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Air permeability and capillary pressure are macroscopic snow properties that are influenced by the pore structure of the snow cover. Formulas for predicting fluid transport, species elution, and acoustive wave propagation require parameterization of one or both of these properties. We report paired measurements of permeability and capillary rise from snow samples at field sites in Hanover, New Hampshire, and Sleepers River Research Watershed, Danville, Vermont. We augment thesedata with laboratory tests on sieved snow and glass beads. Our measurements demonstrate a linear relationship between permeability and the ratio of porosity and the square of capillary rise, which we corroborate theoretically using a simple conduit model of the pore space. We propose that scatter in the data results, in part, from the effect of crystal shape on air flow and imbibition contact angle. Since the early measurements and classification schemes of Bader in 1939, many investigators have expanded the database of permeability observationsfor a wide range of snow types. We summarize these data and report our own recent observations from the New England sites and from an additional site in Manitoba, Canada. Our measurements are in the high range of reported values. However, after normalizing our data by the square of grain diameter, they follow the empirical function of Shimizufairly closely. This agreement supports our measurements, and demonstrates the usefulness of Shimizu's function for snow types other thanthe relatively dense, fine-grained snow used in his analysis. Our normalized permeability data for low density snow, as well as the Shimizu function, are below theoretical predictions for suspensions of spheres and infinite cylinders. By extending the model for spheres to oblate spheroids and discs, we estimate permeability that is in closer agreement with our data. We suggest that a decrease in surface-to-volume ratio as snow ages may account for a relative increase in normalized [ABSTRACT FROM AUTHOR]

Presents an abstract of the article "IgE and Diseases of the Skin," by R. K. Winkelmann, G. J. Gleich, S. A. Muller and R. E. Jordan.

There is some evidence that chronic obstructive pulmonary disease (COPD) and metabolic syndrome may be related, perhaps through systemic inflammation, which is common to both. However, the association between the two conditions has not yet been clearly shown. The present study involved 7,358 adults aged > or =50 yrs from a population-based survey who underwent spirometry, a structured interview and measurement of fasting metabolic marker levels. Airflow obstruction (forced expiratory volume in 1 s/forced vital capacity ratio of less than the lower limit of normal) was present in 6.7%, and the International Diabetes Federation metabolic syndrome criteria were met by 20.0%. The risk of metabolic syndrome was higher in those with airflow obstruction than in those without (odds ratio (OR) 1.47; 95% confidence interval (CI) 1.12-1.92), after controlling for potential confounders. Of the five components of metabolic syndrome, only central obesity was significantly associated with airflow obstruction (OR 1.43; 95% CI 1.09-1.88) after adjusting for body mass index. A similar association was observed in both never and current smokers. In this Chinese sample, airflow obstruction was associated with metabolic syndrome, and, in particular, its central obesity component. This may help explain the increased risk of cardiovascular diseases in COPD, and so could guide future clinical practice.

Every winter, hospitals face a large increase in emergency respiratory admissions in elderly people. A case-control study was undertaken to assess the effect of routine influenza vaccine in preventing such admissions among a cohort of UK elderly presenting with acute respiratory illness during winter 2003-2004. 157 hospitalised cases and 639 controls (matched for age, sex and week of consultation) were interviewed. In a winter typical of levels of circulating influenza in recent years, influenza vaccine did not show a protective effect on emergency respiratory admissions overall (adjusted OR 1.2 (95%CI 0.8, 1.9). Policy makers should not rely solely on influenza vaccine routinely having a large effect on winter pressures, and should focus on additional preventive strategies.

Objective: To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination., Design: Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose., Subjects: 40,000 treated patients and 16,000 patients given placebo., Main Outcome Measures: Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs., Results: All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, beta blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose., Conclusions: Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.

