Ehime Medical Center

The all‐solid, lithium rechargeable battery , which if available would find many applications, is one reason for carrying out research into Li⊕‐conducting solids. Fast Li⊕‐conducting ceramic electrolytes are reviewed with regard to their electrical properties and crystal structure. Both non‐oxide based ceramics and oxide materials are considered, and possibilities for further developments—e.g., the preparation of the electrolyte by thin film techniques—are pointed out.

In Japan we have had two outbreaks of hand, foot, and mouth disease associated with disorders of the central nervous system, one in 1973 and the other in 1978. The isolated virus in both outbreaks was enterovirus 71. Central nervous system disorders were present in 24% of patients in 1973 and in 8% of patients in 1978. These disorders were localised encephalitis with cerebellar signs as the main feature, aseptic meningitis, and polio-like paresis. The enterovirus 71 isolated in Japan had strong dermatotropic as well as neurotropic tendencies. However in cross-neutralisation tests, no difference in antigenicity from the prototype, BrCr strain, was recognised.

Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, significantly increased insulin-mediated 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake into skeletal muscle and attenuated the increase in plasma glucose concentration after a glucose load and plasma concentrations of glucose and insulin. In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-alpha (TNF-alpha) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.

Mentoring can be an effective strategy in improving retention of college students and faculty from fields where historical underrepresentation has occurred. This article reviews the benefits of mentoring in higher education, and identifies components of effective mentoring strategies that promote educational and career advancement. It illustrates how effective programs can be institutionalized and scaled through consortial and national collaborations. Traditional and alternative mentoring models are described through four successful programs designed to increase the academic and professional success of undergraduates, graduate students, and junior faculty. The article concludes with a set of general recommendations and caveats gleaned from the literature and programs reviewed.

The antitumor activity of activated CD 8+ T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. This metabolic unfitness is closely associated with T‐cell exhaustion and impairment of memory formation, which are barriers to successful antitumor adoptive immunotherapy. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD 8 + T cells using a tumor‐inoculated mouse model. The adoptive transfer of tumor‐specific CD 8 + T cells cultured under glutamine‐restricted ( dG ln) conditions or CD 8 + T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to better survival of tumor‐inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD ‐1 and increased Ki67 positivity among tumor‐infiltrating CD 8 + T cells cultured under dG ln conditions suggested that the inhibition of glutamine metabolism prevents CD 8 + T‐cell exhaustion in vivo. Furthermore, the transferred CD 8 + T cells cultured under dG ln conditions expanded more efficiently against secondary OVA stimulation than did CD 8 + T cells under Ctrl conditions. We found that the expression of a pro‐survival factor and memory T cell‐related transcription factors was significantly higher in CD 8 + T cells cultured under dG ln conditions than in those cultured under Ctrl conditions. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD 8 + T cells. The novel adoptive transfer of tumor‐specific CD 8 + T cells cultured in glutamine‐restricted conditions may be a promising approach to improve the efficacy of cell‐based adoptive immunotherapy.

Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10 −12 mol/L) and with a lower dose of Ang II (10 −10 mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT 1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.

OBJECTIVE: Our purpose was to assess the CT features of various subtypes of thymic epithelial neoplasms on the basis of the 1999 World Health Organization classification. MATERIALS AND METHODS: Thymic epithelial neoplasms in 53 patients who underwent thymectomy were retrospectively assessed histologically according to the 1999 World Health Organization classification. Type A and B neoplasms correspond to thymomas and type C, to thymic carcinoma. The study included four patients with type A, 14 with type AB, nine with type B1, 14 with type B2, four with type B3, and eight with type C epithelial tumors. Two observers independently assessed the CT scans without knowledge of the histologic findings. RESULTS: Type A tumors were more likely to have smooth contours on CT (4/4, 100%) and round shapes (3.5/4, 88%) than any other type of thymic epithelial tumor (all, p < 0.05). Type C tumors had a higher prevalence of irregular contours (6/8, 75%) than any other type of thymic epithelial tumor (all, p < 0.05). Calcification was more frequently seen in type B1 (4/9, 44%), type B2 (8.5/14, 61%), and type B3 (3/4, 75%) tumors than in type AB (2/14, 14%) and type C (0.5/8, 6%) tumors (all, p < 0.05). CONCLUSION: Smooth contours and a round shape are most suggestive of type A thymic epithelial tumor, whereas irregular contours are most suggestive of type C tumor. Calcification is suggestive of type B tumors. CT is of limited value, however, in differentiating type AB, B1, B2, and B3 tumors.

