The spatiotemporal electrogram dispersion ablation targeting rotors is more effective for elderly patients than non-elderly population.

Background: Modulating atrial fibrillation (AF) drivers has been proposed as one of the effective ablation strategies for non-paroxysmal AF (non-PAF). However, the optimal non-PAF ablation strategy is still under debate because the exact mechanisms of AF persistence including focal activity and/or rotational activity, are not well-understood. Recently, spatiotemporal electrogram dispersion (STED) assumed to indicate rotors in the form of rotational activity is proposed as an effective target for non-PAF ablation. We aimed to clarify the effectiveness of STED ablation for modulating AF drivers. Methods: STED ablation plus pulmonary vein isolation was applied in 161 consecutive non-PAF patients not undergoing previous ablation. STED areas within the entire left and right atria were identified and ablated during AF. After the procedures, the STED ablation's acute and long-term outcomes were investigated. Results: (1) Despite a more effective acute outcome of the STED ablation for both AF termination and non-inducibility of atrial tachyarrhythmias (ATAs), Kaplan-Meier curves showed that the 24-month freedom ratio from ATAs was 49%, which resulted from the higher recurrence ratio of atrial tachycardia (AT) rather than AF. (2) A multivariate analysis showed that the determinant of ATA recurrences was only a non-elderly age, not long-standing persistent AF, and an enlarged left atrium, which were conventionally considered as key factors. Conclusions: STED ablation targeting rotors was effective in elderly non-PAF patients. Therefore, the main mechanism of AF persistency and the component of the fibrillatory conduction might vary between elders and non-elders. However, we should be careful about post-ablation ATs following substrate modification.

Vaginal Fistulas of the Bladder and Small Bowel After Two-Dimensional Intracavitary Brachytherapy in a Patient With Cervical Cancer.

Image-guided brachytherapy (IGBT) is commonly used for patients with cervical cancer, but two-dimensional intracavitary brachytherapy (2D-ICBT) is also still utilized for certain patients. We report a patient with cervical cancer who developed vaginal fistulas of the bladder and small bowel after chemoradiotherapy with 2D-ICBT. A 61-year-old woman with stage IIB cervical cancer underwent a combination of external beam radiotherapy (EBRT) at a dose of 50.4 Gy in 28 fractions and 2D-ICBT at a dose of 22 Gy in four fractions. As packs were well inserted around the uterus in all fractions of 2D-ICBT, the doses to the surrounding organs at risk (OAR) could be likely to be kept at low levels. She developed a huge fistula between the vagina and bladder approximately 2.5 years after radiotherapy (RT). She also developed a fistula between the vagina and small bowel approximately seven years after RT and underwent bypass from the small bowel to the transverse colon. The OAR were delineated using computed tomography for EBRT planning, and the cumulative dose of 2D-ICBT plus EBRT was evaluated as the source of toxicity. The cumulative dose converted to the equivalent dose in 2-Gy fractions (EQD2) was calculated using the linear-quadratic model with α/ß = 3 for the OAR. The cumulative EQD2 values of the minimum dose to the most irradiated 2 cc (D2cc) of the bladder and small bowel were 90.2 Gy and 79.5 Gy, respectively. These values exceeded the upper limits of the dosimetric criteria of the OAR, suggesting an association with both vaginal fistulas. As the adoption of IGBT is too slow in some countries, it is noteworthy that a reduced bladder volume may result in a significant increase in the dose to the small bowel and bladder in 2D-ICBT.

Torsades de Pointes with QT prolongation related to donepezil use.

An 83-year-old female, who had a history of anterior myocardial infarction, was treated for Alzheimer's disease with donepezil. She suffered from repeated diarrhea and vomiting, and experienced syncope. She was admitted to our hospital and was diagnosed with acute colitis and syncope. On admission, her heart rate was 54 beats/min with regular rhythm. Laboratory data showed a low plasma potassium level. Electrocardiogram (ECG) showed poor R progression, ST elevation, negative T in precordial leads, and marked QT prolongation. Transthoracic echocardiogram showed the enlargement of the left atrium and aneurysmal area at the apex. Torsades de Pointes (TdP) with syncope and convulsion were confirmed on ECG monitoring twice after admission. We treated her with potassium chloride and started magnesium sulfate and lidocaine, and then added isoprenaline injection. After these treatments, her heart rate increased and we did not detect TdP again. With the aging population in Japan, prescriptions for donepezil are increasing. We have to be vigilant for syncope in patients taking donepezil, which is possibly related to QT prolongation and TdP.

Usefulness of transesophageal echocardiographic observation during chemotherapy for cardiac metastasis of non-Hodgkin lymphoma complicated with left ventricular diastolic collapse.

