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PubMed2005

Combining the lattice-sum and reaction-field approaches for evaluating long-range electrostatic interactions in molecular simulations.

A new scheme, the lattice-sum-emulated reaction-field (LSERF) method, is presented that combines the lattice-sum (LS) and reaction-field (RF) approaches for evaluating electrostatic interactions in molecular simulations. More precisely, the LSERF scheme emulates a RF calculation (based on an atomic cutoff) via the LS machinery. This is achieved by changing the form of the electrostatic interactions in a standard LS calculation (Coulombic) to the form corresponding to RF electrostatics (Coulombic plus quadratic reaction-field correction term, truncated at the cutoff distance). It is shown (both analytically and numerically) that in the limit of infinite reciprocal-space accuracy, (i) the LSERF scheme with a finite reaction-field cutoff and a given reaction-field permittivity is identical to the RF scheme with the same parameters (and an atomic cutoff), and (ii) the LSERF scheme is identical to the LS scheme in the limit of an infinite reaction-field cutoff, irrespective of the reaction-field permittivity. This new scheme offers two key advantages: (i) from a conceptual point of view, it shows that there is a continuity between the RF and LS schemes and unifies them into a common framework; (ii) from a practical point of view, it allows us to perform RF calculations with arbitrarily large reaction-field cutoff distances for the same computational costs as a corresponding LS calculation. The optimal choice for the cutoff will be the one that achieves the best compromise between artifacts arising from the dielectric heterogeneity of the system (short cutoff) and its artificial periodicity (long cutoff). The implementation of the LSERF method is extremely easy, requiring only very limited modifications of any standard LS code. For practical applications to biomolecular systems, the use of the LSERF scheme with large reaction-field cutoff distances is expected to represent a significant improvement over the current RF simulations involving comparatively much shorter cutoffs.

Journal Article↗
PubMed2006

A generalized discrete model linking rippling pattern formation and individual cell reversal statistics in colonies of myxobacteria.

Self-organization processes in multicellular aggregates of bacteria and amoebae offer fascinating insights into the evolution of cooperation and differentiation of cells. During myxobacterial development a variety of spatio-temporal patterns emerges such as counterpropagating waves of cell density that are known as rippling. Recently, several models have been introduced that qualitatively reproduce these patterns. All models include active motion and a collision-triggered reversal of individual bacteria. Here, we present a systematic study of a generalized discrete model that is based on similar assumptions as the continuous model by Igoshin et al (2001 Proc. Natl Acad. Sci. USA 98 14913). We find counterpropagating as well as unidirectional rippling waves in extended regions of the parameter space. If the interaction strength and the degree of cooperativity are large enough, rippling patterns appear even in the absence of a refractory period. We show for the first time that the experimentally observed double peak in the reversal statistics of bacteria in rippling colonies (Welch and Kaiser 2001 Proc. Natl Acad. Sci. USA 98 14907) can be reproduced in simulations of counterpropagating rippling waves which are dominant in experiments. In addition, the reversal statistics in the pre-rippling phase is correctly reproduced.

Biological Evolution↗
PubMed1997

Pointing at memorized targets during prolonged microgravity.

BACKGROUND: Watt et al. (15) and Young et al. (17) have demonstrated that during prolonged microgravity, large errors can be made when pointing at memorized targets in the absence of vision. However, those experiments could not distinguish between errors caused by not knowing where the arm was pointed and errors caused by not knowing target location. The primary goal of this study was to determine the relative contribution of each of these potential sources of error. HYPOTHESIS: It was hypothesized that pointing errors would be greater than pre-flight controls if vision was continuously absent during testing, but not greater than pre-flight if vision was restricted only while pointing. METHODS: Five subjects on Spacelab SLS-2 (Part A) pointed at targets while keeping their eyes closed continuously; (Part B) touched various body parts and estimated the position of their arms while the eyes remained closed; and (Part C) pointed at the same targets as in A but closed their eyes only while pointing. RESULTS: On the ground, if the eyes were closed only while pointing, pointing errors averaged 4.5 degrees. After several days n space, errors averaged 7.0 degrees (p < 0.05). Again on the ground, if the eyes were closed continuously while pointing, an additional error of 4.0 degrees was measured. However, after several days in space, the additional error was 10.5 degrees (p < 0.0005). CONCLUSIONS: The results of this study suggest that the major problem encountered when pointing at memorized targets in microgravity is a lack of knowledge of target, not limb, position.

