Temporal Delta Wave and Ischemic Lesions on MRI

Abstract: The present study was designed to determine the clinical significance of a temporal low-voltage irregular delta wave (TLID) on EEG. Among 808 EEG records examined during one year at our hospital, the TLID was commonly detected in patients with clinically diagnosed ischemic brain diseases such as multiple infarction. Subsequently, a relation of the TLID to ischemic lesions on MRI was examined in 50 elderly depressive patients. It was found that there was a close correlation between the occurrence of the TLID and small ischemic lesions on MRI (p<0.001). These results suggest that the TLID is a valuable indicator of minor ischemic changes of the brain.     

Immune responses of graft mesenteric lymph node in small bowel transplantation

BACKGROUND: The high proportions of lymphoid tissues are thought to be one of the underlying factors inducing severe allograft rejection following small bowel transplantation. Mesenteric lymph nodes (MLN) contained in the intestinal graft are not only a source of donor-derived professional antigen-presenting cells, but also offer a field for immune interaction between donor and host cells. We investigated immune responses in graft MLNs with or without FK506 to develop a novel strategy to control small bowel allograft rejection. MATERIALS AND METHODS: Heterotopic small bowel transplantations were performed from Brown Norway donors to Lewis recipients. Changes in population of lymphocytes, expressions of costimulatory molecules, apoptosis, and cytokine profiles in graft MLNs were evaluated. RESULTS: The increase in apoptotic cells and cytokine responses relating to rejection in the graft MLNs developed prior to those in graft jejunum. While donor lymphocytes in graft MLNs were rapidly replaced to host-derived lymphocytes independent of FK treatment, increase in CD8(+) T cells in host population was seen only in recipients without FK506 treatment. The expressions of B7 molecules on donor cells in graft MLNs were significantly lower in the recipients with FK treatment. CONCLUSIONS: Immune responses in graft MLNs have significant impact on the outcome of the small bowel allograft. Apoptosis of graft MLN cells was well correlated with and ahead of progression of acute rejection. Modulation of costimulatory molecules on donor-derived MLN cells in the allograft and specific suppression of host CD8(+) T cells are possible ways to control severe rejection after allogeneic small bowel transplantation.     

Dual role of vascular endothelial growth factor in hepatic ischemia-reperfusion injury

BACKGROUND: Vascular endothelial growth factor (VEGF), a major angiogenic factor, mediates a variety of disease conditions through promotion of angiogenesis. It also plays a critical role as a potent proinflammatory cytokine in a variety of physiologic and pathologic immune responses. In the present study, we evaluated the expression of VEGF in hepatic warm ischemia-reperfusion (I/R) injury and examined the effect of recombinant human (rh)VEGF administration in an established murine model. METHOD: The expression of VEGF in the liver was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry during I/R injury using 70% partial hepatic ischemia model. The effect of rhVEGF administration on I/R injury was evaluated by measuring liver function and histology. In addition, local inducible nitric oxide synthase (iNOS) and endothelial NO synthase expressions were examined to address the underlying mechanisms. RESULTS: The local expression of VEGF was significantly up-regulated at 2 hours after reperfusion after 60 minutes of ischemia compared with that in the naive liver. VEGF was expressed predominantly in CD11b+ cells infiltrating into the ischemic liver. The administration of rhVEGF had a significant protective effect on ischemic injury in the liver. This effect was associated with the up-regulation of iNOS expression in the rhVEGF-treated liver. CONCLUSION: We demonstrate a dual role of VEGF in hepatic warm I/R injury. Although endogenous VEGF is expressed and functional to initiate hepatic I/R injury, exogenous rhVEGF has a beneficial effect on the ischemic liver. These data may provide new insights into the role of VEGF as well as pathophysiology of hepatic I/R injury.     

