A Polymorphism rs6726395 in Nrf2 Contributes to the Development of Emphysema-Associated Age in Smokers Without COPD.

INTRODUCTION: Several studies have reported that single nucleotide polymorphisms (SNPs) in the gene encoding NF-E2-related factor 2 (Nrf2) contribute to airflow limitations in smokers without COPD. Although small airway lesions and emphysema contribute cooperatively to airflow limitation, the relationship between Nrf2 SNPs and the development of emphysema in smokers without COPD is not well understood. METHODS: Healthy subjects who underwent an annual health checkup with computed tomography (CT) of the chest at Osaka City University Hospital were prospectively recruited. The percentage of low-attenuation area (%LAA) on chest CT was quantified, and correlations between %LAA, Nrf2 SNP [rs6726395 (G/A)] genotypes, and clinical characteristics were examined. RESULTS: A total of 245 subjects without COPD [non-/light-smoker: 153 (62.4%) and smoker: 92 (37.6%)] were enrolled. The %LAA in the upper lung field was higher than that in the lower lung field (p < 0.001). The %LAA in smokers was significantly higher than that in non-/light-smokers (p = 0.021). The %LAA showed significant but weak correlation with age in all subjects (r = 0.141, p = 0.028). Divided by genotype, the %LAA of the upper lung field was significantly correlated with age in smokers with genotype GG (wild type) (r = 0.333, p = 0.022), but was not significantly correlated with age in smokers with genotype AG/AA. These correlations were not observed in non-/light smokers. CONCLUSION: A polymorphism rs6726395 in Nrf2 can contribute to the development of emphysema-associated aging in smokers. The Nrf2 SNP may be a predictive factor for smoking-induced emphysema, and genotyping of Nrf2 SNP may serve as biomarker for emphysema prevention.

Mouth breathing, another risk factor for asthma: the Nagahama Study.

BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.

Third heart sound in hospitalised patients with acute heart failure: insights from the ATTEND study.

BACKGROUND: Several previous studies have suggested that detection of a third heart sound (S3) in patients with chronic congestive heart failure is associated with adverse long-term outcomes. However, the short-term prognostic value of identifying an S3 on admission in patients with acute heart failure (AHF) is not well established. We therefore analysed the in-hospital prognostic value of detecting an S3 on admission in hospitalised patients with AHF. METHODS: The Acute Decompensated Heart Failure Syndromes (ATTEND) study investigators enrolled 4107 patients hospitalised with AHF. Investigators evaluated the presence or absence of an S3 during routine physical examination. RESULTS: On admission to hospital, 1673 patients (41%) had an S3. Patients with an S3 had a higher heart rate, higher serum level of B-type natriuretic peptide and higher creatinine levels than patients without an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein and total bilirubin between the two groups. Multivariate analysis adjusted for various markers of disease severity revealed that only the presence of an S3 was independently associated with an increase of in-hospital all cause death [adjusted odds ratio (OR), 1.69; 95% confidence interval (CI), 1.19-2.41; p = 0.003] and cardiac death (adjusted OR, 1.66; 95% CI, 1.08-2.54; p = 0.020) among the congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). CONCLUSIONS: Detecting an S3 on admission was independently associated with adverse in-hospital outcomes in patients with AHF. Our findings suggest that careful bedside assessment is clinically meaningful.

Expression of dihomo-γ-linolenic acid and FADS1/2 and ELOVL2/5 in term rabbit placentas.

Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy.

Region-specific expression of a water channel protein, aquaporin 4, on brain astrocytes.

Cellular activities within the brain display regional specificity and a neuronal and glia interdependence. Components characterizing the regional specificity of neurons have been identified. However, characterization of the astrocyte remains in question. To identify region specific features of astrocytes, we have characterized the molecular phenotype of cells derived from regions with different levels of neuronal excitability, the cortex and striatum. Astrocytes were identified in cryostat sections of adult rat brain by rapid immunostaining for glial fibrillary acidic protein (GFAP), and individual cells were collected from each region by using laser microdissection (LMD). Total RNA was isolated and subjected to DNA microarray analysis. At least eight genes showed a differential expression level. Among them, aquaporin 4 (AQP4), a water channel protein, was expressed at higher levels within the cortex compared with the striatum, as confirmed by immunohistochemistry. Primary cultured astrocytes isolated from rat cortex or striatum also showed a differential expression of AQP4. These data may reflect unique properties of astrocytes across different brain regions. However, they may also reflect the interactive demands of neurons with different activity levels. Further examination of the heterogeneous astrocyte populations within each region will lend additional support to the regional specificity of neuronal functions and neuronal-glial interactions.