Adaptation, Physiological↗
PubMed1997

Detection, visualization and animation of abnormal anatomic structure with a deformable probabilistic brain atlas based on random vector field transformations.

This paper describes the design, implementation and preliminary results of a technique for creating a comprehensive probabilistic atlas of the human brain based on high-dimensional vector field transformations. The goal of the atlas is to detect and quantify distributed patterns of deviation from normal anatomy, in a 3-D brain image from any given subject. The algorithm analyzes a reference population of normal scans and automatically generates color-coded probability maps of the anatomy of new subjects. Given a 3-D brain image of a new subject, the algorithm calculates a set of high-dimensional volumetric maps (with typically 384(2) x 256 x 3 approximately 10(8) degrees of freedom) elastically deforming this scan into structural correspondence with other scans, selected one by one from an anatomic image database. The family of volumetric warps thus constructed encodes statistical properties and directional biases of local anatomical variation throughout the architecture of the brain. A probability space of random transformations, based on the theory of anisotropic Gaussian random fields, is then developed to reflect the observed variability in stereotaxic space of the points whose correspondences are found by the warping algorithm. A complete system of 384(2) x 256 probability density functions is computed, yielding confidence limits in stereotaxic space for the location of every point represented in the 3-D image lattice of the new subject's brain. Color-coded probability maps are generated, densely defined throughout the anatomy of the new subject. These indicate locally the probability of each anatomic point being unusually situated, given the distributions of corresponding points in the scans of normal subjects. 3-D MRI and high-resolution cryosection volumes are analyzed from subjects with metastatic tumors and Alzheimer's disease. Gradual variations and continuous deformations of the underlying anatomy are simulated and their dynamic effects on regional probability maps are animated in video format (on the accompanying CD-ROM). Applications of the deformable probabilistic atlas include the transfer of multi-subject 3-D functional, vascular and histologic maps onto a single anatomic template, the mapping of 3-D atlases onto the scans of new subjects, and the rapid detection, quantification and mapping of local shape changes in 3-D medical images in disease and during normal or abnormal growth and development.

Anatomy, Cross-Sectional↗
PubMed1996

Anatomy of the retroperitoneum: observations of the distribution of pathologic fluid collections.

PURPOSE: To correlate anatomic dissections with clinical observations regarding anatomic distribution of retroperitoneal fluid, and to document the existence of planes that lie between classically described retroperitoneal spaces. MATERIALS AND METHODS: Latex was injected in varying amounts into the pancreatic tail in three fresh cadavers to simulate peripancreatic fluid collections. Spiral computed tomography (CT) was performed of the abdomen and pelvis after each latex injection. Two cadavers were subsequently frozen and sectioned in axial planes; limited dissections were performed on these specimens. One was embalmed and underwent extensive anatomic dissection. Five embalmed, unprepared cadavers were also dissected to confirm observations made in the three prepared cadavers. RESULTS: Latex injected into the tail of the pancreas entered a retromesenteric plane that was posterior to the anterior pararenal space and anterior to the anterior renal fascia. The plane continued superiorly, extending to the diaphragm near the esophageal hiatus; inferiorly, extending to the pelvis along the anterolateral surface of the psoas muscle; and laterally, posterior to the descending colon and its mesentery. The plane also communicated with a retrorenal plane lying between the posterior renal fascia and the posterior pararenal space. CONCLUSION: Embryologic development of the dorsal mesenteries suggests the existence of retromesenteric planes, and clinical observations further support their existence. These findings may explain the observed distribution of retroperitoneal fluid collections from diaphragm to pelvis.

Cadaver↗
PubMed2006

Online data visualization using the neural gas network.

A high-quality distance preserving output representation is provided to the neural gas (NG) network. The nonlinear mapping is determined concurrently along with the codebook vectors. The adaptation rule for codebook positions in the projection space minimizes a cost function that favors the trustworthy preservation of the local topology. The proposed visualization method, called OVI-NG, is an enhancement over curvilinear component analysis (CCA). The results show that the mapping quality obtained with OVI-NG outperforms the original CCA, in terms of the trustworthiness, continuity, topographic function and topology preservation measures.

Algorithms↗
PubMed2006

Optimal neuronal tuning for finite stimulus spaces.

