Search

In a split-litter, cross-fostered design, the numbers of mast cells per 10 micrometer sections within the thalamic boundaries in rats that had been reared by 8 natural or 8 foster mothers were counted 5 days and 10 days after the transfer had occurred on postnatal Day 10. The rats from 4 litters with the highest numbers of thalamic mast cells exhibited marked reductions in these numbers when fostered by mothers of the 4 litters with the fewest numbers of thalamic mast cells. The reverse influence was not observed. These results suggest that adaptation to changing maternal environments for rats with congenitally elevated numbers of mast cells may increase the risk of degranulation and transient anomalies within cerebral vasculature or the blood-brain barrier.

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.

Paule Poulin,1 Lea Austen,1 Catherine M Scott,2 Michelle Poulin,1 Nadine Gall,2 Judy Seidel,3 René Lafrenière1 1Department of Surgery, 2Knowledge Management, 3Public Health Innovation and Decision Support, Alberta Health Services, Calgary, AB, Canada Purpose: Introducing new health technologies, including medical devices, into a local setting in a safe, effective, and transparent manner is a complex process, involving many disciplines and players within an organization. Decision making should be systematic, consistent, and transparent. It should involve translating and integrating scientific evidence, such as health technology assessment (HTA) reports, with context-sensitive evidence to develop recommendations on whether and under what conditions a new technology will be introduced. However, the development of a program to support such decision making can require considerable time and resources. An alternative is to adapt a preexisting program to the new setting. Materials and methods: We describe a framework for adapting the Local HTA Decision Support Program, originally developed by the Department of Surgery and Surgical Services (Calgary, AB, Canada), for use by other departments. The framework consists of six steps: 1) development of a program review and adaptation manual, 2) education and readiness assessment of interested departments, 3) evaluation of the program by individual departments, 4) joint evaluation via retreats, 5) synthesis of feedback and program revision, and 6) evaluation of the adaptation process. Results: Nine departments revised the Local HTA Decision Support Program and expressed strong satisfaction with the adaptation process. Key elements for success were identified. Conclusion: Adaptation of a preexisting program may reduce duplication of effort, save resources, raise the health care providers' awareness of HTA, and foster constructive stakeholder engagement, which enhances the legitimacy of evidence-informed recommendations for introducing new health technologies. We encourage others to use this framework for program adaptation and to report their experiences. Keywords: health technology assessment, evidence-based medicine, program development, program adaptation

Abstract Background Concern has been growing in the academic literature and popular media about the licensing, introduction and adoption of surgical devices before full effectiveness and safety evidence is available to inform clinical practice. Our research will seek empirical survey evidence about the roles, responsibilities, and information and policy needs of the key stakeholders in the introduction into clinical practice of new surgical devices for pelvic floor surgery, in terms of the underlying ethical principals involved in the economic decision-making process, using the example of pelvic floor procedures. Methods/Design Our study involves three linked case studies using, as examples, selected pelvic floor surgery devices representing Health Canada device safety risk classes: low, medium and high risk. Data collection will focus on stakeholder roles and responsibilities, information and policy needs, and perceptions of those of other key stakeholders, in seeking and using evidence about new surgical devices when licensing and adopting them into practice. For each class of device, interviews will be used to seek the opinions of stakeholders. The following stakeholders and ethical and economic principles provide the theoretical framework for the study: Stakeholders - federal regulatory body, device manufacturers, clinicians, patients, health care institutions, provincial health departments, and professional societies. Clinical settings in two centres (in different provinces) will be included. Ethics - beneficence, non-maleficence, autonomy, justice. Economics - scarcity of resources, choices, opportunity costs. For each class of device, responses will be analysed to compare and contrast between stakeholders. Applied ethics and economic theory, analysis and critical interpretation will be used to further illuminate the case study material. Discussion The significance of our research in this new area of ethics will lie in providing recommendations for regulatory bodies, device manufacturers, clinicians, health care institutions, policy makers and professional societies, to ensure surgical patients receive sufficient information before providing consent for pelvic floor surgery. In addition, we shall provide a wealth of information for future study in other areas of surgery and clinical management, and provide suggestions for changes to health policy.

