Impact of comorbidity and relative dose intensity on outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.

BACKGROUND: Comorbidity and relative dose intensity (RDI) have been associated with survival in diffuse large B-cell lymphoma (DLBCL) patients, but both relationships remain unaddressed in the same patients. METHODS: A retrospective review of consecutive DLBCL patients treated from January 2010 to October 2018 was performed. Data for the clinical characteristics of the patients, including the Charlson Comorbidity Index (CCI) and RDI, on their outcomes were evaluated. RESULTS: A total of 211 patients with a median age of 72 years (range 19-90 years) were analyzed. CCI ≥ 2 was associated with poor event-free survival (EFS) and overall survival (OS). RDI < 70% was associated with worse EFS and OS. A multivariate analysis revealed that RDI < 70% was only a poor risk factor for the reduction of OS in elderly DLBCL patients (65 years <) and independent from the presence of CCI. The relationship between CCI and RDI in elderly patients was analyzed in four groups, based on CCI ≥ 2 or less and RDI ≥ 70% or less. The group with CCI ≥ 2 and RDI < 70% had a poorer OS and EFS, as compared to the other three groups. The group with CCI < 2 and RDI ≥ 70% had a superior OS but an identical EFS, as compared to the two groups with CCI < 2 and RDI < 70% and CCI ≥ 2 and RDI ≥ 70%. CONCLUSIONS: CCI ≥ 2 was associated with a poorer outcome, but maintaining RDI ≥ 70% may improve the outcome, especially in elderly DLBCL patients.

Visual exploration of emotional faces in schizophrenia using masks from the Japanese Noh theatre.

Studying eye movements during visual exploration is widely used to investigate visual information processing in schizophrenia. Here, we used masks from the Japanese Noh theatre to study visual exploration behavior during an emotional face recognition task and a brightness evaluation control task using the same stimuli. Eye movements were recorded in 25 patients with schizophrenia and 25 age-matched healthy controls while participants explored seven photos of Japanese Noh masks tilted to seven different angles. Additionally, participants were assessed on seven upright binary black and white pictures of these Noh masks (Mooney-like pictures), seven Upside-down pictures (180° upside-down turned Mooneys), and seven Neutral pictures. Participants either had to indicate whether they had recognized a face and its emotional expression, or they had to evaluate the brightness of the picture (total N = 56 trials). We observed a clear effect of inclination angle of Noh masks on emotional ratings (p < 0.001) and visual exploration behavior in both groups. Controls made larger saccades than patients when not being able to recognize a face in upside-down Mooney pictures (p < 0.01). Patients also made smaller saccades when exploring pictures for brightness (p < 0.05). Exploration behavior in patients was related to depressive symptom expression during emotional face recognition but not during brightness evaluation. Our findings suggest that visual exploration behavior in patients with schizophrenia is less flexible than in controls depending on the specific task requirements, specifically when exploring physical aspects of the environment.

Masked ambiguity - Emotion identification in schizophrenia and major depressive disorder.

Both patients with schizophrenia and with a major depressive disorder (MDD) display deficits in identifying facial expressions of emotion during acute phases of their illness. However, specific deficit patterns have not yet been reliably demonstrated. Tasks that employ emotionally ambiguous stimuli have recently shown distinct deficit patterns in patients with schizophrenia compared to other mental disorders as well as healthy controls. We here investigate whether a task which uses an ambiguous Japanese (Noh) mask and a corresponding human stimulus generates distinctive emotion attribution patterns in thirty-two Caucasian patients with schizophrenia, matched MDD patients and healthy controls. Results show that patients with schizophrenia displayed reaction time disadvantages compared to healthy controls while identifying sadness and anger. MDD patients were more likely to label stimuli with basic compared to subtle emotional expressions. Moreover, they showed more difficulties assigning emotions to the human stimulus than to the Noh mask. IQ, age and cognitive functioning did not modulate these results. Because overall group differences were not observed, this task is not suitable for diagnosing patients. However, the subtle differences that did emerge might give therapists handles that can be used in therapy.

