Heterologous expressing melittin in a probiotic yeast to evaluate its function for promoting NSC-34 regeneration.

Melittin is a bioactive peptide and the predominant component in bee venom (BV), studied for its many medical properties, such as antibacterial, anti-inflammatory, anti-arthritis, nerve damage reduction, and muscle cell regeneration. Melittin is primarily obtained through natural extraction and chemical synthesis; however, both methods have limitations and cannot be used for mass production. This study established a heterologous melittin expression system in the probiotic yeast Kluyveromyces marxianus. This yeast was selected for its advantages in stress tolerance and high secreted protein yields, simplifying purification. A > 95% high-purity melittin (MET) and its precursor promelittin (ProMET) were successfully produced and purified at 1.68 µg/mL and 3.33 µg/mL concentrations and verified through HPLC and mass spectrum. The functional test of the NSC-34 cell regeneration revealed that MET achieved the best activity compared to ProMET and the natural-extracted BV groups. Growth-related gene expressions were evaluated, including microtubule-associated protein 2 (MAP2), microtubule-associated protein Tau (MAPT), growth-associated protein 43 (GAP-43), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and acetylcholine esterase (AChE). The results indicated that treating MET increased MAP2, GAP-43, and VAChT expressions, in which cholinergic signaling is related to neurological functions. A heterologously expressed melittin in a probiotic yeast and its potential for promoting NSC-34 regeneration described here facilitate commercial and therapeutic use. KEY POINTS: • MET and its precursor ProMET were successfully hetero-expressed in K. marxianus • > 95% high-purity MET and ProMET were purified at 1.68 µg/mL and 3.33 µg/mL • MET has no cytotoxicity toward NSC-34 and significantly promotes NSC-34 growth.

Differences between atrial fibrillation diagnosed before and after stroke: A large real-world cohort study.

The clinical characteristics and long-term outcomes of patients with ischemic stroke (IS) and atrial fibrillation detected after stroke (AFDAS) have not been clearly established. Previous studies evaluating patients with AFDAS were limited by the low prescription rates of anticoagulants and short follow-up periods. Consecutive patients hospitalized for IS between 2014 and 2017 were identified from a National Health Insurance Research Database. The included patients were categorized into three groups: (1) known diagnosis of AF (KAF) before the index stroke, (2) AFDAS, and (3) without AF (non-AF). Univariable and multivariable Cox regression analyses were performed to estimate the hazard ratio (HR) for independent variables and recurrent IS, hemorrhagic stroke, or all-cause mortality. We identified 158,909 patients with IS of whom 16,699 (10.5%) had KAF and 7,826 (4.9%) had AFDAS. The patients with AFDAS were younger, more often male, and had lower CHA2DS2-VASc scores (3.8 ± 1.9 versus 4.9 ± 1.8, p < 0.001) than the patients with KAF. Anticoagulant treatment significantly reduced the risks of all outcomes. The standardized mortality rates were 40.4, 28.6, and 18.4 (per 100 person-years) for the patients with KAF, AFDAS, and non-AF, respectively. Compared with AFDAS, KAF was associated with lower risks of recurrent IS [hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.86-0.97, p < 0.01] and hemorrhagic stroke (HR: 0.88, 95% CI: 0.79-0.99, p < 0.01) and a higher risk of all-cause mortality (HR: 1.11, 95% CI: 1.07-1.16, p < 0.001). The risks of recurrent IS and hemorrhagic stroke were higher and of all-cause mortality was lower for patients with AFDAS than with KAF. There is a strong need to refine treatment modalities to reduce the high mortality in patients with KAF and AFDAS.

Transient Global Amnesia Linked to Impairment of Brain Venous Drainage: An Ultrasound Investigation.

