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Aims: We aimed to investigate the characteristics and prognosis of patients with heart failure (HF) with supra-normal ejection fraction (HFsnEF) compared to HF with normal ejection fraction (HFnEF)., Methods and Results: Among 11 573 patients enrolled in the nationwide registry of hospitalized patients with HF in Japan, 1943 patients (16.8%) were classified as HFsnEF (left ventricular ejection fraction [LVEF] >65%), 3277 (28.3%) as HFnEF (50% ≤ LVEF ≤65%), 2024 (17.5%) as HF with mildly reduced ejection fraction (40% ≤ LVEF <50%) and 4329 (37.4%) as HF with reduced ejection fraction (LVEF <40%). Patients with HFsnEF were older, more likely to be women, had lower natriuretic peptide values, and had smaller left ventricles than those with HFnEF. The primary endpoint, the composite of cardiovascular death or HF readmission, did not differ between HFsnEF (802/1943, 41.3%) and HFnEF (1413/3277, 43.1%) during a median follow-up period of 870 days (hazard ratio [HR] 0.96, 95% confidence interval 0.88-1.05, p = 0.346). The incidence of secondary outcomes, including all-cause, cardiovascular, and non-cardiovascular deaths and HF readmission, did not differ between HFsnEF and HFnEF. In the multivariable Cox regression analysis, HFsnEF compared to HFnEF was associated with a lower adjusted HR for HF readmission but not with the primary and other secondary endpoints. HFsnEF was associated with a higher HR for the composite endpoint and all-cause death in women, and a higher HR for all-cause death in patients with renal dysfunction., Conclusions: Heart failure with supra-normal ejection fraction is a common and distinctive phenotype, and has different characteristics and prognoses from HFnEF., (© 2023 European Society of Cardiology.)

We developed an autocorrelation function to resolve the overtaking problem in a multiturn time-of-flight mass spectrometer (TOF-MS). The function analyzes the characteristic period for one lap of each ion packet and derives a mass spectrum from a signal pulse train composed of multiturn ion packets. To detect the ion pulse train, a new nondestructive ion detector was developed and installed in the multiturn orbit of MULTUM-S II. This detector is composed of an electrostatically induced charge detector, a preamplifier, and a digitizer. The electrostatic noises are smaller than the single-ion signals owing to the accumulation of the multiturn TOF spectrum. The conventional ion detector of TOF-MS is operated after collecting the signal pulse train. The multiturn TOF spectrum was convolved with an autocorrelation function to derive the mass spectrum. The convolved mass spectrum performed a mass resolving power (MRP) of 28,200 at m/z 69 and mass accuracy of 28 ppm for the perfluorotributylamine (PFTBA) gas sample., (© 2022 John Wiley & Sons Ltd.)

