Immunological aspects of controlled antigen delivery

Recent advances in controlled delivery systems for protein pharmaceuticals such as microspheres, liposomes, pumps and implants, have provided a new avenue for delivery of vaccine antigens. There has, however, been considerable confusion over the way in which continuous antigen delivery affects the outcome of an immune response. To date, there has been little systematic study of the influence of varying antigen exposure times and release profiles on the phenotype of the immune response, or indeed the balance between immunity and tolerance as most studies have concentrated on optimising responses to a particular antigen of interest in a single model system. As these delivery systems would find particular advantages in management of livestock species, where the use of a single administration vaccine would significantly enhance management practices, it is important to understand the relationship between controlled antigen delivery and immunity. This paper describes how existing controlled antigen delivery studies have contributed to our understanding of the development of the immune response and demonstrates how continuous antigen delivery is useful, and possibly advantageous in the generation of immunity, the maturation of the immune response and the extension of the effector response.     

Physical activity and the prevention of cardiovascular disease

This article summarizes recent evidence on the role of physical activity in the prevention of overt and subclinical vascular disease. Epidemiologic data suggest that as little as 30 minutes per day of moderate-intensity physical activity, including brisk walking, reduces the incidence of clinical cardiovascular events in men and women. Regular exercise may also retard the progression of asymptomatic coronary and peripheral arteriosclerosis. Cardioprotective mechanisms of physical activity include reducing adiposity, blood pressure, diabetes incidence, dyslipidemia, and inflammation, and enhancing insulin sensitivity, glycemic control, fibrinolysis, and endothelial function. In a sedentary society such as the United States, public health initiatives that promote moderate increases in activity represent the optimal balance between efficacy and feasibility to achieve desired improvements in cardiovascular health.     

Longitudinal impedance is independent of outflow resistance

BACKGROUND: Many investigators have measured outflow resistance (R) following peripheral bypass procedures, but correlations with graft patency have been weak. This is because the primary determinants of graft patency are the size and quality of the conduit, not its outflow bed. Efforts at separating conduit resistance from outflow resistance have been unsuccessful. Recently, the concept of longitudinal impedance ( integral Z(L)) has been suggested as a measure of conduit resistance independent of outflow resistance. The purpose of this in vitro experiment was to test the hypothesis that integral Z(L) is independent of R within physiologically relevant ranges. METHODS: Rigid polyethylene tubing of known internal diameter and length (4.3 mm, 375 cm) was perfused with a glycerin/saline mixture mimicking the viscosity of blood (4.1 cp), utilizing a variable pulsatile pump and Windkessel, with outflow into multiply branched tubes of decreasing diameter simulating the hemodynamic conditions of arterial bypass. Flow and pressure were measured using ultrasonic transit time and catheter transduction, respectively, and waveforms digitized at 200 Hz. Flow was varied while maintaining "systemic" pressure and resistance. After Fourier transformation, integral Z(L) was calculated as deltaP/Q at each harmonic and integrated over 4 Hz. RESULTS: integral Z(L) calculations were remarkably reproducible within the same day with a coefficient of variation (CV) = 4.0% (at 100 dyne. s/cm(5); n = 4) or over 4 successive days (CV = 4.3%). Furthermore, integral Z(L) was largely independent of R over the physiologic range tested, with integral Z(L) remaining relatively constant as R was increased sixfold. CONCLUSION: integral Z(L) is a consistent and reproducible measure of conduit resistance independent of R over a wide physiologic range. It may be useful for measuring the adequacy of bypass graft conduits.     

Differential mechanical activation of mitogen-activated protein kinases in intact human blood vessels

