Association between preoperative cortical magnetic susceptibility and postoperative changes in the cerebral blood flow on cognitive improvement following carotid endarterectomy.

INTRODUCTION: While patients who experience improved cognition following carotid endarterectomy (CEA) typically demonstrate restored brain perfusion after the procedure, it is worth noting that less than 50% of patients in whom postoperative cerebral blood flow (CBF) restoration is achieved actually show improved cognition after postoperatively. This suggests that factors beyond the mere restoration of CBF may play a role in postoperative cognitive improvement. Increased iron deposition in the cerebral cortex may cause neural damage, and quantitative susceptibility mapping (QSM) obtained using magnetic resonance imaging (MRI) quantifies magnetic susceptibility in the cerebral cortex, allowing for the assessment of iron deposition in vivo. The purpose of the present study was to determine whether preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA. METHODS: Brain MRI with a three-dimensional gradient echo sequence was preoperatively performed in 53 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≥70%), and QSM with brain surface correction and vein removal was obtained. Cortical magnetic susceptibility was measured in the cerebral hemisphere ipsilateral to surgery on QSM. Preoperatively and at two months after the surgery, brain perfusion single-photon emission computed tomography (SPECT) and neuropsychological assessments were conducted. Using these collected data, we evaluated alterations in CBF within the affected hemisphere and assessed cognitive improvements following the operation. RESULTS: A logistic regression analysis showed that a postoperative greater increase in CBF (95% confidence interval [CI], 1.06-1.90; p = 0.0186) and preoperative lower cortical magnetic susceptibility (95% CI, 0.03-0.74; p = 0.0201) were significantly associated with postoperatively improved cognition. Although sensitivity, specificity, and positive- and negative-predictive values with the cutoff value lying closest to the upper left corner of a receiver operating characteristic curve for the prediction of postoperatively improved cognition did not differ between postoperative changes in CBF and preoperative cortical magnetic susceptibility, the specificity and the positive-predictive value were significantly greater for the combination of postoperative changes in CBF and preoperative cortical magnetic susceptibility (specificity, 95% CI, 93-100%; positive-predictive value 95% CI, 68-100%) than for the former parameter alone (specificity, 95% CI, 63-88%; positive-predictive value 95% CI, 20-64%). CONCLUSION: Preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA.

Low-flow time and outcomes in out-of-hospital cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation.

INTRODUCTION: In out-of-hospital cardiac arrest (OHCA) patients with extracorporeal cardiopulmonary resuscitation (ECPR), the association between low-flow time, the duration between the initiation of conventional cardiopulmonary resuscitation and the establishment of ECPR, and outcomes has not been clearly determined. METHODS: This was a secondary analysis of the retrospective multicenter registry in Japan. This study registered patients ≥18 years old who were admitted to the emergency department for OHCA and underwent ECPR between January, 2013 and December, 2018. Low-flow time was defined as the time from initiation of conventional cardiopulmonary resuscitation to the establishment of ECPR, and patients were categorized into two groups according to the visualized association of the restricted cubic spline curve. The primary outcome was survival discharge. Cubic spline analyses and multivariable logistic regression analyses were performed to assess the nonlinear associations between low-flow time and outcomes. RESULTS: A total of 1,524 patients were included. The median age was 60 years, and the median low-flow time was 52 (42-53) mins. The overall survival at hospital discharge and favorable neurological outcomes were 27.8% and 14.2%, respectively. The cubic spline analysis showed a decreased trend of survival discharge rates and favorable neurological outcomes with shorter low-flow time between 20 and 60 mins, with little change between the following 60 and 80 mins. The multivariable logistic regression analyses showed that patients with long low-flow time (>40 mins) compared to those with short low-flow time (0-40 mins) had significantly worse survival (adjusted odds ratio 0.42; 95% confidence intervals, 0.31-0.57) and neurological outcomes (0.65; 0.45-0.95, respectively). CONCLUSIONS: The survival discharge and neurological outcomes of patients with low-flow time shorter than 40 min are better than those of patients with longer low-flow time.

