Critical Organ Systems Research Articles

0462 CPAP-Experienced Patient Perceptions of CPAP & Novel Nasopharyngeal Airway Device as CPAP Alternative for Obstructive Sleep Apnea

Abstract Introduction Untreated obstructive sleep apnea (OSA) can impact numerous critical organ systems with drastic health ramifications while decreasing daily quality of life of individuals and their family. While Continuous Positive Airway Pressure (CPAP) can be highly effective, adherence is remarkably low. This is a preliminary initiative to gauge patient perceptions of a new non-surgical nasopharyngeal airway (NPA) device in development for OSA. Methods An IRB-approved single-site study surveyed 10 patients with polysomnography-confirmed OSA and at least 3 months’ experience using CPAP therapy. An independent expert in patient-reported outcomes helped develop the instrument to understand perceptions and attitudes towards CPAP and gauge initial reactions to the NPA-OSA device. This was reviewed by three Sleep Medicine experts for content validity. An NPA-OSA device description and insertion training video were provided to elicit feedback. Sixty-minute telephone interviews were conducted with OSA patients and transcribed by the independent expert. Results Ten patients (4 male), participated with an age range from 31 to 82 years. Nine used CPAP nightly, although described situations when they would not. All participants described significant dissatisfaction with some aspect of their CPAP treatment (e.g., restrictions on sleep position, difficulty cleaning and traveling, reliance on electricity), though most cope and appreciate therapeutic benefit. Respondents were motivated to find new treatment options for OSA, but were not actively seeking new options. Surgical treatment was considered by most, but with fear of unsuccessful outcomes/complications. A few of the respondents had previously used oral appliances with limited success. When introduced to the NPA device, most participants were interested in trying it. Positive attributes were non-invasive, portable and not requiring electricity. Ultimately, participants believed that the device had the potential to improve sleep. Primary concerns were the potential of pain during insertion, discomfort during use, and treatment effectiveness. All those interviewed were interested in participating in a clinical trial using the device. Conclusion Patients successfully using CPAP may still be dissatisfied and motivated to explore new options. The NPA-OSA device was considered a compelling option. Support (if any) This work was funded by the University of Michigan Coulter program.

Microvascular dysfunction following cardiopulmonary bypass plays a central role in postoperative organ dysfunction.

Despite significant advances in surgical technique and strategies for tissue/organ protection, cardiac surgery involving cardiopulmonary bypass is a profound stressor on the human body and is associated with numerous intraoperative and postoperative collateral effects across different tissues and organ systems. Of note, cardiopulmonary bypass has been shown to induce significant alterations in microvascular reactivity. This involves altered myogenic tone, altered microvascular responsiveness to many endogenous vasoactive agonists, and generalized endothelial dysfunction across multiple vascular beds. This review begins with a survey of in vitro studies that examine the cellular mechanisms of microvascular dysfunction following cardiac surgery involving cardiopulmonary bypass, with a focus on endothelial activation, weakened barrier integrity, altered cell surface receptor expression, and changes in the balance between vasoconstrictive and vasodilatory mediators. Microvascular dysfunction in turn influences postoperative organ dysfunction in complex, poorly understood ways. Hence the second part of this review will highlight in vivo studies examining the effects of cardiac surgery on critical organ systems, notably the heart, brain, renal system, and skin/peripheral tissue vasculature. Clinical implications and possible areas for intervention will be discussed throughout the review.

Biology and postnatal development of organ systems of cynomolgus monkeys (Macaca fascicularis).

The cynomolgus macaque has become the most used non-human primate species in nonclinical safety assessment during the past decades. This review summarizes the biological data and organ system development milestones of the cynomolgus macaque available in the literature. The cynomolgus macaque is born precocious relative to humans in some organ systems (e.g., nervous, skeletal, respiratory, and gastrointestinal). Organ systems develop, refine, and expand at different rates after birth. In general, the respiratory, gastrointestinal, renal, and hematopoietic systems mature at approximately 3 years of age. The female reproductive, cardiovascular and hepatobiliary systems mature at approximately 4 years of age. The central nervous, skeletal, immune, male reproductive, and endocrine systems complete their development at approximately 5 to 9 years of age. The cynomolgus macaque has no meaningful developmental differences in critical organ systems between 2 and 3 years of age for use in nonclinical safety assessment.

Just When We Thought That COVID Was Over: A Systematic Review.

As the globe continues to grapple and scuffle with new emerging strains of COVID every day, a set of recovered patients continue to show persistent enervating symptoms. Many patients never fully recovered after COVID and had neurological and psychiatric symptoms for weeks or months. The emphasis of our study is on these long haulers, particularly on the two critical organ systems of the body, i.e., the central nervous system and the muscular system. Depending upon the severity of the disease, many signs and symptoms continue to linger, ranging from weeks to months.A total of 29 studies are included in our review after thorough screening, application of inclusion and exclusion criteria, and quality appraisals. The total number of patients included is 6012.We found many long-term effects, but the emphasis of our study continued to remain on the two main organ systems that resulted in prolonged COVID with debilitating symptoms and thus affected the quality of life of these patients. Various factors and underlying pathophysiologic manifestations result in the predominance of these signs and symptoms.Furthermore, the patient's underlying medical conditions and other environmental factors may add to it. More focus is required on the quality of life post-COVID, and this requires a team of specialists. There are still many unanswered questions like which ethnicity is affected more, why females are more prone to the long symptoms, and the effects of various treatments on the long-term signs and symptoms.

The METREPOL criteria—are they still relevant?

The medical management of radiation accidents manual on the acute radiation syndrome proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.

Nutrition and Fetal Origins of Diseases in Adults

Accumulating evidence suggests that the early-life environment has lasting effects on health and disease into adulthood. The current concept of developmental origins of adulthood disease has expanded beyond the original observation by Barker and colleagues correlating low birth weight with adulthood cardiovascular and metabolic disorders. Notably, the fetal-neonatal nutritional environment has a significant role in influencing an individual’s wellness in adulthood. During critical periods of fetal and neonatal development, tissues and organ systems are most vulnerable to nutrient deficiencies. Through fetal programming mechanisms such as epigenetic modification, a biochemical process that regulates gene expression without altering the genetic code, developing tissues adapt to nutrient-poor environments to preserve normal development of critical organ systems, including the brain. However, these programmed adaptations can have negative long-term health consequences if the postnatal environment does not match the fetal-neonatal environment in which the programming occurred. These long-term adverse health outcomes constitute the true cost to society, in both increased medical costs and the indirect cost of lost productivity. Here we review the effects of nutrient deficiencies on fetal programming and subsequent health outcomes, as well as the potential mechanisms that underlie fetal programming. This review contains 3 Figures, 2 Tables and 115 references Key words: critical period, epigenetics, fetal programming, iron, long-chain polyunsaturated fatty acids, neurodevelopment, nutrient deficiency, protein-energy, vitamins, zinc

Renal Toxicodynamic Effects of Extracellular Hemoglobin After Acute Exposure.

Plasma hemoglobin (Hb) is elevated in some hematologic disease states, during exposures to certain toxicants, and with the use of some medical devices. Exposure to free Hb can precipitate oxidative reactions within tissues and alter the normal physiological function of critical organ systems. As kidney structures can be highly sensitive to Hb exposures, we evaluated the acute dose dependent renal toxicologic response to purified Hb isolated from RBCs. Male Hartley guinea pigs (n = 5 per group) were dosed with 0.9% saline (2 ml), 15, 75, 150, or 300 mg of purified Hb, infused over a 2-h period. The primary endpoints of this study were to define toxicokinetic parameters after increasing doses of purified Hb, identify clinically recognized and experimental markers of acute kidney injury (AKI), and determine relevant toxicological parameters and potential causes of renal toxicity in this model. Experimental findings demonstrated a dose dependent increase in Cmax after a 2-h infusion, which correlated with an elevation in serum creatinine, renal Kim-1 mRNA expression and increased urinary Kim-1. Renal NGAL mRNA expression and urinary NGAL excretion were also increased in several groups, but these parameters did not correlate with exposure. Iron increased in the renal cortex as Hb exposure increased and its deposition colocalized with 4-hydroxy-nonenal and 8-Oxo-2-deoxyguanosine immune reactivity, suggesting oxidative stressors may contribute to AKI in animals exposed to Hb. The results presented here suggest that Cmax may effectively predict the risk of AKI in normal healthy animals exposed to Hb.

Human butyrylcholinesterase efficacy against nerve agent exposure.

Acetylcholinesterase is vital for normal operation of many processes in the body. Following exposure to organophosphorus (OP) nerve agents, death can ensue without immediate medical intervention. Current therapies mitigate the cholinergic crisis caused by nerve agents but do not fully prevent long-term health concerns, for example, brain damage following seizures. Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger being investigated as an antidote for OP nerve agent poisoning. HuBChE sequesters OP nerve agent in the bloodstream preventing the nerve agent from reaching critical target organ systems. HuBChE was effective when used as both a pre-treatment and as a post-exposure therapy. HuBChE has potential for use in both military settings and to protect civilian first responders in situations where nerve agent usage is suspected. We reviewed various animal models studies evaluating the efficacy of HuBChE against nerve agent exposure, pursuant to its submission for approval under the FDA Animal Rule.

Serum Retinol Concentrations, Race, and Socioeconomic Status in of Women of Childbearing Age in the United States.

Background: Vitamin A is an essential nutrient during pregnancy and throughout the lifecycle due to its role in the development of critical organ systems. Because maternal tissue is progressively depleted of vitamin A to supply fetal demands, women who become pregnant while possessing marginal vitamin A reserves are at increased risk of vitamin A inadequacy as pregnancy progresses. Few studies have assessed the relationship between socioeconomic factors and retinol status in women of childbearing age. Methods: We used the National Health and Nutrition Examination Survey (NHANES) to assess the relationship between serum retinol concentrations and socioeconomic factors in women of childbearing age. Women 14–45 years of age (n = 3170) from NHANES cycles 2003–2004 and 2005–2006 were included. Serum retinol concentrations were divided into categories according to World Health Organization criteria. All statistical procedures accounted for the weighted data and complex design of the NHANES sample. A p-value of < 0.05 was considered statistically significant. Results: The poverty score and race were significantly associated with vitamin A status after adjustment for confounders. Odds of retinol concentrations of <1.05 µmol/L were 1.85 times higher for those of lower socioeconomic status when compared to those of higher status (95% CI: 1.12–3.03, p = 0.02), and 3.1 times higher for non-Hispanic blacks when compared to non-Hispanic whites (95% CI: 1.50–6.41, p = 0.002). Dietary intakes of retinol activity equivalents were significantly lower in groups with higher poverty scores (p = 0.004). Conclusion There appear to be disparities in serum vitamin A levels in women of childbearing age related to income and race in the United States.

Proteomics-Based Identification of the Molecular Signatures of Liver Tissues from Aged Rats following Eight Weeks of Medium-Intensity Exercise.

Physical activity has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. Here, by combining functional and proteomics analyses, we examined how hepatic phenotypes might respond to exercise treatment in aged rats. 16 male aged (20 months old) SD rats were divided into exercise and parallel control groups at random; the exercise group had 8 weeks of treadmill training with medium intensity. Whole protein samples of the liver were extracted from both groups and separated by two-dimensional gel electrophoresis. Alternatively objective protein spots with >2-fold difference in expression were selected for enzymological extraction and MS/MS identification. Results show increased activity of the manganese superoxide dismutase and elevated glutathione levels in the livers of exercise-treated animals, but malondialdehyde contents obviously decreased in the liver of the exercise group. Proteomics-based identification of differentially expressed proteins provided an integrated view of the metabolic adaptations occurring in the liver proteome during exercise, which significantly altered the expression of several proteins involved in key liver metabolic pathways including mitochondrial sulfur, glycolysis, methionine, and protein metabolism. These findings indicate that exercise may be beneficial to aged rats through modulation of hepatic protein expression profiles.

The cooling tube: A novel small animal model of systemic hypothermia in awake Syrian Golden Hamsters (mesocricetus auratus).

Hypothermia is increasingly used as a therapeutic strategy in a diversity of clinical scenarios. Its impact on mammalian physiology, particularly on the microcirculatory changes of critical organ systems, are, however, incompletely understood. Close examination of the literature reveals a marked paucity of small animal models of rapid systemic hypothermia. All published models introduce important microvascular confounders by investigating either local cooling processes or using anaesthetised animals. Here we present the first rapid systemic hypothermia model in an awake hamster. We developed a waterstream cooled copper tube system for standardized systemic temperature control. With this novel system core body temperature (Tc) in 14 awake animals could be precisely stabilised at temperatures of 30°C and 18°C (7 animals, respectively) within 10-20 min. Rewarming was achieved over 10-15 min. Tolerance of the procedure was excellent. Hamsters did not show any behavioural changes in the mild hypothermia group. In the deep hypothermia group 6 of 7 animals regained normal behaviour within 2-11 hs. As hypothermia was induced in dorsal skinfold chamber bearing animals this model seems suitable for investigation of microcirculatory purposes.Advantages over previously established experimental hypothermia models are significant. Amongst these, the possibility of visualization of microcirculation, the lack of microcirculation confounding factors such as anaesthetic drugs, the ability for precise Tc control and rapid induction of hypothermia are prominent.

Stimulated Saliva Aminotransaminase Alteration After Experiencing Acute Hypoxia Training

ObjectiveAcute hypobaric hypoxia is generally recognized to be the most serious single physiological hazard during flight at altitude. Simulation of acute hypoxia in an altitude chamber is used for the training of military aircrew. Acute hypobaric hypoxia affects critical organ systems in different manners. The purpose of this study was to investigate stimulated saliva glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) alteration after the hypobaric hypoxia process. MethodsA cross-sectional study was performed in 44 normal healthy military aircrew conducted at the hypobaric chamber of physiology at the University of Medical Sciences, Tehran, Iran. The GPT and GOT activities were assayed in stimulated whole saliva before and after the experience of hypobaric hypoxia by the International Federation of Clinical Chemistry method. Statistical analysis of the Student t-test was performed. ResultsThe mean stimulated saliva GPT activity was significantly higher after the experience of the hypobaric hypoxia process (2.83 ± 0.34 vs. 0.42 ± 0.029 U/L, respectively; P = .001). Saliva GOT activity was also increased after this process (3.32 ± 0.43 vs. 1.22 ± 0.18 U/L, respectively; P = .001). ConclusionResults suggest that subsequent to the experience of the hypobaric hypoxia process, there is a rise in the salivary activities of aminotransferases.

Maternal exposure to hurricane destruction and fetal mortality

BackgroundThe majority of research documenting the public health impacts of natural disasters focuses on the well-being of adults and their living children. Negative effects may also occur in the unborn,...

Erdheim-Chester Disease: a comprehensive review of the literature

Erdheim-Chester Disease (ECD) is a rare form of non Langerhans' cell histiocytosis. Individuals affected by this disease are typically adults between their 5th and 7th decades of life. Males and females are almost equally affected. The multi systemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. Among the more common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, kidneys (retroperitoneum) and skin. The most common presenting symptom of ECD is bone pain. The etiology of ECD is unknown yet thought to be associated with an intense TH1 immune response. It may also be associated with the V600E BRAF mutation, as described in as many as half of the patients in recent studies. Bilateral symmetric increased tracer uptake on 99mTc bone scintigraphy affecting the periarticular regions of the long bones is highly suggestive of ECD. However, definite diagnosis of ECD is established only once CD68(+), CD1a(−) histiocytes are identified within a biopsy specimen. At present, this obscure ailment embodies numerous challenges to medical science. Given its rarity, it is diagnostically elusive and requires a high level of clinical suspicion. Therapeutically, it is of limited alternatives. Currently, interferon-α is the most extensively studied agent in the treatment of ECD and serves as the first line of treatment. Treatment with other agents is based on anecdotal case reports and on the basis of biological rationale. Nevertheless, cladribine (2CDA), anakinra and vemurafenib are currently advocated as promising second line treatments for patients whose response to interferon-α is unsatisfactory. Overall, the 5 year survival of ECD is 68%. Herein, the authors mustered and brought about a panoramic consolidation of all the relevant facts regarding ECD. This work highlights the different clinical, radiological and pathological manifestations associated with ECD, the differential diagnoses, the various treatment options and the acknowledged science explaining the disease.

Prediction and management of bleeding in cardiac surgery.

Excessive bleeding after cardiac surgery can result in increased morbidity and mortality related to transfusion- and hypoperfusion-related injuries to critical organ systems. Our objective was to review mechanisms that result in bleeding after cardiac surgery as well as current and emerging interventions to reduce bleeding and transfusion. We discovered that of point-of-care (POC) tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion by facilitating administration of specific pharmacologic or transfusion-based therapy and by allowing physicians to better differentiate between microvascular bleeding and surgical bleeding. Emerging interventions like recombinant FVIIa have the potential to reduce bleeding and transfusion-related sequelae and may be life-saving; however, randomized, controlled trials are needed to confirm safety before they can be used as either first-line therapies for bleeding or bleeding prophylaxis. In conclusion, careful investigation of the role of new interventions is essential as the ability to reduce use of blood products, to decrease operative time and/or re-exploration rates has important implications for overall patient safety and health care costs.

Development of a disease severity scoring system for patients with Pompe disease

A Disease Severity Scoring System (DS3) measures disease burden in patients. It consists of critical health domains, each described by relevant clinical assessment(s) quantified via reliable, valid and feasible methods. DS3s are particularly useful in rare, heterogeneous diseases in which evaluating severity and prognosis is difficult. Properly configured, a DS3 provides inter- and intra-patient comparisons through time across critical organ systems. A DS3 is being developed for Pompe disease, a rare, autosomal recessive, and heterogenous, neuromuscular disorder.

Risks associated with bleeding and transfusion: rationale for the optimal management of bleeding after cardiac surgery

Background and objectives: The main aim of this review is to summarize the literature with respect to transfusion and bleeding risks and the therapeutic strategies with respect to optimal management of perioperative bleeding. Methods: This review was generated using peer-reviewed manuscripts pertinent to this topic that were identified using a computer-based Medline search. Results: Although the pathophysiology of many transfusion-related complications are well-documented, the incidence of these complications is changing. Transfusion Medicine initiatives are being implemented to reduce complications, however, the literature is describing new potential problems related to transfusion in addition to identification of new potential pathogens while blood shortages may limit our ability to adequately manage our anemic and bleeding patients. Excessive bleeding after cardiac surgery can result in increased morbidity and mortality related to transfusion and hypoperfusion related complications as well as injury to critical organ systems. Seven of eight studies have demonstrated that use of point-of-care (POC) tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion after cardiac surgery. Two randomized prospective studies have demonstrated that point-of-care tests that assess platelet function can identify patients at risk for acquired, platelet-related bleeding that may be attenuated with pharmacologic agents such as DDAVP. The current literature contains fifty publications with over 400 patients that describe the fairly consistent efficacy of off-label use of recombinant factor VIIa to manage intractable, life-threatening bleeding. Most of these publications involve either case reports or case series that describe the use of this agent and therefore do not adequately address the safety of this agent. Conclusions: There are substantial risks related to excessive bleeding and transfusion. The literature indicates that use of point-of-care diagnostics with a standardized management algorithm can optimize the management of bleeding and reduce transfusion requirements. Recombinant FVIIa has the potential to reduce transfusion and transfusion-related sequelae and may be life-saving in certain circumstances. However, randomized, controlled trials are warranted to assess both the efficacy and, more importantly, the safety of this intervention (i.e., especially with respect to thrombotic complications) in cardiac surgical patients prior to its use as a first line therapy for bleeding or for bleeding prophylaxis. We must continue to carefully investigate the role of new interventions since the ability to reduce use of blood products, to decrease operative time and/or re-exploration rates has important implications for disease prevention and overall patient safety, blood inventory and associated costs as well as overall health care costs.

THE PROTECTIVE EFFECTS OF PUGNAC ON CARDIAC FUNCTION AFTER TRAUMA-HEMORRHAGE ARE MEDIATED VIA INCREASED PROTEIN O-GlcNAc LEVELS

We have previously shown that administration of glucosamine after trauma-hemorrhage (TH) improved cardiac output and organ perfusion, and this was associated with increased levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins in the heart and brain. An alternative means of increasing O-GlcNAc levels is by inhibition of O-linked N-acetylglucosaminidase, which catalyzes the removal of N-acetylglucosamine from proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc). The goal of this study, therefore, was to determine whether PUGNAc administration after TH also improves recovery of organ perfusion and function. Fasted male rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min, followed by fluid resuscitation. Intravenous administration of PUGNAc (200 micromol/kg body weight) 30 min after the onset of resuscitation significantly improved cardiac output compared with the vehicle controls (12.3 +/- 1.3 mL/min per 100 g body weight vs. 25.5 +/- 2.0 mL/min per 100 g body weight; P < 0.05), decreased total peripheral resistance (6.6 +/- 0.8 mmHg/mL per minute per 100 g body weight vs. 3.7 +/- 0.3 mmHg/mL per minute per 100 g body weight; P < 0.05), and increased perfusion of critical organ systems, including the kidney and liver, determined at 2 h after the end of resuscitation. Treatment with PUGNAc also attenuated the TH-induced increase in plasma IL-6 levels (864 +/- 112 pg/mL vs. 392 +/- 188 pg/mL; P < 0.05) and TNF-alpha levels (216 +/- 21 pg/mL vs. 94 +/- 11 pg/mL; P < 0.05) and significantly increased O-GlcNAc levels in the heart, liver, and kidney. Thus, PUGNAc, like glucosamine, improves cardiac function and organ perfusion and reduced the level of circulating IL-6 and TNF-alpha after TH. The similar effects of glucosamine and PUGNAc support the notion that the protection associated with both interventions is mediated via increased protein O-GlcNAc levels.

Mode of Action: Angiotensin-Converting Enzyme Inhibition—Developmental Effects Associated With Exposure to ACE Inhibitors

Relative to species tested in laboratory studies, the human fetus displays higher vulnerability to enalapril and other angiotensin-converting enzyme inhibitors (ACEI) exhibiting a malformative syndrome that does not appear to have a similar counterpart in experimental animals. An important reason for this higher vulnerability is the earlier intrauterine development of the kidney and the renin–angiotensin–aldosterone (RAS) system in humans, organ systems that are specific targets of ACEI's pharmacological effect. In humans, these systems begin developing prior to the onset of skeletal ossification at the end of the first trimester, with continuing vulnerability throughout the pregnancy. In most animal species tested, these target systems develop close to term, when the fetus is relatively more mature and less vulnerable to the effects of developmental toxicants. For this reason, animal studies that follow standard protocols and evaluate developmental toxicity only for exposures during embryogenesis will miss developmental effects arising secondary to disruption of target systems that develop after the period of major organogenesis. Thus, although the animal mode of action (MOA) for enalapril and other ACEI is plausible in humans, differences in the timing of development of critical target organ systems, particularly the renal system and RAS, explain the absence of definitive structural abnormalities in test animals.

A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure?

Over the past two decades, investigators have increasingly recognised the importance of the endothelium as a central regulator of vascular and body homeostasis. The vascular endothelium is versatile and multifunctional. In addition to its role as a selective permeability barrier, it has many synthetic and metabolic properties, including modulation of vascular tone and blood flow, regulation of immune and inflammatory responses, and regulation of coagulation, fibrinolysis and thrombosis. Perturbations of endothelial structure and function result in pathological states. Following radiation exposure, changes of the vasculature and more specifically of the endothelial cells were a prominent histological finding dating back more than a century. Since then, there have been numerous studies detailing the morphological and functional changes seen in all types of vessels following irradiation of critical organ systems. This review addresses the question of how alterations in endothelial cell functions could play a...