BACKGROUND: Vascular tissue remodels in response to a variety of hemodynamic factors, often transduced through activation of mitogen-activated protein kinases such as extracellular signal-related kinase (ERK1/2) and c-jun N-terminal kinase (JNK). This study tests the hypothesis that these kinases are involved in mechanical signal transduction in intact human arteries and veins. METHODS: Unused portions of human saphenous vein and radial artery were obtained fresh at the time of peripheral or coronary bypass. A sample of the vessel was immediately snap frozen (control(0)) and the remainder separated into three segments. One segment was placed in sterile medium and left undisturbed for 2 h (control(2)), one was perfused with sterile medium for 2 h at a steady rate of 150 ml/min, yielding shear stress values of 8-20 dyne/cm(2) (flow), and one was statically pressurized without flow at 110 mm Hg for 2 h (pressure). After treatment, samples were tested for phosphorylated ERK1/2 and JNK using Western blot. RESULTS: Two hours of culture produced mild increases in ERK1/2 activity in both vessel types. Stimulation with continuous rapid flow produced significantly increased ERK1 activity and a nearly 100% increase in ERK2 in veins. Static pressurization also stimulated ERK1/2, although slightly less than continuous flow. ERK1/2 phosphorylation was only mildly increased in flow-stimulated radial arteries, and exposure to normal systemic pressure showed no appreciable effect. Significant phosphorylation of JNK was not observed in either vessel. CONCLUSION: ERK1/2 phosphorylation is increased in human saphenous veins and radial arteries exposed to the hemodynamic conditions of arterial grafting. This pathway may be involved in the transduction of external stimuli leading to remodeling.     

Attitudes about electric and magnetic fields: do scientists and other risk experts perceive risk similarly?

Wherever there is electric power, 60-hertz (60-Hz) electric and magnetic fields (EMFs) are produced. Recently, conflicting reports have been published by government agencies about adverse health effects linked to EMFs. This paper seeks to identify the demographic and job-related factors that may explain differences among experts' perception of risk attributable to EMFs. Eighty-one participants at a bioelectromagnetics conference completed a survey on risk perceptions. Results indicated that education and employment sector were significant predictors of agreement with the statement that EMFs are not a problem. Future studies should look at the role of risk perception on environmental risk communication and determine the extent of message distortion, if any, based upon employment and demographic characteristics.     

Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces,a potential mechanism for herceptin resistance

Muc4 (also called sialomucin complex), the rat homolog of human MUC4, is a heterodimeric glycoprotein complex that consists of a peripheral O-glycosylated mucin subunit, ASGP-1, tightly but noncovalently linked to a N-glycosylated transmembrane subunit, ASGP-2. The complex is expressed in a number of normal, vulnerable epithelial tissues, including mammary gland, uterus, colon, cornea and trachea. Muc4/SMC is also overexpressed or aberrantly expressed on a number of human tumors including breast tumors. Overexpression of Muc4/SMC has been shown to block cell-cell and cell-matrix interactions, protect tumor cells from immune surveillance and promote metastasis. In addition, as a ligand for ErbB2, Muc4/SMC can potentiate phosphorylation of ErbB2 and potentially alter signals generated from this receptor. Using A375 human melanoma cells and MCF7 human breast adenocarcinoma cells stably transfected with tetracycline regulatable Muc4, we have investigated whether overexpression of Muc4/SMC can repress antibody binding to cell surface-expressed ErbB2. Overexpression of Muc4/SMC does not affect the level of ErbB2 expression in either cell line, but it does reduce binding of a number of anti-ErbB2 antibodies, including Herceptin. Interestingly, overexpression of ErbB2 does not block binding of other unrelated antibodies of the same isotype, suggesting that the reduction in ErbB2 antibody binding is due to complex formation of Muc4/SMC and ErbB2. Furthermore, capping of Muc4/SMC with anti-Muc4/SMC antibodies reduces antibody binding to ErbB2 instead of increasing binding, again suggesting that reduced antibody binding to ErbB2 is due to steric hindrance from complex formation of Muc4/SMC and ErbB2. Thus, overexpression of Muc4/SMC on tumor cells may have both prognostic and therapeutic relevance.     

Routine early postoperative duplex scanning is unnecessary following uncomplicated carotid endarterectomy

