Homogenisation for the monodomain model in the presence of microscopic fibrotic structures.

Computational models in cardiac electrophysiology are notorious for long runtimes, restricting the numbers of nodes and mesh elements in the numerical discretisations used for their solution. This makes it particularly challenging to incorporate structural heterogeneities on small spatial scales, preventing a full understanding of the critical arrhythmogenic effects of conditions such as cardiac fibrosis. In this work, we explore the technique of homogenisation by volume averaging for the inclusion of non-conductive micro-structures into larger-scale cardiac meshes with minor computational overhead. Importantly, our approach is not restricted to periodic patterns, enabling homogenised models to represent, for example, the intricate patterns of collagen deposition present in different types of fibrosis. We first highlight the importance of appropriate boundary condition choice for the closure problems that define the parameters of homogenised models. Then, we demonstrate the technique's ability to correctly upscale the effects of fibrotic patterns with a spatial resolution of 10 µm into much larger numerical mesh sizes of 100- 250 µm . The homogenised models using these coarser meshes correctly predict critical pro-arrhythmic effects of fibrosis, including slowed conduction, source/sink mismatch, and stabilisation of re-entrant activation patterns. As such, this approach to homogenisation represents a significant step towards whole organ simulations that unravel the effects of microscopic cardiac tissue heterogeneities.

Variability in electrophysiological properties and conducting obstacles controls re-entry risk in heterogeneous ischaemic tissue.

Ischaemia, in which inadequate blood supply compromises and eventually kills regions of cardiac tissue, can cause many types of arrhythmia, some life-threatening. A significant component of this is the effects of the resulting hypoxia, and concomitant hyperklaemia and acidosis, on the electrophysiological properties of myocytes. Clinical and experimental data have also shown that regions of structural heterogeneity (fibrosis, necrosis, fibro-fatty infiltration) can act as triggers for arrhythmias under acute ischaemic conditions. Mechanistic models have successfully captured these effects in silico. However, the relative significance of these separate facets of the condition, and how sensitive arrhythmic risk is to the extents of each, is far less explored. In this work, we use partitioned Gaussian process emulation and new metrics for source-sink mismatch that rely on simulations of bifurcating cardiac fibres to interrogate a model of heterogeneous ischaemic tissue. Re-entries were most sensitive to the level of hypoxia and the fraction of non-excitable tissue. In addition, our results reveal both protective and pro-arrhythmic effects of hyperklaemia, and present the levels of hyperklaemia, hypoxia and percentage of non-excitable tissue that pose the highest arrhythmic risks. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

From ionic to cellular variability in human atrial myocytes: an integrative computational and experimental study.

Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na+/Ca2+ exchanger is identified as a primary mechanism underlying diastolic Ca2+ fluctuations in human atrial myocytes.

Space-Limited Mitosis in the Glazier-Graner-Hogeweg Model.

The Glazier-Graner-Hogeweg (GGH) model is a cellular automata framework for representing the time evolution of cellular systems, appealing because unlike many other individual-cell-based models it dynamically simulates changes in cell shape and size. Proliferation has seen some implementation into this modelling framework, but without consensus in the literature as to how this behaviour is best represented. Additionally, the majority of published GGH model implementations which feature proliferation do so in order to simulate a certain biological situation where mitosis is important, but without analysis of how these proliferation routines operate on a fundamental level. Here, a method of proliferation for the GGH model which uses separate cell phenotypes to differentiate cells which have entered or just left the mitotic phase of the cell cycle is presented and demonstrated to correctly predict logistic growth on a macroscopic scale (in accordance with experimental evidence). Comparisons between model simulations and the generalised logistic growth model provide an interpretation of the latter's 'shape parameter', and the proliferation routine used here is shown to offer the modeller somewhat predictable control over the proliferation rate, important for ensuring temporal consistency between different cellular behaviours in the model. All results are found to be insensitive to the inclusion of active cell motility. The implications of these simulated proliferation assays towards problems in cell biology are also discussed.

A mathematical model for the induction of the mammalian ureteric bud.