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial.

OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. CONCLUSIONS: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels.

Toll-like receptor-4 is upregulated in plaque debris of patients with acute coronary syndrome more than Toll-like receptor-2.

Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins, those may lead to acute coronary syndrome (ACS). We investigated the expression level of TLR-4 in ACS, as compared with TLR-2 and patients with stable angina. Fifty-eight consecutive patients who underwent primary percutaneous coronary intervention (PCI, n = 29) because of ACS and elective PCI (n = 29) because of stable angina using a filter-device distal protection device system were prospectively analyzed. mRNA levels of TLR-2 and TLR-4 in debris containing various inflammatory tissues entrapped in the filter device were altogether analyzed using real-time PCR. There were no significant differences in age, sex distribution, between stable angina and ACS groups. TLR-4 expression levels were higher in patients with ACS than in patients with stable angina. TLR-4 might play a more important role than TLR-2 in atherogenesis, especially in ACS.

Benefits of using culturally unfamiliar stimuli in ambiguous emotion identification: A cross-cultural study.

A novel emotion recognition task that employs photos of a Japanese mask representing a highly ambiguous stimulus was evaluated. As non-Asians perceive and/or label emotions differently from Asians, we aimed to identify patterns of task-performance in non-Asian healthy volunteers with a view to future patient studies. The Noh mask test was presented to 42 adult German participants. Reaction times and emotion attribution patterns were recorded. To control for emotion identification abilities, a standard emotion recognition task was used among others. Questionnaires assessed personality traits. Finally, results were compared to age- and gender-matched Japanese volunteers. Compared to other tasks, German participants displayed slowest reaction times on the Noh mask test, indicating higher demands of ambiguous emotion recognition. They assigned more positive emotions to the mask than Japanese volunteers, demonstrating culture-dependent emotion identification patterns. As alexithymic and anxious traits were associated with slower reaction times, personality dimensions impacted on performance, as well. We showed an advantage of ambiguous over conventional emotion recognition tasks. Moreover, we determined emotion identification patterns in Western individuals impacted by personality dimensions, suggesting performance differences in clinical samples. Due to its properties, the Noh mask test represents a promising tool in the differential diagnosis of psychiatric disorders, e.g. schizophrenia.

Gender differences in factors influencing electrocardiographic findings of left ventricular hypertrophy in severe aortic stenosis.

We investigated gender differences in factors influencing the electrocardiographic (ECG) findings of left ventricular hypertrophy (LVH) in patients with severe aortic stenosis (AS). The functional and geometric responses of the left ventricle to chronic pressure overload, such as hypertension and AS, have been reported to be different between men and women. However, gender differences in the factors influencing the ECG findings of LVH in pressure overload remain unknown. We conducted a retrospective observational study in consecutive patients with severe AS (aortic valve area (AVA) assessed by cardiac catheterization <1.0 cm(2)) without concomitant significant aortic regurgitation, mitral stenosis and/or regurgitation, conduction disturbance, or myocardial infarction (n = 35 males, 68 females). The ECG criteria were classified into three categories: (1) high voltage by the Sokolow-Lyon index associated with ST-T wave changes (with no digitalis therapy); (2) high voltage alone; and (3) normal. Groups 1 and 2 were defined as LVH on ECG. We compared the ECG findings in relation to the AS severity between genders. Women were older, but there were no significant differences in the prevalence of hypertension, AVA index (AVAI), mean pressure gradient or peak velocity across the AV, LV mass index (LVMI) derived from echocardiography or the distribution of ECG categories between genders. A multiple logistic regression analysis including age, gender, hypertension, AVAI, mean pressure gradient, and LVMI revealed that the LVMI (P = 0.001) and AVAI (P = 0.0434) were significantly related to the distribution of ECG categories. LVMI significantly predicted LVH on ECG in both genders, but AVAI was a predictive factor in only women. ECG LVH in patients with severe AS may be mainly reflected by LVMI in men and by both LVMI and AVAI in women. Factors other than AVA, such as end-stage disease and/or complicating factors such as hypertension, may underlie the observed differences in ECG findings of LVH between men and women.

