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Severe accidental hypothermia carries high mortality and morbidity and is often treated with invasive extracorporeal methods. Continuous veno-venous hemodiafiltration (CVVHDF) is widely available in intensive care units. We sought to provide theoretical basis for CVVHDF use in rewarming of hypothermic patients. CVVHDF system was used in the laboratory setting. Heat balance and transferred heat units were evaluated for the system without using blood. We used 5L of crystalloid solution at the temperature of approximately 25°C, placed in a thermally insulated tank (representing the "central compartment" of a hypothermic patient). Time of warming the central compartment from 24.9 to 30.0°C was assessed with different flow combinations: "blood" (central compartment fluid) 50 or 100 or 150 mL/min, dialysate solution 100 or 1500 mL/h, and substitution fluid 0 or 500 mL/h. The total circulation time was 1535 minutes. There were no differences between heat gain values on the filter depending on blood flow (P = .53) or dialysate flow (P = .2). The mean heating time for "blood" flow rates 50, 100, and 150 mL/min was 113.7 minutes (95% CI, 104.9-122.6 minutes), 83.3 minutes (95% CI, 76.2-90.3 minutes), and 74.7 minutes (95% CI, 62.6-86.9 minutes), respectively (P

Early detection of kidney disease is of vital importance due to their 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 (e max Φ f>1000 nm 1000 nm ~ 60 M -1 cm -1 ), which is about 10-fold higher than that of previously reported NIR-II renal-clearable 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 ( t 1/2 ~ 6.1 h) and higher brightness than traditional PEGylated renal-clearable control fluorophores ( t 1/2 < 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.

Self‐assembling filomicelles (FMs) are of great interest to nanomedicine due to their structural flexibility, extensive systemic circulation time, and amenability to unique “cylinder‐to‐sphere” morphological transitions. However, current fabrication techniques for preparing FMs are highly variable and difficult to scale. Herein, it is demonstrated that tetrablock copolymers composed of poly(ethylene glycol)‐b‐poly(propylene sulfide) (PEG‐b‐PPS) diblocks linked by a pi‐stacking perylene bisimide (PBI) moiety permit rapid, scalable, and facile assembly of FMs via the flash nanoprecipitation (FNP) method. Coassembling the tetrablocks and PEG‐b‐PPS diblocks at different molar ratios resulted in mixed PBI‐containing FMs (mPBI‐FM) with tunable length and flexibility. The flexibility of mPBI‐FM can be optimized to decrease uptake by macrophages in vivo, leading to increased circulation time versus (−)PBI‐FM without PBI tetrablocks after intravenous administration in mice. While PEG‐b‐PPS diblocks form FM within a narrow range of hydrophilic weight fractions, incorporation of pi‐stacking PBI groups expanded this range to increase favorability of FM assembly. Furthermore, the aggregation‐dependent fluorescence of PBI shifted during oxidation‐induced “cylinder‐to‐sphere” transitions of mPBI‐FM into micelles, resulting in a distinct emission wavelength for filamentous versus spherical nanostructures. Thus, incorporation of pi‐stacking allows for rapid, scalable assembly of FMs with tunable flexibility and stability for theranostic and nanomedicine applications.

The search for more efficient therapeutic strategies and diagnosis tools is a continuous challenge. Advances in understanding the biological mechanisms behind diseases and tissues regeneration have widened the field of applications of particulate systems. Particles are no more just protective systems for the encapsulated drugs, but they play an active role in the success of the therapy. Moreover, particles have been explored for innovative purposes as templates for cells growth and as diagnostic tools. Until few years ago the most relevant parameters in particles formulation were the chemistry and the size. Currently, it is known that other physical characteristics can remarkably affect the performance of particulate systems. Particles with non-conventional shapes exhibit advantages due to the increasing circulation time in blood stream, less clearance by the immune system and more efficient cell internalization and trafficking. Creation of compartments has been found useful to control drug release, to tune the transport of substances across biological barriers, to supply the target with more than one bioactive agent or even to act as theranostic systems. It is expected that such complex shaped and compartmentalized systems improve the therapeutic outcomes and also the patient's compliance, acting as advanced devices that serve for simultaneous diagnosis and treatment of the disease, combining agents of very different features, at the same time. In this review, we overview and analyse the most recent advances in particle shape and compartmentalization and applications of newly designed particulate systems in the biomedical field., Ana Catarina Lima acknowledges to the Portuguese Foundation for Science and Technology (FCT) for the PhD grant SFRH/BD/71395/2010. Work supported by MICINN (SAF2014-52632-R) Spain and FEDER, as well as by the FCT project PTDC/CTM-BIO/1814/2012.