In spite of enormous efforts there have been no solutions to date for preventing/terminating certain acute and chronic disorders of humans by vaccination or drugs. Yet it is well understood that if the target antigen (ag) could be presented appropriately to the cells of the immune system then solutions could be found. Recently, the Barabas research group has introduced and described the third vaccination method - called modified vaccination technique (MVT) - which has the ability to provide a corrective immune response in experimental animals with an autoimmune kidney disease. Injections of immune complexes - made up of the target ag and specific non-pathogenic IgM antibodies directed against the target ag - achieved downregulation of pathogenic immune responses and tolerance to self was regained. Utilizing the immune system's natural abilities to respond to corrective information, the MVT technique was able to prevent an autoimmune kidney disease from occurring (prophylactic effect) in experimental animals, and when present, terminating it (therapeutic effect) specifically and without measurable side effects.It is predicted that the application of the MVT will have the potential in the future to revolutionize the preventative and therapeutic options for dealing with chronic disorders in humans (such as autoimmune disease, cancer and acute chronic infections) and achieve cures.

In addition to active and passive immunizations, there is a third method of immunization, the modified vaccination technique, which is based on injecting a combination of target antigens and antibodies against this antigen. The vaccine is essentially comprised of immune complexes with pre-determined immune-inducing components. When such an immune complex (target antigen × antibody against the target antigen) with a slight antigen excess is administered, it evokes a corrective immune response by the production of the same antibody with the same specificity against the target antigen that is present in the immune complex (pre-determined immune response).

A critical function of the immune system is to maintain tolerance to self by corrective immune responses throughout life, including preventing or correcting changes that may interfere with organ function and architectural integrity. These changes have two broad categories, namely (1) exogenous antigen-induced mishaps (e.g., due to bacterial, viral or fungal infections) and (2) endogenous antigen-caused ailments initiated by modified self-antigens derived from damaged organs following exposure to smoke, certain drugs, chemicals, infectious agents, radiation, etc., resulting in autoimmune diseases or cancer. In some cases, cells of the immune system are unable to respond with a corrective antibody response. For example, presentation of a modified self-antigen can initiate a pathogenic IgG immune response, thereby causing an autoimmune disease. Furthermore, if cancer-associated antigens are not appropriately presented to the cells of the immune system, there is failure to mount a specific pathogenic lytic IgG autoantibody response for recognition and elimination of cancer-associated antigens, and as a consequence, the cancer continues to proliferate.The third vaccination technique that we have developed and designated a modified vaccination technique (MVT) is able to correct these immunological mishaps. The premise of the MVT is that it can prevent both exogenous (infectious and contagious diseases) and endogenous (autoimmune diseases and cancer) antigen-caused diseases, as well as terminate established diseases. Therefore, by exploiting the immune system's natural abilities to make corrective responses, it has both prophylactic and therapeutic actions, with minimal side effects.

Autoimmunity has both beneficial and harmful aspects. Beneficial aspects include: (1) removal of released intracytoplasmic antigens (ags) (cells at the end of their life span or damaged by outside agents) by specific nonpathogenic IgM autoantibodies and mononuclear cells and (2) recognition and elimination of cancerous cells. In contrast, harmful aspects include: (1) mounting a pathogenic autoimmune response against a tissue-derived ag, a 'modified self,' resulting in autoimmune disease and (2) inability to recognize and eliminate a cancerous clone. The immune system continuously faces internal and external influences; however, even when it is compromised or overwhelmed, it will still endeavor to regain and maintain tolerance to self. To promote this, we developed a 'modified vaccination technique' (MVT) (described as the third vaccination method after active and passive immunizations). It has two components: purified exogenous/endogenous ag (i.e., target ag) and a high-titer-specific antibody (ab) against the target ag made into an immune complex (IC) with predetermined immune-inducing components. The MVT works by ab information transfer (production of same class of immunoglobulin with the same specificity against the target ag that is present in the vaccine), thereby re-establishing tolerance to self (caused by exogenous/endogenous ags) following repeated administration of appropriate ICs. This vaccination technique can be used both prophylactically and therapeutically, and it mimics the immune system's natural abilities to respond to corrective information specifically, rapidly, safely and with minimal side effects and makes this approach a novel solution for many disorders that are difficult or impossible to cure or manage.