In which cases of pneumonia should we consider treatments for Stenotrophomonas maltophilia?

BACKGROUND: Stenotrophomonas maltophilia is a pathogen commonly associated with respiratory infection. However, the characteristics of pneumonia caused by S. maltophilia remain unknown. AIM: To evaluate the characteristics of and risk factors for S. maltophilia pneumonia. METHODS: A retrospective evaluation was undertaken of 2002 patients with sputum cultures positive for S. maltophilia between January 2010 and December 2019. Cases were excluded based on clinical information and laboratory results. Included cases were divided into two groups: the S. maltophilia pneumonia group (patients with pneumonia caused by S. maltophilia) and the non-S. maltophilia pneumonia group (patients with pneumonia caused by pathogens other than S. maltophilia). Patient characteristics, clinical data and Sequential Organ Failure Assessment (SOFA) scores were compared between the groups. FINDINGS: Eight and 91 patients were assigned to the S. maltophilia pneumonia and non-S. maltophilia pneumonia groups, respectively. The median age was significantly lower in the S. maltophilia pneumonia group than in the non-S. maltophilia pneumonia group (63.4 vs 73.1 years; P<0.01), and the SOFA score was significantly higher in the S. maltophilia pneumonia group (7.5 vs 3.0; P<0.01). Underlying malignancy and pre-administration of antipseudomonal ß-lactams and steroids were confirmed in seven of the eight cases in the S. maltophilia pneumonia group, suggesting an association with immunosuppression. CONCLUSIONS: Pneumonia due to S. maltophilia is a rare occurrence. Treatment for this pathogen should be considered in cases of pneumonia with: (1) predominance of S. maltophilia in sputum cultures; (2) pre-administration of broad-spectrum antibiotics; (3) immunodeficiency; and (4) a high SOFA score.

Association of Education and Depressive Symptoms with Tooth Loss.

Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between "≤9 y of education" and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between "≤9 y of education" and "depressive symptoms" in the general Japanese population.

Akt-dependent cytokine production in mast cells.

Cross-linking of FcepsilonRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcepsilonRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha promoters. Transcription from the nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IkappaB-alpha, a cytoplasmic protein that binds NF-kappaB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF-alpha in FcepsilonRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-kappaB, NF-AT, and AP-1 that contributes to the production of cytokines.

Increased levels of angiopoietin-2 in induced sputum from smoking asthmatic patients.

BACKGROUND: Active cigarette smoking has detrimental effects on asthma morbidity and severity. Angiopoietin-1 has been shown to protect the microvessels against plasma leakage, whereas angiopoietin-2 enhances vascular permeability and subsequently induces airway mucosal oedema. Therefore, it is recently thought that angiopoietin-2 may contribute to the pathophysiology of asthma. OBJECTIVE: To determine whether angiopoietin-2 levels in the airways are associated with clinical profiles in smoking asthmatics. METHODS: We measured angiopoietin-1 and -2 levels in induced sputum in 35 normal controls (18 non-smokers and 17 smokers) and 49 asthmatics (24 non-smokers and 25 smokers) before and after inhaled beclomethasone dipropionate (BDP: 800 microg/day) therapy for 12 weeks. RESULTS: Angiopoietin-1 and -2 levels in induced sputum were significantly higher in asthmatics than in normal controls. Moreover, angiopoietin-2 levels were significantly higher in smoking asthmatics than in non-smoking asthmatics (P=0.0001). The airway vascular permeability index was also higher in smoking asthmatics than in non-smoking asthmatics. Moreover, the angiopoietin-2 level was positively correlated with the airway vascular permeability index (non-smoking asthmatics: r=0.87, P<0.001, smoking asthmatics: r=0.64, P=0.002). After BDP therapy, angiopoietin-1 levels were significantly decreased in non-smoking asthmatics, smoking-cessation asthmatics, and active-smoking asthmatics. In contrast, angiopoietin-2 levels did not differ from before to after BDP therapy in non-smoking asthmatics and active-smoking asthmatics. However, its levels were significantly decreased from before to after BDP therapy in smoking-cessation asthmatics (P=0.002). Although forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) before BDP therapy was comparable in all subgroups, this parameter after BDP therapy was significantly lower in active-smoking asthmatics than in non-smoking and smoking-cessation asthmatics. Moreover, the reduction in angiopoietin-2 levels after BDP therapy in smoking-cessation asthmatics was significantly correlated with an improvement in FEV(1)/FVC. CONCLUSION: Angiopoietin-2 levels were elevated in the airways of smoking asthmatics, and its levels were associated with impaired airway responses.

