Terminal Arterioles Research Articles

Anatomy of blood microcirculation in the pig epicardial ganglionated nerve plexus

Embolization of coronary arteries and their terminal arterioles causes ischemia of all tissues distributed within a cardiac wall including the intrinsic cardiac ganglionated nerve plexus (ICGP). The disturbed blood supply to the ICGP causes chronic sympathetic activation with succeeding atrial and ventricular arrhythmias. This study analyses the anatomy of microcirculation of epicardial nerves and ganglia using the hearts of 11 domestic pigs. Our findings demonstrate that thicker epicardial nerves are normally supplied with blood via 12 epineural arterioles penetrating the endoneurium regularly along a nerve, and forming an endoneurial capillary network, which drains the blood into the myocardial blood flow. The mean diameter of intraneural capillaries was 7.2 ± 0.2 µm, while the diameters of arterioles were 25.8 ± 0.7 μm and involved 45 endothelial cells accompanied by circular smooth muscle cells. Usually, two or three arterioles with a mean diameter of 28.9 ± 1.7 μm supplied blood to any epicardial ganglion, in which arterioles proceeded into a network of capillaries with a mean diameter of 6.9 ± 0.3 μm. Both the epicardial nerves and the ganglia distributed near the porta venarum of the heart had tiny arterioles that anastomosed blood vessels from the right and the left coronary arteries. The density of blood vessels in the epicardial nerves was significantly lesser compared with the ganglia. Our electron microscopic observations provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation. Structured abstractThis study details the anatomy of microcirculation of epicardial nerves and ganglia, from which intracardiac nerves and bundles of nerve fibers extend into all layers of the atrial and ventricular walls in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our findings provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation.

Calcium-activated chloride channels in pericytes shape capillary electrical signaling

The brain vasculature, composed of penetrating arterioles (PAs) giving rise to the dense capillary network, facilitates continuous energy substrate delivery to neurons and glia by tightly controlling blood flow. The capillaries are covered by perivascular cells known as pericytes, which exhibit varying morphological and physiological properties based on their location in relation to the terminal arteriole, and these contribute to blood flow control within the capillary network in distinct ways. Thin-strand pericytes —the focus of this study—are located in the deep capillary bed. Serendipitously, we have discovered a robust chloride current during perforated patch clamp experiments on these thin-strand pericytes. We hypothesized that this current is mediated by calcium-activated chloride channels (CaCCs), which may influence electrical signaling and thereby regulate blood flow. Our data reveal that this robust current is dependent on external calcium concentration and can be blocked by voltage-gated calcium channel blockers, depletion of endoplasmic reticulum calcium stores, and calcium-activated chloride channel blockers. This suggests a mechanism wherein calcium entry into the cytosol via voltage-gated channels and intracellular calcium release govern the activity of CaCCs in the thin-strand pericyte membrane. Using two-photon microscopy, we further observed that blocking CaCCs led to PA dilation and hyperemia. Together, our data indicate a novel role for CaCCs in thin-strand pericytes, where they modulate electrical signaling across the capillary bed in response to intracellular calcium activity. By providing a depolarizing signal countering hyperpolarizing electrical signaling, these channels contribute to the intricate regulation of blood flow and vessel dilation. This work was supported by the NIH (grants 1R01AG066645, 5R01NS115401, 1DP2NS121347-01), and the American Heart Association (19IPLOI34660108). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

АКУШЕРСКИЙ ГЕМОЛИТИКО-УРЕМИЧЕСКИЙ СИНДРОМ, АССОЦИИРОВАННЫЙ С БЕРЕМЕННОСТЬЮ, У ПАЦИЕНТКИ С ИНФЕКЦИЕЙ И МАССИВНЫМ КРОВОТЕЧЕНИЕМ: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

The study aims to present a clinical case of a rare pathology such as obstetric hemolytic uremic syndrome associated with infection during pregnancy, and complicated by massive bleeding, a critical obstetric condition, and a high risk of maternal mortality in a near-miss case. The study analyzes changes in causes of maternal mortality rate in the Russian Federation, including changes towards extragenital diseases; indirect causes and embolisms; preeclampsia, obstetric bleeding, and sepsis despite their decrease in the causes of maternal mortality rate; and such diseases as thrombotic microangiopathy, which is considered a probable life-threatening maternal condition and named a critical obstetric condition, that can be diagnosed in a highinformation laboratory with an instrumental basis. Thrombotic microangiopathy is attributed to many diseases, therefore, there are many unclear and controversial issues in diagnosing such a disease during pregnancy. Its clinical symptoms include hemolytic microangiopathic anemia, thrombocytopenia, thrombosis of the terminal arterioles and capillaries of the microvascular bed, and multiple organ dysfunction.

