Efficacy and Safety outcomes of a novel model to assess new medical retina referrals in a high-volume medical retina virtual clinic.

BACKGROUND: Ophthalmology outpatient attendances have significantly increased recently with rising pressure from backlogs arising from the pandemic. Medical retina digital surveillance clinics for stable follow-up appointments are well established. We present a model for assessing new referrals and evaluating clinical outcomes and long-term sustainability in a complex high-volume medical retina service. METHODS: Suitable routine new patient referrals were identified from electronic referrals and referred to this new pathway. Structured history, visual acuities, and intraocular pressures were recorded, and widefield colour fundus and optical coherence tomography imaging were performed at a imaging hub for asynchronous consultant-led review. RESULTS: 1458 patients were invited to attend over four months, with a 13.2% did-not-attend (DNA) rate. Common diagnoses included stable diabetic retinopathy (19.9%), early age-related macular degeneration (6.7%), central serous retinopathy (8.8%), and retinal vein occlusion (6.3%). 7 patients (0.05%) required urgent same-day review. 61 (5.0%) required urgent face-to-face (F2F) assessment within two weeks. A total of 727 (59.0%) were either discharged or remained in the virtual pathway following their first visit. CONCLUSION: This study encourages the use of a digital model that efficiently assesses suitable newly referred medical retina patients in both complex and local eye unit settings. This decreased the need for F2F clinics and resources. Further patient satisfaction surveys for digital services are currently being evaluated to guide long-term sustainability of this model.

Legume finishing provides beef with positive human dietary fatty acid ratios and consumer preference comparable with grain-finished beef.

Consumer liking, proximate composition, pH, Warner-Bratzler shear force, fatty acid composition, and volatile compounds were determined from the LM (longissimus thoracis) of cattle ( = 6 per diet) finished on conventional feedlot (USUGrain), legume, and grass forage diets. Forage diets included a condensed tannin-containing perennial legume, birdsfoot trefoil (; USUBFT), and a grass, meadow brome ( Rehmann; USUGrass). Moreover, representative retail forage (USDA Certified Organic Grass-fed [OrgGrass]) and conventional beef (USDA Choice, Grain-fed; ChGrain) were investigated ( = 6 per retail type). The ChGrain had the greatest ( < 0.05) intramuscular fat (IMF) percentage followed by USUGrain, the IMF percentage of which was greater ( < 0.05) than that of USUGrass and OrgGrass. The IMF content of USUBFT was similar ( > 0.05) to that of both USUGrain and USUGrass. Both grain-finished beef treatments were rated greater ( < 0.05) for flavor, tenderness, fattiness, juiciness, and overall liking compared with USUGrass and OrgGrass. Consumer liking of USUBFT beef tenderness, fattiness, and overall liking were comparable ( > 0.05) with that of USUGrain and ChGrain. Flavor liking was rated greatest ( < 0.05) for USUGrain and ChGrain, and that of USUBFT was intermediate ( > 0.05) to those of ChGrain, USUGrass, and OrgGrass. Cumulative SFA and MUFA concentrations were greatest ( < 0.05) in ChGrain and USUGrain, whereas USUGrass and OrgGrass had lower ( < 0.05) concentrations. Concentrations of cumulative SFA and MUFA in USUBFT were intermediate and similar ( > 0.05) to those of USUGrain and USUGrass. Each forage-finished beef treatment, USUGrass, OrgGrass, and USUBFT, had lower ( < 0.001) ratios of -6:-3 fatty acids. Hexanal was the most numerically abundant volatile compound. The concentration of hexanal increased with increasing concentrations of total PUFA. Among all the lipid degradation products (aldehydes, alcohols, furans, carboxylic acids, and ketones) measured in this study, there was an overall trend toward greater quantities in grain-finished products, lower quantities in USUGrass and OrgGrass, and intermediate quantities in USUBFT. This trend was in agreement with IMF content, fatty acid concentrations, and sensory attributes. These results suggest an opportunity for a birdsfoot trefoil finishing program, which results in beef comparable in sensory quality with grain-finished beef but with reduced -6 and SFA, similar to grass-finished beef.

Interaction between a tannin-containing legume and endophyte-infected tall fescue seed on lambs' feeding behavior and physiology.