Multimodal magnetic resonance (MR) imaging, including MR angiography (MRA) and MR perfusion (MRP), plays a critical role in the diagnosis and surveillance of acute ischemic stroke. However, these techniques are hindered by the low T1 relaxivity, short circulation time, and high leakage rate from vessels of clinical Magnevist. To address these problems, nontoxic polyethylene glycol (PEG)ylated upconversion nanoprobes (PEG-UCNPs) are synthesized and first adopted for excellent MRA and MRP imaging, featuring high diagnostic sensitivity toward acute ischemic stroke in high-resolution imaging. The investigations show that the agent possesses superior advantages over clinical Magnevist, such as much higher relaxivity, longer circulation time, and lower leakage rate, which guarantee much better imaging efficiency. Remarkably, an extremely small dosage (5 mg Gd kg(-1) ) of PEG-UCNPs provides high-resolution MRA imaging with the vascular system delineated much clearer than the Magnevist with clinical dosage as high as 108 mg Gd kg(-1) . On the other hand, the long circulation time of PEG-UCNPs enables the surveillance of the progression of ischemic stroke using MRA or MRP. Once translated, these PEG-UCNPs are expected to be a promising candidate for substituting the clinical Magnevist in MRA and MRP, which will significantly lengthen the imaging time window and improve the overall diagnostic efficiency.

To date, only few a types of nanomedicines have been made available for clinical use even in the most common liposomal delivery systems, due to significant constraints, including poor targeting of specific cells, hindered penetration, and accelerated clearance. Various intricate designs have been generated and show improvements, while also bringing new problems. Biological cells, possessing advantages like low immunogenicity, long circulation time, receptors integration, and innate targeting capability. Herein, liposomes are innovatively functionalized with a stem cell membrane through a facile approach. The biomimetic vesicles achieve controlled release, exhibit better stability, longer circulation time, and targeted delivery. Loading with curcumin leads to enhanced survival rate of ischemic stroke mice with a single injection (from ≈30% to over 90%). The versatility of the method is verified by differently charged liposomes modification and erythrocyte membrane derived vesicles preparation. Overall, the cell membrane derived biomimetic vesicles achieve targeted delivery and versatility prepared by a facile approach, as well as effortless preparation.

The efficacy of therapeutics for brain tumors is seriously hampered by multiple barriers to drug delivery, including severe destabilizing effects in the blood circulation, the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB), and limited tumor uptake. Here, a sequential targeting in crosslinking (STICK) nanodelivery strategy is presented to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK-NPs) can sequentially target BBB/BBTB and brain tumor cells with surface maltobionic acid (MA) and 4-carboxyphenylboronic acid (CBA), respectively, and simultaneously enhance nanoparticle stability with pH-responsive crosslinkages formed by MA and CBA in situ. STICK-NPs exhibit prolonged circulation time (17-fold higher area under curve) than the free agent, allowing increased opportunities to transpass the BBB/BBTB via glucose-transporter-mediated transcytosis by MA. The tumor acidic environment then triggers the transformation of the STICK-NPs into smaller nanoparticles and reveals a secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK-NPs significantly inhibit tumor growth and prolong the survival time with limited toxicity in mice with aggressive and chemoresistant diffuse intrinsic pontine glioma. This formulation tackles multiple physiological barriers on-demand with a simple and smart STICK design. Therefore, these features allow STICK-NPs to unleash the potential of brain tumor therapeutics to improve their treatment efficacy.