Abciximab (c7E3 Fab, ReoPro) blocks GPIIb/IIIa and alphavbeta3 and inhibits thrombotic and proliferative events only in humans and non-human primates. The bivalent F(ab')2 fragment is an effective anti-thrombotic agent in canine models. In the present study, 7E3 F(ab')2 was also found to bind to rat GPIIb/IIIa (KD = 27 +/- 4 microg/mL) and alphavbeta3 (KD = 9 +/- 8 microg/mL), to block in vitro rat platelet aggregation (IC50 = 16 +/- 6 microg/mL), and to inhibit alphavbeta3-mediated microvessel sprout formation in a rat aortic ring assay. Following administration of 7E3 F(ab')2 (4 mg/kg) to rats, platelet aggregation was completely blocked for up to 6 h and thrombus formation in response to a rat abdominal aorta double crush injury was prevented. Effective chronic dosing was achieved with 6 mg/kg daily I.P. injections. In vitro mixing experiments indicated that 7E3 F(ab')2 redistributed to unlabeled platelets in 2 h. Ex vivo, 7E3 F(ab')2 was detected on platelets for up to 4 days after a single 4-mg/kg injection. These data suggest that 7E3 F(ab')2 may be a useful agent to study the effects of GPIIb/IIIa and alphavbeta3 blockade in rat models of thrombosis and vascular disease.

Objective: Enhanced GPIIb/IIIa binding and inhibition of platelet aggregation of eptifibatide by the reduction of ionized plasma calcium concentrations have been reported. The present study compared the importance of Ca2+ chelation on the in vitro platelet inhibitory profiles of the GPIIb/IIIa antagonists abciximab, eptifibatide and tirofiban., Methods and Results: Turbidimetric platelet aggregation dose response curves of the various GPIIb/IIIa antagonists were performed using platelet rich plasma (PRP) anticoagulated with either trisodium citrate, or the non-chelating anticoagulant, PPACK. The concentrations of antagonist that resulted in 50% inhibition of TRAP-induced (10 microM) platelet aggregation (IC50) were measured in the presence of either citrate or PPACK. In addition, the influence of Ca2+ chelation on the binding properties (relative affinity, on- and off-rates) of abciximab for the GPIIb/IIIa receptor on platelets was measured. For all three agonists, the IC50 concentrations were lower for platelets treated with citrate than PPACK, but the degree of difference varied among the agents. The mean TRAP IC50 values for citrate and PPACK were 88.2 +/- 12.2 nM and 126.1 +/- 28.4 nM for abciximab (1.4 fold enhancement; p = 0.0007), 75.9 +/- 13.3 nM and 142.6 +/- 32.6 nM for tirofiban (1.9-fold enhancement; p = 0.001), and 260.2 +/- 62.5 nM and 810.3 +/- 182.5 nM for eptifibatide (3.1-fold enhancement; p = 0.001). A similar shift in effective inhibitor concentrations for abciximab was observed with ADP (10 microM). The relative affinities (EC50), on- and off-rates of abciximab for the platelet GPIIb/IIIa receptor in the presence of trisodium citrate and PPACK were equivalent., Conclusions: These data confirm previous observations that Ca2+ chelation afforded by citrate decreases the effective inhibitor concentrations of GPIIb/IIIa antagonists, as assessed by turbidimetric platelet aggregation. However, the extent of decrease was less for abciximab and tirofiban, compared to eptifibatide.

Background: Most people have acne at some stage during their life, with about one per cent being left with permanent acne scars. Recent laser techniques are thought to be more effective than chemical peels and dermabrasion., Objectives: To assess the effects of laser resurfacing for treating facial acne scars., Search Strategy: We searched MEDLINE (1966 to April 1999), EMBASE (1980 to April 1999), Science Citation Index (1981 to April 1999), the Cochrane Controlled Trials Register (April 1999), DARE (April 1999), INAHTA (April 1999), NHS HTA Internet site (April 1999). Dermatological Surgery (1995 to March 1999) and the British Journal of Dermatology (1995 to September 1999) were handsearched. We searched the reference lists of relevant articles and contacted experts and commercial laser manufacturers., Selection Criteria: Randomised controlled trials which compare different laser resurfacing techniques for treating patients with facial acne scars, or compare laser resurfacing with other resurfacing techniques or no treatment., Data Collection and Analysis: Two reviewers independently selected studies, assessed the quality of studies and extracted data., Main Results: No randomised controlled trials where laser treatment was compared to either placebo or a different type of laser were found. Most of the 27 studies uncovered were poor quality case series with small numbers of acne-scarred patients., Reviewer's Conclusions: The lack of good quality evidence does not enable any conclusions to be drawn about the effectiveness of lasers for treating atrophic or ice-pick acne scars. Well designed randomised controlled comparisons of carbon dioxide versus Erbium:YAG laser are urgently needed.