Association between preoperative white matter hyperintensities and postoperative new ischemic lesions on magnetic resonance imaging in patients with cognitive decline after carotid endarterectomy.

Although cognitive decline after carotid endarterectomy (CEA) is mainly related to postoperative cerebral hyperperfusion, approximately 30% of patients with cognitive decline do not have postoperative cerebral hyperperfusion. In patients with acute ischemic events, the development of cognitive decline after such events is associated with the presence of chronic cerebral white matter hyperintensities (WMHs). The present prospective observational study aimed to determine whether preoperative WMHs and postoperative new ischemic lesions (PNILs) are associated with cognitive decline after CEA in patients without cerebral hyperperfusion after CEA. Brain magnetic resonance imaging (MRI) was performed preoperatively, and WMHs were graded according to the Fazekas scale in patients undergoing CEA for severe stenosis of the ipsilateral internal carotid. Diffusion-weighted MRI was performed before and after CEA to determine the development of PNILs. Neuropsychological testing was performed preoperatively and at 2 months postoperatively to determine the development of postoperative cognitive decline (PCD). In 142 patients without postoperative cerebral hyperperfusion, logistic regression analysis revealed that preoperative Fazekas scale of periventricular WMHs (PVWMHs) (95% confidence interval [CI]: 1.78-28.10; P = 0.0055) and PNILs in the eloquent areas (95% CI: 7.42-571.89; P = 0.0002) were significantly associated with PCD. The specificity and positive-predictive value for the prediction of PCD were significantly greater for the combination of preoperative Fazekas scale 2 or 3 of PVWMHs and PNILs in the eloquent areas than for each individually. Preoperative PVWMHs, PNILs in the eloquent areas, and the combination of both were associated with PCD in patients without cerebral hyperperfusion after CEA.

Maternal GABAergic and GnRH/corazonin pathway modulates egg diapause phenotype of the silkworm Bombyx mori.

Diapause represents a major developmental switch in insects and is a seasonal adaptation that evolved as a specific subtype of dormancy in most insect species to ensure survival under unfavorable environmental conditions and synchronize populations. However, the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration in morphological, physiological, behavioral, and reproductive responses remains unclear. In the bivoltine strain of the silkworm Bombyx mori, embryonic diapause is induced transgenerationally as a maternal effect. Progeny diapause is determined by the environmental temperature during embryonic development of the mother. Here, we show that the hierarchical pathway consists of a γ-aminobutyric acid (GABA)ergic and corazonin signaling system modulating progeny diapause induction via diapause hormone release, which may be finely tuned by the temperature-dependent expression of plasma membrane GABA transporter. Furthermore, this signaling pathway possesses similar features to the gonadotropin-releasing hormone (GnRH) signaling system for seasonal reproductive plasticity in vertebrates.

Streamlined Chemoenzymatic Synthesis of Cyclic Peptides by Non-ribosomal Peptide Cyclases.

Macrocyclization improves the pharmaceutical properties of peptides; however, regio- and chemoselective intramolecular cyclizations remain challenging. Here we developed a streamlined chemoenzymatic approach to synthesize cyclic peptides by exploiting non-ribosomal peptide (NRP) cyclases. Linear peptides linked to the resin through a C-terminal diol ester functionality are synthesized on a solid support, to circumvent the installation of leaving groups to the peptidic substrates in the liquid phase which often triggers undesirable epimerization. Cleavage of the resin-bound peptides yielded the diol esters with sufficient purity to be readily cyclized in a head-to-tail manner by SurE, a representative penicillin-binding protein-type thioesterase (PBP-type TE). Explorations of homologous wild-type enzymes as well as rational protein engineering have broadened the scope of the enzymatic macrolactamization. This method will potentially accelerate the exploitation of NRP cyclases as biocatalysts.