BACKGROUND Determination of the volumetric oxygen transfer coefficient (kLa) is very important for bioreactor design and process analysis. Among all the methods available, the gassing-out technique is one of the simplest and most widely used for this task. However, this method is very sensitive to the probe dynamics (due to delay effects), which can lead to inaccuracy in the kLa determination. This is especially pronounced for airlift bioreactors, where the circulation time affects the initial dynamics of the assay (a transient effect). In the present work, a new method for kLa determination is proposed. RESULTS Values of kLa and the electrode response time (τe) were determined experimentally, employing the traditional gassing-out method and the method proposed here. The latter was shown to be reliable, easier to apply, and suitable for the simultaneous determination of kLa and electrode sensitivity (ke = 1/τe), without any need for additional assays. CONCLUSION The new method overcomes the effects of probe delay on kLa determination, making the procedure faster and simpler. © 2016 Society of Chemical Industry

Early diagnosis, standardized treatment, and regular monitoring are the clinical treatment principle of rheumatoid arthritis (RA). The overarching principles and recommendations of treat-to-target (T2T) in RA advocate remission as the optimum aim, especially for patients with very early disease who are initiating therapy with anti-RA medications. However, traditional anti-RA drugs cannot selectively target the inflammatory areas and may cause serious side effects due to its short biological half-life and poor bioavailability. These limitations have significantly driven the research and application of nanomaterial-based drugs in theranostics of RA. Nanomedicines have appropriate sizes and easily modified surfaces which can enhance their biological compatibility and prolong circulation time of drug-loading systems in vivo. Traditional T2T regimens cannot evaluate the efficacy of drugs in real time, while clinical drug nanosizing can realize the integration of diagnosis and treatment of RA. This review bridges clinically proposed T2T concepts and nanomedicine in an integrated system for RA early-stage diagnosis and treatment. The most advanced progress in various nanodrug delivery systems for theranostics of RA is summarized, establishing a clear path and a new perspective for further optimization of T2T. Finally, the key facing challenges are discussed and prospects are addressed.

Controllable biomineralization modification of cisplatin can alter the drug biodistribution with extended circulation time in blood. These changes increase passive tumor target and decrease non-specific accumulation significantly, which can improve chemotherapeutic effect with minimum side effects.

Purpose: Microbubble contrast agents are currently implemented in a variety of both clinical and preclinical ultrasound imaging studies. The therapeutic and diagnostic capabilities of these contrast agents are limited by their short in-vivo lifetimes, and research to lengthen their circulation times is on going. In this manuscript, observations are presented from a controlled experiment performed to evaluate differences in circulation times for lipid shelled perfluorocarbon-filled contrast agents circulating within rodents as a function of inhaled anesthesia carrier gas. Methods: The effects of two common anesthesia carrier gas selections - pure oxygen and medical air were observed within five rats. Contrast agent persistence within the kidney was measured and compared for oxygen and air anesthesia carrier gas for six bolus contrast injections in each animal. Simulations were performed to examine microbubble behavior with changes in external environment gases. Results: A statistically significant extension of contrast circulation time was observed for animals breathing medical air compared to breathing pure oxygen. Simulations support experimental observations and indicate that enhanced contrast persistence may be explained by reduced ventilation/perfusion mismatch and classical diffusion, in which nitrogen plays a key role by contributing to the volume and diluting other gas species in the microbubble gas core. Conclusion: Using medical air in place of oxygen as the carrier gas for isoflurane anesthesia can increase the circulation lifetime of ultrasound microbubble contrast agents. Copyright © 2011 John Wiley & Sons, Ltd.

Neutrophils, the most abundant leukocytes (50-70% of the total leukocytes in circulation), are the major type of cells recruited to sites of inflammation during infection and tumorigenesis, suggesting that neutrophils could contribute to nanotherapeutics for inflammation and cancer therapy. Neutrophil-based delivery has shown great potential in circumventing nanotherapeutics limitations, such as low biocompatibility, short circulation time, and immunogenicity of nanomaterials. In this review, the current development of neutrophil-based nanotherapeutic drugs in the treatment of inflammatory diseases and cancers is summarized. These successful neutrophil-based nanotherapeutic systems indicate that introducing functional nanomaterials into neutrophils and neutrophil-based vesicles may be a promising strategy for improving the nanotherapeutics in more complex conditions. The integration between neutrophils and nanomaterials will create more opportunities for future materials and medical studies.

Type I interferons (IFN) are cytokines with many functions and have been widely used to treat many human diseases such as hepatitis C virus (HCV) infection. By the use of viral transformation and priming properties of Epstein-Barr virus (EBV), we have developed a system that can produce high levels of “personalized” IFNs, which are produced from the cells of the patient to whom the IFNs are to be administrated. We demonstrate the feasibility of the system. This seems to be the first report for the establishment of a personalized IFN production system. The personalized IFNs could have longer circulation time, fewer side-effects but higher efficacy. We anticipate that the system can provide an improved form of IFN for medical uses.