Background: Previous neuroimaging and ultrasound studies suggested that compression and stenosis of the internal jugular vein (IJV) in patients with transient global amnesia (TGA) may impair IJV drainage, while a patent IJV releases intracranial pressure caused by the Valsalva maneuver (VM). Methods: Seventy-nine TGA patients with complete ultrasound examination data during admission were recruited prospectively to evaluate IJV drainage, which included the time-averaged mean velocity, and the cross-sectional lumen area of the IJV at the vein's middle (J2) and distal (J3) segments and the cross-sectional area during a 10-s VM to test for any retrograde or anti-grade flow. Forty-five TGA patients and 45 age- and sex-matched control subjects underwent complete contrast-enhanced magnetic resonance (MR) venous studies, which included time-resolved imaging of contrast kinetics, contrast-enhanced axial T1-weighted MR imaging, and phase-contrast-based non-contrast enhanced magnetic resonance venography (MRV). Results: In those subjects with complete MRV studies, the flow volumes exhibited at both the J2 and J3 segments of the left IJV and left vertebral vein (VV) were significantly lower in the TGA patients than in the control subjects. Although there was no significant difference in the flow volume of right IJV, the total of bilateral IJV, and VV flow volumes was still significantly lower in the TGA patients. As compared with the control subjects, the TGA patients exhibited significantly higher prevalence of completely blocked right IJV drainage at the J3 segment during the VM, but non-significantly higher for the left IJV at the J3 segment and for the right IJV at the J2 segment. Conclusion: Our results confirmed that the total venous flow decreases in the IJVs and VVs of the patients with TGA. This is consistent with the findings of previous MR imaging studies that have reported about compression and stenosis of the draining veins. We also found that IJV drainage is relatively compromised during the VM in the patients with TGA.

Ultrasound diagnosis of transverse sinus hypoplasia using flow profiles of the internal jugular vein.

Accurate diagnosis of subtypes of transverse sinus (TS) hypoplasia requires more expensive methods like magnetic resonance (MR) imaging. We hypothesized ultrasound findings of the internal jugular vein (IJV) can be surrogate indicators for diagnosis of TS hypoplasia. MR images were reviewed in 131 subjects to evaluate TS diameter and the location and degree of venous flow stenosis and obstruction. Ultrasound parameters including the cross-sectional lumen area (CSA), time-average-mean velocity (TAMV), and flow volume (FV) at each IJV segment were also evaluated. Sixty-nine subjects had TS hypoplasia based on MRV criteria, of which 39 TS hypoplasia were considered a subtype of TS hypoplasia, which is secondary to the downstream venous compression/stenosis or left brachiocephalic vein. In the ultrasound study, the CSA of the IJV ipsilateral to TS hypoplasia was significantly smaller. Further, a contralateral/ipsilateral IJV CSA ratio >1.55 provided good sensitivity, specificity, and positive predictive value for discriminating TS hypoplasia.

Robust sub-millihertz-level offset locking for transferring optical frequency accuracy and for atomic two-photon spectroscopy.

Robust sub-millihertz-level offset locking was achieved with a simple scheme, by which we were able to transfer the laser frequency stability and accuracy from either cesium-stabilized diode laser or comb laser to the other diode lasers who had serious frequency jitter previously. The offset lock developed in this paper played an important role in atomic two-photon spectroscopy with which record resolution and new determination on the hyperfine constants of cesium atom were achieved. A quantum-interference experiment was performed to show the improvement of light coherence as an extended design was implemented.

Diagnosis of Transverse Sinus Hypoplasia in Magnetic Resonance Venography: New Insights Based on Magnetic Resonance Imaging in Combined Dataset of Venous Outflow Impairment Case-Control Studies: Post Hoc Case-Control Study.