Objectives were to: 1) induce a lytic IgG antibody (ab) response (via the so called `third vaccination method') against CD38 antigen (ag) residing on the extra-cellular domain of multiple myeloma (MM) cells in recipient rabbits, by combining the CD38 ag with donor-derived anti-CD38 ag lytic IgG ab into an immune complex (IC); and 2) determine whether abs produced would cause complement-mediated lysis (in vitro) of human MM cells containing CD38 ag. The vaccine was created in a two-step process. First, ab (rabbit anti-CD38 ag IgG ab) was raised in donor rabbits by injections of low molecular weight soluble CD38 ag in Freund's complete adjuvant (FCA) and aqueous solution. Second, transfer of pathogenic lytic IgG ab response into recipient rabbits was achieved by injections of ICs composed of CD38 ag and homologous anti-CD38 ag IgG ab. Consequently, recipient rabbits produced the same ab with the same specificity against the target ag as was present in the inoculum, namely agglutinating, precipitating and lytic (as demonstrated in vitro). In an in vitro study, in the presence of complement, donor and recipient rabbits' immune sera caused lysis of CD38 ag associated human MM cells. The most effective lytic ab response causing sera were those from donor rabbits injected with CD38 ag in FCA and those from rabbits injected with ICs, especially when they were administered in adjuvants. These results provided proof of concept that the third vaccination method has good potential as a stand-alone and efficacious method of controlling cancer.

Employing passive immunization - using a heterologous anti-CD38 IgG antibody containing serum - in SCID mice injected subcutaneously with human multiple myeloma cells, we have shown that treatments with the antiserum - especially in the presence of complement - significantly decreased cancer growth. However, administered antibody and complement was not sufficient in amount to prevent cancer cell multiplication and cancer growth expansion to a satisfactory degree. Larger volumes of the same components more than likely would have further reduced cancer growth and prolonged the life of mice. In control mice, cancer growth progressed faster proving that lytic immune response against multiple myeloma cells is necessary for cancer cell kill.

Autoimmune diseases are initiated and maintained by complex immunopathological processes in environmental and genetic factor predisposed patients. In certain autoimmune diseases, the etiologies and pathogenesis of the conditions are quite well understood; yet in others, controversy surrounds as to why and how auto-injurious processes start. Clinical and laboratory examinations reasonably well define the state of progression/remission of an autoimmune disease and allow treatment according to observed findings. However, none of the presently employed treatment options are specific. In fact, they are all nonspecific in their actions and have undesirable side effects. Over the years, experiments carried out in animals have shed light on the complex immunopathological processes which contribute to disease development and progression. At least one experimental autoimmune kidney disease-which we shall describe-helps to understand how pathogenic autoimmune responses can be terminated specifically, without side effects. Since the new vaccination method-that we call modified vaccination technique-was successfully implemented in an experimental autoimmune disease model called slowly progressive Heymann nephritis for the termination of pathogenic immune responses by a target antigen-specific treatment modality, we shall highlight its use in providing insight to physicians and autoimmunologists for its future implementation in human autoimmune diseases.

The experimental models of Heymann nephritis (HN) and slowly progressive Heymann nephritis (SPHN) give us rare opportunities to investigate the etiologies and pathogenesis of two immunopathological processes in rats leading to: (1) autoimmune disease, where the autoimmune disease HN and SPHN is initiated and maintained by cross-reactive pathogenic IgG autoantibodies (aabs) directed against the renal proximal convoluted tubules' brush border (BB) cells - where the nephritogenic antigen (ag) is produced and localized - damaging and releasing BB associated nephritogenic ag into the circulation which in turn contributes to continuation of the autoimmune disease; and (2) immune complex glomerulonephritis, where the glomerular injury is initiated, proceeding into a chronic progressive disease by depositing immune complexes (ICs) - made up of a glomerular epithelial cell produced endogenous nephritogenic ag and the developing pathogenic IgG aab directed against the nephritogenic ag, and complement components - on the epithelial side of the glomerular basement membrane. We also observed how the normally functioning immune system is able to avert autoimmune disease developments by circulating specific non-pathogenic IgM aabs clearing the system of intracytoplasmic ags released from cells at the end of their life spans or following damage by toxic agents. We also described how an autoimmune disease SPHN can be prevented and when present terminated by the implementation of a new vaccination technique we have developed and call modified vaccination technique. By increasing the specific IgM aab production against the native nephritogenic ag - by injecting ICs made up of: [nephritogenic ag X homologous anti-nephritogenic ag IgM ab] in slight ag excess into SPHN rats - pathogenic IgG aab producing native and modified nephritogenic ags were removed from the circulation and termination of the autoimmune disease causing immune events was achieved. Even though HN and SPHN are not well-known disease models, their studies are important because the etiologies and pathogenesis of two conditions - that can also occur in humans, namely autoimmune diseases and membranous glomerulonephritis - can be simultaneously investigated.