A 53-year-old man, who had been treated for penile origin diffuse large B cell type non-Hodgkin lymphoma (NHL), suffered from right femoral pain and dyspnea. Positron emission tomography (PET) revealed abnormal accumulation in his right femur and cardiac segments. Transthoracic echocardiography revealed massive localized pericardial effusion with the collapse of both ventricles and the mass-like echo in the left atrium. We performed emergent pericardiocentesis and diagnosed this case as a recurrence of NHL with cardiac metastasis. With the use of transesophageal echocardiography (TEE), we confirmed the mass-like echo around the inter-atrial septum, which directly invaded to the aortic ring and the right atrial wall. In order to evaluate the effect of chemotherapy, we performed TEE and observed the precise changes of intra-cardiac tumor size. With the use of TEE monitoring, we could select the appropriate chemotherapeutic regimen, and the tumor became smaller and finally diminished. The femoral accumulation detected by PET also disappeared. We experienced a case of cardiac metastasis of NHL complicated with left ventricular diastolic collapse due to the massive localized pericardial effusion. TEE is a useful tool to evaluate precisely the efficacy of chemotherapy for intra-cardiac tumors.

Mitral regurgitation resulting from the consecutive multiple perforations by infective endocarditis mimicking the isolated anterior mitral cleft.

A 60-year-old man, suffering from sustained cough and dyspnea on effort, was diagnosed as congestive heart failure. He did not yield the history of having fever or other inflammatory events. His physical examination disclosed a pan-systolic murmur at the apex. Transthoracic color Doppler echocardiography showed moderate to severe mitral regurgitation originated from the linear tear of the anterior mitral leaflet. The tear reached to the mid-portion of the leaflet just within the postero-medial commissure and the regurgitant flow convergence was not hemispheric, but box-like shaped, suggesting that the linear tear was the isolated mitral cleft. Transesophageal echocardiography showed the almost same findings and we found no other anomalies. Surgical treatment was selected to repair the mitral regurgitation. Under operation, we found three consecutive perforations located linearly in the anterior mitral leaflet. The mitral valve replaced with the prosthetic one. The pathological examination of the resected valve showed mucinous degeneration of the chordae tendineae and fibrinoid change without inflammatory cellular infiltration. These findings were compatible with the healed infective endocarditis. Here we experienced a curious case of mitral regurgitation, caused by consecutive three mitral perforations mimicking the isolated anterior mitral cleft.

Placenta previa increta/percreta in Japan: a retrospective study of ultrasound findings, management and clinical course.

AIM: Placenta accreta is an abnormally firm attachment of placental villi to the uterine wall, which may cause postpartum hemorrhage resulting in maternal morbidity and mortality. The purpose of the present study was to clarify the incidence, clinical background and prognosis of placenta previa increta/percreta treated with different modalities in Japan. METHODS: Medical records of cases with placenta previa increta/percreta in eight tertiary centers between January 1994 and December 2004 were reviewed. Placenta accreta without actual invasion into the myometrium confirmed by pathology was not included in placenta increta/percreta. Details of obstetric history, maternal background, ultrasonographical findings, the course of delivery, subsequent complications and management were noted. RESULTS: Among the total of 59,008 deliveries, 45,261 were by the vaginal route (76.7%) and 13 747 by cesarean section (23.3%). In this study, 408 cases were diagnosed as placenta previa (0.69%), 18 of these being placenta increta and 5 placenta percreta. Only 1.1% of cases of placenta previa without prior cesarean section were increta/percreta, in contrast to 37% of placenta previa after prior cesarean sections. Mean intraoperation blood loss was 3630 +/- 2216 g (increta) and 12,140 +/- 8343 g (percreta). One patient with placenta previa percreta died of hemorrhage. Stepwise treatment (cesarean section without separation of the placenta, arterial embolization and hysterectomy) was applied for 4 cases, which had the least blood loss. CONCLUSIONS: Placenta previa increta/percreta is a life-threatening disease. Patients who undergo hysterectomy after uterine arterial embolization demonstrate reduced intraoperation blood loss, and this treatment should be incorporated to reduce maternal morbidity.

Placental leucine aminopeptidase might regulate the effects of oxytocin with resolution in endothelial cells.

BACKGROUND: Oxytocin (OT) is known to cause vascular relaxation via nitric oxide (NO) production and proliferation of endothelial cells. Previously we revealed that human umbilical vascular endothelial cells (HUVECs) expresses placental leucine aminopeptidase (P-LAP)/insulin regulated aminopeptidase (IRAP), which becomes translocation to the cell surface on activation of oxytocin receptor (OTR). However, the physiological roles of P-LAP in HUVECs have not been elucidated. MATERIAL/METHODS: Actions of OT on HUVECs transfected with a copy of the human P-LAP gene were therefore examined with a focus on changes in parameters linked to OTR such as calcium mobilization, NO production and cell proliferation. RESULTS: Cell surface P-LAP activity was significantly elevated (approximately 3 fold) in P-LAP overexpressing-HUVECs and overexpression of P-LAP resulted in remarkable inhibition of OT effects on HUVECs such as cell proliferation, [Ca2+]i, and NO production. CONCLUSIONS: These findings suggested that P-LAP on the plasma membrane in HUVECs regulates the effects of OT with resolution around OTR.

Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells.