Although early postoperative duplex scanning has become routine after carotid endarterectomy (CEA), it is unclear whether the results of these scans alter clinical management. The purpose of this study was to critically examine the usefulness of early postoperative duplex scans in evaluating the ipsilateral carotid artery (for technical perfection) as well as the contralateral carotid artery (for potential velocity changes after improvements in ipsilateral flow). Consecutive patients undergoing CEA between January 1995 and June 1999 in a tertiary hospital setting were studied. Patients underwent early postoperative duplex scanning according to the discretion of the operating surgeon and the availability of the patient. In 212 patients 236 CEAs were performed with selective use of patch closure (49%), intraluminal shunting (19%), and intraoperative completion imaging studies (14%). Neurologic complications included 3 transient ischemic attacks (TIAs) (1.3%), 3 nondisabling strokes (1.3%), and 3 disabling strokes (1.3%). There was 1 30-day death from myocardial infarction. Patients were followed up for a median of 18 months (range 0-72 months). Sixty-five percent of patients undergoing uncomplicated CEA (147/227) underwent early duplex surveillance within 6 months of operation. Unsuspected sonographic abnormalities were discovered in 8 patients (5%), including 7 cases of mild internal carotid artery (ICA) stenosis (>50% by velocity criteria) and 1 case of common carotid artery (CCA) stenosis (intimal flap). None of the patients with ICA stenosis developed symptoms or required operation at any time. The CCA intimal flap was electively repaired without complication. Postoperative changes in velocity in the contralateral ICA were found in 8/48 (17%) cases. There were 3 cases of increased velocity, upgrading 1 from 0-49% to 50-79% stenosis and upgrading 2 from 50-79% to 80-99% stenosis. The latter patients both underwent uneventful contralateral CEA. There were 6 cases of decreased velocity, resulting in downgrading of stenoses from 50-79% to 0-49% (n=5) or from 80-99% to 50-79% (n=1). Only the latter patient underwent contralateral CEA; the remainder have been followed up without intervention. Early scanning appeared to offer no clinical benefit; survival and neurologic outcome were the same in the 135 patients scanned within the first 6 months as in the 68 patients whose first postoperative scan occurred later (4-year neurologic event rate 0% in both groups; patient survival with early duplex 98 +/- 1.5%, without early duplex 96 +/- 2.6%; = NS). Early ipsilateral duplex abnormalities following CEA are infrequent in asymptomatic patients and, even if found, rarely alter management. Patients with bilateral stenosis being considered for contralateral CEA should undergo repeat duplex scanning after the first operation, because of the significant rate (19%) of contralateral velocity changes induced by ipsilateral CEA.     

Objective assessment of videoconferenced lectures in a surgical clerkship

BACKGROUND: A challenge to the practice of third-year clerkship rotations at remote locations is the maintenance of equivalent didactic lectures, especially in subspecialty components. There has been little objective assessment of the results of videoconference lectures on medical student clerkship education. METHODS: Third-year surgical clerkship students, randomly assigned to a 4-week rotation 75 miles from the medical school, received subspecialty lectures by interactive teleconference via an ISDN line at 128 kb/s. Weekly quiz results (% correct) of students who received videoconference lectures were compared with students receiving conventional lectures, and were analyzed by 2-tailed t tests for equality of means. RESULTS: A mean of 12 students were tested per quiz (range, 5-21 students) after videoconference lectures, and 98 students were tested after conventional lectures (range, 41-146 students). The mean quiz score of students receiving video lectures was 70.5% (range, 65.4% to 73.6%); and after conventional lectures the mean quiz score was 71.4% (range, 69.5% to 76.8%). There were no significant differences in the mean scores of the individual quizzes (P = .16-.92) or between the totals (P = .65). CONCLUSIONS: Telemedicine, using interactive videoconferencing, is an effective method for didactic lectures in a surgical clerkship. This technology allows students to receive interactive lectures at distant clinical sites and limit their travel.     

Immunosuppression and procedure-related complications in 26 patients with type 1 diabetes mellitus receiving allogeneic islet cell transplantation

BACKGROUND: The success of sirolimus and low-dose tacrolimus in islet cell transplantation has influenced many transplant centers to utilize this novel regimen. The long-term safety and tolerability of this steroid-free immunosuppressive protocol for allogeneic islet transplantation has yet to be determined. METHODS: We transplanted 26 adult patients with long standing type 1 diabetes mellitus between April 2000 and June 2004. Immunosuppression consisted of induction with daclizumab and maintenance therapy with tacrolimus and sirolimus. Adverse events (AEs) in patients were followed and graded using the Common Terminology Criteria for Adverse Events, version 3.0 (National Cancer Institute). RESULTS: To date, the majority of patients were able to remain on the immunosuppression combination for up to 22+/-11 months. Four patients were successfully converted to Mycophenolate Mofetil due to tacrolimus-related toxicity. Withdrawal from immunosuppression was decided in four patients due to hypereosinophilic syndrome, parvovirus infection, aspiration pneumonia, and severe depression, respectively. Six patients required filgrastim therapy for neutropenia. Transient elevation of liver enzymes was observed in most patients early after islet infusion. Increased LDL in 20 patients required medical treatment. CONCLUSION: There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.