Photoplethysmography factors associated with undiagnosed hypertension in men with low and moderate cardiovascular risk

Aim. To study the functional state of the terminal arteries and arterioles of the skin using photoplethysmography (PPG) in men with hypertension (HTN) of low and moderate cardiovascular risk (CVR) and to identify morphofunctional diagnostic criteria associated with HTN.Material and methods. A total of 118 healthy men (30-60 years old) underwent clinical and biochemical blood tests, PPG, ultrasound of cardiac and main arteries, 24-hour blood pressure monitoring. According to 24-hour blood pressure monitoring, two groups were formed: the control group — 59 normotensive men, HTN group — 59 men with HTN.Results. According to the PPG data, men with HN had higher normalized augmentation index (Alp75) (3,8 and -5,25%; (p<0,005)), stiffness index (SI) (7,6 and 7,35 m/s) (p<0,05) and reflection index (RI) (36,5 and 28,4%) (p<0,005), respectively. According to multivariate analysis, an increase in RI ≥30,6% (odds ratio, 4,6; p=0,0476) and SI ≥7,9 m/s (odds ratio, 3,69; p=0,019) was significantly associated with HTN. A regression model has been developed that includes age ≥35 years, RI ≥30,6% and SI ≥7,9 m/s, which allows predicting HTN in men with low and moderate cardiovascular risk with a sensitivity of 78% and a specificity of 62,1%.Conclusion. Men with HTN of low and moderate CVR are characterized by an increase in vascular stiffness, tone of smooth muscle cells, terminal muscular arteries and arterioles, and an increase in pulse wave velocity. The developed model can be used to predict hypertension in these patients and determine indications for further examination.

One-dimensional modeling of microvascular hemodynamics in the retina using multimodal imaging

Modeling techniques are an essential complement to clinical studies of the retina, as they provide access to non-measurable parameters throughout the network and enable the simulation of controlled disturbances or pathologies. In this work, we propose the development of a patient-specific one-dimensional model of the arterial circulation in the retina. Our model is based on conservation laws and utilizes morphometric and velocimetric data obtained through clinical multimodal imaging to construct the network topology and impose realistic boundary conditions. Specifically, our model simulates blood flow from the central retina artery to the terminal smallest arterioles. To validate our model, we perform a sensitivity analysis and compare its results to published data. Finally, we use our model to investigate the hemodynamic consequences of focal stenosis on retinal arteries. Overall, our model provides a valuable tool for exploring the complex dynamics of retinal blood flow and their potential clinical implications.

Uveal vascular bed in health and disease: lesions produced by occlusion of the uveal vascular bed and acute uveal ischaemic lesions seen clinically. Paper 2 of 2.

From studies on postmortem anatomical descriptions of the uveal vascular bed, it was generally concluded that occlusion of PCA or its branches should not produce an ischemic lesion. However, in vivo studies have recorded that the PCAs and their branches, right down to the terminal choroidal arterioles, and the choriocapillaris, have a segmental distribution in the choroid, and that PCAs and choroidal arteries function as end-arteries. This explains the basis of the occurrence of isolated inflammatory, ischemic, metastatic, and degenerative choroidal lesions, which are usually localized. Thus, in vivo studies have completely revolutionized our concept of the uveal vascular bed in disease.