Background: We examined the ex vivo platelet aggregation profiles of patients who underwent percutaneous coronary intervention and received either abciximab, ticlopidine, or both agents., Study Design and Methods: The trial was a prospective, nonrandomized, single-center, open-label study of 42 patients undergoing percutaneous coronary intervention who received the following regimens: group 1, abciximab (0.25 mg/kg bolus and 12-hour, 0.125 microg/kg per minute infusion); group 2, ticlopidine (250 mg twice daily for 14 consecutive days, initiated 12 to 18 hours before intervention); group 3, abciximab plus ticlopidine initiated 12 to 18 hours before procedure; and group 4, abciximab plus ticlopidine initiated 72 to 96 hours before procedure. Platelet aggregation measurements to adenosine diphosphate (ADP) and a thrombin receptor activating peptide (TRAP, 8 micromol/L) were obtained before ticlopidine treatment, after initiation of ticlopidine, and immediately before abciximab treatment and intervention, then at several time periods after onset of abciximab treatment. Platelet surface abciximab levels were monitored by flow cytometry., Results: Neither ticlopidine regimen resulted in appreciable platelet inhibition before intervention and before administration of abciximab. In the ticlopidine-only arm, suppression of platelet aggregation to the weakest stimuli (5 micromol/L ADP; 23% +/- 7.5%) was detected within 24 hours after intervention, with maximal inhibition to both 5 and 20 micromol/L ADP observed 7 days after intervention (48% +/- 7.9% and 18% +/- 8.7%, respectively). In contrast, ticlopidine marginally suppressed TRAP-mediated platelet activation at times when maximal effects on ADP-mediated platelet aggregation were evident. Neither ticlopidine regimen appreciably enhanced platelet inhibition during or shortly after cessation of abciximab treatment. For all 3 abciximab treatment arms, profound inhibition of ADP-induced (>80%) and TRAP-induced (>65%) platelet aggregation was observed 2 hours after treatment. In the abciximab-only arm, platelet aggregation responses gradually recovered, with the rate of response directly proportional to the strength of stimuli. However, in the ticlopidine plus abciximab arms, recovery of platelet aggregation at later times (7 and 14 days) reached a plateau and reflected the extent of inhibition observed in ticlopidine-treated patients. No difference in the clearance of surface-bound abciximab from circulating platelets was observed between the abciximab and abciximab plus ticlopidine arms., Conclusions: Concomitant abciximab plus ticlopidine treatment yields a platelet inhibition profile that is a composite of the effects of the 2 agents. In the early stages of treatment, inhibition of ex vivo platelet aggregation was mediated primarily by abciximab; effects were more moderate and were predominately mediated by ticlopidine.

Background: This study evaluated the effect of heparin on the platelet reactivity and the pharmacodynamic profile of abciximab., Methods and Results: Ex vivo studies were performed on patients undergoing elective percutaneous coronary intervention (n = 26) who were at moderate to high risk of ischemic complications. Patients received a 12,000-U bolus of heparin followed by a 0.25-mg/kg bolus of abciximab. Before abciximab treatment, platelet aggregation responses to a variety of stimuli were assessed immediately before and 10 minutes after the heparin bolus. Heparin increased platelet aggregation to 2 and 5 micromol/L adenosine diphosphate (ADP) and 5 microg/mL collagen by 36%, 25%, and 46%, respectively (P < or =.001), but did not influence platelet reactivity to thrombin receptor-activating peptide or 20 micromol/L ADP and had no appreciable effect on platelet surface glycoprotein (GP) IIb/IIIa receptor numbers. To assess the impact of heparin on the pharmacodynamic profile of abciximab, GP IIb/IIIa receptor blockade and platelet aggregation inhibition estimates obtained after abciximab administration were calculated relative to the basal levels observed both before and after the heparin bolus. At 2 and 24 hours after the abciximab bolus, GP IIb/IIIa receptor blockade measurements normalized to either the preheparin or postheparin baseline determinations were equivalent. For all ADP concentrations tested, the 2-hour post-abciximab bolus platelet aggregation inhibition estimates based on the preheparin and postheparin baseline values were comparable. However, for 2 and 5 micromol/L ADP, the 24-hour post-abciximab platelet aggregation inhibition measurements based on preheparin baseline values were significantly lower than postheparin baseline determinations (both P < or =.003). In vitro studies revealed that therapeutic heparin doses induced a concentration-dependent reduction in the extent of platelet inhibition produced by amounts of abciximab that elicit partial inhibition of platelet aggregation. However, at abciximab concentrations that achieved platelet aggregation blockade of >80%, the levels of inhibition of platelet aggregation in the presence and absence of heparin were equivalent., Conclusions: The cumulative ex vivo and in vitro data indicate that for certain stimuli, heparin alters the platelet inhibitory profile of abciximab at concentrations of the agent that yield partial suppression of platelet function.

