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.

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.

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.

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.

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.

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.

Crystallization and preliminary X-ray studies of the liganded lysine, arginine, ornithine-binding protein from Salmonella typhimurium.

The periplasmic binding protein LAO from Salmonella typhimurium, which is involved in lysine, arginine and ornithine transport, has been crystallized together with one of its ligands, arginine (LAO-Arg). Preliminary X-ray diffraction studies of LAO-Arg crystal show that it belongs to the orthorhombic space group P2(1)2(1)2(1) and has the unit cell dimensions of a = 37.65 A, b = 59.45 A, c = 115.91 A. Crystals of the LAO-Arg complex diffract beyond 2.0 A resolution.

Two crystal structures of a potently sweet protein. Natural monellin at 2.75 A resolution and single-chain monellin at 1.7 A resolution.

Two refined structures of the sweet-tasting protein monellin are presented. The structure of natural monellin has been refined at 2.75 A resolution. The final model consists of four monellin molecules in the asymmetric unit, encompassing 3136 non-hydrogen atoms. The crystallographic R-factor is 0.193 for the 8853 reflections between 6.0 A and 2.75 A resolution, and the root-mean-square deviations from ideality are 0.017 A for bond lengths and 3.6 degrees for bond angles. The refined structure generally confirms, with some difference in detail, the initial backbone model of monellin that was based on 3.0 A resolution data. Single-chain monellin (scm) was genetically engineered by fusing the two chains of monellin into a single 94-residue polypeptide. Using the refined monellin coordinates as a search model, the crystal structure of scm has been solved with the techniques of molecular replacement, and has been refined against data to 1.7 A resolution. The final model consists of two scm molecules per asymmetric unit, and includes 137 bound water molecules. The crystallographic R-factor for this model is 0.174 for the 15,053 reflections (magnitude of FO magnitude of > 2 sigma (FO)) between 6.0 A and 1.7 A resolution. The root-mean-square deviations from ideal bond lengths and angles are 0.015 A and 2.86 degrees, respectively, and the average coordinate error is approximately 0.2 A, as estimated from a Luzzati plot. The error in the model was also estimated by comparing the two molecules in the asymmetric unit. The most significant differences between the two molecules occur in loop regions and at the C terminus of the protein, and are generally correlated to differences in crystal packing contacts. Linking the two chains of monellin has not substantially altered the structure beyond the region immediately surrounding the new peptide bond. Like natural monellin, the conformation of scm is dominated by a 17-residue alpha-helix folded into the concave side of a twisted, five-strand anti-parallel beta-sheet. We expect that the availability of a high-resolution structure of scm, along with the convenience of producing site-specific mutants of this protein, will make scm a good model with which to probe the structural basis of sweetness.

Crystallization and preliminary X-ray studies of HisJ and LAO periplasmic proteins from Salmonella typhimurium.

Two periplasmic binding proteins, HisJ and LAO, which are involved in histidine and arginine transport, respectively, have been crystallized. Preliminary X-ray diffraction studies of the HisJ and LAO crystals show that both belong to the orthorhombic space group P2(1)2(1)2(1) and have unit cell dimensions of a = 39.26 A, b = 66.17 A, c = 88.33 A and a = 36.08 A, b = 78.34 A, c = 102.02 A, respectively. Both HisJ and LAO crystals diffract beyond 2.0 A resolution.

Analysis on donor and isolation-related factors of successful isolation of human islet of Langerhans from human cadaveric donors.

We analyzed the preexisting donor factors and isolation variables that affected isolation of human islets of Langerhans. Sixty-nine pancreata from cadaveric donors were analyzed for donor factors of age, gender, body mass index, cause of death as well as graft factors of cold ischemia time, pancreas status, distensibility during intraductal collagenase distension and time of collagenase expansion and digestion. Islet isolations that recovered >100,000 IEQ (n = 53) were compared to those generating less than 100,000 IEQ (n = 16) to analyze the factors affecting islet yield during donor harvest and isolation procedures. The mean islet recovery was 216.0 x 10(3) (IEQ) or 2840 (IEQ) per gram of pancreas. Mean purity was 54%. The success rate of islet isolation was 76%. Mean age was 31 years, and mean cold ischemia time was 6.9 hours. In univariate analysis, the status of the pancreas was the only significant factor for successful isolation, and gender, time of collagenase expansion and digestion were marginal factors. In stepwise multivariate logistic regression analysis of donor and isolation-related factors, donor gender, pancreas status and digestion time were significant factors. During the same period we performed three cases of clinical islet allotransplantation and one autotransplantation. This study confirmed that the same donor factors and variables in the isolation process can affect the ability to obtain successful human islet isolation. Enough experience and pertinent review of donor and isolation factors can make islet isolation consistent, supporting clinical islet transplantation without unnecessary cost.

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."

Activation of the 5-HT1C receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393.

1. A cloned 5-HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1-selective benzazepines at the 5-HT1C receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1C receptors was measured in the choroid plexus of the pig. 2. In voltage-clamped oocytes expressing the cloned 5-HT1C receptor, 5-hydroxytryptamine (5-HT) elicited a characteristic inward current response with an EC50 of 13 nM. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nM. SKF 38393 (1 microM-1 mM), SKF 77434 (100 microM), and SKF 82958 (100 microM) also acted as agonists (or partial agonists) at the cloned 5-HT1C receptor. SKF 38393 was not stereoselective at the 5-HT1C receptor. 3. The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1C receptor. 4. Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1C receptors in the choroid plexus of the pig (Ki = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (Ki = 2.0-2.2 microM).5. It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.

