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The pathogenesis of several major cardiovascular diseases, including atherosclerosis, hypertension, and the metabolic syndrome, is not widely understood because the role of blood viscosity is overlooked. Low-density lipoprotein accelerates atherosclerosis by increasing blood viscosity in areas of low flow or shear, predisposing to thrombosis. Atherosclerotic plaques are organized mural thrombi, as proposed by Duguid in the mid-twentieth century. High-density lipoprotein protects against atherosclerosis by decreasing blood viscosity in those areas. Blood viscosity, at the least, contributes to hypertension by increasing systemic vascular resistance. Because flow is inversely proportional to viscosity, hyperviscosity decreases perfusion and glucose utilization by skeletal muscle, contributing to hyperglycemia in the metabolic syndrome. Therapeutic phlebotomy reduces blood pressure and serum glucose levels in the metabolic syndrome by improving blood viscosity., (© The Author(s), 2014.)

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

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.

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.

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.

Purpose: Previous studies from this laboratory have demonstrated, in a rabbit model of keratitis, a relationship between the corneal virulence of Staphylococcus aureus and the alpha-toxin activity of the infecting bacteria. This study is a histopathological characterization of the action of purified alpha-toxin on corneal tissue., Methods: Alpha-toxin was purified by isoelectric focusing and intrastromally injected into rabbit corneas (2 micrograms per cornea). A kinetic analysis of toxin effect was performed following injection. Normal corneas and corneas injected with phosphate buffered saline (PBS) or heat-inactivated alpha-toxin in PBS served as controls. Eyes were examined from 0 to 4 h by slit lamp examination (SLE) and scored on the basis of seven ocular parameters. Corneal tissue was removed and examined for histopathological changes., Results: From 0.5 to 4 h post-injection, alpha-toxin injection induced a significant increase in the SLE score relative to untreated eyes or eyes injected with PBS (P < 0.0001). Histolo-pathological examination of corneas one-half h after alpha-toxin injection revealed edema of the central cornea and death of epithelial cells by both necrosis and apoptosis. Later times showed continued edema and loss of apparently normal epithelial cells. Development of polymorphonuclear (PMN) leukocyte infiltration from the tear film into the central cornea and from limbal vessels into the peripheral cornea was observed., Conclusions: Purified alpha-toxin mediates cell death by necrosis and apoptosis, sloughing of viable corneal epithelial cells, severe corneal edema, and PMN migration into the cornea from both the tear film and limbal vessels. The pathologic changes revealed by histological studies of corneas injected with purified alpha-toxin included death of cells by necrosis and apoptosis as well as overall changes analogous to that seen by SLE of eyes infected with wild-type, but not alpha-toxin-deficient strains of Staphylococcus aureus.

1. Increased blood or plasma viscosity has been observed in almost all conditions associated with accelerated atherosclerosis. Cognizant of the enlarging body of evidence implicating increased viscosity in atherogenesis, we hypothesize that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis. 2. Blood viscometry was performed on samples from 28 healthy, non-fasting adult volunteers using a capillary viscometer. Data were correlated with haematocrit, fibrinogen, serum viscosity, total cholesterol, high-density lipoprotein-cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol. 3. Low-density lipoprotein-cholesterol was more strongly correlated with blood viscosity than was total cholesterol (r = 0.4149, P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density lipoprotein-cholesterol levels were inversely associated with blood viscosity (r = -0.4018, P = 0.0341). 4. To confirm these effects, viscometry was performed on erythrocytes, suspended in saline, which had been incubated in plasma of various low-density lipoprotein/high-density lipoprotein ratios. Viscosity correlated directly with low-density lipoprotein/high-density lipoprotein ratio (n = 23, r = 0.8561, P < 0.01). 5. Low-density lipoprotein receptor occupancy data suggests that these effects on viscosity are mediated by erythrocyte aggregation. 6. These results demonstrate that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity in healthy subjects correlate with their association with risk of atherosclerosis. These effects on viscosity may play a role in atherogenesis by modulating the dwell or residence time of atherogenic particles in the vicinity of the endothelium.

The author proposes that all major risk factors, including elevated serum low-density lipoprotein, cause atherosclerosis by increasing viscosity, creating larger areas of decreased blood flow, thereby perpetuating the interaction of atherogenic elements with the endothelium. Low-density lipoprotein causes increased viscosity by fostering erythrocyte aggregation. High-density lipoprotein protects against atherosclerosis by antagonizing erythrocyte aggregation, thereby decreasing viscosity. Implications of this theory are discussed.

Severe transfusion reactions occur much less often than minor reactions, but it is difficult to discriminate clinically between impending severe reactions and minor reactions. Therefore, whenever a reaction occurs, the transfusion should be discontinued and a laboratory workup initiated to rule out an acute hemolytic transfusion reaction. At a minimum, a direct antiglobulin (Coombs') test should be performed, and specimens obtained before and after transfusion should be assayed for hemoglobinemia and hemoglobinuria. If the product transfused included red blood cells, then typing and crossmatching should be repeated on a posttransfusion blood specimen. Routine premedication with antipyretics is not recommended, since they may mask early signs and symptoms of more severe reactions and their efficacy is questionable. Recent insights into the mechanisms of transfusion reactions have suggested interventions that may help minimize or prevent potentially serious sequelae.

We report a case of type I cryoglobulinemia with cold agglutinin activity complicating allogeneic bone marrow transplantation. To our knowledge, this complication has not been previously reported. We also discuss possible etiologic mechanisms for this unusual event.