Identification of the Proteins Determining the Blood Circulation Time of Nanoparticles.

The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the in vivo circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time. SPIONs with neutral and positive charges showed the longest and shortest circulation times, respectively. The most striking observation was that corona-coated NPs with similar opsonin/dysopsonin content showed different circulation times, implying these biomolecules are not the only contributing factors. Long-circulating NPs adsorb higher concentrations of osteopontin, lipoprotein lipase, coagulation factor VII, matrix Gla protein, secreted phosphoprotein 24, alpha-2-HS-glycoprotein, and apolipoprotein C-I, while short-circulating NPs adsorb higher amounts of hemoglobin. Therefore, these proteins may be considered to be determining factors governing the NP systemic circulation time.

Circulation Time-Optimized Albumin Nanoplatform for Quantitative Visualization of Lung Metastasis via Targeting of Macrophages.

The development of molecular imaging probes to identify key cellular changes within lung metastases may lead to noninvasive detection of metastatic lesions in the lung. In this study, we constructed a macrophage-targeted clickable albumin nanoplatform (CAN) decorated with mannose as the targeting ligand using a click reaction to maintain the intrinsic properties of albumin in vivo. We also modified the number of mannose molecules on the CAN and found that mannosylated serum albumin (MSA) harboring six molecules of mannose displayed favorable pharmacokinetics that allowed high-contrast imaging of the lung, rendering it suitable for in vivo visualization of lung metastases. Due to the optimized control of functionalization and surface modification, MSA enhanced blood circulation time and active/passive targeting abilities and was specifically incorporated by mannose receptor (CD206)-expressing macrophages in the metastatic lung. Moreover, extensive in vivo imaging studies using single-photon emission computed tomography (SPECT)/CT and positron emission tomography (PET) revealed that blood circulation of time-optimized MSA can be used to discern metastatic lesions, with a strong correlation between its signal and metastatic burden in the lung.

Extracellular vesicles engineered to bind albumin demonstrate extended circulation time and lymph node accumulation in mouse models.

Extracellular vesicles (EVs) have shown promise as potential therapeutics for the treatment of various diseases. However, their rapid clearance after administration could be a limitation in certain therapeutic settings. To solve this, an engineering strategy is employed to decorate albumin onto the surface of the EVs through surface display of albumin binding domains (ABDs). ABDs were either included in the extracellular loops of select EV-enriched tetraspanins (CD63, CD9 and CD81) or directly fused to the extracellular terminal of single transmembrane EV-sorting domains, such as Lamp2B. These engineered EVs exert robust binding capacity to human serum albumins (HSA) in vitro and mouse serum albumins (MSA) after injection in mice. By binding to MSA, circulating time of EVs dramatically increases after different routes of injection in different strains of mice. Moreover, these engineered EVs show considerable lymph node (LN) and solid tumour accumulation, which can be utilized when using EVs for immunomodulation, cancer- and/or immunotherapy. The increased circulation time of EVs may also be important when combined with tissue-specific targeting ligands and could provide significant benefit for their therapeutic use in a variety of disease indications.

Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells.

Peptide receptor radionuclide therapy is used to treat solid tumors by locally delivering radiation. However, due to nephro- and hepato-toxicity, it is limited by its dosage. To amplify radiation damage to tumor cells, radiolabeled nanogels can be used. We show that by tuning the mechanical properties of nanogels significant enhancement in circulation half-life of the gel could be achieved. We demonstrate why and how small changes in the mechanical properties of the nanogels influence its cellular fate. Nanogels with a storage modulus of 37 kPa were minimally phagocytosed by monocytes and macrophages compared to nanogels with 93 kPa modulus. Using PET/CT a significant difference in the blood circulation time of the nanogels was shown. Computer simulations affirmed the results and predicted the mechanism of cellular uptake of the nanogels. Altogether, this work emphasizes the important role of elasticity even for particles that are inherently soft such as nano- or microgels.

A Bright, Renal-Clearable NIR-II Brush Macromolecular Probe with Long Blood Circulation Time for Kidney Disease Bioimaging.

Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near-infrared window (NIR-II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR-II organic renal-clearable probes are hampered by their low brightness (ϵmax Φf>1000 nm <10 M-1 cm-1 ) and limited blood circulation time (t1/2 <2 h), which impede the targeted imaging performance. Herein, we develop the aza-boron-dipyrromethene (aza-BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmax Φf>1000 nm ≈60 M-1 cm-1 ), which is about 10-fold higher than that of previously reported NIR-II renal-clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non-invasively diagnosis of renal ischemia-reperfusion injury (RIR) earlier than clinical serum-based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2 ≈6.1 h) and higher brightness than traditional PEGylated renal-clearable control fluorophores (t1/2 <2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal-to-noise ratio and extended retention time.

Lung-to-finger circulation time can be measured stably with high reproducibility by simple breath holding method in cardiac patients.

Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or < 75 years group, respectively), 0.81 and 0.84 (N = 26, ≥ or < 2.2 L/min/M2). These results show that our new method to measure LFCT is highly stable and feasible for any type of heart failure patients.

Conjugation of oxaliplatin with PEGylated-nanobody for enhancing tumor targeting and prolonging circulation.

Oxaliplatin is a platinum-based drug used in clinic for cancer chemotherapy. Despite of its success, the non-selective effect on normal cells causes severe side-effects and hampers its applications. Targeted delivery of oxaliplatin to cancer cells is an effective approach to enhance drug efficacy and reduce adverse effect. In this work, the Pt(IV) prodrug of oxaliplatin has been conjugated to poly(ethylene glycol) (PEG) modified nanobody in order to achieve tumor targeting as well as improved circulation in vivo. The Pt(IV) prodrug was site-specifically linked to an anti-epidermal growth factor receptor (EGFR) nanobody, so that the drug can be accumulated more pronounced in EGFR positive tumor cells than in normal cells. The effect of different length of PEG on the drug circulation has been investigated, while the fusion of anti-albumin nanobody was used for comparison. The result demonstrates that the prolonged drug circulation significantly increases the in vivo drug efficiency of the oxaliplatin-nanobody conjugate.

Plasmodium falciparum transcription in different clinical presentations of malaria associates with circulation time of infected erythrocytes.

Following Plasmodium falciparum infection, individuals can remain asymptomatic, present with mild fever in uncomplicated malaria cases, or show one or more severe malaria symptoms. Several studies have investigated associations between parasite transcription and clinical severity, but no broad conclusions have yet been drawn. Here, we apply a series of bioinformatic approaches based on P. falciparum's tightly regulated transcriptional pattern during its ~48-hour intraerythrocytic developmental cycle (IDC) to publicly available transcriptomes of parasites obtained from malaria cases of differing clinical severity across multiple studies. Our analysis shows that within each IDC, the circulation time of infected erythrocytes without sequestering to endothelial cells decreases with increasing parasitaemia or disease severity. Accordingly, we find that the size of circulating infected erythrocytes is inversely related to parasite density and disease severity. We propose that enhanced adhesiveness of infected erythrocytes leads to a rapid increase in parasite burden, promoting higher parasitaemia and increased disease severity.

Surface loading of nanoparticles on engineered or natural erythrocytes for prolonged circulation time: strategies and applications.

Nano drug-delivery systems (DDS) may significantly improve efficiency and reduce toxicity of loaded drugs, but a few nano-DDS are highly successful in clinical use. Unprotected nanoparticles in blood flow are often quickly cleared, which could limit their circulation time and drug delivery efficiency. Elongating their blood circulation time may improve their delivery efficiency or grant them new therapeutic possibilities. Erythrocytes are abundant endogenous cells in blood and are continuously renewed, with a long life span of 100-120 days. Hence, loading nanoparticles on the surface of erythrocytes to protect the nanoparticles could be highly effective for enhancing their in vivo circulation time. One of the key questions here is how to properly attach nanoparticles on erythrocytes for different purposes and different types of nanoparticles to achieve ideal results. In this review, we describe various methods to attach nanoparticles and drugs to the erythrocyte surface, and discuss the key factors that influence the stability and circulation properties of the erythrocytes-based delivery system in vivo. These data show that using erythrocytes as a host for nanoparticles possesses great potential for further development.

Normative distribution of posterior circulation tissue time-to-maximum: Effects of anatomic variation, tracer kinetics, and implications for patient selection in posterior circulation ischemic stroke.

