Intravascular Compartment Research Articles

Abstract 369: Role of bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial.

Abstract Background: Based on bone marrow (BM) biopsies, increased angiogenesis has been reported in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients compared with individuals with monoclonal gammopathy of undetermined significance (MGUS). In this prospective clinical trial open for MGUS, SMM and MM patients, we conducted BM biopsies and used immunohistochemistry to define microvessel density (MVD) in every patient; results were compared to results obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and multiplex ELISA-based serum angiogenic cytokine assays. Patients and Methods: We included 10 MGUS, 10 SMM and 10 MM patients. We performed DCE-MRI of entire lumbosacral spine to compare exchange rate constants (contrast agent transit from the extravascular compartment to the intravascular compartment, Kep; movement of contrast agent from plasma to extravascular extracellular space, Ktrans) with bone marrow biopsies immunostained with CD34 as measures of MVD, and serum angiogenic markers By ELISA to include EGF, Ang2, GCSF, BMP9, endoglin, Leptin, Follistatin, IL8, HGF, HBEGF, PLGF, VEGFC, VEGFD, FGF2, VEGFA. The association among continous parameters was determined by Spearman rank correlation. Trends in continuous parameters according to ordered categorical parameter were determined by Jonckheere-Terpstra test for trend. The parameters between two groups were compared using an exact Wilcoxon rank sum test. Results: Both MVD and Kep increased along the myeloma spectrum (MGUS < SMM < MM). MVD and Kep were strongly correlated (r=0.93 and p=0.002). Ktrans was weakly to moderately well correlated with MVD (r=0.43 p=0.03). Higher Kep values were seen in MM/SMM vs. MGUS patients (median 7.1 vs. 3.9; p=0.08). Similarly, higher MVD values were seen in MM/SMM patients versus MGUS (median 20 vs. 15; p=0.01). As regards serum angiogenic markers, levels of HGF (r=0.45; p=0.02), Ang2(r=0.37 and p=0.06), and VEGFD (r=-0.35 and p=0.07), correlated with Kep. The levels of Ang2 (p=0.02), GCSF (p=0.06), follistatin (p=0.06), HGF (p=0.01), and VEGFA (p=0.02), were elevated in MM/SMM patients in comparison to MGUS. Other angiogenic cytokines did not correlate with MVD or Kep. Conclusions: MVD and Kep (measured by DCE-MRI) were highly statistically correlated. MVD increased along the disease spectrum from MGUS to SMM to MM (p=0.008). Some, but not all, angiogenic biomarkers detected in peripheral blood were associated with increased vascularity in the bone marrow. Citation Format: Manisha Bhutani, Esther Mena, Irina Maric, Esther Tan, Neha Korde, Alexandra R. Berg, Alex R. Minter, Brendan M. Weiss, Liza Lindenberg, Baris Turkbey, Omer Aras, Seth Steinberg, Troy Kemp, Katherine R. Calvo, Peter L. Choyke, Karen Kurdziel, Ola Landgren. Role of bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2013-369

Serial Intrauterine Transfusions for a Hydropic Fetus with Severe Anemia and Thrombocytopenia Caused by Parvovirus: Lessons Learned

Introduction Fetal exsanguination is a rare complication of cordocentesis. Successful correction of fetal thrombocytopenia is essential for the reduction of risks.Case Report A 25-year-old, gravida 3, P2-0-0-0-2, was referred at 27 weeks of gestation for evaluation of newly diagnosed nonimmune hydrops secondary to parvovirus infection. Despite the use of ancillary platelet transfusions to correct the severe fetal thrombocytopenia, prolonged bleeding from the cord puncture site still occurred, necessitating five intrauterine transfusions to ultimately correct the fetal anemia.Conclusions The use of a smaller-diameter procedure needle, correction of the fetal thrombocytopenia early in the procedure, and external cord compression with the ultrasound transducer were ultimately successful measures in allowing for minimal loss of transfused red cells from the intravascular compartment.

