Electron‐microscopic examination of effects of yokukansan,a traditional Japanese medicine,on degeneration of cerebral cells in thiamine‐deficient rats

We previously demonstrated that yokukansan ameliorated not only learning disturbance but also behavioral and psychological symptoms of dementia‐like behaviors (anxiety, aggressiveness) and neurological symptoms (opisthotonus) induced in rats by dietary thiamine deficiency (TD). In the present study, the effects of yokukansan on degeneration of cerebral cells were further examined electron‐microscopically during pre‐symptomatic and symptomatic stages in TD rats. In the pre‐symptomatic TD stage, which appeared as increase in aggressive behaviors on the 21st and 28th days of TD diet‐feeding, severe edematous degeneration of astrocytes was detected by electron microscopy, although the changes were not observed by light microscopy. In the symptomatic TD stage (the 34th day) characterized by development of neurological symptoms, severe sponge‐like degeneration and multiple hemorrhages in the parenchyma were obvious by light microscopy. The electron‐microscopic examination showed degeneration in neurons, oligodendroglias, and myelin sheaths in addition to astrocytes. TD rats, which exhibited multiple hemorrhages light microscopically, showed severe edematous changes and hypertrophy of the foot processes of astrocytes surrounding blood vessels. Administration of yokukansan ameliorated not only the TD‐induced aggressive behavior and neurological symptoms but also degeneration of the cerebral cells. These results suggest that the inhibitory effect of yokukansan on degeneration in various brain cells might be closely related to the amelioration of aggression and neurological symptoms in TD rats.     

Germline polymorphism of p53 codon 72 in gynecological cancer

OBJECTIVE: To investigate the biological significance of single nucleotide polymorphism at codon 72 of the p53 gene in the development of gynecological cancer. METHODS: p53 codon 72 polymorphism was examined in a total of 354 blood samples from 95 normal, 83 cervical, 108 endometrial and 68 ovarian cancer cases using polymerase chain reaction and restriction fragment length polymorphism techniques. RESULTS: When p53 codon 72 genotype was classified into two subgroups of Arg/Arg and Arg/Pro + Pro/Pro, the Arg/Arg genotype was associated with an increased risk for the development of endometrial cancer (OR = 1.86, 95% CI = 1.06 to 3.26) compared with the Arg/Pro + Pro/Pro genotype (P = 0.0301). The Arg allele also increased the risk of endometrial cancer (OR = 1.42, 95% CI = 0.93 to 1.52) compared with the Pro allele, but no statistical difference was found (P = 0.1031). There was no significant difference in the genotype or allele prevalence between control subjects and cervical or ovarian cancer patients. CONCLUSION: Homozygous Arg at codon 72 of the p53 gene may be a risk factor for developing endometrial cancer in a Japanese population.     

Short-term effects of low-dose atorvastatin on inflammatory status and lipid profiles in perimenopausal hypercholesterolemic, hypertriglyceridemic women

The short-term and small-dose pleiotropic effects of atorvastatin and influence on sex steroid production were investigated in 35 premenopausal and 71 postmenopausal hypercholesterolemic, hypertriglyceridemic women, as well as the temporal differences in these pleiotropic effects. Atorvastatin (10 mg daily) was given for 6 months and fasting lipid concentrations, high sensitive CRP, and coagulo-fibrinolytic parameters were measured at baseline and after 3 and 6 months of therapy. Atorvastatin reduced the low-density lipoprotein cholesterol, remnant-like particle lipoprotein cholesterol, and malondialdehyde-modified low-density lipoprotein cholesterol after 3 and 6 months in both pre- and postmenopausal women. Atorvastatin decreased significantly high-sensitivity C-reactive protein concentration (-47.6% and -58.0%, P<0.01) and tissue plasminogen activator/plasminogen activator inhibitor-1 ratio (-31.8% and -40.0%, P<0.001) after 6 months in pre- and postmenopausal women. There was no correlation between the pleiotropic effects and the improvement in the lipid profile. Furthermore, atorvastatin has no influence on sex steroid production in both pre- and postmenopausal period. The results indicate some short-term pleiotropic effects of small-dose atorvastatin therapy without influence of endocrinological status, which may be important with respect to the early benefits of statin therapy in the perimenopausal hyperlipidemic women.     

Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients

In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles—R40H, R277W, and Y55D—were identified. In a total of 20 informative parent–offspring pairs, father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, indicating that paternal transmission contributes substantially to the pool of these mutant alleles. Relative reproductive fitness of males and females carrying the mutant alleles was calculated to be 0.49 and 0.89, respectively. Comparison of the life span of the mutant alleles, estimated on the basis of these fitness values with those associated with classic phenotype (neonatal onset) in which reproductive fitness of male patients was nil, revealed that mutant alleles associated with the late-onset phenotype were eliminated more slowly. This would allow the late-onset phenotype mutant alleles to be retained more frequently in a population than those associated with classic phenotype. Although heterozygous females carrying the late-onset phenotype mutant alleles were generally asymptomatic, one female carrying the R40H allele died after a hyperammonemic episode at the age of 18 years. Such heterozygous females should be alerted to possible hyperammonemic crisis. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Anti-allergic inflammatory effects of hepatocyte growth factor

Hepatocyte growth factor (HGF) is known to influence a number of cell types and regulate various biological activities including cytokine production, cell migration, proliferation and survival. Thus, HGF is now recognized to be a key factor in the prevention and attenuation of disease progression. We have reported that HGF reduces allergic airway inflammation, airway hyperresponsiveness, remodeling and development of Th2 cytokines as well as growth factors such as transforming growth factor-beta in vivo. In vitro, HGF directly attenuates chemotaxis of eosinophils in the absence of Th2 cytokines and modulates mitogen-activated protein kinases, which play an important role in eosinophil migration. In this review, we discuss the physiological role of HGF in allergic inflammation and its mechanism of anti-inflammatory effects, including the regulation of eosinophil functions.     

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.     

Reduction in serum levels of substance P in patients with rheumatoid arthritis by etanercept, a tumor necrosis factor inhibitor

We determined the effects of etanercept on the serum concentrations of neuropeptides in RA patients. In a total of 11 patients who had been injected with etanercept, the serum levels of substance P, calcitonin gene-related peptide (CGRP), and gastrin-releasing peptide (GRP) were analyzed. Average levels of serum substance P were significantly reduced from 1.53 to 0.62 ng/ml after the injection of etanercept. In the CGRP and GRP analyses, these average levels dropped from 1.57 and 0.51 ng/ml to 0.44 and 0.04 ng/ml, respectively. Etanercept appears to decrease substance P levels with an improvement in disease activities.     

In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24?weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline

We aimed to evaluate the efficacy of tocilizumab in patients with rheumatoid arthritis (RA), using the clinical disease activity index (CDAI), and to determine the baseline variables associated with CDAI remission. Fifty-eight patients with active RA were enrolled. We tried to evaluate whether baseline variables were associated with CDAI remission at 24?weeks. Twenty-two of the 58 patients (37.9%) had received tumor necrosis factor (TNF) inhibitors. The continuation rate of tocilizumab at 24?weeks was 87.9%. The seropositivity rates of IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline were both 91.4%. The rate of CDAI remission at 24?weeks was 20.7%. We selected baseline variables including age, gender, duration of disease, concomitant use of glucocorticoids, concomitant use of methotrexate (MTX), previous anti-TNF therapy, titer of anti-CCP antibodies (high or low toward median), titer of IgM-RF (high or low toward median), and CDAI, and found that a high titer of IgM-RF was the only variable to be associated with CDAI remission, according to univariate and logistic regression analyses. This is a new finding, and may be specific to tocilizumab as compared with previous observations in anti-TNF therapy.     

Diagnosis of ischemic small bowel disease by measurement of serum intestinal fatty acid-binding protein in patients with acute abdomen: a multicenter, observer-blinded validation study

Background

Intestinal fatty acid-binding protein (I-FABP) is a low-molecular-mass (15?kDa) cytosolic protein found exclusively in the epithelial cells of the small bowel mucosa. We aimed to evaluate the clinical usefulness of serum I-FABP measurement for the diagnosis of ischemic small bowel disease.

Methods

Patients with a clinical diagnosis of acute abdomen were recruited for this multicenter trial at one university hospital and nine city hospitals over a 13-month period. Serum I-FABP levels were measured in 361 eligible patients by an enzyme-linked immunosorbent assay using a specific monoclonal antibody.

Results

Of the 361 patients, 242 underwent surgery, and small bowel ischemia was diagnosed in 52 patients. The mean serum I-FABP level in the patients with small bowel ischemia was 40.7?±?117.9?ng/ml, which was significantly higher than that in patients with non-ischemic small bowel disease (5.8?±?15.6?ng/ml) and those with non-small bowel disease (1.8?±?1.7?ng/ml). The serum I-FABP cutoff level for the diagnosis of small bowel ischemia was 3.1?ng/ml. Serum I-FABP was more efficient than conventional biochemical markers, in terms of sensitivity and positive and negative predictive values, in the diagnosis of small bowel ischemia. However, its specificity was slightly lower than that of creatinine phosphokinase or lactate dehydrogenase. The positive and negative likelihood ratios of serum I-FABP were 3.01 and 0.29, respectively.

Conclusion

Serum I-FABP measurement is a non-invasive method that is potentially useful for the efficient identification of patients with acute abdomen who are at risk of small bowel ischemia.