The generalization of perfusion-based, anterior circulation large vessel occlusion selection criteria to posterior circulation stroke is not straightforward due to physiologic delay, which we posit produces physiologic prolongation of the posterior circulation perfusion time-to-maximum (Tmax). To assess normative Tmax distributions, patients undergoing CTA/CTP for suspected ischemic stroke between 1/2018-3/2019 were retrospectively identified. Subjects with any cerebrovascular stenoses, or with follow-up MRI or final clinical diagnosis of stroke were excluded. Posterior circulation anatomic variations were identified. CTP were processed in RAPID and segmented in a custom pipeline permitting manually-enforced arterial input function (AIF) and perfusion estimations constrained to pre-specified vascular territories. Seventy-one subjects (mean 64 ± 19 years) met inclusion. Median Tmax was significantly greater in the cerebellar hemispheres (right: 3.0 s, left: 2.9 s) and PCA territories (right: 2.9 s; left: 3.3 s) than in the anterior circulation (right: 2.4 s; left: 2.3 s, p < 0.001). Fetal PCA disposition eliminated ipsilateral PCA Tmax delays (p = 0.012). Median territorial Tmax was significantly lower with basilar versus any anterior circulation AIF for all vascular territories (p < 0.001). Significant baseline delays in posterior circulation Tmax are observed even without steno-occlusive disease and vary with anatomic variation and AIF selection. The potential for overestimation of at-risk volumes in the posterior circulation merits caution in future trials.

Red blood cell-hitchhiking chitosan nanoparticles for prolonged blood circulation time of vitamin K1.

Nanocarriers have been extensively applied for intravascular drug delivery. However, rapid clearance from circulation by mononuclear phagocyte system has limited their applications. Erythrocytes carriers are potential solutions to overcome the limitations of nanocarriers and considered to be ideal natural carriers for drug delivery because of their unique properties. The purpose of this work is to combine nanocarriers with erythrocytes carriers for sustained release and prolonged circulation time of vitamin K1. Chitosan nanoparticles loading VK1 (VK-CSNPs) were prepared using ionotropic gelation method, which was optimized using box-behnken design and response surface methodology. VK-CSNPs adsorbed onto red blood cells (RBC-VK-CSNPs) rapidly via electrostatic interactions. The exposure of phosphatidylserine, osmotic fragility and turbulence fragility of RBC loading nanoparticles were investigated to study the toxicity of nanoparticles to erythrocytes. In vivo pharmacokinetic study indicated that Cmax, AUC and MRT of RBC-VK-CSNPs group were remarkably higher than that of VK-CSNPs group. Flow cytometry showed VK-CSNPs steadily retained on the surface of RBC for a long time without affecting the circulation profiles of RBC themselves. The nanoparticles carried on RBC released drug, desorbed and were eliminated in vivo. Therefore, the circulation time of RBC-hitchhiking chitosan nanoparticles was greatly prolonged compared with nanoparticles alone. RBC-hitchhiking could be a valuable hybrid strategy for prolonging the in vivo life of nanocarriers.

Contrast-Enhanced Ultrasonography-Based Hepatic Perfusion for Early Prediction of Prognosis in Acute Liver Failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker. APPROACH AND RESULTS: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively. CONCLUSIONS: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making.

Historia de la administración de éter por vía intravenosa / History of intravenous ether administration

La anestesia con éter por vía intravenosa fue una técnica anestésica utilizada en los años iniciales del siglo XX. Tuvo una granaceptación en Alemania. En la década de los sesenta del siglo pasado fue usada en cirugía endoscópica. El éter ha sido utilizadocon éxito para estudiar los tiempos de la circulación portal. (AU)

Intravenous ether anesthesia was an anesthetic technique used in the initial years of the XX century. It was mostly used in Germany.In the sixties decade of the past century it was used for endoscopic surgery. Ether has been used successfully for the study of circulation time of portal circulation. (AU)

Altered Retinal Hemodynamics and Mean Circulation Time in Spontaneously Hypertensive Rats.