Heterologous IgG antibody (ab) can be produced against Heymann nephritis (HN) antigen (ag) in rabbits by administering it in Freund's complete adjuvant. The developing abs reacted at high titre with rat kidney brush border (BB) regions of the renal proximal tubules in an indirect fluorescence ab test. A single IV injection of the heterologous ab into a susceptible strain of rat resulted in the localization of IgG ab to glomerular fixed ags, producing immune complex glomerular nephritis. The injected ab also reacted with the BB region of the renal proximal tubules. The aim of this experiment was to find out whether heterologous IgG ab against the HN ag can also be produced in recipient rabbits by injecting immune complexes (ICs) composed of a rat kidney tubular preparation [rat kidney fraction 3 (rKF3)] and donor rabbit-derived rabbit anti-rKF3 IgG ab. We found that anti-rKF3 IgG ab--against the BB region of the renal proximal tubules--could be induced in rabbits injected with ICs, and the resulting ab was able to initiate passive HN in rats. This was the first time a pathogenic IgG ab was produced against HN ag in rabbits without the use of adjuvant. Ab responses in recipient rabbits were achieved by ab information transfer. Recipient rabbits injected with the IC produced the same class of immunoglobulin with the same specificity against the target ag rKF3, as was present in the innoculum, namely rabbit anti-rKF3 IgG ab., (© 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.)

The role of an autoimmunologist is to investigate and cultivate knowledge of normal and abnormal immune responses against self, which includes developing practical know-how to manipulate autoimmune activity and direct positive autoimmune outcomes. Where a subject develops an abnormal immune response directed against normal self, resulting in an autoimmune disease, the specialist should be able to diagnose the problem and institute an appropriate treatment. Obversely, where a subject lacks an immune response against cells bearing antigens that are abnormal or not quite self, i.e., cancer cells, the specialist should ideally be able to institute a specific cancer cell killing regimen. Essentially there are two beneficial and two harmful aspects of autoimmunity autoimmunologists should be familiar with. The beneficial aspects are the immune responses that assist in the clearance of cellular breakdown products and the elimination of cancer cells. The harmful aspects consist of immune responses, or lack thereof, that manifest in autoimmune disorders, i.e., autoimmune diseases and cancer. Recent medical discoveries, especially the modified vaccination technique developed by the Barabas research group, show great promise in both preventing and curing autoimmune disorders by utilizing the immune system's natural abilities to re-establish normal health., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Public health can be protected most effectively through vaccination programmes. However, while presently available vaccination techniques protects the individual by provoking immune responses against exogenous antigens (ags), such as those associated with certain bacteria and viruses, they cannot protect against or treat mishaps caused by endogenous ag. Recently, Barabas and colleagues have developed a new vaccination method, called modified vaccination technique (MVT), which allows the presentation of disease causing agents in such a way as to initiate and maintain desired immune response outcomes even in the context of mishaps associated with endogenous ag. For example, in an experimental autoimmune kidney disease, the MVT downregulated/terminated pathogenic immune responses that were causing morphological and functional changes of the kidney. The MVT promises, with appropriate case-specific modifications, both preventative and curative applications for ailments, such as endogenous ag initiated mishaps (i.e. autoimmune diseases and cancer) and diseases caused by chronic infection, that are presently only treatable with drugs. To achieve specific immune responses, purified components of the vaccine (ag and antibodies) must be produced and assembled into immune complexes having the potential of inducing predetermined corrective immune response outcomes.

Our research group has developed a new vaccination technique in experimental animals that has the potential of correcting autoimmune anomalies in humans such as autoimmune disorders, cancer, and chronic infections, both prophylactically and therapeutically. The vaccination method is called Modified Vaccination Technique (MVT). The MVT necessitates the introduction of a purified target antigen (ag) and a specific antibody (ab) against the target ag in the form of immune complex (IC) to evoke the desired immune response outcome by ab information transfer in the injected recipient. The injected IC produces the same class of ab in the host, with the same specificity against the target ag, as resides in the inoculum. The MVT promises to provide a means of upregulating beneficial immune events and downregulating undesirable immune responses in individuals, thereby re-establishing normalcy/tolerance to self.

