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INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new Posterior Fossa Syndrome Questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; M(age at diagnosis) = 10.38 years, SD = 5.09, range 3 – 31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician’s post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children’s Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items Ataxia (100.00%), Dysmetria (95.45%), and Speech/Language Changes (79.55%) were most sensitive. However, Ataxia (26.50%) and Dysmetria (46.61%) demonstrated low specificity. Speech/Language Changes (81.36%), Mutism (95.76%), Orofacial Apraxia (98.29%) and Irritability (96.61%) had high specificity. A principal component analysis found four components: 1) Speech/Language Changes, 2) Apraxias (including mutism), 3) Motor/Oromotor, and 4) Emotional Lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Introduction In response to high rates of chronic disease, the Capital District Health Authority in Nova Scotia recognized a need to move from a focus on acute care in decision making to one that also values a population health approach guided by community health indicators. Methods Stakeholders were surveyed on the choice, knowledge and utility of selected indicators. Results Respondents reported high scores for changes in their knowledge and attitude regarding community health indicators, and identified priority indicators for action.Decision makers’ use of community health indicators was increased by stakeholder involvement, supporting evidence in plain language, and wide dissemination.

Introduction En réaction aux taux élevés de maladies chroniques, la Régie régionale de la santé Capital en Nouvelle-Écosse a reconnu la nécessité de modifier le processus décisionnel axé sur les soins actifs pour privilégier une approche axée sur la santé de la population et guidée par des indicateurs sociosanitaires. Méthodologie Une enquête a été menée auprès des principaux intervenants à propos de leur connaissance des indicateurs socio-sanitaires en lien avec la santé, et à propos de leur opinion sur l’utilité de ces indicateurs dans l’aide à la prise de décision. Résultats Les répondants ont déclaré bien connaître les indicateurs sociosanitaires présentés et les ont trouvé utiles. Ils ont fait un choix plutôt consensuel sur les indicateurs prioritaires aptes selon eux à guider les interventions. Ils sont plutôt favorables à l’utilisation d’indicateurs sociosanitaires pour aider à définir une politique de la santé axée sur la population, du fait qu’ils ont participé au processus de choix, que la présentation des éléments probants a été faite en termes simples et pertinents, et que la diffusion des éléments a été large.

Estimates of US medical costs related to psoriasis treatment are limited and tend to understate the economic burden of moderate to severe psoriasis, which often requires the use of systemic agents, phototherapy or both.To estimate treatment failure rates and direct medical costs associated with the use of systemic agents and phototherapy in US patients with psoriasis.Claims records from a large New England-based health insurer were used to obtain patient-level data. Eligible patients with at least one claim listing an ICD-9-CM code for psoriasis (696.0; 696.1) were identified. Patients not receiving systemic treatments (methotrexate, cyclosporine, acitretin) or phototherapy (ultraviolet B with or without tar or petrolatum, psoralen and ultraviolet A [PUVA]) were excluded. Treatment failure was defined as a switch in therapy, augmentation with non-topical therapies, discontinuation following uptitration of dose or discontinuation following hospitalization. Medical costs included those related to pharmacy (over-the-counter medication excluded), institutional services (inpatient and outpatient) and professional services.A total of 2068 patients with moderate to severe psoriasis were included in the analysis. Over a 1-year period, approximately 20% of patients experienced treatment failure. The mean time to failure among patients who switched therapy ranged from 3 to 6 months. Mean annual pharmacy costs in the various treatment groups (categorized according to initial therapy received) ranged from 257 dollars to 1992 dollars per patient. Mean annual costs for institutional and professional services ranged from 156 dollars to 799 dollars and 183 dollars to 481 dollars per patient, respectively. The 99th percentile annual pharmacy and institutional costs exceeded 10,000 dollars and 18,000 dollars, respectively.Treatment of moderate to severe psoriasis with traditional systemic agents or phototherapy is associated with a high likelihood of treatment failure and a considerable economic burden.

