The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis.

ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1.

Upregulation of Amy1 in the salivary glands of mice exposed to a lunar gravity environment using the multiple artificial gravity research system.

Introduction: Space is a unique environment characterized by isolation from community life and exposure to circadian misalignment, microgravity, and space radiation. These multiple differences from those experienced on the earth may cause systemic and local tissue stress. Autonomic nerves, including sympathetic and parasympathetic nerves, regulate functions in multiple organs. Saliva is secreted from the salivary gland, which is regulated by autonomic nerves, and plays several important roles in the oral cavity and digestive processes. The balance of the autonomic nervous system in the seromucous glands, such as the submandibular glands, precisely controls serous and mucous saliva. Psychological stress, radiation damage, and other triggers can cause an imbalance in salivary secretion systems. A previous study reported that amylase is a stress marker in behavioral medicine and space flight crews; however, the detailed mechanisms underlying amylase regulation in the space environment are still unknown. Methods: In this study, we aimed to elucidate how lunar gravity (1/6 g) changes mRNA expression patterns in the salivary gland. Using a multiple artificial gravity research system during space flight in the International Space Station, we studied the effects of two different gravitational levels, lunar and Earth gravity, on the submandibular glands of mice. All mice survived, returned to Earth from space, and their submandibular glands were collected 2 days after landing. Results: We found that lunar gravity induced the expression of the salivary amylase gene Amy1; however, no increase in Aqp5 and Ano1, which regulate water secretion, was observed. In addition, genes involved in the exocrine system, such as vesicle-associated membrane protein 8 (Vamp8) and small G proteins, including Rap1 and Rab families, were upregulated under lunar gravity. Conclusion: These results imply that lunar gravity upregulates salivary amylase secretion via Rap/Rab signaling and exocytosis via Vamp8. Our study highlights Amy1 as a potential candidate marker for stress regulation in salivary glands in the lunar gravity environment.

Pulmonary Arterial Hypertension in Neurofibromatosis Type 1: A Case with a Novel NF1 Gene Mutation.

Neurofibromatosis type 1 (NF1) is an autosomal dominant multi-organ disease. The clinical manifestations include not only skin lesions and malignant tumors but also lung complications, including pulmonary arterial hypertension (PAH). However, the association between gene mutations in NF1 and the occurrence of PAH has not yet been elucidated. We herein report a case of isolated PAH in a 67-year-old woman with NF1, presumably caused by a novel heterozygous mutation, c.4485_4486delinsAT (p.Lys1496Ter), in the NF1 gene.

Rice SRO1a Contributes to Xanthomonas TAL Effector-mediated Expression of Host Susceptible Genes.

Xanthomonas species infect many important crops and cause huge yield loss. These pathogens deliver transcription activator-like (TAL) effectors into the cytoplasm of plant cells. TAL effectors move to host nuclei, directly bind to the promoters of host susceptible genes, and activate their transcription. However, the molecular mechanisms by which TAL effectors induce host transcription remain unclear. We herein demonstrated that TAL effectors interacted with the SIMILAR TO RCD ONE (SRO) family proteins OsSRO1a and OsSRO1b in nuclei. A transactivation assay using rice protoplasts indicated that OsSRO1a and OsSRO1b enhanced the activation of the OsSWEET14 promoter by the TAL effector AvrXa7. The AvrXa7-mediated expression of OsSWEET14 was significantly reduced in ossro1a mutants. However, the overexpression of OsSRO1a increased disease resistance by up-regulating the expression of defense-related genes, such as WRKY62 and PBZ1. This was attributed to OsSRO1a and OsSRO1b also enhancing the transcriptional activity of WRKY45, a direct regulator of WRKY62 expression. Therefore, OsSRO1a and OsSRO1b appear to positively contribute to transcription mediated by bacterial TAL effectors and rice transcription factors.

Pulmonary pressure-flow responses to exercise in heart failure treated with angiotensin receptor neprilysin inhibitor.

