Effectiveness of transarterial embolisation for intractable postpartum haemorrhage in a disseminated intravascular coagulation state, despite emergency hysterectomy.

PURPOSE: We evaluated the effectiveness of transarterial embolization (TAE) for intractable postpartum hemorrhage in patients with disseminated intravascular coagulation (DIC) despite emergency hysterectomy. MATERIALS AND METHODS: We retrospectively assessed TAE performed after emergency hysterectomy in 15 patients between July 2008 and January 2022. Underlying condition, technical success, clinical success, angiographic findings, laboratory findings, pregnancy-modified DIC score (The International Society on Thrombosis and Haemostasis), blood transfusion, ICU (Intensive care unit) admission day, hospital day, in-hospital mortality, and long-term sequelae were evaluated. RESULTS: All patients were diagnosed with DIC before embolization, with a 43.9 mean DIC score. All patients showed positive angiographic findings for active bleeding. Thirty-eight bleeding arteries were confirmed. The remnant uterine artery (n=25) was the most common focus of persistent bleeding, followed by the cervicovaginal artery (n=6), pudendal artery (n=3), obturator artery (n=2), vesical artery (n=1), and unspecified artery from the internal iliac artery (n=1). Technical and clinical success rates were 100% (15/15) and 93.3% (14/15), respectively. Mean nadir hemoglobin (Hb) level before embolization was 4.9 g/dL. All patients underwent massive transfusion before embolization (mean 33.2 packs of RBC). Postoperatively, a smaller amount of blood was transfused than before the procedure (mean 10.6 packs of RBC). Mean nadir Hb level after embolization was 8.2 g/dL. There was one instance each of in-hospital death, hypoxic brain damage, and ischemic acute kidney injury. CONCLUSION: Despite hysterectomy for postpartum bleeding, there could be multiple residual or uncontrolled bleeding foci, especially in case of DIC, for which TAE could be an effective treatment.

Combination of Limosilactobacillus fermentum MG4231 and MG4244 attenuates lipid accumulation in high-fat diet-fed obese mice.

We investigated the anti-obesity effect and the underlying mechanisms of action of human-derived Limosilactobacillus fermentum MG4231, MG4244, and their combination, in high-fat diet-induced obese mice. Administration of the Limosilactobacillus strains decreased body weight gain, liver and adipose tissue weight, and glucose tolerance. Serum levels of total cholesterol, low-density lipoprotein-cholesterol, and leptin were reduced, while adiponectin increased. The administration of Limosilactobacillus strains improved the histopathological features of liver tissue, such as hepatic atrophy and inflammatory penetration, and significantly reduced the content of triglyceride in the liver. Limosilactobacillus administration discovered a significant reduction in the size of the adipocytes in the epididymal tissue. Limosilactobacillus treatment significantly reduced the expression of important regulators in lipid metabolism, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, fatty acid synthase (FAS), adipocyte-protein 2, and lipoprotein lipase in the epididymal tissue. Also, Limosilactobacillus lowered sterol regulatory element-binding protein 1-c and FAS in the liver tissue. Such changes in the expression of these regulators in both liver and epididymis tissue were caused by Limosilactobacillus upregulating phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase. Therefore, we suggest that the use of the combination of L. fermentum MG4231 and MG4244, as probiotics could effectively inhibit adipogenesis and lipogenesis from preventing obesity.

Asymptomatic Cerebral Vasoconstriction after Carotid Artery Stenting.

BACKGROUND AND PURPOSE: Carotid artery stent placement is widely performed for treatment of carotid stenosis. The purpose of this study is to present our observations on cerebral vasoconstriction in ipsilateral anterior circulation during immediate poststenting angiography in patients with near-total occlusion of the proximal ICA. MATERIALS AND METHODS: We retrospectively reviewed patient data from December 2008 to December 2018. There were 28 patients with carotid near-total occlusion. Two neuroradiologists reviewed the final cerebral angiographic finding of carotid artery stent placement to evaluate the presence of vasoconstriction or vasodilation. RESULTS: A total of 28 patients with near-total occlusion (mean ± standard deviation age, 69.0 ± 6.5 years; 92.9% male) were analyzed. Ten patients showed vasoconstriction in the treated territory, and 18 patients did not show vasoconstriction after carotid artery stenting. There were no statistically significant differences in comorbidity, frequency of symptomatic lesions, antiplatelet medication, mean procedure time, and initial NIHSS and baseline modified Rankin scale scores between the 2 groups. However, vasoconstriction is more likely to happen in patients with isolated territory from the contralateral anterior and posterior circulation (66.7% in the isolated territory group and 12.5% in the not-isolated territory group; P < .05). No headache or neurologic deficit was noted in all 10 patients with cerebral vasoconstriction. CONCLUSIONS: Cerebral vasoconstriction may occur after carotid artery stenting more frequently than expected. It occurs more frequently in patients with near-total occlusion and with isolation of the cerebral circulation. A large-scale study is necessary to assess the clinical implications of cerebral vasoconstriction after carotid artery stenting.