Comparison of the reperfusion efficacy of thrombus aspiration with and without distal protection during primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction.

We evaluated a hypothesis that thrombus aspiration with distal protection is superior to simple thrombus aspiration in patients treated with primary percutaneous coronary intervention (PCI). A total of 176 consecutive patients with ST-segment elevation myocardial infarction were enrolled in this study and assigned to either the thrombus aspiration group (A, n = 104) or the thrombus aspiration with distal protection group using a filter device system (A + DP, n = 72). We compared the angiographic reperfusion grade, left ventricular (LV) function, and clinical outcomes between the 2 groups. There were no significant differences in age, gender distribution, the onset-to-reperfusion time, the peak levels of creatine kinase, or 6-month mortality between the 2 groups. The rate of achieving a Thrombolysis In Myocardial Infarction flow grade of 3 and a myocardial blush grade of 3 was higher in the A + DP group than in the A group. Among the patients who underwent follow-up catheterization 6 months after PCI (A, n = 62; A + DP, n = 52), there were no significant differences in the LV end-diastolic volume index, LV end-systolic volume index, or LV ejection fraction between the 2 groups at the time of PCI or 6 months after PCI. In conclusion, thrombus aspiration with distal protection may be more effective in initially restoring the coronary blood flow than thrombus aspiration alone, although it may not be superior to thrombus aspiration in preventing LV remodeling or preserving the LV function in patients with ST-segment elevation myocardial infarction.

Clinical impact of coronary artery spasm in patients with no significant coronary stenosis who are experiencing acute coronary syndrome.

BACKGROUND AND OBJECTIVE: To clarify the clinical features of coronary artery spasm (CAS) with no significant coronary stenosis in patients with suspected acute coronary syndrome (ACS) in real practice. METHODS: This is a retrospective observational study of patients with suspected ACS (n=645) based on symptoms, electrocardiographic changes, and/or positive cardiac biomarkers and vasospastic angina (VSA, n=90). ACS patients were divided into two groups: (1) organic ACS (n=515), culprit lesion ≥75% coronary stenosis with/without thrombosis; (2) spastic ACS (n=70), coronary stenosis <75%, either with positive acetylcholine (ACh) test (n=51) or without ACh test but verified spontaneous spasm (n=19). The study compared clinical characteristics among organic ACS, spastic ACS, and VSA. RESULTS: One hundred and thirty suspected ACS patients had a coronary organic stenosis <75% (130/645, 20%). Seventy of those patients (70/130, 54%) were confirmed to have CAS, and these accounted for 11% of all ACS patients (70/645). The rate of cigarette smoking was highest in the spastic ACS. No spastic ACS patients died during their hospital stay or after discharge, whereas acute myocardial infarction occurred in 19%, aborted sudden cardiac death in 6%, multivessel spasm was provoked in 78%, and diffuse spasm was more frequently provoked than in the VSA group (82% vs. 62%). CONCLUSIONS: CAS is not a rare cause of ACS. Although the prognosis of spastic ACS is good, there are occasional critical cases. An initial differential diagnosis including an ACh test is thus important to decide the treatment strategy of ACS.

Relationships between inflammatory mediators and coronary plaque composition in patients with stable angina investigated by ultrasound radiofrequency data analysis.