We have surveyed the incidence of adult T-cell leukemia/lymphoma (ATLL) in an endemic area of 290,464 inhabitants for 7 years. We now revise our previous results on the basis of additional findings and estimate the age- and sex-specific cumulative rate for HTLV-I carriers, the adoption of which is recommended by current cancer epidemiology as a new age-standardized incidence rate. An unequivocal age-dependent increase in seroprevalence was observed for both sexes with a characteristic predominance in females. The age-dependent seroconversion in females may be partly explained by additional infection from infected husbands to their wives but the reason for men remains obscure. The mean annual number of incident cases of ATLL was 11.4, giving 3.9 ATLL patients annually per 10(5) inhabitants, 6.1 per 10(5) inhabitants aged over 30, and 85.0 per 10(5) seropositives aged over 30. Crude annual incidence rate of ATLL among 10(5) male seropositives aged over 30 was 145.3 and that for females was 55.2 and 95% confidence intervals of ATLL incidence rates were 34.8 to 255.7 for males and 6.4 to 104.1 for females, respectively. Although the sex ratio of 80 ATLL patients was 1.35, males are more prone to the disease (46 male patients among 4,522 male seropositives aged over 30 vs 34 female patients among 8,801 female seropositives aged over 30; p less than 0.001) for unknown reason(s). Morbidity in male seropositives aged over 30 is 2.6 times as high as that of females. Decennial incidence rates in males in their fifties and sixties were significantly higher than those in females. The remarkable male preponderance in oncogenicity of HTLV-I may be due to the fact that men are more prone to the disease and the number of female carriers in the denominator used to calculate the incidence rate is larger than that of males. The whole life span (0-79) cumulative risk for males was 6.9% and significantly higher than that of females (2.95%).

BACKGROUND AND PURPOSE: Silent brain infarcts (SBI) and white matter lesions are relatively common neuroimaging findings, especially in the elderly population. The genetic background for SBI and white matter lesions in a large Japanese general population was investigated. METHODS: Subjects were recruited from participants in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation and brain MRI examination were performed in 1721 subjects free of any history of stroke. SBI and white matter lesions were diagnosed from MRI findings. RESULTS: Of 1721 MRI examinations, SBI was observed in 178 (10.3%). The prevalence of SBI and white matter lesions increased with age. The prevalence of SBI was significantly higher in subjects with the MTHFR TT genotype compared with the TC+CC genotype (14.6% versus 9.5%; 42 of 288 versus 136 of 1433; chi2=6.71; P=0.010). The stage of white matter lesions was not significantly different. In subjects >or=60 years of age (n=849), the prevalence of SBI was significantly higher in TT than TC+CC (27.7% versus 16.6%; 36 of 130 versus 119 of 719; chi2=9.16; P=0.002). The prevalence of moderately advanced white matter lesions was also significantly higher in TT than TC+CC (60.7% versus 49.0%; 79 of 130 versus 352 of 719; chi2=9.16; P=0.002). After correction for other risk factors, the MTHFR TT genotype was independently associated with SBI (odds ratio [OR], 1.72; 95% CI, 1.10 to 2.68; P=0.018) and moderately advanced white matter lesions (OR, 1.58; 95% CI, 1.07 to 2.33; P=0.02). CONCLUSIONS: These findings indicate that the MTHFR TT genotype is an independent risk factor for SBI and white matter lesions in the general Japanese population, especially in elderly subjects.

BACKGROUND: The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg x kg(-1) x d(-1) and with fluvastatin at a dose of 1 mg x kg(-1) x d(-1), which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (approximately 5 micromol/L) for 24 hours significantly inhibited Ang II (1 micromol/L)-mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II-mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor-mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo. CONCLUSION: These results suggest that the cholesterol-independent inhibition of AT1 receptor-mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.