Ten-year clinical outcomes from a randomized trial comparing new-generation everolimus-eluting stent versus first-generation Sirolimus-eluting stent: Results from the RESET extended study.

BACKGROUND: New-generation drug-eluting stents (DES) achieved technological innovations and reported clinical advantages as compared with first-generation DES in clinical trials with 3-5 years follow-up. However, detailed clinical outcome data in very long-term follow-up is still scarce. OBJECTIVES: To evaluate 10-year clinical outcomes after first- and new-generation DES implantation. METHODS: In this extende follow-up study of the RESET, which is a largest randomized trial comparing everolimus-eluting stent (EES) with Sirolimus-eluting stent (SES), the study population consisted of 2892 patients from 84 centers. The primary efficacy and safety endpoints were target lesion revascularization (TLR) and a composite of death or myocardial infarction (MI), respectively. Complete 10-year follow-up was achieved in 87.9% of patients. RESULTS: Cumulative 10-year incidences of TLR and non-TLR were not significantly different between EES and SES (13.9% vs. 15.7%, Log-rank p = 0.20, and 33.4% vs. 31.3%, Log-rank p = 0.30). The cumulative 10-year incidence of death/MI was also not significantly different between the groups (32.5% vs. 34.4%, Log-rank p = 0.18). Cumulative 10-year incidence of definite stent thrombosis was numerically lower in EES than in SES (1.0% vs. 1.7%, Log-rank p = 0.16). The lower risk of EES relative to SES was significant for a composite endpoint of target lesion failure (TLF: 19.6% vs. 24.9%, Log-rank p = 0.001) and target vessel failure (TVF: 26.7% vs. 31.4%, Log-rank p = 0.006). CONCLUSION: During 10-year of follow-up, the risks for primary efficacy and safety endpoints were not significantly different between new-generation EES and first-generation SES, although EES compared with SES was associated with a lower risk for composite endpoints such as TLF and TVF.

Direct Investigation of Excited C60 Dianion and Its Intramolecular Electron Transfer Behaviors.

For the first time, the dynamics of excited fullerene dianions and associated intramolecular electron transfer (ET) were directly investigated by using femtosecond pump-probe laser flash photolysis on selectively reduced C60, pyrrolidino[60]fullerene (C60H), and dyads including C60-naphthalenediimide (NDI) and C60-pyromellitimide (PI). Upon near-infrared laser excitation, the excited dianion of C60 or C60H displayed two states with lifetimes of less than one and several tens of ps, attributed to prompt internal conversion from the theoretically predicted Sn state. Furthermore, the ET processes from the excited C602- in dyad molecules, including C602--NDI•- and C602--PI•-, were confirmed with varied ET rate constants due to the difference in the driving force for ET. The current findings provide a clear description of the hitherto uncharted excited-state and photoinduced ET characteristics of fullerene dianions, paving the way for photochemical studies of excited multi-ions (excited multi-polarons) and their application in organic semiconducting materials.

Prediction of cerebral hyperperfusion following carotid endarterectomy using intravoxel incoherent motion magnetic resonance imaging.