In previous studies of transverse sinus (TS) hypoplasia, discrepancies between TS diameter measured by magnetic resonance venography (MRV) and contrast T1-weighted magnetic resonance (contrast T1) were observed. To investigate these discrepancies, and considering that TS hypoplasia is associated with neurological disorders, we performed a post hoc analysis of prospectively collected data from 3 case-control studies on transient global amnesia (TGA), transient monocular blindness (TMB), and panic disorders while retaining the original inclusion and exclusion criteria. Magnetic resonance (MR) imaging of 131 subjects was reviewed to evaluate TS diameter and the location and degree of venous flow stenosis and obstruction.MRV without contrast revealed that TS hypoplasia was observed in 69 subjects, whom we classified into 2 subgroups according to the concordance with contrast T1 observations: concordance indicated anatomically small TS (30 subjects), and discrepancy indicated that the MRV diagnosis is in fact flow-related and that TS is not anatomically small (39 subjects). The latter subgroup was associated with at least 1 site of venous compression/stenosis in the internal jugular vein (IJV) or the left brachiocephalic vein (BCV) (P < 0.001), which was significantly larger in patients than controls. Compensatory dilatation of contralateral TS diameter was only observed with MRV, not with contrast T1 imaging.The clinical implication of these results is that using MRV only, IJV/BCV compression/stenosis may be misdiagnosed as TS hypoplasia. And contralateral TS have no compensatory dilatation in its diameter in contrast T1 imaging, just compensatory increased flow volume.

Obstruction of Venous Drainage Linked to Transient Global Amnesia.

Abnormal extracranial venous drainage modality has been considered an etiology of transient global amnesia (TGA). Evidence suggests that the transmission of the intrathoracic/intraabdominal pressure during a Valsalva maneuver (VM) is mainly through the vertebral venous system, and patency of internal jugular vein (IJV) is essential for venous drainage and pressure releasing. We hypothesize that obstruction of IJV venous drainage is a contributing factor in TGA pathogenesis. A magnetic resonance (MR) imaging protocol was used in 45 TGA patients and 45 age- and sex-matched controls to assess the morphologies of IJV, brachiocephalic vein (BCV) and asymmetry of transverse sinus (TS). The IJV was divided into the upper- and middle-IJV segments. Compared to the controls, TGA patients had significantly higher rates of moderate and severe compression/stenosis at the bilateral upper-IJV segment (left: 37.8% vs. 17.8%, P = 0.0393; right: 57.8% vs.15.6%, P<0.0012), in left BCV (60% vs. 8.9%, P<0.0004), and in TS hypoplasia (53.3%% vs. 31.1%, P = 0.0405). The prevalence of at least one site of venous compression/stenosis in IJV or BCV was significantly higher in patients than in controls (91.1% vs. 33.3%, P<0.0004). The diameter of the left TS in MRV, but not in T1 contrast imaging, was significantly smaller in TGA patients than in controls (0.31 ± 0.21 vs. 0.41 ± 0.19, P = 0.0290), which was compatible with downstream venous stenosis/obstruction. TGA patients have a higher prevalence of compression/stenosis of the bilateral IJV and the left BCV and TS hypoplasia, which is new evidence that supports the role of extracranial veins in TGA pathogenesis.

Stroke etiology is associated with outcome in posterior circulation stroke.

OBJECTIVE: Stroke research and clinical trials have focused mainly on anterior circulation stroke (ACS). Since clinical characteristics, mechanisms, and outcomes of posterior circulation stroke (PCS) have been reported different from ACS, more PCS studies are required, particularly researching the etiologies, to help establish an optimal management strategy. METHODS: The present study analyzed patients of PCS who were consecutively admitted and registered in Taipei Veterans General Hospital Stroke Registry between 1 January 2012 to 28 February 2014. We demonstrated the distribution of etiologies, compared the clinical characteristics/outcomes among different etiology groups, and used univariate/multivariate analyses to identify the predictors for poor functional outcome (modified Rankin Scale ≥5) at discharge and 3 month. RESULTS: About 286 patients of PCS were included for analyses. Basilar artery atheromatous branch occlusive disease (BABO, 28.0%) and large artery dissection (25.9%) were the two most common etiologies, followed by large artery atherosclerotic stenosis/occlusion (LAA, 20.6%), cardioembolism (CE, 18.5%) and small vessel disease (7.0%). Age, vascular risk factors, infarct locations and patterns, and outcomes were different among these five etiology groups. Multivariate analyses showed that age >70 y/o (discharge/3 month, OR, 95% CI: 3.05, 1.23-7.56/8.39, 2.32-30.33), admission NIH Stroke Scale >9 (19.50, 8.69-43.75/13.45, 5.59-32.39), and etiology (LAA versus BABO: 5.00, 1.58-15.83/4.00, 1.19-13.4; CE versus BABO: 3.36, 1.02-11.09/4.66, 1.40-15.46) were independently associated with poor functional outcome. INTERPRETATION: The etiologies of PCS are heterogeneous and shown to be associated with functional outcomes. Our results have shed lights on future pathophysiological research and designs of clinical trials for PCS.