FeCo-graphitic carbon shell nanocrystals are a novel MRI contrast agent with unprecedented high per-metal-atom-basis relaxivity (r(1) = 97 mM(-1) sec(-1), r(2) = 400 mM(-1) sec(-1)) and multifunctional capabilities. While the conventional gadolinium-based contrast-enhanced angiographic magnetic MRI has proven useful for diagnosis of vascular diseases, its short circulation time and relatively low sensitivity render high-resolution MRI of morphologically small vascular structures such as those involved in collateral, arteriogenic, and angiogenic vessel formation challenging. Here, by combining FeCo-graphitic carbon shell nanocrystals with high-resolution MRI technique, we demonstrate that such microvessels down to approximately 100 mum can be monitored in high contrast and noninvasively using a conventional 1.5-T clinical MRI system, achieving a diagnostic imaging standard approximating that of the more invasive X-ray angiography. Preliminary in vitro and in vivo toxicity study results also show no sign of toxicity.

Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Better melanoma therapies that are effectively delivered to tumors with minimal toxicity for patients are urgently needed. Nanotechnologies provide one approach to encapsulate therapeutic agents leading to improvements in circulation time, enhanced tumor uptake, avoidance of the reticulo-endothelial system, and minimization of toxicity. Liposomes in particular are a promising nanotechnology that can be used for more effective delivery of therapeutic agents to treat melanoma. Liposomes delivering chemotherapies, siRNA, asODNs, DNA, and radioactive particles are just some of the promising new nanotechnology based therapies under development for the treatment of melanoma that are discussed in this review.

Summary. Recombinant activated factor VII (rFVIIa) is an effective treatment of the haemophilia patient with inhibitors and acquired haemophilia. However, on account of its relatively short half-life (HL), achieving therapeutic efficacy with FVIIa requires repeated injections. The development of a long-acting FVIIa product would therefore be beneficial. The formulation of factor VIII with PEGylated liposomes (PEGLip) was previously shown to extend the bleeding-free period in haemophilia patients. We report here an enhancement of haemostatic efficacy by similarly formulating FVIIa with PEGLip. Surface plasmon resonance analysis indicated that FVIIa binds non-covalently but with high affinity and specificity to PEGLip. A one-stage clotting assay demonstrated that formulation of FVIIa with PEGLip does not affect FVIIa activity and stability. A pharmacokinetic study in rats demonstrated that PEGLip formulation of FVIIa extends circulation time and results in higher FVIIa levels several hours after injection. Thromboelastography experiments indicated that PEGLip-FVIIa induces faster clot formation and higher clot stability than standard formulated FVIIa. These results suggest that formulation of FVIIa with PEGLip may lead to a safe and effective long-acting FVIIa that improves the care of haemophilic patients with inhibitors and acquired haemophilia.

Purpose To dynamically resolve the inlet arteries and outlet veins of the spinal cord, particularly the Adamkiewicz artery (AKA) and great anterior radiculomedullary vein (GARV), using MR angiography (MRA). Materials and Methods First, conventional two-phase angiography (acquisition time = 38–55 seconds) utilizing elliptic centric k-space ordering was applied to aortic-aneurysm patients. Changes of vessel intensity were compared between two subsequent dynamic phases. Computer modeling of bolus enhancement and k-space sampling was performed to demonstrate the relation between vessel enhancement, acquisition time, and vessel diameter. Second, time-resolved (TR, or “keyhole”) angiography using a reduced number of phase-encoding steps was explored in healthy volunteers and aortic-aneurysm patients using acquisition times (range = 6–8.5 seconds) shorter than the spinal cord circulation time. Results Using two-phase angiography the AKA and GARV were covisualized in the early phase, and contrast decreased for the AKA and increased for the GARV in most (70%) but not all cases. Computer modeling showed that the arteriovenous contrast strongly depended on vessel diameter, and complete separation was only obtained with short acquisition times. Using TR MR angiography (TR-MRA), complete temporal separation of the AKA and GARV was realized in all cases (100%). Conclusion The AKA and GARV can be completely separated by TR-MRA. J. Magn. Reson. Imaging 2007;26:31–40. © 2007 Wiley-Liss, Inc.