MOCVD processes for (Ba,Sr)TiO3 (BST) and Pb(Zr,Ti)O3 (PZT) are described based on different metal – organic precursors. In the case of BST, processes using polyamine and tetraglyme adducts of group II metals were compared. Similar incorporation efficiencies were obtained at 640 °C for both adducts, and electrical properties were comparable. Delivery methodologies were compared using the tetraglyme adducts for BST. Composition control was equivalent using liquid mass flow controllers versus a positive displacement pump. For PZT, Zr(thd)4 and Zr(OiPr)2(thd)2 were compared as source materials in combination with Ti(OiPr)2(thd)2 and Pb(thd)2(pmdeta). The mixed ligand Zr source increased Zr incorporation efficiency by a factor of nearly eight for otherwise equivalent processes centred at 590 °C, and run to run repeatability was 0.1 at% for Pb and 0.6 at% for Zr (1 σ) over a series of more than 300 films. The electrical properties of thin film PZT deposited with Zr(OiPr)2(thd)2 compared favourably with those obtained previously with Zr(thd)4. Copyright © 2000 John Wiley & Sons, Ltd.

We report the effect of top electrode structure on the electrical properties of ferroelectric Pb(ZrxTi1-x)O3 (PZT) capacitors. Samples with Ir/PZT/Ir or Ir/IrO2/PZT/Ir stacks were prepared using reactively sputtered Ir/IrO2 (top) and Ir (bottom) electrodes and MOCVD-deposited PZT on TiAIN/SiO2/Si wafers. Capacitor structures were patterned by plasma etching of the top electrode and show evidence for transient fence formation. Electrical measurements of the capacitors showed good ferroelectric properties (2Pr up to 38 μC/cm2, with leakage

For many applications of ferroelectric ICs it is desirable to operate ferroelectric memory at the lowest possible power and voltage. One way to reduce the operating voltage is to reduce film thickness. We report on the electrical properties of MOCVD deposited PZT 40/60 and 20/80 films as a function of film thickness. As the thickness is reduced, switched polarization at saturation (P∗-P⁁) is reduced, but the coercive E-field is not substantially changed. Films also have imprint and fatigue behavior that is independent of film thickness when operated at constant electric field. For films below 60nm the leakage current rises rapidly; this is likely due to the effects of film roughness. For 65nm films of the PZT 20/80 material, we observed well formed hysteresis loops and PSW > 55μC/cm2 at 1.2V; polarization was greater than 90% saturated at that voltage.

In the past 5 years there has been a large amount of work to develop CVD technology for the deposition of the predominant perovskite oxide thin films, (Ba, Sr)TiO3, SrBi2Ta2O9 and Pb(Zr, Ti)O3. For each of these families of materials, CVD processes have matured such that state-of-the-art film properties may be achieved with this technique. Much of the progress is attributed to the use of the liquid delivery technique to transfer relatively involatile metalorganic precursors to the reactor. This paper will discuss common attributes of these thermal CVD processes, particularly the precursors, delivery methodology and reactor hardware. The paper will also highlight unique aspects that differentiate the processes, including the CVD decomposition regime, strategies for film composition control and approaches for forming the crystalline perovskite phase. Representative film properties are presented, demonstrating that these processes are becoming increasingly mature.

From the optical emission of and radiative states in the negative glow of DC pulsed discharges at pressures 1 - 4 Torr (133 - 532 Pa) and current densities , it has been determined that the vibrational excitation of the state deviates from a Boltzmann distribution and strong intensities of the second positive system (especially from v = 1) were also observed in the afterglow. Such strong emission is interpreted in terms of the growing of the vibrational distribution in the post-discharge region as the gas temperature is reduced. The ) states are mainly produced by electron collisions on ions under discharge conditions and quickly disappear in the afterglow as a result of - electron recombination.

A rationale for oral immunotherapy (OIT) might be founded on two potential mechanisms: induction of a mucosal secretory IgA response, or induction of systemic hyporesponsiveness (oral tolerance). Previous studies have shown clinically that there is a beneficial effect of OIT in birch pollinosis, in both children and adults. During OIT, birch pollen antigens in enterocoated capsules were given to 20 adults (participating in a double-blind, placebo-controlled trial) and 10 children, all suffering from birch pollinosis. Saliva and tears (only adults) samples were collected before, during, and after OIT. Each sample was assayed for both IgA antibodies against birch pollen antigens and total IgA by enzyme-linked immunosorbent assay. IgA antibody levels were also expressed in relation to total IgA concentrations, to correct for variations in secretion and flow rate between subjects and at different times. Changes in birch-specific secretory IgA antibodies in saliva and tears could not explain the beneficial effect of OIT in birch pollinosis. Further studies in this field are warranted.