Collapsed Jugular Vein and abnormal cerebral blood flow changes in patients of Panic Disorder.

OBJECTIVE: Panic disorder (PD) is characterized by panic attacks accompanied with respiratory symptoms. Internal jugular vein (IJV) alters its hemodynamics in response to respiration and which might cause cerebral blood flow (CBF) changes. In the present study, we compared (1) respiratory-related IJV hemodynamics and (2) CBF changes during Valsalva maneuver (VM) between PD and normal subjects. METHODS: 42 PD patients and age/gender-matched controls (14 men; 52.3 ± 11.4 years) were recruited. Duplex ultrasonography measured time-averaged mean velocity (TAMV) and lumen in IJV at baseline and deep inspiration. Lumen area <0.10 cm(2) at deep inspiration was defined as IJV collapse. CBF changes during VM were recorded by transcranial Doppler (TCD). RESULTS: Compared with normal group, PD patients had significantly higher frequency of IJV collapse at deep inspiration (Left: 40.0% vs. 7.0%, p = 0.0003, Right: 17.0% vs. 0%, p = 0.0119). IJV collapse was associated with symptoms of respiratory subtype in our PD patients. PD group also had smaller lumen (Left: 0.53 ± 0.29 vs. 0.55 ± 0.26 cm(2), p = 0.8296, Right: 0.63 ± 0.36 vs. 0.93 ± 0.45 cm(2), p = 0.0014) and slower TAMV of IJV at baseline (Left: 11.8 ± 8.43 vs. 20.6 ± 16.5 cm/s, p = 0.0003, Right: 15.9 ± 9.19 vs. 24.1 ± 15.7 cm/s, p = 0.0062). PD patients with inspiration-induced IJV collapse had more decreased CBF during VM compared with the other PD patients and normal individuals respectively. INTERPRETATION: We are the first to show that PD have less IJV flow at baseline and more frequent collapse at deep inspiration. Inspiration-induced IJV collapsed was associated with CBF decrement during VM in PD patients. These results suggest that venous drainage impairment might play a role in the pathophysiology of PD by influencing CBF.

Different doses of recombinant tissue-type plasminogen activator for acute stroke in Chinese patients.

BACKGROUND AND PURPOSE: The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients. METHODS: A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months. RESULTS: There was a significant trend for symptomatic intracerebral hemorrhage with age (P=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (P=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (P=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (P=0.0130) and less good functional outcome (P=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (P=0.0971) at 3 months in these patients. CONCLUSIONS: These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71-80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required.

The interpretation of very high frequency band of instantaneous pulse rate variability during paced respiration.

BACKGROUND: Pulse rate (PR) indicates heart beat rhythm and contains various intrinsic characteristics of peripheral regulation. Pulse rate variability (PRV) is a reliable method to assess autonomic nervous system function quantitatively as an effective alternative to heart rate variability. However, the frequency range of PRV is limited by the temporal resolution of PR based on heart rate and it is further restricted the exploration of optimal autoregulation frequency based on spectral analysis. METHODS: Recently, a new novel method, called instantaneous PRV (iPRV), was proposed. iPRV breaks the limitation of temporal resolution and extends the frequency band. Moreover, iPRV provides a new frequency band, called very high frequency band (VHF; 0.4-0.9 Hz). RESULTS: The results showed that the VHF indicated the influences of respiratory maneuvers (paced respiration at 6-cycle and 30-cycle) and the nonstationary condition (head-up tilt; HUT). CONCLUSIONS: VHF is as a potential indication of autoregulation in higher frequency range and with peripheral regulation. It helps for the frequency exploration of cardiovascular autoregulation.