Co-loading or pre-loading for prevention of hypotension after spinal anaesthesia! a therapeutic dilemma

Neuraxial blockade such as spinal anaesthesia can cause severe hypotension due to pharmacological sympathectomy resulting in potential deleterious consequences for the patient. Prevention of this spinal anaesthesia induced hypotension is of utmost importance especially in pregnant population as the life of mother as well as fetus is at risk. Several techniques and methodologies have been adopted for the prevention of this neuraxial hypotension with varying degree of success. The administration of intravenous fluids to optimize the blood volume during sympathectomy has been the most popular and widely used as the first line of therapy among these techniques. The intravenous fluids can be used both before and during the administration of spinal anaesthesia, the techniques appropriately named as pre-loading and co-loading respectively. Numerous research studies and available literary evidence suggests that both of these techniques can be equally effective in prevention of hypotension. The use of colloids has been observed to be more effective for pre-loading due to their longer half-life in the intravascular compartment. However, it has also been suggested that no technique is efficient in preventing the hypotension alone and has to be coupled with judicious use of vasopressors.

Ovarian Hyperstimulation Syndrome as an Etiology of Obstructive Uropathy

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian hyperstimulation (COH) protocols performed in women undergoing assisted reproductive technologies. Overstimulation of the ovaries results in the overproduction of vasoactive cytokines and mediators by the ovaries, thereby causing a generalized capillary leak and acute shift of protein-rich fluid from the intravascular compartment into the third space. This may lead to the development of ascites, pleural effusions, pericardial effusion, anasarca, intravascular volume depletion, hemoconcentration, oliguria, hypoalbuminemia and hypoproteinemia, electrolyte imbalances, acute renal failure, abdominal compartment syndrome, thromboembolic events, and adult respiratory distress syndrome. The only effective treatment available is prevention of the syndrome from developing by individualizing the stimulation protocol, especially in high-risk patients. Once the syndrome develops, the management is mainly supportive. Oliguria and some degree of acute renal failure commonly develop in patients with moderate to severe OHSS and are usually due to prerenal causes. Acute renal failure (ARF) secondary to obstructive uropathy is rare. Here we report a case of severe, life-threatening OHSS resulting in ARF secondary to obstructive uropathy.

Quantitative imaging assessment of blood-brain barrier permeability in humans

The blood–brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the “post-pre” and the “linear dynamic” methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such “easy to use” and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Surfactant deactivation in a pediatric model induces hypovolemia and fluid shift to the extravascular lung compartment

Surfactant deficiency is the pivotal abnormality in Neonatal and Acute Respiratory Distress Syndrome. Surfactant deactivation can produce hypoxemia, loss of lung compliance, and pulmonary edema, but its circulatory consequences are less understood. To describe the sequential hemodynamic changes and pulmonary edema formation after surfactant deactivation in piglets. Surfactant deactivation was induced by tracheal instillation of polysorbate 20 in 15 anesthetized and mechanically ventilated Large White piglets. The hemodynamic consequences of surfactant deactivation were assessed at 30, 120, and 240min by transpulmonary thermodilution and traditional methods. Surfactant deactivation caused hypoxemia, reduced lung compliance, and progressively increased lung water content (P<0.01). Early hypovolemia was observed, with reductions of the global end-diastolic volume and stroke volume (P<0.05). Reduced cardiac output was observed at the end of the study (P<0.05). Standard monitoring was unable to detect these early preload alterations. Surprisingly, the bronchoalveolar protein content was greatly increased at the end of the study compared with baseline levels (P<0.01). This finding was inconsistent with the notion that the pulmonary edema induced by surfactant deactivation was exclusively caused by high surface tension. Hypovolemia develops early after surfactant deactivation, in part due to the resulting fluid shift from the intravascular compartment to the lungs.

Ischemia–reperfusion impairs blood–brain barrier function and alters tight junction protein expression in the ovine fetus

The blood–brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood–brain barrier. Hypoxic–ischemic damage to the blood–brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood–brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood–brain barrier function in the fetus. Blood–brain barrier function was quantified with the blood-to-brain transfer constant (Ki) and tight junction proteins by Western immunoblot in fetal sheep at 127days of gestation without ischemia, and 4, 24, or 48h after ischemia. The largest increase in Ki (P<0.05) was 4h after ischemia. Occludin and claudin-5 expressions decreased at 4h, but returned toward control levels 24 and 48h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between Ki and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood–brain barrier function after ischemia. We conclude that impaired blood–brain barrier function is an important component of hypoxic–ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (Ki) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4h after ischemia and blood–brain barrier function improves early after injury because the blood–brain barrier is less permeable 24 and 48 than 4h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood–brain barrier permeability after ischemia.