It was hypothesized that a tannin-rich legume such as sainfoin attenuates the negative postingestive effects of ergot alkaloids in tall fescue. Thirty-two 4-mo-old lambs were individually penned and randomly assigned to a 2 × 2 factorial arrangement with 2 legume species, sainfoin (SAN; 2.9% condensed tannins) or cicer milkvetch (CIC; without tannins) and a mixed ration containing tall fescue seed (50:30:20 seed:beet pulp:alfalfa) with 2 levels of endophyte infection (endophyte-infected tall fescue seed [E+; 3,150 ug/L ergovaline] or endophyte-free tall fescue seed [E-]). For a 10-d baseline period, half of the lambs were fed SAN and half were fed CIC and all lambs had ad libitum amounts of E-. In an ensuing 10-d experimental period, the protocol was the same except half of the lambs fed SAN or CIC received E+ instead of E-. Subsequently, all lambs could choose between their respective legume and seed-containing ration and between E+ and E-. Finally, an in vitro radial diffusion assay was conducted to determine whether tannins isolated from SAN would bind to alkaloids isolated from E+. All groups consumed similar amounts of E- during baseline period ( > 0.10), but lambs ate more E- than E+ during the experimental period ( < 0.05) and lambs offered SAN ate more E+ than lambs offered CIC ( < 0.05). Groups fed E- during the baseline and experimental periods had similar rectal temperatures ( > 0.10), but lambs fed E+ had lower rectal temperatures per gram of feed ingested when supplemented with SAN than with CIC ( < 0.05). Lambs fed E+ had greater concentrations of hemoglobin and more red blood cells than lambs fed E- ( < 0.05), but plasmatic concentrations of cortisol and prolactin did not differ among treatments ( > 0.10). All lambs preferred their treatment ration over their treatment legume, but lambs in the SAN and E+ treatment ate more legume + ration than lambs in the CIC and E+ (CIC-E+; < 0.05) treatment. All lambs preferred E- over E+, but lambs in the CIC-E+ treatment ate the least amount of E+ ( < 0.05). Binding of isolated SAN tannins to protein was reduced by the E+ isolate ( < 0.05), suggesting a tannin-alkaloid complexation but only from tannins extracted from SAN fed early in the experimental period. In summary, SAN supplementation increased intake of and preference for E+ and reduced rectal temperatures relative to CIC supplementation. Our results suggest that these effects were mediated by the condensed tannins in SAN through alkaloid inactivation, an interaction that declined with plant maturity.

Beef heifer growth and reproductive performance following two levels of pasture allowance during the fall grazing period.

The objective of this study was to compare heifer growth and reproductive performance following 2 levels of stockpiled fall forage allowance of orchardgrass (30.5%) and tall fescue (14.1%). Spring-born heifers (n = 203 and BW = 246 ± 28.9 kg) of primarily Angus background were allocated to 2 grazing treatments during the fall period (November 12 to December 17 in yr 1, November 7 to January 4 in yr 2, and November 7 to January 14 in yr 3) each replicated 3 times per year for 3 yr. Treatments consisted of daily pasture DM allowance of 3.5% of BW (LO) or daily pasture DM allowance of 7.0% of BW (HI) under strip-grazing management. Throughout the winter feeding period, mixed grass-legume haylage and soybean hulls were fed. Heifers were grazed as 1 group under continuous stocking after the winter period. Heifers in the LO group gained less than heifers in the HI group during the fall grazing period (0.12 vs. 0.40 kg/d; P < 0.0001). For each 1 10 g increase in NDF/kg fall pasture (DM basis), fall ADG decreased 0.14 kg (P = 0.01). During winter feeding, ADG was 0.30 and 0.39 kg/d for LO vs. HI heifers, respectively (P = 0.0008). During the spring grazing period (April 16 to May 24 in yr 1, April 22 to May 26 in yr 2, and April 5 to May 16 in yr 3), LO heifers had numerically greater ADG than HI heifers (1.38 vs. 1.30 kg/d; P = 0.64). Hip height (122.7 vs. 121.4 cm; P = 0.0055), BCS (5.8 vs. 5.6; P = 0.0057), and BW (356 vs. 335 kg; P < 0.0001) at the end of spring grazing was greater for HI than LO heifers. Heifers in the LO group compensated with greater summer ADG than heifers in the HI group (0.74 vs. 0.66 kg/d; P = 0.03). Total ADG from treatment initiation (November) through pregnancy diagnosis (August) was greater for HI than LO heifers (0.61 vs. 0.55 kg/d; P < 0.001) as was BW at pregnancy diagnosis (415 vs. 402 kg; P = 0.0055). Percentage of heifers reaching puberty by the time of AI was 34% for both groups (P = 0.93). Percentage of heifers becoming pregnant to AI tended (P = 0.13) to be greater for HI (44%) than for LO heifers (32%). Fall ADG across treatment groups affected the probability of a heifer becoming pregnant by AI (P = 0.01). Percentage pregnant by natural service (61% for LO vs. 59% for HI; P = 0.80) and final pregnancy rate (74% for LO vs. 77% for HI; P = 0.61) was not different for the 2 groups. These results indicate that altering fall forage allowance may delay the majority of BW gain until late in heifer development without negatively affecting overall pregnancy rates.