Severity of spontaneous echo contrast in the jugular vein associated with ischemic stroke.

This study evaluated the relationship between spontaneous echo contrast (SEC) in the internal jugular vein (JV), atherosclerotic markers and ischemic stroke. One hundred twenty patients with acute ischemic stroke and 120 controls were recruited. SEC score correlated with plasma level of fibrinogen (coefficient: 0.105, p = 0.022), hemoglobin (coefficient: 0.122, p = 0.008) and presence of JV reflux (coefficient: 0.314, p < 0.001) and peak flow velocity (coefficient: -0.244, p < 0.001) in the corresponding JV, but did not correlate with carotid plaque score (coefficient: 0.042, p = 0.358) or intima-media thickness (coefficient: 0.067, p = 0.303). Multivariate regression analysis revealed that fibrinogen level, SEC score, intima-media thickness, plaque score and history of coronary artery disease were associated with acute ischemic stroke. In conclusion, the severity of SEC in the JV might represent the tendency toward thrombogenesis in diseased cerebral circulation possibly through mechanisms other than arterial atherosclerosis.

Frequency range extension of spectral analysis of pulse rate variability based on Hilbert-Huang transform.

Heart rate variability (HRV) is a well-accepted indicator for neural regulatory mechanisms in cardiovascular circulation. Its spectrum analysis provides the powerful means of observing the modulation between sympathetic and parasympathetic nervous system. The timescale of HRV is limited by discrete beat-to-beat time intervals; therefore, the exploration region of frequency band of HRV spectrum is relatively narrow. It had been proved that pulse rate variability (PRV) is a surrogate measurement of HRV in most of the circumstances. Moreover, arterial pulse wave contains small oscillations resulting from complex regulation of cardiac pumping function and vascular tone at higher frequency range. This study proposed a novel instantaneous PRV (iPRV) measurement based on Hilbert-Huang transform. Fifteen healthy subjects participated in this study and received continuous blood pressure wave recording in supine and passive head-up tilt. The result showed that the very-high-frequency band (0.4-0.9 Hz) varied during head-up tilt and had strong correlation (r = 0.77) with high-frequency band and medium correlation (r = 0.643) with baroreflex sensitivity. The very-high-frequency band of iPRV helps for the exploration of non-stationary autoregulation and provides the non-stationary spectral evaluation of HRV without distortion or information loss.

Changes in left atrial functional indexes in ischemic stroke patients.

BACKGROUND: Increased left atrial (LA) size has been proposed as a predictor of multiple adverse cardiovascular events including stroke. LA dysfunction can occur in the absence of increased LA size. However, the relationship between stroke and changes in LA function is not well known. METHODS: Patients with acute ischemic stroke and healthy controls were enrolled prospectively. Stroke patients received standard work-ups to determine the etiology of their strokes. Those patients with significant cardiac arrhythmia and heart failure were excluded. All participants received echocardiography examination. Conventional echocardiographic parameters were calculated and cardiac contractile characteristics of the left atrium and left ventricle were analyzed using vector velocity imaging (VVI) technique. RESULTS: In total, 87 patients with acute ischemic stroke and 20 controls were recruited. The mitral inflow E-wave velocities were lower and A-wave velocities were higher in stroke patients (0.76 ± 0.19 vs. 0.84 ± 0.16, p = 0.048; and 0.97 ± 0.20 vs. 0.76 ± 0.11, p < 0.001 respectively). Stroke patients had a higher active emptying percent of total LA emptying (60.5 ± 19.0%) compared with that in controls (33.5 ± 11.7%, p < 0.001). The minimal LA volume was larger in stroke patients (15.0 ± 10.5 mL) than that in controls (9.9 ± 4.2 mL, p = 0.021), whereas there was no difference in maximal LA volume between stroke patients (37.3 ± 16.5 mL) and controls (33.3 ± 9.9 ml, p = 0.366). The diastolic emptying index of the LA was significantly lower in stroke patients compared with that in controls (61.4 ± 14.6% vs. 70.2 ± 11.0%, p = 0.016). The mitral A-wave velocity and active emptying percent of total LA emptying were significantly higher in all stroke subtypes than those in controls. CONCLUSION: Acute ischemic stroke patients had altered mitral inflow velocities and emptying function of the left atrium. VVI is convenient for quantitative assessment of left atrial volumes and contractile characteristics. Functional changes of LA may occur without significant structural changes. Therefore, the clinical implications of LA functional indexes require further study.