The efficiency of neuronal encoding in sensory and motor systems has been proposed as a first principle governing response properties within the central nervous system. We present a continuation of a theoretical study presented by Zhang and Sejnowski, where the influence of neuronal tuning properties on encoding accuracy is analyzed using information theory. When a finite stimulus space is considered, we show that the encoding accuracy improves with narrow tuning for one- and two-dimensional stimuli. For three dimensions and higher, there is an optimal tuning width.

Action Potentials↗
PubMed2006

Parametric bootstrap for testing model fitting in the proportional hazards framework: an application to the survival analysis of Bruna dels Pirineus beef calves.

Given that correct assumptions on the baseline survival function are determinant for the validity of further inferences, specific tools to test the fit of a model to real data become essential in proportional hazards models. In this sense, we have proposed a parametric bootstrap to test the fit of survival models. Monte Carlo simulations are used to generate new data sets from the estimates obtained through the assumed models, and then bootstrap intervals can be established for the survival function along the time space studied. Significant fitting deficiencies are revealed when the real survival function is not included within the bootstrap interval. We tested this procedure in a survival data set of Bruna dels Pirineus beef calves, assuming 4 parametric models (exponential, Weibull, exponential time-dependent, Weibull time-dependent) and the Cox's semiparametric model. Fitting deficiencies were not observed for the Cox's model and the exponential time-dependent model, whereas the Weibull time-dependent model suffered from moderate overestimation at different ages. Thus, the exponential time-dependent model appears to be preferable because of its correct fit for survival data of beef calves and its smaller computational and time requirements. Exponential and Weibull models were completely rejected due to the continuous over- and underestimation of the survival probability reported. Results here highlighted the flexibility of parametric models with time-dependent effects, achieving a fit comparable to nonparametric models.

Animals↗
PubMed1986

Extracellular calcium transients at single excitations in rabbit atrium measured with tetramethylmurexide.

Extracellular calcium transients were resolved within the time course of single contraction cycles in rabbit left atrium using tetramethylmurexide (2 mM) as the calcium-sensitive dye (150-250 microM total calcium, 80-150 microM free calcium). Net extracellular calcium depletion began within 2-4 ms upon excitation; over the following 5-20 ms, depletion continued steeply and amounted to 0.2 mumol/kg wet weight X 10 ms (135 microM free extracellular calcium). In regularly excited muscles (0.5-2 Hz), net depletion slowed rapidly and stopped early during the rise of contractile motion monitored by transmitted light. Maximum depletions amounted to 0.2-0.5% of total extracellular calcium (0.2-0.5 mumol/kg wet weight with 135 microM free calcium). Replenishment of extracellular calcium began at the latest midway to the peak of the motion signal. Calcium replenishment could be complete for the most part by an early phase of relaxation or could take place continuously through relaxation. The maximal net depletion per beat decreased manyfold with a decrease of frequency from 1 to 0.05 Hz. During paired pulse stimulation (200-300-ms twin pulse separation at basal rates of 0.3-1 Hz), extracellular calcium accumulation was enhanced at the initial potentiated contraction; extracellular calcium depletion was prolonged at the low-level premature contraction. With quadruple stimulation (three premature excitations), the apparent rate of net extracellular calcium accumulation at potentiated contractions approached or exceeded the apparent rate of early net calcium depletion. Under the special circumstance of a strongly potentiated post-stimulatory contraction after greater than 5 s rest, repolarization beyond -40 mV occurred within 10 ms, net extracellular calcium accumulation began with the onset of muscle motion, and net extracellular calcium accumulation (1-3 microM/kg wet weight) coincided with a more positive late action potential in comparison with subsequent action potentials. Consistent changes of the apparent rate of early net calcium depletion were not found with any of the simulation patterns examined. In ryanodine-pretreated atria, the duration of depletion was clearly limited by action potential duration at post-rest stimulations; in the presence of 4-aminopyridine (2 mM), depletion continued essentially undiminished for up to 200 ms. The resulting net depletion magnitudes were greater than 10 times larger than the transient depletions found during steady stimulation.

Animals↗
PubMed1996

A simulation of microbial competition in the human colonic ecosystem.