Ticlopidine and abciximab are two antiplatelet agents that are frequently administered during percutaneous coronary interventions. Although they have different mechanisms of action and pharmacological profiles, the two agents are often concomitantly used in complicated stent placements. The purpose of the study was to evaluate the effect of ticlopidine therapy on the capacity of abciximab to inhibit platelet aggregation, in vitro. Blood samples from 13 ticlopidine-treated stent placement patients and 8 patients undergoing PTCA who did not receive ticlopidine were obtained prior to, 12-36 hours and 7-10 days after initiating ticlopidine treatment. For each patient, the minimal ADP and the thrombin receptor activating peptide (TRAP) concentrations that elicited maximal platelet aggregation responses at baseline were used to measure the extent of platelet aggregation and the abciximab concentration that gave a 50% decrease in aggregation (IC(50)) for both agonists at the three time points. The ticlopidine group baseline and 12-36 hour mean ADP aggregation responses were equivalent, but decreased by 34% (P = 0.009) at 7-10 days. The control group ADP and TRAP, as well as the ticlopidine group TRAP aggregation responses, were equivalent at all time points. The ticlopidine group baseline and 12-36 hour abciximab IC(50) values for ADP were comparable (1.58 +/- 1.1 ng/mL vs. 1.23 +/- 0.5 ng/mL; P = 0.266), but decreased to 1.00 +/- 0.6 ng/mL (36%; P = 0.004) at 7-10 days. In contrast, the abciximab IC(50) for TRAP increased from 1.48 +/- 1.0 ng/mL to 1.85 +/- 1.1 ng/mL (25%; P = 0.033) at 12-36 hours, but returned to baseline at 7-10 days (1.40 +/- 0.8; P = 0.975). The control group IC(50) abciximab values for ADP and TRAP were comparable throughout the monitoring period. The results demonstrate that ticlopidine elicits subtle potentiation of the platelet-inhibitory capacity of abciximab to the agonist ADP, but not TRAP, at 1 week after initiation of treatment.

Even with continued improvements in the technology of percutaneous coronary intervention (PCI), approximately 10% to 20% of patients undergoing PCI will require repeat procedures within 1 year. Furthermore, because of the chronic nature of coronary artery disease, many patients will require additional treatment with PCI well after an initial episode of care. Abciximab (ReoPro), a chimeric (murine/human) monoclonal antibody fragment (c7E3 Fab), has been shown to significantly improve periprocedural and long-term outcomes associated with PCI and to reduce the need for repeat target vessel revascularization. However, because the structure of abciximab is derived from an antibody, concern has been raised about subsequent repeat administration. To prospectively evaluate the safety and efficacy of abciximab readministration, we established the ReoPro Readministration Registry with the intent to determine the efficacy, human antichimeric antibody response and rates of thrombocytopenia, bleeding, intracranial hemorrhage, and anaphylaxis in at least 500 patients being retreated with abciximab. The study was conducted at 19 centers beginning in March 1997. This article details interim data that are based on the first 329 patients. Data to date indicate that readministration with abciximab is safe and efficacious and that the same indications for first-time use should apply to subsequent readministration.