Congenital abnormalities of the kidney and urinary tract collectively form the most common type of prenatally diagnosed malformations. Whilst many of the crucial genes that direct the kidney developmental program are known, the mechanisms by which kidney organogenesis is achieved is still largely unclear. In this paper, we propose a mathematical model for the localisation of the ureteric bud, the precursor to the ureter and collecting duct system of the kidney. The mathematical model presented fundamentally implicates Schnakenberg-like ligand-receptor Turing patterning as the mechanism by which the ureteric bud is localised on the Wolfian duct as proposed by Menshykaul and Iber (2013). This model explores the specific roles of regulatory proteins GREM1 and BMP as well as the domain properties of GDNF production. Our model demonstrates that this proposed pattern formation mechanism is capable of naturally predicting the phenotypical outcomes of many genetic experiments from the literature. Furthermore, we conclude that whilst BMP inhibits GDNF away from the budding site and GREM1 permits GDNF to signal, GREM1 also stabilises the effect of BMP on GDNF signalling from fluctuations in BMP sensitivity but not signal strength.

The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude.

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S) and Hobart (42.8°S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median = 1.1, IQR: 0.5-2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r = 0.23, p < 0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r = 0.50) and at high latitudes (Hobart, r = 0.50; Canberra, r = 0.39), to null or even slightly negative correlations, in summer (r = 0.01) and at low latitudes (Townsville, r = -0.06; Brisbane, r = -0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.

Understanding healing complications in implant-based breast reconstruction using novel metrics for indocyanine green angiography.

INTRODUCTION: Indocyanine green (ICG) angiography for the intraoperative evaluation of tissue perfusion is commonly used in implant-based breast reconstruction (IBR). The assessment of ICG images depends on the surgeon's interpretation and is qualitative or semiqualitative in nature. To quantify ICG metrics, this study aimed to apply a novel assessment of fill-rate dynamics to predict wound-healing complications and provide pragmatic assessment tools in IBR. METHODS: This was a retrospective cohort study of patients who underwent IBR with ICG using the photodynamic eye (PDE-Neo II) qualitative imaging system between April 2021 and September 2023. ICG recordings were reviewed to quantify the relative surface area and fluorescence intensity of visual perfusion deficits using ImageJ. The primary outcome was the incidence of wound-healing complications. t-tests and logistic regression were performed for statistical testing. RESULTS: A total of 112 patients (201 breasts) were included. The incidence of wound-healing complications was 12.9%. A higher relative surface area of ischemic regions was significantly associated with wound-healing complications (3.3% vs. 0.90%; p = 0.001). The rate of change in the surface area of ischemic regions was significantly associated with wound-healing complications (0.35% per second vs. 1.29% per second; p = 0.003%). On average, the duration of transient ischemic areas was significantly longer in breasts with wound-healing complications (46.0 s vs. 36.0 s, p = 0.01). CONCLUSION: A transient ischemic area of > 5% of the breast and/or failure to resolve transient ischemic areas after 60 s may predict wound-healing complications and inform surgical reconstructive decision-making in IBR.

Perlin noise generation of physiologically realistic cardiac fibrosis.

Fibrosis, a pathological increase in extracellular matrix proteins, is a significant health issue that hinders the function of many organs in the body, in some cases fatally. In the heart, fibrosis impacts on electrical propagation in a complex and poorly predictable fashion, potentially serving as a substrate for dangerous arrhythmias. Individual risk depends on the spatial manifestation of fibrotic tissue, and learning the spatial arrangement on the fine scale in order to predict these impacts still relies upon invasive ex vivo procedures. As a result, the effects of spatial variability on the symptomatic impact of cardiac fibrosis remain poorly understood. In this work, we address the issue of availability of such imaging data via a computational methodology for generating new realisations of cardiac fibrosis microstructure. Using the Perlin noise technique from computer graphics, together with an automated calibration process that requires only a single training image, we demonstrate successful capture of collagen texturing in four types of fibrosis microstructure observed in histological sections. We then use this generator to quantitatively analyse the conductive properties of these different types of cardiac fibrosis, as well as produce three-dimensional realisations of histologically-observed patterning. Owing to the generator's flexibility and automated calibration process, we also anticipate that it might be useful in producing additional realisations of other physiological structures.

The AusD Study: a population-based study of the determinants of serum 25-hydroxyvitamin D concentration across a broad latitude range.

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study.

Recurrence quantification analysis for fine-scale characterisation of arrhythmic patterns in cardiac tissue.