A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain.

Methyllycaconitine (MLA) is the most potent and selective antagonist of the alpha-bungarotoxin sensitive neuronal nicotinic acetylcholine receptor (nAChR). In the present study, an accurate and reproducible technique for the extraction and analysis of MLA from rat plasma and brain is described. This study further sought to determine whether pharmacologically relevant concentrations of MLA could be achieved in brain following peripheral administration. The detection limits for MLA were 0.5 ng/ml for plasma samples and 1.0 ng/g for brain samples. The pharmacokinetic properties of MLA in rat are characterized by a short elimination half-life (19 min) following intravenous (i.v.) administration and poor bioavailability following oral (p.o.) administration. Remarkably, the elimination half-life is significantly longer following p.o. administration (408 min). To assess the extent to which MLA can penetrate into brain, brain and plasma levels of MLA were determined at different time points following intraperitoneal (i.p.) administration of a dose of MLA that produced no observable side effects. Maximal plasma and brain levels were 694 +/- 106 ng/ml and 32 +/- 3 ng/g, respectively. These concentrations are within a range previously reported to selectively block alpha 7 nAChR mediated responses in vitro. Peripherally administered MLA may therefore be a useful tool to further probe the central nervous system functions of the alpha 7 nAChR subunit in vivo.

Modifications of the Cox-Maze III procedure.

BACKGROUND: The extended operative time needed for surgery with complicated atrial incisions may preclude application of the Cox-Maze III procedure (CM-III) as a concomitant operation. And after the CM-III, left atrial (LA) contraction has been reported to recover in reduced magnitude compared with right atrial (RA) contraction. METHODS: To decrease operative time, we have modified the CM-III (modification I) by: obliterating the LA appendage instead of excising it; cryoablating the bridge between the LA appendage and margin of the pulmonary vein encircling incision; extending the lateral incision of RA onto the RA appendage without excising it, and extending the incision more inferiorly toward the inferior vena cava; and omitting the T-incision of RA. We compared the clinical results of the conventional CM-III (group 1, n = 18) with those of the modified CM-III group (group 2, n = 23) performed in patients with rheumatic mitral valve (MV) disease. To enlarge the contractile area of the LA, we modified the CM-III to encircle the right and left pulmonary veins separately (modification II), and compared the LA contractilities of the conventional CM-III (group A, n = 15) with those of the second modification (group B, n = 9). RESULTS: Modification I: Mean aortic cross-clamp (ACC) times (135 +/- 29 versus 104 +/- 18 minutes, p < 0.005) and cardiopulmonary bypass (CPB) times (240 +/- 33 versus 185 +/- 42 minutes, p < 0.001) were significantly decreased in group 2 compared with those in group 1. In group 1, sinus rhythm was restored in 16 patients (88.9%). RA contractility was demonstrated in 100% of patients with sinus rhythm (16 of 16) and LA contractility in 75% (12 of 16) in the latest follow-up echocardiography. In group 2, sinus rhythm was restored in 21 patients (91.3%). RA contractility was demonstrated in 100% of patients with sinus rhythm (21 of 22) and LA contractility in 76.2% (16 of 21). Modification II: Mean ACC times were increased in group B compared with group A (133 +/- 32 versus 172 +/- 39 minutes, p = 0.02). The A velocities at LA contraction and the ratio of atrial contraction to peak early diastolic filling velocity (A/E ratio) of the trans-mitral flow were 0.14 +/- 0.20 m/sec and 0.23 +/- 0.11 in group A, and 0.58 +/- 0.33 m/sec and 0.47 +/- 0.19 in group B, respectively, both showing a significant increase in group B compared with group A (p < 0.05). CONCLUSIONS: Our first modification of the CM-III showed comparable sinus conversion rates and incidence of atrial contractility restoration with significantly shorter ACC and CPB times than the conventional CM-III. The second modification of the CM-III significantly increased the LA contractility when compared with the conventional CM-III, although the second modification required a longer ACC time.

Species-related pharmacological heterogeneity of histamine H(3) receptors.

We compared radioligand binding and functional data for histamine H(3) receptor ligands across different tissues or species to evaluate the basis for pharmacological evidence of receptor heterogeneity previously reported. Agonist binding affinities showed correlation coefficients near unity in comparing human, dog, rat, and guinea pig cerebral cortical histamine H(3) receptors. Antagonist binding affinities revealed lower correlations for human compared to dog, rat, or guinea pig, suggesting species-based pharmacological differences. The functional potencies of histamine H(3) receptor antagonists in field-stimulated guinea pig ileum were highly correlated to binding affinities for guinea pig, dog, and, to a lesser extent, rat cerebral cortex. However, antagonist binding affinity at human cerebral cortex did not correlate well with guinea pig ileum functional potency. These results suggest significant interspecies histamine H(3) receptor heterogeneity, consistent with recent receptor gene sequence data. Therefore, genetic heterogeneity, rather than peripheral and central histamine H(3) receptor diversity, is responsible for the pharmacological differences observed.