Angiogenesis plays an essential role in the growth and dissemination of solid tumor cancers. The expression of endothelial cell integrin alpha(v)beta3 has been shown to increase during vascular proliferation associated with human tumors. Selective antagonists of alpha(v)beta3 can block angiogenesis and tumor growth by inducing programmed cell death in proliferating endothelial cells. Monoclonal antibody 7E3, an antagonist of the human, but not murine, integrins alpha(v)beta3 and alphaIIbbeta3 (GPIIb/IIIa), inhibits platelet aggregation. It is the parent antibody of a mouse/human chimeric antibody fragment approved for adjunctive therapy of patients undergoing percutaneous coronary interventions to prevent ischemic complications (c7E3Fab; abciximab; ReoPro). To evaluate the potential of 7E3 to inhibit human angiogenesis and tumor growth independent of its antiplatelet effects, we established integrin alpha(v)beta3-negative human melanoma tumors in full-thickness human skin grafted onto SCID mice. The resulting tumors induce a human angiogenic response as assessed by the immunoreactivity of vascular cells with monoclonal antibodies specific for human CD31. Administration of 7E3 prevented or significantly inhibited the growth of tumors, and this effect correlated with a significant reduction in the number of blood vessels supplying the tumors. These results support the previous findings that blockade of integrin alpha(v)beta3 inhibits angiogenesis and tumor growth and indicates that dual inhibitors of alpha(v)beta3 and alphaIIbbeta3 are effective in blocking tumor growth and angiogenesis.

Because the beta3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the beta3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds beta3 integrins on vascular cells (alphavbeta3) with affinity equal to that for the platelet glycoprotein IIb/IIIa integrin has led to the hypothesis that c7E3 may act directly on the artery wall to prevent restenosis after angioplasty. To test this hypothesis, we studied the effects of c7E3 on structural changes within the artery wall after angioplasty or stent angioplasty in 23 male cynomolgus monkeys with established atherosclerosis. Animals were randomly assigned to receive either a bolus of c7E3 (0.4 mg/kg IV, n=11) followed by a 48-hour infusion (0. 2 microg. kg-1. min-1) or an equal volume of vehicle (n=12). Animals received weight-adjusted aspirin and heparin and then underwent unilateral iliac artery experimental angioplasty and subclavian artery stent angioplasty (Palmaz). Iliac artery lumen diameter (LD) was determined by angiography at baseline (LDPre), after angioplasty (LDPost), and 35 days later (LDDay35). Arteries were then fixed by perfusion and removed for analysis. Lumen, intima, media, and external elastic lamina (EEL) areas were measured in iliac artery cross sections. Values from each injured iliac artery were normalized to the contralateral uninjured iliac artery to control for interanimal variability in baseline artery size and atherosclerosis extent. Intimal area was also measured in subclavian stent cross sections. c7E3 blocked platelet aggregation and prolonged the bleeding time from 2.8+/-1.1 to 19.8+/-2.5 minutes, P<0.001. Experimental angioplasty increased LDPost an average of 28%, and the initial gain was similar in both groups (P=NS). Despite an anti-platelet effect, c7E3 did not inhibit iliac lumen narrowing (LDDay35-LDPost: c7E3, -0.69+/-0.17 versus vehicle, -0.99+/-.17 mm, P=0.35); intimal hyperplasia (neointima area: c7E3, 1.12+/-.28 versus vehicle, 1.22+/-.20 mm2, P=0.77); or decrease in artery wall size (EEL area [percent of uninjured control]: c7E3, 101+/-7% versus vehicle, 121+/-7%). Stent intimal hyperplasia was also unaltered by c7E3 treatment (neointimal area: c7E3, 1.09+/-0.16 versus vehicle, 1. 28+/-0.11 mm2, P=0.36). These results suggest that the benefits of c7E3 treatment in coronary angioplasty were not from inhibition of intimal hyperplasia or improved artery wall remodeling. Alternative mechanisms should be explored to explain improved late outcomes after angioplasty in patients treated with c7E3.