The Potential Role of ANKRD36 in Immune Thrombotic Thrombocytopenic Purpura

A.B. and L.Z. Contribute equally to this work. Background: Immune thrombotic thrombocytopenic purpura (iTTP), caused by autoantibody against ADAMTS13, is characterized by the formation of microvascular thrombosis, resulting in thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. The mechanism underlying autoantibody formation and pathogenesis of iTTP are not fully understood. Our lab previously reported a strong association between mutations in the Ankyrin Repeat Domain 36 (ANKRD36) family genes and iTTP. To further understand the role of ANKRD36 in iTTP, we established a partial deletion mutant of Ankrd36 in mice, which were bred with Adamts13-/- mice to generate double homozygous mice. The role of Ankrd36 in a murine model of TTP and the inflammatory or immunological responses to potential viral infection were assessed. Methods: Mice with various genotypes including wild-type (WT), Adamts13-/- (A13-/-), Ankrd36-/-(AK36-/-), and Ankrd36-/-Adamts13-/- (AK36-/-A13-/-) were treated with 10 mg/kg polyinosinic-polycytidylic acid [Poly (I:C)] via intraperitoneal injection. Complete blood count in anti-coagulated whole blood was performed at baseline, 4, 24, and 72 h post-challenge. Major organ tissues were collected for histology, immunohistochemistry, and flow cytometric analyses from unchallenged animals or 72 h following Poly (I:C) injection. Results: All mice at baseline did not exhibit thrombocytopenia (Fig. 1A, left). Seventy-two hours following the challenge with Poly (I:C), platelet counts were significantly reduced in A13-/- with or without AK36-/- but not in AK36-/- alone mice compared with those in WT controls. Interestingly, the median platelet counts appeared to be the lowest in AK36+/-A13-/- among all groups (Fig. 1A, right). Histology and immunohistochemical analyses revealed occlusive thrombi in terminal arterioles as exemplified by the positive staining with anti-VWF or anti-fibrinogen IgG 72 hours following Poly (I:C) challenge (Fig. 1B). Moreover, our histological analysis demonstrated a consistent drop in the percentage of splenic white pulp following Poly (I:C) treatment in all genotypes with the most dramatic drop in the WT, followed by the AK36-/-A13-/-, then the A13-/-,and AK36-/-mice. Immunohistochemical staining of spleen tissue revealed a significant increase in both B and T cells in the red pulp, which led us to conduct the flow cytometrical experiments. Our flow results demonstrated that following Poly (I:C) treatment the percentage of CD3+ T cells, CD138+ plasma cells, and CD11b+F4/80+ macrophages decreased, while the percentage of B cells increased (Fig. 2). Specifically, within the T cell population, CD3+CD4+ helper T cells increase while CD3+CD8+ natural killer T cells decreased. In all cell types except for macrophages, the AK36-/- group shows no change from the wild type. Interestingly, our AK36-/-A13-/- mice showed similar or more profound changes compared to the WT mice in all cell types. Conclusions: Our results demonstrate for the first time a synergistic role of partial deletion of ANKRD36 protein in pathogenesis of TTP resulting from severe deficiency of plasma ADAMTS13 activity and potential viral infection. Additionally, our results indicate that the ANKRD36 family proteins may play a regulatory role in the immune and inflammatory responses. Further investigation into the interaction between ANKRD36 family protein and ADAMTS13 may help understand the pathogenic mechanism of iTTP and other immune inflammatory disorders. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Alpha-Smooth Muscle Actin Expression and Parafoveal Blood Flow Pathways Are Altered in Preclinical Diabetic Retinopathy.

PurposeTo investigate differences in alpha smooth muscle actin (αSMA) expression and parafoveal blood flow pathways in diabetic retinopathy (DR).MethodsHuman donor eyes from healthy subjects (n = 8), patients with diabetes but no DR (DR–; n = 7), and patients with clinical DR (DR+; n = 13) were perfusion labeled with antibodies targeting αSMA, lectin, collagen IV, and filamentous actin. High-resolution confocal scanning laser microscopy was used to quantify αSMA staining and capillary density in the parafoveal circulation. Quantitative analyses of connections between retinal arteries and veins within the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were performed.ResultsMean age between the groups was not different (P = 0.979). αSMA staining was seen in the SVP and ICP of all groups. The DCP was predominantly devoid of αSMA staining in control eyes but increased in a disease stage–specific manner in the DR– and DR+ groups. The increase in αSMA staining was localized to pericytes and endothelia of terminal arterioles and adjacent capillary segments. Capillary density was less in the DCP in the DR+ group (P < 0.001). ICP of the DR– and DR+ groups received more direct arteriole supplies than the control group (P < 0.001). Venous outflow pathways were not altered (all P > 0.284).ConclusionsAlterations in αSMA and vascular inflow pathways in preclinical DR suggest that perfusion abnormalities precede structural vascular changes such as capillary loss. Preclinical DR may be characterized by a “steal” phenomenon where blood flow is preferentially diverted from the SVP to the ICP and DCP.

Genesis of Antibiotic Resistance (AR) LXXXI: Turbulence Modeling of Simplified Severe Sepsis Protocol‐2 (SSSP‐2), NCT01663701: ERP Induced Fluid Volume Expansion Confer Transition from Laminar to Turbulence by Discontinuity