Use of Extracorporeal Membrane Oxygenation Prior to Lung Transplantation Does Not Jeopardize Short-term Survival.

BACKGROUND: The use of pretransplantation extracorporeal membrane oxygenation (ECMO) has been considered to be a relative contraindication and a risk factor associated with poor outcomes in lung transplantation. However, with a donor shortage, use of ECMO before transplantation is often unavoidable. This study aimed to review our experiences of lung transplantation outcome with regards to the use of pretransplantation ECMO. METHODS: We retrospectively reviewed the clinical data of patients who underwent lung transplantation at our institution. Clinical variables as well as ECMO-related data were analyzed with surgical outcomes. RESULTS: From 2006 to 2014, 27 patients underwent lung transplantation: 26 bilateral sequential lung transplants and 1 right-side single lung transplant. Of these, 12 (44.4%) received ECMO treatment during the pretransplantation waiting period. Pretransplantation ECMO patients showed higher body mass index scores (P = .047) and mechanical ventilation support (P < .001) than the non-ECMO group. All ECMO patients were weaned from ECMO after transplantation. The median ECMO runtime was 12 days. The survival-to-discharge rates of the 2 groups did not differ. Survival after lung transplantation at 1, 6, 12, and 24 months was 100%, 73.3%, 61.1%, and 61.1% in the ECMO group and 100%, 86.7%, 86.7%, and 66.0% in the non-ECMO group, respectively (P = .540). CONCLUSIONS: Use of pretransplantation ECMO did not jeopardize survival-to-discharge and short-term survival rates in our experience. Our result suggests pretransplantation ECMO can provide a chance of receiving lung transplantation to those who were classified as "too sick to be transplanted."

Perihilar branching patterns of renal artery and extrarenal length of arterial branches and tumour-feeding arteries on multidetector CT angiography.

OBJECTIVE: The purpose of our study was to assess the extrarenal length of renal arterial branches and tumour-feeding arteries on multidetector CT (MDCT) angiography, in addition to the perihilar branching patterns, with relevance to segmental artery clamping. METHODS: MDCT angiograms of 64 patients with renal masses <4 cm were retrospectively reviewed by 2 radiologists. The perihilar branching patterns of the single main renal artery were assessed according to the number of pre-segmental and segmental arteries. The extrarenal lengths of segmental plus pre-segmental arteries and the tumour-feeding arteries, measured on volume-rendered images, were compared according to the vascular segmentation and the tumour location, respectively. RESULTS: In the 116 kidneys, 1 pre-segmental plus 5 segmental arteries (n=48) was the most common branching pattern. The mean extrarenal length of the inferior segmental plus pre-segmental arteries (33.05 mm) and the posterior segmental plus pre-segmental arteries (32.30 mm) was longer than any of the other segmental plus pre-segmental arteries (apical, 23.87 mm; superior, 26.80 mm; middle, 29.23 mm) (p<0.05). The mean extrarenal length of the lower pole tumour-feeding arteries (35.94 mm) was longer than those of the upper and mid-pole tumour-feeding arteries (24.95 mm, 29.62 mm), with significant difference between the lower and the upper pole tumour-feeding arteries (p<0.05). CONCLUSION: Tumours in the lower pole, supplied by the inferior or posterior segmental artery, may be more amenable to segmental artery clamping. ADVANCES IN KNOWLEDGE: MDCT angiography with volume rendering can demonstrate the extrarenal length of tumour-feeding arteries and may help in determining the accessibility for segmental artery clamping.

The fate of patients on the waiting list for lung transplantation in Korea.

