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TRPM3 is a non-selective cation channel that is activated by neural steroids such as pregnenolone sulfate, nifedipine, and clotrimazole. Despite the number of TRPM3 variants, few reports have described functional analyses of these different TRPM3 types. Here we identified a new TRPM variant from mouse dorsal root ganglion, termed TRPM3γ3. We classified TRPM3γ3 and another known variant (variant 6) into the γ subtype, and analyzed the TRPM3γ variants. mRNA expression of TRPM3γ was higher than that of TRPM3α variants in the mouse dorsal root ganglion. In Ca 2+ -imaging of HEK293 cells expressing either the TRPM3γ variants or TRPM3α2, increases in cytosolic Ca 2+ concentrations ([Ca 2+ ] i ) induced by pregnenolone sulfate or nifedipine were smaller in cells expressing the TRPM3γ variants compared to those expressing TRPM3α2. On the other hand, co-expression of TRPM3γ variants had no effect on [Ca 2+ ] i increases induced by pregnenolone sulfate or nifedipine treatment of HEK293 cells expressing TRPM3α2. In Xenopus oocytes, small responses of TRPM3γ variants to chemical agonists compared to TRPM3α2 were also observed. Interestingly, Xenopus oocytes expressing TRPM3α2 displayed heat-evoked currents with clear thresholds of about 40 °C that were larger than those evoked in oocytes expressing TRPM3γ variants. Overall, these findings indicate that TRPM3γ variants have low channel activity compared to TRPM3α.

FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca 2+ -imaging experiments, increases in intracellular Ca 2+ concentrations ([Ca 2+ ] i ) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca 2+ ] i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.

To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.

Focal segmental glomerulosclerosis (FSGS) is classified into five variants, with the collapsing variant being the most rare. Collapsing FSGS is characterized by a black racial predominance and is often associated with human immunodeficiency virus-associated nephropathy. However, the number of idiopathic cases is increasing and the presentation of non-black patients becoming more routine. Our analysis of 15 previous reports investigating FSGS variants shows that the collapsing variant accounts for 10.6 % of FSGS cases and its average age of onset is 32 years old. The current case is one of the oldest cases of idiopathic collapsing FSGS identified, being an 81-year-old Japanese woman. She presented with severe renal insufficiency (serum creatinine 7.9 mg/dL, albumin 1.5 g/dL) and so underwent hemodialysis immediately. Urinalysis demonstrated 3+ proteinuria and 3+ hematuria and the serological work up was all negative. Renal biopsy showed wrinkling of capillary walls with collapse lumens in every glomerulus, without endothelial tubuloreticular inclusions. Combined treatment with steroids, cyclosporine and low-density lipoprotein apheresis increased urine output slightly but she was unable to withdraw from hemodialysis and died 3 months later. This variant is reported to have the highest rate of progression to end-stage renal disease, regardless of the therapeutic intervention. However, there are also examples of cases with partial or complete remission in the literature. Progressive cases, like the current case, seem to be difficult to induce remission in, so it is important to diagnose idiopathic collapsing FSGS at an early stage by performing a renal biopsy, even in elderly patients.

The term "epigenetics" refers to clonally inherited stable variability in gene expression without underlying genetic changes. There are two well-known molecular mechanisms for epigenetic information: DNA methylation and histone modifications. Epigenetic changes have been recognized in the past decade as critical factors for physiological phenomena such as embryogenesis and the differentiation of normal cells. There is recent interest regarding the involvement of aberrant DNA methylation and histone modifications in mediating altered physiology in cancer. MDS is characterized by epigenetic changes, mutations in epigenetic regulators, and response to DNA methylation inhibitors, suggesting that epigenetic changes are unique features of MDS patients. In this article, recent progress in the understanding of MDS epigenetics and epigenetics-based therapies is reviewed.