Many investigations of the interactions of microbial competitors in the gastrointestinal tract used continuous-flow anaerobic cultures. The simulation reported here was a deterministic 11-compartment model coded by using the C programming language and based on parameters from published in vitro studies and assumptions were data were unavailable. The resource compartments were glucose, lactose and sucrose, starch, sorbose, and serine. Six microbial competitors included indigenous nonpathogenic colonizers of the human gastrointestinal tract (Escherichia coli, Enterobacter aerogenes, Bacteroids ovatus, Fusobacterium varium, and Enterococcus faecalis) and the potential human enteropathogen Salmonella typhimurium. Flows of carbon from the resources to the microbes were modified by resource and space controls. Partitioning of resources to the competitors that could utilize them was calculated at each iteration on the basis of availability of all resources by feeding preference functions. Resources did not accumulate during iterations of the model. The results of the computer simulation of microbial competition model and for various modifications of the model. The results were based on few measured parameters but may be useful in the design of user-friendly software to aid researchers in defining and manipulating the microbial ecology of colonic ecosystems as relates to food-borne disease.

Carbohydrates↗
PubMed1999

The relationship between synchronization among neuronal populations and their mean activity levels.

In the past decade the importance of synchronized dynamics in the brain has emerged from both empirical and theoretical perspectives. Fast dynamic synchronous interactions of an oscillatory or nonoscillatory nature may constitute a form of temporal coding that underlies feature binding and perceptual synthesis. The relationship between synchronization among neuronal populations and the population firing rates addresses two important issues: the distinction between rate coding and synchronization coding models of neuronal interactions and the degree to which empirical measurements of population activity, such as those employed by neuroimaging, are sensitive to changes in synchronization. We examined the relationship between mean population activity and synchronization using biologically plausible simulations. In this article, we focus on continuous stationary dynamics. (In a companion article, Chawla (forthcoming), we address the same issue using stimulus-evoked transients.) By manipulation parameters such as extrinsic input, intrinsic noise, synaptic efficacy, density of extrinsic connections, the voltage-sensitive nature of postsynaptic mechanisms, the number of neurons, and the laminar structure within the populations, we were able to introduce variations in both mean activity and synchronization under a variety of simulated neuronal architectures. Analyses of the simulated spike trains and local field potentials showed that in nearly every domain of the model's parameter space, mean activity and synchronization were tightly coupled. This coupling appears to be mediated by an increase in synchronous gain when effective membrane time constants are lowered by increased activity. These observations show that under the assumptions implicit in our models, rate coding and synchrony coding in neural systems with reciprocal interconnections are two perspectives on the same underlying dynamic. This suggests that in the absence of specific mechanisms decoupling changes in synchronization from firing levels, indexes of brain activity that are based purely on synaptic activity (e.g., functional magnetic resonance imaging) may also be sensitive to changes in synchronous coupling.

Brain↗
PubMed2005

Microsurgical skills training: a new concept for simulation of vessel-wall suturing.

Initiation of training in basic microsurgical suturing technique usually involves placing sutures on incisions made on latex sheets, and then progressing to a live anastomosis in a rat model. A straight incision resembles a skin incision and does not mechanically simulate vessel wall suturing, and various modifications and innovative prosthetic models continue to be developed to bring the simulation closer to a live anastomosis. We developed two models which closely simulate vessel wall suturing and require the application of similar skills by the trainee. In the first model (the "I" model), the straight 1-cm incision is converted to an I-shaped incision which increases the instability of the edge to be sutured, depending on the length of the horizontal incision, putting greater demand on dexterity in suture placement similar to a vessel. The length (1 cm) of the edge does not constrain the spacing of the sutures and can be used for the beginner. The second model (the "double triangle" model) creates a narrow and unstable edge for placing sutures, and puts greater demand on bimanual coordination and instrument control for training in accuracy of suture placement as well as spacing between sutures. Both these models are cost-effective and simple to construct.

Anastomosis, Surgical↗
PubMed2005

Effect of chain stiffness and entanglements on the elastic behavior of end-linked elastomers.

The effect of chain stiffness and entanglements on the elastic behavior and microscopic structure of cross-linked polymer networks was studied using Monte Carlo simulations. We investigated the behavior of entangled and entanglement-free networks at various degrees of chain stiffness and densities. Based on previous results that indicated that trapped entanglements prevent strain-induced order-disorder transitions in semiflexible chain networks, we prepared the entangled networks by end-linking the chains in very dilute conditions so as to minimize the extent of trapped entanglements. We also considered the entanglement-free case by using a "diamond" structure. We found that the presence of even a very small amount of trapped entanglements is enough to prevent a discontinuous strain-induced transition to an ordered phase. In these mildly entangled networks, a nematiclike order is eventually attained at high extensions but the elastic response remains continuous and the cross-links remain uniformly distributed through the simulation box. The entanglement-free diamond networks on the other hand show discontinuities in their stress-strain data. Networks at higher densities exhibit a more stable ordered phase and show an unusual staircaselike stress-strain curve. This is the result of a stepwise extension mechanism in which the chains form ordered domains that exclude the cross-links. Extension is achieved by increasing the number of these ordered domains in the strain direction. Cross-links aggregate in the spaces between these ordered domains and form periodic bands. Each vertical upturn in the stress-strain data corresponds to the existence of an integer number of ordered domains. This stepwise elastic behavior is found to be similar to that exhibited by some tough natural materials.