Effects of an ionic and nonionic contrast agent on von Willebrand factor assessed during coronary angiography.

This study shows an increase in von Willebrand factor antigen in blood collected from the coronary sinus shortly after coronary angiography with an ionic contrast agent (diatrizoate), but not a nonionic contrast agent (iohexol). These findings suggest that ionic contrast agents may cause more endothelial injury than nonionic contrast agents.

The utility of animal models in the preclinical study of interventions to prevent human coronary artery restenosis: analysis and recommendations. On behalf of the Subcommittee on Animal, Cellular and Molecular Models of Thrombosis and Haemostasis of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.

Small animal models have several advantageous characteristics, but those used in preclinical restenosis research have lacked efficacy in predicting the success of interventions to inhibit restenosis in humans. Large animal models have been more successful than small animal models in predicting efficacy of interventions to inhibit restenosis in humans, but the results of studies carried out with these models have not been uniformly predictive. Confirmation of the results of small animal studies in large animals has not always yielded information predictive of success in humans; however, the absence of such confirmation has had strong negative predictive value. Small animal models used for evaluation of interventions to inhibit luminal narrowing following arterial instrumentation have failed to closely simulate human atherosclerosis and the stenotic lesions subjected to instrumentation in humans. Transgenic, atherosclerotic animals hold promise for the development of more useful small animal models to study mechanisms of the response of diseased arteries to angioplasty and stents. The pig has been the most useful large animal to study stenosis/ restenosis, but more information is needed to overcome the limitations of this model.

Is physical activity or aerobic power more influential on reducing cardiovascular disease risk factors?

PURPOSE: This study determined the relationship between aerobic power (VO2max), physical activity (PA), and cardiovascular disease (CVD) risk factors. The study also determined how increased VO2max and increased PA levels influence CVD risk factors of 576 low-fit adults (VO2max < 30 mL.kg-1.min-1). METHODS: PA (Baeke questionnaire) and VO2max (submaximal cycle test) of 1664 law enforcement trainees were evaluated with respect to the CVD risk factors of total cholesterol, blood pressure (BP) [BP], smoking, and obesity using separate logistic regression, adjusting for age, gender, and the other major CVD risk factors. RESULTS: Compared with the lowest tertile of VO2max, the highest tertile had a reduced relative risk (RR) for elevated cholesterol (RR, 0.56; CI, 0.36-0.43), BP (RR, 0.32; CI, 0.15-0.62) and obesity (RR, 0.09; CI, 0.06-0.12). The middle tertile of VO2max compared with the lowest had reduced RR for elevated diastolic BP (RR, 0.44; CI, 0.23-0.66) and obesity (RR: 0.38; CI 0.28-0.50). High PA tertile, compared with low PA tertile, only had lower RR for high systolic BP (RR, 0.48; CI, 0.23-0.95). Compared with the low PA tertile, moderate or high PA had no reduction in any of the RR (P > 0.05). Participation in a 9-wk exercise program by low-fit individuals resulted in a 9% increase in PA levels (P < 0.02); however, only those subjects who increased VO2max (> 3 mL.kg-1.min-1; N = 345) had a reduction in RR for high cholesterol (RR: 0.62; CI 0.42-0.92) and systolic BP (RR: 0.57; CI 0.40-0.80). No reduction in RR were noted for diastolic BP or obesity. CONCLUSIONS: Aerobic power appears to have more of an influence on CVD risk factors than PA levels. Further, in low-fit persons, it appears that PA resulting in an increased aerobic power is associated with a reduction in CVD risk factors of cholesterol and BP in as little as 9 wk.

von Willebrand factor does not influence atherogenesis in arteries subjected to altered shear stress.