In response to high rates of chronic disease, the Capital District Health Authority in Nova Scotia recognized a need to move from a focus on acute care in decision making to one that also values a population health approach guided by community health indicators.Stakeholders were surveyed on the choice, knowledge and utility of selected indicators.Respondents reported high scores for changes in their knowledge and attitude regarding community health indicators, and identified priority indicators for action.Decision makers' use of community health indicators was increased by stakeholder involvement, supporting evidence in plain language, and wide dissemination.

The immune response of the female rat genital tract was evaluated with Lewis rats given primary and secondary immunizations with keyhole limpet hemocyanin (KLH) alone or coupled to the cholera toxin (CT) B subunit (CTB) by the oral or intravaginal-uterine route or a combination of routes. CT (2 to 5 micrograms) was administered as an adjuvant with the KLH-CTB conjugate. While a significant mucosal immunoglobulin A (IgA) response was induced by KLH, there were no significant differences among the immunized groups in the levels of IgA antibodies in salivary gland, gut, vaginal, and uterine secretions, with the exception that rats immunized only orally with the KLH-CTB conjugate lacked a detectable vaginal response. Levels of IgA antibodies to CT, however, were significantly increased in genital tract secretions of rats immunized locally versus orally with the KLH-CTB conjugate. Antibody activity of the IgG isotype against both KLH and CT was significantly elevated in genital tract secretions of rats immunized with KLH-CTB by the oral or intravaginal-uterine route and given genital tract boosters, in comparison with the results for the other groups. IgM antibody titers were generally negligible in the different secretions. An enzyme-linked spot-forming assay revealed IgA and IgG antibody-secreting cells in salivary gland and uterine tissues. A highly significant correlation between the numbers of antibody-secreting cells and antibody titers existed for uterine IgG but not IgA responses to KLH among the different groups of rats. In conclusion, a vigorous local immune response was induced after immunization of the female rat reproductive tract alone or in combination with peroral challenge with the KLH-CTB conjugate.

The measured switched polarization properties of integrated Pb(Zr,Ti)O3 (PZT) capacitors arrays have been found to show a small dependence on individual capacitor size in the range from 0.17 and 100 μm2. These thin (90 nm) PZT capacitors have low voltage switching properties with polarization saturation of

BACKGROUND In pediatric settings, measures of health-related quality of life (HRQL) are often obtained by proxy, especially from parents, but the correlation between parental report and patient report has not been clearly established. In the current study, the authors examined the agreement between child and parent reports of HRQL in children with cancer (both those receiving treatment and those off treatment) and healthy controls. METHODS Two groups of children with cancer who differed with regard to treatment status (n = 199) and a group of healthy control children (n = 108) were assessed using a standardized measure of HRQL. Both children and parents reported on the child's HRQL using parallel forms of the Children's Health Questionnaire. RESULTS Significant parent-child correlations were found for all 10 HRQL scales, and these correlations were higher in the cancer groups compared with controls. Parents in the cancer groups tended to underestimate the HRQL of their children compared with the child report, although there were no significant parent-child mean differences in the group of patients who were off treatment and only 2 significant differences in the group of children receiving treatment. In contrast, parents in the control group tended to overestimate the HRQL of their children, and the parent-child differences were found to be larger, achieving statistical significance on 8 of 10 scales. CONCLUSIONS Parents and children tend to report comparable child HRQL outcomes, and this is particularly true in oncology populations. In cases in which the child is either too young or too ill to provide a self-report, parent-reported HRQL can be viewed as a reliable substitute. Cancer 2006. © 2006 American Cancer Society.

Summary form only given. High-density, embedded ferroelectric memory (FeRAM) has the potential to replace embedded flash, embedded DRAM, and non-cache SRAM and could be a key enabler for future system-on-a-chip applications. Despite this appeal, the evidence that ferroelectric capacitors can be scaled to the submicron regime has been limited. In this paper, we report the fabrication and electrical properties of submicron PZT capacitors formed using both planar bottom electrodes and W plug contact structures. We observe that the aggregate saturation polarization value is nearly independent of individual capacitor area in the measured range from the contact-limited size of 0.12 /spl mu/m/sup 2/ to 10/sup 4/ /spl mu/m/sup 2/. This result suggests that high-density, embedded FeRAM technology may be feasible.