Anisotropy↗
PubMed2006

Vector-velocity estimation in swept-scan using a K-space approach.

The swept-scan technique (i.e., continuously moving a single-crystal transducer during pulse-echo data acquisition) is used in high-frequency, ultrasonic flow imaging. Relative to the conventional step-scan technique, swept scanning improves the rate of data acquisition and enables near-real-time, high-frequency color flow mapping. However, the continuous transducer movement may have non-negligible effects on accuracy of velocity estimation. This paper introduces a spatial frequency domain (i.e., k-space) approach that quantifies the effects of both lateral and axial motions in a swept scan. It is shown that the k-space representation is equivalent to a Doppler-radio frequency (RF) frequency domain representation, and that transducer movement in the swept-scan technique results in a change in Doppler bandwidth. In addition, a vector velocity estimator is developed based on the proposed k-space approach. Both simulations and flow-phantom experiments were performed to evaluate the performance of the proposed vector velocity estimator. A 45-MHz transducer was scanned at 20 mm/s. The Doppler angle ranged from 29 degrees to 90 degrees, and the flow velocities ranged from 15 to 30 mm/s. The results show that the proposed k-space vector velocity estimator exhibited a mean error of 2.6 degrees for flow-direction estimation, with the standard deviation ranging from 2.2 degrees to 8.2 degrees. In comparison, for the conventional spectral-broadening-based vector velocity estimator ignoring the swept-scan effect, the mean error became 15 degrees and the standard deviations were from 2.7 degrees to 6.6 degrees.

Algorithms↗
PubMed1996

Cognitive fatigue and complex decision making under prolonged isolation and confinement.

Cognitive fatigue and subjective state were assessed in four healthy subject (three males and one female), confined for a period of 60 days in a hyperbaric chamber stimulating a space station environment. They were required to carry out daily a working memory/decision-making test, simulating the management of the levels of contaminants present in a spacecraft atmosphere. Information about a set of contaminants is presented on a 'reference screen.' This has to be memorized, then used to make decisions about the need for corrective action across a sequence of four 'status screens.' Subjects may check back to the reference information at any time. A low error rate was emphasized in the instructions and training. In addition to error rate, performance was also measured in terms of the time taken to make decisions and checks of reference screens (decision time and check time). Subjective measures were also made of workload and environmental resources (personal control and support), levels of anxiety and fatigue before the task, and cognitive effort expended during the task. The search for decrements during the second half of the isolation period was complicated by evidence of a continued learning process during the first half, probably because of insufficient practice before isolation. Learning curves (negative exponential functions) were fitted to the data points for the first half of the isolation period, and residuals between predicted and observed data for the second four weeks were analyzed. All subjects showed increases in decision time and check time during the last weeks of isolation, with one subject also showing an increase in errors. Workload levels were reported as moderate, but varied across the four subjects, The same was true for resources. Anxiety was low and relatively stable over the entire 60-day period, but fatigue levels were elevated during the second half. This was particularly true for the two subjects who maintained the required low error rate. Effort was also quite stable, through it tended to follow changes in work demands and fatigue. Individual subjects are seen to adapt to the stress of prolonged isolation in different ways. Two subjects maintained low error rates under increasing subjective demands by additional cognitive effort and slowing of performance. The other two subjects exhibit more widespread decrement, including high error rates, without increase in subjective demands. The analysis of individual patterns of adaptation is recommended as a way of understanding and predicting the impact of isolation and confinement during spaceflights.

Adaptation, Psychological↗
PubMed2001

Broad-spectrum and selective serine protease inhibitors prevent expression of platelet-derived growth factor-BB and cerebral vasospasm after subarachnoid hemorrhage: vasospasm caused by cisternal injection of recombinant platelet-derived growth factor-BB.