Machine parameters that possibly influence the dye-uptake rate on textile jet dyeing equipment are reviewed in this study. Some of these parameters can be adjusted on a pilot-scale jet machine so as to reproduce bulk conditions, whereas others cannot. It was impossible, for example, to simultaneously achieve appropriate values for the nozzle flow velocity and the dyebath circulation time. The fabric-liquor interchange in the storage area of the machine was also different on pilot scale and on bulk scale. Experiments on a pilot machine with a direct dye on cotton yielded, for most cases, no influence of fabric speed and dyebath flow rate on the dye-uptake rate despite high substantivity conditions. Only when the flow rate dropped below 50 dm 3 min - 1 kg -1 , the exhaustion rate diminished approximately proportionally to the square root of the flow rate, probably because of dye depletion in the storage chamber. On the pilot machine, the jet nozzle did not appear to contribute to the overall fabric-liquor interchange. Implications for bulk jet dyeing machines are discussed.

The vesicle is one of the most intriguing platforms for drug delivery, which is believed to improve drug efficacy. In the past few decades, a great deal of materials have been explored to make vesicles, including lipids, block copolymers, dendrons, erythrocyte membranes, and even DNA. Other than shape and size control, most efforts are focused on achieving certain functions, for example, an abundance of stimuli-responsive features are introduced to vesicles, which can be applied to controllable release, such as pH, redox, light, radiation, enzyme etc. Besides, crosslinking or pegylation is used to increase vesicles' stability and elongate circulation time. By incorporating affinity ligands, vesicles can further accumulate to diseased cells or tissues to achieve targeting properties. Recently, multidrug delivery is believed to show a synergy effect in cancer therapy and has become a new direction in this field. However, coloading hydrophilic-hydrophobic small molecules, oligonucleotides, and peptides in the same size- and shape-controlled vesicle through a stepwise manner with high efficiency is still challenging. Herein, a modularly designable vesicle is reported for sequential multiple loading based on frame-guided assembly, which is believed to be an outstanding platform for drug delivery in the future.

Transfer of MPEG1900-DSPE from micellar phase to pre-formed liposomes imparts long in vivo circulation half-life to an otherwise rapidly cleared lipid composition. MPEG1900-DSPE transfers efficiently and quickly in a time and temperature dependent manner. There is negligible content leakage and a strong correlation between assayed mol% MPEG1900-DSPE, liposome diameter increase, and pharmacokinetic parameters such as distribution phase half-life. Since a biological attribute (liposome clearance rate) can be modified by the insertion process, it suggests a simple and economical way to impart site-specific targeting to a variety of liposome delivery systems. This method is also a convenient way to measure the ‘brush’ thickness of such conjugates directly.

Nanomedicine is the biomedical application of nanoscale materials for diagnosis and therapy of disease. Recent advances in nanotechnology and biotechnology have contributed to the development of multifunctional nanoparticles as representative nanomedicine. They were initially developed to enable the target-specific delivery of imaging or therapeutic agents for biomedical applications. Due to their unique features including multifunctionality, large surface area, structural diversity, and long circulation time in blood compared to small molecules, nanoparticles have emerged as attractive preferences for optimized therapy through personalized medicine. Multimodal imaging and theragnosis are the cutting-edge technologies where the advantages of nanoparticles are maximized. Because each imaging modality has its pros and cons, the integration of several imaging agents with different properties into multifunctional nanoparticles allows precise and fast diagnosis of disease through synergetic multimodal imaging. Moreover, nanoparticles are not only used for molecular imaging but also applied to deliver therapeutic agents to the disease site in order to accomplish the simultaneous imaging and therapy called theragnosis. This tutorial review will highlight the recent advances in the development of multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine.

Protein therapeutics represent a powerful class of clinically approved drugs for the prevention and treatment of various diseases. Once administered, the biological fate of protein therapeutics is governed by the body's various complex biochemical and biophysical clearance mechanisms, several of which may decrease the drug's circulation time and efficiency. In this tutorial review, we introduce the concepts of physiological protein clearance from the body, and describe several chemical modification and protein engineering approaches used to improve the life span of administered protein therapeutics.