Purpose: Although it is known that the retinal arteriolar vasculature is constricted in hypertension, the details of retinal hemodynamics and perfusion of the retinal circulation have yet to be adequately characterized. Methods: Male and female spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls were anesthetized before measurements of mean arterial blood pressure and preparation for intravital microscopy of the retinal microcirculation. Retinal vascular velocities were measured with the use of fluorescent microspheres, and diameters and mean circulation times were measured after the infusion of fluorescent dextran. Arteriolar and venular shear rates were calculated from the ratio of velocity to diameter. Results: In the retinas of SHR, velocities were elevated (compared with control WKY) in arterioles, but not in venules. Both arteriolar and venular diameters were significantly smaller in SHR versus WKY, with substantial increases in shear rates. Despite a tendency toward lower retinal blood flow rates, the mean circulation time through the SHR retina was much faster than can be explained by the measured arteriolar and venular velocities. Conclusions: The pattern of hypertension-induced increases in blood velocity, dissipating from the arteriolar to venular side of the retinal circulation, indicates a potential transfer of the extra kinetic energy through the vasculature. The combination of elevated velocities through narrower retinal arterioles resulted in a markedly higher level of wall shear rate that may induce changes in the vessel wall. Finally, significantly more rapid transits through the hypertensive retina could be a result of altered blood flow distribution.

The effect of zwitterionic surface content on blood circulation time of nanocapsule.

Zwitterionic modification can prolong the blood circulation time of nanocarrier in vivo, but zwitterionic content will affect the functions of nanocarrier such as enzyme-responsive and intracellular or extracellular delivery. Therefore, it is necessary to explore the relationship between the zwitterionic content and circulation time of nanocarrier so as to figure out what content of zwitterion can enable the nanocarrier to obtain both the long blood circulation ability and other functions mentioned above. Herein, using nanocapsule as a research model, we investigated the nanocapsule modified with zwitterion of phosphorylcholine (PC) or carboxybetaine (CB) respectively, and through 1H-NMR quantification we determined the zwitterionic surface content, so as to study the effect of PC or CB surface content on blood circulation performance of nanocapsule. In vivo study showed that the nanocapsule possessed an optimal surface filling ratios range for blood circulation of 43-68% for PC and of 20-68% for CB, with the longest t1/2=37.35 h for PC-nanocapsule and t1/2=45.27 h for CB-nanocapsule. Furthermore, the protein adsorption and macrophage endocytosis experiments indicated that when the surface filling ratio reached 43% for PC-nanocapsule and 20% for CB-nanocapsule, it could effectively reduce the protein adsorption and weaken macrophage endocytosis, thus explaining the phenomenon of long circulation time of nanocapsules from the point of protein adsorption and interaction with immune cells. This study proposes a new direction for designing long-circulating nanocarrier, and provides basis for constructing enzyme-responsive and intracellular or extracellular delivery platform.

A phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug with a long circulation time and charged conversion for enhanced chemotherapy.

In recent years, zeolitic imidazolate framework-8 (ZIF-8) has become an attractive metal organic framework (MOF) material in drug delivery for cancer chemotherapy. However, as a drug delivery system, ZIF-8 still shows some disadvantages, such as short blood circulation time and poor tumor targeting, leading to reduced drug delivery efficiency and unsatisfactory treatment. Herein, we developed a phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug (DOX@ZIF-8@P(MPC-co-C7A)), and the obtained nanodrug was prepared via a charge-conversional zwitterionic copolymer coating on DOX@ZIF-8 composites. In this system, DOX was encapsulated in the framework of ZIF-8, which could reduce the drug leakage in the bloodstream. The phosphorylcholine-based zwitterionic copolymer effectively extended the blood circulation time, resulting in enhanced tumor accumulation of the nanodrug. Once the nanodrug reached the tumor site, the surface charge of the system could rapidly convert to positive, resulting in an enhanced tumor cellular uptake. Finally, in the acidic environment inside intracellular organelles, DOX will be released rapidly for chemotherapy owing to the fast disintegration of ZIF-8 frameworks. Therefore, the obtained nanodrug could effectively inhibit the growth of A549-bearing tumors (93.2% tumor inhibition rate) with negligible side effects. Overall, this work significantly improved the drug delivery efficiency of ZIF-8, which may pave the way for the biomedical applications of ZIF-8 crystals in anti-tumor drug delivery.