BACKGROUND: The role of the angiotensin receptor neprilysin inhibitor (ARNI) in cardiac function, particularly its impact on pulmonary circulation, remains underexplored. Recent studies have described abnormal mean pulmonary artery pressure (mPAP)-cardiac output (CO) responses as having the potential to assess the disease state. The aim of this study was to assess the effects of ARNI on pulmonary circulation in heart failure. We measured echocardiographic parameters post 6-min walk (6 MW) and compared the changes with baseline and follow-up. Our hypothesis was that pulmonary pressure-flow relationship of the pulmonary circulation obtained by 6 MW stress echocardiography would be improved with treatment. METHODS: We prospectively enrolled 39 heart failure patients and conducted the 6 MW test indoors. Post-6 MW echocardiography measured echocardiographic variables, and CO was derived from electric cardiometry. Individualized ARNI doses were optimized, with follow-up echocardiographic evaluations after 1 year. RESULTS: Left ventricular (LV) volume were significantly reduced (160.7 ± 49.6 mL vs 136.0 ± 54.3 mL, P < 0.001), and LV ejection fraction was significantly improved (37.6 ± 11.3% vs 44.9 ± 11.5%, P < 0.001). Among the 31 patients who underwent 6 MW stress echocardiographic study at baseline and 1 year later, 6 MW distance increased after treatment (380 m vs 430 m, P = 0.003). The ΔmPAP/ΔCO by 6 MW stress decreased with treatment (6.9 mmHg/L/min vs 2.8 mmHg/L/min, P = 0.002). The left atrial volume index was associated with the response group receiving ARNI treatment for pulmonary circulation. CONCLUSIONS: Initiation of ARNI was associated with improvement of left ventricular size and LVEF. Additionally, the 6 MW distance increased and the ΔmPAP/ΔCO was improved to within normal range with treatment.

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a nonhemophilic state.

BACKGROUND: Emicizumab, a factor (F) VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment option for people with hemophilia A (PwHA). However, a small proportion of PwHA still experience bleeds even under emicizumab prophylaxis, as observed in the long-term outcomes of clinical studies. A more potent BsAb may be desirable for such patients. OBJECTIVES: To identify a potent BsAb to FIXa and FX, NXT007, surpassing emicizumab by in vitro and in vivo evaluation. METHODS: New pairs of light chains for emicizumab's heavy chains were screened from phage libraries, and subsequent antibody optimization was performed. For in vitro evaluation, thrombin generation assays were performed with hemophilia A plasma. In vivo hemostatic activity was evaluated in a nonhuman primate model of acquired hemophilia A. RESULTS: NXT007 exhibited an in vitro thrombin generation activity comparable to the international standard activity of FVIII (100 IU/dL), much higher than emicizumab, when triggered by tissue factor. NXT007 also demonstrated a potent in vivo hemostatic activity at approximately 30-fold lower plasma concentrations than emicizumab's historical data. In terms of dose shift between NXT007 and emicizumab, the in vitro and in vivo results were concordant. Regarding pharmacokinetics, NXT007 showed lower in vivo clearance than those shown by typical monoclonal antibodies, suggesting that the Fc engineering to enhance FcRn binding worked well. CONCLUSION: NXT007, a potent BsAb, was successfully created. Nonclinical results suggest that NXT007 would have a potential to keep a nonhemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab.

Superiority of Endovascular Coiling Over Surgical Clipping for Clinical Outcomes at Discharge in Patients With Poor-Grade Subarachnoid Hemorrhage: A Registry Study in Japan.