A unique, single-step damascene approach was used to form ferroelectric capacitors with noble metal electrodes. In this study an oxidized Si substrate was coated with a blanket W film and a patterned SiO/sub 2/ film. Capacitors were formed by conformal deposition of a sputtered bottom electrode structure (100 nm Ir/50 nm TiAlN), MOCVD ferroelectric (130 nm (Pb,Ca)ZrTiO/sub 3/), and sputtered top electrode (150 nm Ir). A halide-based slurry was used in a single multi-layer polish to define planar, recessed capacitors between 100/spl times/100 /spl mu/m/sup 2/ and 10/spl times/10 /spl mu/m/sup 2/. The Ir removal rate was 14 nm/minute. Annealed capacitors had ferroelectric and dielectric properties that were similar to conventionally processed capacitors. 2P/sub r/ and switched charge at 2V were found to be 42 /spl mu/C/cm/sup 2/ and 40 /spl mu/C/cm/sup 2/ respectively with a leakage current density of 10/sup -4/ A/cm/sup 2/ at 2V.

To evaluate the retention of memory in the mucosal immune system of aged animals, 2-year-old mice that had been immunized intragastrically at 3 months of age with Streptococcus mutans protein AgI/II coupled to the B subunit of cholera toxin (CTB) were evaluated by ELISA for antibodies to AgI/II and CT in serum, saliva, and vaginal wash. To evaluate recall responses, mice were then immunized intragastrically with AgI/II-CTB, in comparison with previously unimmunized controls. Those that had been primed in their youth showed a more rapid antibody response in serum (immunoglobulin G (IgG)) and secretions (IgA), but all animals eventually responded to a similar degree after the third dose. Mice immunized at 3 months also retained for 2 years spleen cells capable of proliferating in vitro in response to AgI/II. These data show that aged mice retain the ability to mount immune responses to mucosally presented immunogens and that memory to mucosally presented immunogens can persist for almost the whole lifetime of a mouse.

To assess the cost effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy, particularly atorvastatin, in primary and secondary prevention of coronary artery disease (CAD) in Canada.A Markov model was developed in which costs and effectiveness of atorvastatin were compared with those of other statins and with no drug therapy in primary and secondary prevention of CAD.Cost effectiveness was assessed for cohorts of patients with risk profiles defined by CAD status, age, sex, pretreatment low density lipoprotein cholesterol level and presence of sentinel coronary risk factors. Coronary risk was estimated by using initial and subsequent event coronary risk equations from the Framingham Heart Study, and risk factors were estimated by using Canadian population survey data. Recent estimates of the costs of CAD-related medical care in Canada were used to assign costs to health states and acute coronary events.Interventions included atorvastatin 10 mg, simvastatin 10 mg, pravastatin 20 mg, fluvastatin 20 mg, lovastatin 20 mg and no pharmacological therapy.Incremental cost effectiveness ratios (CDN$/year of life gained) relative to no therapy were lowest for atorvastatin and highest for pravastatin across all risk profiles. Atorvastatin was less costly and more effective than lovastatin, pravastatin and simvastatin in primary and secondary prevention, and conferred additional health benefits at a reduced cost per year of life gained compared with fluvastatin.Atorvastatin was found to be the most cost effective statin in primary and secondary prevention of CAD.

Current consensus guidelines recommend reliance on anti-inflammatory drugs to treat asthma, reserving theophylline and other long-acting bronchodilators as adjuncts for patients whose symptoms are not well controlled with anti-inflammatory therapy. The effect of such recommendations on total costs of asthma care has not yet been examined, however.To explore the relation between choice of maintenance therapy with anti-inflammatory agents vs long-acting bronchodilators and annual costs of asthma care using data from the Asthma Outcomes Registry.Patients 16 years and older were selected from the Asthma Outcomes Registry cohort if they had received either anti-inflammatories (inhaled corticosteroids or cromones) or long-acting bronchodilators (theophylline, salmeterol, oral beta-agonists, or ipratropium bromide), but not both, for at least 1 year before study entry. Oral corticosteroid-dependent patients, those with other chronic lung disease, and those with incomplete cost data during the 365 days before and after their enrollment in the Asthma Outcomes Registry (baseline and follow-up years) were excluded. The effect of anti-inflammatory vs bronchodilator therapy was assessed by comparing the change (follow-up minus baseline) in total costs of asthma care.A total of 314 patients met criteria for study inclusion (237 treated with anti-inflammatories and 77 treated with bronchodilators). Median costs during the baseline year were similar in the anti-inflammatory and bronchodilator groups ($341 and $335, respectively). In the follow-up year, the median change in cost in the anti-inflammatory group was a decline of $93 compared with an increase of $76 in the bronchodilator group (P.0001). This treatment effect was consistent across subgroups defined by age and amount of medication consumed.These findings add support to current guidelines recommending reliance on anti-inflammatory therapy to control asthma. The emergence of new therapeutic agents to control inflammation may continue to reduce the costs of treating this important disease.