Background: A heterogeneous clinical phenotype is a characteristic of coronavirus disease 2019 (COVID-19). Therefore, investigating biomarkers associated with disease severity is important for understanding the mechanisms responsible for this heterogeneity and for developing novel agents to prevent critical conditions. This study aimed to elucidate the modulations of sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties., Methods: We measured the serum sphingolipid and glycerophospholipid levels in a total of 887 samples from 215 COVID-19 subjects, plus 115 control subjects without infectious diseases and 109 subjects with infectious diseases other than COVID-19., Results: We observed the dynamic modulations of sphingolipids and glycerophospholipids in the serum of COVID-19 subjects, depending on the time course and severity. The elevation of C16:0 ceramide and lysophosphatidylinositol and decreases in C18:1 ceramide, dihydrosphingosine, lysophosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol were specific to COVID-19. Regarding the association with maximum severity, phosphatidylinositol and phosphatidylcholine species with long unsaturated acyl chains were negatively associated, while lysophosphatidylethanolamine and phosphatidylethanolamine were positively associated with maximum severity during the early phase. Lysophosphatidylcholine and phosphatidylcholine had strong negative correlations with CRP, while phosphatidylethanolamine had strong positive ones. C16:0 ceramide, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine species with long unsaturated acyl chains had negative correlations with D-dimer, while phosphatidylethanolamine species with short acyl chains and phosphatidylinositol had positive ones. Several species of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin might serve as better biomarkers for predicting severe COVID-19 during the early phase than CRP and D-dimer. Compared with the lipid modulations seen in mice treated with lipopolysaccharide, tissue factor, or histone, the lipid modulations observed in severe COVID-19 were most akin to those in mice administered lipopolysaccharide., Conclusion: A better understanding of the disturbances in sphingolipids and glycerophospholipids observed in this study will prompt further investigation to develop laboratory testing for predicting maximum severity and/or novel agents to suppress the aggravation of COVID-19., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: In addition to potent agonist properties for sphingosine 1-phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme., Methods: The mRNA levels of sphingolipid-related and other cancer-related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients' tumours and in their adjacent non-tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence., Results: Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression-enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL-mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG-GPR55 axis and the suppression of autophagy in a GPR55-independent manner., Conclusion: A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: LPA is a small bioactive phospholipid that acts as an extracellular signaling molecule and is involved in cellular processes, including cell proliferation, migration, and differentiation. LPA acts by binding and activating at least six known G protein-coupled receptors: LPA 1-6 . In recent years, LPA has been suggested to play an important role both in normal neuronal development and under pathological conditions in the nervous system., Results: We show the expression pattern of LPA receptors during mouse brain development by using qRT-PCR, in situ hybridization, and immunocytochemistry. Only LPA 1 , LPA 2, LPA 4, and LPA 6 mRNA transcripts were detected throughout development stages from embryonic day 16 until postnatal day 30 of hippocampus, neocortex, cerebellum, and bulbus olfactorius in our experiments, while expression of LPA 3 and LPA 5 genes was below detection level. In addition to our qRT-PCR results, we also analyzed the cellular protein expression of endogenous LPA receptors, with focus on LPA 1 and LPA 2 within postnatal brain slices and primary neuron differentiation with and without cytoskeleton stabilization and destabilization., Conclusions: The expression of LPA receptors changes depends on the developmental stage in mouse brain and in cultured hippocampal primary neurons. Interestingly, we found that commercially available antibodies for LPA receptors are largely unspecific., (© 2019 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.)

Background and Purpose: The safety and feasibility of intravenous thrombolysis using recombinant tissue plasminogen activator (IV-tPA) were retrospectively compared between patients with unknown onset time and no ischemia on fluid-attenuated inversion recovery (negative FLAIR) and patients receiving standard therapy., Methods: Acute stroke patients with unknown onset times were treated using IV-tPA if they had: negative FLAIR; internal carotid artery and/or middle cerebral artery occlusion; and a diffusion-weighted imaging (DWI)-Alberta Stroke Programme Early CT Score ≥5. All patients had abnormal DWI scans indicating an acute stroke. IV-tPA therapy was performed within 3-4.5 h of first found abnormal time (FAT). Patients who were admitted within 3-4.5 h of FAT and did not receive IV-tPA therapy despite the same imaging findings were extracted from our registry as controls., Results: There were 24 patients in the IV-tPA group and 28 in the control group. None of the IV-tPA group and 1 (4%) of the control group patients experienced symptomatic intracerebral hemorrhage (P = 1.000). The rate of dramatic recovery at day 7 (≥10-point reduction in the total National Institutes of Health Stroke Scale [NIHSS] score or NIHSS score of 0-1) was 46% in the IV-tPA group and 18% in the control group (P = .038). Multivariate regression analysis revealed that IV-tPA was an independent predictor of dramatic recovery at day 7 (odds ratio 13.74; 95% confidence interval, 1.95-96.92; P = .009)., Conclusions: IV-tPA may safely increase the rate of dramatic recovery in acute stroke patients with unknown onset times and negative FLAIR., (Copyright © 2015 by the American Society of Neuroimaging.)