OBJECTIVES: One of the risk factors for cerebral hyperperfusion following carotid endarterectomy (CEA) is a chronic reduction in cerebral perfusion pressure due to internal carotid artery (ICA) stenosis, which is clinically detected as increased cerebral blood volume (CBV). The perfusion fraction (f) is one of the intra-voxel incoherent motion (IVIM) parameters obtained using magnetic resonance (MR) imaging that theoretically reflects CBV. The present study aimed to determine whether preoperative IVIM-f on MR imaging predicts development of cerebral hyperperfusion following CEA. MATERIALS AND METHODS: Sixty-eight patients with unilateral ICA stenosis (≥ 70%) underwent preoperative diffusion-weighted 3-T MR imaging, and IVIM-f maps were generated from these data. Quantitative brain perfusion single-photon emission computed tomography (SPECT) was performed before and immediately after CEA. Regions-of-interest (ROIs) were automatically placed in the bilateral middle cerebral artery territories in all images using a three-dimensional stereotactic ROI template, and affected-to-contralateral ratios in the ROIs were calculated on IVIM-f maps. RESULTS: Nine patients (13%) exhibited postoperative hyperperfusion (cerebral blood flow increases of ≥ 100% compared with preoperative values in the ROIs on brain perfusion SPECT). Only high IVIM-f ratios were significantly associated with the occurrence of postoperative hyperperfusion (95% confidence interval, 253.8-6774.2; p = 0.0031) on logistic regression analysis. The sensitivity, specificity, and positive and negative predictive values of the IVIM-f ratio to predict the occurrence of postoperative hyperperfusion were 100%, 81%, 45%, and 100%, respectively. CONCLUSIONS: Preoperative IVIM-f on MR imaging can predict development of cerebral hyperperfusion following CEA.

The consumers' response to product design: a narrative review.

This paper reviews the research ideas around consumer response to product design. From the product side, we discuss the most significant design features preferred by average consumers, such as aesthetics and utility. And from the consumer side, we investigate the human factors influencing consumer perceptions. We present the main approaches used to measure the consumer response to product design and summarize the multiple biases that occur during the evaluation. Finally, we present in detail the most commonly used methods to analyze consumer response data and their roles in the design evaluation context. Practitioner Summary: To answer the question: What causes differences in design response? We summarise the research findings related to product design features and human factors. We highlight the biases that can emerge from the measurement approach. And discuss the most common analysis methods used for product design response information.

The intrinsically disordered N-terminal region of mouse DNA polymerase alpha mediates its interaction with POT1a/b at telomeres.

Mouse telomerase and the DNA polymerase alpha-primase complex elongate the leading and lagging strands of telomeres, respectively. To elucidate the molecular mechanism of lagging strand synthesis, we investigated the interaction between DNA polymerase alpha and two paralogs of the mouse POT1 telomere-binding protein (POT1a and POT1b). Yeast two-hybrid analysis and a glutathione S-transferase pull-down assay indicated that the C-terminal region of POT1a/b binds to the intrinsically disordered N-terminal region of p180, the catalytic subunit of mouse DNA polymerase alpha. Subcellular distribution analyses showed that although POT1a, POT1b, and TPP1 were localized to the cytoplasm, POT1a-TPP1 and POT1b-TPP1 coexpressed with TIN2 localized to the nucleus in a TIN2 dose-dependent manner. Coimmunoprecipitation and cell cycle synchronization experiments indicated that POT1b-TPP1-TIN2 was more strongly associated with p180 than POT1a-TPP1-TIN2, and this complex accumulated during the S phase. Fluorescence in situ hybridization and proximity ligation assays showed that POT1a and POT1b interacted with p180 and TIN2 on telomeric chromatin. Based on the present study and a previous study, we propose a model in which POT1a/b-TPP1-TIN2 translocates into the nucleus in a TIN2 dose-dependent manner to target the telomere, where POT1a/b interacts with DNA polymerase alpha for recruitment at the telomere for lagging strand synthesis.

Five-Year Outcomes of Medical Management Alone for Adult Patients with Ischemic Moyamoya Disease without Cerebral Misery Perfusion.