BACKGROUND AND PURPOSE: Plasma serine protease cascade, including the complement system and thrombin, is activated in the subarachnoid space during the acute phase after subarachnoid hemorrhage (SAH). To examine the effect of protease cascade-based inflammation and subsequent vascular repair in the development of cerebral vasospasm, we examined the effect of 2 synthetic serine protease inhibitors-FUT-175, an inhibitor of thrombin and the complement system, and argatroban, a selective inhibitor of thrombin-on the development of cerebral vasospasm in a rabbit SAH model. METHODS: One hundred Japanese White male rabbits were used in the study. The SAH was simulated by a single injection of autologous arterial blood into the cisterna magna. To evaluate the development of cerebral vasospasm, the caliber of the basilar artery was measured on x-ray film before and at 2 days after SAH. Nine groups of rabbits (n=6 each) were treated with continuous intravenous injection of FUT-175 (2.5, 5, 10, or 20 mg/d), argatroban (1.25, 2.5, or 5 mg/d), or the same amount of saline (vehicle) for 48 hours, starting 40 minutes after SAH. Two days after SAH, the expression of homodimer of platelet-derived growth factor-BB (PDGF-BB) in the basilar artery was examined with immunohistochemical techniques. In 20 normal rabbits, 5 microg of recombinant PDGF-BB or vehicle was injected into the cisterna magna, and the basilar arteries were examined on angiograms for 48 hours. RESULTS: Significant differences were observed in the caliber of the basilar arteries between the vehicle group and the groups with the 3 larger doses of FUT-175 (vehicle, 52+/-5.0%; 5 mg, 79+/-5.7%; 10 mg, 80+/-2.5%; 20 mg, 80+/-3.7%) and between the vehicle group and the groups with the 2 larger doses of argatroban (vehicle, 52+/-6.4%; 2.5 mg, 81+/-9.0%; 5 mg, 85+/-4.1%) (P<0.05). In the histological examination, administration of effective doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the endothelial and medial smooth muscle cell layers. Exogenous PDGF-BB caused delayed and prolonged vasoconstriction on normal basilar arteries. CONCLUSIONS: Activation of the serine protease cascade and/or thrombin after SAH was demonstrated to play an essential role in the development of cerebral vasospasm. The expression of PDGF-BB-like protein in the arterial walls correlated with the development of cerebral vasospasm. Elevated PDGF-BB level in the subarachnoid space was found to induce delayed and chronic vasoconstriction.

Animals↗
PubMed2005

Continuously moving table SENSE imaging.

A combination of continuously moving table imaging and parallel imaging based on sensitivity encoding (SENSE) is presented. One specific geometry is considered, where the receiver array is fixed to the MR magnet and does not move with the table, which allows for head-to-toe imaging with a small total number of coils. Sensitivity maps are defined for the enlarged virtual field of view and are composed according to the k-space sampling scheme such that established parallel reconstruction techniques are applicable to good approximation. In vivo experiments show the feasibility of this approach, and simulations determine the application range. Three-dimensional head-to-toe imaging of volunteers is performed in 77 s with a SENSE reduction factor of 2 in a virtual field of view of 1800 x 460 x 100 mm(3).

Computer Simulation↗
PubMed1984

Insulin responses to varying profiles of subcutaneous insulin infusion: kinetic modelling studies.

Refinement of continuous subcutaneous insulin infusion for diabetes therapy requires improved knowledge of subcutaneous insulin absorption kinetics. We have used kinetic modelling to quantitate systemic insulin delivery produced by subcutaneously-infused insulin (i.e. simulated meal and basal delivery). Profiles were studied in normal subjects, with endogenous insulin suppressed. Paired studies of intravenous insulin infusion enabled systemic insulin delivery to be quantitated. High rate subcutaneous delivery (10 U in 5 min) resulted in a systemic delivery of approximately 8 U in 4 h. Increasing infused insulin concentration delayed systemic delivery (p less than 0.025). Both continuous and pulsatile low-rate infusions (2.4 U/h) gave similar slow increases in systemic delivery to 1 U after 4 h. Computer fitting to a two-pool model of the subcutaneous space suggested a low rate of insulin degradation for all profiles (rate constant less than 10%/h). We conclude that: systemic insulin delivery following subcutaneous infusion conforms reasonably to a two-pool model, subcutaneous insulin degradation is low regardless of input profile, a long delay in basal systemic delivery should be taken into account when initiating or resuming interrupted subcutaneous insulin infusion. Kinetic modelling of subcutaneous insulin absorption should be useful to predict the impact of programming strategies for continuous subcutaneous insulin infusion therapy.

Adult↗