NCT01663701(PMID:28973227) observed that a primary outcome of in‐hospital mortality (ihm) occurred in 51 of 106 patients (48.1%) in the sepsis protocol group vs 34 of 103 patients (33.0%) in the usual care group while the vital status after hospital discharge at day 28 reported for 97 patients in each study group; 28‐day mortality was 67.0% with the sepsis protocol vs 45.3% with usual care. Hypothesis: Based on the data on risk of ihm by subgroup for patients treated with the sepsis protocol vs usual care (Fig3), compared to elements of sepsis resuscitation (Table 2), and baseline characteristics of the patients (Table 1), we hypothesize that the discontinuity in fluid volume due to ERP is the pivotal determining factor for an exacerbated mortality rate in NCT0166370. Relevance of Central Venous Pressure(CVP) or Jugular Venous Pressure (JVP) for the Determination of Fluid Overload(PMID: 23774337, PMID: 24132054):NCT01663701, p1237, Table 1: The JVP data indicate that the baseline: by proximity to the sternal angle, ≥4cm below: sepsis protocol cohort: 32.1% vs usual care: 40.8%; 1‐3cm below:sepsis protocol cohort: 28.3% vs usual care 21.4%; At the sternal angle, 20.8% vs 27.2%; ≥1 cm above: sepsis protocol 20.8% vsusual care 10.7%. Cause(s) of elevated CVP or JVP:A plausible cause would be RV failure (pulmonary edema!) due to fluid volume overload by excessive fluid administration. Geometry, Governing Eq. &amp; Analysis: The mass continuity eq: 2.17, (p14‐ISBN‐13:978‐0521598866); where V1= fluid velocity, ρ1= fluid density, at terminal arteriole (cross‐sectional area) = A1and tis time interval dt, prior to ERP, length dl1=V1dt mass that enters the A1in the time interval is: dm1=ρ1dV1= ρ1A1dl1=ρ1A1v1dt. After the ERP, the expanded fluid volume passing through metarteriole (cross‐sectional area) =A2and length dl2=V2dt in the time interval dt is=dm2=ρ2dV2=ρ2A2dl2=ρ2A2v2dt. As per the mass continuity equation, (flow at any given point in a closed hydraulic system will be equal to flow at any other points) an equal amount of mass that enters the area A1in the time interval dt, must pass through area A2,therefore, dm1=dm2or ρ1A1v1dt=ρ2A2v2dt.Dividing by dt, will result ρ1A1v1=ρ2A2v2for a steady flow pattern referred to as mass continuity equation for steady flow. Our simulation analysis implicates that for the ERP induced fluid volume overload fluid flow is A1v1≠A2v2 . The rationale is that, the laminar fluid flow is in streamlines with equal space but ERP induced will not be in streamline but widely spaced, ⬆viscosity, ⬆ rate of LPE aggregation and ⬇velocity, ⬆torque &amp; drag with an unknown angular momentum, on endothelial layer in terminal arteriole. Prospects: It is suggested that the total mass of expanded fluid vol. within 6 hrs, entering/exiting the terminal arteriole (Cerebral BBB) elicit CCP rupturing the pre‐capillary vessels due to an adverse pressure gradient (APG). Differential shear stress due to APG, induce temporal regulation of ARGR expression in clinical persisters in vivo w/ orw/o vasoplegia may have been the cause for an exacerbated mortality in NCT01663701.

Capillary ultrastructure anatomy and physiology: What is known, what is unknown or missing, what is wrong and what is new?

This article summarizes what is already known about the capillary ultrastructure anatomy and physiology that includes one wrong physiological law of Starling and two misconceptions on capillaries cross section area and blood speed in its lumen. It also identifies missing data such as the number and diameters of capillaries branching from the terminal arteriole, and the speed of blood at the arterial and venous ends. It also summaries the evidence on new knowledge on capillary physiology namely the hydrodynamic of the porous orifice (G) tube built on a scale to capillary ultrastructure anatomy of pre-capillary sphincter and inter-cellular slits pores. It proves Starling’s law wrong and provide its correct replacement. The Tree Branching Law (TBL) corrects both misconceptions on capillaries cross section area being larger that the aorta and capillary blood speed is “very slow”. The TBL proves that the cross-section area of all capillaries is less than that of the aorta, and the blood speed in capillary is faster than generally received. The G tube’ magnetic field like hydrodynamics is the correct replacement for Starling’s law on the capillary-ISF transfer. This new capillary-ISF transfer allows for fast efficient function that meets cells and tissue demands at rest and during strenuous exercise.

Capillary module haemodynamics and mechanisms of blood flow regulation in skeletal muscle capillary networks: Experimental and computational analysis.

The capillary module (CM), consisting of parallel capillaries from terminal arteriole to post-capillary venule, is classically considered to be the building block of complex capillary networks. In skeletal muscle, CMs form interconnected columns spanning thousands of microns, which we recently described as the capillary fascicle. However, detailed evaluation of CM haemodynamics has not been described, and may provide insight into mechanisms of blood flow regulation in the microcirculation. We used intravital videomicroscopy from resting extensor digitorum longus muscle in rats (n=9 networks, 112 capillary modules), as well as dual-phase computational modelling of blood flow in simulated CM geometries. We found that the mean driving pressure across CMs was 3.236±1.833mmHg. Red blood cell (RBC) flow was independent of CM resistance, and the ratio of blood flow in adjacent modules was not correlated with their ratio of resistances. In simulated CM geometries, increases to driving pressure produced a direct linear increase to RBC and plasma flow, with no changes to RBC distribution; increases to arteriolar inflow haematocrit resulted in increased RBC flow, but with viscosity-dependent increases to CM resistance. CM RBC flow heterogeneity was higher than plasma flow heterogeneity in experimental data, in contrast to simulated geometries, suggesting that time-dependent flow variability may have important consequences for RBC distribution. In summary, these findings suggest that CMs are active participants in microvascular flow regulation, likely achieved through adjustments to CM driving pressure using pre- and post-capillary loci of flow control. Increases to CM viscosity may be important during the regulation of functional hyperaemia. KEY POINTS: The capillary module (CM), consisting of parallel capillaries from the arteriole to venule, is classically considered to be the building block of capillary networks in skeletal muscle. A detailed evaluation of module haemodynamics may provide insight into mechanisms of blood flow regulation in the microcirculation. Using experimental data from resting skeletal muscle in rats, as well as dual-phase computational models of blood flow, we analysed haemodynamic relationships and the impact of variations to boundary conditions on red blood cell and plasma distribution. We showed that driving pressure across CMs is low, and that simulated increases to inflow haematocrit have important viscosity-dependent effects on module resistance. We found that red blood cell flow was independent from module resistance, which strongly suggests the regulation of driving pressure at the level of the capillary module using pre- and post-capillary loci of flow control. These findings place CMs as central participants in microvascular flow regulation, with important consequences for disease and functional hyperaemia.