Characterization of lung-to-finger circulation time in sleep study assessment: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: Lung-to-finger circulation time (LFCT) measured from sleep studies may reflect underlying cardiac dysfunction. We aimed to examine the distribution of LFCT in community-dwelling men and women in order to better understand the factors determining LFCT between and within subjects. APPROACH: We included participants of the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep with polysomnography-based evidence of sleep apnea (defined by apnea hypopnea index >15 hr-1). In a randomly selected subset of the analytical dataset, we tested an automated LFCT measurement method against the visual method. Using the automated method we then scored LFCTs from all eligible respiratory events for all included participants. A multiple regression model was constructed to determine factors independently associated with average LFCT across subjects. We also explored factors that are associated with LFCT within subjects using linear mixed-effect models. MAIN RESULTS: In a subset of the cohort (N = 39) there was a high correlation in average LFCT obtained by automated and visual methods (r = 0.96). In the analysis of 596 participants, men [19.6 (2.8)] (vs. women [17.9 (2.7) s], p < 0.0001) and older age (> 69 (vs. ≤ 69) had longer average LFCT (19.4 [2.8] vs. 18.5 [2.9] s, p < 0.0001). These associations persisted in multivariable analysis. No association was found with body habitus. Within subject analysis revealed trivial associations between apnea/hypopnea duration, apnea (vs. hypopnea), nadir O2 saturation and sleep stages (NREM vs. REM) and individual LFCT. SIGNIFICANCE: Automated LFCT measurement was highly correlated with visual-based LFCT measurement. In this group of community-dwelling adults, male sex and older age were associated with higher average LFCT.

Cambio en la enolasa neuroespecífica de los supervivientes de parada cardiorrespiratoria extrahospitalaria: herramienta útil para predecir el pronóstico neurológico / Change in neuron specific enolase levels in out-of-hospital cardiopulmonary arrest survivors as a simple and useful tool to predict neurological prognosis

INTRODUCCIÓN Y OBJETIVOS: La enolasa neuronal específica (ENE) es un marcador pronóstico en pacientes con parada cardiorrespiratoria extrahospitalaria (PCR-EH) tratados con hipotermia moderada terapéutica (HMT). OBJETIVOS: analizar la correlación entre cambios dinámicos en ENE y eventos principales; y determinar los tiempos de medición de ENE que mejor pronostican el estado neurológico. MÉTODOS: Estudio de cohortes multicéntrico de pacientes ingresados después de un PCR-EH con ritmo desfibrilable y tratados con HMT. Se determinó la ENE sérica en dos fechas y se calculó DELTA-ENE (%) como 100 X (DELTA-ENE 2-DELTA-ENE 1) / DELTA-ENE 1. La mortalidad y el estado neurológico, según la escala Cerebral Performance Category (CPC), se evaluaron durante la hospitalización y a los 6 meses. RESULTADOS: Se incluyeron 166 pacientes ingresados en cuatro hospitales. La mortalidad intrahospitalaria fue del 31.9%. El 58,2% tuvo buena recuperación neurológica (CPC 1-2). El incremento de ENE se asoció, en el análisis de regresión logística, con mayor mortalidad hospitalaria y peor CPC al alta y a los 6 meses (p < 0,001). DELTA-ENE positiva obtuvo un OR=9,28 (95%IC 4,40-19,57) para mortalidad, OR=11,23 (95%IC 5,24-24,11) para CPC 3-5 al alta y OR=11,14 (95% IC 5,05-24,55) para CPC 3-5 a 6 meses (p < 0,001). Una primera determinación de ENE realizada 18 a 24 horas y una segunda 69 a 77 horas después del PCR-EH, mostraron una área bajo la curva ROC buena en la predicción de CPC al alta (0,9389 y 0,9909 respectivamente, 0,8096). CONCLUSIONES: El cambio dinámico de ENE es un buen marcador de eventos clínicos después de un PCR-EH por ritmo desfibrilable en pacientes tratados con HMT. Las mediciones de ENE en intervalos específicos después del PCR-EH pueden incrementar la precisión pronóstica