The large surface area of mucosal surfaces, particularly of the gastrointestinal tract, is protected against microorganisms and environmental antigens by various innate factors (e.g., mucins, lactoferrin, and others) and specific antibodies which are of IgA, or in some species, IgG Isotypes. Passive protection provided by effective prenatal transplacental transport of maternal antibodies and/or post-natal consumption of milk antibodies in breastfed newborns, is essential for the survival of neonates. Passive protection of mucosal surfaces by pre-formed antibodies in non-breast juveniles or adults is currently used only on an experimental basis: IgA-enriched preparations of gamma-globulin have been successfully given to children, and antibodies specific for several gastrointestinal pathogens have been isolated from immunized cows' milk, hens' eggs, or transgenic plants. Systemic administration of pre-formed antibodies is effective for protection against intestinal pathogens in species (e.g., mice, rats) endowed with efficient hepatobiliary transport of IgA into the gut lumen. However, this route of antibody administration is of limited efficiency in other species, including humans, in which almost all intestinal antibodies are produced locally by plasma cells in the gut mucosa and are not derived to a significant degree from the circulation. Active immunization is preferable for long-lasting protection. The site of immunization and presence of lymphoid tissues with inductive potential play an essential role in generating humoral immune responses in mucosal secretions. The relative efficiency of immunization routes (e.g., oral, nasal, rectal or genital) in the induction of preferential antibody responses in the intestinal secretion has not been studied extensively. Furthermore, suitable antigen delivery systems for achieving this goal must also be considered.

To generate current incidence-based estimates of the direct medical costs of coronary artery disease (CAD) in the United States, a Markov model of the economic costs of CAD-related medical care was developed. Risks of initial and subsequent CAD events (sudden CAD death, fatal/nonfatal acute myocardial infarction [AMI], unstable angina, and stable angina) were estimated using new Framingham Heart Study risk equations and population risk profiles derived from national survey data. Costs were assumed to be those related to treatment of initial and subsequent CAD events ("event-related") and follow-up care ("nonevent-related"), respectively. Cost estimates were derived primarily from national public-use databases. First-year direct medical costs of treating CAD events are estimated to be $17,532 for fatal AMI, $15,540 for nonfatal AMI, $2,569 for stable angina, $12,058 for unstable angina, and $713 for sudden CAD death. Nonevent-related direct costs of CAD treatment are estimated to be $1,051 annually. The annual incidence of CAD in the United States is estimated at 616,900 cases, with first-year costs of treatment totaling $5.54 billion. Five- and 10-year cumulative costs in 1995 dollars for patients who are initially free of CAD are estimated at $9.2 billion and $16.5 billion, respectively; for all patients with CAD, these costs are estimated to be $71.5 billion and $126.6 billion, respectively. The direct medical costs of CAD create a large economic burden for the United States health-care system.

Numerous experiments performed in humans and animals have revealed that stimulation of mucosal lymphoid inductive sites such as intestinal Peyer's patches results in parallel immune responses manifested by the appearance of S-IgA antibodies in the external secretions of remote glands. However, recent experiments suggest that inductive sites associated with the upper respiratory tract, rectum, and perhaps genital tract may also function as sources of lymphoid cells that populate, with some selectivity, certain remote mucosal effector sites. Furthermore, antigen-specific IgA antibodies can be induced in certain secretions (e.g., female genital tract) not only by immunization in the vicinity of corresponding mucosal tissues (e.g., vagina and rectum) but also by oral and especially intranasal immunization. The ineffectiveness of simple delivery of soluble antigens to mucosal membranes for immunization has stimulated extensive studies of strategies for effective delivery systems that would (a) increase the antigen absorption, (b) prevent its degradation, and (c) skew the outcome of immunization to a desired goal (protective response to infectious diseases vs. tolerance; B vs. T cell responses; mucosal vs. systemic). The induction of immune responses at a desired mucosal site can be accentuated with the use of a suitable antigen-delivery system including relevant bacterial or viral vectors, edible transgenic plants expressing microbial antigens, incorporation of antigens in biodegradable microspheres or liposomes, and linkage or coadministration of antigens with cholera toxin B subunit. However, only a few antigen-delivery systems extensively used in animal experimentation have been evaluated for their efficacy in humans. The combination of various immunization routes and the use of suitable antigen-delivery systems may accomplish an important task-the induction of mucosal immune responses at a location relevant to the site of entry of a given pathogen.