Background: The goals of this meta-analysis were to determine survival rates in patients with heart failure (HF) assessed by ¹²³I-MIBG imaging results using recently published studies and to determine the prognostic value of ¹²³I-MIBG imaging., Methods: We reviewed published cohort studies carried out in Japan that compared the prognosis of patients with their ¹²³I-MIBG activity quantified as late heart-to-mediastinum ratio (H/M) or washout rate by performing a PubMed search for articles in English up to December 2006. Studies were selected if they analyzed a clearly defined lethal outcome (cardiovascular death) using life tables to estimate the odds ratio at 24 months after enrollment., Results: Of 158 articles related to cardiac ¹²³I-MIBG, seven referred to studies that met the inclusion criteria: 5 evaluated H/M via ¹²³I-MIBG in a total of 866 patients and 4 calculated washout rate in a total of 491 patients. A low H/M indicated a high risk of cardiac death: pooled odds ratio, 5.2; 95% confidence interval (CI) of 3.1-5.7. A high washout was also associated with lethal events with a pooled odds ratio of 2.8 (CI: 1.6-5.0). The association between washout and cardiac death was heterogeneous (Chi-square = 11.0, P < 0.02), whereas that between late H/M and fatal events was homogeneous (Chi-square = 2.3, P = no significance)., Conclusion: This meta-analysis of published studies of ¹²³I-MIBG studies conducted in Japan indicated that both a decreased cardiac ¹²³I-MIBG activity (H/M) and an increased washout rate are indicative of a poor prognosis in patients with chronic heart failure.

Objective: Various clinical trials for dilated cardiomyopathy (DCM) have demonstrated that the prognosis as well as cardiac function is improved by the administration of beta-blocker therapy. On the other hand, 123I-betamethyl-p-iodophenyl-pentadecanoic acid (BMIPP) reflects myocardial fatty acid metabolism and is considered to be a more sensitive tracer than perfusion tracers. In this study, the efficacy of DCM for the evaluation of myocardial damage and the prediction of cardiac events was studied using 123I-BMIPP and 201TI (Tl) myocardial scintigraphy., Methods: Study subjects comprised 33 DCM patients, divided into a cardiac event group (event, n = 9) and an event-free group (event free, n = 24). An extent score (ES) and severity score (SS) were calculated for each BMIPP image. BMIPP and Tl images were divided into 17 segments, and total defect scores (TDS) were calculated for each. The TDS of the BMIPP and Tl images were compared with score differences greater than or equal to 4 and less than 4 defined as mismatch and non-mismatch, respectively., Results: The TDS of BMIPP was significantly higher in the event group than in the event-free group (P < 0.05). The ES and SS were significantly higher in the event group than in the event-free group (P < 0.01). The comparison in the 2 x 2 contingency tables showed that the occurrence of non-mismatch was significantly higher in the event-free group (chi2 test; P < 0.01). The ES of BMIPP was a significant predictor of cardiac events in the multivariate analysis (P < 0.01)., Conclusions: These results suggest that the ES for BMIPP is useful as a predictor of cardiac events in DCM.

Objective: The purpose of this study was to clarify the usefulness of 99mTc-sestamibi (MIBI) delayed imaging in the assessment of the severity of myocardial ischemia in patients with coronary artery stenosis., Methods: Forty-three angina pectoris with coronary stenosis of greater than 75% were enrolled in this study. Myocardial perfusion SPECT images were obtained 1 and 6 hours after an intravenous injection of MIBI at rest. Stress myocardial perfusion SPECT images were also acquired after the injection of MIBI. And myocardial fatty acid metabolism images were obtained 30 minutes after the injection of BMIPP at rest. Myocardial perfusion SPECT images were divided into 20 segments which were semiquantitatively assessed according to a 4-level defect score scale: score 0 (normal) to score 3 (severely); then the extent score (ES) and severity score (SS) were calculated., Results: The sensitivity for myocardial ischemia showed the highest rate at 88.3% with MIBI delayed SPECT. According to the coronary angiography findings, MIBI stress SPECT and MIBI delayed SPECT detected the severity and extent of ischemia with more sensitivity than MIBI early SPECT in 12 patients (group A) with stenosis of more than 75% but less than 90% (p < 0.01). Even though MIBI stress SPECT detected the severity and extent of ischemia in 31 patients (group B) with stenosis of more than 90% but less than 100%, there was no significant difference between MIBI stress SPECT and MIBI delayed SPECT. BMIPP SPECT revealed significant differences between group A and group B regarding the severity of myocardial ischemia. MIBI reverse redistribution was observed in 33 patients and no significant difference existed between groups A and B., Conclusions: Myocardial washout of MIBI was frequently observed in patients with angina pectoris and the detection accuracy for ischemia was high. MIBI imaging is considered useful for assessment not only of myocardial perfusion but also mitochondrial function. The imagings with BMIPP and delayed MIBI could serve to determine the severity of myocardial ischemia more accurately.