Mixing behaviour of submersed reactors. New improved measuring techniques lead to new insights into the local mixing behaviour of submerse reactors. As exemplified by airlift tower loop reactors, it is shown that it is possible to obtain more information from gas residence time distributions if the signal-to-noise ratio of the measurement can be improved significantly. Additional information is obtained, e.g., on that part of the gas recirculated around the loop or the circulation time of the gas phase. The recirculated gas significantly influences the gas backmixing in such reactors. A more thorough investigation of the gas phase motion requires locally resolved data. For the properties of the gas phase, local measuring techniques are available, which allow for measurements of the mean bubble velocity profile even during production runs in large aerated stirred tank reactors. The results show that the gas backmixing is acutely dependent on the viscosity of the continuous liquid phase. Complementary measurements on the properties of the continuous liquid phase can be investigated by means of the heat-pulse-technique. This also is applicable in real media, e.g., during biotechnological cultivation runs. Besides the measurement of the mean liquid velocity, one can, furthermore, obtain some information on the locally dominating mixing mechanism. One significant result of such investigations is that in the airlift reactors investigated the bubble-wake mixing mechanism dominates, whereas the isotropic turbulence in terms of the statistical turbulence theory plays a secondary role. This even holds at very high energy inputs.

The hydrodynamic behavior of a bubble column has been studied for various Newtonian and non-Newtonian liquids (water, glycerol, carboxymethylcellulose and polyacrylamide solutions). The mixing time, the power consumption, the circulation time and the gas hold-up have been measured in a cylindrical column (diameter: 0.254 m, height: 0.9 m) for three air sparger plates with different numbers and distributions of 1 mm diameter orifices. It is shown that the mixing efficiency decreases as the viscosity or the shear-thinning and elastic properties of the liquid increase. The viscosity of the liquid has little influence on the gas hold-up which is, however, strongly affected by the sparger plate characteristics and increases as the liquid phase becomes more elastic. A model for predicting gas hold-up is proposed. Le comportement hydrodynamique d'une colonne a bulles utilisant differents liquides newtoniens et non-newtoniens (eau, glycerol, solutions de carboxymethylcellulose et de polyacrylamide) a ete etudie. Le temps dc melange, la puissance dissipee, le temps de circulation et le taux de vide ont ete determines dans une colonne cylindrique (diametre: 0.254 m, hauteur: 0.9 m). Trois differents types de distributeur d'air ont ete utilises. Tous possedent des orifices de I mm de diametre, mais le nombre et la repartition des orifices different de l'un a l'autre. On constate que l'efficacite de l'action de melange decroit lorsque la viscosite du liquide augmente ou lorsque ses proprietes rheofluidisantes et elastiques deviennent plus importantes. La viscosite du liquide a peu d'influence sur le taux de vide observe qui, par contre, varie beaucoup selon le type de plaque distributrice utilise et augmente avec le caractere elastique du liquide. Un modele pour la prediction du taux de vide est propose.

The Oldendorf "brain uptake index" method for estimating and characterizing the transport of circulating substances across the blood-brain barrier in the rat has been widely applied. The present study illustrates that minimizing the volume injected into the circulation to 10 microliters or less is necessary. Otherwise the flow artefacts, induced by the injected volume and the rate of injection, will influence the index. This principle is also relevant to techniques using intracarotid injections for the direct study of cerebral blood flow. The study also elucidates the need for reducing the circulation time after injection to about 5 sec, to avoid artefacts due to metabolism and back diffusion to the circulation of the substances studied.

Mixing time and power consumption have been measured in baffled, paddle-agitated cylindrical tanks with single- and double-impellers, and mixing efficiency has been defined by a reciprocal of the product of the mixing time and power consumption. The mixing efficiency and mixing time of double-impeller agitation have been compared with those of single-impeller agitation, and they have been related, through a circulation time, to the flow patterns obtained from the measurements of mean axial and radial velocities.

Measurements of the circulation time during batch mixing of Newtonian and non-Newtonian fluids were used to analyse and compare the performance of six different helical-ribbon impellers and a screw impeller inside a draft coil. The distribution of circulation times obtained from two hundred repeated measurements is shown to depend markedly on the impeller geometry. Mixing time data with the helical-ribbon impellers are correlated with the mean value and the reduced standard deviation of the circulation times. Effective (rapid) mixing corresponds to a large circulation capacity and a wide distribution of the circulation times. The mixing mechanism of Newtonian fluids with the helical-ribbon impellers is qualitatively described by the Voncken model. The helical impellers' circulation capacities are not affected by the shear-thinning properties of non-Newtonian fluids. However, in highly shear-thinning fluids, the presence of important stagnant zones is responsible for much longer mixing times which consequently do not correlate with the circulation parameters. The relative efficiencies of the different impellers in Newtonian fluids are compared using a criterion based on the the total energy required to achieve a certain degree of mixing. The wide blade impeller is the most efficient of the helical-ribbon impellers but is considerably less efficient than the screw impeller in a draft coil.