We recently identified two novel aminopeptidases, placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP). Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin. In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n = 26), gestational choriocarcinoma (n = 8), and placental site trophoblastic tumor (n = 3). On immunoblot analysis both P-LAP and A-LAP proteins were detected in normal placenta and five choriocarcinoma tissues, as well as in two choriocarcinoma cell lines. Immunohistochemical staining of normal placental tissues demonstrated that P-LAP was not only localized in villous syncytiotrophoblasts but also highly expressed in extravillous trophoblasts (EVTs) invading the decidua or maternal spiral arteries. The expression level of P-LAP on these invasive EVTs reached a maximum during the late first to second trimesters of pregnancy, and it decreased in the third trimester. Similarly, A-LAP was strongly expressed in EVTs invading the decidua or spiral arteries in the second trimester of pregnancy, while it was weakly or moderately expressed in villous cytotrophoblasts or EVTs located in the cell columns. These two aminopeptidases were more strongly expressed in all eight choriocarcinomas and three placental site trophoblastic tumors and mainly localized to the intermediate-type trophoblastic tumor cells invading the uterine myometrium or stromal vessels. In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms. These results suggest the involvement of these aminopeptidases in invasiveness of both normal and malignant intermediate-type trophoblasts possibly through degradation of specific peptide substrates.

Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway.

Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, exerting its actions not only as a vasoconstrictor, but also as a growth promoter. In human placenta, type 1 Ang II receptors (AT(1)R) are predominantly expressed in trophoblasts, and we previously reported that aminopeptidase A (APA), a cell surface peptidase that converts Ang II to Ang III, is also expressed in both normal and neoplastic trophoblasts. However, the roles of Ang II and APA in trophoblast function remain to be clarified. In the present study we examined the effects of Ang II on proliferation and APA expression in trophoblast-like BeWo choriocarcinoma cells. Treatment of BeWo cells with Ang II significantly increased DNA synthesis in a dose-dependent manner. Ang II also enhanced APA mRNA and cell surface expression in BeWo cells analyzed by Northern blotting, flow cytometry, and enzyme activity assay. The Ang II-induced proliferation and APA up-regulation were blocked by the AT(1)R antagonist candesartan, but not by the AT(2)R antagonist PD123319. Furthermore, these Ang II effects were abolished by the protein kinase C inhibitor bisindolylmaleimide I and the MAPK inhibitor PD98059. Immunohistochemistry using choriocarcinoma tissues demonstrated that APA was expressed on the cell surface of AT(1)R-positive cytotrophoblastic cells in vivo. With these findings we demonstrate that Ang II stimulates the proliferation of trophoblastic cells via AT(1)R that are linked to protein kinase C /MAPK-dependent signaling pathways, and that the Ang II-degrading enzyme APA is up-regulated during Ang II-induced cell proliferation. These observations suggest the possible regulatory mechanism by the local renin-angiotensin system, especially the Ang II-AT(1)R-APA system, for the growth of human choriocarcinoma cells.

Possible activation of the renin-angiotensin system in the feto-placental unit in preeclampsia.

The purpose of this study was to elucidate the mechanisms underlying the regulation of feto-placental circulation mediated by the renin-angiotensin system under preeclamptic conditions. We measured angiotensin-converting enzyme (ACE) activity, protein expression, and mRNA expression in uncomplicated and preeclamptic placentas and examined the localization of ACE. In addition, ACE activity and mRNA expression in human umbilical venous endothelial cells (HUVECs) under hypoxic conditions were analyzed. ACE activity, protein expression, and mRNA expression in placental tissues from preeclampsia were all significantly higher than those from uncomplicated pregnancies. ACE activity in vessel fractions was extensively higher than that in trophoblast-rich or macrophage-rich fractions. Additionally, ACE activity in HUVECs was significantly higher than that in human arterial endothelial cells, and ACE mRNA was primarily localized to venous endothelial cells of stem villous in placentas. Furthermore, hypoxic condition induced both ACE activity and mRNA expression in HUVECs. These results suggested that venous endothelial cells within placental stem villous tissues and umbilicus play an important role in the regulation of the feto-placental renin-angiotensin system, and in response to hypoxic conditions the feto-placental unit seemed to induce ACE activity in the placenta; such an effect would be likely to lead to regulation of the fetal circulation.

Immunological detection of 4-hydroxynonenal protein adducts in developing pontine and Purkinje neurons and in karyorrhexis in pontosubicular neuronal necrosis.

Four-hydroxynonenal (HNE) has been proposed as an important marker of radical-induced lipid peroxidation. The principal objective of this study was to assess the occurrence of lipid peroxidation in normal perinatal brain and brains with one form of pontosubicular neuronal necrosis (PSN). Immunochemical studies using an antibody against HNE-modified protein were performed in controls aged from 20 weeks of gestation to 64 years, and patients with PSN. Immunohistochemical study showed developmental and aging changes of positive staining in Purkinje cells and pontine neurons (27 weeks-7 months, 50 and 64 years). In addition, karyorrhectic cells in pontine nuclei with PSN were positively stained. Immunoblotting revealed that a 75-kDa protein, which is speculated to be mitochondrial complex-1 protein, was the most intensely expressed among multiple immunoreactive proteins. Our results identified the presence of oxidative stress in the perinatal neuron, and this oxidative stress may contribute to some forms of karyorrhectic death.