1. The aim of the present study was to validate the Cytosensor microphysiometer, a novel system that measures the extracellular acidification rate as a reliable index of the integrated functional response to receptor activation, as a method for studying NK3 receptor pharmacology, and then to use this system to assess the functional activity of novel compounds at this receptor. 2. The selective NK3 agonist senktide caused reproducible, concentration-related increases in acidification ratein CHO-NK3 cells, with a pEC50 value of 8.72+/-0.11 (n=15). [Beta-Ala8]NKA(4-10), the selective NK2 agonist, elicited a much weaker response (pEC50=6.68+/-0.08, n=4), while the NK1-selective agonist substance P methylester only caused a very weak response at concentrations > or =3 microM (n=2). The rank order of potency for the endogenous tachykinins NKB>NKA>substance P (n=3) confirmed the response was mediated by the NK3 receptor. Moreover, the actual potencies obtained were consistent with affinities measured in radioligand binding studies. 3. The novel compounds PD156319-121 (0.3-1 microM), PD161182 (10-300 nM), PD168001 (10-100 nM) and PD168073 (10-100 nM) all acted as surmountable antagonists of the senktide-induced acidification response, with pA2 values of 7.49, 8.67, 9.17 and 9.25 respectively (n=3-5). In comparison the known NK3 antagonist SR142801 (10-100 nM) had a pA2 value of 8.83 (n=8) for the interaction with senktide. Again, these values are consistent with the radioligand binding data. 4. Amiloride (1 mM) inhibited the senktide-induced acidification response by 68.3+/-3.3 (n=4), indicating that the Na+/H+ antiporter plays an important role in this response, and this is consistent with the importance of this antiporter in other acidification responses. 5. Inhibition of protein kinase C with staurosporine (0.1 microM), or depletion of the intracellular Ca2+ stores with thapsigargin (1 microM), both resulted in a reduction in the maximum response to senktide (63.3+/-1.7 and 68.9+/-3.2% respectively, n=3-5), and co-application of these inhibitors abolished the response (n=3). This strongly suggested that the NK3 receptor was coupling via phospholipase C (PLC), as would be expected, although this could not be confirmed by the use of the putative PLC/PLA2 inhibitor U73122. 6. In conclusion, we have demonstrated the utility of the Cytosensor in the characterization of functional responses to agonists, and assessment of the affinities of antagonists in CHO cells expressing the human NK3, and have shown that our series of novel compounds are non-peptide NK3 antagonists of high affinity, as exemplified by PD168073.

Background: Large, randomized, and blinded clinical trials (EPIC, EPILOG, and CAPTURE) have demonstrated that abciximab (ReoPro, chimeric 7E3 Fab) markedly reduces thrombotic events associated with percutaneous transluminal coronary interventions. The marked early benefits at 30 days were sustained at 6 months and 3 years. Initially developed because of its efficacy in blocking GP IIb/IIIa (alphaIIb/beta3) receptors on platelets, abciximab also binds with equivalent affinity to alpha(v)beta3., Methods and Results: This study presents a detailed characterization of the alphavss3 interaction, including the ability of abciximab to (1) bind with comparable affinity to alpha(v)beta3 and GP IIb/IIIa, (2) inhibit alpha(v)beta3 and GP IIb/IIIa-mediated cell adhesion in vitro with IC50 values approximating binding KD values, and (3) redistribute between GP IIb/IIIa and alpha(v)beta3 integrins in vitro., Conclusions: As an antagonist of not only GP IIb/IIIa but also alpha(v)beta3, abciximab may provide additional clinical benefit in preventing alpha(v)beta3-mediated effects such as thrombin generation, clot retraction, or smooth muscle cell migration and proliferation. Abciximab binds with equivalent affinity to both GP IIb/IIIa and alphavss3 and redistributes between the 2 integrin receptors in vitro. Abciximab has been previously shown to circulate on platelets for up to 2 weeks. Taken together, these findings suggest that abciximab may have the ability to inhibit both GP IIb/IIIa and alpha(v)beta3 for extended periods.

