The modified vaccination technique designed to prevent and cure acute and chronic disorders.

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.

The Modified Vaccination Technique.

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).

Antibody-initiated beneficial and harmful immune responses.

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.

Global characterization of copy number variants in epilepsy patients from whole genome sequencing.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy.

Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors.

Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes.

Quantitative assessment of haemolysis secondary to modern infusion pumps.

Background: Although most studies have shown that little haemolysis is induced by infusion pumps, there are some notable exceptions. Only limited data are available on the actual infusion pumps that are most used in hospitals in Quebec and elsewhere, namely, the Infusomat Space (peristaltic), Plum A+™ (piston) and Colleague CXE (shuttle) pumps.

Methods: Haemolysis and potassium levels were compared before and after the use of the three different infusion pumps.

Suppression of tumor growth by a heterologous antibody directed against multiple myeloma dominant CD38 antigen in SCID mice injected with multiple myeloma cells.

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.

A novel modified vaccination technique produces IgG antibodies that cause complement-mediated lysis of multiple myeloma cells carrying CD38 antigen.

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.

Tolerance, loss of tolerance and regaining tolerance to self by immune-mediated events.

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.

Introduction of new technologies and decision making processes: a framework to adapt a Local Health Technology Decision Support Program for other local settings.

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.

Family-based exome-sequencing approach identifies rare susceptibility variants for lithium-responsive bipolar disorder.

Bipolar disorder (BD) is a psychiatric condition characterized by the occurrence of at least two episodes of clinically disturbed mood including mania and depression. A vast literature describing BD studies suggests that a strong genetic contribution likely underlies this condition; heritability is estimated to be as high as 80%. Many studies have identified BD susceptibility loci, but because of the genetic and phenotypic heterogeneity observed across individuals, very few loci were subsequently replicated.

Multi-criteria development and incorporation into decision tools for health technology adoption.

Purpose: When introducing new health technologies, decision makers must integrate research evidence with local operational management information to guide decisions about whether and under what conditions the technology will be used. Multi-criteria decision analysis can support the adoption or prioritization of health interventions by using criteria to explicitly articulate the health organization's needs, limitations, and values in addition to evaluating evidence for safety and effectiveness. This paper seeks to describe the development of a framework to create agreed-upon criteria and decision tools to enhance a pre-existing local health technology assessment (HTA) decision support program.

Comparative analysis of the expression profile of Wnk1 and Wnk1/Hsn2 splice variants in developing and adult mouse tissues.

The With No lysine (K) family of serine/threonine kinase (WNK) defines a small family of kinases with significant roles in ion homeostasis. WNK1 has been shown to have different isoforms due to what seems to be largely tissue specific splicing. Here, we used two distinct in situ hybridization riboprobes on developing and adult mouse tissues to make a comparative analysis of Wnk1 and its sensory associated splice isoform, Wnk1/Hsn2.

WNK1/HSN2 mutation in human peripheral neuropathy deregulates KCC2 expression and posterior lateral line development in zebrafish (Danio rerio).

Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare pathology characterized by an early onset of severe sensory loss (all modalities) in the distal limbs. It is due to autosomal recessive mutations confined to exon "HSN2" of the WNK1 (with-no-lysine protein kinase 1) serine-threonine kinase. While this kinase is well studied in the kidneys, little is known about its role in the nervous system.

Regaining tolerance to a self-antigen by the modified vaccination technique.

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.

Identification of novel genes involved in migraine.

Background: Migraine is a common form of headache affecting about 12% of the population. Genetic studies in the rare form of familial hemiplegic migraine have identified mutations in 3 genes (CACNA1A, ATP1A2, and SCN1A) encoding proteins involved in ion homeostasis and suggesting that other such genes may be involved in the more common forms of migraine.

Objectives: To test this proposition, the coding regions of 150 brain-expressed genes involved in ion homeostasis (ion channels, transporters, exchangers, and accessory subunits) were systematically screened to identify DNA variants in a group of 110 migraine probands and 250 control samples.

Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease.

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.

Genetic control of high density lipoprotein-cholesterol in AcB/BcA recombinant congenic strains of mice.

Epidemiological studies show that high HDL-cholesterol (HDLc) decreases the risk of cardiovascular disease. To map genes controlling lipid metabolism, particularly HDLc levels, we screened the plasma lipids of 36 AcB/BcA RC mouse strains subjected to either a normal or a high-fat/cholesterol diet. Strains BcA68 and AcB65 showed deviant HDLc plasma levels compared with the parental A/J and C57BL/6J strains; they were thus selected to generate informative F2 crosses.

Functional analysis of missense variants in the TRESK (KCNK18) K channel.

A loss of function mutation in the TRESK K2P potassium channel (KCNK18), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity.

Production of heterologous IgG antibody against Heymann nephritis antigen by injections of immune complexes.

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.

Voltage-gated Na+ channel β1B: a secreted cell adhesion molecule involved in human epilepsy.

Scn1b-null mice have a severe neurological and cardiac phenotype. Human mutations in SCN1B result in epilepsy and cardiac arrhythmia. SCN1B is expressed as two developmentally regulated splice variants, β1 and β1B, that are each expressed in brain and heart in rodents and humans.

New technologies and surgical innovation: five years of a local health technology assessment program in a surgical department.

There is pressure for surgical departments to introduce new and innovative health technologies in an evidence-based manner while ensuring that they are safe and effective and can be managed with available resources. A local health technology assessment (HTA) program was developed to systematically integrate research evidence with local operational management information and to make recommendations for subsequent decision by the departmental executive committee about whether and under what conditions the technology will be used. The authors present a retrospective analysis of the outcomes of this program as used by the Department of Surgery & Surgical Services in the Calgary Health Region over a 5-year period from December 2005 to December 2010.

Migraine: Role of the TRESK two-pore potassium channel.

Migraine is a severe episodic headache disorder affecting one in five people. Genetic studies have identified mutations in the CACNA1, ATP1A2 and SCN1A genes in the rare familial hemiplegic migraine. Recently, a mutation in the KCNK18 gene, encoding the TRESK two-pore domain potassium channel, was described in a large family with migraine with aura.