Perimembrane Aurora-A Expression is a Significant Prognostic Factor in Correlation with Proliferative Activity in Non-Small-Cell Lung Cancer (NSCLC)

Purpose Aurora-A, also known as STK15/BTAK, is a member of the protein serine/threonine kinase family, and experimental studies have revealed that Aurora-A plays critical roles in cell mitosis and in carcinogenesis. However, no clinical studies on Aurora-A expression in non-small-cell lung cancer (NSCLC) have been reported. Thus, the present study was conducted to assess the clinical significance of Aurora-A status. Experimental Design A total of 189 consecutive patients with resected pathologic (p-)stage I-IIIA, NSCLC were retrospectively reviewed, and immunohistochemical staining was used to detect Aurora-A expression. Results Aurora-A expression was negative in 31 patients (16.4%); among Aurora-A positive patients, 124 patients showed pure diffuse cytoplasmic Aurora-A expression and the other 34 patients showed perimembrane Aurora-A expression. Perimembrane Aurora-A tumors showed the highest proliferative index (PI) (mean PIs for negative, diffuse cytoplasmic, and perimembrane tumors: 49.2, 41.7, and 63.5, respectively; P < .001). Five-year survival rates of Aurora-A negative, diffuse cytoplasmic, and perimembrane patients were 67.8%, 66.7%, and 47.6%, respectively, showing the poorest postoperative survival in perimembrane patients (P = .033). Subset analyses revealed that perimembrane Aurora-A expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. A multivariate analysis confirmed that perimembrane Aurora-A expression was an independent and significant factor to predict a poor prognosis. Conclusions Perimembrane Aurora-A status was a significant factor to predict a poor prognosis in correlation with enhanced proliferative activity in NSCLC.     

Vagally mediated acid hypersecretion and lesion formation in anesthetized rat under hypothermic conditions

The pathophysiological changes associated with hypothermia were investigated in the rat stomach under anesthetized conditions. The animal was placed in a styrene foam box and the core body temperature was kept between 24 and 36°C using a heat lamp and refrigerant pack. Lowering of body temperature (<30°C) produced acid hypersecretion and induced hemorrhagic lesions in the gastric mucosa; these responses reached the maximum at 28°C, and a significant relationship was found between acid output and lesion score. Hypothermia (28°C) also caused a marked increase of gastric contractile activity and mucosal blood flow (MBF), but the ratio of acid output to MBF became greater when compared to that obtained under normothermic conditions. These changes induced by hypothermia (28°C) were completely blocked by vagotomy and were significantly inhibited by atropine, hexamethonium, clonidine, or TRH antiserum. However, lowering body temperature did not significantly affect acid secretory, motility, and ulcerogenic responses induced by carbachol in the vagotomized rat, excluding local mechanisms (suppression of the inhibitory nerves) in the hypothermia-induced changes. We conclude that hypothermia alone stimulates vagally dependent acid secretion and motility, resulting in damage in the gastric mucosa. These changes may be centrally mediated by TRH, which is released in association with the thermogenic response to hypothermia.     

Ovariectomy Aggravated Sodium Induced Hypertension Associated With Altered Platelet Intracellular Ca in Dahl Rats

Our purpose was to determine the effect of ovariectomy on intracellular Ca²⁺ mobilization and platelet aggregation in sodium induced hypertension. At the age of 12 weeks ovariectomy or sham operation was performed in female Dahl-Iwai salt sensitive rats on a 0.3% NaCl diet. Four weeks later we assessed the effects of ovariectomy and an 8% NaCl diet on agonist induced intracellular Ca²⁺ mobilization in fura-2 loaded platelets and platelet aggregation. Ovariectomy enhanced the increase of systolic blood pressure and heart to body weight ratio on an 8% NaCl diet. However, thrombin evoked intracellular Ca²⁺ was not correlated with systolic blood pressure (r = −0.338, P = .17), and was lowered by sodium loading and ovariectomy (360 ± 23 to 285 ± 9, 296 ± 10 nmol/L, P < .05). Furthermore, the ionomycin induced intracellular calcium fraction in the absence of external Ca²⁺ that reflected internal Ca²⁺ discharge capacity was reduced in ovariectomized rats compared with sham operated rats on an 8% NaCl diet (648 ± 15 v 768 ± 35 nmol/L, P < .05). The internal Ca²⁺ discharge capacity was inversely correlated with systolic blood pressure (r = −0.506, P = .03). In addition to the decreased internal Ca²⁺ discharge capacity, intracellular Ca²⁺-independent platelet aggregation by phorbol 12-myristate 13-acetate, a protein kinase C activator, was significantly enhanced in hypertensive rats. We concluded that ovariectomy enhanced sodium induced hypertension associated with the decreased internal Ca²⁺ discharge capacity and increased platelet aggregation in Dahl-Iwai salt-sensitive rats.     

CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC–mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.     

Development of a time-resolved fluoroimmunoassay for insulins and its application to monitoring of insulin secretion induced by feeding in the barfin flounder, Verasper moseri

A time-resolved fluoroimmunoassay (TR-FIA) system was developed to quantify insulin levels in the barfin flounder. This TR-FIA system is a solid-phase assay based on competition of unlabeled insulins and biotinylated barfin flounder insulin-II against an anti-barfin flounder insulin-II antibody. The minimum detectable level of barfin flounder insulin-I and -II in this TR-FIA was 10 pg/well which corresponded to 1.0 ng/ml, and insulin-II showed slightly higher crossreactivity than insulin-I. The accuracy of this TR-FIA was assured by specificity test, validation test, and recovery test using plasma added insulin-II. The results indicated the high specificity and sufficient accuracy of this assay system for insulin level measurement. This system was applied to the measurement of plasma insulin levels of fed and fasted barfin flounders. Plasma insulin levels (average +/- SEM) in fed flounders reached a maximum 2 h (9.3 +/- 1.7 ng/ml) and decreased gradually thereafter, while those in fasted flounders remained at low levels (1.1 +/- 0.1-2.0 +/- 0.2 ng/ml) during the experiment. After removing proteins by acidification and subsequent gel filtration, plasma samples taken from fed and fasted flounders at 2 h after feeding were fractionated separately by reversed-phase HPLC. In fed flounders, insulin immunoreactivity was detected in fractions corresponding to those of insulin-I or -II. The ratio of integrated insulin immunoreactivities of each peak was 0.378 +/- 0.044 (average +/- SD). This value was in good agreement with those (0.355 +/- 0.019) of absorbance areas of each insulin from Brockmann body extracts of the barfin flounder on reversed-phase HPLC. In fasted flounders, very weak insulin immunoreactivities were observed at retention times corresponding to those of insulin-I and -II. These results indicated that both insulin-I and -II were secreted into the blood being induced by feeding stimulation with approximately the same ratio as that of the quantities harbored in the Brockmann body.     

Serial brain imaging analysis of stroke-like episodes in MELAS

We report 2 patients of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and consider the pathophysiology of stroke-like lesions, using magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) on MRI, perfusion imaging on MRI, and 1H magnetic resonance spectroscopy (1H-MRS). In Patient 1, T2-weighted imaging (T2-WI) on MRI at onset and even at 44 days after onset of the stroke-like episode showed high intensity in left parietal, temporal, and occipital lobe lesions. In the temporal lobe lesion, the apparent diffusion coefficient (ADC) at 44 days after onset was higher (average: 1.219x10(-3)mm2/s) than that in a normal region (average: 0.796x10(-3)mm2/s). (1)H-MRS of the left parietal lobe lesion at the same day showed a decrease in N-acetylaspartate/(creatine+phosphocreatine) (NAA/Cr) (0.43) and a peak in lactate. 1H-MRS of the contralateral side at the same day showed NAA/Cr (1.57) and no peak in lactate. Thereafter, ADC gradually decreased and NAA/Cr gradually increased, and the peak in lactate disappeared in the lesion. In Patient 2, T2-WI at onset showed high intensity in bilateral occipital lobe lesions. In the left occipital lobe lesion, ADC at the same day was higher (1.082x10(-3)mm2/s) than that in a normal region (average: 0.841x10(-3)mm2/s). (1)H-MRS of the left occipital lobe lesion at the same day showed a decrease of NAA (3.0mM) and a peak in lactate (13.1mM) (measured by LCModel). In 1H-MRS of the normal left parietooccipital lobe at 4 months before onset, NAA was 7.6mM and there was no peak in lactate (0mM). Perfusion imaging at onset showed high intensity in bilateral occipital lobes, which indicated hyperperfusion in stroke-like lesions. Thereafter, ADC gradually decreased and the peak in lactate partially decreased, and the low concentration of NAA persisted (regardless of the partial recovery) in the lesion. These results suggest that the stroke-like episodes is related to vasogenic edema, hyperperfusion, and neuronal damage. Acute oxidative phosphorylation defect may have a crucial role in the pathophysiology of stroke-like episodes.