The role of von Willebrand factor (vWF) in arterial neointimal formation that develops in arteries with altered shear stress was investigated using normal, heterozygous, and homozygous von Willebrand disease pigs (ie, vWD, or lacking vWF) that were fed normal pig chow. Shear stress was applied to carotid and femoral arteries with a Goldblatt clamp for 14 days, producing a > or = 80% stenosis. Neointimal lesion size was measured by computer-assisted morphometry. Expression of proliferative cell nuclear antigen (PCNA) by neointimial and medial cells was used as a relative index of proliferative activity. For shear-stressed arteries, there was no significant difference in the number of smooth muscle cell layers in the lesion, lesion size, and percent of PCNA-positive neointimal or medial cells among normal, heterozygous, and homozygous vWD pigs (P> or =.1, ANOVA). Lesions in pigs that expressed vWF (normals and heterozygotes) contained large amounts of vWF in the neointima, whereas lesions in vWD pigs had no detectable vWF. Moreover, no foam cells were detected in the lesions. Thus, the absence of vWF apparently does not alter the size of lesions in shear-stressed arteries in vWD pigs or the number of neointimal or medial cells expressing PCNA. Mechanism(s) involved with shear-induced modulation of smooth muscle cell proliferation, then, can operate independently of vWF in normolipemic pigs.

Assessment of platelet activation by coronary sinus blood sampling during balloon angioplasty and directional coronary atherectomy.

Three markers of platelet activation (platelet-derived microparticles, fibrinogen binding and expression of P-selectin) were assessed by flow cytometry during diagnostic coronary angiography and therapeutic coronary interventions. In 24 patients undergoing diagnostic angiography, blood was collected to determine if our sampling techniques or coronary angiography caused platelet activation. Changes during diagnostic angiography were used to establish baseline values and interpret changes during coronary interventions. In 21 patients, blood samples were obtained at 5 time points during percutaneous transluminal coronary angioplasty (PTCA) (n = 17) or directional coronary atherectomy (DCA) (n = 4). During coronary interventions, mean values for the percentage of platelets expressing P-selectin or binding fibrinogen increased, but with considerable variation among patients. Individual responses for platelet activation markers in each patient were characterized using a twofold increase to indicate elevation related to the intervention. Patients were classified as having complicated or uncomplicated procedures based on the presence of acute closure, dissection, or thrombus observed by angiography. There were no differences in the percentage of elevated markers between patients with uncomplicated (12.5%) and complicated (19%) PTCA procedures. However, patients treated with DCA had more elevated markers (38%) than those treated with PTCA (15%) (p = 0.04). Our data suggest that the extent of platelet activation in individual patients cannot be predicted by common angiographic findings or complications. More markers of platelet activation were present after DCA and may reflect a greater degree of vascular trauma associated with this procedure.

An occupation based physical activity intervention program: improving fitness and decreasing obesity.

The purpose of this quasi-experimental study was to determine the effectiveness of an occupation based health and fitness program. Subjects were 1,504 police trainees (85% male, 15% female) with an ethnic distribution of 82% white, 16% African American, and 2% other. Data were collected at 25 sites across the state of North Carolina. The sites were randomly assigned to either the experimental group (implemented the intervention) or the control group (continued usual training). As compared with controls, subjects at the experimental sites improved significantly in cardiovascular fitness (aerobic power), general muscular strength (number of sit ups per minute), and flexibility, and lowered their body fat. The intervention required minimal equipment and was taught primarily by peers who received a 1 week training program. This occupational approach to improving health could be particularly useful in occupations with many workers who seldom engage in leisure time physical activity.

An experimental model for testing von Willebrand factor function: successful SLA-matched crossed bone marrow transplantations between normal and von Willebrand pigs.