Using autologous s e r u m as medium, localized leukocyte mobilization into a plastic chamber at the site of mechanical abrasion was quantified in 5 patients with florid CML, one patient with chronic eosinophilic leukemia in the florid state, 3 patients (5 studies) with CML and partial response (remission or relapse), 6 patients with CML in good remission, and in 7 patients with CML in the blastic phase. The cumulative total number of cells was expressed as totaI leukocyte mobilization (TLM) x lOS/cm~ at 24 hrs. Leukocyte dearance/cm2 in 24 hrs. was expressed in milliliters of blood and was obtained by dividing TLM (corrected for non-granulocytes) by the absolute granulocyte count in the peripheral blood. Although the median TLM was found to be elevated in CML with florid disease (130 x 106/cm2 at 24 hrs.) and in CML with partial remission and relapse (104 x lw), it fell to 74 x 106 in 6 patients in remission. This is to be compared with the median TLM for 46 normal subjects (76 x IW/cm2 at 24 hrs.). Median leukocyte clearances showed the lowest values in CML in the florid state (1.0 ml/cmz in 24 hrs), improving to 4.4 ml when a partial response was present, and to 9.3 ml in remission. This compares with 19.7 ml/cm2 in 24 hours for 46 normal subjects. The median T L M in 7 patients with CML in blastic phase was 14 x 1Oe/cm2 a t 24 h, and the leukocyte clearance was reduced to 1.4 ml. These data suggest a defeft in cell-migration in all stages of CML, which is inversely correlated with clinical state. The data reinforce the reported prolongation of circulation time of leukocytes in CML, and suggest a mechanism for this in the impaired ability of CML leukocytes to migrate across the vessel wall.

The relationship between drop size and location in an agitated liquid-liquid system was investigated, with a new sampling method in which the dispersion was sampled in a specially designed trap and immediately encapsulated by a polymer film. The liquid-liquid system used was water and a mixture of isooctane and carbon tetrachloride with a density closed to that of the water. Dispersed phase holdup was varied from 0.025 to 0.34 volume fraction. For this system, which has low mutual sulubility and high interfacial tension, there is almost no dependence of drop size on location for the mixing geometries studied. This was due to the fact that the coalescence rate is low compared to the circulation time. An increase in impeller speed and drop size decreased the coalescence rate while an increase in holdup increased it. The mean drop diameter was related to the Weber number and holdup by an equation. By comparison of mean drop diameters obtained using different impellers, it was shown that the criterion of equal power per volume can be used for estimating drop size when going from one mixing geometry ot another, not too different, geometry at moderate impeller speeds.

Summary A short account is given of current methods- for determining the circulation time. Using the decholin method, 182 children between the ages of three and fifteen years were examined; the results are analyzed statistically and the error in the method calculated from duplicate tests. Resume Un resume des methodes courantes de determination du temps de la circulation est donne. 182 enfants, de 3 a 15 ans, ont ete examines au moyen de la methode decholine; les resultats sont calcules statistiquement et l'erreur de la methode est calculee a l'aide de tests doubles. Zusammenfassung Ein kurzer Bericht wird gegeben uber die gebrauchlichen Methoden zur Bestimmung der Umlaufszeit. Unter Anwendung der Decholin-Methode wurden 182 Kinder zwischen 3 und 15 Jahren untersucht. Die Resultate wurden statistisch analysiert, und der Fehler in der Methode wurde mittels doppelter Versuchen berechnet. Sumario Se da un breve informe sobre los metodos corrientes para determinar el tiempo de circulacion. Usando el metodo decolino, se examinaron 182 ninos de entre 3 y 15 anos; se analizan estadisticamente los resultados y se calcula el error del metodo mediante ensayos duplicados.

Summary. A new formula for calculation of cardiac output by dilution method is developed by means of integration of the area included under the exponential curve. An analogous one is proposed for calculation of mean circulation time.