RATIONALE: A growing evidence base suggests a benefit of using high-flow nasal cannula oxygen therapy in the acute setting. However, the clinical benefit of domiciliary use of high-flow nasal cannula oxygen therapy in patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease remains unclear. OBJECTIVES: To evaluate the efficacy and safety of high-flow nasal cannula oxygen therapy use in patients with stable chronic obstructive pulmonary disease. METHODS: We conducted a multicenter, randomized crossover trial comparing high-flow nasal cannula oxygen therapy plus long-term oxygen therapy with long-term oxygen therapy only in 32 adults with stable hypercapnic chronic obstructive pulmonary disease. Participants were randomized to receive either 6 weeks of high-flow nasal cannula oxygen therapy/long-term oxygen therapy using the myAIRVO 2 device followed by another 6 weeks of long-term oxygen therapy only or long-term oxygen therapy only followed by high-flow nasal cannula oxygen therapy/long-term oxygen therapy. The primary outcome was the change in quality of life as assessed by St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease. A linear mixed-effects model was used to account for treatment effect, time effect, allocation effect, and participant effect. RESULTS: Of 32 study participants, 29 completed the study. At the end of 12 weeks, high-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the mean total St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease score compared with long-term oxygen therapy only (7.8 points; 95% confidence interval, 3.7 to 11.9; P < 0.01). Similarly, high-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the arterial partial pressure of carbon dioxide (adjusted treatment effect, -4.1 mm Hg; 95% confidence interval, -6.5 to -1.7 mm Hg), pH (adjusted treatment effect, +0.02; 95% confidence interval, 0.01 to 0.02), and median nocturnal transcutaneous carbon dioxide pressure (adjusted treatment effect, -5.1 mm Hg; 95% confidence interval, -8.4 to -1.8 mm Hg). High-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment did not improve the arterial partial pressure of oxygen, dyspnea, spirometry, lung volume, 6-minute walk test, or physical activity. The most frequent high-flow nasal cannula oxygen therapy-related adverse event encountered was nocturnal sweating (n = 6 [20.7%]). Four severe adverse events occurred (two in each group) and were deemed unrelated to the intervention. CONCLUSIONS: Six weeks of treatment with high-flow nasal cannula oxygen therapy improved health-related quality of life and reduced hypercapnia in patients with stable hypercapnic chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT02545855) and www.umin/ac.jp (UMIN000017639).

Abstract Rationale The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2–4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48–5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1–47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

The molecular mechanisms of the contribution of angiotensin II type-1 receptor blockers to neuronal protection are still unclear. Here, we investigated the effect of angiotensin II type-2 (AT2) receptor stimulation on neurons and cognitive function involving a new neuroprotective factor, methyl methanesulfonate sensitive 2 (MMS2). Angiotensin II treatment of neurospheres enhanced their differentiation and increased MMS2 expression. Knockdown of the MMS2 gene by small interference RNA (siRNA) significantly reduced the number of neurospheres, with loss of sphere formation. An angiotensin II type-1 receptor blocker, valsartan, enhanced such neurosphere differentiation and MMS2 induction, whereas an AT2 receptor antagonist, PD123319, inhibited them. After mice underwent permanent middle cerebral artery occlusion, AT2 receptor mRNA expression was significantly increased in the ischemic side of the brain. Passive avoidance rate to evaluate cognitive function was significantly impaired in AT2 receptor null (Agtr2-) mice compared with wild-type mice. Treatment with valsartan prevented the cognitive decline in wild-type mice, but this effect was weaker in Agtr2- mice. In ischemic brain regions, MMS2 was increased in wild-type mice, but not in Agtr2- mice. Valsartan also enhanced MMS2 expression to a greater degree in wild-type mice. Finally, intracerebroventricular administration of MMS2 siRNA showed more impaired avoidance rate after middle cerebral artery occlusion compared with that in control siRNA-transfected mice. These findings experimentally support the clinical evidence and indicate a unique mechanism of the AT2 receptor in brain protection.