Jugular venous reflux and plasma endothelin-1 are associated with cough syncope: a case control pilot study.

BACKGROUND: Jugular venous reflux (JVR) has been reported to cause cough syncope via retrograde-transmitted venous hypertension and consequently decreased cerebral blood flow (CBF). Unmatched frequencies of JVR and cough syncope led us to postulate that there should be additional factors combined with JVR to exaggerate CBF decrement during cough, leading to syncope. The present pilot study tested the hypothesis that JVR, in addition to an increased level of plasma endothelin-1 (ET-1), a potent vasoconstrictor, is involved in the pathophysiology of cough syncope. METHODS: Seventeen patients with cough syncope or pre-syncope (Mean[SD] = 74.63(12.37) years; 15 males) and 51 age/gender-matched controls received color-coded duplex ultrasonography for JVR determination and plasma ET-1 level measurements. RESULTS: Multivariate logistic analysis showed that the presence of both-side JVR (odds ratio [OR] = 10.77, 95% confident interval [CI] = 2.40-48.35, p = 0.0019) and plasma ET-1 > 3.43 pg/ml (OR = 14.57, 95% CI = 2.95-71.59, p = 0.001) were independently associated with the presence of cough syncope/ pre-syncope respectively. There was less incidence of cough syncope/ pre-syncope in subjects with the absence of both-side JVR and a plasma ET-1 ≦3.43 pg/ml. Presence of both side JVR and plasma ET-1 level of > 3.43 pg/ml, increased risk for cough syncope/pre-syncope (p < 0.001). CONCLUSIONS: JVR and higher plasma levels of ET-1 are associated with cough syncope/ pre-syncope. Although sample size of this study was small, we showed a synergistic effect between JVR and plasma ET-1 levels on the occurrence of cough syncope/pre-syncope. Future studies should confirm our pilot findings.

Relationship between acute stroke outcome, aspirin resistance, and humoral factors.

BACKGROUND: The relationship between biochemical aspirin resistance (AR) and functional outcome of acute ischemic stroke is uncertain. METHODS: Prospectively, 269 patients with acute ischemic stroke were recruited. Their responsiveness to aspirin was evaluated by platelet function analyzer (PFA-100). All patients received blood tests for fibrinogen, high-sensitivity C-reactive protein (hs-CRP), CD40-ligand, P-selectin, intercellular adhesion molecule -1, von Willebrand factor (vWF), and D-dimer. The patients' National Institutes of Health Stroke Scale and modified Rankin Scale scores were recorded on admission, at 30 days, and at 90 days after stroke. RESULTS: Closure-time measured by PFA-100 equipped with epinephrine/collagen cartridge (Epi-CT) was <193 seconds (defined as AR) in 83 patients (30.9%). Patients with AR were less likely to have favorable outcome at 30 days (47.0%, p = 0.047; odds ratio: 0.69, 0.48-0.99) and 90 days (57.8%, p = 0.037; odds ratio: 0.69, 0.47-0.97) after stroke compared with those of patients without AR (60.2% and 71.0%, respectively). The Epi-CT correlated with closure-time measured by adenosine diphosphate/collagen cartridge (r = 0.241, p < 0.001), blood white cell count (r = -0.125, p = 0.041), low density lipoprotein cholesterol (r = 0.120, p = 0.050), hs-CRP (r = -0.150, p = 0.015), vWF (r = -0.134, p = 0.028), and body mass index (r = 0.143, p = 0.019). Multivariate logistic regression analysis showed that higher National Institutes of Health Stroke Scale at admission, atrial fibrillation, increased plasma levels of hs-CRP, and D-dimer were independent predictors for unfavorable stroke outcome at 90 days. CONCLUSION: Aspirin resistance evaluated by PFA-100 test was associated with unfavorable 90-day outcome. However, AR determined by PFA-100 dose not predict 90-day functional outcome. The results of PFA-100 testing represented a complex interaction between drug effect, inflammatory reaction, and prothrombotic activity.