Previous attempts to induce mucosal antibodies in rhesus monkeys by enteric immunization have resulted in only modest and short-lived responses, dominated by immunoglobulin M (IgM) antibodies in the plasma. In this study, two groups of rhesus monkeys were immunized intranasally three times at 2-week intervals with a bacterial protein antigen (AgI/II) either chemically coupled to or mixed with the B subunit of cholera toxin (CT), a known potent mucosal immunogen and carrier for other immunogens. Cells secreting antibodies, predominantly of the IgA isotype, to AgI/II and to CT were detected in the peripheral blood 1 week after each immunization, indicating the dissemination of IgA-secreting precursor cells through the mucosal immune system. IgG and, to a lesser extent, IgA antibodies to both proteins were induced in the plasma commencing after the second immunization. Plasma IgE concentrations and IgE antibody levels were not consistently raised during the immunization period. IgA antibodies were found in nasal and vaginal washes. Nasal IgG but not IgA antibodies showed a significant positive correlation with plasma IgG antibody levels, suggesting that they were largely derived by transudation from the circulation. Analysis of the molecular form of vaginal IgA indicated that both secretory and monomeric forms of IgA were present in various proportions. Furthermore, neither IgG nor IgA antibodies in vaginal washes were correlated with plasma antibody responses, suggesting the contribution of locally synthesized antibodies of both isotypes. Comparison of the responses between the two groups of animals showed only sporadic significant differences, indicating that intranasal immunization with AgI/II either coupled to or mixed with the B subunit of CT was equally effective at inducing generalized IgA antibody responses in the mucosal immune system and predominantly IgG antibodies in the plasma.

In contrast to antigen-antibody complexes containing native human IgA, solid-phase-deposited IgA activates the alternative complement pathway and binds C3b. To investigate the role of carbohydrate chains in this, various human IgA preparations were treated with neuraminidase alone or together with N-glycanase or O-glycanase, or with mixed glycosidases from the oral bacterium, Streptococcus mitis. Depletion of oligosaccharides was determined by carbohydrate analysis. Removal of sialic acid and N-linked glycan chains greatly increased the C3b-fixing properties of normal serum IgA1 and IgA2. Myeloma IgA1 and IgA2 proteins and secretory IgA had higher C3b-binding activity than normal serum IgA, and this was further increased by removal of sialic acid and N-linked glycans. Fc alpha and Fc alpha-SC fragments of myeloma and secretory IgA1, respectively, but not Fab alpha fragments, obtained by cleavage with bacterial IgA1 proteases and also free secretory component, fixed C3b by the alternative pathway.

Polyclonal human secretory IgA1 and IgA2 antibodies to a bacterial protein antigen Streptococcus mutans AgI/II, and polyclonal human serum IgA1 and IgA2 antibodies to staphylococcal alpha-toxin, were found to interfere with antigen-mediated C3b fixation. In fluid phase, immune complexes of antigen and IgA failed to fix C3b, whereas antigen-IgG complexes did fix C3b. Partial removal of glycan chains with Streptococcus mitis SK96 glycosidases diminished the capacity of IgA antibodies to interfere with antigen-mediated C3b fixation by the alternative complement pathway. The authors conclude that native serum or secretory IgA antibodies suppress C3b fixation, and that the glycan chains play a significant role in maintaining this property.

Intraperitoneal immunization with a bacterial protein antigen conjugated to cholera toxin B subunit (CTB) was generally less effective than intragastric or intranasal immunization in generating mucosal IgA antibodies, and in priming the mucosal immune system to respond to intragastric or intranasal boosting. Previous intragastric or intranasal immunization which generated high levels of mucosal and circulating antibodies to CTB did not suppress mucosal IgA responses induced by intragastric or intranasal immunization with bacterial antigen conjugated to or mixed with CTB, but serum antibody responses were inhibited depending on the route of immunization and whether CTB was conjugated to or mixed with the antigen.

e16515 Background: Zoledronic acid (ZA) has been the mainstay for prevention of skeletal related events (SREs) in patients with bone metastases. FDA recently approved denosumab for prevention of SR...