INTRODUCTION: No clear guidelines for treating adult patients with ischemic moyamoya disease (MMD) without cerebral hemodynamic compromise such as misery perfusion have been established. Our previous prospective cohort study of adult patients with MMD without misery perfusion who were treated with medical management alone, including an antiplatelet drug, showed a recurrent ischemic event rate of 3% per 2 years. The present prospective study aimed to elucidate the 5-year clinical, cerebral perfusion, and cognitive outcomes of medical management alone for Japanese adult patients with ischemic MMD without cerebral misery perfusion by following the same patients for another 3 years. METHODS: In total, 68 patients without recurrent events at a 2-year follow-up were prospectively followed up for another 3 years. Cerebral blood flow (CBF) in the symptomatic cerebral hemisphere was measured using brain perfusion single-photon emission computed tomography at inclusion and at the end of the subsequent 3-year follow-up. Neuropsychological testing was performed at inclusion and at the end of the initial 2- and subsequent 3-year follow-ups. RESULTS: During the subsequent 3-year follow-up, 2 patients (3%) developed further ischemic events. In patients without further ischemic events, CBF was significantly greater at the end of the subsequent 3-year follow-up than at inclusion (p = 0.0037), and all neuropsychological test scores improved or remained unchanged at the end of initial 2- and subsequent 3-year follow-ups compared with that at inclusion. CONCLUSION: In adult patients receiving medical management alone for ischemic MMD without cerebral misery perfusion, the incidence of further ischemic events was 6% per 5 years and did not change between the initial 2 years after the last is-chemic event and the subsequent 3 years. In patients without further ischemic events, CBF and cognitive function had not deteriorated at 5 years after the last ischemic event.

Angiographic disease progression in medically treated adult patients with ischemic moyamoya disease without cerebral misery perfusion: supplementary analysis of a 5-year prospective cohort.

Angiographic disease progression reportedly develops in adult moyamoya disease (MMD). However, more than half of patients analyzed underwent revascularization surgery. The present supplementary analysis of a 5-year prospective cohort with follow-up using magnetic resonance angiography (MRA) and cerebral blood flow (CBF) measurements was to elucidate the incidence and clinical features of angiographic disease progression in adult patients receiving medical management alone for ischemic MMD. Sixty-eight patients without misery perfusion in the symptomatic cerebral hemispheres underwent MRA and CBF measurement using brain perfusion single-photon emission computed tomography at inclusion and at the end of the 5-year follow-up. When neurological symptoms recurred or newly developed during the 5-year follow-up period, additional MRA and CBF measurements were also performed at that time. All four patients with further ischemic events during the 5-year follow-up period exhibited angiographic disease progression on MRA at such events. Of the remaining 64 patients without further events during the 5-year follow-up period, four exhibited angiographic disease progression on MRA at the end of the 5-year follow-up. CBF was significantly lower at the time of further ischemic events or at the end of the 5-year follow-up than at inclusion in eight patients with angiographic disease progression (p = 0.0117). The incidence of angiographic disease progression was 12% for 5 years in medically treated adult patients with ischemic MMD without cerebral misery perfusion. Patients with further ischemic events always exhibited angiographic disease progression. Cerebral perfusion was reduced in patients with angiographic disease progression even when further ischemic events did not occur.

Changes in periventricular anastomosis after indirect revascularization surgery alone for adult patients with misery perfusion due to ischemic moyamoya disease.

Periventricular anastomosis in moyamoya disease (MMD) is an unusual angiographic finding that arises from perforating arteries such as the lenticulostriate artery (LSA), thalamic artery (THA), and anterior choroidal artery (AChA). This anastomosis is associated with increased hemorrhagic risk in MMD and can be corrected by direct revascularization surgery. The present supplementary analysis on a prospective cohort aimed to elucidate changes in periventricular anastomosis after indirect revascularization surgery alone for adult patients with misery perfusion due to ischemic MMD. Twenty-two patients with misery perfusion in the symptomatic cerebral hemisphere who underwent indirect revascularization surgery alone also underwent six-vessel cerebral angiography via arterial catheterization before and at 6 months after surgery. Before surgery, two patients (9%) had positive periventricular anastomosis from the LSA and another (5%) from the AChA; all three of these periventricular anastomoses regressed after surgery, but these changes were not statistically significant (p = 0.0833). The degree of formation of collateral vessels from the LSA significantly decreased after surgery (p = 0.0143), but the degree of collateral vessels from the THA or AChA did not differ between pre- and postoperative conditions. Eight patients with postoperative regression of the collateral vessels from any perforating artery exhibited postoperative rich collateral flow from indirect revascularization. Periventricular anastomosis tended to regress after indirect revascularization surgery alone for adult patients with misery perfusion due to ischemic MMD. Collateral vessels formed from the LSA likely regressed after indirect revascularization surgery alone for such patients, but those vessels from the THA or AChA seldom changed.