Spontaneous echo contrast in internal jugular veins: a probable indicator for systemic inflammation and a prothrombotic state.

The hypothesis that spontaneous echo contrast (SEC) in the internal jugular vein (IJV) is a clinical indicator for systemic inflammation and thrombogenesis is investigated in this study. Fifty-two patients with cardiovascular diseases and 25 nondiseased subjects were evaluated. SEC was observed in 96 of 154 IJVs. The visual grading of SEC showed good interobserver agreement on SEC grades (κ value: 0.846, p < 0.001). Generalized estimating equations analysis was used for univariate and multivariate analysis. Univariate analysis showed that peak flow velocity in corresponding IJV (coefficient -0.001 [95% CI -0.019, -0.001], p = 0.031), jugular venous reflux (JVR, -0.010 [-0.019, -0.001], p = 0.002), plasma levels of fibrinogen (0.464 [0.208, 0.719], p < 0.001) and hs-C-reactive protein (hs-CRP) (0.479 [0.184, 0.774], p = 0.001) and previous history of ischemic stroke (0.779 [0.139, 1.417]; p = 0.017) correlated with the grades of SEC in IJV. Increased plasma levels of fibrinogen and hs-CRP, previous ischemic stroke, lower peak velocity in corresponding IJV and JVR were also independent predictors for the higher grades of SEC in IJV in multivariate regression analysis. SEC in IJV could be evaluated easily and semiquantitatively. SEC in IJVs could be a putative marker of cerebral circulation disturbance and an indicator of systemic inflammatory or prothrombotic state.

Transcranial Doppler studies on cerebral autoregulation suggest prolonged cerebral vasoconstriction in a subgroup of patients with orthostatic intolerance.

We studied the cerebral autoregulation in a subgroup of patients with orthostatic intolerance, who exhibited excessively decreased middle cerebral artery flow velocity (MCAFV) on transcranial Doppler sonography (TCD) during head-up tilt (HUT) test but without orthostatic hypotension or postural tachycardia. Twenty patients and 20 age- and sex-matched controls underwent Valsalva maneuver (VM) and HUT test with simultaneous monitoring of MCAFV by TCD and blood pressure, heart rate recordings. The pulsatility index (PI), cerebrovascular resistance (CVR) and autoregulatory indices were calculated. During HUT, patients had marked MCAFV reduction (-29.0 ± 5.25% vs. -8.01 ± 4.37%), paradoxically decreased PI (0.68 ± 0.17 vs. 0.96 ± 0.28) but increased CVR (45.7 ± 16.7% vs. 14.3 ± 12.6%). The MCAFV decreased similarly during early phase II of VM in both groups but did not recover to baseline in patients during late phase II, phase III and less overshoot in phase IV (-11 ± 16.7% vs. +2.2 ± 17.9 %; -15.4 ± 16.5% vs. -2.4 ± 17.8% and 16.7 ± 22.9% vs. 38.7 ± 26.5%, respectively). We concluded that in these patients, cerebrovascular vasoconstriction in response to physiologic stimulation was normal but relaxation during and after stimulation were impaired, indicating prolonged cerebral vasoconstriction.

Synthesis of selenophene derivatives as novel CHK1 inhibitors.

A series of selenophene derivatives 3 were synthesized as potential CHK1 inhibitors. The effects of substitution on the 4'- or 5'-position of selenophene moiety and shifting the hydroxyl group position on C6- phenolic ring of oxindole were explored. This study led to the discovery of the most potent CHK1 inhibitors 29-33 and 39-43, which had IC(50) values in the subnanomolar range.