The development of a vaccine against dental caries involves identification of appropriate antigens of mutans streptococci against which protective immune responses can be mounted, and the selection of a method of immunization that will generate sustained levels of salivary antibodies. Antigens receiving most attention include streptococcal surface proteins that are involved in attachment to tooth surfaces and glucosyltransferases that synthesize adhesive glucans from sucrose. Recent advances in mucosal immunology and the introduction of novel strategies for inducing mucosal immune responses now raise the possibility of constructing an effective and safe vaccine. Passive immunization by the oral application of performed antibodies against selected antigens of mutans streptococci has also shown promise and may facilitate understanding of the mechanisms of protective immunity against caries.

In this brief review, emphasis was placed on the effectiveness of liposomes as carriers/vehicles of soluble antigens and as adjuvants for use in oral vaccine development. Evidence was provided that oral administration of antigen in liposomes resulted in a mucosal response which was higher than that obtained when the oral vaccine consisted of antigen alone. Specific mucosal responses were enhanced by incorporating lipophilic MDP into the antigen/liposome vaccines. Antigens shown to be effective in inducing a protective mucosal response when given in an oral liposome vaccine were anti-idiotypic antibodies, purified S. mutans GTF, CHO and Ag I/II. Evidence is also provided that CTB may be an effective oral adjuvant when coupled to proteins or peptides by either chemical or genetic methods. Further studies, however, will be required to characterize the effectiveness and safety of CTB in conjugate vaccines for inducing specific mucosal responses and to develop practical means to prepare oral liposome vaccines for use in humans.

The principal characteristic immunoglobulin of mucosal surfaces, secretory immunoglobulin A (S-IgA), is the product of two different types of cell present in mucosal and glandular tissues. Submucosal plasma cells, which are generated largely within the common mucosal immune system, synthesize predominantly polymeric, J chain-containing IgA, which is selectively bound by polymeric immunoglobulin receptor or secretory component (SC) on the basolateral surfaces of mucosal and glandular epithelial cells. The molecular and cellular events involved in SC expression, its intravesicular transport together with its polymeric IgA ligand to the apical surface of the epithelial cell, during which IgA becomes covalently linked to SC, and the proteolytic cleavage of SC from the apical membrane to release S-IgA into the lumen have been elucidated. Additional receptors and mechanisms for the uptake, catabolism, and transport of IgA exist, especially in the liver. The biologic significance of IgA transport lies in the secretion of large quantities of S-IgA antibodies for the protection of huge areas of mucosal surfaces and for the provision of passive immunity to suckling infants, and in the immune elimination of antigenic materials by hepatobiliary transport.

Streptococcus mutans is known to be a major causative organism of human dental caries. A surface protein Ag with a molecular mass of 190 kDa of S. mutans (PAc) is receiving attention as an anticaries vaccine. We have recently determined the complete nucleotide sequence of the gene for PAc. In this study, four peptides were synthesized on the basis of amino acid sequence of PAc. Among these peptides, PAc(301-319) corresponding to the alanine-rich repeating amino acid region was the most strongly bound by polyclonal murine anti-rPAc antibodies. The peptide partially inhibited the binding of polyclonal anti-rPAc antibodies to rPAc. The peptide induced the proliferation of T cells from BALB/c mice immunized with rPAc. Subcutaneous immunization with PAc(301-319) or rPAc emulsified in CFA/IFA induced high serum IgG responses to rPAc and PAc(301-319). In addition, serum IgG responses to a surface protein Ag with a molecular mass of 210 kDa of Streptococcus sobrinus were elicited in mice immunized by s.c. injection with PAc(301-319) or rPAc. Intranasal immunization with PAc(301-319) coupled to cholera toxin B subunit (CTB) or with rPAc and free CTB induced high serum IgG responses to rPAc. The immunization with PAc(301-319) coupled to CTB or rPAc and free CTB suppressed the colonization of murine teeth by S. mutans. These results suggest that intranasal immunization with the peptide or rPAc may be effective for the prevention of dental caries.

To determine whether benzodiazepine tranquilizers increase the risk of accidental injury requiring medical attention, we used pharmacy claims submitted to a large third-party payer to identify 4,554 persons who had been prescribed these agents and a matched control group of 13,662 persons who had been prescribed drugs other than benzodiazepines. We then used diagnoses recorded on claims submitted by medical care providers to identify all accident-related care received by these persons during three months before their first-observed prescription for a benzodiazepine or nonbenzodiazepine agent, respectively, and six months subsequently. We found accident-related care was more likely among persons who had been prescribed benzodiazepines; among these persons, the probability of an accident-related medical encounter was higher during months in which a prescription for a benzodiazepine had recently been filled compared to other months; and persons who had filled three or more prescriptions for these agents in the six months following initiation of therapy had a significantly higher risk of an accident-related medical event than those who had filled only one such prescription. Approximately two-fold risks of accident-related care were found, after controlling for age, sex, and prior utilization.