This paper uses recurrence quantification analysis (RQA) combined with entropy measures and organization indices to characterize arrhythmic patterns and dynamics in computer simulations of cardiac tissue. We performed different simulations of cardiac tissues of sizes comparable to the human heart atrium. In these simulations, we observed four classic arrhythmic patterns: a spiral wave anchored to a highly fibrotic region resulting in sustained re-entry, a meandering spiral wave, fibrillation, and a spiral wave anchored to a scar region that breaks up into wavelets away from the main rotor. A detailed analysis revealed that, within the same simulation, maps of RQA metrics could differentiate regions with regular AP propagation from ones with chaotic activity. In particular, the combination of two RQA metrics, the length of the longest diagonal string of recurrence points and the mean length of diagonal lines, was able to identify the location of rotor tips, which are the active elements that maintain spiral waves and fibrillation. By proposing low-dimensional models based on the mean value and spatial correlation of metrics calculated from membrane potential time series, we identify RQA-based metrics that successfully separate the four different types of cardiac arrhythmia into distinct regions of the feature space, and thus might be used for automatic classification, in particular distinguishing between fibrillation driven by self-sustaining chaos and that created by a persistent rotor and wavebreak. We also discuss the practical applicability of such an approach.

Reducing the rate of negative ureteroscopy: predictive factors and the role of preoperative imaging.

INTRODUCTION: The aim of this study was to investigate factors that may predict a negative ureteroscopy (URS) performed for ureteric calculi in prestented patients and to assess preoperative imaging in reducing the rate of negative URS. METHODS: Data were collected on emergency stent placement for a ureteric calculus from April 2011 to February 2016 (Group A) and October 2016 to October 2019 (Group B). Data included patient demographics, indication for a stent, stone characteristics, baseline bloods, urine culture, readmission, negative URS rate and the use of pre-URS imaging. Multivariate logistic regression was used for statistical analysis. RESULTS: Of 257 patients who underwent emergency stent insertion, 251 underwent deferred URS for a ureteric calculus and 6 avoided URS due to pre-URS imaging. Indications for stent were pain (42%), sepsis (39%) and acute kidney injury (19%). Mean stone size was 7.8mm, mean stone density was 699 Hounsfield units (HU) and the stone locations were upper (62%), mid (13%) and lower ureter (25%). The overall negative URS rate was 12%. The negative URS rate was lower in patients with pre-URS imaging compared with those with none, 6% and 14%, respectively (OR=2.33, 95% CI: 0.69-7.56, p=0.2214). Logistic regression analysis indicated stone size as the only significant predictor of a negative URS, where the greater the size of the stone the less likely URS would be negative (ß=0.75, 95% CI: 0.60-0.94 p=0.011). CONCLUSIONS: Utilising pre-URS imaging can lead to a reduction in negative URS rate. Stone size <5mm appears to be the subgroup most likely to benefit from imaging.

Graph-based homogenisation for modelling cardiac fibrosis.

Fibrosis, the excess of extracellular matrix, can affect, and even block, propagation of action potential in cardiac tissue. This can result in deleterious effects on heart function, but the nature and severity of these effects depend strongly on the localisation of fibrosis and its by-products in cardiac tissue, such as collagen scar formation. Computer simulation is an important means of understanding the complex effects of fibrosis on activation patterns in the heart, but concerns of computational cost place restrictions on the spatial resolution of these simulations. In this work, we present a novel numerical homogenisation technique that uses both Eikonal and graph approaches to allow fine-scale heterogeneities in conductivity to be incorporated into a coarser mesh. Homogenisation achieves this by deriving effective conductivity tensors so that a coarser mesh can then be used for numerical simulation. By taking a graph-based approach, our homogenisation technique functions naturally on irregular grids and does not rely upon any assumptions of periodicity, even implicitly. We present results of action potential propagation through fibrotic tissue in two dimensions that show the graph-based homogenisation technique is an accurate and effective way to capture fine-scale domain information on coarser meshes in the context of sharp-fronted travelling waves of activation. As test problems, we consider excitation propagation in tissue with diffuse fibrosis and through a tunnel-like structure designed to test homogenisation, interaction of an excitation wave with a scar region, and functional re-entry.

Analysis of sloppiness in model simulations: Unveiling parameter uncertainty when mathematical models are fitted to data.