Background: The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is approved for use in high-risk percutaneous coronary interventions. The purpose of the present study was to establish the pharmacodynamic profile and platelet-bound life span of abciximab., Methods and Results: The pharmacodynamics of abciximab (inhibition of ex vivo platelet aggregation and GP IIb/IIIa receptor blockade) were measured in 41 individuals who were randomized to receive a 0.25-mg/kg bolus and a 12-hour infusion of either 10 microg/min (EPIC regimen) or 0.125 microg x kg(-1) x min(-1) (EPILOG regimen) of the antiplatelet agent. At extended times, the amount and distribution of platelet-bound abciximab were monitored by flow cytometry. The EPIC and EPILOG infusion regimens exhibited equivalent blockade of both GP IIb/IIIa receptors and platelet aggregation throughout the duration of abciximab treatment. Flow cytometry revealed a single, highly fluorescent platelet population during treatment, consistent with complete saturation and homogeneous distribution of abciximab on circulating platelets. For 15 days after treatment, the fluorescence histograms remained unimodal with gradually diminishing fluorescence intensity, indicating decreasing levels of platelet-bound abciximab. At 8 and 15 days, which exceeds the normal circulating life span of platelets, median relative fluorescence intensity corresponded to 29100 (29% GP IIb/IIIa receptor blockade) and 13300 (13% GP IIb/IIIa receptor blockade) abciximab molecules bound per platelet, respectively., Conclusions: These results are consistent with continuous reequilibration of abciximab among circulating platelets and may explain the gradual recovery of platelet function and long-term prevention of ischemic complications by abciximab after coronary intervention.

Background: The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no "point of care" exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside., Methods and Results: GP IIb/IIIa receptor blockade, impedance (5 microg/mL collagen), and turbidimetric aggregation (5 and 20 micromol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was > 91%, and both impedance and turbidimetric aggregation were inhibited by > or = 90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 65+/-20% and 49+/-14%, respectively, and inhibition of impedance aggregation was 69+/-12%. GP IIb/IIIa receptor blockade was 67+/-8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 44+/-21% and 30+/-14%, respectively, whereas impedance aggregation was inhibited by 60+/-14%. GP IIb/IIIa receptor blockade was 57+/-7%., Conclusions: During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 micromol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.

Background: Thrombosis is an important limitation of metallic coronary stents, especially in smaller vessels in which shear rates are high. Monoclonal antibody to platelet glycoprotein IIb/IIIa receptor (7E3) has been shown to inhibit shear-induced platelet aggregation. In this study, we compared the effects of 7E3, heparin, and aspirin on stent thrombosis in an ex vivo arteriovenous shunt model of high-shear blood flow., Methods and Results: An ex vivo arteriovenous shunt was created in 10 anesthetized dogs. Control rough-surface slotted-tube nitinol stents (n = 72) expanded to 2 mm in diameter in a tubular perfusion chamber were interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100s-1 for 20 minutes. The animals were treated with intravenous murine 7E3 (Fab')2 (0.2, 0.4, and 0.8 mg/kg), heparin (100 U/kg), or aspirin (10 mg/kg). Effects of the test agents on thrombus weight, platelet aggregation, platelet P-selectin expression, bleeding time, and activated clotting time (ACT) were quantified. 7E3 reduced stent thrombosis by 95% (20 +/- 1 to 1 +/- 1 mg, P < .001) and platelet aggregation by 94% (14 +/- 2 to 1 +/- 1 omega, P < .001) at the highest dose (0.8 mg/kg). 7E3 significantly prolonged bleeding time but had no effect on ACT and platelet P-selectin expression. Heparin prolonged ACT but had no significant effect on stent thrombosis or platelet aggregation. Aspirin, although it inhibited platelet aggregation by 65%, had no effect on stent thrombosis (19 +/- 2 versus 20 +/- 1 mg in controls)., Conclusions: 7E3 produced a dose-dependent inhibition of acute stent thrombosis under high-shear flow conditions. Stent thrombosis was resistant to heparin and aspirin. Thus, 7E3 may be an effective agent for preventing stent thrombosis.