It is anticipated that the ultimate solution for the prevention and termination of autoimmune disorders will be based on somehow manipulating the cells of the immune system to attain antigen (ag) specific downregulation and termination. In the last few years we have developed a new vaccination technique that we call "modified vaccination technique" (MVT). It has with equal effectiveness both prevented and terminated autoimmune disease causing events in an experimental autoimmune kidney disease model. We expect that our technique will be similarly applicable to the specific treatment and cure of numerous other chronic disorders presently treated only by drugs. The vaccine is composed of two components, an ag and a specific antibody against it. When these are combined at slight ag excess they constitute a vaccine which is capable of treating chronic ailments by redirecting immune response outcomes in the vaccinated host. Both components, like drugs, will have to be produced ex vivo in order to maintain uniformity, safety, efficacy, and specificity.

Background: Higher hospital and surgeon volumes have been associated with improved outcomes after hepatic resection. Subspecialty training has not previously been associated with improved outcomes after hepatic resection. The objective of this study was to determine what effects, if any, surgeon's volume and training had on the outcomes after hepatic resection., Methods: Administrative procedure codes were used to identify all adult patients from the fiscal year 1991-1992 to 2003-2004 who underwent a hepatic resection in two large urban health regions in Canada (Calgary and Capital health regions). The primary outcomes were operative mortality and postoperative complications., Results: There were 1107 hepatic resections in the stated time period performed by a total of 72 surgeons. There were 66 deaths, resulting in an in-hospital mortality rate of 6.0%, and an overall complication rate of 46%. Statistically significant predictors of operative mortality were: urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and increasing burden of comorbid medical illness. Surgeon training along with patient's sex, the urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and increasing comorbidity were predictive of postoperative complications., Conclusions: This study found surgeon training to be highly predictive of postoperative complications after hepatic resection.

Neither autoimmune disorders nor cancer can be prevented with treatment modalities that are currently available. These diseases are generally treated with immunosuppressive agents and cytotoxic drugs, both of which can cause numerous side effects. However, scientific evidence now exists to suggest that such endogenous antigen-derived ailments can be controlled and even terminated by immunological approaches. Both autoimmune disorders and cancer can progress into chronic, irreversible conditions because of the abnormal presentation of endogenous antigens to the cells of the immune system. By appropriate regulation of the autoimmune system, both types of ailments could be curable. This feature review describes various autoimmune events that may occur both to the benefit and the detriment of the host, and highlights a new vaccination technique against slowly progressive Heymann nephritis. This modified vaccination technique holds promise in the prevention and cure of autoimmune system-related disorders. The vaccination has been employed both against endogenous antigen-induced diseases (autoimmune disorders and cancer) and against exogenous antigens. In each study performed to date, the technique has been demonstrated to induce specific, predetermined immune response outcomes.

The main purpose of this article is to introduce a promising new vaccination technique and to outline its efficacy and safety as demonstrated in an experimental autoimmune kidney disease. We have found that antigen (AG)-specific downregulation and/or upregulation of immune responses can be achieved by injections of immune complexes (ICs) which contain prepackaged information. This result is attained with the new vaccination method, a method developed in our laboratory which we have called "modified vaccination technique" (MVT). This MVT not only enables the prevention of pathogenic autoimmune events leading to the development of an experimental autoimmune kidney disease; it also allows, with equal effectiveness, therapeutic intervention to terminate the disease. With an injected IC containing predetermined immune response-inducing components, the process effectuates a specific antibody information transfer conferring advantages that go beyond its prophylactic and therapeutic applicability. Its specificity can induce a precise immune response to correct mishaps, for example, in conditions where the immune system overreacts to an autologous antigen or fails to recognize unwanted self (as in autoimmune disorders, cancer, etc.) Preformed ICs are nontoxic and nonirritant, evoke a predetermined antibody response without the use of adjuvants, cause no disturbance in the overall regulatory function of the immune system, and produce no side effects. We firmly believe that proper implementation of the MVT will be able to induce and maintain specific preventive and/or curative responses in a way that is both natural and more effective in patients with chronic ailments presently treatable only with drugs.