Background: Diagnostic accuracies of standard NCCT, CTA, CTA-SI, FLAIR, and DWI to detect the diffusion-perfusion mismatch (DPM) were compared., Methods: Stroke patients considered for endovascular therapy within 8 hours of onset were enrolled. DPM was defined as at least 160% mismatch between DWI and PWI volume., Results: DPM was seen in 35 (71%) of 49 patients. ASPECTS on NCCT, CTA-SI, and DWI was 9 (8-9), 8 (6-9), and 7 (5-9) in mismatch group, and 6 (4-9), 6 (2-7), 5 (2-6) in nonmismatch group, respectively (P = .027, .006, and .001). Ischemic volume on CTA-SI and DWI was 4.6 (.2-13.0) cm(3) and 21.5 (9.7-44.0) cm(3) in mismatch group, and 61.5 (6.6-101.1) cm(3) and 94.9 (45.7-139.8) cm(3) in nonmismatch group (P = .003 and <.001). Significant collateralization on CTA-SI and FLAIR was seen in 80% and 88% in mismatch group, and 42% and 58% in nonmismatch group (P = .026 and .039). Odds ratios (95% CI) of DWI volume of ≤ 70 cm(3) to predict the mismatch was 30.17 (2.06-442.41) after adjusting for ASPECTSs on NCCT, CTA-SI, and DWI, 44.90 (2.75-732.73) for ischemic volume on CTA-SI, and 42.80 (3.05-601.41) for significant collateralization on CTA-SI and FLAIR (P = .013, .008, and .005)., Conclusions: DWI volume was the best predictor of DPM., (Copyright © 2014 by the American Society of Neuroimaging.)

Background and Purpose: Intraarterial (IA) mechanical thrombectomy has an excellent recanalization rate but does not always correlate with good clinical outcomes. We aimed to investigate whether hyperdense middle cerebral artery sign (HMCAS) on preintervention nonenhanced CT (NECT) predicts IA therapy outcome for acute stroke., Methods: Data were abstracted from our Hyperacute Ischemic Stroke database. Patients with occlusion in ICA, MCA, or MCA M2 branches who underwent IA therapy were included., Results: Among 126 patients who underwent IA treatment, 64 (51%) had hyperdense M1 MCA sign (M1 HMCAS), 11 (9%) had hyperdense M2, and 51 (40%) had No HMCAS (NHMCAS).M1 HMCAS and NHMCAS group has comparable baseline stroke severity and infarct volume (P > .05); and the differences of favorable outcome (modified Rankin Score 0-2) at 30 days were not significant (21% vs. 30%, P = .259). For those with HMCAS, favorable 30-day outcome was most frequent in Distal HMCAS (39%), followed by hyperdense M2 (27%), HMCAS proximal (11%), and HMCAS full length (0%)., Conclusions: For acute ischemic stroke due to large vessel occlusion, the lack of HMCAS on NECT does not predict favorable outcome after IA therapy. Among those with HMCAS, proximal and longer HMCAS predicts unfavorable outcome., (Copyright © 2014 by the American Society of Neuroimaging.)

Background and Purpose: Sleep-disordered breathing (SDB) is a risk factor for stroke. The frequency of SDB in Japanese patients with acute intracerebral hemorrhage (ICH) was investigated, as well as factors associated with SDB severity., Methods: Between April 2010 and April 2013, patients with ICH within 24 h of onset were prospectively enrolled to participate in a sleep study within 7 days of admission. SDB was defined as a respiratory disturbance index (RDI: apnea or hypopnea events per hour) of ≥ 5. Patients were assigned to groups based on RDI values of ≥ 30 (severe SDB) and <30 (absent or not severe SDB). The frequency of SDB and factors associated with its severity were investigated using multivariate logistic regression analysis., Results: Of 97 patients (55 males; mean age 68.1 years) enrolled in the study, 91 (94%) had SDB. Severe SDB was evident in 29 (30%) patients. Compared with the RDI< 30 group, the RDI ≥ 30 group had a higher frequency of dysarthria plus dysphagia (76% vs. 47%, P = 0.008), larger waist circumference [86 (84-92) vs. 84 (78-88) cm, P = 0.019] and a greater body mass index [23.8 (21.1-26.8) vs. 21.5 (19.4-25.0) kg/m(2), P = 0.046]. Multivariate logistic regression analysis showed that dysarthria plus dysphagia was independently associated with severe SDB (odds ratio 3.4; 95% confidence interval 1.250-9.252, P = 0.017)., Conclusion: Most Japanese patients with acute ICH had SDB, and dysarthria plus dysphagia was associated with severe SDB., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background: We investigated how many contrast-transcranial Doppler (c-TCD) examinations should be performed on different days in patients with acute stroke., Methods: Consecutive acute stroke patients within 24 hours of onset were enrolled. Presence of RLS was examined using c-TCD examinations on days 1, 7, and 14. Each c-TCD examination used one test without Valsalva maneuver (VM) and three tests with VM. Patients were diagnosed with RLS when TCD detected ≥1 microembolic signal on ≥1 c-TCD examination on any of the days 1, 7, or 14., Results: One hundred seventy patients (105 men [62%]; median age, 74 [IQR, 66-81] years) were enrolled. RLS was diagnosed in 45 patients (26%). RLS was identified on day 1 in 30 patients (18%), on day 7 in 28 patients (16%), and on day 14 in 23 patients (14%; P = .143). Detection rate of RLS by combining day 1 and 7 examinations was significantly higher than that of day 1 alone (25% vs. 18%, P < .001). However, the rate did not increase when results of day 14 were added (25% vs. 26%, P = .250)., Conclusions: c-TCD examinations should be performed on at least two different days to assess the prevalence of RLS., (Copyright © 2011 by the American Society of Neuroimaging.)