Better lung protection following death due to rapid exsanguination in rats

Background: This study aims to investigate the effects of death due to rapid exsanguination on the viability of lung tissue. Methods: Fourty-six Sprague-Dawley male rats with a weight range of 310-370 g were included in the study. Rats were divided into six groups: (i) ischemic alone (I group; n=8); (ii) passive exsanguination group of whose major abdominal veins were cut following death (PE group; n=8) (iii) group of whose major abdominal veins were cut and sacrified with rapid exsanguination (RE group; n=8); (iv) lung perfusion group with saline (SP group; n=8); (v) lung perfusion group with Perfadex (PP group; n=8) and (vi) control group (C group; n=6). Rats in all experiement groups except rapid exsanguination ones and all in the control group were euthanized with intrahepatic pentobarbital. Lungs were removed following euthanasia in the controls. In all study groups, lungs were ventilated in the cadavers at room temperature for 120 minutes and kept in warm ischemia. Results: Myeloperoxidase (MPO) activity, luminol chemiluminescence (CL) values and non-viable cell rate were higher in the ischemia group. The PE group had increased MPO activity, lucigenin CL values and nonviable cell rate, whereas the RE group had reduced MPO activity and luminol CL values, compared to ischemia group. MPO activity, lucigenin CL levels and non-viable cell rate were lower in the RE group, compared to PE. The PP had lower MPO activity and luminol CL values, compared to SP or ischemia group, whereas non-viable cell rate increased. Conclusion: Death following rapid exsanguination results in better preservation of lung viability and minimal oxidative injury. This may be explained by rapid loss of platelets and inflammatory cells in the tissue and shift of extravascular fluid to intravascular compartment.

Evaluation of Equine Albumin Solution in Fluid Therapy in Horses with Colic

Equine albumin solution can be a good therapeutic option in fluid replacement for treatment of horses with colic. The purpose of this study was to evaluate the effects of initial fluid therapy with equine albumin solution in horses presenting with colic and mild-to-moderate dehydration, and to compare this therapy with fluid therapy based on crystalloids alone. Nineteen horses of both genders presenting with colic and mild-to-moderate dehydration were used. Animals were randomly assigned to one of two groups (control: fluid therapy based on crystalloid solutions; experimental: fluid therapy based on equine albumin and crystalloid solutions). Physical examination, hematocrit determination, blood gas analysis, serum biochemistry, blood and peritoneal lactate assessment, and measurement of colloid osmotic and arterial pressure were performed at predetermined times. Good results were obtained with equine albumin solution. More fluid is attracted into and maintained in the intravascular compartment, despite infusion of small volumes, as indicated by higher arterial pressure, lower capillary refill time, lower hematocrit and serum protein concentrations, lower colloid osmotic pressure, and better skin turgor. Equine albumin solution has good oncotic action and is a safe fluid therapy option for horses with colic and mild-to-moderate dehydration. Our results suggest it can be a good choice of fluid for correction of severe dehydration, although further research is necessary to determine the adequate dose in such cases.

Pathophysiology, staging and therapy of severe sepsis in baboon models

We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which – depending on its intensity – activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD100 and LD50 E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.

Percutaneous Intraluminal Intravascular Retrieval of Foreign Body Under Ultrasound Guidance

Percutaneous retrieval of intravascular foreign body is a safe and effective procedure with the use of various imaging modalities. However, fluoroscopy is used extensively in most of the procedures, because the broken fragments which gets retained in intravascular compartments are radiopaque. In our case, the broken fragment, which was retained in the internal jugular vein, was radiolucent. Retrieval of a radiolucent foreign body under fluoroscopy is not only difficult but also can lead to serious sequelae during retrieval. We report such a case of real time ultrasound-guided retrieval of the foreign body in adjunct with fluoroscopy.

How Accurate Is Pulse Pressure Variation as a Predictor of Fluid Responsiveness?