Lung transplantation for end-stage lung disease results in prolonged actuarial survival and improved pulmonary function. However, the shortage of donor lungs has been a major limiting factor in transplantation. The purpose of this study was to analyze the waiting time and mortality rate for each disease entity. The medical records of all patients listed in The Korean Network for Organ Sharing (KONOS) from May 1996 to May 2011 were analyzed to identify waiting times and causes of death. During the study period, 146 patients (86 males and 60 females) of mean age of 46.6 years (range; 5 to 73 years) showed idiopathic pulmonary fibrosis (IPF; n = 61), chronic obstructive pulmonary disease (COPD; n = 19) or bronchiectasis (n = 15). Sixty-five patients (44.5%) underwent lung or heart-lung transplantation. Sixty-two patients (42.5%) expired during the waiting period, and 19 patients are still on the waiting list. The mortality rate while waiting was highest among patients with primary pulmonary hypertension (62.5%) followed by IPF (57.4%), and acute respiratory distress syndrome (ARDS) (55.6%). The mean time from diagnosis to registration in KONOS was 15.5 months among the expired and 13.2 months in the transplanted group (P = .455). The mean time on waiting list was 8.2 months in the expired group and 3.7 months in the transplanted group (P = .012). In the expired group, the mean survival time was significantly shorter among patients with ARDS (2.2 months, P = .004) compared to IPF (7.9 months), COPD (10.7 months), and primary pulmonary hypertension (PPH) (30.0 months). The high mortality rate (42.5%) during the waiting period in Korea may result from the lack of donors and the delay in registration.

Donor evaluation for lung transplantation in Korea.

Lung transplantation for end-stage lung disease results in prolonged survival and improved pulmonary function. However, the shortage of donor lungs has been a major limiting factor in Korea. We sought to investigate the number and utilization of donor lungs by the five institutions performing LTx in Korea, retrospectively reviewing outcomes of organs registered in the Korean Network for Organ Sharing from January to December, 2010. Lungs were offered from 270 brain-dead patients (189 males and 81 females) of mean age of 45.2 ± 14.2 years (range, 12 to 77 years). The most common cause of brain death was hemorrhage (n = 219, 81%). Only 18 (6.7%) donor lungs were used, which was low compared with kidney (93.3%), liver (86.3%), heart (26.7%), and pancreas (11.1%) use. The mean age of donors of transplanted lungs was 35.7 years (range, 14 to 51 years) compared with 45.9 years for other organs (P = .003). The characteristics of utilized donor lungs were: mean partial pressure of oxygen (PaO(2)), 300.9 mm Hg; mean smoking history, as 2.7 pack-years; and mean body mass index, 21.2 kg/m(2). The causes of refusal were medical ineligibility (n = 129) including poor PaO(2), abnormal chest x-ray, long smoking history, older age (n = 46), no properly matched recipient (n = 46), unknown (n = 17), and family withdrawal (n = 14). Only 8 (33.3%) were transplanted from standard criteria and 10 from the lungs that did not satisfy these criteria. An efficient utilization system is needed to improve lung transplantations.

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase.

AIMS/HYPOTHESIS: Sirtuin 1 (SIRT1) is a longevity-associated protein, which regulates energy metabolism and lifespan in response to nutrient deprivation. It has been proposed to be a therapeutic target for obesity and metabolic syndrome. We investigated whether α-lipoic acid (ALA) exerts a lipid-lowering effect through regulation of SIRT1 activation and production in C(2)C(12) myotubes. METHODS: ALA-stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), adipose triacylglycerol lipase (ATGL) and fatty acid synthase (FAS) production, as well as intracellular triacylglycerol accumulation and fatty acid ß-oxidation were analysed in the absence or presence of a SIRT1 inhibitor (nicotinamide), SIRT1 small interfering (si) RNA and an AMPK inhibitor (compound C) in C(2)C(12) myotubes. Mice with streptozotocin/nicotinamide-induced diabetes and db/db mice fed on a high-fat diet were used to study the ALA-mediated lipid-lowering effects in vivo. RESULTS: ALA increased the NAD(+)/NADH ratio to enhance SIRT1 activity and production in C(2)C(12) myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate ß-oxidation and decreased intracellular triacylglycerol accumulation in C(2)C(12) myotubes. In cells treated with nicotinamide or transfected with SIRT1 siRNA, ALA-mediated AMPK/ACC phosphorylation, intracellular triacylglycerol accumulation and palmitate ß-oxidation were reduced, suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein production in C(2)C(12) myotubes. Oral administration of ALA in diabetic mice fed on a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content. CONCLUSIONS/INTERPRETATION: ALA activates both SIRT1 and AMPK, which leads to lipid-lowering effects in vitro and in vivo. These findings suggest that ALA may have beneficial effects in the treatment of dyslipidaemia and obesity.