Delayed development of cerebral atrophy after cerebral hyperperfusion following arterial bypass for adult patients with ischemic moyamoya disease: supplementary analysis of a 5-year prospective cohort.

BACKGROUND: Adult patients with moyamoya disease (MMD) occasionally exhibit cerebral hyperperfusion after arterial bypass surgery, leading to persistent cognitive decline. The present supplementary analysis of a prospective 5-year cohort study aimed to determine whether cerebral hyperperfusion after arterial bypass surgery for adult patients with misery perfusion due to ischemic MMD causes cerebral atrophy, and whether the development of cerebral atrophy is related to persistent cognitive decline. METHODS: In total, 31 patients who underwent arterial bypass surgery also underwent fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and neuropsychological testing before surgery and at the end of a 5-year follow-up. The development of cerebral hyperperfusion and hyperperfusion syndrome after surgery was defined based on brain perfusion single-photon emission computed tomography (SPECT) findings and clinical symptoms. Univariate and multivariate logistic regression analyses of factors related to the development of cerebral atrophy on FLAIR MRI or cognitive decline on neuropsychological testing at the end of the 5-year follow-up were performed. RESULTS: Eleven patients (35%) developed cerebral atrophy in the frontal lobe where the superficial temporal artery was anastomosed. Cerebral hyperperfusion on brain perfusion SPECT (odds ratio [OR], 50.6; p = 0.0008) or cerebral hyperperfusion syndrome (OR, 41.8; p = 0.0026) was independently associated with the development of cerebral atrophy, and cerebral atrophy development was significantly associated with cognitive decline (OR, 47.7; p = 0.0010). CONCLUSIONS: Cerebral hyperperfusion after arterial bypass surgery for adult patients with misery perfusion due to ischemic MMD can cause cerebral atrophy related to persistent cognitive decline.

Outcomes of Medical Management Alone for Adult Patients with Cerebral Misery Perfusion Due to Ischemic Moyamoya Disease.

OBJECTIVES: Although revascularization surgery is recommended for adult patients with moyamoya disease (MMD) who present with ischemic symptoms due to hemodynamic compromise, the clinical course of such patients who are treated with medical management alone remains unclear. Here, we report outcomes of adult patients with cerebral misery perfusion due to ischemic MMD who received medical management alone. MATERIALS AND METHODS: We prospectively followed up patients who showed misery perfusion in the symptomatic cerebral hemisphere on 15O gas positron emission tomography (PET) and received strict medical management alone after refusing revascularization surgery. RESULTS: Of 57 patients who showed symptomatic misery perfusion on 15O gas PET, three (5%) were included into the present study. Two of these patients suffered further ischemic events at 7 and 8 months after inclusion, after which, their modified Rankin disability scale scores deteriorated. In the remaining patient, fatal intracerebral hemorrhage developed at 10 months after inclusion. CONCLUSIONS: These findings suggest that receiving medical management alone is associated with considerably poor outcomes for adult patients with cerebral misery perfusion due to ischemic MMD.

De Novo Cerebral Microbleeds and Cognitive Decline in Cerebral Hyperperfusion After Direct Revascularization for Adult Moyamoya Disease.