A diffusion-weighted imaging (DWI) lesion changed dramatically in a hyperacute stroke case treated with intravenous tissue-plasminogen activator (IV t-PA). The initial hyperintense lesion on DWI disappeared completely immediately after IV t-PA treatment without improvement of neurological symptoms. However, the lesion reappeared 24 hours later. Successful thrombolysis can resolve DWI lesions but does not always improve the neurological symptoms., (Copyright © 2011 by the American Society of Neuroimaging.)

Background and Purpose: Sleep-disordered breathing (SDB) is a risk factor for cerebrovascular disease. We investigated the frequency of SDB in Japanese patients with acute ischaemic stroke and transient ischaemic attack (TIA), as well as factors associated with SDB severity., Methods: Between April 2010 and March 2011, we prospectively enrolled patients with ischaemic stroke and TIA within 24 h of onset to participate in a sleep study within 7 days of admission. We defined SDB as a respiratory disturbance index (RDI) (number of apnoeas or hypopnoeas per hour) of ≥ 5. Patients were assigned to groups based on RDI values of ≥ 30 (severe) and <30 (absent or not severe). The frequency of SDB and factors associated with severity were investigated using multivariate regression analysis., Results: We enrolled 150 patients amongst whom 126 (84%) had SDB. The frequencies of SDB were 21 (75%) patients with TIA, 105 (86%) with ischaemic stroke, 8/10 (80%) with large artery atherosclerosis, 14/14 (100%) with small vessel occlusion, 37/41 (90%) with cardioembolism and 46/57 (81%) with other causes of stroke/undetermined. Severe SDB was evident in 44 (29%) patients. The frequency of males (75% vs. 56%, P = 0.027), atrial fibrillation (AF) (39% vs. 23%, P = 0.045), higher body mass index (23.8 ± 3.8 vs. 22.3 ± 3.8, P = 0.043) and a larger neck circumference (37.8 ± 4.3 vs. 35.8 ± 4.2, P = 0.012) was significantly higher in the group with severe SDB. Multivariate regression analysis found that AF (OR 2.4; 95% CI 1.079-5.836, P = 0.0359) was independently associated with severe SDB., Conclusion: Most Japanese patients with acute ischaemic stroke and TIA had SDB, and AF was associated with SDB., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Background: We investigated whether combined transcranial Doppler (TCD) and magnetic resonance angiography (MRA) can diagnose significant stenosis (s-stenosis) of the siphon portion of the internal carotid artery (S-ICA) on digital subtraction angiography (DSA)., Methods: TCD criteria cut-off peak systolic blood-flow velocity of 75 cm/s or mean blood-flow velocity of 50 cm/s, with both values more than 30% higher than in the contralateral S-ICA. MRA criterion was defined as a ≥50% signal reduction of the column width. Combined TCD and MRA criteria were fulfillment of both TCD and MRA criteria., Results: Among 295 vessels, seven (2%) had s-stenosis on DSA. Using TCD criteria, 16 vessels (5%) were identified to have s-stenosis, of which six (38%) had s-stenosis on DSA (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV] were .86, .97, .38, and .99). Using MRA criteria, 17 (6%) vessels were s-stenosis, of which seven (41%) had s-stenosis on DSA. Sensitivity, specificity, and NPV were 1.00, .97, and 1.00; however, PPV was low (.41). Combined TCD and MRA criteria identified six (2%) vessels as having s-stenosis, all were s-stenosis on DSA (PPV was 1.00)., Conclusion: Combined TCD and MRA examinations have similar diagnostic power to DSA., (Copyright © 2011 by the American Society of Neuroimaging.)

