedback control laws, and focused on the mechanisms that generate behavior online. This approach has allowed researchers to fit previously unrelated concepts and observations into what may become a unified theoretical framework for interpreting motor function. At the heart of the framework is the relationship between high-level goals, and the real-time sensorimotor control strategies most suitable for accomplishing those goals.     

Association of CyclinD1 copy number changes with histological type in ovarian tumors

Literature data on the occurrence of CCND1 alterations in ovarian tumors are insufficient. The objective of this study was to assess the incidence of CCND1 copy number changes in a large number of ovarian tumors and its relation to the tumor phenotype: degree of malignancy, histological type, tumor stage, and grade. Fluorescence in situ hybridization (FISH) for analysis of CCND1 copy number changes was applied on a collection of 1 006 ovarian tumors--468 malignant, 48 with low malignant potency, and 490 benign tumors--arranged in tissue microarray. CCND1 amplification was found in 8.46% of the malignant cases and in 8.11% of those with low malignant potency. It was not found in benign ovarian tumors. CCND1 amplification was associated with the mucinous type of ovarian cancer (p<0.0001). CCND1 genetic gain was revealed in 9.06% of the malignant tumors, in 2.70% of the tumors with low malignant potency, and in 4.87% of the benign ovarian tumors. CCND1 gains and amplifications were not associated with the tumor grade and stage. Our results suggest that CCND1 gains are early events in ovarian tumorogenesis.     

Organizational strategy use in obsessive-compulsive disorder

It has been reported that the balance between T-helper type 1 (Th1) cytokines and T-helper type 2 (Th2) cytokines plays a role in psychiatric disorders such as bipolar disorder. The T-helper type 3 (Th3) cytokine, which transforming growth factor beta-1 (TGF-β1), has been shown to modulate the production of Th1 and Th2 cytokines. However, the role of TGF-β1 in bipolar disorder has not yet been explored. A total of 70 manic patients with bipolar disorder and 96 normal controls was recruited. The plasma levels of IFN-γ, IL-4, and TGF-β1 were studied at the time of admission and 8 weeks after mood stabilizer treatment. The detection rate and plasma concentrations of IFN-γ and IL-4 and the IFN-γ/TGF-β1 and IL-4/TGF-β1 ratios were significantly higher in patients than in controls, while the TGF-β1 level was significantly lower. The TGF-β1 level increased significantly after treatment and the IFN-γ/TGF-β1 and IL-4/TGF-β1 ratios returned to control values. TGF-β1 may play a role in the pathophysiology of bipolar disorder through the action of TGF-β1 in modulating the IL-4/TGF-β1 ratio.     

Rheological evaluation of the influence of sterilisation on ocular gels using an experimental design

Different rheological characterisation methods are employed to investigate the influence of the sterilisation method (autoclaving), the polymer concentration (0.50, 0.75 and 1.00%) and the dispersing medium (i.e. isotonic phosphate buffer and mannitol solution) on Carbopol 974 P NF dispersions, used as ocular gels. The evaluation of the different polyacrylic acid-based dispersions was performed using flow and oscillatory shear measurements, and herewith an experimental design was set up. The rheological data show that the choice of the dispersing medium has a significant influence on the rheological behaviour of the ocular gels prepared. The dispersions in mannitol exhibit higher elastic properties than those made in the phosphate buffer solution (PBS). Sterilisation increases only the elastic properties of the 0.50% (w/w) Carbopol 974 P NF/PBS dispersion but has no influence on the other dispersions prepared.     

The age-related changes in the incidence of 'natural' anti-sperm antibodies suggest they are not auto-/isoantibodies

PROBLEM: Establishing the age-dependent patterns of sperm antibody levels among normal humans. METHODS OF STUDY: Sera samples from 498 healthy subjects aged 0-97 years - 246 males and 252 females - were tested by the gelatin agglutination test of Kibrick, tray agglutination test of Friberg, sperm immobilization test of Isojima and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found a significant increase in the level of sperm agglutinins after 40 years, which decreased after 88 years. The antibodies detected by ELISA were the highest among prepubertal subjects and also declined with aging. No age-dependent changes were established for the sperm immobilizins. With few exceptions, there were no significant differences between male and female sera, as well as between sera of newborn and their mothers. CONCLUSIONS: These data are similar to those established for the age-dependent changes of antibodies towards exogenous antigens, suggesting that the 'naturally occurring' antibodies against human spermatozoa are not auto-/isoantibodies.