OBJECTIVES: Adult patients with moyamoya disease (MMD) occasionally develop cognitive decline due to cerebral hyperperfusion following direct revascularization surgery. However, how the hyperperfusion phenomenon contributes to declines in cognitive function remains unclear. The present supplementary analysis of a prospective study aimed to determine whether cerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion leads to development of de novo cerebral microbleeds (CMBs) and whether postoperative cognitive decline is related to these CMBs. MATERIALS AND METHODS: In total, 32 patients who underwent direct revascularization surgery also underwent T2*-weighted magnetic resonance imaging (T2*WI) and neuropsychological testing before and 2 months after surgery. Development of cerebral hyperperfusion and hyperperfusion syndrome following surgery was defined based on brain perfusion single-photon emission computed tomography (SPECT) findings and clinical symptoms. RESULTS: Cerebral hyperperfusion on brain perfusion SPECT (95% confidence interval [CI], 1.1-10.8; p = 0.0175) or cerebral hyperperfusion syndrome (95%CI, 1.3-15.3; p = 0.0029) was significantly associated with postoperatively increased CMBs on T2*WI. Postoperatively increased CMBs were significantly associated with postoperative cognitive decline (95%CI, 1.8-20.4, p = 0.0041). For patients with cerebral hyperperfusion on brain perfusion SPECT, the incidence of postoperative cognitive decline was significantly greater in patients with than in those without postoperatively increased CMBs (p = 0.0294). CONCLUSIONS: Cerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion contributes to the development of de novo CMBs and postoperative cognitive decline is related to these CMBs.

Assessment of Impaired Cerebrovascular Reactivity in Chronic Cerebral Ischemia using Intravoxel Incoherent Motion Magnetic Resonance Imaging.

BACKGROUND: The severity of chronic cerebral ischemia can be assessed using cerebrovascular reactivity (CVR) to acetazolamide (ACZ) challenge, which is measured by single-photon emission computed tomography (SPECT); however, this is an invasive method. We investigated whether intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) can assess impaired CVR in preoperative patients with chronic cerebral ischemia and compared it to SPECT-CVR. METHODS: Forty-seven patients with unilateral cervical carotid artery stenosis underwent diffusion-weighted MRI with 11 b-values in the range of 0-800 s/mm2 and cerebral perfusion SPECT with the ACZ challenge. The perfusion fraction (f) and diffusion coefficient (D) of the IVIM parameters were calculated using a bi-exponential model. The f and D values and these ratios of the ipsilateral middle cerebral artery territory against the contralateral side were compared with the CVR values of the affected side calculated from the SPECT data. RESULTS: The IVIM-f and D values in the affected side were significantly higher than those in the unaffected side (median: 7.74% vs. 7.45%, p = 0.027; 0.816 vs. 0.801 10-3mm2/s, p < 0.001; respectively). However, there were no significant correlations between the f or D values and SPECT-CVR values in the affected side. In contrast, the f ratio showed a moderate negative correlation with the SPECT-CVR values (r = -0.40, p = 0.006) and detected impaired CVR (< 18.4%) with a sensitivity/specificity of 0.71/0.90. CONCLUSION: The IVIM perfusion parameter, f, can noninvasively assess impaired CVR with high sensitivity and specificity in patients with unilateral cervical carotid artery stenosis.

NMR in target driven drug discovery: why not?

No matter the source of compounds, drug discovery campaigns focused directly on the target are entirely dependent on a consistent stream of reliable data that reports on how a putative ligand interacts with the protein of interest. The data will derive from many sources including enzyme assays and many types of biophysical binding assays such as TR-FRET, SPR, thermophoresis and many others. Each method has its strengths and weaknesses, but none is as information rich and broadly applicable as NMR. Here we provide a number of examples of the utility of NMR for enabling and providing ongoing support for the early pre-clinical phase of small molecule drug discovery efforts. The examples have been selected for their usefulness in a commercial setting, with full understanding of the need for speed, cost-effectiveness and ease of implementation.

Comparison of Subjective and Objective Assessments on Improvement in Gait Function after Carotid Endarterectomy.