Myofibre injury induces capillary disruption and regeneration of disorganized microvascular networks.

Injury to skeletal muscle disrupts myofibres and their microvascular supply. While the regeneration of myofibres is well described, little is known of how the microcirculation is affected by skeletal muscle injury or its recovery during regeneration. Nevertheless, the microvasculature must also recover to restore skeletal muscle function. We aimed to define the nature of microvascular damage and time course of repair during muscle injury and regeneration induced by the myotoxin BaCl2 . To test the hypothesis that microvascular disruption occurred secondary to myofibre injury, isolated microvessels were exposed to BaCl2 or the myotoxin was injected into the gluteus maximus (GM) muscle of mice. In isolated microvessels, BaCl2 depolarized smooth muscle cells (SMCs) and endothelial cells while increasing intracellular calcium in SMCs but did not elicit death of either cell type. At 1day post-injury (dpi) of the GM, capillary fragmentation coincided with myofibre degeneration while arteriolar and venular networks remained intact; neutrophil depletion before injury did not prevent capillary damage. Perfused capillary networks reformed by 5dpi in association with more terminal arterioles and were dilated through 10dpi. With no change in microvascular area or branch point number in regenerating capillary networks, fewer capillaries aligned with myofibres and were no longer organized into microvascular units. By 21dpi, capillary orientation and microvascular unit organization were no longer different from uninjured GM. We conclude that following their disruption secondary to myofibre damage, capillaries regenerate as disorganized networks that remodel into microvascular units as regenerated myofibres mature. KEY POINTS: Skeletal muscle regenerates after injury; however, the nature of microvascular damage and repair is poorly understood. Here, the myotoxin BaCl2 , a standard experimental method of acute skeletal muscle injury, was used to investigate the response of the microcirculation to local injury of intact muscle. Intramuscular injection of BaCl2 induced capillary fragmentation with myofibre degeneration; arteriolar and venular networks remained intact. Direct exposure to BaCl2 did not kill microvascular endothelial cells or smooth muscle cells. Dilated capillary networks reformed by 5days post-injury (dpi) in association with more terminal arterioles. Capillary orientation remained disorganized through 10dpi. Capillaries realigned with myofibres and reorganized into microvascular units by 21dpi, which coincides with the recovery of vasomotor control and maturation of nascent myofibres. Skeletal muscle injury disrupts its capillary supply secondary to myofibre degeneration. Reorganization of regenerating microvascular networks accompanies the recovery of blood flow regulation.

Resolution of Purtscher's retinopathy validated with imaging over a period of three months

Purtscher's retinopathy is a well-known finding post trauma. It is microangiopathy occurring due to occlusion of peripapillary terminal arterioles that supply the superficial capillaries. There are numerous reports in literature describing this entity, but seldom any report describing its course and nature of resolution supported with imaging. We present a case of a 21-year-old young male who developed Purtscher's retinopathy post head trauma, with sequential follow-up imaging over a period of 3 months, till near complete resolution of the condition. The supportive imaging also aids in understanding the pathology in a simplified way.

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation.

Impaired blood flow and oxygenation contribute to many ocular pathologies, including glaucoma. Here, a mathematical model is presented that combines an image-based heterogeneous representation of retinal arterioles with a compartmental description of capillaries and venules. The arteriolar model of the human retina is extrapolated from a previous mouse model based on confocal microscopy images. Every terminal arteriole is connected in series to compartments for capillaries and venules, yielding a hybrid model for predicting blood flow and oxygenation throughout the retinal microcirculation. A metabolic wall signal is calculated in each vessel according to blood and tissue oxygen levels. As expected, a higher average metabolic signal is generated in pathways with a lower average oxygen level. The model also predicts a wide range of metabolic signals dependent on oxygen levels and specific network location. For example, for high oxygen demand, a threefold range in metabolic signal is predicted despite nearly identical PO2 levels. This whole-network approach, including a spatially nonuniform structure, is needed to describe the metabolic status of the retina. This model provides the geometric and hemodynamic framework necessary to predict ocular blood flow regulation and will ultimately facilitate early detection and treatment of ischemic and metabolic disorders of the eye.