Background: Active immunization techniques against exogenous source antigens (ags - such as bacteria, virus) proved to be successful in preventing many acute infectious diseases from occurring in a susceptible population. However, an active immunization technique that could be employed both prophylactically and therapeutically has so far not been described. We have developed a new vaccination technique that employs specific immune complex (IC) containing components which is able to redirect immune-response outcomes in both preventative and curative regimens in an experimental autoimmune kidney disease. The technique with appropriate modifications was assessed using an exogenous ag in our present experiment., Material/methods: We prepared an exogenous ag on a HiTrap affinity column and injected it by five different vaccination techniques into rats. Antibody (ab) responses against the ag were evaluated by ELISA. Statistical analysis assessed possible significant differences in ab responses., Results: The most powerful immune response was initiated following intraperitoneal (IP) injections of normal rabbit immunoglobulin G (nRIgG) in Freund's complete adjuvant (FCA). The second most powerful immune response was evoked when the same ag (nRIgG) was injected in the form of IC at ag excess., Conclusions: 1. Induction of a powerful ab response, without the use of an adjuvant, can be achieved in rats injected with ICs. 2. IC is non-toxic, non-irritant, and able to initiate the production of the same class of immunoglobulin with the same specificity/function that resides in the inoculum.

We describe a new vaccination method called modified vaccination technique (MVT). The technique is able to achieve downregulation of pathogenic autoimmune events leading to a chronic progressive disorder in rats called slowly progressive Heymann nephritis. Downregulation of immunopathological events is achieved by injections of immune complex (IC) made up of the target native antigen (ag) and specific naturally occurring immunoglobulin M (IgM) antibody (ab) directed against it. Repeated injections of IC maintain high levels of specific circulating IgM autoantibodies (aabs) against the kidney ag. The developing physiologic IgM aabs assist in the catabolism of both modified and unmodified renal ags from the circulation. No disease-causing renal ags in the circulation results in no stimulation of pathogenic immunoglobulin G aab producing cell lines. Such specific targeted therapy leads to termination of disease-causing processes and reestablishment of tolerance. The MVT can be employed both prophylactically and therapeutically with equal effectiveness. A redirected immune response is achieved by specifically stimulating the animals' own IgM-producing cell lines with the injected ICs, resulting in a natural cure. Such ICs are nontoxic and nonirritant and cause no side effects. We surmise that the MVT, employing the appropriate components in each instance, can also be used to treat human ailments.

The aim of the present study was to find out if specific IgM (M) antibody (directed against rat kidney fraction 3 (rKF3)) or rKF3 antigen were able to influence disease progression in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN). The level of circulating autoantibodies (aabs) and the morphological and functional changes to the kidney were studied in six groups of rats. All of the treatment components (except post-treatment with M) used in the SPHN pre- and post-treated rats and post-treated-only rats had measurable beneficial effects (even during restimulation with the chemically modified renal antigen, 22 weeks after the induction of the disease) as demonstrated by diminished pathogenic IgG aab production, less severe kidney lesions, and proteinuria reductions. The injected rKF3 minimized progression best in this experiment, especially when administered in a pre- and post-treatment regimen. It is thought that the effect of rKF3 in the reduced progression of SPHN was due to increased production of specific IgM aabs, which in turn limited pathogenic aab production and continuous buildup of immune complexes in the glomeruli by facilitating removal or blockage of nephritogenic autoantigens from the circulation.

The purpose of the study was to find out if a new modified vaccination technique would be effective in downregulating immunopathological events during the course of an experimental autoimmune kidney disease (which is morphologically and functionally similar to Heymann nephritis) called 'slowly progressive Heymann nephritis' (SPHN). We have shown that the pathogenic IgG autoantibody (aab)-induced experimental autoimmune kidney disease process can be downregulated early on as well as during the chronic progressive phase, when rats were restimulated. The IgM aab, resulting from stimulation by immune complexes made up of rat kidney fraction 3 (rKF3) antigen and rat anti-rKF3 IgM antibody in antigen excess (MIC), can greatly diminish pathogenic aab production by removing or blocking nephritogenic antigens. Reduced IgG aab production limits the formation of damaging immune complexes (IC) in the glomeruli and development of proteinuria. At the end of the experiment 60% and 80% of the MIC-treated groups had no pathogenic IgG aab in their circulation, while all the untreated SPHN rats had high levels of IgG aab associated with disease progression manifesting in increased proteinuria and severe immune complex glomerulonephritis.