The purpose of the present study was to determine whether objective gait test scores obtained using a tri-axial accelerometer can detect subjective improvement in gait as determined by the patient after carotid endarterectomy (CEA). Each patient undergoing CEA for ipsilateral internal carotid artery stenosis determined whether their gait was subjectively improved at six months after CEA when compared with preoperatively. Gait testing using a tri-axial accelerometer was also performed preoperatively and six months postoperatively. Twelve (15%) of 79 patients reported subjectively improved gait. Areas under the receiver operating characteristic curve for differences between pre- and postoperative test values in stride time, cadence, and ground floor reaction for detecting subjectively improved gait were 0.995 (95% confidence interval (CI), 0.945-1.000), 0.958 (95%CI, 0.887-0.990), and 0.851 (95%CI, 0.753-0.921), respectively. Cut-off points for value differences in detecting subjectively improved gait were identical to mean -1.7 standard deviation (SD) for stride time, mean +1.6 SD for cadence, and mean +0.4 SD for ground floor reaction of control values from normal subjects. Objective gait test scores obtained using the tri-axial accelerometer can detect subjective gait improvements after CEA. When determining significant postoperative improvements in gait using a tri-axial accelerometer, optimal cut-off points for each test value can be defined.

Identification of the Distal End of Carotid Plaque Using 3-Dimensional Fast Spin Echo T1-Weighted Magnetic Resonance Plaque Imaging.

BACKGROUND: Complete removal of the distal end of the plaque is an important requirement in carotid endarterectomy (CEA) to avoid postoperative complication. Preoperative identification of the distal end of plaque contributes to complete plaque removal. Three-dimensional (3D) magnetic resonance (MR) plaque imaging has been widely used to evaluate carotid plaque characterization. The purpose of the present study was to determine whether preoperative 3D fast spin echo (FSE) T1-weighted MR plaque imaging could identify the distal end of carotid plaque. METHODS: This study was designed as a prospective cohort study. We examined 50 patients with cervical internal carotid artery (ICA) stenosis who underwent CEA. 3D-FSE T1-weighted MR plaque imaging of the affected carotid bifurcation was preoperatively performed using a 1.5-T scanner. Identification of the distal end of plaque (DEMRI) on MR plaque imaging was performed and the distance from the baseline (DistanceMRI) was measured. Intraoperatively, the superimposed distal end of carotid plaque (Esim) was marked on the ICA according to the measurement on MR plaque imaging. The actual distal end of plaque (DECEA) was then identified after arteriotomy and the difference (DifferenceCEA-MRI) between Esim and DECEA was measured. Contrast ratio of carotid plaque and tortuosity of the ICA were calculated using MR plaque imaging. RESULTS: Interobserver agreements in measurement of DistanceMRI were excellent (intraclass correlation coefficient, .955; 95% confidence interval, .922-.974). In 28 patients (56%), Esim was identical to DECEA. Mean DifferenceCEA-MRI was 1.32 ± 1.77 mm. DifferenceCEA-MRI was significantly greater with fibrotic plaque (4.14 ± 1.21 mm) than with lipid-rich or necrotic plaque (.43 ± .87 mm; P < .05) or hemorrhagic plaque (1.27 ± 1.64 mm; P < .05). Mean DifferenceCEA-MRI was significantly greater in the group with tortuosity of the ICA less than 120° (3.86 ± 1.77 mm) than in the group with greater than or equal to 120° but less than or equal to 150° (1.15 ± 1.51 mm; P < .05) or greater than150° (0.50 ± 1.10 mm; P < .05). No patients showed residual stenosis after surgery on postoperative MR angiography. CONCLUSIONS: Using 3D-FSE T1-weighted MR plaque imaging allowed identification of the distal end of carotid plaque and contributed to complete removal of the plaque, although it may be reduced for cases with low-signal-intensity plaque or severe tortuosity of the ICA.