To assess the relative in vivo roles of von Willebrand factor (vWF) of different origins, we performed crossed bone marrow transplantations (BMTs) among normal pigs and pigs with the von Willebrand disease(vWF). The two groups were fully compatible immunologically according to typing by swine leukocyte antigen (SLA). After total-body irradiation (8-10 Gy), all pigs received 0.5X10(9) to 10(10)/kg mononuclear bone marrow cells without any immunosuppression. The nadir of aplasia occurred between days 5 and 7 after irradiation (white blood cell [WBC] count 0.6X10(9)/L, platelet [Plt] count 76X10(9)/L. Three weeks after the graft, WBC and Plt counts had returned to normal levels. Animals were followed for at lease 50 days, during which no bone marrow rejection occurred; no evidence of graft-vs-host disease (GVHD) was observed. Each BMT was confirmed by karyotype analysis. In the six homozygous pigs with vWD grafted with normal marrow, platelet vWF antigen (vWFAg) and platelet vWF activity rose from <3 to 450 U/dl with a normal multimeric pattern; plasma vF increases slightly. No correction of bleeding time was observed. In the five normal pigs grafted with bone marrow form pigs with vWD, platelet vWFAg and platelet vWF activity decreased from >100 U/dl to undetectable levels; bleeding time and plasma vWFAg remained unchanged. A derivative of normal porcine plasma, a concentrate containing factor VIII and vWF, was infused into a homozygous vWD pig before and after BMT from a normal pig. Co correction of bleeding time was obtained, even though plasma nd platelet vWFAg levels were normal. W concluded that crossed BMT among SLA-identical pigs is a feasible model of studying the synthesis and the roles of vWF in hemostasis and thrombosis.

Preservation of hemostatic and structural properties of rehydrated lyophilized platelets: potential for long-term storage of dried platelets for transfusion.

Currently, therapeutic platelet concentrates can be stored for only 5 days. We have developed a procedure that permits long-term storage of fixed and lyophilized platelets that retain hemostatic properties after rehydration. These rehydrated lyophilized platelets (RL platelets) restore hemostasis in thrombocytopenic rats and become incorporated in the hemostatic plug of bleeding time wounds of normal dogs as well as von Willebrand disease dogs with partially replenished plasma von Willebrand factor. Ultrastructurally, these platelets are well preserved and are comparable to control normal washed platelets. Flow cytometry analysis shows that RL platelets react with antibodies to the major surface receptors, glycoprotein (GP)Ib and GPIIb/IIIa. These receptors are involved in platelet agglutination, aggregation, and adhesion. In vitro functional tests document the ability of RL platelets to adhere to denuded subendothelium and to spread on a foreign surface. Circulating RL platelets participated in carotid arterial thrombus formation induced in normal canine subjects. The participation of RL platelets in these vital hemostatic properties suggests that with further development they could become a stable platelet product for transfusion.

Familial and diet-induced hypercholesterolemia in swine. Lipid, ApoB, and ApoA-I concentrations and distributions in plasma and lipoprotein subfractions.

Low levels of high-density lipoproteins (HDLs) may constitute an independent risk factor that may be as important as elevated low-density lipoproteins (LDLs) in coronary artery disease (CAD). Concentrations and distributions of lipids, apolipoprotein (apo) B, and apoA-I in the plasma and lipoprotein subfractions of two groups of swine, one with familial hypercholesterolemia (FHC) and the other with diet-induced hypercholesterolemia (DHC), were examined. Normolipidemic (NL) animals served as controls. All pigs carried the Lpb5 apoB mutation, which is known to influence the formation of atherosclerotic lesions. Mean concentrations of serum total cholesterol in NL, DHC, and FHC were 80.0 +/- 9.3, 774.3 +/- 54.5, and 316.5 +/- 36.1 mg/dL, respectively; HDL cholesterol (HDL-C), 33.5 +/- 1.9, 137.0 +/- 9.9, and 22.3 +/- 2.2 mg/dL; triglycerides, 33.0 +/- 16.3, 40.3 +/- 11.7, and 56.8 +/- 7.2 mg/dL; apoB, 35.7 +/- 3.1, 142.0 +/- 4.8, and 169.3 +/- 13.9 mg/dL; and apoA-I, 62.4 +/- 9.3, 170.9 +/- 6.9, and 42.6 +/- 4.8 mg/dL. The distributions of total cholesterol, apoB, and apoA-I in plasma lipoprotein subfractions were also examined. Compared with NL, FHC had fourfold and 4.7-fold increases in total cholesterol and apoB, respectively, distributed in the lower densities (d < 1.043 g/mL), and low HDL-C and apoA-I levels, resulting in a high total cholesterol/HDL-C ratio (14.4:1) and elevated triglyceride levels. DHC was characterized by 10-fold and fourfold increases in total cholesterol and apoB, respectively, resulting in an LDL particle highly enriched in cholesterol, a fourfold increase of HDL-C, an almost threefold increase in apoA-I, and a normal triglyceride level.(ABSTRACT TRUNCATED AT 250 WORDS)

The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A.