Inflammation has been recognized as a critical process in the progression of coronary atherosclerosis. Virtual Histology-intravascular ultrasound (VH-IVUS) has been reported to be a useful tool for tissue characterization of coronary atherosclerotic plaque. We investigated relationships between plaque composition and inflammation-related factors possibly contributing to atheromatous plaque formation and progression, since these are largely unknown. Using VH-IVUS, we measured plaque volume and composition at the culprit lesions in patients with stable angina undergoing elective percutaneous coronary intervention (n = 33, 39 de novo lesions), and then analyzed correlations between plaque components and serum levels of inflammatory factors in both aorta and culprit coronary artery obtained by aspiration using a distal protection device. Linear regression analysis revealed that both aortic and coronary LDL cholesterol levels correlated with %plaque burden along the culprit lesions (r = 0.535 and 0.539, respectively), but with none of the plaque components. Of %plaque components, fibro-fatty (FF) correlated positively with both aortic and coronary T cell/B cell ratios (r = 0.335 and 0.359, respectively) whereas necrotic core (NC) correlated negatively with both aortic and coronary T cell/B cell ratios (r = -0.373 and -0.483, respectively). These results suggest that LDL cholesterol may be a good marker for total coronary plaque volume whereas the lymphocyte subset of T cell/B cell ratios may be a good marker for plaque composition, especially FF and NC components volume.

Scavenging free radicals improves endothelial dysfunction in human coronary arteries in vivo.

The effect of a novel free radical scavenger, edaravone, on coronary endothelial dysfunction was examined in patients who had no significant stenosis of coronary arteries, to elucidate the role of free radicals on coronary endothelial dysfunction. The coronary blood flow (CBF) responses to acetylcholine (ACh) were measured by quantitative coronary arteriography and the intracoronary Doppler technique before and after the administration of edaravone. Twenty-four patients were divided into two groups on the basis of CBF responses to ACh; those with "attenuated" (%Delta CBF < 300%, n = 12) and "normal" (%Delta CBF > 300%, n = 12) flow responses. An intracoronary infusion of edaravone significantly improved ACh-induced increases in CBF in patients with attenuated flow responses; however, edaravone had no effect in those with normal flow responses (36.8% +/- 7.3% vs 0.0% +/- 5.1%, P < 0.01). The plasma levels of nitric oxide compounds (NOx) in the attenuated response group were lower than those in the normal group (35.7 +/- 2.3 vs 49.4 +/- 6.2 muM, P < 0.01) and correlated with the magnitude of CBF improvement by edaravone (r = 0.566, P < 0.01). The plasma level of malondialdehyde and 4-hydroxynonenal, which indicates the level of oxidative stress, in the attenuated group was higher than that in the normal group (6.9 +/- 0.9 vs 3.3 +/- 0.5 muM, P < 0.01) and correlated with the magnitude of CBF improvement by edaravone (r = 0.854, P < 0.01). A free radical scavenger improved the ACh-induced CBF response in patients with coronary atherosclerosis in vivo. Therefore, the current results suggest that scavenging free radicals has a beneficial effect for patients with coronary endothelial dysfunction.

Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function.

BACKGROUND: Phosphorylation of the regulatory light chain of myosin (MLC) has roles in cardiac function. In vitro, myosin phosphatase target subunit 2 (MYPT2) is a strongly suspected regulatory subunit of cardiac myosin phosphatase (MP), but there is no in-vivo evidence regarding the functions of MYPT2 in the heart. METHODS AND RESULTS: Transgenic mice (Tg) overexpressing MYPT2 were generated using the alpha-MHC promoter. Tg hearts showed an increased expression of MYPT2 and concomitant increase of the endogenous catalytic subunit of type 1 phosphatase (PP1cdelta), resulting in an increase of the MP holoenzyme. The level of phosphorylation of ventricular MLC was reduced. The pCa-tension relationship, using beta-escin permeabilized fibers, revealed decreased Ca(2+) sensitization of contraction in the Tg heart. LV enlargement with associated impairment of function was observed in the Tg heart and ultrastructural examination showed cardiomyocyte degeneration. CONCLUSIONS: Overexpression of MYPT2 and the increase in PP1cdelta resulted in an increase of the MP holoenzyme and a decrease in the level of MLC phosphorylation. The latter induced Ca(2+) desensitization of contraction and decreased LV contractility, resulting in LV enlargement. Thus, MYPT2 is truly the regulatory subunit of cardiac MP in-vivo and plays a significant role in modulating cardiac function. (Circ J 2010; 74: 120 - 128).

Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study.

OBJECTIVE: To establish an optimal adjuvant therapy for intermediate- and high-risk endometrial cancer patients, we conducted a multi-center randomized phase III trial of adjuvant pelvic radiation therapy (PRT) versus cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy in women with endometrioid adenocarcinoma with deeper than 50% myometrial invasion. METHODS: Among 385 evaluated patients, 193 patients received PRT and 192 received CAP. The PRT group received at least 40 Gy. The CAP group received cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) every 4 weeks for 3 or more courses. RESULTS: No statistically significant differences in progression-free survival (PFS) and overall survival (OS) were observed. The 5-year PFS rates in the PRT and CAP groups were 83.5% and 81.8% respectively, while the 5-year OS rates were 85.3% and 86.7% respectively. These rates were also not significantly different in a low- to intermediate-risk group defined as stage IC patients under 70 years old with G1/2 endometrioid adenocarcinoma. However, among 120 patients in a high- to intermediate-risk group defined as (1) stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology), the CAP group had a significantly higher PFS rate (83.8% vs. 66.2%, log-rank test P=0.024, hazard ratio 0.44) and higher OS rate (89.7% vs. 73.6%, log-rank test P=0.006, hazard ratio 0.24). Adverse effects were not significantly increased in the CAP group versus the PRT group. CONCLUSION: Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.

Reliability and validity of questionnaire for neurobehavioral disability following traumatic brain injury.

The neurobehavioral disability recognized in traumatic brain injury (TBI) is a severe sequela, but there is no appropriate classification due to its various manifestations. In the present study a questionnaire for a simple investigation of this disability was prepared, and its reliability and validity verified. The survey was conducted on 72 patients with TBI by the caregiver of each patient. As a result, good reliability was indicated by the split-half method (coefficient of reliability: 0.95, obtained using Spearman-Brown correction formula). The total score of the questionnaire had a significant correlation with the total score of the simultaneously conducted Japanese version of Neuropsychiatry Inventory at the 0.01 level (Spearman's rank correlation, 0.47). It also had a significant correlation with the total score of the simultaneously conducted Japanese version of the Dysexecutive Questionnaire at the 0.05 level (Spearman's rank correlation, 0.36). Six factors constituting this neurobehavioral disability were extracted from a factor analysis of the questionnaire survey. These factors are angry outburst, avolition, deficits of sympathy, depressed mood, discourse deficits, and degradation of appearance. Each factor indicated good internal consistency (Cronbach alpha, 0.86-0.94). The present results indicate that this questionnaire has good reliability and validity, therefore it can be a significant indicator in TBI neurobehavioral disability study.

Three fatal cases of rapidly progressive infective endocarditis caused by Staphylococcus aureus: one case with huge vegetation.

Staphylococcus aureus (S. aureus) infective endocarditis (IE) is a severe disease with a high mortality despite intensive therapy. Three cases of S. aureus IE had a rapidly progressive fatal clinical course despite intensive antimicrobial therapy. One case was methicillin-sensitive S. aureus IE, which formed rapidly growing a huge vegetation on a prosthetic mitral valve, complicated with multiple systemic emboli. The other 2 cases were methicillin-resistant S. aureus IE without any predisposing heart disease.

Re-expression of proteins involved in cytokinesis during cardiac hypertrophy.