To the Editor: We read with interest the Perioperative Medicine article “Assessing the Diagnostic Accuracy of Pulse Pressure Variations for the Prediction of Fluid Responsiveness: A ‘Gray Zone’ Approach” by Cannesson et al. 1and its accompanying editorial: “Insights in a ‘Gray Zone.’”2Fluid responsiveness is based on the proposition that an increase in cardiac output by at least a certain amount may be achieved by a specific bolus of a specified fluid, whereas nonresponders will require other means to increase the cardiac output. There are a number of limitations with this definition. The type of fluid used will have an impact on the amount of expansion of the intravascular compartment. In the study, iso-oncotic colloid was used, but even the volume effect of this will depend on the volume status of the patient (context sensitive).3Associated with this is the fact that the endothelial glycocalyx is degraded by the release of cytokines during surgery or the release of atrial naturietic peptide caused by hypervolemia.4The minimally required increase in cardiac output will have a direct impact on the size of the “gray zone,” as was demonstrated in the study, and the utility of bolus fluid therapy has been questioned following the publication of the Feast trial.5Fluid responsiveness assessed by pulse pressure variation cannot distinguish between an increase in variation caused by fluid loss from that caused by vasodilation.The concept of pulse pressure variation is closely related to the respiratory cycle and changes in pleural pressure. Pleural pressure changes are impacted by either smaller tidal volumes or poor lung compliance. As an extreme example, high-frequency oscillation ventilation results in minimal pulse pressure variation irrespective of the volume status of the patient. For patients within the “gray zone,” increasing the tidal volume may increase the pulse pressure variation indicating fluid responsiveness.Although it may be reasonable to give a fluid bolus to patients above the upper limit of the gray zone, a knowledge of the cardiac output is extremely useful to make an informed decision on treatment for patients in or below the gray zone and avoid overloading the interstitial space with fluids. Lichtenstein6has suggested that transthoracic ultrasound of the lungs may be useful in the early detection of interstitial syndrome (because of fluid overload, cardiac failure, or increased capillary permeability) by observing a change from A-line predominance to B-line predominance.There are several limitations of the study that may make it difficult to apply to a more general population, including the male predominance in the study (75%) and the selection of mainly cardiac or abdominal aortic surgery (88%) with only 22% being general surgery.

Management of fluid balance

Managing fluid balance mandates a clear identification of what goals are being sought at a particular point in the patient's pathway, an accurate assessment of both filling status and the degree of tissue hypoperfusion (if present), and a precise evaluation of response. As no definitive data exist to show how the above targets should be optimally achieved, and with what fluid, many opinions of varied veracity currently exist. A perception from recent surveys is that critical care and intraoperative patients in Europe are more likely to receive synthetic colloid as the primary resuscitation fluid and to have cardiac output monitored by noninvasive or minimally invasive monitoring techniques. However, these preferences are based largely on tradition and local technology developments, albeit with an increasing evidence base for high-risk surgery. There is an increasing consensus that excess fluid should be avoided and that, after the initial resuscitation phase, efforts should be made to keep the patient in neutral (or perhaps negative) balance, unless clinically indicated. Likewise, the intravascular compartment should not remain underfilled if tissue hypoperfusion exists, acknowledging the above difficulties in agreeing upon definition and diagnosis. Achieving and maintaining optimal fluid balance remains a significant challenge; better monitoring tools and definitive studies are needed.

Multi-organ intravascular large B-Cell lymphoma: a case report

Intravascular large B-cell lymphoma (IVLBCL), a subtype of diffuse large B-cell lymphoma, is a rare entity characterised by proliferation of malignant lymphocytes within the intravascular compartment usually without involvement of lymph nodes. It has a heterogeneous clinical presentation and aggressive, often fatal, clinical course. As such the diagnosis is often made at autopsy. This case report presents a 46-year-old male in whom the diagnosis of IVLBCL affecting multiple organs was established at autopsy. The variable presenting and clinical features of this entity are discussed with the aim of heightening the awareness of this aggressive disease.