BACKGROUND AND OBJECTIVES: The differences in clinical outcomes between endovascular coiling (EC) and surgical clipping (SC) in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) are controversial. Therefore, this study aimed to evaluate whether EC is superior to SC and identify risk factors in patients with poor-grade aSAH. METHODS: We used data from the "Predict for Outcome Study of aneurysmal SubArachnoid Hemorrhage." World Federation of Neurological Societies (WFNS) grade III-V aSAH was defined as poor-grade aSAH, and unfavorable clinical outcomes (modified Rankin Scale scores 3-6) were compared between SC and EC after propensity score matching (PSM). In-hospital mortality was similarly evaluated. Predictors of unfavorable clinical outcomes were identified using multivariable analysis. RESULTS: Ultimately, 1326 (SC: 847, EC: 479) and 632 (SC: 316, EC: 316) patients with poor-grade aSAH were included before and after PSM, respectively. Unfavorable clinical outcomes at discharge were significantly different between SC and EC before (72.0% vs 66.2%, P = .026) and after PSM (70.6% vs 63.3%, P = .025). In-hospital mortality was significantly different between groups before PSM (10.5% vs 16.1%, P = .003) but not after PSM (10.4% vs 12.7%, P = .384). Predictors of unfavorable clinical outcomes in both SC and EC were WFNS grade V, older than 70 years, and Fisher computed tomography (CT) grade 4. Predictors of unfavorable clinical outcomes only in SC were WFNS grade IV (odds ratio: 2.46, 95% CI: 1.22-4.97, P = .012) and Fisher CT grade 3 (4.90, 1.42-16.9, P = .012). Predictors of unfavorable clinical outcome only in EC were ages of 50s (3.35, 1.37-8.20, P = .008) and 60s (3.28, 1.43-7.52, P = .005). CONCLUSION: EC resulted in significantly more favorable clinical outcomes than SC in patients with poor-grade aSAH, without clear differences in in-hospital mortality. The benefit of EC over SC might be particularly remarkable in patients with WFNS grade IV and Fisher CT grade 3.

Beyond i.i.d. in the Resource Theory of Asymmetry: An Information-Spectrum Approach for Quantum Fisher Information.

Energetic coherence is indispensable for various operations, including precise measurement of time and acceleration of quantum manipulations. Since energetic coherence is fragile, it is essential to understand the limits in distillation and dilution to restore damage. The resource theory of asymmetry (RTA) provides a rigorous framework to investigate energetic coherence as a resource to break time-translation symmetry. Recently, in the independent and identically distributed (i.i.d.) regime where identical copies of a state are converted into identical copies of another state, it was shown that the convertibility of energetic coherence is governed by a standard measure of energetic coherence, called the quantum Fisher information (QFI). This fact means that QFI in the theory of energetic coherence takes the place of entropy in thermodynamics and entanglement entropy in entanglement theory. However, distillation and dilution in realistic situations take place in regimes beyond i.i.d., where quantum states often have complex correlations. Unlike entanglement theory, the conversion theory of energetic coherence in pure states in the non-i.i.d. regime has been an open problem. In this Letter, we solve this problem by introducing a new technique: an information-spectrum method for QFI. Two fundamental quantities, coherence cost and distillable coherence, are shown to be equal to the spectral QFI rates for arbitrary sequences of pure states. As a consequence, we find that both entanglement theory and RTA in the non-i.i.d. regime are understood in the information-spectrum method, while they are based on different quantities, i.e., entropy and QFI, respectively.

Association and Implications of Blood and Plaque n-3 Polyunsaturated Fatty Acid Composition in Patients Treated with Oral Eicosapentaenoic Acid before Carotid Endarterectomy.

Long-chain n-3 polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), have been shown to prevent atherosclerosis-related cardiovascular disease, including stroke. Recently, the ratio of serum EPA to arachidonic acid (AA; EPA/AA ratio) has been reported to be a biomarker to prevent cardiovascular disease. In this study, we evaluate whether the serum EPA/AA ratio would be a useful biomarker for determining the efficacy of orally administered EPA in preventing stroke by investigating tissue and serum EPA/AA ratios, serum inflammatory markers, and carotid artery intimamedia thickness (IMT). Patients with dyslipidemia, as the primary illness scheduled for carotid endarterectomy (CEA), were included and randomly assigned to the EPA group (EPA: 1,800 mg/day plus statin; 10 patients) or non-EPA group (statin only; 15 patients). PUFA fraction was evaluated in the tissue (post-CEA) and serum (pre-CEA and 6 months thereafter). As for the tissue PUFA fraction in the plaque, the EPA group had a significantly higher EPA/AA ratio (EPA group, 0.46; non-EPA group, 0.28; p = 0.01). At 6 months postoperatively, the EPA group had a significantly higher serum EPA/AA ratio (baseline, 0.83; follow-up, 1.60; p = 0.05). No significant differences were found for inflammatory markers and IMT. Both serum and tissue EPA/AA ratios were higher in patients treated with oral EPA. Serum EPA/AA ratio might be a useful biomarker for the efficacy of orally administered EPA.