We have studied the roles of von Willebrand factor (vWF) and factor VIII in arterial thrombosis in four canine phenotypes: normal (n = 6), hemophilia A (n = 11), von Willebrand disease (vWD) (n = 9), and hemophilia A/vWD (n = 1). vWF activity was determined by botrocetin-induced agglutination of fixed human platelets and vWF antigen (vWF:Ag) by Laurell electroimmunoassay and crossed immunoelectrophoresis. Plasma from normal dogs and those with hemophilia A had vWF activity, vWF:Ag, and a full range of vWF:Ag multimers on gel electrophoresis equivalent to normal canine plasma pool. Platelet cytosol contents were isolated by freezing and thawing, triton X-100 solubilization, or sonication of washed platelets with and without protease inhibitors and inhibitors of platelet activation. Washed platelets were also stimulated with calcium ionophore and MgCl2. There was no measurable vWF activity or vWF:Ag in platelet lysates or releasates in any dog regardless of phenotype. All dogs were studied using a standard arterial stenosis and injury procedure to induce arterial thrombosis. Thromboses were detected by cyclic reductions in Doppler blood flow velocity. Vessels were examined by light and scanning electron microscopy. Thrombosis developed in the arteries of normal (9 of 10) and hemophilia A dogs (16 of 16) but in none of the vWD dogs (0 of 10). Infusion of canine vWF cryoprecipitate into vWD dogs markedly shortened bleeding time but did not support thrombosis as seen in dogs with vWF in the plasma and subendothelium. Thrombosis, then, fails to occur when vWF is absent from the plasma and subendothelial compartments or present only in the plasma compartment. These data are consistent with the hypothesis that vWF in the plasma and subendothelium supports thrombosis. Neither plasma FVIII nor platelet vWF is essential for thrombosis in this model.

Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).

Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Porcine von Willebrand disease and atherosclerosis. Influence of polymorphism in apolipoprotein B100 genotype.

The relationship of apolipoprotein-B genotype (Lpb) to diet-induced hypercholesterolemia and atherosclerosis was studied in von Willebrand disease (vWD) and normal pigs. Von Willebrand and normal pigs developed comparable levels of hypercholesterolemia (respectively, 757.9 +/- 49.4 versus 772.8 +/- 47.9 mg/dl, P = 0.95). Pigs with Lpb1/5 and Lpb5/8 genotypes, however, developed significantly higher serum cholesterol levels than those with other Lpb genotypes (866.1 +/- 64.0 mg/dl, P = 0.0343). Coronary and aortic atherosclerosis, measured by computer-assisted automated image analyzer, were not significantly different between vWD and normal pigs. Pigs with an Lpb5 allele developed significantly more atherosclerosis than those with the Lpb3/8 or Lpb8/8 genotypes or the rare Lpb1 allele (r greater than or equal to 0.434, P less than or equal to 0.05). Polymorphism in apolipoprotein B100 genotype, then, significantly influenced the severity of diet-induced hypercholesterolemia and atherosclerotic plaque formation in vWD and normal swine without regard to the vWD genotype.

von Willebrand factor and animal models: contributions to gene therapy, thrombotic thrombocytopenic purpura, and coronary artery thrombosis.

Use of animal models of von Willebrand factor (vWF) deficiency, both inherited and induced, continues to advance the knowledge of vWF-related diseases. Three examples are reviewed in this article--von Willebrand's disease (vWD), thrombotic thrombocytopenic purpura, and coronary artery thrombosis. The success of gene transfer by liver and bone marrow transplantation in porcine vWD and canine hemophilia A, with a change in phenotype that establishes improved hemostasis, portends imminent testing of gene therapy in these models. With use of recombinant technology, the phenotype of hemophilia B fibroblasts has been transformed to normal, as evidenced by secretion of the normal hemostatically active protein. This result is a prelude to implantation in hemophilic animals. Thrombotic thrombocytopenic purpura is characterized by qualitative and quantitative alterations in vWF. A new animal model induced by the venom factor botrocetin, a cofactor of vWF, closely mimics the human syndrome. A proposed pathophysiologic mechanism for thrombotic thrombocytopenic purpura is outlined. The third contribution is recognition that occlusive coronary thrombosis is a vWF-dependent condition. Without vWF, as in porcine vWD or normal pigs treated with a monoclonal anti-vWF antibody, occlusive thrombi do not develop, even with luminal stenosis. The thrombogenicity of coronary atheromas, including those with fissures of the fibrous cap, is also vWF-dependent.