Surgical management of the esophageal leiomyoma: lessons from a retrospective review.

Esophageal leiomyoma is the most common benign tumor of the esophagus. Although enucleation via thoracotomy has been considered standard treatment, minimally invasive surgery is increasingly used for the treatment of this disease. We analyzed our surgical outcomes by comparing thoracotomy and the thoracoscopic approach. A retrospective review was performed of patients who underwent surgical resection of esophageal leiomyomas at the Seoul National University Hospital. Between 1982 and 2005, 63 patients were identified (male, n= 39; female, n= 24) at a mean age of 44.5 years. Thirty-two patients (51%) were symptomatic. Forty-five patients underwent thoracotomy, and 18 patients were resected using thoracoscopy. There was no mortality. The mean length of hospital stay was 10.3 days in the open group and 8.0 days in thoracoscopy group. Intraoperative mucosal repair was required in eight patients. Preoperative endoscopic mucosal biopsy within 1 month was identified as a risk factor for mucosal injury. Among the 11 patients with tumors less than 1.5 cm in size, thoracoscopic resection was attempted on four patients, and three out of the four cases required conversions to thoracotomy. Minimally invasive surgery for esophageal leiomyoma can be performed with good results. Our results suggest that the thoracoscopic approach should be considered as a standard surgical method for the treatment of esophageal leiomyoma. However, in cases of small tumors less than 1.5 cm in size, localization of the tumor may be difficult, and if asymptomatic, a regular monitoring should be considered as an alternative approach in such small tumors.

Aberrant promoter CpG island hypermethylation of the adenomatosis polyposis coli gene can serve as a good prognostic factor by affecting lymph node metastasis in squamous cell carcinoma of the esophagus.

There has been no clear evidence demonstrating whether DNA hypermethylation can affect the prognosis of esophageal cancer. We collected tissue from 50 cases of squamous cell carcinoma of the esophagus and tested them for DNA hypermethylation using methylation-specific polymerase chain reaction. CpG island hypermethylations were observed in 10% for p16, 34% for RARbetaP2, 46% for adenomatosis polyposis coli (APC), 14% for RASSF1A, 84% for FHIT, and 8% for hMLH1. APC promoter hypermethylation was frequently found in patients without lymph node metastasis compared with those with lymph node metastasis (62.5% : 30.8%, P = 0.025). The number of metastatic lymph nodes were lower in patients with APC promoter hypermethylation (0.87 +/- 0.30 : 3.07 +/- 0.72, P = 0.008). Excluding operative mortalities and incomplete resections, 42 patients were analyzed for long-term outcome. During the mean follow-up period of 35 months, 17 developed recurrence and 14 died of cancer. Ten patients died of other causes. In univariable analysis, unmethylation of APC (P = 0.0015) and FHIT (P = 0.0044), as well as presence of lymph node metastasis (P = 0.0038), were risk factors for recurrence. In multivariable analysis, lymph nodes metastasis (P = 0.050) and unmethylation of APC promoter (P = 0.023) remained as significant risk factors. In conclusion, promoter hypermethylation of the APC gene is related to a lower number of metastatic lymph nodes and to superior prognosis in terms of recurrence, which suggests it might be involved in the process of lymph node metastasis in esophageal cancer.

Ultrasound-guided radiofrequency neurotomy in cervical spine: sonoanatomic study of a new technique in cadavers.