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.

Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Effectiveness of surveillance by echocardiography for cancer therapeutics-related cardiac dysfunction of patients with breast cancer.

BACKGROUND: Cancer therapeutics-related cardiac dysfunction (CTRCD) affect the prognosis of patients with breast cancer. Echocardiographic surveillance of patients treated with anti-human epidermal growth factor receptor type 2 (HER2) antibodies has been recommended, but few reports have provided evidence on patients with breast cancer only. We aimed to evaluate the effectiveness of echocardiographic surveillance for breast cancer patients. METHODS: We identified 250 patients with breast cancer who were treated with anti-HER2 antibodies from July 2007 to September 2021. We divided 48 patients with echocardiographic surveillance every 3 months into the surveillance group and 202 patients without echocardiographic surveillance into the non-surveillance group. In the surveillance group, patients with a considerable reduction in global longitudinal strain of 15 % were considered for the initiation of cardioprotective drugs. The composite outcome of CTRCD and acute heart failure was the study endpoint. RESULTS: The mean age was 59 ±â€¯12 years. During the follow-up period of 15 months (12-17 months), 12 patients reached the endpoint. The surveillance group had significantly lower incidence of the composite outcome (2.1 % vs. 5.5 %, adjusted odds ratio: 0.28, 95 % confidential intervals: 0.09-0.94; p = 0.039) and higher rates of prescriptions of cardioprotective drugs than the non-surveillance group. CONCLUSIONS: The incidence of cardiac complications was significantly lower in the surveillance group than the non-surveillance group, which supports the effectiveness of echocardiographic surveillance in patients with breast cancer.

Bilateral symptomatic large cavernous carotid artery aneurysms treated by extracranial-intracranial bypass with parent artery occlusion.

Bilateral large cavernous sinus internal carotid aneurysms (CCAs) occur very rarely. While the choice of treatment method is important, the timing of contralateral side treatment is equally important. We herein report the case of a 72-year-old woman who presented with progressive bilateral visual impairment and was treated by two-stage. First, the left CCAs had been treated, and the aneurysm was thrombosed, but her left visual acuity did not recover; the right CCA was becoming larger 2 years later, and her right visual acuity began worsening. The right CCAs was treated by almost same method. Her right visual acuity improved compared with the second preoperative findings. Our case findings suggest the importance of considering the appropriate timing to avoid symptom aggravation in patients with bilateral CCAs.

Benefits of guideline-directed medical therapy to loop diuretics in management of heart failure.

BACKGROUND: We sought to compare the outcomes of patients receiving combination therapy of diuretics and neurohormonal blockers, with a matched cohort with monotherapy of loop diuretics, using real-world big data. METHODS: This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 78,685 patients who were first hospitalized with heart failure (HF) between April 2015 and March 2017. Propensity score (PS) was estimated with logistic regression model, with neurohormonal blockers (angiotensin-converting enzyme inhibitor : ACEi or angiotensin receptor blocker : ARB, ?-blockers and mineralocorticoid receptor antagonists : MRA) as the dependent variable and 24 clinically relevant covariates to compare the in-hospital mortality between monotherapy of loop diuretics and combination therapies. RESULTS: On PS-matched analysis, patients with ACEi?/?ARB, ?-blockers, and MRA had lower total in-hospital mortality and in-hospital mortality within 7 days, 14 days and 30 days. In the sub-group analysis, regardless of clinical characteristics including elderly people and cancer, patients treated with a combination of loop diuretics and neurohormonal blockers had significantly lower in-hospital mortality than matched patients. CONCLUSIONS: Our data indicate the benefits of guideline-directed medical therapy to loop diuretics in the management of HF. J. Med. Invest. 70 : 41-53, February, 2023.