A slowly progressive Heymann nephritis (SPHN) was induced in three groups of rats by weekly injections of a chemically modified renal tubular antigen in an aqueous medium. A control group of rats received the chemically unmodified version of the antigen in an aqueous solution. One group of SPHN rats were pre- and post-treated with weekly injections of IC made up of rKF3 and rarKF3 IgM antibody at antigen excess (MIC) (immune complexes [ICs] containing sonicated ultracentrifuged [u/c] rat kidney fraction 3 [rKF3] antigen and IgM antibodies specific against the antigen, at slight antigen excess). One group of SPHN rats were post-treated with MIC 3 weeks after the induction of the disease and one group of SPHN animals received no treatment. The control group of rats received pre- and post-treatment with sonicated u/c rKF3. The incidence of immune-complex glomerulonephritis (ICGN) in the untreated SPHN rats was 87%, in the pre- and post-treated animals 13%, and in the post-treated-only rats 20%. Rats receiving sonicated ultracentrifuged rKF3 antigen did not develop ICGN. The present experiment demonstrates that the development of SPHN can be not only prevented but also effectively terminated by our newly developed modified vaccination technique.

Heymann nephritis (HN) is an experimental autoimmune disease of rats characterized by immune-complex (IC) depositions on the epithelial side of the glomerular basement membrane (GBM) and by proteinuria. Several forms of HN have been produced by various investigators, but one thing has been common to all of them, namely their inducement by the development of pathogenic IgG autoantibodies (aabs). The aim of this review is to describe how pathogenic IgG aab production (which initiates and maintains the disease) in slowly progressive HN (SPHN) can be specifically terminated by injections of ICs made up of native rat renal tubular antigens and IgM antibodies directed against them.

In the present article, we describe an antigen-specific down-regulation of a pathogenic autoantibody (aab)-mediated disease process in an experimental autoimmune kidney disease in rats called slowly progressive Heymann nephritis (SPHN). This autoimmune disease is initiated and maintained by pathogenic immunoglobulin G (IgG) autoantibodies (aabs), which cause an immune-complex (IC) glomerulonephritis associated with proteinuria. We achieved down-regulated pathogenic aab response in SPHN rats by injections of an IC containing the native nephritogenic antigen and specific high-titred nonpathogenic IgM aabs, in antigen excess. The injected IC increased the level of circulating nonpathogenic IgM aabs; the increased levels of specific IgM aabs in turn facilitated the removal of the injected altered nephritogenic and liberated autoantigens from the renal tubules and greatly diminished the production of pathogenic aabs and the build up of immune deposits in the glomeruli. While animals treated early had advantages over rats whose kidney disease was well established before treatment; animals treated late into the disease still manifested noticeable improvements in similar areas, i.e. with lessened proteinuria, kidney lesion reduction and a decreased pathogenic aab response. At the end of the experiment at 29 weeks, 80% of all the treated rats had insignificantly low levels of circulating IgG aabs, indicating cessation of pathogenic aab production and corresponding termination of the disease process. In contrast, most untreated rats with the kidney disease still had high levels of circulating pathogenic aabs at the end of the experiment, which maintained disease progression.

An autoimmune kidney disease morphologically and functionally similar to Heymann nephritis (HN) was induced in mature male Sprague Dawley rats by repeated weekly IP injections of a chemically modified azo sonicated ultracentrifuged (u/c) rat kidney fraction 3 (rKF3) antigen in an aqueous medium. The experiment was terminated 15 weeks after the first injection of the chemically altered antigen. Serum samples collected and analysed by an indirect fluorescent antibody test on normal rat kidney sections during the course of the experiment showed a gradual rise in circulating pathogenic autoantibodies directed against the proximal tubular brush border regions. Proteinuria was present and significantly increased in the urine of two of eight rats. The arising immune-complex glomerulonephritis (ICGN) revealed typical HN kidney disease lesions in 70% of the rats in histological, direct fluorescent antibody and electron-microscopical examinations. Control rats injected similarly with the an unmodified version of the same antigen did not develop the HN-characteristic morphological and functional changes. To our knowledge, this is the first time that the autoimmune kidney disease designated as an active HN has been produced by the administration of a chemically altered renal antigen in an aqueous solution and not by the usual presentation of the nephritogenic renal antigen in an adjuvant.