Effects of electrical and chemical stimulation of the ventromedial (VMH) and lateral hypothalamic (LH) nuclei on glucose uptake in peripheral tissues were studied by the 2-deoxy-D-[3H]glucose (2-[3H]DG) method in anesthetized rats. Electrical stimulation of the VMH increased the rate constant of glucose uptake in brown adipose tissue (BAT; 8 times), heart (3 times), and skeletal muscles (1.5 times) but not in white adipose tissue, diaphragm, and brain, without detectable changes in plasma insulin levels. Chemical stimulation of the VMH by microinjection of L-glutamate also enhanced the rate constant of glucose uptake in BAT, heart, and skeletal muscles preferentially, which indicates that the enhancement of glucose uptake in these tissues is derived from activation of VMH neurons. The increased rate of glucose uptake in BAT in response to VMH stimulation was effectively suppressed by surgical sympathetic denervation, suggesting a mediation of the sympathetic nerve in this effect. On the other hand, electrical stimulation of the LH had no appreciable effect on 2-[3H]DG uptake in any tissues. It is concluded that glucose uptake in certain peripheral tissues is accelerated selectively by activation of VMH neurons, the action of which is independent of plasma insulin but which is probably via the sympathetic nervous system.

Glioblastoma is the most malignant type of primary brain tumor that has been shown to contain a small population of cancer stem cells. Recent studies have suggested that cancer stem cells cause tumor recurrence based on their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of glioblastoma cells is also implicated in the failure of current therapies, it is not clear whether cancer stem cells are involved in invasiveness. In this study, we isolated tumor sphere-forming cells bearing cancer stem-like characteristics such as self-renewal, multipotency, drug-resistibility, and in vivo tumorigenicity, from the human glioblastoma cell line U251, under serum-free neural stem cell culture condition, and assessed their migratory and invasive ability. These cells showed enhanced migratory and invasive ability on both Matrigel and organotypic brain slices compared to parental U251 cells. The expression of matrix metalloproteinase (MMP)-13 was specifically expressed in tumor sphere-forming cells derived from U251 and primary human glioma cells. Knockdown of MMP-13 expression by shRNA suppressed the migration and invasion of these cells. The results suggest that the highly invasive potential of cancer stem cells depends on MMP-13 enzymatic activity, thus MMP-13 might be a potential therapeutic target for glioblastomas.

BACKGROUND: Most studies have investigated the association between parental socioeconomic factors and dental caries in children based on educational and income levels; studies focusing on parental occupation, however, have been relatively limited. This cross-sectional study examined the associations between parental occupations and levels of education and household income and the prevalence of dental caries in Japanese children aged 3 years. METHODS: Study subjects were 6315 children. Oral examination results were obtained from the parents or guardians, who transcribed the information recorded by medical staff at a public health center from their maternal and child health handbooks to our self-administered questionnaire. Children were classified as having dental caries if one or more primary teeth had decayed or had been filled. Adjustment was made for sex, age, region of residence, breastfeeding duration, between-meal snack frequency, toothbrushing frequency, use of fluoride, regular dental check-ups, maternal smoking during pregnancy, and living with at least one household smoker. RESULTS: The prevalence of dental caries was 14.7%. Compared with having an unemployed father, having a father employed in professional and engineering, clerical, sales, security, or manufacturing process was significantly associated with a lower prevalence of dental caries. Compared with having an unemployed mother, having a mother employed in professional and engineering or service was significantly inversely associated with the prevalence of dental caries. Significant inverse associations were observed between parental levels of education and household income and the prevalence of dental caries. CONCLUSIONS: The findings of our study suggest that parental occupation affects the prevalence of dental caries in children. We confirm that higher levels of parental education and household income decreased the prevalence of dental caries.