Enterprise Treatment for Recurrent Basilar Tip Aneurysm after PulseRider-assisted Coil Embolization: A Case Report.

PulseRider (Cerenovus, Irvine, CA, USA) is a relatively novel device used for the treatment of wide-neck aneurysms with a coil-assisted effect. However, treatment options for recurrent aneurysms after PulseRider-assisted coil embolization remain controversial. Here we report a case of recurrent basilar tip aneurysm (BTA) treated with Enterprise 2 after PulseRider-assisted coil embolization. A woman in her 70s underwent coil embolization for a subarachnoid hemorrhage with ruptured BTA 16 years ago. Recurrence was detected at 6-year follow-up, and an additional coil embolization was performed. Nevertheless, gradual recurrence still occurred, and PulseRider-assisted coil embolization was performed without any complications 9 years after the second treatment. However, recurrence was detected once more at 6-month follow-up. Thus, stent-assisted coil embolization using Enterprise 2 (Cerenovus) through PulseRider was selected for angular remodeling. Enterprise 2 was deployed between the right P2 segment of the posterior cerebral artery (PCA) and basilar artery (BA) after an effective coil embolization, which achieved effective angular remodeling between the right PCA and BA. The patient's postoperative course was uneventful, and no recanalization was detected after half a year. Although PulseRider is effective for wide-neck aneurysm treatment, recurrence remains a possibility. Additional treatment using Enterprise 2 is safe and effective with the expectation of angular remodeling.

Subclavian Artery-Carotid Artery Bypass for Subclavian Artery or Common Carotid Artery Severe Stenosis or Occlusion.

Various surgical treatments are available for occlusive subclavian and common carotid artery diseases. Nevertheless, to date, when cerebral endovascular treatment is utilized, revascularization via direct surgery may be required. This study reported five symptomatic cases of revascularization for CCA and SCA occlusive and stenotic lesions that were expected to be challenging to treat with endovascular treatment. We performed subclavian artery-common carotid artery or internal carotid artery bypass using artificial blood vessels or saphenous vein grafts in five patients with subclavian steal syndrome, symptomatic common carotid artery occlusion, and severe proximal common carotid artery stenosis. In this study, good bypass patency was achieved in all five cases. Although there were no intraoperative complications, one patient had a postoperative lymphatic leak. Moreover, there was no recurrence of stroke during postoperative follow-up for an average of 2 years. Conclusively, subclavian artery-common carotid artery bypass can be an effective surgical treatment for common carotid artery occlusion, proximal common carotid artery stenosis, and subclavian artery occlusion.

Efficacy of 3D evaluation of unruptured paraclinoid aneurysms within Leksell GammaPlan® for determination of their intradural localization.