Cardiomyocytes stop dividing after birth and postnatal heart growth is only achieved by increase in cell volume. In some species, cardiomyocytes undergo an additional incomplete mitosis in the first postnatal week, where karyokinesis takes place in the absence of cytokinesis, leading to binucleation. Proteins that regulate the formation of the actomyosin ring are known to be important for cytokinesis. Here we demonstrate for the first time that small GTPases like RhoA along with their downstream effectors like ROCK I, ROCK II and Citron Kinase show a developmental stage specific expression in heart, with high levels being expressed in cardiomyocytes only at stages when cytokinesis still occurs (i.e. embryonic and perinatal). This suggests that downregulation of many regulatory and cytoskeletal components involved in the formation of the actomyosin ring may be responsible for the uncoupling of cytokinesis from karyokinesis in rodent cardiomyocytes after birth. Interestingly, when the myocardium tries to adapt to the increased workload during pathological hypertrophy a re-expression of proteins involved in DNA synthesis and cytokinesis can be detected. Nevertheless, the adult cardiomyocytes do not appear to divide despite this upregulation of the cytokinetic machinery. The inability to undergo complete division could be due to the presence of stable, highly ordered and functional sarcomeres in the adult myocardium or could be because of the inefficiency of degradation pathways, which facilitate the division of differentiated embryonic cardiomyocytes by disintegrating myofibrils.

Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis.

Transient receptor potential (TRP) proteins have been identified as cation channels that are activated by agonist-receptor coupling and mediate various cellular functions. TRPC7, a homologue of TRP channels, has been shown to act as a Ca2+ channel activated by G protein-coupled stimulation and to be abundantly expressed in the heart with an as-yet-unknown function. We studied the role of TRPC7 in G protein-activated signaling in HEK293 cells and cultured cardiomyocytes in vitro transfected with FLAG-tagged TRPC7 cDNA and in Dahl salt-sensitive rats with heart failure in vivo. TRPC7-transfected HEK293 cells showed an augmentation of carbachol-induced intracellular Ca2+ transient, which was attenuated under a Ca2+-free condition or in the presence of SK&F96365 (a Ca2+-permeable channel blocker). Upon stimulation with angiotensin II (Ang II), cultured neonatal rat cardiomyocytes transfected with TRPC7 exhibited a significant increase in apoptosis detected by TUNEL staining, accompanied with a decrease in the expression of atrial natriuretic factor and destruction of actin fibers, as compared with non-transfected cardiomyocytes. Ang II-induced apoptosis was inhibited by CV-11974 (Candesartan; Ang II type 1 [AT1] receptor blocker), SK&F96365, and FK506 (calcineurin inhibitor). In Dahl salt-sensitive rats, apoptosis and TRPC7 expression were increased in the failing myocardium, and a long-term treatment with temocapril, an angiotensin-converting enzyme inhibitor, suppressed both. Our findings suggest that TRPC7 could act as a Ca2+ channel activated by AT1 receptors, leading to myocardial apoptosis possibly via a calcineurin-dependent pathway. TRPC7 might be a key initiator linking AT1-activation to myocardial apoptosis, and thereby contributing to the process of heart failure.

Ca2+ stimulates COX-2 expression through calcium-sensing receptor in fibroblasts.

Fibroblasts isolated from jaw cysts expressed calcium-sensing receptor (CasR). In the fibroblasts elevated extracellular Ca(2+) ([Ca(2+)](o)) increased fluo-3 fluorescence intensity, and the production of inositol(1,4,5)trisphosphate and active protein kinase C. Phospholipase C inhibitor U-73122 attenuated the Ca(2+)-induced increase in fluo-3 fluorescence intensity. Elevated [Ca(2+)](o) enhanced the expression of cyclooxygenase-2 (COX-2) mRNA and protein, and the secretion of prostaglandin E(2) in the fibroblasts. CasR activator neomycin also increased the expression of COX-2 mRNA, and U-73122 attenuated the Ca(2+)-induced expression of COX-2 mRNA. Elevated [Ca(2+)](o)-induced phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK), and U-73122 inhibited the Ca(2+)-induced phosphorylation. The inhibitors for each kinase, PD98059, SB203580, and SP600125, attenuated the Ca(2+)-induced expression of COX-2 mRNA. These results suggest that in jaw cyst fibroblasts elevated extracellular Ca(2+) may enhance COX-2 expression via the activation of ERK1/2, p38 MAPK, and JNK through CasR.