Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)-4 (C-590T), IL-4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL-10 (C-627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patient's attitude, indoor environment, and so on, were also investigated in this study. Our study was retrospective, and the correlation was analyzed by our defined clinical scores divided into three terms: worst symptoms, recent symptoms and general amelioration at the most recent examination during the disease course. Our results indicated that IL-10 AA, the genotype with lower IL-10 production, is associated with higher IgE levels in the serum (p < 0.0001, estimate; 0.912). Marginal liver abnormalities were observed in the subject group with both FA and AE (p < 0.1191, estimate; 0.1490). Our defined clinical scores enabled evaluation of various aspects of disease severity. Based on the scores, while no single SNP selected in this study determined severity, the combination of the SNP with laboratory data and environmental factors appeared to determine severity.     

A new method for producing temporary complete cerebral ischemia in rats

A new model of temporary complete cerebral ischemia was developed and tested in 64 rats. With use of microsurgical techniques, both pterygopalatine and external carotid arteries were occluded and the basilar artery was coagulated to reduce potential collateral CBF during ischemia. After this preliminary five-vessel occlusion, temporary global ischemia was induced by occluding the common carotid arteries (CCAs) with microclips. To validate the method, CBF was measured autoradiographically in 24 anatomical regions at death after 5 min of ischemia or after 15 min of ischemia followed by 5 min of reperfusion. Mean arterial blood pressure and arterial blood gases remained stable under controlled endotracheal ventilation and anesthesia (halothane, 70% N2O, and 30% O2) throughout the CBF experiments, except for a 10-15% increase in mean arterial blood pressure for 1-5 min after bilateral CCA occlusion. After the initial five-vessel occlusion, the EEG did not change, and local CBF levels were comparable to those in anesthetized non-surgical controls. When the CCAs were occluded, the EEG flattened rapidly; after 5 min of ischemia, autoradiography showed no detectable blood flow in the forebrain and cerebellum. The local CBF levels measured after 15 min of temporary global ischemia and 5 min of reperfusion demonstrated relatively homogeneous postischemic hyperperfusion; only two of eight rats had several 1- to 3-mm areas of no-reflow. Survival studies showed increasing motor impairment after 10, 15, 30, and 60 min of temporary CCA occlusion. Ischemic neuronal damage was observed histologically in the hippocampus and basal ganglia 24 h after 10 min of temporary ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple sclerosis with higher cerebral dysfunction: a case report

Higher cerebral dysfunctions such as aphasia, apraxia and agnosia have seldom been reported in multiple sclerosis (MS). 12 year-old right-handed boy felt unsteadiness of the body and headache for several days. Two months later, he had the same episode and complained of visual disturbance, and weakness and sensory disturbance on the face and the extremities. Additionally, he showed amnestic aphasia, acalculia, ideomotor apraxia, finger agnosia and right-left disorientation. Cerebrospinal fluid examinations revealed increases IgG, myelin basic protein and neuron specific enolase (11%, 25 ng/ml and 28.8 ng/ml, respectively). X-ray CT scan and MRI-CT examinations revealed sclerotic lesions on the left parietal white matter and the right mid-brain. The diagnosis was made as MS. He was treated with m-PSL (methyl-prednisolone) pulse therapy for three weeks and consecutively treated with PSL for four weeks. He recovered gradually, but visual disturbance and facial palsy remained. After seven months MRI-CT showed a high signal intensity on the left parietal white matter in spite of the disappearance of the lesion on X-ray CT scan. We suggest that these higher cerebral dysfunctions may result from the lesion of the left parietal white matter which produces a disconnection between each cortical area.     

X-ray CT of Duchenne muscular dystrophy skeletal muscles--chronological study for five years]

To clarify when and how rapidly individual muscles are damaged in the course of Duchenne muscular dystrophy (DMD), we followed X-ray CT of whole body skeletal muscles from 29 cases of DMD patients (age ranging 3 to 23 years) for a period of 2 to 6 years. Each patient had 2 to 5 scans with an average of 3.3. We evaluated chronological changes of 23 muscles from the entire body using the muscle damage stage defined as follows. The stages were classified into the following 5 stages: stage 0; normal, 1; area of fatty replacement less than 10% of whole muscle area, 2; area of fatty replacement between 10 to 50%, 3; area of fatty replacement 50 to 90%, 4; almost complete fatty replacement. Each muscle had its own period of rapid degeneration starting at 5 to 10 years of age and, continuing 5 to 10 years. In some muscles such as gluteus maximus or quadriceps femoris, fatty replacement started at 5 years or earlier and progressed for five years, while other muscles such as splenius capitis, damage started much later, e.g. around 10 years of age and the progression was much slower. There was a variation of at least 5 years among individual patients in any muscle damage stage, reflecting the variability of clinical severity in each patient. On the basis of the above results we defined the whole body muscle damage index as a summation of the muscle damage stages of the following five muscles: gluteus maximus, quadriceps femoris, gracilis, medial head of gastrocnemius and splenius capitis.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of parathyroid hormone-related peptide producing gallbladder carcinoma presenting humoral hypercalcemia of malignancy]

Humoral hypercalcemia of malignancy (HHM) in neoplastic syndrome has been most commonly reported in squamous cell carcinoma. Gallbladder carcinoma with HHM is uncommon. In this report, we describe a male case of gallbladder carcinoma with marked hypercalcemia and a high level of serum parathyroid hormone-related peptide (PTHrP). An immunohistochemical examination using PTHrP was also positive.     

Big mitogen-activated protein kinase 1 (BMK1)/extracellular signal regulated kinase 5 (ERK5) is involved in platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration

Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1-SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5alpha, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1-SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.     

Independent determinants of second derivative of the finger photoplethysmogram among various cardiovascular risk factors in middle-aged men.

The second derivative of the finger photoplethysmogram (SDPTG) has been used as a non-invasive examination for arterial stiffness. The present study sought to elucidate independent determinants of the SDPTG among various cardiovascular risk factors in middle-aged Japanese men. The SDPTG was obtained from the cuticle of the left-hand forefinger in 973 male workers (mean age: 44+/-6 years) during a medical checkup at a company. The SDPTG indices (b/a and d/a) were calculated from the height of the wave components. Multiple logistic regression analyses revealed that the independent determinants of an increased b/a (highest quartile of the b/a) were age (odds ratio [OR]: 1.12 per 1-year increase, 95% confidence interval [CI]: 1.09-1.15), hypertension (OR: 1.65, 95% CI: 1.03-2.65), dyslipidemia (OR: 1.51, 95% CI: 1.09-2.09), impaired fasting glucose/diabetes mellitus (OR: 2.43, 95% CI: 1.16-5.07), and a lack of regular exercise (OR: 2.00, 95% CI: 1.29-3.08). Similarly, independent determinants of a decreased d/a (lowest quartile of the d/a) were age (OR: 1.11 per 1-year increase, 95% CI: 1.08-1.14), hypertension (OR: 3.44, 95% CI: 2.20-5.38), and alcohol intake 6 or 7 days per week (OR: 2.70, 95% CI: 1.80-4.06). No independent association was observed between the SDPTG indices and blood leukocyte count or serum C-reactive protein levels. In conclusion, the SDPTG indices reflect arterial properties affected by several cardiovascular risk factors in middle-aged Japanese men. The association between inflammation and the SDPTG should be evaluated in further studies.     

Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette-Guérin immunotherapy

AIM: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. METHODS: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12. RESULTS: After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. CONCLUSIONS: We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.