Eliminating or blocking 12/15-lipoxygenase reduces neutrophil recruitment in mouse models of acute lung injury

IntroductionAcute lung injury (ALI) is a common disease in critically ill patients with a high morbidity and mortality. 12/15-lipoxygenase (12/15-LO) is an enzyme generating 12-hydroxy-eicosatetraenoic acid (12-HETE) and 15-HETE from arachidonic acid. It has been shown that 12/15-LO is involved in the regulation of vascular permeability during ALI.MethodsTo test whether 12/15-LO participates in leukocyte recruitment into the lung, we investigated the role of 12/15-LO in mouse models of lipopolysaccharide (LPS)-induced pulmonary inflammation and acid-induced ALI, a clinically relevant model of acute lung injury.ResultsThe increase in neutrophil recruitment following LPS inhalation was reduced in 12/15-LO-deficient (Alox15-/-) mice and in wild-type (WT) mice after the blocking of 12/15-LO with a pharmacological inhibitor. Bone marrow chimeras revealed that 12/15-LO in hematopoietic cells regulates neutrophil accumulation in the interstitial and alveolar compartments, whereas the accumulation of neutrophils in the intravascular compartment is regulated by 12/15-LO in non-hematopoietic and hematopoietic cells. Mechanistically, the increased plasma levels of the chemokine CXCL1 in Alox15-/- mice led to a reduced response of the neutrophil chemokine receptor CXCR2 to stimulation with CXCL1, which in turn abrogated neutrophil recruitment. Alox15-/- mice also showed decreased edema formation, reduced neutrophil recruitment and improved gas exchange in an acid-induced ALI model.ConclusionsOur findings suggest that 12/15-LO modulates neutrophil recruitment into the lung by regulating chemokine/chemokine receptor homeostasis.

Chapter 8. Hyperosmolar therapy

Chapter 8. Hyperosmolar therapy

Novel Molecular Imaging Detects Evidence of Altered Bone Marrow Biology in Myeloma Precursor Disease (MGUS and smoldering myeloma): A Prospective Clinical Study

Abstract▪2888▪This icon denotes a clinically relevant abstractDespite its poor sensitivity to detect bone lesions, its inability to define focal disease in the bone marrow, and its incapacity to identify extramedullary disease; skeletal survey remains the gold standard in multiple myeloma (MM). We conducted a prospective clinical study to evaluate novel molecular imaging in MM and its precursors (monoclonal gammopathy of undetermined significance, MGUS; smoldering myeloma, SMM).We included 10 MGUS, 10 SMM, and 10 MM (2/8; untreated/treated) patients. To define evidence of osteolytic lesions and extramedullary disease, all patients were assessed by skeletal survey, fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), 18F-sodium fluoride (18F-NaF) PET/CT. To assess bone marrow vascularity we conducted dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). Using DCE-MRI, we compared exchange rate constants (contrast agent transit from the extravascular compartment to the intravascular compartment, kep ; movement of contrast agent from plasma to extravascular extracellular space, ktrans) with bone marrow biopsies immunostained with CD34 as measures of microvessel density (MVD).All but one MGUS patients were negative by 18F-FDG. One had indeterminate uptake in possible early myelomatous lesions but was negative on 18F-NaF. Two MGUS patients had unexplained focal uptake in bone (one in the left orbital sphenoid and another in the left temporal bone) without CT abnormalities. Two SMM patients had abnormalities by PET/CT. One SMM patient had subtle increased 18F-NaF PET uptake in T12 which corresponded to CT, MRI and DCE-MRI abnormalities in this region; 18F-FDG PET and skeletal survey were negative. Another SMM patient had increased 18F-FDG PET uptake in the left clavicle with negative 18F-NaF that was biopsy proven to be consistent with disease. In 8 MM patients, both 18F-FDG and 18F-NaF PET/CT showed mild to moderate positive PET uptake corresponding with CT abnormalities; the remaining 2 MM patients had CT abnormalities, which were 18F-NaF positive, corresponding with skeletal survey, while 18F-FDG PET was negative. Immunohistochemistry and kep were correlated (r=0.64 and p=0.0003), and DCE-MRI showed higher kep levels in MM versus MGUS patients (mean kep 9.4 vs. 5.0; p<0.05); suggesting that increased MVD may be associated with transformation from early precursor disease to frank malignancy. In 2 MGUS patients and 1 SMM patient, DCE-MRI showed focal disease in the bone marrow.Novel molecular imaging techniques detected evidence of altered bone marrow biology in myeloma precursor disease, which was not found on skeletal survey. Our results emphasize the broad biological and clinical heterogeneity in myeloma precursor disease, and the need for molecularly defined phenotypes. This study provides new avenues for future investigations designed to (1) initiate/monitor early treatment in high-risk myeloma precursor disease and (2) to monitor minimal residual disease and/or to detect early relapse. Detailed imaging, clinical, and molecular data will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.