Purpose: There have been some reports on right-to-left shunt as a cause of cryptogenic stroke. Although contrast transcranial Doppler (c-TCD) can detect RLS, an insufficient temporal window has occasionally restricted its applicability. Thus, we compared the rates of detecting RLS among temporal windows for the middle cerebral arteries (MCAs) and the orbital window for the internal carotid artery (ICA) on c-TCD., Methods: We used c-TCD to detect RLS in patients with suspected ischemic stroke. We enrolled patients who had both sufficient bilateral temporal windows for MCAs and a right orbital window for ICA and performed c-TCD using all three windows simultaneously., Results: We enrolled 106 consecutive patients and identified microembolic signals (MES) in 30 (28%) of them. Among these 30 patients, 15 had MES from all 3 windows. When these 30 patients were defined as being positive for RLS, the rates of detection were 67%, 73%, and 80% from the right temporal, left temporal, and right orbital windows, respectively (P= .795)., Conclusion: The right orbital window as well as the temporal window for c-TCD could detect RLS. Insonation from the orbital window should be useful for patients who lack temporal windows., (Copyright © 2010 by the American Society of Neuroimaging.)

Background and Purpose: Transcranial color-coded duplex sonography (TCCS) is a useful tool for evaluating cerebral structures. The aim of this study was to examine whether TCCS is useful for evaluation of hematoma volume., Methods: Patients with supratentorial intracranial hemorrhage within 24 hours of onset were enrolled. We measured major longitudinal, sagittal in axial plane, and coronal diameter of hematoma on computed tomography (CT) and on TCCS. We estimated hematoma volume using the formula, V = longitudinal × sagittal × coronal/2. The correlation between the hematoma volume on TCCS and CT was studied., Results: Of 48 patients with acute supratentorial cerebral hemorrhage admitted to our hospital, 20 patients with temporal windows (age, 67.5 ± 14.8 years; male, 15) were enrolled. A good correlation was found between TCCS and CT for longitudinal, sagittal, coronal diameter, and hematoma volume (r= .907, P < .0001; r= .811, P < .0001; r= .595, P= .0056; and r= .856, P < .0001). Bland-Altman test showed a good agreement between CT and TCCS, the mean difference between both methods was .31., Conclusion: TCCS appears to be a useful method for evaluating hematoma volume., (© 2010 by the American Society of Neuroimaging.)

Background and Purpose: atrial fibrillation (AF) is the most powerful predictor of early death in patients with acute ischaemic stroke. We investigated whether the plasma brain natriuretic peptide (BNP) level on admission can serve as a biological marker of in-hospital death in acute ischaemic stroke and transient ischaemic attack (TIA) patients with AF., Methods: we prospectively enrolled ischaemic stroke and TIA patients with AF within 24 h of onset and measured plasma BNP on admission. Patients were divided into two groups: the deceased group, who died during hospitalization, and the survival group. The factors associated with in-hospital death were investigated by multivariate logistic regression analysis., Results: a total of 221 patients with AF were enrolled. Death occurred in 24 (10.9%) patients. The mean ± SD of the plasma BNP level of the deceased group was significantly higher than that of the survival group (714.1 ± 716.3 vs. 320.0 ± 380.7 pg/ml, P < 0.0001). The optimal cutoff level, sensitivity, and specificity of BNP levels to distinguish the deceased group from the survival group were 320 pg/ml, 79.2, and 69.0%, respectively. Multivariate logistic regression analysis demonstrated that age per 10 years increase (OR, 3.56; 95% CI, 1.728-7.346, P = 0.0006), internal carotid artery occlusion (OR, 10.20; 95% CI, 2.525-41.177, P = 0.0011), NIHSS score of >17 (OR, 4.68; 95% CI, 1.137-19.286, P = 0.0325), and plasma BNP level of > 320 pg/ml (OR, 4.74; 95% CI, 1.260-17.800, P = 0.0213) were independent factors associated with in-hospital death., Conclusion: the plasma BNP level on admission can predict in-hospital death in acute ischaemic stroke and TIA patients with AF.