Binasal Visual Field Defects Due to Sickle Cell Maculopathy.

A 26-year-old African American man with sickle cell disease noticed blurry vision in both eyes after a recent complicated hospital admission for sickle cell crisis. Anterior and posterior segment examination of each eye was normal, but visual field testing revealed binasal scotomas. Optical coherence tomography of the macula demonstrated severe thinning of the temporal inner retina, suggesting previous bilateral occlusions of terminal retinal arterioles involving the temporal macula, an uncommon complication of sickle cell disease. This case is a reminder that retinal pathology should always be considered as a potential cause of unexplained visual field defects and highlights the role of macular OCT in evaluation of these patients.

MO1030THE FIRST CASE OF ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS) FEATURES IN AN EXPERIMENTAL MODEL

Abstract Background and Aims Thrombotic Microangiopathies (TM) are three distinct clinical syndromes presenting the same histological renal pattern: typical and atypical Hemolytic Uremic Syndrome (SEU- aSEU) and Thrombotic Thrombocytopenic Purpura (TTP). So far, the first report of a TM has been generally attributed to Eli Moschowitz. In 1922 he described the case of a 16 years old girl who died after acute onset of fever with petechial lesions and autoptic findings of hyaline thrombosis of terminal arterioles and capillaries, thus profiling the first case of TTP. Only in the 1955, Conrad Gasser described the first medical record of HUS, describing the case of a patient with a manifestation of bilateral necrosis of the renal cortex. We describe the first reported case of a Thrombotic Microangiopathy, in particular an experimentally induced aHUS by Richard M. Pearce in 1909. In this case, the trigger leading to aHUS was represented by snake venom injection in an experimental rabbit model. Method Pearce described acute glomerular lesions produced in the rabbit using dried venom of rattlesnake Crotalus Adamanteus. It was dissolved in salt solution in the proportion of 0.25 of a milligram to one cubic centimeter, rising gradually to two milligrams, and then followed by doses of 0.5 of a milligram of fresh venom at various intervals. The intervals between injections depended on the general condition of the animal and the amount of albuminuria. Results Rabbit kidneys showed well marked hemorrhagic and exudative lesions in the glomeruli; hyaline, granular, blood, and hemoglobin casts in both convoluted and collecting tubules; and granular degeneration of the epithelium of the convoluted tubules and loops of Henle. Pearce also described a “penetration of the cells of the compressed glomerular tuft into the mass of hemorrhage lying either in the tuft itself or in the capsular space” (Figure 1). In animals surviving 20-30 days after the first injection of the venom, the acute lesions were demonstrated to subside at the microscopic examination and their earlier presence was marked by “occasional casts and compressed masses of red cells in the glomerular spaces and tufts”. At the same time other models also showed “extensive granular degeneration of the convoluted tubules and many casts”. The renal autoptic findings presented the features of a vascular nephritis with severe endothelial changes. Conclusion Glomerular and tubular lesions of rabbits’ kidneys induced by crotalus’s venom showed typical features of what is today defined as aHUS. In this first experiment, the author described a glomerular tuft as “more analogous to the organization of a red thrombus than it is to any form of glomerular lesion known in man”, so we can affirm that Pearce described, ante litteram TMA histological features many years before other scientists.

Genesis of Antibiotic Resistance (AR) LXXV: Turbulence Modeling of Simplified Severe Sepsis Protocol‐2 (SSSP‐2), NCT01663701: Simulation of Contributing factors that Protract &amp; Métier Torque Thrusted LPE Aggregates’ in Coandă effect Cause Critical Closing Pressure (CCP)