Sympathetically Mediated Changes in Capacitance

“To be accepted as a paradigm, a theory must seem better than its competitors, but it need not, and in fact never does, explain all the facts with which it can be confronted.” Thomas Kuhn, The Structure of Scientific Revolutions ### Heard on Rounds “A 57-year-old patient with a history of heart failure states that she began experiencing worsening shortness of breath 4 days prior to admission, with lower extremity edema developing 1 day prior to admission. She is compliant with her medications, though has had similar admissions previously. She states that her weight at home increased by “a couple of pounds” 2 days ago and that she increased her diuretic dose but her symptoms worsened. She says that she generally adheres to her low salt diet, but admits to eating pretzels 5 days ago. The physical examination showed BP 136/84, HR 94, weight 3 lbs above baseline, elevated JVP, basilar rales, and 1+ pedal edema.” As the intern finishes the presentation, the Senior expresses surprise that the patient's weight had increased only 3 pounds, and comments about salt and volume overload leading to acute decompensated heart failure (ADHF). The Attending adds that recent data reveal that many patients presenting with ADHF have minimal or no weight gain, but that there is no clear mechanism to explain this phenomenon. They set in place plans for diuresis, increasing vasodilators, and further patient education. On the surface, there is nothing remarkable about this case, and the usual approaches to treat this entity have remained remarkably consistent since the advent of loop diuretics over 50 years ago: salt restriction, patient education, uptitration of medications if not already at optimal doses, and diuresis. However, approximately 1 in 4 such patients are readmitted to the hospital within 30 days,1 and the disease continues to progress. It is clear …

Blood‐Ocular Barriers and Macular Edema

AbstractThe blood‐ocular barrier system is formed by two main barriers: the blood‐aqueous barrier (BAB) and the blood‐retinal barrier (BRB). Homeostasis in the retina microenvironment is maintained by the function of the BRB which regulates the movement of chemicals and cells between the intravascular compartment and the retina. The BRB consists of two major topographically distinct components: the endothelium of the retinal vessels (inner BRB) and the retinal pigment epithelium (outer BRB). The barrier function of the retinal vascular endothelium depends on its continuous epithelial‐like arrangement with the endothelial cells united by tight junctions, whereas the ability of the retinal pigment epithelium to regulate solute transport depends on the apical tight junctions between these cells. The tight junctions are membrane fusion areas between adjacent cells that serve as a diffusion barrier for paracellular transport and as a “molecular fence”, restricting the free movement of transmembrane proteins, and thus maintaining cell polarity and the asymmetric distribution of transmembrane proteins. Among the most important proteins that are associated with tight junctions are occludin, zonula occludens and claudins. Pathologic increase in blood retinal permeability can be caused by endothelial damage, tight junction disassembly, or cytokines such as vascular endothelial growth factor. Several methods have been developed to allow detection, quantification and monitoring of BRB breakdown in experimental and clinical settings. In humans, fluorescein angiography, vitreous fluorophotometry and OCT are the most commonly used. Alterations of the BRB play a crucial role in the development of retinal edema. Macular edema is the result of an accumulation of fluid in the retinal layers around the fovea, contributing to vision loss by altering the functional relationship in the retina and promoting an inflammatory reparative response. The accumulation of fluid is directly associated with an alteration of the BRB. In this situation the protective effect of the BRB is lost and Starling’s law applies.

E-016 Intracranial endoluminal waveform analysis to understand the underlying pathophysiology and quantify treatment effect: case illustration involving venous sinus stenosis

IntroductionExtracranial waveform analysis of both arterial and venous intravascular compartments is common. Any catheter with a fluid-filled lumen that is of sufficient inner diameter to support transducing a pressure waveform...