Platelet-derived growth factor and transforming growth factor-beta modulate the expression of matrix metalloproteinases and migratory function of human airway smooth muscle cells.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) have been suggested to be involved in the pathogenesis of asthma. Their expression in airway smooth muscle (ASM) cells could be involved in collagen turnover and migration of these cells and thus may contribute to airway remodelling. OBJECTIVE: To examine the effect of pro-fibrotic growth factors TGF-beta and platelet-derived growth factor (PDGF) on the expression of MMPs/TIMPs in cultured human ASM cells and to examine the role of MMP in the migration of ASM cells. METHODS: ASM cells were stimulated with TGF-beta and/or PDGF. Expression and activity of MMP-1, MMP-2, MMP-3, TIMP-1 and TIMP-2 were evaluated by quantitative RT-PCR, Western blot and zymography. Modified Boyden-chamber migration assay was performed to investigate the effect of secreted MMP-3 and TIMP-1 on ASM-cell migration. RESULTS: PDGF strongly up-regulated the expression of MMP-1 at mRNA and protein levels. PDGF, when combined with TGF-beta, caused synergistic up-regulation of MMP-3. TIMP-1 was additively up-regulated by TGF-beta and PDGF. These growth factors had no effect on the expression of MMP-2 and TIMP-2. U0126, an extracellular signal-regulated kinase (ERK) pathway inhibitor, inhibited the up-regulation of MMP-1 by PDGF. The synergistic/additive up-regulation of MMP-3 and TIMP-1 was inhibited by U0126 and SB431542, a Smad pathway inhibitor. Supernatant from ASM cells in which MMP-3 production was knocked down by RNA interference showed a decreased migratory effect on ASM cells, whereas supernatant from cells with suppressed TIMP-1 expression resulted in increased migration. CONCLUSION: Our results suggest that PDGF with/without TGF-beta could facilitate migration of ASM cells by modification of MMP-TIMP balance through the ERK pathway.

Use of modified U1 snRNAs to inhibit HIV-1 replication.

Control of RNA processing plays a central role in regulating the replication of HIV-1, in particular the 3' polyadenylation of viral RNA. Based on the demonstration that polyadenylation of mRNAs can be disrupted by the targeted binding of modified U1 snRNA, we examined whether binding of U1 snRNAs to conserved 10 nt regions within the terminal exon of HIV-1 was able to inhibit viral structural protein expression. In this report, we demonstrate that U1 snRNAs complementary to 5 of the 15 regions targeted result in significant suppression of HIV-1 protein expression and viral replication coincident with loss of viral RNA. Suppression of viral gene expression is dependent upon appropriate assembly of a U1 snRNP particle as mutations of U1 snRNA that affect binding of U1 70K or Sm proteins significantly reduced efficacy. However, constructs lacking U1A binding sites retained significant anti-viral activity. This finding suggests a role for these mutants in situations where the wild-type constructs cause toxic effects. The conserved nature of the sequences targeted and the high efficacy of the constructs suggests that this strategy has significant potential as an HIV therapeutic.

Long-Term Results and Follow-Up Examinations after Endovascular Embolization for Unruptured Cerebral Aneurysms.

BACKGROUND AND PURPOSE: The appropriate period of follow-up examinations after endovascular embolization for cerebral aneurysms using time-of-flight MR angiography is not well-known. We retrospectively investigated long-term results after endovascular embolization for unruptured cerebral aneurysms and evaluated the periods from embolization to recanalization and retreatment. MATERIALS AND METHODS: Between April 2006 and March 2011, one hundred forty-eight unruptured aneurysms were treated with endovascular coil embolization. Among them, we investigated 116 unruptured aneurysms, which were followed up for >5 years. Time-of-flight MR angiography was performed at 1 day, 3-6 months, 1 year after the procedure, and every year thereafter. RESULTS: The mean follow-up period was 7.0 ± 1.4 years. Recanalization was observed in 19 (16.3%) aneurysms within 2 years. Among them, retreatment for recanalization was performed in 8 (6.8%) aneurysms. No recanalization was detected in any aneurysms that had been stable in the first 2 years after embolization. A larger maximum aneurysm size was significantly correlated with recanalization (P = .019). CONCLUSIONS: Aneurysms in which recanalization was not observed within 2 years after endovascular coil embolization were stable during a mean follow-up of 7 years. This result may be helpful in considering the appropriate span or frequency of follow-up imaging for embolized cerebral aneurysms.