This work introduces a comprehensive approach to assess the sensitivity of model outputs to changes in parameter values, constrained by the combination of prior beliefs and data. This approach identifies stiff parameter combinations strongly affecting the quality of the model-data fit while simultaneously revealing which of these key parameter combinations are informed primarily by the data or are also substantively influenced by the priors. We focus on the very common context in complex systems where the amount and quality of data are low compared to the number of model parameters to be collectively estimated, and showcase the benefits of this technique for applications in biochemistry, ecology, and cardiac electrophysiology. We also show how stiff parameter combinations, once identified, uncover controlling mechanisms underlying the system being modeled and inform which of the model parameters need to be prioritized in future experiments for improved parameter inference from collective model-data fitting.

Machine Learning Identification of Pro-arrhythmic Structures in Cardiac Fibrosis.

Cardiac fibrosis and other scarring of the heart, arising from conditions ranging from myocardial infarction to ageing, promotes dangerous arrhythmias by blocking the healthy propagation of cardiac excitation. Owing to the complexity of the dynamics of electrical signalling in the heart, however, the connection between different arrangements of blockage and various arrhythmic consequences remains poorly understood. Where a mechanism defies traditional understanding, machine learning can be invaluable for enabling accurate prediction of quantities of interest (measures of arrhythmic risk) in terms of predictor variables (such as the arrangement or pattern of obstructive scarring). In this study, we simulate the propagation of the action potential (AP) in tissue affected by fibrotic changes and hence detect sites that initiate re-entrant activation patterns. By separately considering multiple different stimulus regimes, we directly observe and quantify the sensitivity of re-entry formation to activation sequence in the fibrotic region. Then, by extracting the fibrotic structures around locations that both do and do not initiate re-entries, we use neural networks to determine to what extent re-entry initiation is predictable, and over what spatial scale conduction heterogeneities appear to act to produce this effect. We find that structural information within about 0.5 mm of a given point is sufficient to predict structures that initiate re-entry with more than 90% accuracy.

Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR.

BACKGROUND: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. EXPERIMENTAL DESIGN: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. RESULTS: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. CONCLUSIONS: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment.

Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling.

BACKGROUND: The expression of side-population (SP) cells and their relation to tumour-initiating cells (T-ICs) have been insufficiently studied in breast cancer (BC). We therefore evaluated primary cell cultures derived from patients and a panel of human BC cell lines with luminal- or basal-molecular signatures for the presence of SP and BC stem cell markers. METHODS: The SPs from luminal-type BC were analysed for BC T-IC characteristics, including human epidermal growth factor receptor 2 (HER2), ERalpha, IGFBP7 expression and their ability to initiate tumours in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice. Pharmacological modulators were used to assess the effects of HER2 signalling and breast cancer-resistance protein (BCRP) expression on SPs. RESULTS: The SP was more prevalent in the luminal subtype of BC compared with the basal subtype. HER2 expression was significantly correlated with the occurrence of an SP (r(2)=0.75, P=0.0003). Disappearance of SP in the presence of Ko143, a specific inhibitor of the ATP-binding cassette transporter BCRP, suggests that BCRP is the predominant transporter expressed in this population. The SP also decreased in the presence of HER2 signalling inhibitors AG825 or trastuzumab, strengthening the notion that HER2 contributed to the SP phenotype, likely through downstream AKT signalling. The SP cells from luminal-type MCF-7 cells with enforced expression of HER2, and primary cells with luminal-like properties from a BC patient, displayed enrichment in cells capable of repopulating tumours in NOD/SCID mice. Engraftment of SP cells was inhibited by pretreatment with AG825 or by in vivo treatment with trastuzumab. INTERPRETATION: Our findings indicate an important role of HER2 in regulating SP and hence T-ICs in BC, which may account for the poor responsiveness of HER2-positive BCs to chemotherapy, as well as their aggressiveness.

Intrauterine growth retardation associated with precocious puberty and sertoli cell hyperplasia.

The original description of patients with Russell-Silver syndrome included precocious puberty, the mechanism of which was unclear. We describe a child with a Russell-Silver syndrome-like phenotype who presented with precocious puberty that was associated with hyperplasia of the Sertoli cells. The patient was found to have an immature cryptorchid testicle; hyperplastic Sertoli cells were also aneuploid carrying trisomy 8. This chromosomal abnormality was present in Sertoli cells only and could not be detected in peripheral lymphocytes, tunica vaginalis, or other, normal, testicular tissue. Sertoli cells in culture showed excess aromatization providing an explanation for the rapid advancement of the patient's bone age. We conclude that in a patient with a Russell-Silver syndrome-like phenotype, Sertoli cell hyperplasia was associated with somatic trisomy 8, increased aromatization, and gonadotropin-independent precocious puberty.

Spontaneous rupture of hepatic artery aneurysm associated with polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a vasculitis, which often involves small and medium sized visceral arteries. This condition may result in multifocal aneurismal formation and end-organ damage. Uncommonly, PAN may present with rupture of hepatic artery aneurysms. Here, we report a rare case of a ruptured intrahepatic aneurysm associated with PAN. A 79-year-old woman presenting with abdominal pain had CT scan of the abdomen, which revealed hematoma in the right hepatic lobe. Visceral angiogram confirmed pseudo-aneurysm of a right hepatic arterial branch, and this was managed with endovascular coil embolization. The diagnosis of PAN was made and corticosteroid therapy was initiated. We also performed a literature review to define this condition's demographics, clinical presentations, and appropriate management. The review revealed 17 published cases of ruptured PAN-related intrahepatic aneurysms. We conclude that unexplained findings of visceral arterial aneurysms should prompt investigations for vasculitis as the etiology.

Comparison of Traditional and Skin-Sparing Approaches for Surgical Treatment of Necrotizing Soft-Tissue Infections.

Background: A skin-sparing approach for the treatment of necrotizing soft-tissue infections (NSTIs) removes necrotic tissue planes while leaving viable overlying skin. Subsequent closure of the spared skin may decrease the need for graft-based reconstruction, which is associated with contracture, pain, and deformity. This study compared the outcomes of a traditional approach (excision of overlying skin with diseased fascia) with that of a skin-sparing approach for patients with NSTI treated at a major metropolitan medical center. Methods: Demographic, clinical, and operative details for patients treated for NSTI between July 2012 and December 2016 at a single institution were reviewed retrospectively. Pre-operative and post-operative photographs were evaluated independently by three surgeons to determine reconstructive outcomes. Cohen's κ was used to assess inter-rater reliability. Multiple regression and Poisson regression models were used to assess the association between outcomes and the surgical approach. Results: A total of 487 patients were divided into two cohorts: Traditional approach (TA), treated between July 2012 and December 2014 (n = 230), and skin-sparing approach (SS), treated after January 2015 (n = 257). The mortality rate in the two groups was equal at approximately 10%. The median percentage of each wound closed by skin graft was significantly lower for the SS group than for the TA group (20% versus 90%; p < 0.0001) with a correspondingly higher median percentage of primary skin closure for the SS group (50% versus 0; p < 0.0001). Conclusions: Relative to traditional debridement, skin-sparing debridement for source control of NSTI results in significantly more wounds closed completely by delayed primary suture of existing skin flaps and a significantly lower overall wound percentage closed by skin graft, while demonstrating equivalent efficacy of source control and a similar low mortality rate.

Extraparticulate chain interaction between different electron transport particles.

Interaction or cross-linking between the respiratory chains of the electron transport particles of bacterial origin occurs with a mixture of active and inactive particles. Interaction between bacterial particles and liver sub-mitochondrial particles also occurs. Irradiation of the bacterial particles at 360 nanometers resulted in the destruction of quinone and consequent loss of ability of reduced nicotinamide adenine, dinucleotides to reduce cytochromes b, c(1), c, and a plus a(3). A mixture of both irradiated and untreated particles in the presence of the reduced dinucleotide resulted in the reduction of cytochromes c and a plus a(3), in an amount equivalent to the total concentration of these cytochromes in both types of particles. In contrast, the amount of cytochrome b reduced was equivalent to half the particle concentration or to that observed with the active particles alone. The rate of reduction of cytochromes c and a plus a(3) with the mixture of particles was similar to that with the active particles alone. The interaction or cross-linking between the particulate respiratory chains of bacteria or of bacterial and mammalian systems occurs after cytochrome b and before or at cytochrome c.