Hypothesis: EGDT-ERP is directly inducing blood volume expansion, altering the BP, alter the velocity, shear stress, hematocrit forming an LPE aggregate’ and an adverse pressure gradient in vivo smite NFP lead to CCP subsequent CVA/comatose. An effort is made to test a unifying (holistic) hypothesis that has the potential to lull LPE aggregates, alongside AR clinical persisters in the cerebrovascular capillary bed with intrinsic torque of LPE (bluff body) in tandem dragging on the capillary lumen, alongside LE (large eddies), vortices would rupture true capillaries eliciting CCP in an asymmetric velocity profile through anisotropic mode with the collapse of NFP is tested with fluid flow. Geometry: We take inspiration from the impact of torque-drag of a moving object in time sequence: a: torque- and drag sustain damage to the runway – correlate LPR torque – drag on the capillary bed: https://www.youtube.com/watch?v=DFOynlRYT54YouTube©– (time scale: seconds)– b: https://www.youtube.com/watch?v=u5axFVRdNRU; c:splash on the landing: https://www.youtube.com/watch?v=9poWj5eu5rE- (time scale: seconds) – d:https://www.youtube.com/watch?v=2u7jY3V-GJ0– rejected take-off – LPE aggregates lead abrupt occlusion; Governing equations: Darcy's law: Q=kA∆P/μl, -Eq3.27, where Q=discharge flow rate, k=permeability, A= cross-section of the media (blood), ∆P=pressure drop, μ=viscosity, L=length, derived eq. 3.28 – 3.34; (p104-105, ISBN 9780128024089); Torque: τ = r x F, where force F, that act on a particle at position, r(p250 eq;7.6 (ISBN 9780521198110). Experimental Observation: The following experimental observations is an archetype for our hypothesis ad hoc momento. PMID:27319318: Fig2 b, d, f, h compares to the Fig 1, III and V, E, would be lysed passing through the occlusion, releasing lysate, in turn, activating L, P, and E forming LPE; Fig 3d-F represent an LPE aggregate in vivo of sepsis cohort in NCT01663701; Fig 4c the stenosed vessels energy level declined; Fig 5c location II, high energy location VI favor LPE aggregate upstream causing CCP; penultimate to losing NFP, CVA cloture comatose. PMID: 31297646: indicate that RBC(E) aggregate occurs upstream of stenosis forming thin cell free layer (CFL) and decreased flow velocity are in favor of our hypothesis. PMID 31010931 Fig 5 C in the CLP group continuous accumulation of heparin sulfate in the hippocampus of sepsis model (PMID 31297646, PMID 29195076), Fig 7E, implicit of LPE aggregate at the arterial end of the capillary bed;p9213 reinternalize cecum–a trauma-lack≡DDx!; ( PMID: 30720464 PMID: 31337421; PMID: 31201739), patient-specific, TM-CFD; Simulation: Our effort to simulate for water/sewage flow system indicate that a. monitors the aggregate formation, b. utilizes the degreaser/blood-thinning agent, c. coating the pipe agents to repair glycocalyx-endothelium to restore the structure and laminar flow. At present, attempting the simulation of role of CFL in eliciting the adverse pressure gradient / vasomotion in the terminal arteriole - exchange vessels - postcapillary venule in vivo.

Genesis of Antibiotic Resistance LXXIII: Turbulence Modeling of Simplified Severe Sepsis Protocol‐2 (SSSP‐2), NCT01663701: Mechanism(s) of Fluid Overload, Concurrent Endotoxemia Exacerbate Leucocyte(S)‐Platelet(S)‐Erythrocyte(S) Aggregates’ (LPE) Consummate Vasoplegia Lead Torque Rifled Viscoelasticity: Connotation of Kolmogorov's scaling theory

NCT01663701 SSSP-2 (PMID: 28973227) noted that within 6 hours of ERP, among sepsis protocol cohort 11 patients sustained GCS score 3-8 with in-hospital mortality 10 patients, with a median jugular vein pressure (JVP) of ~ 2 cm H20 below the clavicle or -2cm H20 implicit of hypovolemia, (ref table 3, p1239, ibid). Here, we present a plausible physiological sequel of the patient(s) from the time of presentation to the emergency dept. and 6 hours after ERP, and the onset of comatose followed with mortality. The geometry for this analysis are following: PMN 8-15μm, eosinophils ~15 μm, basophils ~12-15 μm, monocytes ~14-25 μm, lymphocytes (T, B & NK cells) ~8-15 μm, platelets ~2-3 μm, erythrocytes ~ 7.7 ± 0.7 μm; capillaries (med. size) internal diameter 6 μm, wall thickness, 1 μm, length ~0.1cm, ~blood viscosity 0.03 cm/s (human) (p48, 63: ISBN 9780128024089). Elements: Fahraeus Effect, the hematocrit in true capillaries (Hctv) is lower compare to that of blood entering (due to cell-free layer formation (p95-96, Fig3.8. ibid) vs discharge hematocrit (HctD) and Fahraeus-Lindqvist effect where the apparent viscosity of (μapp) blood is the function of capillary diameter for a range of 10μm ≤ D ≤ 300μm. For the thoroughfare channel, to venules, the viscosity will be reversed as it increases in viscosity (μrel) (Fig 3.10, p98 ibid). Platelet and RBC morphological deformity as shown in Fig 1, panel a; fig 6 a-c, turning, crossing, and riding of platelet and tracer particle deflections in presence of a tumbling RBC; streamlines around a tank-treading RBC Fig 9 panel a-c, platelet crossing, rolling; from PMID: 24231958; Fig 1, of PMID: 17208982; PMID: 24896133; PMID: 17851167; Fig 3 and 5 for skewed hematocrit, PMID: 31933711, would likely to be rapid in vivo., extrapolated to sepsis cohort in NCT01663701. It is suggested that the LPE either forms or part of the bluff body at the junction of precapillary sphincters & thoroughfare channel / true capillaries impede the vasomotion into the arterial end of capillary bed, which may lead terminal arteriole directly connecting metarteriole to venules (bypassing true capillaries, thoroughfare channel) causing vascular shunt with no blood flow in capillary bed en masse. As a result NFP for filtration and net reabsorption pressure is impaired. It is envisioned that LPE anchoring on the scruffy (Awol?) glycocalyx on the endothelial surface of arteries will generate torque Ref Eq-1 (PMCID: PMC5437748, PMID: 28529430 and PMID: 8304490), increase in Kolmogorov length - scale (l) ratio eq. 3.1a, Time-scale ratio (t) eq 3.1b, Velocity-scale ratio (v) eq 3.1c, p43(ISBN:9780131274983) for bluff bodies/large eddies, causing cyclical, relaxation, creep and hysteresis, impairing viscoelasticity, rupturing the capillary bed en masse, resulting in irreversible traumatic brain injury (CVA!). It is implicit that under such conditions onset of CCP in true capillaries. Such a scenario would likely be the contributing factor for the investiture of comatose in turn mortality.