AIM: To develop an ultrasound-guided technique for radiofrequency (RF) cervical medial branch neurotomy and to validate the accuracy of this new method. MATERIALS AND METHODS: Five non-embalmed, fresh cadavers were used; three male and two female cadavers with a median age at death of 67.2 years (range 50-84 years). This study was conducted in two parts. First, two of the cadavers were used to define the sonographic target point for RF cervical medial branch neurotomy using high-resolution ultrasound (12 to 5 MHz). The needles were guided to five consecutive cervical medial branches in the cadavers under ultrasound guidance. Subsequently, the position of the ultrasound-guided needle was verified using C-arm fluoroscopy. Ultrasound-guided RF neurotomy was performed to the C5 medial branches in all five cadavers. In the three cadavers not used in the first part of the study, ultrasound-guided RF neurotomy without C-arm fluoroscopic confirmation was performed to the C3-C7 medial branches. The accuracy of neurotomy was assessed by pathological examination of the cervical medial branches obtained through cadaver dissection. RESULTS: In all five cadavers, the sonographic target point was identified in all C3-C7 segments with the 12 to 5 MHz linear transducer. In all 20 needle placements for the first and second cadavers, C-arm fluoroscopy validated proper needle tip positions. In all five cadavers, successful neurotomy was pathologically confirmed in 30 of 34 cervical medial branches. CONCLUSIONS: Ultrasound-guided cervical medial branch neurotomy was successfully performed in 30 of 34 cervical medial branches in five cadavers. However, before eliminating fluoroscopic validation of final needle tip positioning, the technique should be validated in symptomatic patients.

MRI of paraspinal muscles in lumbar degenerative kyphosis patients and control patients with chronic low back pain.

AIM: To compare lumbar musculature in lumbar degenerative kyphosis (LDK) patients and chronic low-back pain (CLBP) patients. MATERIALS AND METHODS: The study group comprised LDK patients (54 women, aged 44-74 years, mean 60 years) and a control group with CLBP (54 women, aged 45-73 years, mean 60 years). The cross-sectional areas (CSA) of psoas, erector spinae, multifidus, and disc, were measured at the L4-L5 level using magnetic resonance imaging (MRI). Lumbar muscularity was expressed as three ratios: the ratio between CSA of psoas, erector spinae, multifidus and CSA of disc (PS:disc, ES:disc, MF:disc). Multifidus and erector spinae atrophy were evaluated at the L3-L4 level and the degree of fatty atrophy was estimated using three grades: mild, moderate, and severe. The shapes of thoracolumbar fascia were analysed at the L5-S1 level and were classified as flat or convex. RESULTS: Lumbar muscularity was found to be significantly smaller (p<0.001) in LDK patients (PS:disc=0.79, SD 0.22; ES:disc=1.36, SD 0.49; MF:disc=0.55, SD 0.21) than the control group patients (PS:disc=0.98, SD 0.23; ES:disc=1.71, SD 0.46; MF:disc=0.86, SD 0.30). Patients with LDK had a higher proportion of fat deposits in the multifidus and erector spinae muscle (p<0.001), and the thoracolumbar fascia at the L5-S1 level was more commonly flat (p<0.01). CONCLUSION: Evaluation of paraspinal musculature should be considered when assessing MRI images of the lumbar spine. Measurement of the CSA, visual grading of fatty atrophy and the assessment of the fascia may help physician and radiologist reach a more confident diagnosis for the patients with clinically suspicious LDK.

Comparison of the amount of nuclides released from the spent fuel in contact with and without a compacted bentonite block.

A spent LWR fuel specimen between Ca-bentonite blocks was leached in a simulated bentonite-saturated granitic water (SBGW) for 165 days and its results were compared with those of a specimen leached without a bentonite block. The amounts of Cs, Sb, Sr, Eu, Am, U and Pu released from a 4.3 mm thickness of a fuel pellet with a 50,400 MWD/MTU burn-up in the SBGW without a bentonite block were 2.2, 0.25, 0.15, 0.02, 0.01, 0.01 and approximately 5 x 10(-4)% of their inventories, respectively. However, the amounts of nuclides released from the specimen between the 1.4 Mg/m(3) bentonite blocks were decreased by three times at least. Moreover, the concentrations of the nuclides in the leachate were very low because most of them were retained in the bentonite blocks.

The metallic composition of aerosols at three monitoring sites in Korea during winter 2002.

In the present study, the distribution patterns of various metals were analyzed and compared using PM samples collected concurrently from three monitoring sites located in Korea (Seoul, Busan, and Jeju island) in December 2002. As these sites can represent metal pollution with different degrees of anthropogenic activities, their concentration levels were distinguished in a systematic manner in the order of Jeju, Busan, and Seoul. By comparing the present data sets with those measured previously from other locations in Korea and around the world, we attempted to diagnose the general status of elemental pollution on the Korean peninsula. Through an application of different statistical approaches, the major processes controlling elemental levels were assessed for each of the three study sites. The results indicated the importance of both crustal and anthropogenic sources in all sites with their relative roles varying significantly from each other. The results of the metal analysis data, when examined in relation to back trajectory analysis, confirmed that their concentration changes are affected quite sensitively with air mass movement patterns. The overall results of this study consistently indicated the contribution of a strong anthropogenic source area (e.g., China) to the observed metal concentration levels in the study area, but the strengths of such signals vary considerably across the Korean peninsula.