BACKGROUND: Angiotensin II plays a prominent role in the progression of heart failure after acute myocardial infarction (AMI). Although both angiotensin type 1 (AT1) and type 2 (AT2) receptors are known to be present in the heart, comparatively little is known about the latter. We therefore examined the role played by AT2 receptors in post-AMI heart failure. METHODS AND RESULTS: In wild-type mice subjected to AMI by coronary artery ligation, AT2 receptor immunoreactivity is upregulated in the infarct and border areas. Among AT2 receptor-null (-/-) mice, the 7-day survival rate after AMI was significantly lower than among wild-type mice (43% versus 67%; P<0.05). All sham-operated animals of both genotypes survived through the study. Ventricular mRNA levels for brain natriuretic peptide were elevated in both genotypes 24 hours after coronary occlusion, with levels in AT2-/- significantly higher than in wild-type mice, as were their lung weights, and histological examination revealed marked pulmonary congestion in the AT2-/- mice. Cardiac function was significantly decreased in AT2-/- mice 2 days after AMI. CONCLUSIONS: AT2 receptor deficiency exacerbates short-term death rates and heart failure after experimental AMI in mice. The AT2 receptor may thus exert a protective effect on the heart after AMI.

Histamine is inactivated by the histamine-metabolizing enzyme histamine N-methyltransferase (HNMT) in bronchus, kidney, and the central nervous system. HNMT seems to be localized in the cytoplasm, but histamine is unable to easily enter the intracellular space. Therefore, two hypotheses can be elicited: one is the plasma membrane hypothesis that HNMT can be translocated to the plasma membrane and function at the cell surface under growth factor stimulation and the other is the transporter hypothesis that organic cation transporter (OCT)-2 and -3 can function as a histamine transporter as well. To investigate the involvement of OCT2, HEK293 cells stably double transfected with C-terminal hemagglutinin (HA)-tagged HNMT cDNA and/or C-terminal myc-tagged rat OCT2 were prepared for analysis of HNMT activity associated with OCT2 function. After 60-min incubation of these cells with PBS including HA (100 microM), N(tau)-methylhistamine (MHA) concentration of the supernatants was determined by the HPLC-fluorometry method. MHA from cells with HNMT plus OCT-2 was produced at about 3-fold higher level than that from cells with HNMT alone, suggesting that OCT-2 could function as a histamine transporter as well and that HNMT function could partly depend on OCT-2 transporter activity. Using OCT-3 knockout (OCT-3-/-) mice, histamine content and survival rates were investigated in lipopolysaccharide (LPS)-induced endotoxemia model. Without LPS stimulation, histamine content was compared between OCT-3-/- and wild mice. Histamine content in the spleen of OCT-3-/- mice was higher than that f wild mice. With LPS stimulation, the survival rate of OCT-3-/- mice was significantly decreased 12 h after LPS (20 mg/kg) stimulation, suggesting that before immunological stimulation, a higher content of histamine in spleen could stimulate histamine receptors in mast cells, macrophages, dendritic cells, as well as T lymphocytes and explaining the decreased survival rate in OCT-3-/- mice possibly due to the functional changes of immunological cells.

The aim of this study was to determine the role of the AT2 receptor (AT2R) in left ventricular (LV) remodeling after myocardial infarction (MI). The left anterior descending arteries were ligated in AT2R gene knockout (Agtr2-) and wild-type (Agtr2+) mice. The LV remodeling was evaluated by echocardiography and histology over a period of 2 weeks after MI. The infarct sizes in hearts excised from Agtr2+ and Agtr2- mice on day 1 were similar. The mortality rate of Agtr2- mice (62.9%) on day 14 after MI was significantly (P<0.05) higher than that of Agtr2+ mice (39.7%). Accordingly, LV/body weight ratios (3.7+/-0.2 versus 3.0+/-0.1 on day 14) and LV end-diastolic (4.8+/-0.3 versus 3.9+/-0.4 mm on day 7) and end-systolic (4.4+/-0.3 versus 3.2+/-0.6 mm on day 7) dimensions evaluated by echocardiography were significantly greater in Agtr2- than in Agtr2+ mice. The rates of ventricular arrhythmia, rates of cardiac rupture, and blood pressures in the 2 strains were similar after MI. Myocyte cross-sectional areas were increased after MI, but the magnitudes were similar in Agtr2+ and Agtr2- mice, indicating the greater increases in LV dimensions and weight in Agtr2- mice are due to elongation of myocyte length and/or an increase in the interstitial weight (including vasculatures, infiltrated cells, and interstitial fluid). Interstitial fibrosis in remote myocardium was not evident in either strain. These results indicate AT2R plays a significant role in the protection against early development of LV dilation, thereby reducing the early mortality rate after MI.