Human colostral IgA and myeloma proteins of both IgA1 and IgA2 subclasses were susceptible to cleavage by Pseudomonas aeruginosa elastase. Detailed analysis of the cleavage products of IgA myeloma proteins revealed complete degradation of Fab with no evidence of intact Fab fragments as intermediate cleavage products. In contrast, both IgA1 and IgA2 proteins were resistant to cleavage by alkaline protease from P. aeruginosa. The susceptibility of human IgA proteins to elastase suggests a mechanism by which P. aeruginosa might evade the potentially protective function of IgA by producing this enzyme.

A surface protein antigen of Streptococcus mutans having two sets of antigenic determinants (antigens I and II) was purified by column chromatography from culture supernatants of S. mutans serotype c. The protease-resistant component, antigen II, was purified from pronase-digested antigen I/II. The antigens were analyzed chemically and immunologically, and their physicochemical properties were investigated. Antigen I/II consisted of more than 80% protein, and its peptide chain molecular weight was estimated to be 185,000. Antigen II consisted of approximately 60% protein, with a peptide chain molecular weight of 48,000. Antisera to antigens I/II and II were raised in rabbits and used to investigate the presence of the antigens in cells of other streptococci. This indicated that not only serotype c but also serotypes e and f possessed antigen I and II determinants, whereas serotypes a, d, and g possessed a determinant related to antigen I but not one related to antigen II.

The complement-fixing properties of human IgA antibodies bound to specific antigen, or coated directly on plastic surfaces, were examined in comparison with those of IgG antibodies. Use was made of antigen-binding (anti-staphylococcal alpha-toxin) IgA and IgG monoclonal antibodies and normal polyclonal IgA and IgG, purified greater than 99.9% by avoidance of denaturing processes. Complement-fixation ELISA was used, with a high density of biotin-conjugated staphylococcal alpha-toxin bound to avidin-coated plates for the efficient capture of antibodies, and conditions were adjusted for the assessment of classical and alternative pathways of complement activation. Although IgA coated directly on plastic surfaces activated the alternative complement pathway in a dose-dependent manner, IgA antibodies bound to antigen failed to fix complement by either classical or alternative pathways. In contrast, IgG antibodies, either bound to antigen or coated directly on plastic, activated complement mainly by the classical pathway. It was concluded that the complexation of IgA antibodies with antigen is insufficient to elicit complement activation: rather a degree of denaturation seems to play a part in the expression of alternative complement pathway-activating properties by IgA.

An antigenic component (antigen I) of the cell surface of Streptococcus mutans has been purified from culture supernatants and shown to be immunologically identical to the protease-susceptible moiety of antigen I/II. Ion-exchange and gel filtration chromatography failed to yield a physicochemically homogeneous product. Immunoasbsorbent chromatography on single and tandem columns containing immobilized antibodies to antigens I/II and II yielded identical products which were homogeneous in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and which when injected into rabbits induced monospecific antisera to antigen I. This antigen consisted of approximately 70% protein. Its molecular weight was estimated as 150,000, and the isoelectric point was estimated to be 5.1. Immunofluorescence microscopy using monospecific antiserum to antigen I showed that a similar antigen was present on cells of S. mutans serotypes a, c, d, e, f, and g, but not b.

Peroxidase-conjugated antibodies to antigens I/II and III were used to stain cells of Streptococcus mutans serotypes a through g. Under the electron microscope, serotypes that possessed these antigens showed deposits of peroxidase reaction products in association with the cell surface.

Generation of local and systemic immune responses by the oral administration of antigens is frequently inefficient, requiring large quantities of immunogens and yielding only modest antibody responses. In this study, we have demonstrated that oral administration of microgram amounts of Streptococcus mutans protein antigen I/II covalently coupled to the B subunit of cholera toxin elicits vigorous mucosal as well as extramucosal immunoglobulin A and G antistreptococcal antibody responses in mice. These responses were manifested by the presence of large numbers of antibody-secreting cells in salivary glands, mesenteric lymph nodes, and spleens and by the development of high levels of circulating antibodies. This novel immunization strategy may find broad application in the construction of oral vaccines for the control of infectious diseases caused by pathogens encountered at mucosal and extramucosal sites.