Cardiovascular benefits of phlebotomy: relationship to changes in hemorheological variables.

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.

Staphylococcus corneal virulence in a new topical model of infection.

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

Lysostaphin is effective in treating methicillin-resistant Staphylococcus aureus endophthalmitis in the rabbit.

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

Common bile duct measurements in an elderly population.

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.

Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

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.

The distribution of oxidatively-modified lysine in the human vasculature.

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.

Increased peak blood velocity in association with elevated blood pressure.

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.

Cellular pathogenesis of Alzheimer's disease.

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.

Histologic sectioning produces TUNEL reactivity. A potential cause of false-positive staining.

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.

A critical analysis of the role of cholesterol in atherogenesis.

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.

Acute inflammation of the eyelid and cornea in Staphylococcus keratitis in the rabbit.

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.

A description of two morphologic patterns of aortic fatty streaks, and a hypothesis of their pathogenesis.

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.

Insights into the relationship of fatty streaks to raised atherosclerotic lesions provided by the hemorheologic-hemodynamic theory of atherosclerotic lesions provided by the hemorheologic-hemodynamic theory of atherogenesis.

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.

Decreased prevalence of symptomatic atherosclerosis in arthritis patients on long-term aspirin therapy.

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.