A large number of glycoprotein (GP) IIb/IIIa receptors are present on the surface of platelets. Studies to define precisely the number of GPIIb/IIIa receptors using specific monoclonal antibodies (MoAbs) or fibrinogen binding have, however, yielded varying estimates of receptor number. To refine the quantitative estimation of GPIIb/IIIa receptors on resting platelets, we have used the MoAb 7E3, which has high affinity for GPIIb/IIIa. Quantitative binding studies were performed using radiolabeled conjugates of 7E3 IgG, as well as fragments and derivatives of 7E3. For platelets obtained from any single individual, the numbers of 7E3 F(ab')2 and IgG molecules bound per platelet were equivalent (approximately 40,000), whereas the number of Fab molecules bound per platelet was consistently approximately twofold higher (approximately 80,000). To investigate the basis of the quantitative disparity in binding of intact 7E3 and 7E3 F(ab')2 versus 7E3 Fab, we studied the binding of a newly constructed, bispecific (Fab')2 molecule containing only a single 7E3 combining site. Because this construct bound to the same extent as the Fab species, the larger size of the intact 7E3 and 7E3 F(ab')2 molecules could not explain the reduced number of molecules that bound per platelet compared to the Fab fragment. Rather, it appears that the valency of the antibody is the critical factor determining the number of antibody molecules bound per platelet. Thus, we conclude that the binding of 7E3 Fab corresponds most closely with surface GPIIb/IIIa number and that the number of GPIIb/IIIa receptors is approximately 80,000 per platelet.

The new generation of dentin bonding materials can withstand the contraction shrinkage of composite materials. A two-year clinical trial of one material showed an excellent retention rate.

This study evaluated the clinical effectiveness of a new generation bonding material, used for conservative restoration of cervical erosion lesions. One hundred lesions were selected. At two-year recall, 79 have been reviewed to date. In those, 97.5% of the restorations were still present; 95% of restorations present had retained color, 96% had retained marginal integrity, and 100% had retained abrasion resistance, surface texture, and staining resistance.

A conservative technique for treatment of incisal erosion lesions using a new light-cured ionomer restorative cement is described.

Despite its increased use, composite resin is still technique-sensitive. The authors offer correct placement steps and indicate where these restorations will do well.

The technique used to treat cervical erosion lesions that are buried beneath the crest of the gingival tissue is described. With proper isolation of the field and careful gingival retraction as prerequisites, the surface topography of the completed restoration is almost indistinguishable from the adjacent enamel, and the gingival tissue response is good.

Glass ionomer cement characteristics of biological acceptability, fluoride release, dentin bondability, and marginal integrity are excellent; at the same time, they have always been regarded as secondary choices for anterior and posterior restorations. Slow set, brittleness, poor finishability, lack of translucency, and the technique-sensitive nature of the glass ionomers hardly compare with the composite resins which are easier to handle, polishable, and esthetically acceptable. The combined ionomer-composite restoration provides a reliable chemical bond to dentin, micromechanical bonding of the composite to ionomer surface, and an acceptable esthetic result.

To investigate the pathogeneic significance of immune complexes in cutaneous vasculitis, 107 patients with various forms of cutaneous vasculitis, including 59 patients with necrotizing (leukocytoclastic) vasculitis (group 1), and 48 patients with lymphocytic vasculitis, or a predominately lymphocytic perivascular infiltrate (group 2), were studied. Immunoglobulins or complement components in cutaneous blood vessels were detected by direct immunofluorescence in high frequency in both groups (91 and 88%, respectively). Using two radioassays for circulating immune complexes, Clq or monoclonal rheumatoid factor (mRF) reactive material was detected in 68% of the patients with necrotizing vasculitis but only 44% of the patients in the lymphocytic-perivascular group. The mRF radioassay was elevated in 58% of the first group of patients and 41% of the patients in group 2, although Clq binding activity was increased in 54% of the patients with necrotizing vasculitis but only in 9% of the patients with a lymphocytic vasculitis or lymphocytic perivascular infiltrate. By using both sucrose density gradient ultracentrifugation and Sepharose 6B gel filtration, the Clq and mRF reactive material detected in some patients with necrotizing vasculitis eluted in high molecular weight fractions that were also anticomplementary. In one patient with necrotizing vasculitis and hepatitis B antigenemia, these heavy molecular weight Clq and mRF reactive fractions contained a two- to three-fold increase in hepatitis B surface antigen when compared with lighter molecular weight fractions. Heavy and light molecular weight mRF reactive material could be detected in selected patients in the lymphocytic-perivascular group as well as in the necrotizing vasculitis group. These studies suggest that cutaneous vasculitis, including acute necrotizing (leukocytoclastic) vasculitis and some forms of lymphocytic vasculitis, and perhaps some diseases characterized by a lymphocytic perivascular infiltrate, may represent cutaneous expressions of immune complex disease.