Summary Diffuse distribution of small, faintly staining, beaded deposits of rat immunoglobulin M (IgM) around the glomerular capillary blood vessels, and a more intensely staining larger deposition in the mesangium, were observed on the kidney sections of normal rats. As glomerular-fixed nephritogenic antigens are known to be present on the epithelial aspect of the glomerular basement membrane (GBM), especially at the soles of foot processes and at the slit pores, it was assumed that the IgM antibodies were directed against these antigens. Investigation by immunofluorescent antibody double-staining techniques of rat kidney sections obtained from normal and rabbit anti-FX1A-injected rats stained for the nephritogenic antigen showed that a number of antigenic sites in the glomeruli and in the mesangium shared antibody hits by heterologous rabbit IgG and autologous rat IgM antibodies. Most sites in the glomeruli stained specifically for rat IgM or rabbit IgG, but preferentially for the latter. The intensely fluorescent mesangial deposits stained mainly for rat IgM, indicating that at these sites the antigenic material was virtually saturated, while areas at the entry to the mesangial space also stained for rabbit IgG, indicating that at these locations free nephritogenic epitopes were still available for reaction with the anti-FX1A antibody. Western blot analysis have shown that the rabbit anti-rat FX1A IgG and the rat anti-rat KF3 IgM antibodies are directed against the same renal tubular-derived antigen with a molecular weight of 70,000. These experimental findings collectively demonstrate that the heterologous IgG and autologous IgM antibodies are directed against the same nephritogenic antigen, which is found in the glomeruli, the mesangium and the proximal convoluted tubules. Thus, the IgM autoantibody has a possible physiological role but, in addition, there is evidence of active immunophagocytic events, manifested in a rapid and continuous entrapment and expulsion of macromolecules after their processing by the mesangial cells of normal and passive Heymann nephritis rats.

A slowly progressive autoimmune kidney disease was induced in Sprague Dawley rats by subcutaneous injection of a chemically modified kidney antigen (rKF3), incorporated into Alum and Distemper complex vaccine, followed by subcutaneous injections of an aqueous preparation of the same antigen. Pathogenic autoantibodies developed, which reacted with fixed glomerular nephritogenic antigen. Subsequently, immunopathological events lead to chronic progressive immune complex glomerulonephritis and proteinuria. The slowly developing disease was morphologically and functionally similar to Heymann nephritis (HN). The damage observed in the kidneys of experimental animals at 8 weeks and at the end of the experiment was examined by direct fluorescent antibody test, histology and electron microscopy. The changes were similar to the typical lesions found in HN rat kidneys, but less severe. Animals became proteinuric from 17 weeks onward (instead of the usual 4-8 weeks). By the end of the experiment, at 8 months, 100% of the rats were proteinuric. This new experimental model of autoimmune kidney disease, which is not complicated by intraperitoneal deposition and retention of Freund's complete adjuvant and renal tubular antigens, allowed us to investigate the pathogenesis of the disease processes from a different aspect, and promises to be a useful and improved model for the investigation of future treatment options.

Objective: To find out if the cost of health services was artificially increased because of a delay in surgery due to a lack of resources., Design: A retrospective cohort study., Setting: Three urban hospitals in Calgary, Alta., Patients: The study cohort comprised 4441 patients (1 index procedure for each patient)., Interventions: Cholecystectomy, discectomy, hysterectomy, total knee and total hip replacements., Outcome Measures: The costs for physician claims, use of home care and pharmaceutical prescriptions 1 year before and after the selected procedures, using 1997/98 administrative records and waiting times maintained by Alberta Health and Wellness and Calgary Regional Health Authority., Results: The median wait for joint surgery (88 d for knee replacements and 65 d for hip replacements) was longer than for the other selected procedures (29 d for cholecystectomies, 21 d for discectomies and 42 d for hysterectomies). Total per patient physician claim costs decreased after surgery (cholecystectomy--30%, discectomy--24%, hip replacement--6%, hysterectomy--23% and knee replacement--4%). Seeing the procedure specialist more than once preoperatively was associated with a greater decrease in postoperative physician claim costs. Longer waits were not associated with more physician claim costs or Blue Cross prescriptions claim costs for seniors (> or = 65 yr) in the year before or after surgery nor were they associated with more physician claim costs during the actual wait compared with a matched postoperative time period., Conclusions: No evidence was found to suggest that waiting for 1 of 5 common surgical procedures is correlated with greater health service expenditures pre- or postoperatively. In this study, wait time is not a proxy for health service use nor do health service costs decrease markedly after surgery.