Revisiting the vascularity of the keratinized gingiva in the maxillary esthetic zone

BackgroundThe active arterial-to-arterial collaterals are a significant factor in the prevention of ischemia and extensive tissue necrosis in the case of arterial blockage of various tissues. The present study investigates the mucogingival vasculature in the maxillary esthetic zone mucosa in human cadavers and functionally evaluates the area, which is supplied by the terminal arterioles, on the individual level.MethodsIn the human cadaver study, macroscopic arterial analyses of the anterior maxillary vestibule in 7 specimens were scrutinized by latex milk injection. The tracks of the mucosal branches in relation to the mucogingival junction were investigated. In the functional study, individual gingival blood flow (GBF) changes were measured by laser speckle contrast imaging (LSCI) in 31 young subjects with healthy gingiva before and during 30-s compressions. This was conducted with a ball-shaped condenser. The data was analyzed by the linear mixed model.ResultsThe vertically aligned branches of the superior labial artery (SLA) divided into small, slightly deviating sub-branches near the mucogingival junction. These arteries created collateral plexuses and supplied the attached gingiva. The compression of these branches resulted in ischemia coronally with significant individual variation. The ischemia was either apico-mesial, apico-distal, or straight apical to the compression. A significant correlation was found between the ischemic area and the magnitude of the decrease in GBF (r = 0.81, p < 0.001). In males, 77% of the subjects, and 50% of the female subjects had an ischemic response in either region. The horizontal extension of the ischemic area ranged between 0.26 mm and 8.76 mm. Males had significantly higher baseline GBF and larger ischemia than females. At the base of the papilla, significant restoration of GBF was observed during compression in males, but not in females.ConclusionThe arcade anastomoses formed by the small arteries in the keratinized gingiva of the upper esthetic zone explain the consequences of vertical incisions. The considerable individual variations in ischemic responses might be the reason for unexpected surgical outcomes in some cases. Furthermore, there is increasing evidence that men have different vascular reactivity and/or regulation of collateral circulation than women, which may affect wound healing.

The capillary fascicle in skeletal muscle: Structural and functional physiology of RBC distribution in capillary networks.

The capillary module, consisting of parallel capillaries from arteriole to venule, is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres. Using intravital video microscopy of resting extensor digitorum longus muscle in rats, we demonstrated the capillary fascicle as a series of interconnected modules forming continuous columns that align naturally with the dimensions of the muscle fascicle. We observed structural heterogeneity for module topology, and functional heterogeneity in space and time for capillary-red blood cell (RBC) haemodynamics within a module and between modules. We found that module RBC haemodynamics were independent of module resistance, providing direct evidence for microvascular flow regulation at the level of the capillary module. The capillary fascicle is an updated paradigm for characterizing blood flow and RBC distribution in skeletal muscle capillary networks. Capillary networks are the fundamental site of oxygen exchange in the microcirculation. The capillary module (CM), consisting of parallel capillaries from terminal arteriole (TA) to post-capillary venule (PCV), is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres, requiring co-ordination from numerous modules. It has previously been recognized that TAs and PCVs interact with multiple CMs, creating interconnected networks. Using label-free intravital video microscopy of resting extensor digitorum longus muscle in rats, we found that these networks form continuous columns of linked CMs spanning thousands of microns, herein denoted as the capillary fascicle (CF); this structure aligns naturally with the dimensions of the muscle fascicle. We measured capillary-red blood cell (RBC) haemodynamics and module topology (n=9 networks, 327modules, 1491 capillary segments). The average module had length 481μm, width 157μm and 9.51parallel capillaries. We observed structural heterogeneity for CM topology, and functional heterogeneity in space and time for capillary-RBC haemodynamics within a module and between modules. There was no correlation between capillary RBC velocity and lineal density. A passive inverse relationship between module length and haemodynamics was remarkably absent, providing direct evidence for microvascular flow regulation at the level of the CM. In summary, the CF is an updated paradigm for characterizing RBC distribution in skeletal muscle, and strengthens the theory of capillary networks as major contributors to the signal that regulates capillary perfusion.