Objective: It is not rare for patients with cardiomyopathy to be asymptomatic for long periods or to show improved cardiac function following various medical interventions. Conversely, cardiac events sometimes occur in those patients, requiring close observation. We assessed the usefulness of 123I-metaiodobenzylguanidine myocardial scintigraphy (MIBG) to predict the occurrence of cardiac events in patients with stable cardiomyopathy., Methods: The subjects comprised 74 outpatients with stable cardiomyopathy. MIBG was performed calculate the extent score, severity score, washout rate (WR), and heart-to-mediastinum ratio. At about the same time, the left ventricular ejection fraction (LVEF) by echocardiography and the plasma brain natriuretic peptide were measured. The mean observation period extended for 741+/-437 days with an end point of cardiac events (cardiac death, heart failure requiring hospitalization, and arrhythmias requiring hospitalization)., Results: During the mean follow-up period, 15 cardiac events occurred. Results of multivariate analysis revealed that LVEF was the most powerful predictor of cardiac events (0.006, p < 0.01). However, WR was the only significant predictor of hard events such as cardiac death (1.171, p < 0.001) and cardiac events in the group of patients who preserved cardiac function with LVEF 0.4 or higher (1.079, p < 0.05)., Conclusion: Combined use of LVEF and WR is useful to predict the occurrence of cardiac events in patients with stable cardiomyopathy.

Primary chylopericardium is an extremely rare disease. This report presents two cases of this disease, in a 47-year-old man and 21 -year-old woman. Both cases were given diagnosis of primary chylopericardium by chylous pericardial fluid examination and lymphangio-scintigraphy which demonstrated abnormal communication between the left thoracic duct and the pericardial cavity.

Objective: 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is currently used to evaluate cardiac sympathetic nerve function, but MIBG also has the capacity to evaluate dilated cardiomyopathy (DCM) severity and therapeutic effectiveness. In this study, we administered beta-blockers to a DCM hamster model and evaluated the effect of therapy using MIBG. We also pathologically compared the effects of myocardial fibrosis suppression., Methods: BIO 53.58 hamsters were divided into the following five groups based on beta-blocker administration: vehicle (COT), 2 mg/kg/day carvedilol (CLT), 20 mg/kg/day (CHT) carvedilol, 4 mg/kg/day (MLT) metoprolol, 40 mg/kg/day (MHT) metoprolol. F1B hamsters were administered a vehicle (COF). Plasma catecholamine, noradrenaline (p-NADR), adrenaline (p-ADR), and dopamine (p-DOPA) were assayed, and MIBG was performed. The count ratio of the heart to the mediastinum (H/M) and left ventricle myocardial washout ratio (WR) were calculated. We then performed an autopsy and calculated the percent change in fibrotic area from myocardial sections., Results: H/M of the initial image in the COT group was significantly lower at 2.4 +/- 0.2 than the 2.9 +/- 0.7 in the COF group (p < 0.05). The CLT and CHT groups had higher H/M values compared to the COT group (3.1 +/- 0.6, 3.0 +/- 0.6 versus 2.4 +/- 0.2: p < 0.05). Significant correlations were evident between the H/M of the delayed image and p-NADR and p-DOPA (p < 0.05, p < 0.01, respectively) as well as between WR and p-NADR and p-DOPA (p < 0.05). Percent change in fibrotic area was significantly lower in the beta-blocker groups than in the COT group (p < 0.05). Significant negative correlations were seen between the H/M of the delayed image and the percent change in fibrosis area., Conclusions: The delayed image H/M and WR acutely reflected cardiac disorder and sympathetic nerve function disorder in BIO 53.58 hamsters. In the carvedilol-administered groups, there was improvement compared to the initial H/M image, indicating the efficacy of the beta-blocker in DCM.