Prognostic factors for surgical resection in patients with multidrug-resistant tuberculosis.

Although surgical lung resection could improve prognosis in some patients with multidrug-resistant tuberculosis (MDR-TB), there are no reports on the optimal candidates for this surgery. The aim of the present study was to elucidate the prognostic factors for surgery in patients with MDR-TB. Patients who underwent lung resection for the treatment of MDR-TB between March 1993 and December 2004 were included in the present study. Treatment failure was defined as greater than or equal to two of the five cultures recorded in the final 12 months of treatment being positive, any one of the final three cultures being positive, or the patient having died during treatment. The variables that affected treatment outcomes were identified through univariate and multivariate logistic regression analysis. In total, 79 patients with MDR-TB were included in the present study. The treatment outcomes of 22 (27.8%) patients were classified as failure. A body mass index <18.5 kg x m(-2), primary resistance, resistance to ofloxacin and the presence of a cavitary lesion beyond the range of the surgical resection were associated with treatment failure. Low body mass index, primary resistance, resistance to ofloxacin and cavitary lesions beyond the range of resection are possible poor prognostic factors for surgical lung resection in multidrug-resistant tuberculosis patients.

Outcome after one-stage repair of tetralogy of Fallot.

AIM: The purpose of this study was to evaluate the outcome after one-stage repair of tetralogy of Fallot (TOF). METHODS: Between May 1997 and December 2002, 240 patients with a median age of 9 months (1 month-48 years) underwent one-stage repair of TOF. Closure of ventricular septal defect (VSD) was accomplished through the right atrium in 171 (71.3%) patients and through the right ventricle in 69 (28.7%) patients. For the reconstruction of the right ventricular outflow tract (RVOT), transannular repair was performed in 151 (62.9%) patients, and non-transannular repair was performed in 89 (37.1%) patients. Follow-up was complete, averaging 40+/-17.6 months (3 months-5.8 years). RESULTS: There were 2 (0.8%) operative deaths. Between early repair group (age under 6 months) and late repair group (age above 6 months), there were no differences in the method of RVOT reconstruction (transannular vs non-transannular) and the need for branch pulmonary artery angioplasty. Early repair group had more transventricular VSD closure than late repair group (46% vs 22%, P < 0.05). Duration of inotropic support and intensive care unit (ICU) stay were longer in the early repair group (P < 0.05). Five patients required reoperations due to RVOT obstruction (n = 3), and residual VSD (n = 2). Kaplan-Meier freedom from reoperation at 5 years was 98.3+/-1%. Nine patients underwent catheter intervention for branch pulmonary artery stenosis. Freedom from reintervention at 5 years was 95.4+/-1.5%. All survivors are currently asymptomatic. CONCLUSIONS: One-stage repair of TOF could be performed with low mortality and morbidity. Especially, early one-stage repair in symptomatic infant could be performed with low risk, eliminating the need for palliative procedures.

AtBAG6, a novel calmodulin-binding protein, induces programmed cell death in yeast and plants.

Calmodulin (CaM) influences many cellular processes by interacting with various proteins. Here, we isolated AtBAG6, an Arabidopsis CaM-binding protein that contains a central BCL-2-associated athanogene (BAG) domain. In yeast and plants, overexpression of AtBAG6 induced cell death phenotypes consistent with programmed cell death (PCD). Recombinant AtBAG6 had higher affinity for CaM in the absence of free Ca2 + than in its presence. An IQ motif (IQXXXRGXXXR, where X denotes any amino-acid) was required for Ca2 +-independent CaM complex formation and single amino-acid changes within this motif abrogated both AtBAG6-activated CaM-binding and cell death in yeast and plants. A 134-amino-acid stretch, encompassing both the IQ motif and BAG domain, was sufficient to induce cell death. Agents generating oxygen radicals, which are known to be involved in plant PCD, specifically induced the AtBAG6 transcript. Collectively, these results suggest that AtBAG6 is a stress-upregulated CaM-binding protein involved in plant PCD.

Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor.

Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology.