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Renewed interest in the age-old concept of “bloodletting”, a therapeutic approach practiced until as recently as the 19th century, has been stimulated by the knowledge that blood loss, such as following regular donation, is associated with significant reductions in key hemorheological variables, including whole blood viscosity (WBV), plasma viscosity, hematocrit and fibrinogen. An elevated WBV appears to be both a strong predictor of cardiovascular disease and an important factor in the development of atherosclerosis. Elevated WBV through wall shear stress is the most direct physiological parameter that influences the rupture and erosion of vulnerable plaques. In addition to WBV reduction, phlebotomy may reduce an individual’s cardiovascular risk through reductions in excessive iron, oxidative stress and inflammation. Reflecting these findings, blood donation in males has shown significant drops in the incidence of cardiovascular events, as well as in procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Collectively, the available data on the benefits of therapeutic phlebotomy point to the importance of monitoring WBV as part of a cardiovascular risk factor, along with other risk-modifying measures, whenever an increased cardiovascular risk is detected. The development of a scanning capillary tube viscometer allows the measurement of WBV in a clinical setting, which can prove to be valuable in providing an early warning sign of an increased risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

The article discusses the importance of monitoring blood viscosity during cardiopulmonary bypass (CPB), which involves interventions; hemodilution and lowering core body temperature, which have opposing effects on blood viscosity. The Edinburgh Artery Study reported on the relationship of blood viscosity and elevated carotid intima-media thickening (IMT). Blood viscosity data in this population could provide a better basis for intra-operative and post-operative management of patients in an effort to minimize neurological complications.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sloop et al.)

A 76-year-old female followed closely for five years with IgM monoclonal gammopathy of uncertain significance developed anemia, worsened plasma creatinine concentration, and markedly elevated serum viscosity. This case illustrates the scope of pathology that can be caused by elevated blood viscosity. Our patient's anemia was a homeostatic response to normalize systemic vascular resistance and resulted from activation of the systemic vascular resistance response. The elevated plasma creatinine resulted from decreased renal perfusion because of elevated blood viscosity. Recent insights in hemorheology (the study of blood flow) are discussed, namely the recent identification of preferential blood flow patterns and erythrocyte autoregulation of deformability. These insights confirm that blood viscosity is part of the "milieu intérieur.", Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sloop et al.)

Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a distinctive hyperviscosity syndrome which affects areas of high and low shear. A change in blood viscosity causes a threefold inverse change in blood flow, which increases the risk of thrombosis in both arteries and veins despite prophylactic anticoagulation. Increased blood viscosity decreases perfusion of all tissues, including the lungs, heart, and brain. Decreased perfusion of the lungs causes global ventilation-perfusion mismatch which results in silent hypoxemia and decreased efficacy of positive pressure ventilation in treating pulmonary failure in COVID-19. Increased blood viscosity causes a mismatch in oxygen supply and demand in the heart, resulting in myocarditis and ventricular diastolic dysfunction. Decreased perfusion of the brain causes demyelination because of a sublethal cell injury to oligodendrocytes. Hyperviscosity can cause stasis in capillaries, which can cause endothelial necrosis. This can lead to the rarefaction of capillary beds, which is noted in "long-COVID." The genome of the virus which causes COVID-19, severe acute respiratory syndrome coronavirus 2, contains an extraordinarily high number of the oligonucleotide virulence factor 5'-purine-uridine-uridine-purine-uridine-3', which binds to toll-like receptor 8, hyperactivating innate immunity. This can lead to a marked elevation in fibrinogen levels and an increased prevalence of neutrophil extracellular traps in pulmonary failure, as seen in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sloop et al.)

Background The copy number of the oligonucleotide 5'-purine-uridine-uridine-purine-uridine-3' (purUUpurU) motif in a viral genome was previously shown to correlate with the severity of acute illness. This study aimed to determine whether purUUpurU content correlates with virulence in other single-strand RNA (ssRNA) viruses that vary in clinical severity. Methodology We determined the copy number of purUUpurU in the genomes of two subtypes of human respiratory syncytial virus (RSV), respiratory syncytial virus A (RSV-A), and respiratory syncytial virus B (RSV-B), which vary in clinical severity. In addition, we determined the purUUpurU content of the four ebolaviruses that cause human disease, dengue virus, rabies virus, human rhinovirus-A, poliovirus type 1, astrovirus, rubella, yellow fever virus, and measles virus. Viral nucleotide sequence files were downloaded from the National Center for Biotechnology Information (NCBI)/National Institutes of Health website. In addition, we determined the cumulative case fatality rate of 20 epidemics of the Ebola virus and compared it with that of the other human ebolaviruses. Results The genomic purUUpurU content correlated with the severity of acute illness caused by both subtypes of RSV and human ebolaviruses. The lowest purUUpurU content was in the genome of the rubella virus, which causes mild disease. Conclusions The quantity of genomic purUUpurU is a virulence factor in ssRNA viruses. Blood hyperviscosity is one mechanism by which purUUpurU causes pathology. Comparative quantitative genomic analysis for purUUpurU will be helpful in estimating the risk posed by emergent ssRNA viruses., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sohn et al.)

Background Coronavirus disease 2019 (COVID-19) can be associated with pathologic inflammation. The authors hypothesize that a high copy number of a purine-uridine-rich nucleotide motif is present in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hyperactivates innate immunity. Methods The number of purine-uridine-uridine-purine-uridine (purUUpurU) motifs was counted in the genomes of SARS-CoV-2 and other single-strand RNA viruses. The nucleotides of SARS-CoV-2 in random order were used as a control. Results PurUUpurU occurred 2.8 times more often in the actual SARS-CoV-2 genome than the randomized genome. The number of purUUpurU motifs correlates with the potential severity of acute illness caused by these viruses, except for influenza A. Conclusion The large number of purUUpurU in SARS-CoV-2 may hyperactivate innate immunity, potentially causing the markedly increased concentrations of cytokines, acute phase reactants, and blood viscosity that can be seen in COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sloop et al.)

Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Sloop et al.)

Apolipoprotein(a) [apo(a)] is an apolipoprotein unique to lipoprotein(a) [Lp(a)]. Although it has no known function, Lp(a) is a risk factor for accelerated atherothrombosis. We hypothesize that LPA, the gene which encodes apo(a), is a heretofore unrecognized unprocessed pseudogene created by duplication of PLG, the gene which encodes plasminogen. Unprocessed pseudogenes are genes which were created by duplication of functional genes and subsequently lost function after acquiring various mutations. This hypothesis explains many of the unusual features of Lp(a) and apo(a). Also, this hypothesis has implications for the therapy of elevated Lp(a) and atherothrombosis theory. Because apo(a) is functionless, the diseases associated with elevated levels of Lp(a) are due to its impact on blood viscosity., Competing Interests: The authors have declared that no competing interests exist.

Deaths due to atherothrombosis are increasing throughout the world except in the lowest socio-demographic stratum. This is despite 60 years of study and expenditure of billions of dollars on lipid theory. Nevertheless, mainstream atherothrombosis theory persists even though it has failed numerous tests. Contrary data are ignored, consistent with the practice of science as envisioned by Thomas Kuhn. This paper examines defects in mainstream atherogenesis theory and the flawed logic which allows its persistence in the face of what should be obvious shortcomings., Competing Interests: The authors have declared that no competing interests exist.

The authors hypothesize that consumption of interesterified fats may be the cause of the continuous increase in cardiovascular deaths in the United States which began in 2011. Interesterification is a method of producing solid fats from vegetable oil and began to supplant partial hydrogenation for this purpose upon recognition of the danger of trans fats to cardiovascular health. Long, straight carbon chains, as are present in saturated and trans fatty acids, decrease the fluidity of the erythrocyte cell membrane, which decreases erythrocyte deformability and increases blood viscosity. This decrease in cell membrane fluidity is caused by increased van der Waals interactions, which also solidify dietary fats. Elevated blood viscosity is favored as the pathogenic mechanism by which trans fats increase cardiovascular mortality because changes in lipoprotein levels do not account for all the mortality attributable to their consumption. The rapid changes in cardiovascular mortality noted with the introduction and withdrawal of trans fats from the food supply are reviewed. The evidence implicating elevated blood viscosity in cardiovascular disease is also reviewed. Data regarding the production and consumption of interesterified fats in the US should be released in order to determine if there is an association with the observed increase in cardiovascular deaths.

The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or "chronic oxidative stress", such as the development of fatty streaks, "endothelial dysfunction," "vulnerable plaques," and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity., Competing Interests: The authors have declared that no competing interests exist.

Uric acid may be a risk factor for atherosclerotic cardiovascular disease, although the data conflict and the mechanism by which it may cause cardiovascular disease is uncertain. This study was performed to test the hypothesis that uric acid, an anion at physiologic pH, can cause erythrocyte aggregation, which itself is associated with cardiovascular disease. Normal erythrocytes and erythrocytes with a positive direct antiglobulin test for surface IgG were incubated for 15 minutes in 14.8 mg/dL uric acid. Erythrocytes without added uric acid were used as controls. Erythrocytes were then examined microscopically for aggregation. Aggregates of up to 30 erythrocytes were noted when normal erythrocytes were incubated in uric acid. Larger aggregates were noted when erythrocytes with surface IgG were incubated in uric acid. Aggregation was negligible in controls. These data show that uric acid causes erythrocyte aggregation. The most likely mechanism is decreased erythrocyte zeta potential. Erythrocyte aggregates will increase blood viscosity at low shear rates and increase the risk of atherothrombosis. In this manner, hyperuricemia and decreased zeta potential may be risk factors for atherosclerotic cardiovascular disease.

Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing 'anemia of chronic disease or inflammation' or 'hemolytic anemia' both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension., (© The Author(s), 2015.)

To evaluate the effect of age and other risk factors for atherosclerosis on arterial blood velocity, carotid arteries in 179 healthy individuals ranging from 21 to 102 years old were examined using color Doppler ultrasonography. Velocity in common and internal carotid arteries decreased consecutively from young adults to very elderly people except for peak internal carotid artery velocity. Peak common carotid artery velocity in the elderly (> or = 65 years old) people was inversely associated with age and diastolic blood pressure and directly associated with pulse pressure. Minimum velocity of common carotid artery was inversely correlated with age and diastolic blood pressure in the elderly people. In elderly group, peak internal carotid artery velocity correlated only with serum high-density lipoprotein cholesterol. Minimum internal carotid artery velocity correlated inversely with systolic blood pressure in adults and diastolic blood pressure in elderly people. Blood velocity in the very elderly population approaches the critical level for thrombogenesis.

A case of furuncular myiasis is reported. The life cycle of the parasite, differential diagnosis, host response, and therapy are briefly discussed.

Purpose: To investigate the corneal virulence of toxin-deficient mutants of Staphylococcus aureus in young and aged mice in a topical inoculation model of keratitis., Methods: Corneas of young and aged A/J mice were scarified and topically inoculated with a log phase S. aureus parent strain (8325-4), an alpha-toxin-deficient mutant (DU1090), or an Agr-defective mutant (ISP546) deficient in production of multiple toxins or with purified alpha-toxin. Slit lamp examination (SLE) and histopathology were performed, and bacterial colony-forming units (CFU) and myeloperoxidase (MPO) activity were determined., Results: The infection of young mice with the mutant strains demonstrated significantly lower SLE scores (P < or = 0.0001) and reduced histopathologic changes compared with infections with the parent bacterial strain. Either mutant strain of S. aureus produced SLE scores in aged mice through 9 days after infection (PI) that were significantly lower than those of aged mice similarly infected with the toxin-producing parent strain (P < or = 0.0001). Despite use of identical inocula, the CFU per eye were greater for the parent than the mutant strains from 1 to 5 days PI in the young mice (P < or = 0.0372) and from 1 to 3 days PI in the aged mice (P < or = 0.0018). MPO activities were at the maximum at day 1 PI and were similar overall for all infections. Administration of purified alpha-toxin caused greater gross and histopathologic changes in eyes of aged mice than in those of young mice., Conclusions: Bacterial toxins, and especially alpha-toxin, can mediate corneal disease in mice. Differences in severity of S. aureus keratitis in aged versus young mice correlates with their susceptibility to alpha-toxin.

Background and Aims: Interferon regulatory factor-1 (IRF-1) is a transcription factor with antiviral, proinflammatory and tumor suppressor properties. We examined the role of IRF-1 in dextran sulfate sodium colitis, a murine model of inflammatory bowel disease, to determine if absence of the gene would protect against colitis., Methods: C57BL/6J mice with a targeted disruption of IRF-1 and wild-type C57BL/6J controls received five 7-day cycles of 2% dextran sulfate sodium alternating with five 7-day cycles of water. Colonic tissue was formalin fixed for histological analysis and total RNA extracted for gene chip and SYBR green real-time polymerase chain reaction (PCR) analysis., Results: Histological analysis revealed increased distortion of crypt architecture in the dextran sulfate sodium-treated, IRF-1 -/- animals as compared to dextran sulfate sodium-treated wild-type animals. Five of 15 dextran sulfate sodium-treated IRF-1 -/- mice, but only one of 14 dextran sulfate sodium-treated wild-type mice, developed colonic dysplasia. Microarray analysis comparing colonic gene expression in IRF-1 -/- and wild-type animals revealed decreased expression of caspases, genes involved in antigen presentation, and tumor suppressor genes in the IRF-1 -/- animals. Increased expression of genes involved in carcinogenesis and immunoglobulin and complement genes was also noted in the knock-out animals., Conclusions: Absence of IRF-1 is not protective in dextran sulfate sodium colitis.

Purpose: To assess the frequency of shedding of herpes simplex virus type 1 (HSV-1) DNA in tears and saliva of asymptomatic individuals., Methods: Fifty subjects without signs of ocular herpetic disease participated. Serum samples from all subjects were tested for HSV IgG antibodies by enzyme-linked immunosorbent assay (ELISA) and for HSV-1 by neutralization assay. HSV-1 DNA copy number and frequency of shedding were determined by real-time polymerase chain reaction (PCR) analysis of tear and saliva samples collected twice daily for 30 consecutive days., Results: Thirty-seven (74%) of the 50 subjects were positive for HSV IgG by ELISA. The percentages of positive eye and mouth swabs were approximately equivalent: 33.5% (941/2806) and 37.5% (1020/2723), respectively. However, the percentage of samples with high HSV-1 genome copy numbers was greater in saliva than in tears, which may have been a result of the sample volume collected. Shedding frequency in tears was nearly the same in men (347/1003; 34.6%) and women (594/1705; 34.8%); in saliva, men had a higher frequency of shedding (457/1009; 45.3% vs. 563/1703; 33.1%, men versus women). Overall, 49 (98%) of 50 subjects shed HSV-1 DNA at least once during the course of the 30-day study., Conclusions: The percentage of asymptomatic subjects who intermittently shed HSV-1 DNA in tears or saliva was higher than the percentage of subjects with positive ELISA or neutralization antibodies to HSV. Because most HSV transmission occurs during asymptomatic shedding, further knowledge of the prevalence of HSV-1 DNA in tears and saliva is warranted to control its spread. Shedding is simple to study, and its suppression may be an efficient way to evaluate new antivirals in humans.

Purpose: To determine the effect of age on the extent of pathogenesis of Staphylococcus keratitis in the mouse., Methods: Corneas of young and aged mice (BALB/c, A/J, and C57BL/6) were scarified and topically inoculated with S. aureus. Slit lamp examination (SLE) and histopathology were performed, and bacterial colony forming units and myeloperoxidase activity were determined., Results: SLE scores of infected eyes of aged mice were significantly higher at days 1 and 3 postinfection (PI) as compared to infected young mice. Histopathological changes observed in all aged mice were more severe than those in young mice. Young BALB/c and A/J mice demonstrated minimal signs of keratitis by day 3 PI, whereas aged mice of both strains demonstrated severe keratitis by day 3. Young C57BL/6 mice showed no clinical signs of keratitis, whereas aged C57BL/6 mice demonstrated moderate keratitis., Conclusions: Aged mice with S. aureus keratitis demonstrated increased pathology as compared to young mice.

Peripheral facial nerve palsy is a common sequela of traumatic craniofacial injury, often resulting in dramatic and sometimes permanent functional deficits. Exogenous agents and methods of repair that accelerate axonal regeneration would be of great benefit to the multitude of patients with facial nerve injuries. The objective of this study was to evaluate the effect of FK506 at the time of facial nerve repair using entubulation neurorrhaphy, and to compare entubulation neurorrhaphy versus interposition autograft in critical facial nerve gap defects. The study design was a prospective, randomized, blinded animal study with a control group. Twenty-five New Zealand White rabbits were assigned to 4 experimental groups and a control group. The buccal branch of the facial nerve was used in all procedures. Group 1 was the control group. Rabbits in group 2 underwent sham surgery. Group 3 was an interposition autograft group in which a 6-mm segment of nerve was transacted, flipped, and followed by epineural repair. Groups 4 and 5 underwent transection followed by entubulation neurorrhaphy with topical administration of either a carrier molecule (group 4) or an FK506 carrier molecule (group 5). Outcome measures included daily subjective assessment of upper lip movement; electromyographic studies at weeks 3, 5, and 8 postoperatively; and blinded quantitative histomorphometric evaluation after 8 weeks. All rabbits in all groups were noted to have spontaneous movement after 8 weeks, with 1 rabbit in group 5 obtaining the highest functional score among all study groups. Electrophysiologic studies showed polyphasic potentials, indicating reinnervation in 1 rabbit in group 5. Histomorphometric examination of group 5 rabbits revealed a similar cross-sectional area distal to transection and remyelination. Other groups showed decreased cross-sectional area and/or incomplete remyelination distal to the transection. FK506 applied topically at the time of facial nerve repair using entubulation neurorrhaphy demonstrated superior results in nerve regeneration versus entubulation neurorrhaphy carrier protein alone, and interposition autograft.

Objective: To examine whether the atherosclerotic risk from cholesterol is modified by serum glucose level., Methods: Data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study of 1530 individuals with complete autopsy data for total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and hemoglobin A1c (HbA1c) were examined with any atherosclerotic raised lesions (RL) >0% of surface area on any of three arterial specimens as the outcome. A TC/HDL-C ratio was categorized into quintiles and HbA1c was dichotomized as the upper quartile versus lower three quartiles. Odds ratios (ORs) were estimated from logistic regression models adjusting for sex, race, age, body mass index, smoking and hypertension., Results: An interaction product term of TC/HDL x HbA1c was statistically significant (P=0.006) despite adjustment for the main effects and other covariates. In models stratified by HbA1c, ORs (3.0, 3.9, 1.9, 3.5) for four upper quintiles of TC/HDL-C in the upper HbA1c stratum were substantially higher than those in the lower HbA1c stratum (0.9, 1.3, 1.4 and 1.1). Strata differences were even more striking in the subset of those > or =25 years old., Conclusions: These results suggest a synergistic interaction between glucose and cholesterol that magnifies the atherosclerotic risk associated with TC/HDL-C for those with higher HbA1c levels.

Purpose: To define factors that protect the eye from Staphylococcus aureus keratitis and limit tissue damage once keratitis occurs., Methods: Rabbit tears were analyzed for bactericidal and phospholipase A(2) (PLA(2)) activities on S. aureus. Inhibition by spermidine of PLA(2) anti-staphylococcal activity in tears was tested in vitro and in vivo. Rabbits immunized with heat-inactivated alpha-toxin were challenged with intrastromal injection of S. aureus., Results: Arachidonic acid was cleaved from S. aureus by purified PLA( 2) or rabbit tears. Spermidine inhibited these reactions in vitro and facilitated keratitis in vivo. PLA(2) activity decreased with advanced age and shortly following sleep, but increased with keratitis. Antibody to alpha-toxin significantly reduced corneal damage and epithelial cell sloughing during keratitis., Conclusions: PLA(2) is a major host-defense component of rabbit tears. Alpha-toxin is a major mediator of corneal damage, and antibody to alpha-toxin reduces pathologic changes during keratitis.

Purpose: To establish, in the scarified mouse eye, a new model of Staphylococcus aureus keratitis suitable for studies of pathogenesis and host defense mechanisms., Methods: Corneas of three strains of mice (BALB/c, A/J, and C57BL/6) were scarified and inoculated with S. aureus strain 8325-4. Mice underwent slit lamp examination (SLE) at 1, 3, 5, 7, and 9 days after infection and were killed. Histopathologic analyses, determination of bacterial colony-forming units (CFU), and myeloperoxidase (MPO) activity assays were performed at each time point., Results: S. aureus keratitis developed in both BALB/c and A/J strains of mice, but not in C57BL/6. The BALB/c and A/J strains demonstrated greater susceptibility to infection, as evidenced by significantly higher SLE scores and more viable bacteria per infected eye than in C57BL/6 mice at 5, 7, and 9 days after infection (P

Purpose: To determine the pathogenic role of gamma- and alpha-toxin in a rabbit model of Staphylococcus aureus keratitis., Methods: S. aureus strains Newman (expressing gamma-toxin), Newman Delta(hlg) (deficient in gamma-toxin), Newman Delta(hlg)/pCU1 hlg(+) (chromosomal gamma-toxin-deficient mutant rescued by a plasmid encoding gamma-toxin), and Newman Delta(hla) (alpha-toxin-deficient) were intrastromally injected into rabbit corneas. Eyes were scored by slit lamp examination (SLE), and bacterial colony-forming units (CFU) per cornea were determined at 15, 20, and 25 hours after infection. Histologic examination of corneas was performed. Rabbits were immunized against alpha-toxin and subsequently challenged with S. aureus strain Newman. Western blot analyses of culture supernatants were performed to detect alpha-toxin production., Results: All strains grew equivalently, producing approximately 7 log CFU per cornea at 25 hours after infection. SLE scores at 20 and 25 hours after infection revealed that strains Newman Delta(hlg) and Newman Delta(hla), although virulent, caused significantly less ocular damage and inflammation than their parent or the gamma-toxin genetically rescued strain (P

Atherosclerotic plaque-like lesions are prevalent in synthetic arteriovenous shunts created to provide vascular access for hemodialysis. Similarities to atherosclerotic plaques in native arteries include eccentric location, immunoreactivity for smooth muscle actin, dystrophic calcifications, superimposed thrombi, and foam cells. Fatty streaks were not grossly identified on Sudan IV staining. Because of the similarities to atherosclerosis in native vessels, these findings may have several implications for atherogenesis. The development of raised, fibrous lesions does not require decades. The presence of smooth muscle in atherosclerotic plaque-like lesions does not require a source from tunica media. A precursor fatty streak may not be required for the development of raised, fibrous lesions. Finally, development of atherosclerotic plaque-like lesions does not require putative inflammatory effects from cholesterol or LDL accumulation, or even a native vessel that can respond to injury. The atherosclerotic plaque-like lesions in this study probably developed from organization of mural thrombi.

Purpose: To develop a topical inoculation model of Staphylococcus aureus keratitis in which scarification, contact lenses, and spermidine are used to inhibit the host defenses and to investigate the role of alpha-toxin in this infection., Methods: An alpha-toxin-positive parent strain (8325-4), its isogenic alpha-toxin-negative mutant (DU1090), and a genetically rescued form of the mutant (DU1090/pDU1212) were bound to rabbit-specific contact lenses, treated with spermidine (50 mM), and applied to scarified rabbit corneas. Eyes were treated topically with spermidine before and after lens application. Eyes were graded for disease by slit lamp examination (SLE) every 6 hours until 24 hours PI (PI), and erosion diameters were measured. Histopathologic changes and colony forming units (CFUs) of bacteria were determined., Results: Spermidine treatment and inoculation of eyes with Staphylococcus on contact lenses resulted in significant increases in both CFUs per cornea (P = 0.0041) and SLE score (P or= 0.1959) multilog increase in CFUs over the inoculum at 24 hours PI. The alpha-toxin-producing strains, 8325-4 and DU1090/pDU1212, caused significantly more disease than the alpha-toxin-deficient mutant DU1090 at 24 hours PI (P

Purpose: To determine the effectiveness of lysostaphin treatment of experimental endophthalmitis caused by methicillin-resistant Staphylococcus aureus (MRSA)., Methods: In one experiment, rabbits were injected in the mid-vitreous with 50 or 200 CFU of S. aureus; untreated groups and groups injected intra-vitreally at 8 or 24 hours postinfection with vehicle or lysostaphin (0.1 mg/ml) were compared in terms of CFU/ml vitreous at 24 or 48 hours postinfection. Histopathology of untreated and treated eyes was also compared. To quantify the potency of lysostaphin, additional rabbits were injected with 50 CFU of S. aureus and untreated eyes and eyes treated at 8 hours with 0.001, 0.01 or 0.05 mg/ml were compared in terms of CFU/ml vitreous at 24 hours postinfection., Results: Vitreous of untreated eyes or vehicle-treated eyes injected with 50 or 200 CFU of S. aureus contained 5-10 million CFU/ml at 24 or 48 hours postinfection. All eyes treated with lysostaphin at 8 hours postinfection had less than 1 log CFU/ml in the vitreous (P >or= 0.0001). Similarly, eyes treated with lysostaphin at 24 hours postinfection had approximately 1 log of CFU/ml at 48 hours postinfection. None of the untreated eyes were sterile and 88% or 50% of the eyes treated at 8 or 24 hours postinfection, respectively, were sterile. Eyes treated with lysostaphin at 8, but not 24, hours postinfection had less pronounced pathologic changes than the untreated eyes (P = 0.002). A significant reduction in the CFU/ml vitreous at 24 hours postinfection was obtained by treating infected eyes at 8 hours postinfection with lysostaphin at concentrations of >or=0.001 mg/ml (P

To test the hypothesis that peak blood velocity in the common carotid artery is increased in association with elevated blood pressure, the authors measured peak common carotid blood velocity in 458 subjects by color Doppler ultrasonography. Blood pressure was measured at the time of ultrasound examination by automated sphygmomanometer. Peak blood velocity was increased in subjects with elevated blood pressure (right common carotid: 72.5 +/- 2.0 cm/s vs. 62.7 +/- 2.5 cm/s, left common carotid: 72.0 +/- 1.8 cm/s vs. 63.9 +/- 2.0 cm/s, p < 0.001). Peak blood velocity was significantly correlated with systolic blood pressures between 135 and 160 mmHg (r = 0.47 in right common carotid, 0.45 in left common carotid, n = 123, p < 0.001). No correlation was found between peak blood velocity and blood pressures less than 135 mmHg or greater than 160 mmHg. By increasing erythrocyte momentum, increased peak blood velocity may play a role in the pathogenesis of arterial diseases associated with hypertension.

We prospectively evaluated the diameter of the common bile duct in 1,018 patients between the ages of 60 to 96 over a 4 year period to determine if there is a significant change in its size with aging. All of the patients included in the study were being evaluated primarily for carotid or peripheral vascular disease. Any patients with a history of biliary disease (i.e., bilirubin level greater than 1.5 mg/ml, cholecystectomy, or cholelithiasis) were excluded. Ultrasonography of the common bile duct was performed only in those patients with no subjective abdominal pain or icterus. Our results demonstrated a small although statistically significant increase in the caliber of the common bile duct with increasing age (60 years old or less, mean diameter 3.6 mm +/- 0.2mm, versus over 85 years old, mean diameter 4 mm +/- 0.2 mm, P = 0.009). Although the common bile duct did increase in size with aging, 98% of all ducts remained below 6 to 7 mm, the commonly accepted upper range of normal.

The raised fatty streak (fatty plaque) is the gross term for the lesion intermediate between the juvenile (flat) fatty streak and the raised lesion of atherosclerosis. We measured the percentage of intimal surface involved with flat fatty streaks, raised fatty streaks, and raised lesions in the aortas and right coronary arteries of 2876 autopsied persons aged 15 through 34 years who died of external causes. Raised fatty streaks were present in the abdominal aortas of approximately 20% of 15- to 19-year-old subjects, and this percentage increased to approximately 40% for 30- to 34-year-old subjects. Raised fatty streaks were present in the right coronary arteries of approximately 10% of 15- to 19-year-old subjects, and this percentage increased to approximately 30% for 30- to 34-year-old subjects. The percent intimal surface involved with raised fatty streaks increased with age in both arteries and was associated with high non-high density lipoprotein (HDL) and low HDL cholesterol concentrations in the abdominal aorta and right coronary artery, with hypertension in the abdominal aorta, with obesity in the right coronary artery of men, and with impaired glucose tolerance in the right coronary artery. Associations of risk factors with raised fatty streaks became evident in subjects in their late teens, whereas associations of risk factors with raised lesions became evident in subjects aged >25 years. These results are consistent with the putative transitional role of raised fatty streaks and show that coronary heart disease risk factors accelerate atherogenesis in the second decade of life. Thus, long-range prevention of atherosclerosis should begin in childhood or adolescence.

Fifty-seven sections of human vessels, collected in the Pathobiological Determinants of Atherosclerosis in Youth study from individuals aged 25-34, were stained with two monoclonal antibodies to oxidatively-modified lysine. Intensity and extent of immunoreactivity were graded by three pathologists. Aorta from a Watanabe heritable hyperlipidemic (WHHL) rabbit was stained as a positive control. Intimal immunoreactivity in the rabbit was predominantly localized to lesions. Although immunoreactivity in humans was somewhat more intense in atherosclerotic plaques, substantial staining was present in intima with diffuse intimal thickening and coronary veins. Localization of oxidatively-modified lysine in humans did not correlate with localization or severity of atherosclerosis. Localization of immunoreactivity for oxidatively-modified lysine to intimal lesions in the WHHL rabbit may be due to absence of diffuse intimal thickening, which prevents retention of epitopes throughout the intima.

The author proposes that paired helical filaments, which contain the protein tau in the fibrillar or beta-pleated sheet conformation, compete with microtubules for binding to nascent, soluble tau. Binding of nascent tau to tau in the beta-pleated sheet conformation autocatalyzes the conformational change into the beta-pleated sheet conformation. As long as sufficient tau is present to stabilize microtubules, neuronal function is normal. However, because paired helical filaments are resistant to proteolysis, they accumulate and eventually bind the bulk of nascent tau. This results in progressive microtubule instability and eventually neuronal death. Senile plaques are involved in Alzheimer's disease pathogenesis in that they contain fibrillar proteins which may function as heteronucleants, catalyzing the fibrillogenesis of other proteins such as tau. In this paradigm, apolipoprotein E4 serves as a heteronucleant for fibrillogenesis of tau.

Objective: To determine if the DNA strand breaks caused by tissue sectioning result in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) reactivity., Methods: The incidence and location of TUNEL-positive nuclei were determined in 5- and 15-micron sections of human stomach. Five- and 15-micron sections of tonsil were stained as a positive control., Results: In 5-micron gastric sections, 69% of nuclei were labeled; in 15-micron sections, only 30% were labeled. In the latter sections, almost all labeled nuclei were located at the cut surface of sections. Labeled nuclei did not have apoptotic morphology. Apototic bodies and tingible body macrophages were labeled throughout 15-micron sections of tonsil., Conclusions: Tissue sectioning creates TUNEL reactivity. The morphologic findings on routine stains should be considered the gold standard for the detection of apoptosis on tissue sections.

Purpose: The inflammatory response during Staphylococcus keratitis was analyzed biochemically and histologically to determine the source of the neutrophils infiltrating the tear film and cornea., Methods: Rabbit eyes were swabbed and then examined by slit-lamp microscopy at 0, 5, 10, 15, 20, and 25 hours after intracorneal inoculation with Staphylococcus aureus. Bacterial colony-forming units were quantified in the cornea, eyelid, and acute inflammatory exudate. Myeloperoxidase activity of ocular swabs of acute inflammatory exudate, corneal homogenates, and eyelid homogenates was determined. Gross and microscopic examinations of corneas and eyelids were performed., Results: The colony-forming units per cornea exceeded 10(7) after 10 hours, whereas no bacteria were cultured from the eyelid until 15 hours postinfection. Slit-lamp examination revealed progressive pathology, and the myeloperoxidase activities of ocular swabs, corneas, and eyelids increased markedly by 15 hours postinfection. Corneas showed a wave of neutrophils moving from the tear film toward bacteria in the central corneal stroma and early neutrophil migration from the limbus into the stroma. In the eyelid, neutrophils migrated from the stromal vessels to the tear film., Conclusions: Staphylococcus keratitis in the rabbit causes acute inflammation in the overlying eyelid. Neutrophils of the acute inflammatory exudate interact with the infected cornea, whereas neutrophils migrating through the cornea from the limbus remained distant from the site of infection.

Serum hypercholesterolemia is theorized to accelerate atherogenesis by augmenting cholesterol accumulation (insudation) in the arterial intima. The author views this theory as an example of what the noted philosopher of science Imre Lakatos called 'degenerative science', because data have forced several modifications of the theory. Although the theory that some fraction of intimal cholesterol causes atherosclerosis is not yet disproved, the author favors the hypothesis that serum hypercholesterolemia accelerates atherogenesis and contributes to symptomatic atherosclerosis by increasing blood viscosity and the mechanical fragility of atherosclerotic plaques, making them vulnerable to rupture and thrombosis.

The hemorheologic-hemodynamic theory of atherogenesis suggests that atherosclerosis is a disease of low shear, which prolongs the residence time of atherogenic particles on the endothelium. Prolonged residence of lipid-rich particles results in a fatty streak. Prolonged residence of platelet microthrombi results in a raised lesion (atherosclerotic plaque). Thus, fatty streak and raised lesion development are independent processes. In contrast, received wisdom holds that fatty streaks are the precursors to raised lesions. The author examines anatomic and risk factor data for fatty streaks and raised lesions, including the results of the recent multicenter Pathobiological Determinants of Atherosclerosis in Youth study, in light of these two theories.

Two morphologic patterns of fatty streak were identified on examination of 74 aortas from the Pathobiological Determinants of Atherosclerosis in Youth study. Pattern 1, which predominated in 78% of aortas, is characterized by broad bands of intense stain which extend to the proximal edge of ostia. Pattern 2, which predominated in 11%, is characterized by less intense staining which is concave to the associated ostium. Pattern 1 predominated in older subjects and smokers. Aging and smoking decrease arterial elasticity, thereby decreasing the volume and duration of retrograde blood flow in diastole. Doppler ultrasonography of the posterior intercostal arteries and aorta in 42 healthy subjects revealed that retrograde blood flow in late systole/early diastole is normal in subjects in the 15-34 age group. Transition from retrograde to antegrade flow was associated with transient blood stasis. This stasis should prolong the residence time of lipid-rich particles, enhancing diffusion into the vessel wall. A region of lower flow velocity was noted in the periostial region in all patients during diastole. The anatomic, hemodynamic, and risk factor data suggest that the morphology of fatty streaks is determined by interaction of retrograde with antegrade blood flow as modulated by arterial elasticity.

Given the enlarging body of evidence implicating increased blood viscosity in atherogenesis, the authors hypothesize that lipoproteins modulate the atherogenic process by affecting blood viscosity. In order to define the magnitude of the effect of lipoproteins on blood viscosity, capillary viscometry was performed on blood from 16 healthy, fasting subjects, and results were correlated with lipoprotein-cholesterol levels. Low-density lipoprotein-cholesterol was positively associated with blood viscosity (r = 0.610, p = 0.01). High-density lipoprotein-cholesterol was negatively associated with blood viscosity (r = -0.479, p = 0.06). A multiple regression model was developed with these data, revealing that 54% of variation in blood viscosity was attributable to these lipoproteins. This model was validated on a second dataset, in which these lipoproteins accounted for 28% of variation in blood viscosity. A second model, including hematocrit, serum viscosity, and high-density lipoprotein-cholesterol levels, explained 73% of variation in blood viscosity. By modulating blood viscosity and flow, lipoproteins may affect the residence time of atherogenic particles and atherogenesis.

To determine the effect of long-term aspirin therapy on the prevalence of symptomatic atherosclerosis, autopsy results from 44 arthritis patients taking aspirin were compared with a cohort from the general autopsy population. No decrease in the prevalence of symptomatic atherosclerosis was noted in patients with less than 8 years of arthritis, compared with controls. In contrast, the prevalence of symptomatic atherosclerosis was significantly decreased in arthritis patients with 8 or more years of arthritis and aspirin use. In these subjects, the prevalence of symptomatic atherosclerosis was inversely related to duration of arthritis. The inverse relationship between prevalence of symptomatic atherosclerosis and duration of aspirin therapy, as well as the decrease in all forms of symptomatic atherosclerosis, raise the possibility that this decrease is due to primary prevention of atherosclerosis.