Parotid gland carcinoma: 32 years' experience from a single institute.

BACKGROUND: Parotid gland carcinoma is a rare and complicated histopathological classification. Therefore, assembling a sufficient number of cases with long-term outcomes in a single institute can present a challenge. METHOD: The medical records of 108 parotid gland carcinoma patients who were treated at Kyushu University Hospital, Fukuoka, Japan, between 1983 and 2014 were reviewed. The survival outcomes were analysed according to clinicopathological findings. RESULTS: Forty-six patients had low clinical stage tumours (I-II), and 62 patients had high clinical stage tumours (III-IV). Fifty-two, 10 and 46 patients had low-, intermediate- and high-grade tumours, respectively. Twenty-seven of 65 cases had positive surgical margins. In high clinical stage and intermediate- to high-grade tumours, adjuvant radiation therapy was correlated with local recurrence-free survival (p = 0.0244). Intermediate- to high-grade tumours and positive surgical margins were significantly associated with disease-specific survival in multivariate analysis (p = 0.0002 and p = 0.0058). CONCLUSION: The results of this study show that adjuvant radiation therapy is useful for improved local control in patients with high clinical stage and intermediate- to high-grade tumours.

Third Dentition Is the Main Cause of Premolar Supernumerary Tooth Formation.

While the prevalence of supernumerary teeth (ST) is high in permanent dentition, the etiology of ST in humans remains unclear. However, multiple murine models of ST have elaborated on dated mechanisms traditionally ascribed to ST etiology: one involves the rescue of rudimental teeth, and the second considers the contribution of odontogenic epithelial stem cells. It remains unclear whether these mechanisms of ST formation in mice are applicable to humans. The third dentition is usually regressed apoptotic-that is, the teeth do not completely form in humans. Recently, it was suggested that ST result from the rescue of regression of the third dentition in humans. The present investigation evaluates the proportion of collected general ST cases that evinced a third dentition based on the clinical definition of ST derived from the third dentition. We also investigated the contribution of SOX2-positive odontogenic epithelial stem cells to ST formation in humans. We collected 215 general ST cases from 15,008 patients. We confirmed that the general characteristics of the collected ST cases were similar to the results from previous reports. Of the 215 cases, we narrowed our analysis to the 78 patients who had received a computed tomography scan. The frequency of ST considered to have been derived from the third dentition was 26 out of 78 cases. Evidence of a third dentition was especially apparent in the premolar region, was more common in men, and was more likely among patients with ≥3 ST. SOX2-positive odontogenic epithelial stem cells within the surrounding epithelial cells of developing ST were observed in non-third dentition cases and not in third dentition cases. In conclusion, the third dentition is the main cause of ST in humans. The odontogenic epithelial stem cells may contribute to ST formation in cases not caused by a third dentition.

[The relation between the frequency of exercise oxygen desaturation following major lung resection and the predictions of postoperative pulmonary function].

The predictors of oxygen desaturation during exercise in patients submitted to major pulmonary resection for lung cancer are to be determined. We analyzed retrospectively the relation between the oxygen saturation by pulse oxymetry (Spo2) during exercise and the predictions of postoperative pulmonary function. A hundred twenty-two patients with lung cancer who underwent lung resection from January 1999 to May 2004 were included (79 men, 43 women, average age 66.9 +/- 9.2). A fall over 5% in Spo2 during exercise was termed 'desaturation'. Twenty-eight patients developed desaturation [group D(+)] and 94 patients did not [group D(-)]. We compared the predictions of postoperative pulmonary function (%ppoVC, %ppoFEV1.0, %ppoDLco) between these 2 groups. As a result, only %ppoDLco was significantly different between 2 groups [D(+) 68.7 +/- 19.1%, D(-) 83.8 +/- 24.9%]. Patients with poor %ppoDLco are at increased risk to develop a postoperative exercise oxygen desaturation.

Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse.

Transgenic (TG) mice with cardiac G(salpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with G(salpha) overexpression could be averted with chronic beta-adrenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type littermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of older TG mice, and abolished premature mortality. Propranolol also prevented the increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 9-month-old TG mice, was actually eliminated by chronic propranolol. This study indicates that chronic sympathetic stimulation over an extended period is deleterious and results in cardiomyopathy. Conversely, beta-AR blockade is salutary in this situation and can prevent the development of cardiomyopathy.

Overexpression of myocardial Gsalpha prevents full expression of catecholamine desensitization despite increased beta-adrenergic receptor kinase.

Inotropic and chronotropic responses to catecholamines in young adult transgenic mice overexpressing myocardial Gsalpha are enhanced. One might predict that over the life of the animal, this chronically enhanced beta-adrenergic receptor stimulation would result in homologous catecholamine desensitization. To test this hypothesis, old transgenic Gsalpha mice and age-matched controls were studied physiologically in terms of responsiveness of left ventricular function (ejection fraction) to isoproterenol in vivo and in vitro in terms of beta-adrenergic receptor signaling. Old transgenic mice still responded to isoproterenol with augmented (P < 0.05) left ventricular ejection fraction (+44+/-3%) compared with age-matched controls (+24+/-1%). Although total beta-adrenergic receptor density was reduced in the old transgenic mice, and G protein receptor kinase 2 (beta-adrenergic receptor kinase) levels were increased, the fraction of receptors binding agonist with high affinity as well as isoproterenol- and G protein-stimulated adenylyl cyclase activities were enhanced. Thus, classical catecholamine desensitization is not effective in attenuation of persistently enhanced responses to sympathetic stimulation in mice overexpressing myocardial Gsalpha. To support this conclusion further, experiments were performed with chronic isoproterenol, which elicited effective desensitization in wild-type controls, but failed to elicit desensitization in overexpressed Gsalpha mice. The results of this study suggest that the lack of protective desensitization mechanisms may be responsible in part for the dilated cardiomyopathy which develops with chronic sympathetic stress over the life of these animals.

Differential regulation of inotropy and lusitropy in overexpressed Gsalpha myocytes through cAMP and Ca2+ channel pathways.

We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gsalpha myocytes. Although baseline contractile function (percent contraction) in Gsalpha mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca2+transients, and Ca2+ channel currents (ICa) were greater in Gsalpha mice in response to 10(-8) M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accelerated at baseline in Gsalpha but did not increase further with ISO. In vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gsalpha mice. Forskolin and CaCl2 increased contraction similarly in WT and Gsalpha mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gsalpha. It also blocked the accelerated relaxation in Gsalpha at baseline but not the contractile response to ISO in Gsalpha myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsalpha compared with WT. These data indicate that overexpression of Gsalpha accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity; i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMP-dependent pathway.

Neural responses to human voice and hemisphere dominance for lexical-semantic processing--an fMRI study.

OBJECTIVES: In our previous functional magnetic resonance imaging (fMRI) study, we determined that there was distinct left hemispheric dominance for lexical-semantic processing without the influence of human voice perception in right-handed healthy subjects. However, the degree of right-handedness in the right-handed subjects ranged from 52 to 100 according to the Edinburgh Handedness Inventory (EHI) score. In the present study, we aimed to clarify the correlation between the degree of right-handedness and language dominance in the fronto-temporo-parietal cortices by examining cerebral activation for lexical-semantic processing. METHODS: Twenty-seven normal right-handed healthy subjects were scanned by fMRI while listening to sentences (SEN), reverse sentences (rSEN), and identifiable non-vocal sounds (SND). Fronto-temporo-parietal activation was observed in the left hemisphere under the SEN - rSEN contrast, which included lexical-semantic processing without the influence of human voice perception. Laterality Index was calculated as LI = (L - R)/(L + R) x 100, L: left, R: right. RESULTS: Laterality Index in the fronto-temporo-parietal cortices did not correlate with the degree of right-handedness in EHI score. CONCLUSIONS: The present study indicated that the degree of right-handedness from 52 to 100 in EHI score had no effect on the degree of left hemispheric dominance for lexical-semantic processing in right-handed healthy subjects.