The diencephalon is the embryonic anlagen of the higher integration centers of the brain. Recent studies have elucidated how the cells in the rostral diencephalon acquire their regional identities. However, the understanding of the mechanisms under which the caudal diencephalon is formed is still limited. Here we focus on the role of Autotaxin (ATX), a lysophospholipid-generating exoenzyme, whose mRNA is detected in the caudal diencephalon. RNA interference against ATX altered the expression pattern of Pax6-regualted genes, Tcf4, Lim1, and En1, implying that ATX is required for the maintenance of the regional identity of the caudal diencephalon and the diencephalon-mesencephalon boundary (DMB). Furthermore, ATX-RNAi inhibited neuroepithelial cell proliferation on both sides of the DMB. We propose a dual role of ATX in chick brain development, in which ATX not only contributes to the formation of caudal diencephalon as a short-range signal, but also regulates the growth of mesencephalon as a long-range signal.

Background and Purpose: The aim of this study was to investigate whether physiological factors, including body mass index (BMI), are associated with detection of right-to-left shunt (RLS) by contrast transcranial Doppler ultrasonography (c-TCD)., Methods: After prospective c-TCD for stroke patients, we compared clinical backgrounds between patients with positive and negative results for RLS. After counting microembolic signals (MES), RLS were functionally graded as follows (grade 0 = 0 MES, grade I = 1-10 MES, grade II = 11-30 MES, grade III = 31-100 MES if countable, grade IV = over 100 MES or uncountable like a shower., Results: Subjects comprised 584 patients (203 men, 381 women) with a mean age of 67.9 +/- 11.1 years. RLS was detected in 134 of 584 patients (23%). In univariate analysis, mean BMI was 22.1 in patients with RLS and 23.3 in those without RLS (P= .004). Mean BMI in concordance with RLS grade gradually decreased (grade 0; 22.7, grade I; 20.8, grade II; 20.1, grade III; 19.6, P= .001). After performing the Valsalva maneuver, mean BMI in concordance with RLS grade linearly increased (grade I; 20.6, grade II; 23.2, grade III; 24.8, grade IV; 25.8, P < .001)., Conclusion: Although smaller body size may be associated with detection of RLS, a patient with significant RLS (grade III or IV) had larger body.

Lysophospholipids (LPs) such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are known to mediate various biological responses, including cell proliferation, migration, and differentiation. To better understand the role of these lipids in mammalian early development, we applied whole-mount in situ hybridization techniques to E8.5 to E12.5 mouse embryos. We determined the expression patterns of the following LP receptor genes, which belong to the G protein-coupled receptor (GPCR) family: EDG1 to EDG8 (S1P1 to S1P5 and LPA1 to LPA3), LPA4 (GPR23/P2Y9), and LPA5 (GPR92). We found that the S1P/LPA receptor genes exhibit overlapping expression patterns in a variety of organ primordia, including the developing brain and cardiovascular system, presomitic mesoderm and somites, branchial arches, and limb buds. These results suggest that multiple receptor systems for LPA/S1P lysophospholipids may be functioning during organogenesis., (Copyright (c) 2008 Wiley-Liss, Inc.)

We have discovered that an N-terminal deletion mutant of a membrane protein, CD63, (CD63DeltaN) blocks entry of CXCR4-using, T-cell tropic human immunodeficiency virus type 1 (X4 HIV-1) by suppressing CXCR4 surface expression. This suppression was observed for CXCR4 but not for CD4, CCR5, CD25, CD71 or other tetraspanin proteins. The suppression of CXCR4 expression on the plasma membrane appeared to be caused by mislocalization of CXCR4 and exclusive transportation of CXCR4 toward intracellular organelles, mainly late endosomes/lysosomes. Our data suggest that CXCR4 trafficking can be modified in terms of its recruitment to the plasma membrane without enhancing the degradation or arresting vesicular transport of CXCR4.

Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that generates bioactive phospholipids that act on G protein-coupled receptors. Here we show the expression patterns of the ATX gene in mouse and chicken embryos. ATX has a dynamic spatial and temporal expression pattern in both species and the expression domains during neural development are quite distinct from each other. Murine ATX (mATX) is expressed immediately rostral to the midbrain-hindbrain boundary, whereas chicken ATX (cATX) is expressed in the diencephalon and later in the parencephalon-synencephalon boundary. In the neural tube, cATX is expressed in the alar plate in contrast to mATX in the floor plate. ATX is also expressed in the hindbrain and various organ primordia such as face anlagen and skin appendages of the mouse and chicken. These results suggest conserved and non-conserved roles for ATX during neural development and organogenesis in these species.

Chronic total occlusion of the left main coronary artery (LMCA) is rare. Recently, percutaneous coronary intervention has been increasingly applied to unprotected LMCA lesions. We describe a patient with chronic total occlusion of the LMCA who was successfully treated with bifurcation stenting with sirolimus-eluting stents.

The aim of this study was to investigate the structure-activity relationship of S-alkyl-L-isothiocitrulline-containing dipeptides towards three partially purified recombinant human nitric oxide synthase (NOS) isozymes, as well as the effects of these compounds on cytokine-induced NO production by human DLD-1 cells. In an in vitro assay, S-methyl-L-isothiocitrulline (L-MIT) was slightly selective for human neuronal NOS (nNOS) over the inducible (iNOS) or endothelial (eNOS) isozyme, but the combination of a hydrophobic L-amino acid (L-Phe, L-Leu or L-Trp) with L-MIT dramatically altered the inhibition pattern to give selective iNOS inhibitors. Introduction of a hydroxy, nitro, amino or methoxy group at the para position of the aromatic ring of L-MIT-L-Phe (MILF) decreased the selectivity and inhibitory potency. A longer or larger S-alkyl group also decreased the selectivity and potency. Dixon analysis showed that all of the dipeptides were competitive inhibitors of the three isoforms of human NOS. The enzymatic time course curves indicated that MILF was a slow binding inhibitor of human iNOS. These results suggest that the human NOS isozymes have different-sized cavities in the binding site near the position to which the C-terminal of L-arginine binds, and the cavity of iNOS is hydrophobic. Interestingly, L-MIT-D-Phe (MIDF) showed little inhibitory activity or selectivity, suggesting that the cavity of human iNOS is located in a well-defined direction from the alpha carbon atom. NO production in cytokine-stimulated human DLD-1 cells was measured with a fluorescent indicator, DAF-FM. MILF, L-MIT-L-Trp(-CHO) (MILW) and L-MIT-L-Tyr (MILY) showed more potent activity than L-MIT in this whole-cell assay. Thus, S-alkyl-L-isothiocitrulline-containing dipeptides are selective inhibitors of human iNOS, and work efficiently in cell-based assay.

Osteolytic characteristics of bone metastasis from renal cell carcinoma were morphologically and biochemically investigated. First, undecalcified ground sections of bone metastases were made from four patients with renal cell carcinoma. Second, renal cell carcinoma cell line (RCC-K1) was established from one of the four patients, and its effect on bone resorption in vitro was examined. Marked proliferation and activation of osteoclasts around the tumor cells was histologically demonstrated. Conditioned medium from the RCC-K1 cells contained potent bone-resorbing activity in vitro. The activity was reduced to basal level by calcitonin, but was not blocked by indomethacin. The activity was lost after dialysis (MW cutoff 3500), while it was retained after 2 weeks of storage. Levels of prostaglandin E2 and 1,25-dihydroxyvitamin D of the RCC-K1-conditioned medium were insufficient to cause bone resorption in vitro. The conditioned medium did not stimulate cAMP accumulation in rat osteoblastic cells. These results suggest that renal cell carcinoma causes bone destruction through the stimulation of osteoclasts by locally secreting an unknown humoral factor or factors.