INTRODUCTION AND OBJECTIVES: Neuron-specific enolase (NSE) is a prognostic marker in out-of-hospital cardiopulmonary arrest (OHCA) survivors treated with mild therapeutic hypothermia (MTH). The objectives were to analyze the correlation between dynamic changes in NSE and outcomes and to determine the measurement timing that best predicts neurological status. METHODS: Multicenter cohort study including patients admitted after shockable rhythm OHCA and treated with MTH. Serum NSE was sampled at 2 different times and DELTA-NSE (%) was calculated as 100 X (NSE2-NSE1)/NSE1. In-hospital mortality and neurological outcome, as assessed by the Cerebral Performance Category (CPC) scale, were evaluated during admission and after a 6-month follow-up. RESULTS: We included 166 patients admitted to 4 hospitals. In-hospital mortality was 31.9%. Almost 60% of patients had a good neurological recovery (CPC 1-2). On univariate and multivariate logistic regression analyses, an increase in NSE levels was associated with higher in-hospital mortality and worse CPC on discharge and after 6-months (P<.001). Positive DELTA-NSE showed an OR=9.28 (95% CI 4.40-19.57) for mortality, OR=11.23 (95% CI 5.24-24.11) for CPC 3-5 at discharge and OR=11.14 (95% CI 5.05-24.55) for CPC 3-5 after 6-months' follow-up (P<.001). The first NSE measurement, conducted at 18 to 24hours, and the second measurement at 69 to 77 hours after OHCA showed a high area under the curve in predicting CPC at discharge (0.9389 and 0.9909, respectively; 0.8096 for the whole cohort). CONCLUSIONS: Dynamic changes in NSE serum levels are good markers of hard clinical outcomes after an OHCA due to shockable rhythm in an MTH-treated cohort. NSE measurements at specific intervals after OHCA may predict events even more precisely

Change in neuron specific enolase levels in out-of-hospital cardiopulmonary arrest survivors as a simple and useful tool to predict neurological prognosis.

INTRODUCTION AND OBJECTIVES: Neuron-specific enolase (NSE) is a prognostic marker in out-of-hospital cardiopulmonary arrest (OHCA) survivors treated with mild therapeutic hypothermia (MTH). The objectives were to analyze the correlation between dynamic changes in NSE and outcomes and to determine the measurement timing that best predicts neurological status. METHODS: Multicenter cohort study including patients admitted after shockable rhythm OHCA and treated with MTH. Serum NSE was sampled at 2 different times and Δ-NSE (%) was calculated as 100 x (NSE2-NSE1)/NSE1. In-hospital mortality and neurological outcome, as assessed by the Cerebral Performance Category (CPC) scale, were evaluated during admission and after a 6-month follow-up. RESULTS: We included 166 patients admitted to 4 hospitals. In-hospital mortality was 31.9%. Almost 60% of patients had a good neurological recovery (CPC 1-2). On univariate and multivariate logistic regression analyses, an increase in NSE levels was associated with higher in-hospital mortality and worse CPC on discharge and after 6-months (P<.001). Positive Δ-NSE showed an OR=9.28 (95% CI 4.40-19.57) for mortality, OR=11.23 (95% CI 5.24-24.11) for CPC 3-5 at discharge and OR=11.14 (95% CI 5.05-24.55) for CPC 3-5 after 6-months' follow-up (P<.001). The first NSE measurement, conducted at 18 to 24hours, and the second measurement at 69 to 77hours after OHCA showed a high area under the curve in predicting CPC at discharge (0.9389 and 0.9909, respectively; 0.8096 for the whole cohort). CONCLUSIONS: Dynamic changes in NSE serum levels are good markers of hard clinical outcomes after an OHCA due to shockable rhythm in an MTH-treated cohort. NSE measurements at specific intervals after OHCA may predict events even more precisely.

Radiolabeling of cidofovir with technetium-99m and biodistribution studies

Radiolabeling cidofovir with technetium-99m (99mTc-CDV) is an innovative procedure that enables real-time monitoring of the drug. Essays were performed in vitro, showing high radiolabel stability within 24 h. Blood clearance, biodistribution studies, and scintigraphic images were performed in healthy mice in order to evaluate the profile of the drug in vivo. 99mTc-CDV showed biphasic blood circulation time and significant kidney uptake, indicating that 99mTc-CDV is preferentially eliminated by the renal route. Bones also showed important uptake throughout the experiment. In summary, cidofovir was successfully labeled with technetium-99m and might be used in further studies to track the drug.