To evaluate left ventricular (LV) wall motion stereoscopically from all directions and to calculate the LV volume by three-dimensional (3D) imaging. 99mTc-DTPA human serum albumin-multigated cardiac pool-single photon emission computed tomography (99mTc-MUGA-SPECT) was performed. A new data processing program was developed with the Application Visualization System-Medical Viewer (AVS-MV) based on images obtained from 99mTc-MUGA-SPECT. In patients with previous myocardial infarction, LV function and LV wall motion were evaluated by 3D-99mTc-MUGA imaging. The LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were obtained from 3D-99mTc-MUGA images by the surface rendering method, and the left ventricular ejection fraction (LVEF) was calculated at thresholds of 35% (T1), 40% (T2), 45% (T3), and 50% (T4). There was a strong correlation between the LV volume calculated by 3D-99mTc-MUGA imaging at a threshold of 40% and that determined by contrast left ventriculography (LVEDV: 194.7 +/- 36.0 ml vs. 198.7 +/- 39.1 ml, r = 0.791, p < 0.001; LVESV: 91.6 +/- 44.5 ml vs. 93.3 +/- 41.3 ml, r = 0.953, p < 0.001), respectively. When compared with the LVEF data obtained by left ventriculography, significant correlations were found for 3D images reconstructed at each threshold (T1: r = 0.966; T2: r = 0.962; T3: r = 0.958; and T4: r = 0.955). In addition, when LV wall motion obtained by 3D-99mTc-MUGA imaging (LAT and LAO views) was compared with the results obtained by left ventriculography (RAO and LAO views), there was good agreement. 3D-99mTc-MUGA imaging was superior in allowing evaluation of LV wall motion in all directions and in assessment of LV function, since data acquisition and image reconstruction could be done within a short time with the three-detector imaging system and AVS-MV. This method appears to be very useful for the observation of both LV wall motion and LV function in patients with ischemic heart disease, because it is a noninvasive examination.

To investigate the clinical applicability of the three-dimensional (3D) myocardial imaging using a newly developed system (the Application Visualization System-Medical Viewer), thallium-201 myocardial single photon emission computed tomography was performed in 19 patients with previous myocardial infarction before and after treatment with nisoldipine. We have developed a new method for automatically reconstructing 3D imaging for the stereoscopic evaluation of myocardial perfusion. The left ventricular myocardial volume with a radioisotope count > or = 50% of maximum was calculated by using the conventional surface rendering method. With these images, the effect of nisoldipine on myocardial perfusion was assessed and the myocardial volume with a radioisotope count > or = 50% of maximum was compared. In fifteen (88%) of 19 patients, myocardial perfusion increased in the infarct areas after nisoldipine treatment. Nisoldipine significantly increased the myocardial volume with a radioisotope count > or = 50% of maximum from 141 +/- 17 to 153 +/- 18 ml on the stress 3D imagings. These findings indicate that nisoldipine improved myocardial perfusion during exercise. 3D imaging provided stereoscopic assessment of the changes in myocardial perfusion following treatment with nisoldipine and also detected transient enlargement of the left ventricular lumen induced by exercise.

Evaluation of viral myocarditis is essential for the clinician to assess the prognosis. In this study, Tl-201 myocardial scintigraphy and Tc-99m gated cardiac blood pool scan were performed in 16 patients with myocarditis diagnosed by clinical symptoms and laboratory findings and these nuclear medicine techniques were followed up for 5 years. Exercise Tl-201 scintigraphy using a bicycle ergometer was performed in 8 patients by SPECT imaging. There were mild to severe persistent defects found in all cases (100%), but pressure rate products showed normal response. The Tl-201 defect ratio improved gradually, but did not change significantly. In the resting Tl-201 image one of 16 patients showed severe multifocal defects. LVEF increased significantly from 1 year to 5 years after onset, while RVEF measured by gated blood pool scans showed slight increases 3 years to 5 years after diagnosis. It was concluded that myocardial perfusion improved only incompletely. Cardiac function (LVEF and RVEF) improved gradually, and pressure rate products were normal. Myocarditis should therefore be followed up in order to assess the prognosis; moreover, the relationship of myocarditis to dilated cardiomyopathy needs to be further studied.