BACKGROUND: Determination of the intradural unruptured paraclinoid aneurysm localization is difficult, but critical for selection of the optimal treatment strategy. OBJECTIVE: To assess efficacy of the three-dimensional (3D) evaluation of unruptured paraclinoid aneurysms within Leksell GammaPlan® (LGP; Elekta AB; Stockholm, Sweden) for determination of their intradural localization. METHODS: Overall, 125 incidentally diagnosed unruptured paraclinoid aneurysms in 118 patients (mean age, 55 years) underwent 3D evaluation of their localization within LGP using post-contrast thin-slice constructive interference in steady state (CISS) images, which in 41 cases were additionally co-registered and fused with the axial computed tomography angiography (CTA) source images. RESULTS: According to the evaluation within LGP, paraclinoid aneurysms were considered intradural, transitional, and extradural in 75, 25, and 25 cases respectively. Overall, 51 of 75 aneurysms deemed to be intradural, underwent microsurgical management, and intraoperative visual inspection confirmed their intradural localization in 45 cases, whereas it was transitional in 3, and extradural in 3. If during preoperative 3D evaluation within LGP only post-contrast CISS images were used, prediction of the pure intradural localization of aneurysm was correct in 88 % of cases (95 % CI: 79-97 %), and of the pure or partial (i.e., transitional) intradural localization in 94 % of cases (95 % CI: 88-100 %), whereas it was 100 % if co-registration and fusion of the contrast-enhanced CISS and CTA source images was done. CONCLUSION: Intradural localization of the unruptured paraclinoid aneurysms may be effectively predicted based on their 3D evaluation within LGP using post-contrast thin-slice CISS and CTA source images, which may help with clinical decision-making.

Isoproterenol loading transesophageal echocardiography in atrial fibrillation.

In patients with sludge or severe spontaneous echo contrast (SEC) in the left atrial appendage (LAA), cases with isoproterenol loading transesophageal echocardiography (ISP-TEE) have been reported to identify the presence of thrombus in the LAA. This study aimed to assess the validity and hemodynamic changes of ISP-TEE in the LAA. We prospectively enrolled patients with atrial fibrillation (AF) who underwent ISP-TEE. The degree of sludge/SEC was categorized as being either absent (grade 0), mild SEC (grade 1), moderate SEC (grade 2), severe SEC or sludge (grade 3). The hemodynamic evaluation was performed by measuring LAA flow velocity, LAA tissue Doppler imaging (LAA-TDI) velocity, and pulmonary vein systolic forward flow velocity (PVS). In total, 35 patients (mean age 71 ± 7 years; 71% male) underwent ISP-TEE. Among 35 patients, 30 patients had grade 3 or 2 SEC, 5 patients had grade 1 SEC. After ISP loading, 23 patients (66% of all patients) showed improved sludge/SEC and one patient was diagnosed with thrombus in the LAA. There were 25 patients with grade 1 SEC, or no SEC (classified as Group1), 10 patients had residual sludge or grade 2 to 3 SEC (classified as Group2) after ISP administration. LAA flow, LAA-TDI, and PVS velocities were significantly higher in group 1 than in group 2 after ISP administration. There was no complication during the examination and after 24 h and 3 months. ISP infusion may be a potential tool to recognize LAA thrombus under the sludge/SEC during TEE in AF.

Simultaneous Analysis of Zolpidem, Four Hydroxyzolpidems and Two Zolpidem Carboxylic Acids in Postmortem Urine Using Liquid Chromatography--Tandem Mass Spectrometry.

Zolpidem (ZOL) is a short-acting hypnotic that is sometimes used in drug-facilitated crimes such as sexual assaults, robbery and homicides. Therefore, it is important to understand the metabolism of ZOL. This study quantified ZOL and its metabolites, including two carboxylic acids (zolpidem phenyl-4-carboxylic acid [M1] and 6-carboxylic acid [M2]) and four hydroxyzolpidems (4-(hydroxymethyl)phenyl zolpidem [M3], 6-hydroxymethyl zolpidem [M4], 7-hydroxyzolpidem [7OH] and 8-hydroxyzolpidem [8OH]) in postmortem urine using liquid chromatography--triple quadrupole mass spectrometry. The concentration of M1 was highest in all cases, followed by total 7OH in five of six samples. The concentrations of M2 and total M4 were relatively high. Most of M4 and 8OH were excreted as conjugates, whereas up to 55% of 7OH was excreted in its free form. Peaks corresponding to zolpidem dihydrodiol (ZHDH), dihydro(hydroxy)zolpidem cysteine adduct (DHZCys) and zolpidem cysteine adduct (ZCys) were also detected in all the urine samples. ZDHD was excreted as conjugates, whereas almost all DHZCys and ZCys were in their free form.